English
Tiếng Việt
(en)The present invention relates to pyrrolidine derivatives of the formula (I),
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes. The pyrrolidine derivatives are GlyT1 inhibitors.
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes. The pyrrolidine derivatives are GlyT1 inhibitors.
1.ApplicationNumber: US-201414216222-A
1.PublishNumber: US-9656955-B2
2.Date Publish: 20170523
3.Inventor: AMBERG WILHELM
POHLKI FRAUKE
LANGE UDO
WANG YING X.
ZHAO HONGYU H.
LI HUAN-QIU
BREWER JASON T.
ZANZE IRINI
DIETRICH JUSTIN
VASUDEVAN ANIL
Djuric Stevan W.
LAO YANBIN
HUTCHINS CHARLES W.
4.Inventor Harmonized: AMBERG WILHELM(DE)
POHLKI FRAUKE(DE)
LANGE UDO(DE)
WANG YING X(US)
ZHAO HONGYU H(US)
LI HUAN-QIU(US)
BREWER JASON T(US)
ZANZE IRINI(US)
DIETRICH JUSTIN(US)
VASUDEVAN ANIL(US)
DJURIC STEVAN W(US)
LAO YANBIN(US)
HUTCHINS CHARLES W(US)
5.Country: US
6.Claims:
(en)The present invention relates to pyrrolidine derivatives of the formula (I),
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes. The pyrrolidine derivatives are GlyT1 inhibitors.
7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
This claims priority to U.S. Patent Application No. 61/789,382, filed on Mar. 15, 2013, the entire contents of which are fully incorporated herein by reference.
The present invention relates to pyrrolidine derivatives, pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes.
BACKGROUND OF THE INVENTION
The pyrrolidine motif is an important pharmacophore possessing biological activity against a number of different targets and thus has found use in various advanced pharmaceutical research compounds and clinical candidates (such as Factor Xa inhibitors, NK3 receptor antagonists, DPP-IV inhibitors, PDE-IV inhibitors, or MC4 receptorselective agonists).
A pyrrolidine compound already known in the art as type IV phosphodiesterase inhibitor (PDE-IV) is for example:
WO 9508534, US 2006074123, WO 2001047915, US 20020169196, WO 2001047879 and WO 2001047914 describe further PDE-IV inhibitors having related structures.
Further, the synthesis of certain trisubstituted pyrrolidine derivatives has been reported in Baumann Marcus, et al., ACS Comb. Sci. 2011, 13, 405-413.
Dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease and bipolar disorder. A large number of studies in animal models lend support to the NMDA hypofunction hypothesis of schizophrenia.
NMDA receptor function can be modulated by altering the availability of the co-agonist glycine. This approach has the critical advantage of maintaining activity-dependent activation of the NMDA receptor because an increase in the synaptic concentration of glycine will not produce an activation of NMDA receptors in the absence of glutamate. Since synaptic glutamate levels are tightly maintained by high affinity transport mechanisms, an increased activation of the glycine site will only enhance the NMDA component of activated synapses.
Two specific glycine transporters, GlyT1 and GlyT2 have been identified and shown to belong to the NaCl-dependent family of neurotransmitter transporters which includes taurine, gamma-aminobutyric acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2 have been isolated from different species and shown to have only 50% identity at the amino acid level. They also have a different pattern of expression in mammalian central nervous system, with GlyT2 being expressed in spinal cord, brainstem and cerebellum and GlyT1 present in these regions as well as forebrain areas such as cortex, hippocampus, septum and thalamus. At the cellular level, GlyT2 has been reported to be expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1 appears to be preferentially expressed by glial cells. These expression studies have led to the suggestion that GlyT2 is predominantly responsible for glycine uptake at glycinergic synapses whereas GlyT1 is involved in monitoring glycine concentration in the vicinity of NMDA receptor expressing synapses. Recent functional studies in rat have shown that blockade of GlyT1 with the potent inhibitor (N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS) potentiates NMDA receptor activity and NMDA receptor-dependent long-term potentiation in rat.
Molecular cloning has further revealed the existence of three variants of GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions.
The physiological effects of GlyT1 in forebrain regions together with clinical reports showing the beneficial effects of GlyT1 inhibitor sarcosine in improving symptoms in schizophrenia patients suggest that selective GlyT1 inhibitors represent a new class of antipsychotic drugs.
Glycine transporter inhibitors are already known in the art, for example:
(see also Hashimoto K., Recent patents on CNS Drug Discovery, 2006, 1, 43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13, 1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997; Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6, 771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6, 1883-1896).
Further glycine transporter inhibitors are known from the following documents.
WO 2009024611 describes 4-benzylaminoquinolines of formula:
WO 2009121872 describes tetrahydroisoquinoline of formula:
WO 2010092180 describes aminotetraline derivatives of formula:
WO 2010092181 describes heterocyclic compounds of formula:
WO 2012020131 describes aminoindane derivatives of formula:
WO 2012020130 describes phenalkylamine derivatives of formula:
WO 2012020133 describes tetraline and indane derivatives of formula:
WO 2012152915 describes benzazepine derivatives of formula:
WO 2012020134 describes phenalkylamine derivatives of formula:
and of formula:
US 20130035323 describes aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives of formula:
It was one object of the present invention to provide further glycine transporter inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to pyrrolidine derivatives of the formula (I)
wherein
R 1 is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 2a , R 2b
are independently hydrogen, halogen, or C 1 -C 3 -alkyl; or
R 2a , R 2b
together with the carbon atom to which they are bound may form a C═O;
R 3a
is C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, or optionally substituted C 3 -C 12 -heterocyclyl;
R 3b is hydrogen, C 1 -C 6 -alkyl, or hydroxy; Y 1 is >CR 6 — or >N—; R 6 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 6 -alkyl, or hydroxy; R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —NR 8e SO 2 R 17 , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl; R 7a , R 7b
are independently hydrogen or C 1 -C 6 -alkyl;
n1 is 1, 2, 3, or 4; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 7c , R 7d
are independently hydrogen or C 1 -C 6 -alkyl;
n2 is 1, 2, 3, or 4; R 11a is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 11b
is hydrogen or C 1 -C 6 -alkyl;
R 7e , R 7f
are independently hydrogen or C 1 -C 6 -alkyl;
n3 is 1, 2, 3, or 4; R 12
is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heterocyclyl;
R 8a , R 8b , R 8c , R 8d , R 8e
are independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -alkylcarbonyl, or
R 6 and one of R 8a , R 8b , R 8c , R 8d , or R 8e
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 9a , R 9b
are independently hydrogen, halogen, C 1 -C 6 -alkyl, hydroxy, or C 1 -C 6 -alkoxy;
n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, C 2 -C 6 -alkenyl, optionally substituted C 3 -C 6 -cycloalkenyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryloxy, optionally substituted C 3 -C 12 -heterocyclyloxy, optionally substituted C 3 -C 12 -heterocyclyl, or tri-(C 1 -C 4 -alkyl)-silyloxy; R 14 is C 1 -C 8 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonyl-C 1 -C 4 -alkyl, optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 15 is C 1 -C 8 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 16b is hydrogen or C 1 -C 6 -alkyl; R 17 is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 9c , R 9d
are independently hydrogen, halogen, or C 1 -C 6 -alkyl;
n5 is 0, 1, 2, 3, or 4; R 18 is hydrogen, C 1 -C 8 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, optionally substituted C 6 -C 12 -aryl, C 1 -C 6 -alkylamine, (C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl)amino, (halogenated C 1 -C 6 -alkyl)amino, (C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl)amino, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)amino, C 1 -C 6 -dialkylamine, optionally substituted C 6 -C 12 -arylamine, or optionally substituted C 3 -C 12 -heterocyclyl; R 19 is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heterocyclyl; R 20a is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 20b is hydrogen or C 1 -C 8 -alkyl; R 21 is optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; and R 5a , R 5b
are independently hydrogen, halogen, or C 1 -C 3 -alkyl, or
R 5a , R 5b
together with the carbon atom to which they are bound may form a C═O,
or a physiologically tolerated salt thereof.
Said compounds of formula (I), i.e., the pyrrolidine derivatives of formula (I) and their physiologically tolerated salts, are glycine transporter inhibitors and thus useful as pharmaceuticals.
The present invention thus further relates to the compounds of formula (I) for use in therapy.
The present invention also relates to pharmaceutical compositions which comprise a carrier and a compound of formula (I).
In particular, said compounds, i.e., the pyrrolidine derivatives and their physiologically tolerated salts, are inhibitors of the glycine transporter GlyT1.
The present invention thus further relates to the compounds of formula (I) for use in inhibiting the glycine transporter.
The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 and corresponding methods of inhibiting the glycine transporter GlyT1.
Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are known to be useful in treating a variety of neurologic and psychiatric disorders.
The present invention thus further relates to the compounds of formula (I) for use in treating a neurologic or psychiatric disorder.
The present invention further relates to the compounds of formula (I) for use in treating pain.
The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating a neurologic or psychiatric disorder and corresponding methods of treating said disorders. The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating pain and corresponding methods of treating pain.
DETAILED DESCRIPTION OF THE INVENTION
Provided that the pyrrolidine derivatives of the formula (I) of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, the invention relates to the corresponding enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, as well as to the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formula (I) and/or of their salts.
According to one embodiment, an enantiomer of the pyrrolidine derivatives of the present invention has the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b are as defined herein.
According to another embodiment, an enantiomer of the pyrrolidine derivatives of the present invention has the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b are as defined herein.
If Y 1 is >CR 6 — it is preferred that R 3a and R 4 are in trans position.
Accordingly, the invention relates in particular to an enantiomer of the pyrrolidine derivatives having the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 6 , R 5a , R 5b are as defined herein.
Preferably, the invention relates to an enantiomer of the pyrrolidine derivatives having the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 6 , R 5a , R 5b are as defined herein.
The physiologically tolerated salts of the pyrrolidine derivatives of the formula (I) are especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C 1 -C 4 -alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other utilizable acids are described, e.g., in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of the isoindoline derivatives also include salts of a physiologically tolerated anion with an isoindoline derivatives wherein one or more than one nitrogen atom is quaternized, e.g. with an alkyl residue (e.g. methyl or ethyl).
The present invention moreover relates to compounds of formula (I) as defined herein, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 12 C by 13 C, 14 N by 15 N, 16 O by 18 O) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.
Of course, such compounds contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds (I).
Stable isotopes (e.g., deuterium, 13 C, 15 N, 18 O) are nonradioactive isotopes which contain one or more additional neutron than the normally abundant isotope of the respective atom. Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non-deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).
Incorporation of a heavy atom particularly substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This effect is usually insignificant if the label is placed at a metabolically inert position of the molecule.
Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.
Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to “kinetic isotope effect”. A reaction involving breaking a C—D bond can be up to 700 percent slower than a similar reaction involving breaking a C—H bond. If the C—D bond is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If a deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C—D bond is the rate limiting step. There is evidence to suggest that whenever cleavage of an aliphatic C—H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway a process called “metabolic switching”.
Deuterium tracers, such as deuterium-labeled drugs and doses, in some cases repeatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.
The weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).
Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
The hydrogens present on a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient. Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D 2 SO 4 /D 2 O. Alternatively, deuterium atoms may be incorporated in various combinations during the synthesis of compounds of the invention. Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.
Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471, the methods are hereby incorporated by reference.
The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
Unless indicated otherwise, the term “substituted” means that a radical is substituted with 1, 2 or 3, especially 1, substituent which, according to a particular embodiment of the invention, are independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 3 -C 6 -aryl-C 1 -C 4 -alkyl, halogenated-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, C 2 -C 4 -alkenyl, —CN, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, alkylamino)carbonyl, C 6 -C 12 -arylaminocarbonyl, C 3 -C 12 -heterocyclylaminocarbonyl, C 6 -C 12 -aryl, oxo (═O), OH, C 1 -C 4 -alkoxy, halogenated-C 1 -C 4 -alkoxy, C 3 -C 7 -cycloalkoxy, carboxy-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, SH, alkylthio, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylaminosulfonyl, di-C 1 -C 4 -alkylaminosulfonyl, C 3 -C 6 -arylsulfonyl, aminosulfonyl, C 3 -C 6 -arylaminosulfonyl, C 3 -C 12 -heterocyclylaminosulfonyl, NH 2 , C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, C 6 -C 12 -aryl-C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonylamino, C 3 -C 6 -arylcarbonylamino, C 3 -C 12 -heterocyclylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, C 3 -C 6 -arylsulfonylamino, C 3 -C 12 -heterocyclylsulfonylamino and C 3 -C 12 -heterocyclyl, wherein aryl and heterocyclyl may be unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy.
The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.
C 1 -C 4 -Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, C 2 -C 4 -alkyl such as ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl or tert-butyl. C 1 -C 2 -Alkyl is methyl or ethyl, C 1 -C 3 -alkyl is additionally n-propyl or iso-propyl.
C 1 -C 6 -Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include methyl, C 2 -C 4 -alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
C 1 -C 8 -Alkyl is a straight-chain or branched alkyl group having from 1 to 8 carbon atoms. Examples include methyl, C 2 -C 4 -alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,2,3-trimethylbutyl 1-ethyl-2-methylbutyl, 1-methyl-2-ethylbutyl, octyl, 1-methyl-heptyl, 2-methylheptyl, 3-methyl-heptyl, 4-methyl-heptyl, 5-methylheptyl, 6-methylheptyl, 1-methyl-2-ethylpentyl, 1,1-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 3,3-dimethylhexyl, 4,5-dimethylhexyl, 1,2,3-trimethylpentyl, 1,2-dimethyl-3-ethylbutyl, 1-ethyl-2-ethylbutyl and 1,3-dimethyl-2-ethylbutyl.
Halogenated C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethyl, dihalogenomethyl, trihalogenomethyl, (R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl, 1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl, (R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl, 3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl, 3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl, (R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl, (R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl, (R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl, (R)-2,2,2-trihalogeno-1-methylethyl, (S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl, 1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl, (S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl, 1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl, 4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, 1,1-dihalogenopentyl, 4,4-dihalogenopentyl etc. Particular examples include the fluorinated C 1 -C 4 alkyl groups as defined, such as trifluoromethyl.
C 3 -C 12 -Cycloalkyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a cycloaliphatic radical having from 3 to 12 carbon atoms such as in cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
C 1 -C 6 -Alkylcarbonyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or 2 carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylcarbonyl group, in particular by a C 1 -C 4 -alkylcarbonyl group, such as in methylcarbonylmethyl, methylcarbonylethyl, methylcarbonylpropyl, ethylcarbonylmethyl, n-propylcarbonylmethyl, iso-propylcarbonylmethyl, n-butylcarbonylmethyl, 2-butylcarbonylmethyl or iso-butylcarbonylmethyl.
C 1 -C 6 -Alkoxycarbonyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkoxycarbonyl group, in particular by a C 1 -C 4 -alkoxycarbonyl group, such as in methoxycarbonylmethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, n-butoxycarbonylmethyl, 2-butoxycarbonylmethyl or iso-butoxycarbonylmethyl.
C 6 -C 12 -Aryl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 6 -C 12 -aryl, such as in benzyl.
Hydroxy-C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl, (S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl, (S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl, (S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, (R)-1-hydroxypentyl, (S)-1-hydroxypentyl, 2-hydroxypentyl and 4-hydroxypentyl.
Hydroxy-(halogenated C 1 -C 4 -alkyl) is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least two, e.g. 2, 3, 4 or all of the hydrogen atoms are replaced by a number of identical or different halogen atoms and by one or two hydroxyl groups, such as in hydroxyhalogenomethyl, hydroxydihalogenomethyl, (R)-1-hydroxy-1-halogenoethyl, (S)-1-hydroxy-1-halogenoethyl, (R) 2,2-dihalogeno-1-hydroxyethyl, (S) 2,2-dihalogeno-1-hydroxyethyl, (R) 2,2,2-trihalogeno-1-hydroxyethyl, (S) 2,2,2-trihalogeno-1-hydroxyethyl (R)-1-hydroxy-1-halogenopropyl, (S)-1-hydroxy-1-halogenopropyl, (R)-2-halogeno-2-hydroxypropyl, (S)-2-halogeno-2-hydroxypropyl, 3-halogeno-2-hydroxypropyl, 1,1-dihalogeno-1-hydroxypropyl, 2,2-dihalogeno-1-hydroxypropyl, 3,3,3-trihalogeno-1-hydroxypropyl, (R)-2-halogeno-1-methyl-1-hydroxyethyl, (S)-2-halogeno-1-methyl-1-hydroxyethyl, (R)-2,2-dihalogeno-1-methyl-1-hydroxyethyl, (S)-2,2-dihalogeno-1-methyl-1-hydroxyethyl, (R)-2,2,2-trihalogeno-1-methyl-1-hydroxyethyl, (S)-2,2,2-trihalogeno-1-methyl-1-hydroxyethyl, (R)-1-(halogenomethyl)-1-hydroxyethyl, (S)-1-(halogenomethyl)-1-hydroxyethyl, (R)-1-(dihalogenomethyl)-1-hydroxyethyl, (S)-1-(dihalogenomethyl)-1-hydroxyethyl, (R)-1-(trihalogenomethyl)-1-hydroxyethyl, (S)-1-(trihalogenomethyl)-1-hydroxyethyl, etc. Particular examples include the hydroxyfluorinated C 1 -C 4 alkyl groups as defined, such as 1-(trifluoromethyl)-1-hydroxyethyl.
C 1 -C 6 -Alkoxy-C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4, in particular 1 or 2 carbon atoms, such as in methoxymethyl, (R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl, (R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, (R)-2-methoxy-1-methylethyl, (S)-2-methoxy-1-methyl ethyl, 2-methoxy-1-(methoxymethyl)ethyl, (R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, (R)-1-methoxypentyl, (S)-1-methoxypentyl, 2-methoxypentyl, 3-methoxypentyl, 4-methoxypentyl, (R)-1-methoxyhexyl, (S)-1-methoxyhexyl, 2-methoxyhexyl, 3-methoxyhexyl, 4-methoxyhexyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl, 2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl, 3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methyl ethyl, 2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl, 2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl, (R)-1-ethoxypentyl, (S)-1-ethoxypentyl, 2-ethoxypentyl, 3-ethoxypentyl, 4-ethoxypentyl, 5-ethoxypentyl, (R)-1-ethoxyhexyl, (S)-1-ethoxyhexyl, 2-ethoxyhexyl, 3-ethoxyhexyl and 6-ethoxybutyl.
C 6 -C 12 -Aryloxy-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a radical of the formula R—O—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxymethyl, (4-F-phenoxy)methyl.
Amino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by an amino group, such as in aminomethyl, 2-aminoethyl.
C 1 -C 6 -Alkylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylamino group, in particular by a C 1 -C 4 -alkylamino group, such as in methylaminomethyl, ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl, n-butylaminomethyl, 2-butylaminomethyl, isobutylaminomethyl or tert-butylaminomethyl.
Di-C 1 -C 6 -Alkylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-C 1 -C 6 -Alkylamino group, in particular by a di-C 1 -C 4 -alkylamino group, such as in dimethylaminomethyl.
C 1 -C 6 -Alkylcarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylcarbonylamino group, in particular by a C 1 -C 4 -alkylcarbonylamino group, such as in methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl, 2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl or tert-butylcarbonyl aminomethyl.
C 1 -C 6 -Alkylaminocarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylaminocarbonylamino group, in particular by a C 1 -C 4 -alkylaminocarbonylamino group, such as in methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl, n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl, n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl, iso-butylaminocarbonylaminomethyl or tertbutylaminocarbonylaminomethyl.
Di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-C 1 -C 6 -alkylaminocarbonylamino group, in particular by a di-C 1 -C 4 -alkylaminocarbonylamino group, such as in dimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl, dimethylaminocarbonylamino-propyl.
C 1 -C 6 -Alkylsulfonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylsulfonylamino group, in particular by a C 1 -C 4 -alkylsulfonylamino group, such as in methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl, iso-propylsulfonylaminomethyl, n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl, iso-butylsulfonylaminomethyl or tertbutylsulfonylaminomethyl.
(C 6 -C 12 -Aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a (C 6 -C 17 -aryl-C 1 -C 6 -alkyl)amino group, in particular a (C 6 -C 12 -aryl-C 1 -C 2 -alkyl)amino group, such as in benzylaminomethyl.
C 3 -C 12 -Heterocyclyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 3 -C 12 -heterocyclyl, such as in N-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl, tetrahydropyran-2-yl-methyl.
C 3 -C 12 -Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4 C 1 -C 4 alkyl radicals, preferably one or more methyl radicals.
Carbonyl is >C═O.
C 1 -C 6 -Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.
Halogenated C 1 -C 6 -alkylcarbonyl is C 1 -C 6 -alkylcarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms. Examples include fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are 1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.
C 6 -C 12 -Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include benzoyl.
C 1 -C 6 -Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methoxycarbonyl and tert-butoxycarbonyl.
Halogenated C 1 -C 6 -alkoxycarbonyl is a C 1 -C 6 -alkoxycarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenoxycarbonyl.
Cyano is —C≡N.
Aminocarbonyl is NH 2 C(O)—.
C 1 -C 6 -Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methylaminocarbonyl.
(Halogenated C 1 -C 4 -alkyl)aminocarbonyl is a C 1 -C 4 -alkylaminocarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different hydrogen atoms.
C 6 -C 12 -Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylaminocarbonyl.
C 2 -C 6 -Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like. C 3 -C 5 -Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl, 2-hexen-1-yl.
C 3 -C 6 -Cycloalkenyl is a carbocyclic radical having at least one carbon-carbon double bond and from 3 to 6 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic structure, such as 2-cyclopenten-1-yl, 2-cyclohexen-1-yl. The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4 C 1 -C 4 alkyl radicals, preferably one or more methyl radicals.
C 2 -C 6 -Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl, 2-propyn-2-yl and the like. C 3 -C 5 -Alkynyl is, in particular, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl.
C 1 -C 5 -Alkylene is straight-chain or branched alkylene group having from 1 to 5 carbon atoms. Examples include methylene and ethylene. A further example is propylene.
C 2 -C 4 -Alkenylene is straight-chain or branched alkenylene group having from 2 to 4 carbon atoms.
C 2 -C 4 -Alkynylene is straight-chain or branched alkynylene group having from 2 to 4 carbon atoms. Examples include propynylene.
C 6 -C 12 -Aryl is a 6- to 12-membered, in particular 6- to 10-membered, aromatic cyclic radical which can be a monocyclic aromatic ring, for example, phenyl etc., or a fused polycyclic aromatic ring comprising a first monocyclic aromatic ring and one or more carbocycles which are saturated, partially unsaturated or aromatic, for example, naphthyl, indenyl, tetrahydronaphthyl, indanyl.
C 3 -C 12 -Arylene is an aryl diradical. Examples include phen-1,4-ylene and phen-1,3-ylene.
Hydroxy is —OH.
Oxo is ═O.
C 1 -C 6 -Alkoxy is a radical of the formula R—O—, wherein R is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy), tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.
Halogenated C 1 -C 6 -alkoxy is a straight-chain or branched alkoxy group having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethoxy, dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy, (S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy, 2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy, (S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy, 1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy, 3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy, (S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy, (S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy, (S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy, (S)-2,2,2-trihalogeno-1-methylethoxy, 2-halogeno-1-(halogenomethyl)ethoxy, 1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy, (S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy, 4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy, 3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy, etc. Particular examples include the fluorinated C 1 -C 4 alkoxy groups as defined, such as trifluoromethoxy.
C 1 -C 6 -Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by hydroxy. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and the like.
C 1 -C 6 -Alkoxy-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by one or two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.
Amino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an amino group. Examples include 2-aminoethoxy.
C 1 -C 6 -Alkylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy, iso-propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy, iso-butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy, 2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy, 2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy, 2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy, 2-(tertbutylamino)ethoxy.
Di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a di-alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy, 2-(N-methyl-N-ethylamino)ethoxy.
C 1 -C 6 -Alkylcarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylcarbonylamino group wherein the alkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylcarbonylaminomethoxy, ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy, iso-propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy, 2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy, tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy, 2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonylamino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.
C 6 -C 12 -Arylcarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -arylcarbonylamino group as defined herein. Examples include 2-(benzoylamino)ethoxy.
C 1 -C 6 -Alkoxycarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy, iso-propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy, 2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy, tertbutoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy, 2-(isobutoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.
C 2 -C 6 -Alkenyloxy is a radical of the formula R—O—, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy (2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy (2-methylprop-2-en-1-yloxy) and the like. C 3 -C 5 -Alkenyloxy is, in particular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy, 3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy, 4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.
C 6 -C 12 -Aryl-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -aryl group as defined herein. Examples include benzyloxy.
C 1 -C 6 -Alkylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy, 2-[(2-methylpropyl)sulfonylamino]ethoxy.
(Halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein the alkyl group is halogenated. Examples include 2-(trifluoromethylsulfonylamino)ethoxy.
C 6 -C 12 -Arylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -arylsulfonylamino group as defined herein. Examples include 2-(phenylsulfanylamino)ethoxy, 2-(naphthylsulfonylamino)ethoxy.
(C 6 -C 12 -Aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino group, preferably by a (C 6 -C 12 -aryl-C 1 -C 2 -alkyl)sulfonylamino group. Examples include 2-(benzylsulfonylamino)ethoxy.
C 3 -C 12 -Heterocyclylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -C 12 -heterocyclylsulfonylamino group as defined herein. Examples include 2-(pyridin-3-ylsulfonylamino)ethoxy.
C 3 -C 12 -Heterocyclyl-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -C 12 -heterocyclyl group as defined herein. Examples include 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.
C 1 -C 2 -Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is a straight-chain or branched alkylene group having from 1 or 2 carbon atoms as defined herein. Examples include methylenedioxo.
C 6 -C 12 -Aryloxy is a radical of the formula R—O—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxy.
C 3 -C 12 -Heterocyclyloxy is a radical of the formula R—O—, wherein R is a C 3 -C 12 -heterocyclyl group having from 3 to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples include pyridin-2-yloxy.
C 1 -C 6 -Alkylthio is a radical of the formula R—S—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
Halogenated C 1 -C 6 -alkylthio is a radical of the formula R—S—, wherein R is a halogenated alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include halogenomethylthio, dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio, (S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio, 2,2-dihalogenoethylthio, 2,2,2-trihalogeno ethylthio, (R)-1-halogenopropylthio, (S)-1-halogenopropylthio, 2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio, 2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio, 3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio, (S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio, (S)-2,2-dihalogeno-1-methylethylthio, (R)-1,2-dihalogeno-1-methylethylthio, (S)-1,2-dihalogeno-1-methylethylthio, (R)-2,2,2-trihalogeno-1-methylethylthio, (S)-2,2,2-trihalogeno-1-methylethylthio, 2-halogeno-1-(halogenomethyl)ethylthio, 1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio, (S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio, 4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio, 3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio, 4,4,4-trihalogenobutylthio, etc. Particular examples include the fluorinated alkylthio groups as defined, such as trifluoromethylthio.
C 1 -C 6 -Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
C 1 -C 6 -Alkylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexyl sulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
(Halogenated C 1 -C 6 -alkyl)sulfonyl is a C 1 -C 6 -alkylsulfonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonyl.
(C 6 -C 12 -Aryl-C 1 -C 4 -alkyl)sulfonyl is a radical of the formula R—S(O) 2 —, wherein R is a C 6 -C 12 -aryl-C 1 -C 4 -alkyl radical, in particular a C 6 -C 12 -aryl-C 1 -C 2 -alkyl radical as defined herein. Examples include benzylsulfonyl.
C 3 -C 12 -Heterocyclylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is C 3 -C 12 -heterocyclyl as defined herein.
Aminosulfonyl is NH 2 —S(O) 2 —.
C 1 -C 6 -Alkylaminosulfonyl is a radical of the formula R—NH—S(O) 2 — wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, iso-propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl, tert-butylaminosulfonyl.
Di-C 1 -C 6 -alkylaminosulfonyl is a radical of the formula RR′N—S(O) 2 — wherein R and R′ are independently of each other an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminosulfonyl, diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl.
C 6 -C 12 -Arylaminosulfonyl is a radical of the formula R—NH—S(O) 2 — wherein R is an aryl radical having from 6 to 12, preferably 6 carbon atoms as defined herein.
Amino is NH 2 .
C 1 -C 6 -Alkylamino is a radical of the formula R—NH— wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino, tertbutylamino.
(Halogenated C 1 -C 6 -alkyl)amino is a C 1 -C 6 -alkylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
Di-C 1 -C 6 -alkylamino is a radical of the formula RR′N— wherein R and R′ are independently of each other an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.
Di-(halogenated C 1 -C 6 -alkyl)amino is a di-C 1 -C 6 -alkylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 1 -C 6 -Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include acetamido (methylcarbonylamino), propionamido, n-butyramido, 2-methylpropionamido (iso-propylcarbonylamino), 2,2-dimethylpropionamido and the like.
(Halogenated C 1 -C 6 -alkyl)carbonylamino is a C 1 -C 6 -alkylcarbonylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylcarbonylamino.
C 2 -C 6 -Alkenylamino is a radical of the formula R—NH—, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinylamino, allylamino (2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino, methallylamino (2-methylprop-2-en-1-ylamino) and the like. C 3 -C 5 -Alkenylamino is, in particular, allylamino, 1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino, methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino, 4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or 2-ethylprop-2-en-1-ylamino.
C 6 -C 12 -Arylamino is a radical of the formula R—NH—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenylamine.
C 1 -C 6 -Alkylsulfonylamino is a radical of the formula R—S(O) 2 —NH—, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, iso-propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino, iso-butylsulfonylamino, tert-butylsulfonylamino.
(Halogenated C 1 -C 6 alkyl)sulfonylamino is a C 1 -C 6 -alkylsulfonylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylsulfonylamino is a radical of the formula R—S(O) 2 —NH—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonylamino.
Nitro is —NO 2 .
C 3 -C 12 -Heterocyclyl is a 3- to 12-membered heterocyclic radical including a saturated heterocyclic radical, which generally has 3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring forming atoms, and a heteroaromatic radical (heteroaryl), which generally has 5, 6 or 7 ring forming atoms. The heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclic radicals comprise 1 nitrogen atom as ring member atom and optionally 1, 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N. Likewise preferred heterocyclic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms as ring members.
Examples of C 3 -C 12 -heterocyclyl include:
C- or N-bound 3-4-membered, saturated rings, such as 2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl;
C-bound, 5-membered, saturated rings, such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl, tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl, 1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, 1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;
C-bound, 6-membered, saturated rings, such as tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl, 1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl, tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl, tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl, tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl, tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl, tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl, tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl, tetrahydro-1,2-oxazin-6-yl;
N-bound, 5-membered, saturated rings, such as tetrahydropyrrol-1-yl(pyrrolidin-1-yl), tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;
N-bound, 6-membered, saturated rings, such as piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl(morpholin-1-yl), tetrahydro-1,2-oxazin-2-yl;
C-bound, 5-membered, partially unsaturated rings, such as 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl, 2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl, 4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl, 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl, 2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl, 2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;
C-bound, 6-membered, partially unsaturated rings, such as 2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl, 2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl, 2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl, 2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-, 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl, 4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl, 1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl, 1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl, 1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl, 1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl, 1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or 3,4-dihydropyrimidin-6-yl;
N-bound, 5-membered, partially unsaturated rings, such as 2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;
N-bound, 6-membered, partially unsaturated rings, such as 1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl, 2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl, 1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;
C-bound, 5-membered, heteroaromatic rings, such as 2-furyl, 3-furyl, 5-furyl, 2-thienyl, 3-thienyl, 5-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrrol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-imidazol-4-yl, 4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl;
C-bound, 6-membered, heteroaromatic rings, such as pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;
N-bound, 5-membered, heteroaromatic rings, such as pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl.
Heterocyclyl also includes bicyclic heterocycles, which comprise one of the described 5- or 6-membered heterocyclic rings and a further anellated, saturated or unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a further anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring being saturated or unsaturated or aromatic. These include quinolinyl, isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl, benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[b]thiazolyl, thieno[b]pyridyl, imidazo[a]pyridyl, pyrazo[a]pyridyl and pyrrol[d]pyrimidyl. Examples of 5- or 6-membered heteroaromatic compounds comprising an anellated cycloalkenyl ring include dihydroindolyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzofuryl, chromanyl, chromanyl, dihydropyrrolo[a]imidazolyl and tetrahydro benzothiazolyl.
C 3 -C 12 -Heteroarylene is a heteroaryl diradical. Examples include pyrid-2,5-ylene and pyrid-2,4-ylene.
With respect to the compounds' capability of inhibiting glycine transporter 1, the variables R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b , R 6 , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8a , R 8d , R 8e , R 9a , R 9b , R 9c , R 9d , R 10 , R 11a , R 11b , R 12 , R 13 , R 14 , R 15 , R 16a , R 16b , R 17 , R 18 , R 19 , R 20a , R 20b , R 21 , n1, n2, n3, n4 and n5 preferably have the following meanings which, when taken alone or in combination, represent particular embodiments of the pyrrolidine derivatives of the formula (I) or any other formula disclosed herein.
R 1 is C 1 -C 8 -alkyl (e.g. methyl; ethyl, or n-propyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. tetrahydropyran-2-yl-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclobutyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 2,4-dichlorophenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-CN-phenyl, 2-aminocarbonyl-phenyl, or 4-OMe-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2,5-dimethyl-furan-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-ethyl-thiophen-2-yl, 2,5-dimethyl-thiophen-3-yl, 5-Cl-thiophen-2-yl, 2-methoxycarbonyl-thiophen-3-yl, 3-methoxy-4-methoxycarbonyl-thiophen-2-yl, 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, 2-methylcarbonylamino-1,3-thiazol-5-yl, 3-pyridyl, 2-CF 3 -pyrid-5-yl, 2-(morpholin-1-yl)-pyrid-5-yl, 2-OMe-pyrid-5-yl, 1-methylcarbonyl-indolin-5-yl, 1,2-benzoxazol-5-yl, 1,4-dihydroquinoxaline-2,3-dion-6-yl, 6-chloro-imidazo[2,1-b]thiazol-5-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 3H-1,3-benzoxazol-2-on-5-yl, 3,3-dimethylindolin-2-on-5-yl, indolin-2-on-5-yl, 1,3-dihydrobenzimidazol-2-on-5-yl, 1H-quinazoline-2,4-dion-6-yl, 6-Me-4H-1,4-benzoxazin-3-on-7-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzodioxol-5-yl, isoquinoline-5-yl, 3,4-dihydro-1H-quinolin-2-on-6yl, 1-Me-indol-5yl, pyrrolidin-1-yl, 4-Me-piperidin-1-yl, morpholin-1-yl).
Preferably, R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl).
According to one embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to an alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 , substituted 5-membered heterocyclic rings containing at least 1 N atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular include 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 6 -alkylcarbonylamino.
Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl.
In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl).
According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
According to a further particular embodiment, 1,2,3-triazolyl is substituted with C 1 -C 6 -alkyl as described herein. According to a further specific embodiment, R 1 is 1-methyl-1,2,3-triazol-4-yl.
R 2a , R 2b are independently hydrogen, halogen (e.g. F), or C 1 -C 3 -alkyl (e.g. methyl, ethyl, n-propyl, or iso-propyl), or R 2a , R 2b together with the carbon atom to which they are bound may form a C═O.
According to one particular embodiment R 2a is hydrogen, halogen (e.g. F) or C 1 -C 3 -alkyl (e.g. methyl or ethyl), and R 2b is hydrogen. Preferably, R 2a , R 2b are both hydrogen.
R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy) halogenated C 1 -C 6 -alkoxy (e.g OCF 3 ), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy, or 2-(N-imidazolyl)ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
In particular, R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
According to one preferred embodiment, R 3a is optionally substituted C 6 -C 12 -aryl wherein C 6 -C 12 -aryl is phenyl, in particular phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-F-phenyl, 2-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, or 2,4,5-trifluoro-phenyl).
According to a further preferred embodiment, R 3a is optionally substituted C 3 -C 12 -heterocyclyl wherein C 3 -C 12 -heterocyclyl is in particular tetrahydrofuranyl or tetrahydropyranyl, preferably unsubstituted tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl) or unsubstituted tetrahydropyranyl (e.g. tetrahydropyran-2-yl).
According to an additional aspect, R 3a is not 3,4-di-O-substituted phenyl if R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl). According to a further additional aspect, there is not more than one O-bound substituent on the aryl group if R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
In connection with R 3a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.
Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a , substituted C 6 -C 12 -aryloxy in particular includes C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
Preferably, the substituent(s) on C 6 -C 12 -aryloxy are independently selected from the group consisting of halogen.
In connection with R 3a , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, piperidinyl, isoxazolyl, diazolyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 3 -C 6 -cycloalkyl.
Preferably, the substituent(s) on C 3 -C 12 -heterocyclyl are independently selected from the group consisting of halogen.
R 3b is hydrogen, C 1 -C 6 -alkyl, or hydroxy. Preferably, R 3b is hydrogen.
Y 1 is >CR 6 — or >N—.
Preferably, Y 1 is >CR 6 —.
R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, or iso-butyl), halogenated C 1 -C 6 -alkyl (e.g. CF 3 or CF 2 H), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH or —(CH 2 ) 2 OH), C 1 -C 4 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxymethyl, 2-ethoxypropyl, or 3-ethoxypropyl), or hydroxy.
In particular, R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl or ethyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl or phenethyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH, or —(CH 2 ) 2 OH), or hydroxy, i.e., R 6 is, e.g., hydrogen, methyl, benzyl, hydroxymethyl, or hydroxy.
Preferably, R 6 is hydrogen.
According to some embodiments, Y 1 is >N—. In particular, Y 1 is >N— if R 4 is —(CR 7e R 7f ) n3 R 12 .
R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 - aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —NR 8e SO 2 R 17 , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl).
In particular, R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , (CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b ), —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, or 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl).
Preferably, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 or —O(CR 9c R 9d ) n5 R 18 . More preferably, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 .
In connection with R 4 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 4 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, isoxazolyl, diazolyl, 1,2,3-triazolyl, dihydroquinazolyn, or isoindolinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl and hydroxy.
In particular, R 5a , R 5b are independently hydrogen, halogen, or C 1 -C 3 — alkyl (e.g. methyl, ethyl, n-propyl, or iso-propyl) or R 5a , R 5b together with the carbon atom to which they are bound may form a C═O.
Preferably, R 5a is hydrogen, halogen or C 1 -C 3 -alkyl (e.g. methyl or ethyl), and R 5b is hydrogen. More preferably, R 5a , R 5b are both hydrogen.
According to a one embodiment, R 4 is —(CR 7a R 7b ) n1 OR 10 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ia):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7a , R 7b
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n1 is 1, 2, 3 or 4, in particular 1; and R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl).
In connection with R 10 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
In connection with R 10 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, pyrimidyl, or pyridazyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ia)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ia)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ia)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ia)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ia)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula—(Ia) are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ia) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7a , R 7b
are hydrogen;
n1 is 1; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl); and R 5a , R 5b
are hydrogen.
According to a particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to an alternative particular embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further particular alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ia), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ia), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ia)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ia) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7a , R 7b
are hydrogen;
n1 is 1; R 10 is hydrogen, C 6 -C 12 -aryl (e.g. phenyl) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy, or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —(CR 7c R 2d ) n2 NR 11a R 11b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ib):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7c , R 7d
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n2 is 1, 2, 3, or 4, in particular, 1; R 11a is C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-propyl, or n-butyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxypropyl, 3-ethoxy-propyl, or 3-isopropoxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl; and R 11b is hydrogen or (e.g. methyl, ethyl, n-propyl or n-butyl).
In particular, R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)phenyl).
In connection with R 11a substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, amino-carbonyl and halogenated C 1 -C 4 -alkoxy.
In particular, R 11b is hydrogen.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ib)—are, in particular, both hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ib)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4 Cl phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ib)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ib)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ib)—is, in particular, hydrogen.
R 5a , R 5b in the pyrrolidine derivatives of formula (Ib)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ib) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7c , R 7d
are hydrogen;
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; and R 5a , R 5b are
hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ib)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ib)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ib), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ib), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ib)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ib) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7c , R 7d
are hydrogen;
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, aminocarbonyl and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —(CR 7e R 7f ) n3 R 12 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ic):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7e , R 7f
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n3 is 1, 2, 3, or 4, in particular, 1; and R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl).
In connection with R 12 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 12 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl or triazolyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
R 2a , R 2b —in pyrrolidine derivatives of formula (Ic)—are, in particular, hydrogen.
R 3a —in pyrrolidine derivatives of formula (Ic)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ic)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ic)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ic)—is, in particular, hydrogen or hydroxy.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ic)—are, in particular, hydrogen or together with the carbon atom to which they are bound may form a C═O.
If Y 1 —in the pyrrolidine derivatives of formula (Ic)—is >N—R 5a , R 5b together with the carbon atom to which they are bound form, in particular, a C═O.
Particular embodiments of pyrrolidine derivatives of formula (Ic) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 or >N—; R 6 is hydrogen or hydroxy; R 7e , R 7f
are hydrogen;
n3 is 1; R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); and R 5a , R 5b
are hydrogen or together with the carbon atom to which they are bound may form a C═O.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ic)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ic)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ic), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ic), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ic)—is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ic) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl and preferably 1-methyl-1,3-diazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl) or C 6 -C 12 -aryl optionally substituted with halogen (e.g. phenyl, 2-Br-phenyl, or 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 or >N—; R 6 is hydrogen or hydroxy; R 7e , R 7f
are hydrogen;
n3 is 1; R 12 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); and R 5a , R 5b
are hydrogen or together with the carbon atom to which they are bound may form a C═O.
According to a further embodiment, R 4 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
In connection with R 4 being optionally substituted C 6 -C 12 -aryl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
R 2a , R 2b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1 methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; R 4 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl, substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkylcarbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl and preferably 1-methyl-1,3-diazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; R 4 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Id):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O (e.g. —C(O)OCH 2 —);
R 9a , R 9b
are independently hydrogen, halogen (e.g. F, Cl, or Br), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), hydroxy, or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy);
n4 is 0, 1, 2, 3, or 4; and R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl or cyclohexyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propyloxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-iso-propyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-yl 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-8-yl, 5-methyl-imidazo[1,2-a]pyridine-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-iso-propyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri(C 1 -C 4 -alkyl)-silyloxy.
In particular, R 9a , R 9b are independently hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy).
In particular, R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propyloxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tert-butyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-iso-propyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)silyloxy.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Id)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Id)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy), halogenated C 1 -C 6 -alkoxy (e.g OCF 3 ), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl). Preferably, R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy) or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl).
R 3b —in the pyrrolidine derivatives of formula (Id)—is, in particular, hydrogen or hydroxy.
Y 1 —in the pyrrolidine derivatives of formula (Id)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Id)—is, in particular, hydrogen, C 1 -C 6 -alkyl (e.g. methyl), or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH).
R 5a , R 5b —in the pyrrolidine derivatives of formula (Id)—are, in particular, hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Id) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy) or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 ; R 6 is hydrogen, C 1 -C 6 -alkyl, or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH); R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
are together optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O e.g. —C(O)OCH 2 —);
R 9a is hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy); R 9b is hydrogen; n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutoxy-pyrimid-4-yl, 6-cyclopentoxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; and R 5a , R 5b
are hydrogen.
According to a particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to a further particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further particular embodiment, R 11 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 2 N and, in particular, R 1 is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 3 N and, in particular, R 1 is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Id), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl. According to a further particular embodiment, 1,2,3-triazolyl is substituted with C 1 -C 6 -alkyl as described herein. According to a further specific embodiment, R 1 is 1-methyl-1,2,3-triazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 6 -C 12 -aryloxy in particular includes is C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, piperidinyl, isoxazolyl, diazolyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Id)—is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, or cyclohexyl), C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl), or hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl, in particular tetrahydrofuranyl or tetrahydropyranyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 3 -C 6 -cycloalkyl (tetrahydropyran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl).
According to a preferred embodiment, R 9a , R 9b —in the pyrrolidine derivatives of formula (Id)—are independently hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy).
More preferably, R 9a is hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy) and R 9b is hydrogen.
In connection with R 13 , substituted C 3 -C 12 -cycloalkyl in particular includes C 3 -C 12 -cycloalkyl, such as cyclopropyl, cyclopentyl, or cyclohexyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl.
In connection with R 13 , substituted C 3 -C 6 -cycloalkenyl in particular includes C 3 -C 6 -cycloalkenyl, such as cyclohexenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl.
In connection with R 13 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-carbonylamino and C 3 -C 12 -heterocyclyl.
In connection with R 13 , substituted C 6 -C 12 -aryloxy in particular includes C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
In connection with R 13 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as furanyl, pyrrolyl, thiophenyl, oxazolyl, diazolyl, thiazolyl, triazolyl, pyridyl pyrimidyl, pyrazyl, pyridazyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl or isoquinolinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl.
According to a preferred embodiment, R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), or C 2 -C 6 -alkenyl (e.g. hex-2-enyl), C 3 -C 6 -cycloalkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-carbonylamino and C 3 -C 12 -heterocyclyl, (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), or C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), C 6 -C 12 -aryloxy optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl (e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-ylmethoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)silyloxy.
Further preferred embodiments of the pyrrolidine derivatives of formula (Id) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl), or 1,2,3-triazolyl optionally substituted with C 1 -C 4 -alkyl (e.g. 1-methyl-1,2,3-triazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, or cyclohexyl) C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl), or hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen or C 3 -C 6 -cycloalkyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 ; R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl), or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH); R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
are together optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O e.g. —C(O)OCH 2 —);
R 9a is hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy); R 9b is hydrogen; n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), or C 2 -C 6 -alkenyl (e.g. hex-2-enyl), C 3 -C 6 -cycloalkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 alkyl sulfonyl, C 1 -C 4 -alkylcarbonylamino and C 3 -C 12 -heterocyclyl, (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), or C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), C 6 -C 12 -aryloxy optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 1 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; and R 5a , R 5b
are hydrogen.
According to a particularly preferred embodiment of the pyrrolidine derivatives of the formula (Id), R 3a is phenyl, 4-F-phenyl, tetrahydrofuran-2-yl or tetrahydropyran-2-yl.
According to a further particularly preferred embodiment of the pyrrolidine derivatives of the formula (Id), R 13 is a group of the formula (Id1):
wherein
X is >CH— or >N—;
Z is >C—R 13c or >N—;
R 13b is halogen (e.g. fluoro or chloro), C 1 -C 4 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, tert-butyl), halogenated C 1 -C 4 -alkyl (e.g. CHF 2 , CF 3 ), hydroxy-(halogenated C 1 -C 4 -alkyl) (e.g. 1-OH-1-CF 3 -Et), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), C 3 -C 6 -cycloalkyl (e.g. cyclopropyl), CN, C 6 -C 12 -aryl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl), C 1 -C 4 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy), halogenated C 1 -C 4 -alkoxy (e.g. —OCHF 2 , —OCH 2 CF 3 , —OCF 3 ), C 3 -C 6 -cycloalkoxy (e.g. cyclobutoxy, cyclopentyloxy, cyclohexyloxy), C 6 -C 12 aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. pyrrolid-3-yl-methoxy, pyrrolid-2-yl-methoxy, azetid-3-yl-methoxy), C 6 -C 12 -aryloxy (e.g. phenoxy), C 1 -C 4 -alkyl-sulfonyl (e.g. methylsulfonyl), C 1 -C 4 -alkyl-carbonylamino (e.g. 2-methylcarbonylamino) or C 3 -C 12 -heterocyclyl (e.g. piperidin-4-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimid-5-yl); and
R 13c is hydrogen or halogen (e.g. fluoro, chloro).
Especially preferred among the pyrrolidine derivatives of the formula (Id) wherein R 13 is a group of the formula (Id1) are those wherein X is >CH— or >N—, and Z is >C—R 13c . According this embodiment it is particularly preferred if X is >CH—, Z is >C—R 13c and R 13c is hydrogen or fluoro, especially fluoro, or X is >N—, Z is >C—R 13c and R 13c is hydrogen or fluoro, especially fluoro.
In the pyrrolidine derivatives of the formula (Id) wherein R 13 is a group of the formula (Id1), R 8a , n4, R 9a and R 9b are as defined herein. Preferably, R 8a is hydrogen n4 is, in particular, 0 or 1, with n4=0 being particularly preferred. R 9a and R 9b are preferably both hydrogen if n4 is 1.
According to a further embodiment, R 4 is —NR 8b COR 14 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ie):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8b is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8b
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O; and
R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxyl-methyl or 1-hydroxy-pentyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl, ethoxy-methyl, or ethoxy-ethyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), C 1 -C 6 -alkylaminocarbonyl-C 1 -C 4 -alkyl (e.g. 3-methylaminocarbonyl-propyl), optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. 2-pyridyl-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
In particular, R 8b is hydrogen.
In particular, R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
R 2a , R 2b —in pyrrolidine derivatives of formula (Ie)—are hydrogen.
R 3a —in pyrrolidine derivatives of formula (Ie)—is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
R 3b —in pyrrolidine derivatives of formula (Ie)—is hydrogen or hydroxy. Preferably, R 3b is hydrogen.
Y 1 —in pyrrolidine derivatives of formula (Ie)—is >CR 6 .
R 6 —in pyrrolidine derivatives of formula (Ie)—is hydrogen.
R 5a , R 5b —in pyrrolidine derivatives of formula (Ie)—are hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Ie) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8b is hydrogen; R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ie)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ie)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ie), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ie), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ie)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkoxy (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl).
In connection with R 14 , substituted C 6 -C 12 -aryloxy-C 1 -C 4 -alkyl in particular includes C 6 -C 12 -aryloxy-C 1 -C 4 -alkyl, such as benzyloxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 14 , substituted C 3 -C 12 -cycloalkyl in particular includes C 3 -C 12 -cycloalkyl, such as cyclopropyl or cyclohexyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
In connection with R 14 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy. Preferably the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of C 1 -C 4 -alkyl and CN.
In connection with R 14 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridazyl or pyrazyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxyl-methyl or 1-hydroxy-pentyl), (halogenated C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. 4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, 3-CN-phenyl, or 4-CN-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ie) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkoxy (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl)yl; R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8b is hydrogen; R 14 is C 1 -C 8 -alkyl (e.g. pentyl or n-butyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (halogenated C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. 4-F-phenoxy)methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonylpropyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl(e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); and R 5a , R 5b
are hydrogen.
According to a particularly preferred embodiment, R 3a is phenyl, or halogenated phenyl (e.g. 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl), 4-OMe-phenyl, or pyrid-2-yl.
According to a further embodiment, R 4 is —NR 8c COOR 15 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (If):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8c is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8c
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O. Preferably R 8c is hydrogen; and
R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 2-Cl-4-F-phenyl or 2-Me-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-pyridazyl or 5-pyrazyl).
In particular, R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl), or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 2-Cl-4-F-phenyl or 2-Me-phenyl). Preferably, R 15 is C 1 -C 6 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl) or C 6 -C 12 -aryl (e.g. phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (If)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (If)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4 Cl phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (If)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (If)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (If)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (If)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (If) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8c is hydrogen; R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-bu) or C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (If)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (If)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (If), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (If), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a particular embodiment, R 3a —in the pyrrolidine derivatives of formula (If)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
Further preferred embodiments of pyrrolidine derivatives of formula (If) result if:
R 1 is 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, or 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8c is hydrogen; R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl) or C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen;
According to a further embodiment, R 4 is —NR 8d CONR 16a R 16b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ig):
wherein R 1 , R 2a R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8d is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8d
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl), optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. 2-pyridyl-methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (2-pyridyl, 5-pyrazyl, or 6-pyridazyl); and R 16b is hydrogen or C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl).
In particular, R 8d is hydrogen.
In particular, R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
In particular, R 16b is hydrogen.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ig)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ig)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 3 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 3 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ig)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ig)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ig)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ig)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (If) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8d is hydrogen; R 16a is (optionally substituted C 3 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ig)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ig)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ig), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ig), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ig)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 16a , substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl in particular includes C 3 -C 12 -aryl-C 1 -C 4 -alkyl, such as benzyl, wherein C 6 -C 12 -aryl, such as phenyl, is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 16a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
According to a preferred embodiment, R 16a is C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 6 -C 12 -aryl, with C 6 -C 12 -aryl being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. benzyl or (2-Cl-phenyl)-methyl and phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
Preferred embodiments of the pyrrolidine derivatives of formula (Ig) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 26
are hydrogen;
R 3a is C 6 -C 12 aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8d is hydrogen; R 16a is C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 6 -C 12 -aryl, with C 6 -C 12 -aryl being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. benzyl or (2-Cl-phenyl)-methyl and phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —O(CR 9e R 9d ) n5 R 18 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ih):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 9c , R 9d
are independently hydrogen, halogen (e.g. F), or C 1 -C 6 -alkyl (e.g. methyl or ethyl);
n5 is 0, 1, 2, 3, or 4; and R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl or pentyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl or cyclohexyl), C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), halogenated C 1 -C 6 -alkoxycarbonyl (e.g. —C(O)OCF 3 ), C 6 -C 12 -aryloxycarbonyl (e.g. phenoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -arylaminocarbonyl (e.g. phenylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl)amino (e.g. cyclopropylmethyl-amino), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), (C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl)amino (e.g. 2-methoxyethylamine), (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)amino (e.g. benzylamine), C 1 -C 6 -dialkylamine (e.g. dimethylamino), optionally substituted C 6 -C 12 -arylamino (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
In particular, R 9c , R 9d are hydrogen.
In particular, n5 is 0, 1, or 2.
In particular, R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, isopropyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 6 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
R 2a , R 2b in pyrrolidine derivatives of formula (Ih) are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ih)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1-yl, 3-Me-piperidin-1-yl, 4-Me-piperidin-1-yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1-yl, or azepan-1-yl).
R 3b —in the pyrrolidine derivatives of formula (Ih)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ih)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ih)—is, in particular, hydrogen or C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl). According to a particular embodiment, R 6 is hydrogen or benzyl. Preferably, R 6 is hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ih)—are, in particular, hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Ih) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ih)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ih)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ih), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ih), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives of formula (Ih), substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl, or azepanyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 3 -C 12 -heterocyclyl are independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ih)—is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
In connection with R 18 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl.
In connection with R 18 , substituted C 6 -C 12 -arylamine in particular includes C 6 -C 12 -arylamine, such as phenylamine, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 18 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as 2-pyridyl or 4-pyrimidyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 18 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), or C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), C 6 -C 12 -arylamine optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-Cl-phenylamine), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ih) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1-yl, or azepan-1-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), or C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), C 6 -C 12 -arylamine optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-Cl-phenylamine), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —COR 19 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ii):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 6b are as defined herein, and
R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl or 6-pyrimidyl).
In particular, R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ii)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ii)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ii)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ii)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ii)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ii)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ii) result if
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ii)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ii)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ii), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ii), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ii)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 19 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
According to a preferred embodiment, R 19 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ii) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 19 C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); and R 5a , R 5b
are hydrogen.
According to a further particular embodiment R 4 is —CONR 20a R 20b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (II):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methy 1, (3,4-diF-phenyl)methy 1, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl); and R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl).
In particular, R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Il)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Il)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Il)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Il)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Il)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Il)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Il) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl); R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Il)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Il)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Il), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Il), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Il)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 20a , substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl in particular includes C 6 -C 12 -aryl-C 1 -C 4 -alkyl, such as benzyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
In connection with R 20a , substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl in particular includes C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, such as pyridyl-methyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
In connection with R 20a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy.
In connection with R 20a , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl wherein C 6 -C 12 -aryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), or C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl wherein C 3 -C 12 -heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Il) result if
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl wherein C 6 -C 12 -aryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), or C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl wherein C 3 -C 12 -heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl); R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. n-butyl); and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —SO 2 R 21 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Im):
wherein R 1 , R 2a , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 21 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, or 4-Me-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl).
In particular, R 21 is C 6 -C 12 -aryl (e.g. phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Im)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Im)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Im)—is, in particular, hydrogen. Y 1 —in the pyrrolidine derivatives of formula (Im)—is, in particular, >CR 6 . R 6 —in the pyrrolidine derivatives of formula (Im)—is, in particular, hydrogen. R 5a , R 5b —in the pyrrolidine derivatives of formula (Im)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Im) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl);
R 3b is hydrogen;
Y 1 is >CR 6 ; R 6 is hydrogen; R 5a , R 5b
are hydrogen; and
R 21 is C 6 -C 12 -aryl (e.g. phenyl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Im)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Im)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Im), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Im)—is C 6 -C 12 -aryl (e.g. phenyl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Im) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl (e.g. phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 21 is C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen.
According to a further embodiment R 4 is optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl).
R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 3 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
R 3b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of the invention result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; R 4 is optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-F-phenyl), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
In connection with R 4 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as triazolyl or isoindolinonyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 4 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is C 3 -C 12 -heterocyclyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-chloroisoindolin-1-onyl, 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, or 1-propyl-1,2,3-triazol-4-yl).
Further preferred embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; R 4 is C 3 -C 12 -heterocyclyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
Particular embodiments of pyrrolidine derivatives of the invention result if
R 1 is optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-1,3-diazol-4-yl or 1-methyl-1,2,3-triazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl)hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propyloxy, iso-propoxy, or iso-butoxy) C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (cyclopropylmethoxy, cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy, 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy, 4-F-phenoxy); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 — or >N—; R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl or ethyl), C 3 -C 12 -aryl-C 1 -C 21 -alkyl (e.g. benzyl or phenethyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH, or —(CH 2 ) 2 OH), or hydroxy; R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, or 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl); R 7a , R 7b
are hydrogen, or
n1 is 1; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl); R 7c , R 7d
are hydrogen, or
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, or n-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; R 7e , R 7f
are hydrogen, or
n3 is 1; R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); R 8a , R 8b , R 8c , R 8d , R 8e
are independently hydrogen or C 1 -C 6 -alkyl (e.g. pentyl or hexyl), or
R 6 and one of R 8a , R 8b , R 8c , R 8d , or R 8e
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 9a , R 9b
are independently hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy);
n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid 2-yl-5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, imidazo[1,2-a]pyridin-8-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); R 15 is C 1 -C 6 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-bu) or C 6 -C 12 -aryl (e.g. phenyl); R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropoxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl). R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl); R 21 is C 6 -C 12 -aryl (e.g phenyl); and R 5a , R 5b
are hydrogen; or
R 5a , R 5b
together with the carbon atom to which they are bound may form a C═O.
Further particular compounds of the present invention are the individual pyrrolidine derivatives of the formula (Id2) as listed in the following tables 1 to 8 and physiologically tolerated salts thereof:
Table 1 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is H and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 2 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is F and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 3 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is Cl and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 4 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is H and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 5 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is F and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 6 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is Cl and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-44).
Table 7 Compounds of the formula (Id2) wherein X is ═N—, Z is ═N— and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
R 1
R 3a
R 13b
A-1.
1-methyl-1,3-diazol-4-yl
Ph
H
A-2.
1-methyl-1,3-diazol-4-yl
4-F—Ph
H
A-3.
1-methyl-1,3-diazol-4-yl
2-THP
H
A-4.
1-methyl-1,3-diazol-4-yl
2-THF
H
A-5.
1-methyl-1,2,3-triazol-4-yl
Ph
H
A-6.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
H
A-7.
1-methyl-1,2,3-triazol-4-yl
2-THP
H
A-8.
1-methyl-1,2,3-triazol-4-yl
2-THF
H
A-9.
1-methyl-1,3-diazol-4-yl
Ph
F
A-10.
1-methyl-1,3-diazol-4-yl
4-F—Ph
F
A-11.
1-methyl-1,3-diazol-4-yl
2-THP
F
A-12.
1-methyl-1,3-diazol-4-yl
2-THF
F
A-13.
1-methyl-1,2,3-triazol-4-yl
Ph
F
A-14.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
F
A-15.
1-methyl-1,2,3-triazol-4-yl
2-THP
F
A-16.
1-methyl-1,2,3-triazol-4-yl
2-THF
F
A-17.
1-methyl-1,3-diazol-4-yl
Ph
Cl
A-18.
1-methyl-1,3-diazol-4-yl
4-F—Ph
Cl
A-19.
1-methyl-1,3-diazol-4-yl
2-THP
Cl
A-20.
1-methyl-1,3-diazol-4-yl
2-THF
Cl
A-21.
1-methyl-1,2,3-triazol-4-yl
Ph
Cl
A-22.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
Cl
A-23.
1-methyl-1,2,3-triazol-4-yl
2-THP
Cl
A-24.
1-methyl-1,2,3-triazol-4-yl
2-THF
Cl
A-25.
1-methyl-1,3-diazol-4-yl
Ph
—CH 3
A-26.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 3
A-27.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 3
A-28.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 3
A-29.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 3
A-30.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 3
A-31.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 3
A-32.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 3
A-33.
1-methyl-1,3-diazol-4-yl
Ph
—CH 2 CH 3
A-34.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 2 CH 3
A-35.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 2 CH 3
A-36.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 2 CH 3
A-37.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 2 CH 3
A-38.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 2 CH 3
A-39.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 2 CH 3
A-40.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 2 CH 3
A-41.
1-methyl-1,3-diazol-4-yl
Ph
—CH 2 CH 2 CH 3
A-42.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 2 CH 2 CH 3
A-43.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 2 CH 2 CH 3
A-44.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 2 CH 2 CH 3
A-45.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 2 CH 2 CH 3
A-46.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 2 CH 2 CH 3
A-47.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 2 CH 2 CH 3
A-48.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 2 CH 2 CH 3
A-49.
1-methyl-1,3-diazol-4-yl
Ph
—CH(CH 3 ) 2
A-50.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH(CH 3 ) 2
A-51.
1-methyl-1,3-diazol-4-yl
2-THP
—CH(CH 3 ) 2
A-52.
1-methyl-1,3-diazol-4-yl
2-THF
—CH(CH 3 ) 2
A-53.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH(CH 3 ) 2
A-54.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH(CH 3 ) 2
A-55.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH(CH 3 ) 2
A-56.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH(CH 3 ) 2
A-57.
1-methyl-1,3-diazol-4-yl
Ph
—C(CH 3 ) 3
A-58.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—C(CH 3 ) 3
A-59.
1-methyl-1,3-diazol-4-yl
2-THP
—C(CH 3 ) 3
A-60.
1-methyl-1,3-diazol-4-yl
2-THF
—C(CH 3 ) 3
A-61.
1-methyl-1,2,3-triazol-4-yl
Ph
—C(CH 3 ) 3
A-62.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—C(CH 3 ) 3
A-63.
1-methyl-1,2,3-triazol-4-yl
2-THP
—C(CH 3 ) 3
A-64.
1-methyl-1,2,3-triazol-4-yl
2-THF
—C(CH 3 ) 3
A-65.
1-methyl-1,3-diazol-4-yl
Ph
—CF 3
A-66.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CF 3
A-67.
1-methyl-1,3-diazol-4-yl
2-THP
—CF 3
A-68.
1-methyl-1,3-diazol-4-yl
2-THF
—CF 3
A-69.
1-methyl-1,2,3-triazol-4-yl
Ph
—CF 3
A-70.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CF 3
A-71.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CF 3
A-72.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CF 3
A-73.
1-methyl-1,3-diazol-4-yl
Ph
—CHF 2
A-74.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CHF 2
A-75.
1-methyl-1,3-diazol-4-yl
2-THP
—CHF 2
A-76.
1-methyl-1,3-diazol-4-yl
2-THF
—CHF 2
A-77.
1-methyl-1,2,3-triazol-4-yl
Ph
—CHF 2
A-78.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CHF 2
A-79.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CHF 2
A-80.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CHF 2
A-81.
1-methyl-1,3-diazol-4-yl
Ph
—CH(OH)(CF 3 )CH 3
A-82.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH(OH)(CF 3 )CH 3
A-83.
1-methyl-1,3-diazol-4-yl
2-THP
—CH(OH)(CF 3 )CH 3
A-84.
1-methyl-1,3-diazol-4-yl
2-THF
—CH(OH)(CF 3 )CH 3
A-85.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH(OH)(CF 3 )CH 3
A-86.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH(OH)(CF 3 )CH 3
A-87.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH(OH)(CF 3 )CH 3
A-88.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH(OH)(CF 3 )CH 3
A-89.
1-methyl-1,3-diazol-4-yl
Ph
cyclopropyl
A-90.
1-methyl-1,3-diazol-4-yl
4-F—Ph
cyclopropyl
A-91.
1-methyl-1,3-diazol-4-yl
2-THP
cyclopropyl
A-92.
1-methyl-1,3-diazol-4-yl
2-THF
cyclopropyl
A-93.
1-methyl-1,2,3-triazol-4-yl
Ph
cyclopropyl
A-94.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
cyclopropyl
A-95.
1-methyl-1,2,3-triazol-4-yl
2-THP
cyclopropyl
A-96.
1-methyl-1,2,3-triazol-4-yl
2-THF
cyclopropyl
A-97.
1-methyl-1,3-diazol-4-yl
Ph
phenyl
A-98.
1-methyl-1,3-diazol-4-yl
4-F—Ph
phenyl
A-99.
1-methyl-1,3-diazol-4-yl
2-THP
phenyl
A-100.
1-methyl-1,3-diazol-4-yl
2-THF
phenyl
A-101.
1-methyl-1,2,3-triazol-4-yl
Ph
phenyl
A-102.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
phenyl
A-103.
1-methyl-1,2,3-triazol-4-yl
2-THP
phenyl
A-104.
1-methyl-1,2,3-triazol-4-yl
2-THF
phenyl
A-105.
1-methyl-1,3-diazol-4-yl
Ph
4-Cl-phenyl
A-106.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-Cl-phenyl
A-107.
1-methyl-1,3-diazol-4-yl
2-THP
4-Cl-phenyl
A-108.
1-methyl-1,3-diazol-4-yl
2-THF
4-Cl-phenyl
A-109.
1-methyl-1,2,3-triazol-4-yl
Ph
4-Cl-phenyl
A-110.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-Cl-phenyl
A-111.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-Cl-phenyl
A-112.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-Cl-phenyl
A-113.
1-methyl-1,3-diazol-4-yl
Ph
3-Cl-phenyl
A-114.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-Cl-phenyl
A-115.
1-methyl-1,3-diazol-4-yl
2-THP
3-Cl-phenyl
A-116.
1-methyl-1,3-diazol-4-yl
2-THF
3-Cl-phenyl
A-117.
1-methyl-1,2,3-triazol-4-yl
Ph
3-Cl-phenyl
A-118.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-Cl-phenyl
A-119.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-Cl-phenyl
A-120.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-Cl-phenyl
A-121.
1-methyl-1,3-diazol-4-yl
Ph
4-F-phenyl
A-122.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-F-phenyl
A-123.
1-methyl-1,3-diazol-4-yl
2-THP
4-F-phenyl
A-124.
1-methyl-1,3-diazol-4-yl
2-THF
4-F-phenyl
A-125.
1-methyl-1,2,3-triazol-4-yl
Ph
4-F-phenyl
A-126.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-F-phenyl
A-127.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-F-phenyl
A-128.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-F-phenyl
A-129.
1-methyl-1,3-diazol-4-yl
Ph
3-F-phenyl
A-130.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-F-phenyl
A-131.
1-methyl-1,3-diazol-4-yl
2-THP
3-F-phenyl
A-132.
1-methyl-1,3-diazol-4-yl
2-THF
3-F-phenyl
A-133.
1-methyl-1,2,3-triazol-4-yl
Ph
3-F-phenyl
A-134.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-F-phenyl
A-135.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-F-phenyl
A-136.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-F-phenyl
A-137.
1-methyl-1,3-diazol-4-yl
Ph
2-F-phenyl
A-138.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-F-phenyl
A-139.
1-methyl-1,3-diazol-4-yl
2-THP
2-F-phenyl
A-140.
1-methyl-1,3-diazol-4-yl
2-THF
2-F-phenyl
A-141.
1-methyl-1,2,3-triazol-4-yl
Ph
2-F-phenyl
A-142.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-F-phenyl
A-143.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-F-phenyl
A-144.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-F-phenyl
A-145.
1-methyl-1,3-diazol-4-yl
Ph
2-Me-phenyl
A-146.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-Me-phenyl
A-147.
1-methyl-1,3-diazol-4-yl
2-THP
2-Me-phenyl
A-148.
1-methyl-1,3-diazol-4-yl
2-THF
2-Me-phenyl
A-149.
1-methyl-1,2,3-triazol-4-yl
Ph
2-Me-phenyl
A-150.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-Me-phenyl
A-151.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-Me-phenyl
A-152.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-Me-phenyl
A-153.
1-methyl-1,3-diazol-4-yl
Ph
3-Me-phenyl
A-154.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-Me-phenyl
A-155.
1-methyl-1,3-diazol-4-yl
2-THP
3-Me-phenyl
A-156.
1-methyl-1,3-diazol-4-yl
2-THF
3-Me-phenyl
A-157.
1-methyl-1,2,3-triazol-4-yl
Ph
3-Me-phenyl
A-158.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-Me-phenyl
A-159.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-Me-phenyl
A-160.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-Me-phenyl
A-161.
1-methyl-1,3-diazol-4-yl
Ph
4-Me-phenyl
A-162.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-Me-phenyl
A-163.
1-methyl-1,3-diazol-4-yl
2-THP
4-Me-phenyl
A-164.
1-methyl-1,3-diazol-4-yl
2-THF
4-Me-phenyl
A-165.
1-methyl-1,2,3-triazol-4-yl
Ph
4-Me-phenyl
A-166.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-Me-phenyl
A-167.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-Me-phenyl
A-168.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-Me-phenyl
A-169.
1-methyl-1,3-diazol-4-yl
Ph
—CN
A-170.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CN
A-171.
1-methyl-1,3-diazol-4-yl
2-THP
—CN
A-172.
1-methyl-1,3-diazol-4-yl
2-THF
—CN
A-173.
1-methyl-1,2,3-triazol-4-yl
Ph
—CN
A-174.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CN
A-175.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CN
A-176.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CN
A-177.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 3
A-178.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 3
A-179.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 3
A-180.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 3
A-181.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 3
A-182.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 3
A-183.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 3
A-184.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 3
A-185.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 CH 3
A-186.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 CH 3
A-187.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 CH 3
A-188.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 CH 3
A-189.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 CH 3
A-190.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 CH 3
A-191.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 CH 3
A-192.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 CH 3
A-193.
1-methyl-1,3-diazol-4-yl
Ph
—O(CH 2 ) 2 CH 3
A-194.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O(CH 2 ) 2 CH 3
A-195.
1-methyl-1,3-diazol-4-yl
2-THP
—O(CH 2 ) 2 CH 3
A-196.
1-methyl-1,3-diazol-4-yl
2-THF
—O(CH 2 ) 2 CH 3
A-197.
1-methyl-1,2,3-triazol-4-yl
Ph
—O(CH 2 ) 2 CH 3
A-198.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O(CH 2 ) 2 CH 3
A-199.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O(CH 2 ) 2 CH 3
A-200.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O(CH 2 ) 2 CH 3
A-201.
1-methyl-1,3-diazol-4-yl
Ph
—O(CH 2 ) 3 CH 3
A-202.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O(CH 2 ) 3 CH 3
A-203.
1-methyl-1,3-diazol-4-yl
2-THP
—O(CH 2 ) 3 CH 3
A-204.
1-methyl-1,3-diazol-4-yl
2-THF
—O(CH 2 ) 3 CH 3
A-205.
1-methyl-1,2,3-triazol-4-yl
Ph
—O(CH 2 ) 3 CH 3
A-206.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O(CH 2 ) 3 CH 3
A-207.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O(CH 2 ) 3 CH 3
A-208.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O(CH 2 ) 3 CH 3
A-209.
1-methyl-1,3-diazol-4-yl
Ph
—OCH(CH 3 ) 2
A-210.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH(CH 3 ) 2
A-211.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH(CH 3 ) 2
A-212.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH(CH 3 ) 2
A-213.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH(CH 3 ) 2
A-214.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH(CH 3 ) 2
A-215.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH(CH 3 ) 2
A-216.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH(CH 3 ) 2
A-217.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (CH 3 ) 2
A-218.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (CH 3 ) 2
A-219.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (CH 3 ) 2
A-220.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (CH 3 ) 2
A-221.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (CH 3 ) 2
A-222.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (CH 3 ) 2
A-223.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (CH 3 ) 2
A-224.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (CH 3 ) 2
A-225.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (pyrrolyd-3yl)
A-226.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-3yl)
A-227.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (pyrrolyd-3yl)
A-228.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (pyrrolyd-3yl)
A-229.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (pyrrolyd-3yl)
A-230.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-3yl)
A-231.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (pyrrolyd-3yl)
A-232.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (pyrrolyd-3yl)
A-233.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (pyrrolyd-2yl)
A-234.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-2yl)
A-235.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (pyrrolyd-2yl)
A-236.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (pyrrolyd-2yl)
A-237.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (pyrrolyd-2yl)
A-238.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-2yl)
A-239.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (pyrrolyd-2yl)
A-240.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (pyrrolyd-2yl)
A-241.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (azetid-3yl)
A-242.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (azetid-3yl)
A-243.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (azetid-3yl)
A-244.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (azetid-3yl)
A-245.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (azetid-3yl)
A-246.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (azetid-3yl)
A-247.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (azetid-3yl)
A-248.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (azetid-3yl)
A-249.
1-methyl-1,3-diazol-4-yl
Ph
—OCF 3
A-250.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCF 3
A-251.
1-methyl-1,3-diazol-4-yl
2-THP
—OCF 3
A-252.
1-methyl-1,3-diazol-4-yl
2-THF
—OCF 3
A-253.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCF 3
A-254.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCF 3
A-255.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCF 3
A-256.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCF 3
A-257.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 CF 3
A-258.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 CF 3
A-259.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 CF 3
A-260.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 CF 3
A-261.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 CF 3
A-262.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 CF 3
A-263.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 CF 3
A-264.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 CF 3
A-265.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclobutyl
A-266.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclobutyl
A-267.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclobutyl
A-268.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclobutyl
A-269.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclobutyl
A-270.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclobutyl
A-271.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclobutyl
A-272.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclobutyl
A-273.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclopentyl
A-274.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclopentyl
A-275.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclopentyl
A-276.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclopentyl
A-277.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclopentyl
A-278.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclopentyl
A-279.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclopentyl
A-280.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclopentyl
A-281.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclohexyl
A-282.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclohexyl
A-283.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclohexyl
A-284.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclohexyl
A-285.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclohexyl
A-286.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclohexyl
A-287.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclohexyl
A-288.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclohexyl
A-289.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 Ph
A-290.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 Ph
A-291.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 Ph
A-292.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 Ph
A-293.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 Ph
A-294.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 Ph
A-295.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 Ph
A-296.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 Ph
A-297.
1-methyl-1,3-diazol-4-yl
Ph
—SO 2 Me
A-298.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—SO 2 Me
A-299.
1-methyl-1,3-diazol-4-yl
2-THP
—SO 2 Me
A-300.
1-methyl-1,3-diazol-4-yl
2-THF
—SO 2 Me
A-301.
1-methyl-1,2,3-triazol-4-yl
Ph
—SO 2 Me
A-302.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—SO 2 Me
A-303.
1-methyl-1,2,3-triazol-4-yl
2-THP
—SO 2 Me
A-304.
1-methyl-1,2,3-triazol-4-yl
2-THF
—SO 2 Me
A-305.
1-methyl-1,3-diazol-4-yl
Ph
2-pyridyl
A-306.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-pyridyl
A-307.
1-methyl-1,3-diazol-4-yl
2-THP
2-pyridyl
A-308.
1-methyl-1,3-diazol-4-yl
2-THF
2-pyridyl
A-309.
1-methyl-1,2,3-triazol-4-yl
Ph
2-pyridyl
A-310.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-pyridyl
A-311.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-pyridyl
A-312.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-pyridyl
A-313.
1-methyl-1,3-diazol-4-yl
Ph
3-pyridyl
A-314.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-pyridyl
A-315.
1-methyl-1,3-diazol-4-yl
2-THP
3-pyridyl
A-316.
1-methyl-1,3-diazol-4-yl
2-THF
3-pyridyl
A-317.
1-methyl-1,2,3-triazol-4-yl
Ph
3-pyridyl
A-318.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-pyridyl
A-319.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-pyridyl
A-320.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-pyridyl
A-321.
1-methyl-1,3-diazol-4-yl
Ph
4-pyridyl
A-322.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-pyridyl
A-323.
1-methyl-1,3-diazol-4-yl
2-THP
4-pyridyl
A-324.
1-methyl-1,3-diazol-4-yl
2-THF
4-pyridyl
A-325.
1-methyl-1,2,3-triazol-4-yl
Ph
4-pyridyl
A-326.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-pyridyl
A-327.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-pyridyl
A-328.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-pyridyl
A-329.
1-methyl-1,3-diazol-4-yl
Ph
5-pyrimidyl
A-330.
1-methyl-1,3-diazol-4-yl
4-F—Ph
5-pyrimidyl
A-331.
1-methyl-1,3-diazol-4-yl
2-THP
5-pyrimidyl
A-332.
1-methyl-1,3-diazol-4-yl
2-THF
5-pyrimidyl
A-333.
1-methyl-1,2,3-triazol-4-yl
Ph
5-pyrimidyl
A-334.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
5-pyrimidyl
A-335.
1-methyl-1,2,3-triazol-4-yl
2-THP
5-pyrimidyl
A-336.
1-methyl-1,2,3-triazol-4-yl
2-THF
5-pyrimidyl
A-337.
1-methyl-1,3-diazol-4-yl
Ph
4-piperidyl
A-338.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-piperidyl
A-339.
1-methyl-1,3-diazol-4-yl
2-THP
4-piperidyl
A-340.
1-methyl-1,3-diazol-4-yl
2-THF
4-piperidyl
A-341.
1-methyl-1,2,3-triazol-4-yl
Ph
4-piperidyl
A-342.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-piperidyl
A-343.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-piperidyl
A-344.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-piperidyl
Further particular compounds of the present invention are the pyrrolidine derivatives disclosed in preparation examples and physiologically tolerated salts thereof. These include for each preparation example the exemplified compound as well as the corresponding free base and any other physiologically tolerated salts of the free base (if the exemplified compound is a salt), or any physiologically tolerated salt of the free base (if the exemplified compound is a free base). These further include enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
It is noted that the following compounds of formula (Il)
wherein R 1 , R 3a and R 14 are as defined in the following table
R 1 R 3a R 14 4-F—Ph 4-CF 3 —Ph 2-OMe—Ph 2-OMe-4-OCF 3 —Ph 4-F-phenyl 4-CF 3 -phenyl 2-OMe-phenyl 2-OMe-4-OCF 3 -phenyl 4-F-phenyl 4-CF 3 -phenyl 4-F-phenyl 4-F-phenyl 2-OMe-phenyl 4-F-phenyl 4-OMe-phenyl 4-F-phenyl 2-furyl 4-F-phenyl
are described in Baumann Marcus, et al., ACS Comb. Sci. 2011, 13, 405-413 and therefore the present invention does not encompass these compounds and physiologically tolerated salts thereof per se. However, the present invention does encompass pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes, as described herein.
The compounds of the formula (I) can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of compounds of formula (I) are outlined in the following schemes.
The process depicted in scheme 1 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —N(CR 9a R 9b ) n4 R 13 , —NHCOR 14 or —NHCONHR 16a .
In scheme 1, the variables R 1 , R 3a , R 13 , R 14 , R 16a are as defined herein.
As shown in the above scheme 1, the intermediate of general formula 1 can be alkylated to give compounds of formula 2. Alternatively, 1 can be transformed to compounds 3 via reductive amination or can yield amides of formula 4 by coupling reaction with the corresponding acid. Reaction with isocyanates of formula 5 affords compounds of formula 6.
The process depicted in scheme 2 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —(CR 7c R 7d ) n2 NR 11a R 11b or —CONR 20a R 20b .
As shown in the above scheme 2, cycloaddition followed by benzyl deprotection afford pyrrolidine 7. Sulfonylation, methylester hydrolysis and coupling with amines yield compounds of formula 8. Reduction of compounds of formula 8 affords the corresponding amines 9.
The process depicted in scheme 3 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —(CR 7a R 7b ) n1 NR 10 .
As shown in the above scheme 3, reduction with LiAlH 4 of intermediate 10 affords the corresponding alcohol which then can be transformed in the alkoxy derivatives of formula 11 via Mitsunobu coupling.
The process depicted in scheme 4 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —COR 19 .
As shown in the above scheme 4, the pyrrolidine intermediate 12 can be converted in the corresponding Weinreb amide. Treatment of the Weinreb amide with Grignard reagents affords the ketones of formula 13.
The process depicted in scheme 5 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —O(CR 9c R 9d ) n5 R 18 .
As shown in the above scheme 5, alkylation of alcohol 14 affords the compounds of formula 15.
Schemes 1 to 5 refer also to the preparation of the enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
The acid addition salts of the pyrrolidine derivatives of formula (I) are prepared in a customary manner by mixing the free base with a corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
The compounds of the formula (I) are capable of inhibiting the activity of glycine transporter, in particular glycine transporter 1 (GlyT1).
The utility of the compounds in accordance with the present invention as inhibiting the glycine transporter activity, in particular GlyT1 activity, may be demonstrated by methodology known in the art. For instance, human GlyT1c expressing recombinant hGlyT1c_5_CHO cells can be used for measuring glycine uptake and its inhibition (IC 50 ) by a compound of formula (I).
Amongst the compounds of the formula (I) those are preferred which achieve effective inhibition at low concentrations. In particular, compounds of the formula (I) are preferred which inhibit glycine transporter 1 (GlyT1) at a level of IC 50 <1 μMol, more preferably at a level of IC 50 <0.5 μMol, particularly preferably at a level of IC 50 <0.2 μMol and most preferably at a level of IC 50 <0.1 μMol.
The compounds of formula (I) display good to moderate metabolic stability.
The metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (R S Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved. The stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver. The slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the compounds of the invention is increased. Increased and/or longer-lasting active levels may lead to a better activity of the compound in therapeutic treatment. In addition, an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degradation in the liver (so-called first pass effect). An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
Amongst the compounds of the formula (I) those are particularly preferred which display good to moderate metabolic stability towards human liver microsomes. In particular, compounds of the formula (I) are preferred which display a microsomal clearance at a level of mCl <1000 μl/min/mg, more preferably at a level of mCl <500 μl/min/mg, particularly preferably at a level of mCl <100 μl/min/mg and most preferably at a level of mCl <50 μl/min/mg.
The compounds of the formula (I) according to the present invention are thus useful as pharmaceuticals.
The present invention therefore also relates to pharmaceutical compositions which comprise an inert carrier and a compound of the formula (I).
The present invention also relates to the use of the compounds of the formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1, and to corresponding methods of inhibiting the glycine transporter GlyT1.
The NMDA receptor is central to a wide range of CNS processes, and its role in a variety of diseases in humans or other species has been described. GlyT1 inhibitors slow the removal of glycine from the synapse, causing the level of synaptic glycine to rise. This in turn increases the occupancy of the glycine binding site on the NMDA receptor, which increases activation of the NMDA receptor following glutamate release from the presynaptic terminal Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus known to be useful in treating a variety of neurologic and psychiatric disorders. Further, glycine A receptors play a role in a variety of diseases in humans or other species. Increasing extracellular glycine concentrations by inhibiting glycine transport may enhance the activity of glycine A receptors. Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus useful in treating a variety of neurologic and psychiatric disorders.
The present invention thus further relates to the use of the compounds of the formula (I) for the manufacture of a medicament for treating a neurologic or psychiatric disorder, and to corresponding methods of treating said disorders.
According to a particular embodiment, the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.
According to a further particular embodiment, the disorder is one or more of the following conditions or diseases: schizophrenia or a psychotic disorder including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder, including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or cognitive impairment including age related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including attention-deficit hyperactivity disorder (ADHD) and conduct disorder; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias [including tremor (such as rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia)]; urinary incontinence; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders including insomnia and narcolepsy.
According to a further particular embodiment, the disorder is pain, in particular chronic pain and especially neuropathic pain.
Pain can be classified as acute and chronic pain. Acute pain and chronic pain differ in their etiology, pathophysiology, diagnosis and treatment.
Acute pain, which occurs following tissue injury, is self-limiting, serves as an alert to ongoing tissue damage and following tissue repair it will usually subside. There are minimal psychological symptoms associated with acute pain apart from mild anxiety. Acute pain is nociceptive in nature and occurs following chemical, mechanical and thermal stimulation of A-delta and C-polymodal pain receptors.
Chronic pain, on the other hand, serves no protective biological function. Rather than being the symptom of tissue damage it is a disease in its own right. Chronic pain is unrelenting and not self-limiting and can persist for years, perhaps decades after the initial injury. Chronic pain can be refractory to multiple treatment regimes. Psychological symptoms associated with chronic pain include chronic anxiety, fear, depression, sleeplessness and impairment of social interaction. Chronic non-malignant pain is predominantly neuropathic in nature and involves damage to either the peripheral or central nervous systems.
Acute pain and chronic pain are caused by different neuro-physiological processes and therefore tend to respond to different types of treatments. Acute pain can be somatic or visceral in nature. Somatic pain tends to be a well localised, constant pain and is described as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing or colicky in nature. Examples of acute pain include post-operative pain, pain associated with trauma and the pain of arthritis. Acute pain usually responds to treatment with opioids or non-steroidal anti-inflammatory drugs.
Chronic pain, in contrast to acute pain, is described as burning, electric, tingling and shooting in nature. It can be continuous or paroxysmal in presentation. The hallmarks of chronic pain are chronic allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus that normally does not ellicit a painful response, such as a light touch. Hyperalgesia is an increased sensitivity to normally painful stimuli. Primary hyperalgesia occurs immediately within the area of the injury. Secondary hyperalgesia occurs in the undamaged area surrounding the injury. Examples of chronic pain include complex regional pain syndrome, pain arising from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension-type headache, pain arising from mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic disease, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain arising as a consequence of or associated with stress or depressive illness.
Although opioids are cheap and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity. In addition the doses of opioids which can be administered are limited by nausea, emesis, constipation, pruritis and urinary retention, often resulting in patients electing to receive sub-optimal pain control rather than suffer these distressing side-effects. Furthermore, these side-effects often result in patients requiring extended hospitalisation. Opioids are highly addictive and are scheduled drugs in many territories.
The compounds of formula (I) are particularly useful in the treatment of schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including Attention-Deficit/Hyperactivity Disorder, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.
Particular cognitive disorders are dementia, delirium, amnestic disorders and cognitive impairment including age-related cognitive decline.
Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack.
Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
Particular neurologic disorders that can be treated with the compounds of the formula (I) include in particular a cognitive disorder such as dementia, cognitive impairment, attention deficit hyperactivity disorder.
Particular psychiatric disorders that can be treated with the compounds of the formula (I) include in particular an anxiety disorder, a mood disorder such as depression or a bipolar disorder, schizophrenia, a psychotic disorder.
Within the context of the treatment, the use according to the invention of the compounds of the formula (I) involves a method. In this method, an effective quantity of one or more compounds or the formula (I), as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other drugs or drug-containing preparations.
The invention also relates to the manufacture of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being. Thus, the compounds of the formula (I) are customarily administered in the form of pharmaceutical compositions which comprise an inert carrier (e.g. a pharmaceutically acceptable excipient) together with at least one compound according to the invention and, where appropriate, other drugs. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.
When producing the compositions, the compounds according to the invention are optionally mixed or diluted with one or more carriers (excipients). Carriers (excipients) can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
Suitable carriers (excipients) are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.
The compounds of formula (I) may also be suitable for combination with other therapeutic agents.
Thus, the present invention also provides:
i) a combination comprising a compound of formula (I) with one or more further therapeutic agents;
ii) a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient;
iii) the use of a combination as defined in i) above in the manufacture of a medicament for treating or preventing a disorder, disease or condition as defined herein;
iv) a combination as defined in i) above for use in treating or preventing a disorder, disease or condition as defined herein;
v) a kit-of-parts for use in the treatment of a disorder, disease or condition as defined herein, comprising a first dosage form comprising a compound of formula (I) and one or more further dosage forms each comprising one or more further therapeutic agents for simultaneous therapeutic administration,
vi) a combination as defined in i) above for use in therapy;
vii) a method of treatment or prevention of a disorder, disease or condition as defined herein comprising administering an effective amount of a combination as defined in i) above;
viii) a combination as defined in i) above for treating or preventing a disorder, disease or condition as defined herein.
The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) and at least one further therapeutic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component.
The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides a combination of compounds of formula (I) and at least one antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder. The invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder.
In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
Antipsychotic agents include both typical and atypical antipsychotic drugs. Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldlinc, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from OrthoMcNeil); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE®, from Pfizer); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman); perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE (D; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used. Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
Examples of agents suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease that are useful in the present invention include, but are not limited to: cholinesterase inhibitors, agents targeting nicotinic or muscarinic acethylcholine receptors, NMDA receptors, amyloid formation, mitochondrial dysfunctions, disease associated calpain activity, neuroinflamation, tumor necrosis factor receptors, NF-kappaB, peroxisome proliferator activator receptor gamma, Apolipoprotein E variant 4 (ApoE4), disease-associated increase of the HPA axis, epileptic discharges, vascular dysfunction, vascular risk factors, and oxidative stress.
Suitable cholinesterase inhibitors which may be used in combination with the compounds of the inventions include for example tacrine, donepezil, galantamine and rivastigmine.
Suitable NMDA receptors targeting agents which may be used in combination with the compounds of the inventions include for example memantine.
Suitable agents affecting increased HPA axis activity which may be used in combination with the compounds of the inventions include for example CRF1 antagonists or V1b antagonists.
In a further aspect therefore, the invention provides a method of treatment of pain by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain.
In a further aspect, the invention provides a method of treatment of pain by adjunctive therapeutic administration of at least one agent suitable for the treatment of pain to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of pain for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of pain by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of pain. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of pain. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain for simultaneous therapeutic administration in the treatment of pain. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain. The invention further provides at least one agent suitable for the treatment of pain for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain.
Examples of agents suitable for the treatment of pain that are useful in the present invention include, but are not limited to: NSAIDs (Nonsteroidal Antiinflammatory Drugs), anticonvulsant drugs such as carbamazepine and gabapentin, sodium channel blockers, antidepressant drugs, cannabinoids and local anaesthetics.
Suitable agents used in combination with the compounds of the inventions include for example celecoxib, etoricoxib, lumiracoxib, paracetamol, tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion, gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam, remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil, pethidine, diamorphine and butorphanol.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as cognitive enhancers.
Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
The following examples serve to explain the invention without limiting it.
The compounds were characterized by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
Preparation Examples
Abbreviations:
APCI for atmospheric pressure chemical ionization; AcOH for acetic acid; Boc for tert-butoxy carbonyl; Bu for butyl; DCI for desorption chemical ionization; DCM for dichloromethane; dimethylsulfoxide for dimethyl sulfoxide; eq for equivalent(s); ESI for electrospray ionization; EtOAc for ethyl acetate; HATU for [o-(azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate]; HCl for hydrochloric acid; HPLC for high performance liquid chromatography; id for internal diameter; LCMS for liquid chromatography/mass spectrometry; MeOH for methanol; MgSO4 for magnesium sulfate; MP for macroporous resin; NaOAc for sodium acetate; PS for polymer supported; psi for pounds per square inch; SFC for supercritical fluid chromatography; SPE for solid phase extraction, and tBu for tert-butyl.
Definitions:
Similarly indicates that that reactants may be substituted for other the reactants described, the temperature may vary by 50° C., the equivalents may differ by upto 2 fold, or any combination thereof.
Preparative HPLC Procedure:
Samples were purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm) A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). With specified samples, ammonium acetate was used instead of trifluoroacetic acid. A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SATIN module, Alltech Varex III evaporative light-scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software, automated using an Abbott developed Visual Basic application for fraction collector control and fraction tracking. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan LCQ using 70:30 methanol:10 mM NH 4 OH(aqueous) at a flow rate of 0.8 mL/minute. Loop-injection mass spectra were acquired using a Finnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquid handler for fraction injection controlled by an Abbott developed Visual Basic application.
For chiral compounds the absolute configuration is indicated in their chemical names. A chemical name with “trans” or no stereochemistry information does not refer to a chiral compound (even if the corresponding formula depicts a chiral compound).
Example 1
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 1A
To a solution of trans-tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate (0.305 g, 1.163 mmol) and 2-chloro-3-(trifluoromethyl)benzoic acid (0.261 g, 1.163 mmol) in dichloromethane (4.65 ml) was added triethylamine (0.486 ml, 3.49 mmol) and HATU (0.663 g, 1.744 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned with water, the organic fraction was collected, and the aqueous fraction was washed with dichloromethane. The organic fractions were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (Anal ogix IntelliFlash 280, SF15-12) eluting with 30% ethyl acetate hexanes to afford the title compound. MS (ESI) m/z 469.3 [M+H] +
Example 1B
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide hydrochloride
To a solution of Example 1A (0.32 g, 0.682 mmol) in dioxane (0.682 ml) was added HCl in dioxane (4M, 1.706 ml, 6.82 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the solid was triturated twice with dichloromethane and the solvent was evaporated to afford the title compound. MS (ESI) m/z 369.2 [M+H]+
Example 1C
2-chloro-N-(trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
To a solution of Example 1B (0.075 g, 0.185 mmol) in dichloromethane (0.740 ml) was added triethylamine (0.077 ml, 0.555 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.033 g, 0.185 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. The crude product was purified by HPLC to afford the title compound. MS (ESI) m/z 513.1 [M+H]+
Example 2
2-chloro-N-{trans-4-(4-methoxyphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 2A trans-1-benzyl-3-(4-methoxyphenyl)-4-nitropyrrolidine
To a solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (5.09 g, 28.4 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (8.07 g, 34.0 mmol) in 75 mL of dichloromethane at 0° C. under nitrogen was added trifluoroacetic acid (388 mg, 3.4 mmol) in one portion. The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was then partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic fraction was collected. The aqueous portion was washed with additional dichloromethane and the combined organic fractions were washed with water, brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (7:3 hexane:ethyl acetate) to afford the title compound. MS (DCI) m/z 313.1 (M+H) + .
Example 2B
trans-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine
Example 2A (4.85 mg, 15.5 mmol) and tetrahydrofuran (100 mL) were added to a Raney nickel water slurry (Grace 2800, 5.00 g) in a stainless steel reactor. The vessel was pressurized with 30 psi of hydrogen and shaken at room temperature for 16 hours. The mixture was filtered through a nylon membrane concentrated and purified on a silica gel flash column (95:5 dichloromethane: 2N ammonia in methanol) to afford the title compound as colorless oil. MS (DCI) m/z 283.1 (M+H) + .
Example 2C
tert-Butyl trans-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-ylcarbamate
To a solution of 2.5 g (8.86 mmol) of Example 2B in tetrahydrofuran (20 ml) was added saturated sodium bicarbonate solution (20 ml) followed by di-tert-butyl dicarbonate (1.0 M solution in tetrahydrofuran, 10 ml, 10.0 mmol) at room temperature under nitrogen. The reaction was stirred for 1 hour and then partitioned between ethyl acetate and water. The organic fraction was collected. The aqueous portion was washed several additional times with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (3:2 ethyl acetate hexane) to afford the title compound. MS (DCI) m/z 383.2 (M+H) + .
Example 2D
tert-butyl (3S,4R)-4-(4-methoxyphenyl)pyrrolidin-3-ylcarbamate
Example 2C (2.65 mg, 6.93 mmol) and 2,2,2-trifluoroethanol or tetrahydrofuran (40 mL) were added to 20% Pd(OH) 2 /C (50% water, 0.530 g) in a stainless steel reactor. The vessel was pressurized with 30 psi of hydrogen and shaken at 50° C. for 30 minutes. The mixture was filtered through a nylon membrane, and the product was purified on a silica gel column (95:5 dichloromethane:2N ammonia in methanol) to afford the title compound. MS (DCI) m/z 293.1 (M+H) + .
Example 2E
tert-butyl (trans-4-(4-methoxyphenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)carbamate
To a solution of the product from Example 2D (154 mg, 0.53 mmol), and triethylamine (152 mg, 1.5 mmol) in dichloromethane (8 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (108 mg, 0.60 mmol) in one portion at room temperature. 4-(dimethylamino)-pyridine (4 mg, 0.03 mmol) was added and the reaction stirred for two hours at room temperature. The reaction was concentrated and purified on a silica gel flash column (97:3 dichloromethane: 2N ammonia in methanol) to afford the title compound. MS (DCI) m/z 425.1 (M+H) + .
Example 2F
trans-4-(4-methoxyphenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-amine
The product from Example 2E (195 mg, 0.46 mmol) was stirred with 1,4-dioxane (4 ml) and hydrogen chloride in 1,4-dioxane (4M, 4 ml, 16.0 mmol) at room temperature under nitrogen overnight. The reaction was concentrated and concentrated to afford the title compound as the hydrochloride salt. MS (DCI) m/z 325.0 (M+H) + .
Example 2G
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
A mixture of Example 2F, 2-chloro-3-(trifluoromethyl)benzoic acid (101 mg, 0.45 mmol), and N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) was stirred in a 1:1 solution of pyridine and N,N-dimethylformamide (5 ml) at room temperature under nitrogen for 16 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic fraction was collected and the aqueous portion was washed with additional ethyl acetate. The combined organic fractions were washed with water, brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (95:5 dichloromethane 2N ammonia in methanol) to afford the title compound. MS (ESI) m/z 543.2 (M+H) + .
Example 3
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 3A
trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 3B
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 2G substituting Example 3A for Example 2F. MS (ESI) m/z 531 (M+H) + .
Example 4
2-chloro-N-[trans-1-(methylsulfonyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
Example 4A
(E)-1,2,4-trifluoro-5-(2-nitrovinyl)benzene
A stirred solution containing 2,4,5-trifluorobenzaldehyde (16.2 g, 80.1 mmol), ammonium acetate (17.3 g, 225 mmol), nitromethane (12.2 mL, 225 mmol), and acetic acid (75 mL) was heated to 100° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic fraction was collected and the aqueous fraction was washed with dichloromethane. The organic fractions were combined and washed with sodium bicarbonate (aq.), brine, and water. The organic fraction was dried with sodium sulfate and purified via flash chromatography (0-100% EtOAc/hexanes) to provide the title compound.
Example 4B
trans-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Examples 2A-2B substituting Example 4A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 4C
N-(trans-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)-2-chloro-3-(trifluoromethyl)benzamide
To a stirred solution of Example 4B (3.3 g, 10.7 mmol) in a 1:1 dimethylformamide:pyridine solution (20 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (2.9 g, 12.9 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.85 g, 15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrate. The reaction mixture was partitioned between, EtOAc (100 mL) and 1 M HCl (200 mL). The organic layer was collected. The aqueous fraction was washed with EtOAc (100 mL). The organic fractions were combined. Purification via flash chromatography (0-100% EtOAc/hexanes) provided the title compound.
2-chloro-3-(trifluoromethyl)-N-(trans-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)benzamide
To a stirred solution of Example 4C (3.4 g, 6.63 mmol) in dichloroethane was added 1-chloroethyl carbonochloridate (1.0 g, 7.29 mmol). The reaction mixture was stirred at 80° C. for 2 hours. Some precipitate was collected via filtration to provide the title compound. The filtrate was concentrated and purified via flash chromatography (0-30% methanol/DCM) to provide the title compound.
Example 4E
2-chloro-N-[(trans-1-(methylsulfonyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
To a stirred solution of Example 4D (50 mg, 0.18 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction mixture stirred at 60° C. for 18 hours. The reaction mixture was then concentrated and purified via HPLC. MS (ESI) m/z 501 (M+H) + .
Example 13
2-chloro-N-{trans-4-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-chloro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene. MS (DCI) m/z 547.0 (M+H) +
Example 14
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
Example 14A
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 14B
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 15
3-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 16
4-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 17
2-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 18
3-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 19
4-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 20
2-methoxy-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-methoxy-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 21
3-methoxy-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-methoxy-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 22
2-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 23
3-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 24
4-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 25
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 411 (M+H) + .
Example 26
2,4-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2,4-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 27
2-chloro-4-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-4-fluorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 463 (M+H) + .
Example 29
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,4-diphenylpyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 14A (50 mg, 0.15 mmol), bromobenzene (23 mg, 0.15 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (5.0 mg, 0.02 mmol), tris(dibenzylidene-acetone)dipalladium(0) (6.7 mg, 7.3 μmol), sodium tert-butoxide (18 mg, 0.19 mmol), and toluene (1 mL). The reaction mixture was stirred at 80° C. for 3 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 383 (M+H) + .
Example 30
3,5-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 31
2,3-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2,3-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 32
2-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 33
3-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 34
4-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 35
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 36
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 37
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 38
2-chloro-N-([trans-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
Example 38A
(trans)-1-benzyl-4-phenylpyrrolidin-3-amine
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Examples 2A-2B substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 38B
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C-4D substituting Example 38A for Example 4B.
Example 38C
2-chloro-N-[trans-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4E substituting Example 38B for Example 4D and substituting 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 581 (M+H) + .
Example 39
2-chloro-N-[trans-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (EST) m/z 577 (M+H) + .
Example 40
2-chloro-N-{trans-1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tort-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 561 (M+H) + .
Example 41
2-chloro-N-{trans-1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 527 (M+H) + .
Example 42
2-chloro-N-{trans-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 527 (M+H) + .
Example 43
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 44
2-chloro-N-{trans-1-[(6-methoxypyridin-3-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 6-methoxypyridine-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 540 (M+H) + .
Example 45
2-chloro-N-[trans-4-phenyl-1-(pyridin-3-ylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting pyridine-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 510 (M+H) + .
Example 46
2-chloro-N-[trans-4-phenyl-1-(1-pyrazol-4-ylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 47
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-5-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 48
2-chloro-N-{trans-1-[(5-chloro-1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 5-chloro-1-methyl-1H-imidazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 547 (M+H) + .
Example 49
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 50
trans-N-(4-methoxyphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 29 substituting 1-bromo-4-methoxybenzene for bromobenzene. MS (ESI) m/z 413 (M+H) + .
Example 51
3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 3-bromobenzenenitrile for bromobenzene. MS (EST) m/z 408 (M+H) + .
Example 52
4-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 4-bromobenzenenitrile for bromobenzene. MS (ESI) m/z 408 (M+H) + .
Example 53
3-fluoro-4-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 4-bromo-3-fluorobenzonitrile for bromobenzene. MS (ESI) m/z 426 (M+H) + .
Example 54
2-chloro-N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 530.9 (M+H) +
Example 55
2-chloro-N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures as described in Example 2 substituting (E)-1-fluoro-3-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 531.2 (M+H) +
Example 56
2-chloro-N-{trans-4-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to procedures described in Example 2 substituting (E)-1-chloro-3-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 547.5 (M+H) +
Example 57
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylphenyl)-4-phenylpyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 14A as a hydrochloric salt (100 mg, 0.30 mmol), 1-bromo-2-methylbenzene (55 mg, 0.32 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (10 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.02 mmol), sodium tert-butoxide (70 mg, 0.729 mmol), and toluene (2 mL). The reaction mixture was stirred at 80° C. for 6 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 397 (M+H) + .
Example 58
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 397 (M+H) + .
Example 59
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(4-methylphenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 397 (M+H) + .
Example 60
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 513 (M+H) + .
Example 61
3-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 513 (M+H) + .
Example 62
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 2-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 531 (M+H) + .
Example 63
3-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 3-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 531 (M+H) + .
Example 64
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 497 (M+H) + .
Example 65
3,5-dichloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 497 (M+H) + .
Example 66
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 67
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 68
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 69
trans-N-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 70
trans-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (APCI) m/z 401 (M+H) + .
Example 71
trans-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 72
3-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromo-benzenonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 73
trans-N-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-chlorobenzene for 1-bromo-2-methylbenzene. MS (APCI) m/z 418 (M+H) + .
Example 74
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 417 (M+H) + .
Example 75
trans-N-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 417 (M+H) + .
Example 76
4-fluoro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (APCI) m/z 426 (M+H) + .
Example 77
2-fluoro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-2-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 78
3-fluoro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 79
2-chloro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 80
3-chloro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 81
4-chloro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 82
4-methyl-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 83
2-methyl-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-2-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 84
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A. MS (ESI) m/z 415 (M+H) + .
Example 85
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 415 (M+H) + .
Example 86
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(4-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 415 (M+H) + .
Example 87
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 88
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 89
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 90
trans-N-(2-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 91
trans-N-(3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 92
trans-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 93
trans-N-(2-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 94
trans-N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 95
trans-N-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 100
2-methoxy-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-methoxybenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 438 (M+H) + .
Example 101
3-methyl-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 102
5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-2-(trifluoromethoxy)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-(trifluoromethoxy)benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 476 (M-CH 3 ) + .
Example 115
2-chloro-N-{trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 547.2 (M+H) + .
Example 122
N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
Example 122A
trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting ethanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 122B
N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 427 (M+H) + .
Example 123
3,5-dichloro-N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 427 (M+H) + .
Example 124
2-chloro-N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B. MS (ESI) m/z 461 (M+H) + .
Example 125
N-[trans-4-phenyl-1-(propyl sulfonyl)pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
Example 125A
The title compound was prepared as an HCl salt similarly to the procedures described for Examples 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting propanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 125B
N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 125A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 126
3,5-dichloro-N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]benzamide
The title compound was prepared similarly to Example 4C substituting Example 125A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 127
2-chloro-N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 125A for Example 4B. MS (ESI) m/z 475 (M+H) + .
Example 128
N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 128A
trans-1-(cyclopropylmethylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting cyclopropylmethanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 128B
N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (EST) m/z 453 (M+H) + .
Example 129
3,5-dichloro-N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 453 (M+H) + .
Example 130
2-chloro-N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B. MS (ESI) m/z 487 (M+H) + .
Example 131
3-{[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 122A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 356 (M+H) + .
Example 132
3-{[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 125A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 370 (M+H) + .
Example 133
3-({trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 128A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 382 (M+H) + .
Example 134
N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 134A
trans-1-(4-methoxyphenylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 4-methoxybenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 134B
N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 505 (M+H) + .
Example 135
3,5-dichloro-N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 505 (M+H) + .
Example 136
2-chloro-N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B. MS (ESI) m/z 539 (M+H) + .
Example 137
3-({trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 134A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 142
3,5-dichloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]benzamide
Example 142A
trans-4-phenyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 142B
3,5-dichloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 142A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 543 (M+H) + .
Example 143
2-chloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 142A for Example 4B. MS (ESI) m/z 577 (M+H) + .
Example 144
3-{[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 142A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 472 (M+H) + .
Example 145
4-{[trans-3-benzyl-4-phenylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 145A
(1-benzyl-4-phenylpyrrolidin-3-yl)(phenyl)methanone
A solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (5.9 g, 0.025 mole) in dichloromethane (30 mL) was stirred under nitrogen, in an ice/methanol bath. Chalcone (4.16 g, 0.02 mole) was added dropwise and the mixture was stirred in the cold bath overnight. The reaction mixture was washed with aqueous sodium bicarbonate, brine, and dried over sodium sulfate. The solvent was evaporated to provide the title compound. MS (ESI) m/z 342 [M+H] + .
Example 145B
3-benzyl-4-phenylpyrrolidine hydrochloride
Example 145A (8.5 g, 0.025 mole) was hydrogenated with 10% Pd/C (0.25 g) in methanol (200 mL). The reaction mixture was filtered, dissolved in methanol (100 mL) and passed through Amberlite resin. The filtrate was concentrated, redissolved in toluene and concentrated. This procedure was repeated several times until the residue was dry. MS (ESI) m/z 338 [M+H] + .
Example 145C
4-(trans-3-benzyl-4-phenylpyrrolidin-1-ylsulfonyl)-1-methyl-1H-imidazole
To a solution of Example 145B (0.0767 g, 0.280 mmol) in dichloromethane (1.121 ml) was added triethylamine (0.156 ml, 1.121 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.051 g, 0.280 mmol), The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated. The crude material was purified by HPLC to afford the title compound. MS (ESI) m/z 382.2 [M+H] + .
Example 148
trans-N-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a stirred solution of Example 3A (100 mg, 0.28 mmol) in a buffer 4 pH solution (5 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added benzaldehyde (24 mg, 0.22 mmol) and MgSO 4 (334 mg, 2.77 mmol). The reaction was allowed to stir for 1 hour at room temperature before MgSO 4 was removed via filtration. To the filtrate was added MP-cyanoborohydride (2.19 mmol/g, 380 mg, 0.83 mmol) and the reaction was allowed to stir for 24 hours. The resin was removed via filtration and purification via HPLC provided the title compound. MS (ESI) m/z 415 (M+H) + .
Example 149
trans-N-[2-chloro-3-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chloro-3-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 150
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 151
trans-N-[3-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 152
3-[({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)methyl]benzonitrile
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-cyanobenzaldehyde for benzaldehyde. MS (ESI) m/z 440 (M+H) + .
Example 153
trans-4-(4-fluorophenyl)-N-(2-methylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 154
trans-4-(4-fluorophenyl)-N-(3 ethylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 155
trans-4-(4-fluorophenyl)-N-(4-methylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 156
trans-N-(4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 157
(cis)-N-benzyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 157A
1-benzyl-3-(benzylamino)-4-chloro-1H-pyrrole-2,5-dione
To a stirred solution of 3,4-dichlorofuran-2,5-dione (5 g, 30 mmol) in acetic acid (17 mL) was added benzylamine (3.2 g, 30 mmol) and the reaction was stirred at room temperature for 1 hour. More benzylamine (3.2 g, 30 mmol) was added and the reaction was heated to 100° C. for 2 hours. The reaction mixture was concentrated. The mixture was neutralized with aqueous sodium hydroxide and partitioned with ethyl acetate. The organic fraction was collected and concentrated. Purification via flash chromatography (0-60% EtOAc/hexanes) provided the title compound.
Example 157B
1-benzyl-3-(benzylamino)-4-chloro-1H-pyrrole-2,5-dione
To a solution of Example 157A (5.5 g, 16.8 mmol) in 1,2-dimethoxyethane (60 mL) was added phenylboronic acid (2.46 g, 20.2 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (691 mg, 1.68 mmol), palladium(II) acetate (189 mg, 0.848 mmol), and potassium carbonate (2 M, 16.8 mL, 33.7 mmol). The reaction mixture was refluxed for 2 hours. The reaction was partitioned between water and EtOAc. The organic layer was collected and concentrated. Purification via flash chromatography (0-80% EtOAc/hexanes) provided the title compound.
Example 157C
tert-butyl benzyl (1-benzyl-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-3-yl)carbamate
To a stirred solution of Example 157B (4.13 g, 11.2 mmol) and triethylamine (113 mg, 1.12 mmol) in dichloromethane (50 mL) at 0° C. was added di-tert-butyl dicarbonate (1 M in tetrahydrofuran, 12.3 mL, 12.3 mmol) and N,N-dimethylpyridin-4-amine (137 mg, 1.12 mmol). The reaction was allowed to warm to room temperature after 1 hour and stirred at room temperature for 24 hours. More di-tert-butyl dicarbonate (1 M in tetrahydrofuran, 3 mL, 3 mmol) was added and the reaction mixture stirred for 2 more hours. The reaction mixture was then concentrated. Purification via flash chromatography (0-10% methanol/DCM) provided the title compound.
Example 157D
tert-butyl benzyl(cis-1-benzyl-2,5-dioxo-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 157C (25 mg, 0.053 mmol) in trifluoroethane (4 ml) in a 50 ml pressure bottle was added 20% Pd(OH) 2 /C, wet (6.25 mg, 0.045 mmol). The reaction mixture stirred for 16 hours at 30 psi hydrogen and 50° C. The mixture was filtered through a nylon membrane and the filtrate was concentrated to provide the title compound.
Example 157E
tert-butyl benzyl((cis)-1-benzyl-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 157D (2.5 g, 5.3 mmol) in tetrahydrofuran (50 mL) was added borane (1 M in tetrahydrofuran, 21.3 mL, 21.3 mmol). The reaction mixture was heated to 70° C. for 18 hours. The reaction was cooled to 50° C. and methanol (20 mL) was added slowly. The reaction mixture stirred for 1 hour. The reaction mixture was concentrated. Purification via flash chromatography (0-100% EtOAc/hexanes) provided the title compound.
Example 157F
tert-butyl benzyl((cis)-4-phenylpyrrolidin-3-yl)carbamate
To a pressure vial was added Example 157E (801 mg, 1.810 mmol), tetrahydrofuran (20 ml) and Pd(OH) 2 /C, (20%, wet, 160 mg, 1.141 mmol) and the reaction mixture was stirred for 16 hours at 30 psi of hydrogen at 50° C. The mixture was filtered through a nylon membrane and the filtrate was concentrated to provide the title compound.
Example 157G
(cis)-N-benzyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2E-2F substituting Example 157F for Example 2D. MS (ESI) m/z 397 (M+H) + .
Example 158
trans-N-(3,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 159
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 160
trans-N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 161
trans-N-(3,4-dichlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1,2-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 162
trans-N-(4-chloro-3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-chloro-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 163
trans-N-(2,3-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 164
trans-N-(2,5-di fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 165
trans-N-(2,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 166
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2,3,4-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,3,4-trifluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 455 (M+H) + .
Example 167
trans-4-(4-fluorophenyl)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 168
trans-4-(4-fluorophenyl)-N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 169
trans-4-(4-fluorophenyl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 170
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-isopropylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 443 (M+H) + .
Example 171
trans-N-(3-tert-butylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-tert-butylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 457 (M+H) + .
Example 172
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 173
trans-N-[3-chloro-4-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-chloro-1-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 174
trans-N-(3-chloro-5-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chloro-5-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 175
trans-N-(3-chloro-4,5-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chloro-4,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 471 (M+H) + .
Example 176
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 177
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromopyridine hydrochloride for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 178
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 179
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 180
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 181
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 182
4-{[3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 182A
2-(3-chlorobenzyl)-3-(4-fluorophenyl)-4-nitrobutanal
To a solution of (E)-1-fluoro-4-(2-nitrovinyl)benzene (1 g, 6.0 mmol) in dichloromethane (10 mL) was added 3-(3-chlorophenyl)propanal (1 g, 5.9 mmol), triethylamine (50 mL), and L-proline (50 mg, 0.43 mmol). The mixture was allowed to stir for 16 hours and the crude material was purified by silica gel column chromatography e(25% ethyl acetate/hexanes) to provide the title compound (4:1 mixture of 2 diastereomers).
Example 182B
3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidine
To a solution of Example 182A (0.92 g, 2.7 mmol) in methanol (5 mL) was added 50% acetic acid (aq) (5 mL) followed by zinc (6×200 mg, 19 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol). The mixture was allowed to stir for 30 minutes. Sodium hydroxide (1 M) was added to adjust the pH value to 8. Ethyl acetate was added and the solution partitioned. The organic fraction was collected and concentrated to provide the crude title compound.
Example 182C
4-{[3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
To a solution of Example 182B (289 mg, 1.0 mmol) in dichloromethane (5 mL) was added triethylamine (130 mg, 1.3 mmol), and 1-methyl-1H-imidazole-4-sulfonyl chloride (180 mg, 1.0 mmol). The mixture was allowed to stir for 20 minutes and purified by silica gel column chromatography (100% ethyl acetate). The product was recrystallized in ethyl acetate to provide the title compound. MS (ESI) m/z 434/436 (3:1) (M+H) + .
Example 183
2-chloro-N-{(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 183A
A 20 mL pressure vial was charged with Example 157 (891.1 mg, 2.247 mmol), ethanol (6 mL) and dihydroxypalladium (60.2 mg, 0.429 mmol). The mixture was stirred under 60 psi of hydrogen at 50° C. for 1.5 hours. Another 60 mg of catalyst was added, and the hydrogenation was continued for 2 hours more. The mixture was filtered through a polypropylene membrane and concentrated to provide the title compound.
Example 183B
2-chloro-N-{(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 183A for Example 4B. MS (ESI) m/z 513 (M+H) + .
Example 184
(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,4-diphenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 183A for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 383 (M+H) + .
Example 185
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
Example 185A
(E)-1-fluoro-3-(2-nitrovinyl)benzene
A stirred solution containing 3-fluorobenzaldehyde (9.95 g, 80.1 mmol), ammonium acetate (17.3 g, 225 mmol), nitromethane (12.2 mL, 225 mmol), and acetic acid (75 mL) was heated to 100° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic fraction was collected and the aqueous fraction was washed with dichloromethane. The organic fractions were combined and washed with sodium bicarbonate (aq.), brine, and water. The organic fraction was dried with sodium sulfate and purification via flash chromatography (10% EtOAc/hexanes) provided the title compound.
Example 185B
trans-4-(3-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as the HCl salt similarly to the procedures described in Example 2A-2F substituting Example 185A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 185C
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 186
trans-N,4-bis(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 187
trans-4-(3-fluorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 188
trans-N-(3-chlorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 189
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-(trifluoromethane)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 190
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-(trifluoromethane)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 191
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 4-bromopyridine hydrochloride for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 192
trans-N-(3,4-dichlorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3,4-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 193
trans-N-(4-chloro-3-fluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-chloro-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 194
trans-N-(3-chloro-4-fluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 195
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 196
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 197
trans-N-(3,4-difluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 198
trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl) sulfonyl]-N-phenylpyrrolidin-3-amine
Example 198A
trans-4-(2-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-(2-nitrovinyl)benzene.
Example 198B
trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 199
trans-4-(2-fluorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 200
trans-4-(2-fluorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 201
trans-N-(3-chlorophenyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 202
trans-N-(4-chlorophenyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 203
N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 204
N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 205
4-{[3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 205A
2-(2-bromobenzyl)-3-(2-bromophenyl)-4-nitrobutanal
The title compound was prepared using the conditions described in Example 182A substituting (E)-1-bromo-2-(2-nitrovinyl)benzene for (E)-1-fluoro-4-(2-nitrovinyl)benzene and 3-(2-bromophenyl)propanal for 3-(3-chlorophenyl)propanal.
Example 205B
3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidine
The title compound was prepared using the conditions described in Example 182B substituting Example 205A for Example 182A.
Example 205C
4-{[3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the conditions described in Example 182C substituting Example 205B for Example 182B. MS (ESI) m/z 537/539/541 (1:2:1) (M+H) + .
Example 206
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanol
To a solution of Example 242C (620 mg, 1.69 mmol) in 6 mL of tetrahydrofuran at −30° C. was added lithium aluminum hydride (2N in tetrahydrofuran, 0.93 mL, 1.86 mmol). The reaction mixture stirred at −30° C. for 30 min. The reaction mixture was quenched with a saturated sodium bicarbonate solution, and the solution was partitioned with EtOAc. The organic fraction was collected, washed with water dried over sodium sulfate, and concentrated to give the title compound. MS (ESI) m/z 340.0 (M+H) + .
Example 207
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 208
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 209
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 210
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 211
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 212
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 213
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 214
trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 215
trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 216
trans-N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1,2-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 217
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 218
trans-N-(3,4-dichlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1,2-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 219
trans-N-(3-chloro-4,5-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 5-bromo-1-chloro-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 220
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(propan-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-isopropylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 425 (M+H) + .
Example 221
trans-N-(3-tert-butylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-tert-butyl-benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 439 (M+H) + .
Example 222
trans-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 223
trans-N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 224
trans-N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 225
trans-N-(3-chloro-5-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-chloro-5-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 226
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 467 (M+H) + .
Example 227
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyrimidin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-4-(trifluoromethyl)pyrimidine for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 228
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}quinolin-7-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 7-bromoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 229
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}quinolin-6-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 6-bromoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 230
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}isoquinolin-6-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 6-bromoisoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 231
trans-N-(2,3-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 232
trans-N-(2,5-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 233
trans-N-(2,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 234
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2,3,4-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,3,4-trifluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 235
6-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-6-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 236
2-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 237
5-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromo-5-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 238
6-fluoro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-6-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 420 (M+H) + .
Example 239
2-fluoro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 420 (M+H) + .
Example 240
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 241
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}isoquinolin-7-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 7-bromoisoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 242
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidine-3-carboxamide
Example 242A
A solution of (E)-methyl 3-(4-fluorophenyl)acrylate (10.52 g, 58.4 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (19.41 g, 81.8 mmol) in 110 mL of dichloromethane was cooled to 0° C. Trifluoroacetic acid (0.495 ml, 6.42 mmol) was slowly added under N 2 . The reaction mixture was stirred at 0° C. for 1 hour, then stirred at room temperature for 18 hours. The reaction mixture was partitioned with saturated sodium bicarbonate. The organic fraction was collected, concentrated, and purified by flash-chromatography on silica gel (20-30% ethyl acetate in hexane) to provide the title compound. MS (ESI) m/z 314.3 (M+H) +
Example 242B
Trans-methyl 4-(4-fluorophenyl)pyrrolidine-3-carboxylate
Example 242A (17.98 g, 57.4 mmol) and tetrahydrofuran (10 ml) were added to 20% Pd(OH) 2 /C, wet (3.60 g, 25.6 mmol) in a 250 mL SS pressure bottle and stirred for 16 hours under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound. MS (ESI) m/z 224.0 (M+H) + .
Example 242C
Trans-methyl 4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxylate
To Example 242 B (12.74 g, 57.1 mmol) in 15 mL of dichloromethane were added triethylamine (12.13 g, 120 mmol) and 4-dimethylaminopyridine (0.35 g, 2.85 mmol). The reaction mixture was cooled to 0° C. 1-methyl-1H-imidazole-4-sulfonyl chloride (10.82 g, 59.9 mmol) was added portion wise at 0° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hour. The reaction mixture was partitioned with dichloromethane, and water. The organic fraction was collected, washed with water, concentrated, and purified by flash-chromatography on silica gel (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 368.0 (M+H) + .
Example 242D
Trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxylic acid
To Example 242C (3.67 g, 9.99 mmol) was added 4 mL of methanol. To this solution was added lithium hydroxide (1 M, methanol:water=5:3, 15 mL, 15 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was then treated with hydrochloric acid (1 M, aq.) until pH=5. The reaction mixture was partitioned with ethyl acetate and the organic fraction was collected. The aqueous fraction was washed with ethyl acetate (3×), and the organic fractions were combined and concentrated to provide the title product. MS (ESI) m/z 354.0 (M+H) + .
Example 242E
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidine-3-carboxamide
To solution of Example 242D (150 mg, 0.42 mmol) in dimethylformamide/pyridine (1:1. 15 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.45 mmol) and aniline (41.5 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated purified by HPLC to provide the title product. MS (ESI) m/z 429.1 (M+H) + .
Example 243
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the same sequence of steps described in Example 242 substituting 4-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 497.0 (M+H) + .
Example 244
Trans-N-(3,5-dichlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedures described in Example 242 substituting 3,5-dichloroaniline for aniline. MS (ESI) m/z 497.1 (M+H) + .
Example 245
4-{[trans-3-(4-fluorophenyl)-4-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
To a solution of Example 206 (52 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added phenol (21.6 mg, 0.23 mmol), PS-triphenylphosphine (105 mg, 0.34 mmol, 3.2 mmol/g), and di-tert-butylazodicarboxylate (70.6 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and washed with methanol. The filtrate was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 416.1 (M+H) + .
Example 246
4-{[trans-3-[(2,4-dichlorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 2,4-dichlorophenol for phenol. MS (ESI) m/z 484.1 (M+H) + .
Example 247
4-{[trans-3-(4-fluorophenyl)-4-{[3-(trifluoromethoxy)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-(trifluoromethoxy)phenol for phenol. MS (ESI) m/z 500.1 (M+H) + .
Example 248
4-{[trans-3-[(3-chlorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-chlorophenol for phenol. MS (ESI) m/z 450.1 (M+H) + .
Example 249
4-{[trans-3-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedures described in Example 245 substituting 4-chloro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 518.2 (M+H) + .
Example 250
4-{[trans-3-{[2-chloro-3-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedures as in Example 245 substituting 2-chloro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 518.1 (M+H) + .
Example 251
4-{[trans-3-[(3-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-fluorophenol for phenol. MS (ESI) m/z 434.1 (M+H) + .
Example 252
trans-4-(2-chlorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 252A
trans-4-(2-chlorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 252B
trans-4-(2-chlorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 252A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 253
trans-4-(2-chlorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 253A
trans-4-(2-chlorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 3A substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-(2-nitrovinyl)benzene.
Example 253B
trans-4-(2-chlorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 254
trans-4-(2-chlorophenyl)-N-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 255
trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 256
trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 257
trans-N-(3-chloro-4-fluorophenyl)-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 258
trans-4-(2-chlorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 259
N-{trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 486 (M+H) + .
Example 260
trans-N-(2-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 261
trans-N-(3-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 262
trans-N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 263
trans-N-(2-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 264
trans-N-(3-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 265
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 266
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 267
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 268
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting picolinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 269
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting nicotinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 270
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-4-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting isonicotinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 271
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(phenyl)methanone
Example 271A
Trans-4-(4-fluorophenyl)-N-methoxy-N-methyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxamide
To a solution of Example 242D (610 mg, 1.73 mmol) in dimethylformamide (5 mL) was added triethylamine (0.52 mL, 3.71 mmol), N,O-dimethylhydroxylamine hydrochloride (236 mg. 2.42 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (665 mg, 2.07 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was collected. The aqueous fraction was washed with ethyl acetate 3 more times. The combined organic fractions were dried over sodium sulfate, concentrated, and purified by flash-chromatography on silica gel (5-10% methanol in dichloromethane (with 0.5% volume triethylamine added)) to afford the title compound. MS (ESI) m/z 397.0 (M+H) + .
Example 271B
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(phenyl)methanone
To a solution of Example 271A (113 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) was added phenylmagnesium bromide (0.57 mL, 0.57 mmol, 1.0 M in tetrahydrofuran) slowly at room temperature. The solution stirred for 1 hour. The reaction mixture was partitioned with saturated ammonium chloride (aq.) and the organic fraction was collected. The organic fraction was dried over sodium sulfate, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 414.1 (M+H) + .
Example 272
Trans-N-[2-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 2-chloro-3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 273
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 513.1 (M+H) + .
Example 274
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoro-3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 515.1 (M+H) + .
Example 275
trans-N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-chloro-4-fluoroaniline for aniline. MS (ESI) m/z 481.1 (M+H) + .
Example 276
trans-N-[3-chloro-4-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-chloro-4-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 277
1-methyl-4-[(3-phenoxy-4-phenylpyrrolidin-1-yl)sulfonyl]-1H-imidazole
To a stirred solution of tert-butyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate (200 mg, 0.76 mmol) in tetrahydrofuran (5 mL) was added (Z)-di-tert-butyl diazene-1,2-dicarboxylate (262 mg, 1.1 mmol), phenol (72 mg, 0.76 mmol), and polystyrene triphenylphosphine resin (2.37 mmol/g, 961 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 18 hours before the resin was filtered off. The filtrate was concentrated. The concentrate was dissolved in dichloromethane (2 mL) and HCl (4M in dioxane, 2 mL, 8 mmol) was added. When LCMS showed that the reaction was complete the reaction mixture was concentrated. To a stirred solution of the concentrate in pyridine (4 mL) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (165 mg, 0.91 mmol). The reaction mixture was warmed to 60° C. for 18 hours. The reaction was then concentrated. Purification via HPLC provided the title compound.
Example 278
trans-4-(2-chlorophenyl)-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 252A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 279
trans-N-(2,4-dichlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 280
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 14A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 465 (M+H) + .
Example 281
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 14A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 499 (M+H) + .
Example 282
trans-N-(2,4-dichlorobenzyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 282A
trans-4-(2-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as the HCl salt similarly to the procedure described in Example 2A-2F substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 282B
trans-N-(2,4-dichlorobenzyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 282A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 283
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 282A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 284
trans-4-(2-chlorophenyl)-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 252A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 501 (M+H) + .
Example 285
trans-4-(2-chlorophenyl)-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 252A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 533 (M+H) + .
Example 286
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)pyrrolidin-3-amine
Example 286A
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(pyridin-3-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-3-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 286B
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 286A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 466 (M+H) + .
Example 287
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 288
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 289
Trans-N-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting phenylmethanamine for aniline. MS (ESI) m/z 443.1 (M+H) + .
Example 290
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
To a solution of Example 242E (106.7 mg, 0.25 mmol) in dry tetrahydrofuran (0.7 mL) under argon, was added borane dimethyl sulfide complex (0.5 mL, 1.0 mmol, 2M in tetrahydrofuran). The reaction mixture was stirred at 60° C. for 5 hours and stirred at room temperature for 18 hours. Hydrochloric acid (0.5 mL of 0.5 N HCl) was carefully added. The reaction mixture was refluxed for 2 hours, then treated with sodium hydroxide (1N) to pH=8-9. The reaction mixture was portioned with ethyl acetate. The organic fraction was collected. The aqueous fraction was washed with dichloromethane. The organic fractions were combined, dried over sodium sulfate, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 415.1 (M+H) + .
Example 291
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
The title compound was prepared using the procedure described in Example 290 substituting Example 243 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 292
3,5-dichloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared using the procedure described in Example 290 substituting Example 244 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 293
4-{[trans-3-(4-fluorophenyl)-4-{[3-(trifluoromethyl)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 484.1 (M+H) +
Example 294
4-{[trans-3-{[2-chloro-4-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-chloro-4-hydroxybenzotrifluoride for phenol. MS (ESI) m/z 518.1 (M+H) +
Example 295
4-{[trans-3-(4-fluorophenyl)-4-{[4-fluoro-3-(trifluoromethyl)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-fluoro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 502.1 (M+H) + .
Example 296
4-({trans-3-(4-fluorophenyl)-4-[(3-methylphenoxy)methyl]pyrrolidin-1-yl}sulfonyl)-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting m-cresol for phenol. MS (ESI) m/z 430.1 (M+H) + .
Example 297
(3-chlorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-chlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 448.1 (M+H) + .
Example 298
trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 299
trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 501 (M+H) + .
Example 300
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(3-methylphenyl)methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting m-tolylmagnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 428.0 (M+H) + .
Example 301
(3-fluorophenyl){(trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 432.1 (M+H) + .
Example 302
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[3-(trifluoromethyl)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-(trifluoromethyl)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 303
(4-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methasone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 432.1 (M+H) + .
Example 304
trans-N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-chloro aniline for aniline. MS (ESI) m/z 463.0 (M+H) + .
Example 305
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A For Example 14A and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (EST) m/z 503 (M+H) + .
Example 306
trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A For Example 14A and substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 519 (M+H) + .
Example 307
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
Example 307A
(E)-2-(2-nitrovinyl)pyridine
To a stirred solution of nitromethane (15.2 mL, 280 mmol) and 2-pyridinecarboxaldeyde (8.9 mL, 93 mmol) in toluene (100 mL) at room temperature was added 1,1,2,2,-tetramethylguanidine (1.2 mL, 9.3 mmol) followed by methanesulfonyl chloride (14.5 mL, 187 mmol). The reaction mixture was stirred for 5 minutes before triethylamine (26.1 mL, 187 mmol) was added. The reaction mixture was stirred for 30 minutes, then quenched with sodium bicarbonate (aq.) The organic fraction was collected. The aqueous fraction was washed with dichloromethane. All organic fractions were combined. Purification via flash chromatography provided the title compound.
Example 307B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Example 2A-2F substituting Example 307A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 307C
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 307B for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 466 (M+H) + .
Example 308
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 286A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 309
4-{[3-(3-chlorobenzyl)-4-cyclopropylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 309A
2-(3-chlorobenzyl)-3-cyclopropyl-4-nitrobutanal
The title compound was prepared using the conditions described in Example 182A substituting (E)-(2-nitrovinyl)cyclopropane for (E)-1-fluoro-4-(2-nitrovinyl)benzene.
Example 309B
3-(3-chlorobenzyl)-4-cyclopropylpyrrolidine
The title compound was prepared using the conditions described in Example 182B substituting Example 309A for Example 182A.
Example 309
4-{[3-(3-chlorobenzyl)-4-cyclopropylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the conditions described in Example 182C substituting Example 309B for Example 182B. MS (ESI) m/z 380/382 (3:1) (M+H) + .
Example 310
N-[3-(difluoromethyl)-4-fluorophenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a 10 mL microwave vial was added 4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride (100 mg, 0.277 mmol) and premixed tris(dibenzylidene-acetone)dipalladium(0)sodium tert-butoxide 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (100 mg, 0.05:0.15:2), aldrich 715530). The solids were suspended in 1,2-dimethoxyethane, and 4-bromo-2-(difluoromethyl)-1-fluorobenzene (74.8 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) for 15 min at 130° C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% methanol/dimethylsulfoxide, and purified by HPLC to provide the title compound. MS (ESI) m/z 469 (M+H) + .
Example 311
3-chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 276 for Example 242E. MS (ESI) m/z 517.0 (M+H) + .
Example 312
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 273 for Example 242E. MS (ESI) m/z 499 (M+H) + .
Example 313
4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 274 for Example 242E. MS (ESI) m/z 501.1 (M+H) + .
Example 314
3-chloro-4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 275 for Example 242E. MS (ESI) m/z 467.1 (M+H) + .
Example 315
N-benzyl-1-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 289 for Example 242E. MS (ESI) m/z 429.1 (M+H) + .
Example 316
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting m-toluidine for aniline. MS (ESI) m/z 443.0 (M+H) +
Example 317
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 497.0 (M+H) + .
Example 318
4-{[Trans-3-[(3-chloro-4-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-chloro-4-fluorophenol for phenol. MS (ESI) m/z 468.1 (M+H) + .
Example 319
(4-Chloro-3-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-chloro-3-fluorophenyl) magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 466.1 (M+H) + .
Example 320
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 286A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 500 (M+H) + .
Example 321
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 321A
tert-butyl (3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the conditions described in Example 2A-2E substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene. A Chiral SFC separation provided the title compound. (Instrument: SFC200 Column: AD-H, 50×250 mm, 5 μm; Column Temperature: 35° C.; Mobile Phase: CO 2 /methanol/diethylamine=80200.1; Flow rate: 180 g/min; Back Pressure: 100 Bar; Wavelength: 214 nm; Cycle time: 5.1 min; Injection: 2.0 mL Sample solution: 55 g in 500 mL methanol). Retention Time=4.03 minutes.
Example 321B
(3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2F substituting Example 321A for Example 2E.
Example 321C
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 321B for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 322
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 322A
tert-butyl (3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to Example 321A. RT=5.73 minutes.
Example 322B
(3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2F substituting Example 322A for Example 2E.
Example 322C
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 323
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 321B (100 mg, 0.27 mmol), 1-bromo-3-(trifluoromethoxy)benzene (67 mg, 0.27 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (9.5 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.014 mmol), sodium tert-butoxide (107 mg, 1.1 mmol), and dioxane (4 mL). The reaction mixture was stirred at 80° C. for 2 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 485 (M+H) + .
Example 324
(3S,4R)—N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-4-fluorobenzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 419 (M+H) + .
Example 325
(3S,4R)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-3-chlorobenzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 435 (M+H) + .
Example 326
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-3-(trifluoromethyl)benzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 469 (M+H) + .
Example 327
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 322B (100 mg, 0.28 mmol), 1-bromo-3-(trifluoromethyl)benzene (62 mg, 0.28 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (9.5 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.014 mmol), sodium tert-butoxide (107 mg, 1.1 mmol), and dioxane (4 mL). The reaction mixture was stirred at 80° C. for 2 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 469 (M+H) + .
Example 328
(3R,4S)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but the reaction only stirred for 1 hour. MS (ESI) m/z 435 (M+H) + .
Example 329
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 330
(3R,4S)-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-fluorobenzene for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 419 (M+H) + .
Example 331
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-2-one
Example 331A
methyl 2-(3-chlorobenzyl)-4-nitro-3-phenylbutanoate
To a solution of diisopropylamine (210 mg, 2 mmol) in tetrahydrofurane (1 mL) at −78° C. was added butyllithium (1 mL, 2N, 2 mmol). The mixture was allowed to stir for 10 minutes. Then methyl 3-(3-chlorophenyl)propanoate in tetrahydrofurane (1 mL) was added. The mixture was allowed to stir for 30 minutes. (E)-(2-nitrovinyl)benzene in tetrahydrofuran (1 mL) was added. The mixture was allowed to stir for 1 hour, and partitioned with ammonium chloride (aq) and ethyl acetate. The organic fraction was collected and concentrated to provide the crude title compound.
Example 331B
3-(3-chlorobenzyl)-4-phenylpyrrolidin-2-one
To a solution of Example 331A in methanol (2 mL) was added an acetic acid solution (2 mL. 50% aq.), and zinc (6×130 mg, 12 mmol). The reaction mixture stirred for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and enough NaOH (1M aq.) to adjust the pH value to 10. The insoluble material was filtered off through celite. The organic fraction was collected, and dried over sodium hydroxide pellets for 16 hours. The mixture was washed with HCl(aq) and purified by silica gel flash chromatography (100% ethyl acetate) to afford the title compound.
Example 331C
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-2-one
To a solution of Example 331B (150 mg, 0.53 mmol) in tetrahydrofuran (1 mL) at −78° C. was added butyllithium (0.3 mL, 2 N, 0.6 mmol). The mixture was allowed to stir for 10 minutes. 1-Methyl-1H-imidazole-4-sulfonyl chloride (95 mg, 0.53 mmol) was added. The reaction stirred for 2 hours. The mixture was warmed to 20° C. and quenched with ammonium chloride (aq.) The mixture was extracted with ethyl acetate and purified by flash chromatography (10% methanol/ethyl acetate) followed by trituration in methanol. The precipitates were collected to afford the title compound. MS (ESI) m/z 430432 (3:1) (M+H) + .
Example 332
2-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
Example 332A
Trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carb aldehyde
To a solution of Example 206 (180 mg, 0.53 mmol) in dichloromethane (2 mL) was added Dess-MartinPeriodinane (450 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated to afford the title compound. MS (EST) m/z 338.0 (M+H) + .
Example 332B
2-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
To Example 332A (150 mg, 0.45 mmol) in methanol acetate buffer (2 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added 2-chloro-4-(trifluoromethyl)aniline (104 mg, 0.53 mmol) and sodium cyanoborohydride (42 mg, 0.67 mmol). The mixture was allowed to stir overnight. It was partitioned between dichloromethane and saturated sodium bicarbonate. Purification via HPLC afford the title compound. MS (ESI) m/z 517.0 (M+H) + .
Example 333
3-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 304 for Example 242E. MS (EST) m/z 449.1 (M+H) + .
Example 334
N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-methylaniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 316 for Example 242E. MS (ESI) m/z 429.1 (M+H) + .
Example 335
N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethyl)aniline
The title compound was prepared using the procedure as described in Example 290 substituting Example 317 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 336
4-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-6-(trifluoromethyl)pyrimidine
The title compound was prepared using the procedure as described in Example 245 substituting 6-(trifluoromethyl)pyrimidin-4-ol for phenol. MS (ESI) m/z 486.1 (M+H) + .
Example 337
Trans-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Example 337A
Trans-1-benzyl-3-cyclopropyl-4-nitropyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting (E)-(2-nitrovinyl)cyclopropane for trans-4-methoxy-beta-nitrostyrene.
Example 337B
Trans-1-benzyl-4-cyclopropylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 337A for Example 2A.
Example 337C
tert-butyl (trans-1-benzyl-4-cyclopropylpyrrolidin-3-yl)carbamate
To a solution of Example 337B (1.0 g, 4.6 mmol) in ethyl acetate (10 mL) was added di-tert-butyl dicarbonate (1.4 g, 6.4 mmol). The mixture was allowed to stir for 1 hour. The mixture was concentrated and purified by silica gel column chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 337D
tert-butyl ((trans-4-cyclopropylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 337C for 2C.
Example 337E
tert-butyl ((trans-4-cyclopropyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 337D for Example 2D.
Example 337F
Trans-4-cyclopropyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-amine
To Example 337E (0.82 g, 2.2 mmol) in dioxane (5 mL), was added hydrochloric acid (4N in dioxane, 3 mL). The mixture was stirred overnight, concentrated, and partitioned between ethyl acetate and sodium hydroxide (1M). The organic fraction was dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 337G
Trans-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
To a solution of Example 337F (135 mg, 0.5 mmol) in dioxane (1 mL) was added 1-bromo-3-(trifluoromethyl)benzene (101 mg, 0.5 mmol), tris(dibenzylidene-acetone)dipalladium(0) (46 mg, 0.05 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48 gm, 0.1 mmol), and sodium 2-methylpropan-2-olate (48 mg, 0.5 mmol). The mixture was heated at 110° C. for 2 hours, partitioned between ethyl acetate and ammonium chloride (aq), and purified by HPLC to give the title compound. MS (ESI) m/z 415 (M+H) + .
Example 338
Trans-N-(3-chlorophenyl)-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 381/383 (3:1) (M+H) + .
Example 339
4-{[3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 339A
2-(2-chlorophenyl)acetaldehyde
To 2-(2-chlorophenyl)ethanol (1 g, 6.39 mmol) in 10 mL of dichloromethane was added Dess-MartinPeriodinane (3.52 g, 8.3 mmol) at 0° C. This mixture was stirred at 0° C. for 1 hour. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated to afford the title product.
Example 339B
2-(2-Chlorophenyl)-3-(4-fluorophenyl)-4-nitrobutanal
The title compound was prepared similarly to the procedure described in Example 182A substituting Example 339A for 3-(3-chlorophenyl)propanal.
Example 339C
Trans-3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 182B substituting Example 339B for Example 182A.
Example 339D
4-{[3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 339C for Example 182 B. MS (ESI) m/z 420.3 (M+H) + .
Example 340
4-{[3-(4-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 340A
2-(4-Chlorophenyl)acetaldehyde
The title compound was prepared similarly to the procedure described in Example 339A substituting 2-(4-chlorophenyl)ethanol for 2-(2-chlorophenyl)ethanol.
Example 340B
2-(4-Chlorophenyl)-3-(4-fluorophenyl)-4-nitrobutanal
The title compound was prepared similarly to the procedure described in Example 182A substituting Example 340A for 3-(3-chlorophenyl)propanal.
Example 340C
The title compound was prepared similarly to the procedure described in Example 182B substituting Example 340B for Example 182A.
Example 340D
4-{[3-(4-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 340C for Example 182B. MS (ESI) m/z 420.2 (M+H) + .
Example 341
2-chloro-4-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
A 10 mL microwave vial was charged with Example 322B (100 mg, 0.277 mmol) and 100 mg of premixed tris(dibenzylidene-acetone)dipalladium(0)sodium tert-butoxide/2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05:0.15:2), aldrich 715530). The solids were suspended in 1,2-dimethoxyethane and 4-bromo-2-chlorobenzonitrile (72.1 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture heated under microwave conditions for 15 min at 130° C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% MeOH/dimethylsulfoxide, and purified by reverse phase HPLC to obtain the title compound. MS (ESI) m/z 460 (M+H) + .
Example 342
2-fluoro-4-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 341 substituting 4-bromo-2-fluorobenzonitrile for 4-bromo-2-(difluoromethyl)benzonitrile. MS (ESI) m/z 444 (M+H) + .
Example 343
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylimidazolidin-2-one
Example 343A
N1-(3-chlorobenzyl)-1-phenylethane-1,2-diamine
To (3-chlorophenyl)methanamine (0.28 g, 2 mmol) in methanol (5 mL) was added (E)-(2-nitrovinyl)benzene (0.30 g, 2 mmol). The mixture was allowed to stir for 4 hours. A solution of acetic acid in water (50%, 2 mL) was added, followed by zinc (5×130 mg, 10 mmol). The mixture was allowed to stir for 1 hour and concentrated. NaOH (1 M) was added to adjust the pH to 10. Ethyl acetate was added and the solution partitioned. The organic fraction was collected, dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 343B
1-(3-chlorobenzyl)-5-phenylimidazolidin-2-one
To a solution of Example 343A in dichloromethane (5 mL) at −78° C. was added triethylamine (100 mg, 1 mmol) and triphosgene (60 mg, 0.2 mmol). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. The crude material was purified by flash chromatography (100% ethyl acetate) to afford the title compound.
Example 343C
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylimidazolidin-2-one
To a solution of Example 343B (60 mg, 0.2 mmol) in tetrahydrofuran (1 mL) at 0° C. was added sodium hydride (40 mg, 60%, 1 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (38 mg, 0.2 mmol). The mixture was stirred for 18 hours, quenched with ammonium chloride (aq). Ethyl acetate was added then the solution partitioned. The organic fraction was collected and concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 431433 (3:1) (M+H) + .
Example 344
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 307B for Example 337F. MS (ESI) m/z 452 (M+H) + .
Example 345
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 307B for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 418420 (3:1) (M+H) + .
Example 346
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-4-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-(trifluoromethyl)pyridin-2-ol for phenol. MS (ESI) m/z 485.1 (M+H) + .
Example 347
Trans-N-(3-cyanophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-aminobenzonitrile for aniline. MS (ESI) m/z 454.1 (M+H) + .
Example 348
4-{[Trans-3-[(4-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-fluorophenol for phenol. MS (ESI) m/z 434.1 (M+H) + .
Example 349
4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yloxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 1-bromo-3-isopropoxybenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 459 (M+H) +
Example 350
N-[4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl]pyridazin-3-amine
Example 350A
6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)pyridazin-3-amine
4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine (100 mg, 0.308 mmol), 3,6-dichloro-pyridazine (46 mg, 0.308 mmol), N,N-diisopropylethyl amine (53.8 μl, 0.308 mmol), and 4 mL ethanol were placed in a 2-5 mL microwave vial and irradiated in a microwave (Biotage Initiator™, maximum 400 Watts) for 1 hour at 175° C. The reaction contents were concentrated, redissolved in 2 mL 50% dimethylsulfoxide/methanol and purified via reverse phase HPLC to yield the title compound.
Example 350B
N-{4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridazin-3-amine
Example 350A (18 mg, 0.041 mmol) and methanol (4 ml) were added to 5% Pd/C, wet (4 mg, 0.940 μmol) and triethyl amine (8 mg, 0.082 mmol) in a 50 ml pressure bottle. The mixture stirred for 2 hours under 30 psi of hydrogen until HPLC indicated complete conversion. The mixture was filtered through a nylon membrane. Purification via HPLC provided the title compound. MS (ESI) m/z 459 (M+H) + .
Example 351
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 2-bromo-6-(trifluoromethyl)pyridine for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 470 (M+H) + .
Example 352
(3R,4S)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 4-bromo-2-chloro-1-fluorobenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 453 (M+H) + .
Example 353
(3R,4S)—N-(3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 1-bromo-3-fluorobenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 419 (M+H) + .
Example 354
Trans-N-(4-chlorobenzyl)-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 354A
Trans-1-benzyl-3-methyl-3-nitro-4-phenylpyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting Example (E)-(2-nitroprop-1-en-1-yl)benzene for 4-methoxy-beta-nitrostyrene.
Example 354B
Trans-1-benzyl-3-methyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 354A for Example 2A.
Example 354C
Trans-3-methyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 354B for 2C.
Example 354D
Trans-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 354C for Example 182B.
Example 354E
Trans-N-(4-chlorobenzyl)-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To a solution of Example 354D (100 mg, 0.28 mmol) in methanol acetate buffer (pH4, 1M, 1 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added 4-chlorobenzaldehyde (40 mg, 0.28 mmol) and sodium cyanoborohydride (40 mg, 0.65 mmol). The mixture was stirred for 18 hours and partitioned between ethyl acetate and NaOH (1 M). The organic fraction was collected, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 445447 (3:1) (M+H) + .
Example 355
Trans-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 479 (M+H) + .
Example 356
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 514/516 (3:1) (M+H) + .
Example 357
(3,4-Difluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,4-difluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 450.2 (M+H) + .
Example 358
Trans-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoroaniline for aniline. MS (ESI) m/z 447.1 (M+H) + .
Example 359
(3,4-Dichlorophenyl) {trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,4-dichlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 360
(3,5-Dichlorophenyl) {trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,5-dichlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 361
(3-Chloro-5-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-chloro-5-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 466.2 (M+H) + .
Example 362
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[3-(trifluoromethoxy)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-(trifluoromethoxy)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 498.1 (M+H) + .
Example 363
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[4-(trifluoromethoxy)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-(trifluoromethoxy)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 498.1 (M+H) + .
Example 364
3-[({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)amino]benzamide
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 347 for Example 242E. MS (ESI) m/z 458.1 (M+H) + .
Example 365
3-(Aminomethyl)-N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 347 for Example 242E. MS (ESI) m/z 444.1 (M+H) + .
Example 366
4-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 245 substituting 2-(trifluoromethyl)pyridin-4-ol for phenol. MS (ESI) m/z 485.1 (M+H) + .
Example 367
4-Fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 358 for Example 242E. MS (ESI) m/z 433.1 (M+H) + .
Example 368
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 470 (M+H) + .
Example 369
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-(trifluoromethyl)pyridin-2-amine for aniline. MS (ESI) m/z 498.1 (M+H) + .
Example 370
Trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoro-3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 371
Trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-chloro-3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 547.1 (M+H) + .
Example 372
N-[4-chloro-2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]acetamide
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 3A for Example 337F and N-(2-bromo-4-chlorophenyl)acetamide for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 492/494 (3:1) (M+H) + .
Example 373
Trans-4-[(3-chlorophenyl)amino]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-ol
Example 373A
(trans)-tert-butyl 3-((3-chlorophenyl)amino)-4-hydroxypyrrolidine-1-carboxylate
A mixture of 3-chloroaniline (0.38 g, 3 mmol) and tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.56 g, 3 mmol) in ethanol (3 mL) was heated at 100° C. for 3 days. The mixture was concentrated and purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 373B
Trans-4-((3-chlorophenyl)amino)pyrrolidin-3-ol
To a solution of Example 373A (0.97 g, 3.1 mmol) in dioxane (3 mL) at 0° C. was added hydrochloric acid (4N in dioxane, 5 mL). The mixture was allowed to stir for 5 hours. Concentration provided the title compound as the hydrochloride salt.
Example 373C
Trans-4-[(3-chlorophenyl)amino]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin
To a solution of Example 373B in dichloromethane (5 mL) was added triethylamine (1 g, 10 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (540 mg, 3.0 mmol). The mixture was allowed to stir for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and NaOH (1 M). The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 357359 (3:1) (M+H) + .
Example 374
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 307B for 242D and substituting 1-(trifluoromethyl)cyclopropanecarboxylic acid for aniline. MS (ESI) m/z 444.0 (M+H) +
Example 375
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-(trifluoromethyl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 322B for Example 242D and substituting 1-(trifluoromethyl)cyclopropanecarboxylic acid for aniline. MS (ESI) m/z 461.1 (M+H) + .
Example 376
4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 370 for Example 242E. MS (ESI) m/z 517.2 (M+H) + .
Example 377
4-chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 371 for Example 242E. MS (ESI) m/z 533.2 (M+H) + .
Example 378
Trans-N-(3-chlorophenyl)-4-(4-fluorophenoxy)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a solution of Example 373 (142 mg, 0.4 mmol) in dimethylformamide (0.2 mL) was added copper(I) iodide (40 mg, 0.2 mmol), cesium carbonate (300 mg, 0.92 mmol), and 1-fluoro-4-iodobenzene (88 mg, 0.4 mmol). The mixture was stirred at 110° C. for 16 hours, then partitioned between ethyl acetate and water. The organic fraction was collected, concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 452/454 (3:1) (M+H) + .
Example 379
2-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-4-(trifluoromethyl)pyridine
Example 379A
Trans-tert-butyl 3-(4-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate
To a solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.93 g, 5 mmol) in tetrahydrofuran (5 mL) at −78° C. was added copper(I) iodide (85 mg, 0.5 mmol) then (4-fluorophenyl)magnesium bromide (7 mL, 1 M, 7 mol). The mixture was warmed to room temperature and, allowed to stir for 3 hours. The reaction mixture was partitioned with ammonium chloride (aq). The organic fraction was collected dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 379B
Trans-4-(4-fluorophenyl)pyrrolidin-3-ol
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 379A for Example 373A.
Example 379C
Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-ol
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 379B for Example 373B.
Example 379D
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-4-(trifluoromethyl)pyridine
To a solution of Example 379C (110 mg, 0.34 mmol) in dimethylsulfoxide (0.3 mL) was added potassium 2-methylpropan-2-olate (50 mg, 0.45 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (70 mg, 0.43 mmol). The mixture was stirred at 100° C. for 16 hours, then partitioned between ethyl acetate and water. Purification by HPLC provided the title compound. MS (ESI) m/z 471 (M+H) + .
Example 380
3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-amino)benzonitrile
Example 380A
(3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
Example 322B (2.53 g, 7.03 mmol) was partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate (aq. 10 mL). The organic fraction was collected. The aqueous fraction was washed with ethyl acetate 3 times. The combined organic fractions were dried over sodium sulfate and concentrated to give the title compound. MS (EST) m/z 325.3 (M+H) + .
Example 380B
3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 3-bromobenzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426.1 (M+H) + .
Example 381
6-chloro-2-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-2,3-dihydro-1H-isoindol-1-one
Example 381A
Trans-N-(2-bromo-4-chlorobenzyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 307B for Example 354D and 2-bromo-4-chlorobenzaldehyde for 4-chlorobenzaldehyde.
Example 381B
6-chloro-2-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-2,3-dihydro-1H-isoindol-1-one
To a solution of Example 381A (500 mg, 0.98 mmol) in methanol (5 mL) in a 50 mL pressure bottle was added 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), (36 mg, 0.048 mmol) and triethylamine (0.27 mL, 2 mmol). The mixture was pressurized with Carbon Monoxide (60 psi), and stirred for 4 hours at 80° C. The insoluble materials were filtered off and the filtrate was purified by HPLC to provide the title compound. MS (ESI) m/z 458460 (3:1) (M+H) + .
Example 382
3-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-ol
Example 382A
4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-one
To a solution of Example 379C (0.43 g, 1.3 mmol) in dichloromethane (3 mL) was added Dess-Martin periodinane (0.67 g, 1.6 mmol). The mixture was stirred overnight and partitioned between ethyl acetate and sodium hydroxide (1M aq.). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 382B
3-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-
To a solution of Example 382A (50 mg) in tetrahydrofuran (0.5 mL) at −78° C. was added benzylmagnesiumbromide (1 M, 1 mL, 1 mmol). The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was partitioned between Ammonium chloride (aq) and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 416 (M+H) + .
Example 383
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridazin-3-amine
Example 383A
Trans-6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyridazin-3-amine
Example 3A (100 mg, 0.308 mmol), 3,6-dichloro-4-(trifluoromethyl)pyridazine (67 mg, 0.308 mmol), diisopropylethylamine (53.8 μl, 0.308 mmol), and ethanol (4 mL) were placed in a 2-5 mL microwave vial and irradiated for 1 hr at 175° C. The reaction contents were concentrated, redissolved in 2 mL 50% dimethylsulfoxide/methanol and purified via HPLC to provide the title compound. MS (ESI) m/z 505 (M+H) + .
Example 383B
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridazin-3-amine
The title compound was prepared similarly to the procedure described in Example 350B substituting 6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-5-yl)-4-(trifluoromethyl)pyridazin-3-amine for 6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)pyridazin-3-amine. MS (ESI) m/z 471 (M+H)+
Example 384
N-{4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridazin-3-amine
The title compound was prepared similarly to the procedure described in Example 350A-350B As both isomers are formed in 350A. MS (ESI) m/z 471 (M+H)+
Example 385
1-methyl-4-{[trans-3-phenyl-4-(phenylsulfonyl)pyrrolidin-1-yl]sulfonyl}-1H-imidazole
Example 385A
Trans-1-benzyl-3-phenyl-4-(phenylsulfonyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting phenyl trans-styryl sulfone for 4-methoxy-beta-nitrostyrene. MS (ESI) m/z 378.1 (M+H) + .
Example 385B
Trans-3-phenyl-4-(phenylsulfonyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 385A for 2C. MS (ESI) m/z 288.1 (M+H) + .
Example 385C
1-Methyl-4-{trans-3-phenyl-4-(phenylsulfonyl)pyrrolidin-1-yl]sulfonyl}-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 385B for Example 2D. MS (ESI) m/z 432.1 (M+H) + .
Example 386
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 375 for Example 242E. MS (ESI) m/z 447.1 (M+H) + .
Example 387
(3S,4R)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 389A for Example 337F and 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 453.2 (M+H) + .
Example 388
N-{Trans-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 354D for Example 337F and 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 466 (M+H) + .
Example 389
3-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
Example 389A
(3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 321B for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 389B
3-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting 389A for Example 337F and substituting 3-bromobenzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426.3 (M+H) + .
Example 390
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 471.2 (M+H) + .
Example 391
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[5-(trifluoromethyl)furan-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 5-(trifluoromethyl)furan-2-carbaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 473.1 (M+H) + .
Example 392
1,1,1-trifluoro-2-[3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]propan-2-ol
Example 392A
2-(3-Bromophenyl)-1,1,1-trifluoropropan-2-ol
To 1-(3-bromophenyl)ethanone (364 mg, 1.83 mmol) and (trifluoromethyl)trimethylsilane (3 mL, 1.46 mmol, 0.5 M in tetrahydrofuran) was added tetrabutylammonium fluoride (1 M in tetrahydrofurane, 2.0 mL, 2.0 mmol) at 0° C. The reaction mixture stirred at room temperature for 3 hours. The reaction mixture was partitioned with saturated sodium carbonate (aq.) and dichloromethane. The organic fraction was collected. The aqueous fraction was washed with dichloromethane 3 times. The combined organic fractions were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by flash chromatography (5:1 EtOAc/hexanes) to afford the title compound.
Example 392B
1,1,1-trifluoro-2-[3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]propan-2-ol
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting Example 392A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 513.3 (M+H) + .
Example 393
(3R,4S)—N-[(5-chlorothiophen-2-yl)methyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 5-chlorothiophene-2-carbaldehyde for 4-chlorobenzaldehyde and. MS (ESI) m/z 455.3 (M+H) + .
Example 394
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 455.3 (M+H) + .
Example 395
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 395A
(3S,4R)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and separating the enantiomers produced from the procedure of Example 2C via Chiral SFC separation (SFC 200 Column: Whelk-O1, 50×250 mm, 5 μm Column Temperature: 35° C. Mobile Phase: CO 2 /IPA/DEA=70/30/0.1 Flow rate: 70 g/min Back Pressure: 100 Bar Wavelength: 214 nm Cycle time: 5.0 min Injection: 4.0 mL Sample solution: 41000 mg in 250 mL methanol) RT=6.00 minutes.
Example 395B
(3S,4R)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 395A for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 395 C
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 395B for Example 354D and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 499.2 (M+H) + .
Example 396
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
Example 396A
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 574A for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 396B
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 452.2 (M+H) + .
Example 397
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F. MS (ESI) m/z 452.2 (M+H) + .
Example 398
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and Example 396A Example 354D. MS (ESI) m/z 465.1 (M+H) + .
Example 399
1,1,1-trifluoro-2-[3-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)phenyl]propan-2-ol
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and Example 392A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 495.1 (M+H) + .
Example 400
Trans-4-(benzyloxy)-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a solution of Example 373C (71 mg, 0.2 mmol) in tetrahydrofuran (0.5 mL) was added potassium tert-butoxide (22 mg, 0.2 mmol) and benzyl bromide (40 mg, 0.23 mmol). The mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was then partitioned with water and ethyl acetate. The organic fraction was collected, concentrate, and purified by HPLC to provide the title compound. MS (ESI) m/z 447/449 (3:1) (M+H) + .
Example 401
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-3-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-yl]methanol
Example 401A
(E)-2-nitro-3-phenylprop-2-en-1-ol
To (E)-(2-nitrovinyl)benzene (1.5 g, 10 mmol) in tetrahydrofuran (10 mL) was added formaldehyde (37%, aq., 10 mL), imidazole (0.68 g, 10 mmol), and anthranilic acid (14 mg, 0.1 mmol). The mixture was allowed to stir for 16 hours. The reaction mixture was partitioned between ethyl acetate and hydrochloric acid (1N). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 401B
(E)-((2-nitro-3-phenylallyl)oxy)methyl acetate
To a solution of Example 401A (900 mg, 5 mmol) in dichloromethane (5 mL) was added triethylamine (600 mg, 6 mmol) and acetyl chloride (400 mg, 5.1 mmol) at 0° C. The mixture was allowed to stir for 1 hour. Water was added and the solution partitioned. The organic fraction was collected, concentrated, and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the title compound.
Example 401C
((1-benzyl-3-nitro-4-phenylpyrrolidin-3-yl)methoxy)methyl acetate
The title compound was prepared similarly to the procedure described in Example 2A substituting Example 401B for 4-methoxy-beta-nitrostyrene.
Example 401D
7-benzyl-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 401C for Example 2A.
Example 401E
tert-butyl 7-benzyl-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 401D for Example 337B.
Example 401F
tert-butyl 9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 401E for 2C.
Example 401G
tert-butyl 7-((1-methyl-1H-imidazol-4-yl)sulfonyl)-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 401F for Example 373B.
Example 401H
7-((1-methyl-1H-imidazol-4-yl)sulfonyl)-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 401G for Example 373A
Example 401I
[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-3-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-yl]methanol
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and Example 401H for Example 354D MS (ESI) m/z 495 (M+H) + .
Example 402
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(prop-2-en-1-yloxy)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting allyl bromide for benzyl bromide. MS (ESI) m/z 397/399 (3:1) (M+H) + .
Example 403
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2-methylprop-2-en-1-yl)oxy]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting 3-bromo-2-methylprop-1-ene for benzyl bromide. MS (ESI) m/z 411413 (3:1) (M+H) + .
Example 404
3-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
Example 404A
N-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-nitro-5-(trifluoromethyl)benzamide
To Example 14A (140 mg, 0.4 mmol) in dimethylformamide (0.5 mL) was added 2-nitro-5-(trifluoromethyl)benzoic acid (96 mg, 0.4 mmol), triethylamine (100 mg, 1 mmol), and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (160 mg, 0.5 mmol). The mixture was allowed to stir overnight. Water was added and the precipitates were collected to provide the title compound.
Example 404B
Trans-N-(2-amino-5-(trifluoromethyl)benzyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
To a solution of Example 404A (110 mg, 0.21 mmol) in tetrahydrofuran (1 mL) was added borane dimethyl sulfide complex (2N, 1.4 mL, 2.8 mmol). The mixture was stirred at 60° C. for 2 days and quenched with hydrochloric acid (1 M aq.). The mixture was allowed to stir for 30 minutes. Sodium hydroxide (1 M, aq.) was added to adjust the pH value to 10. The mixture was partitioned with ethyl acetate. The organic fraction was collected and dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 404C
3-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
To a solution of Example 404B (130 mg, 0.27 mmol) in dichloromethane (10 mL) was added triethylamine (100 mg, 1 mmol) and triphosgene (28 mg, 0.094 mmol). The mixture was allowed to stir for 1 hour, and then methanol was added. The mixture was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 506 (M+H) + .
Example 405
4-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-4-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 402.1 (M+H) + .
Example 406
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-7H-pyrrolo[2,3-D]pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 424.2 (M+H) + .
Example 407
Trans-7-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-9-phenyl-1-[4-(trifluoromethyl)benzyl]-3-oxa-1,7-diazaspiro[4.4]nonan-2-one
The title compound was prepared similarly to the procedure described in Example 404C substituting Example 401I for Example 404B. MS (ESI) m/z 521 (M+H) + .
Example 408
3,5-difluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To Example 396A (100 mg, 0.33 mmol) in dimethylsulfoxide (0.5 mL) was added potassium tert-butoxide (50 mg, 0.45 mmol) and 2,3,5-trifluoro-4-(trifluoromethyl)pyridine (80 mg, 0.4 mmol). The mixture was stirred at 80° C. for 2 hours, and then partitioned between water and ethyl acetate. The organic fraction was collected, dried over potassium carbonate, filtered, concentrated, and purified by reversed phase HPLC to provide the title compound. MS (ESI) m/z 488 (M+H) + .
Example 409
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 574A for Example 354D and substituting 5-(trifluoromethyl)picolinaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 466.1 (M+H) + .
Example 410
5-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-5-cyclopropyl-pyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425.3 (M+H) + .
Example 411
5-cyclobutyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-5-cyclobutylpyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439.3 (M+H) + .
Example 412
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(2-methylprop oxy)pyrrolidin-3-amine
To Example 403 (17 mg, 0.041 mmol) in tetrahydrofuran (4 mL) was added 5% Pt/C (20 mg, 0.041 mmol). The mixture was stirred for 45 minutes under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and purified by reversed phase HPLC to provide the title compound. MS (ESI) m/z 413415 (3:1) (M+H) + .
Example 413
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(pyrrolidin-1-yl)pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 2-bromo-5-(pyrrolidin-1-yl)pyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 454.3 (M+H) + .
Example 414
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(trifluoromethyl)pyrazine-2-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and 5-(trifluoromethyl)pyrazine-2-carboxylic acid for Example 242D. MS (ESI) m/z 481.2 (M+H) + .
Example 415
5-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazine-2-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and 5-chloropyrazine-2-carboxylic acid for Example 242D. MS (ESI) m/z 447.1 (M+H) + .
Example 416
(3R,4S)—N-(4-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 574A for Example 354D. MS (ESI) m/z 431.1 (M+H) +
Example 417
(3R,4S)—N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene MS (ESI) m/z 435.1 (M+H) + .
Example 418
(3R,4S)—N-(3,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 437.1 (M+H) + .
Example 419
6-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridazine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and substituting 6-chloropyridazine-3-carboxylic acid for Example 242D. MS (ESI) m/z 447.2 (M+H) + .
Example 420
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(morpholin-4-yl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-(4-bromopyrimidin-2-yl)morpholine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470.2 (M+H) + .
Example 421
4-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-2,3-dihydro-1H-isoindol-1-one
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-(4-bromopyrimidin-2-yl)morpholine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470.2 (M+H) + .
Example 422
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(methylsulfonyl)phenyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 1-bromo-3-(methylsulfonyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 461.2 (M+H) + .
Example 423
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(trifluoromethyl)piperazin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared using the same procedures as described in Example 290 substituting Example 414 for Example 242E. MS (ESI) m/z 473.2 (M+H) + .
Example 424
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-5-fluoropyrimidine for 1-bromo-2-methylbenzene MS (ESI) m/z 403.2 (M+H) +
Example 425
Trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 425A
(E)-(2-nitrovinyl)cyclohexane
A solution of cyclohexane carboxaldehyde (5.0 g, 44.6 mmol) and nitromethane (4.1 g, 66.9 mmol) in tetrahydrofuran (25 ml) and tert butanol (25 ml) was stirred and chilled in an ice bath under nitrogen. Potassium-t-butoxide (1.0 g, 9.0 mmol) was added as a solid in one portion and the reaction was allowed to stir and warm to room temperature over one hour. The reaction was stirred for an additional four hours and was then partitioned with a saturated solution of ammonium chloride. The organic fraction was collected, and the aqueous portion was washed with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting liquid was dissolved in dichloromethane (100 ml) and chilled in an ice bath. Trifluoroacetic anhydride (9.8 g, 46.7 mmol) was added in one portion, and the solution stirred for five minutes. Triethylamine (9.5 g, 93.5 mmol) was added dropwise. Stirring was continued for one hour, and then the reaction was allowed to warm to room temperature and stir for two hours. The reaction was partitioned with a solution of saturated ammonium chloride. The organic fraction was collected. The aqueous portion was washed with dichloromethane. The organic fractions were combined and washed with water and brine, and dried over sodium sulfate. The mixture was filtered, concentrated and chromatographed on a silica gel flash column eluting with 98:2 heptane:ethyl acetate to afford 5.1 g of a slightly tinted liquid. MS (DCI) m/z 173.1 (M+NH 4 ) +
Example 425B
trans-4-cyclohexyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting Example 425A for trans-4-methoxy-beta-nitrostyrene in Example 2A. MS (DCI) m/z 313.1 (M+H) +
Example 425C
trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 57 substituting Example 425B for Example 14A and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 473.2 (M+H) + .
Example 426
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(4,4,4-trifluorobutyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,4,4-trifluorobutanol for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) +
Example 427
(3R,4S)—N-(2-cyclopentylethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-cyclopentylacetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 403.0 (M+H) +
Example 428
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(5-propylfuran-2-yl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-propylfuran-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 429.0 (M+H) + .
Example 429
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyltetrahydro-2H-pyran-4-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methyltetrahydro-2H-pyran-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) + .
Example 430
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(4-phenyl-1,3-thiazol-5-yl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-phenylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 480.0 (M+H) +
Example 431
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) +
Example 432
(3R,4S)—N-[(3,5-dichloropyridin-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,5-dichloroisonicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 467.0 (M+H) +
Example 433
(3R,4S)—N-(2-ethylhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylhexanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) +
Example 434
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) +
Example 435
(3R,4S)—N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,4-dichlorothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 473.0 (M+H) +
Example 436
(3R,4S)—N-(2,2-dimethylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pivalaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) +
Example 437
(3R,4S)—N-[(5-methyl-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylbenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 467.0 (M+H) + .
Example 438
(3R,4S)—N-[(2-bromo-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-bromothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 483.0 (M+H) + .
Example 439
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylpropyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting isobutyraldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 363.0 (M+H) + .
Example 440
(3R,4S)—N-[(3-chloro-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-chlorobenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 487.0 (M+H) + .
Example 441
(3R,4S)—N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,4-dimethylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 432.0 (M+H) + .
Example 442
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(thieno[2,3-b]pyridin-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting thieno[2,3-b]pyridine-2-carbaldehyde for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 454.0 (M+H) + .
Example 443
(3R,4S)—N-[(2-methyl-1-benzofuran-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylbenzofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 451.0 (M+H) + .
Example 444
(3R,4S)—N-[(6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 6-chloro-2-methylimidazo[1,2-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 485.0 (M+H) + .
Example 445
(3R,4S)—N-{[5-(4-fluorophenyl)pyridin-3-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-(4-fluorophenyl)nicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 492.0 (M+H) + .
Example 446
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylpentyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylpentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 447
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(tetrahydro furan-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting tetrahydrofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 448
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) + .
Example 449
(3R,4S)—N-(2-ethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 450
(3R,4S)—N-(2,2-dimethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,2-dimethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) + .
Example 451
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) + .
Example 452
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) + .
Example 453
(3R,4S)—N-(1,3-benzothiazol-2-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting benzo[d]thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 454.0 (M+H) + .
Example 454
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) + .
Example 455
(3R,4S)—N-[(4,5-dimethylthiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,5-dimethylthiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 431.0 (M+H) + .
Example 456
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,5,6,7-tetrahydrobenzo[d]thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 458.0 (M+H) + .
Example 457
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(1,3-thiazol-5-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting thiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 404.0 (M+H) + .
Example 458
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 457.0 (M+H) + .
Example 459
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[1-(propan-2-yl)piperidin-4-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 1-isopropylpiperidine-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 446.0 (M+H) + .
Example 460
(3R,4S)—N-{[4-(4-fluorophenyl)-1,3-thiazol-2-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(4-fluorophenyl)thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 498.0 (M+H) + .
Example 461
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(4-methylphenyl)ethyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(p-tolyl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 425.0 (M+H) + .
Example 462
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylthiophen-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylthiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) + .
Example 463
(3R,4S)—N-(3-methylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-methylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) + .
Example 464
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(3,5,5-trimethylhexyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,5,5-trimethylhexanal for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 433.0 (M+H) + .
Example 465
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-phenylpropyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-phenylpropanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 425.0 (M+H) + .
Example 466
(3R,4S)—N-(3,3-dimethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,3-dimethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) + .
Example 467
(3R,4S)—N-[(1-methylcyclohexyl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 1-methylcyclohexanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) + .
Example 468
(3R,4S)—N-[2-(3-chlorophenyl)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(3-chlorophenyl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 445.0 (M+H) + .
Example 469
(3R,4S)—N-[2-(4-tert-butylphenoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(4-(tert-butyl)phenoxy)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 483.0 (M+H) + .
Example 470
(3R,4S)—N-(2-ethyl-3-methylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethyl-3-methylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 405.0 (M+H) + .
Example 471
(3R,4S)—N-[3-(3-chlorophenyl)propyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-(3-chlorophenyl)propanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 459.0 (M+H) + .
Example 472
(3R,4S)—N-[(4-bromo-1,3-thiazol-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-bromothiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 482 (M+H) + .
Example 473
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methyl-2-phenylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 494 (M+H) + .
Example 474
N-(3,4-difluorophenyl)-1-[(2,4-dim ethyl-1,3-thiazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 474A
N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
To a 100 mL round bottom flask with magnetic stir bar under argon was added cesium carbonate (28.7 g, 88 mmol)], 4-bromo-1,2-difluorobenzene (5.66 g, 29.3 mmol), 1-benzyl-4-phenylpyrrolidin-3-amine (7.4 g, 29.3 mmol), and Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), (0.928 g, 1.173 mmol). 1,2-dimethoxyethane (25 mL) was added and the reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled, concentrated onto celite, and purified via flash chromatography (5-50% EtOAc/Hex, 220 g column) to provide the title compound.
Example 474B
N-(3,4-difluorophenyl)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
A 4 mL vial with a magnetic stir bar was charged with Example 474A (40 mg, 0.146 mmol) and a solution of diisopropylethylamine in dichloromethane (1 mL of a 5 wt % diisopropylethylamine). A solution of 2,4-dimethylthiazole-5-sulfonyl chloride (972 μl, 0.292 mmol, 0.3 mM in 5% diisopropylethylamine in dichloromethane) was added and the reaction mixture was allowed to stir for 4 hours. The reaction was concentrated, redissolved in 2 mL of 50% dimethylsulfoxide/methanol and purified via HPLC to provide the title compound. MS (ESI) m/z 450 (M+H) + .
Example 475
N-(3,4-difluorophenyl)-1-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-isopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 461 (M+H) + .
Example 476
N-(3,4-difluorophenyl)-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 487 (M+H) + .
Example 477
N-(3,4-difluorophenyl)-4-phenyl-1-(pyridin-3-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting pyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 416 (M+H) + .
Example 478
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 3,3-dimethyl-2-oxoindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 498 (M+H) + .
Example 479
1-[(1-cyclopentyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-cyclopentyl-3-methyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 487 (M+H) + .
Example 480
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)quinazoline-2,4(1H,3H)-dione
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 481
7-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-6-methyl-2H-1,4-benzoxazin-3(4H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 500 (M+H) + .
Example 482
N-(3,4-difluorophenyl)-1-[(1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 483
N-(3,4-difluorophenyl)-1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 484
N-(3,4-difluorophenyl)-1-[(4-methylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 4-methylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 435 (M+H) + .
Example 485
N-(3,4-difluorophenyl)-4-phenyl-1-(pyrrolidin-1-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting pyrrolidine-1-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 408 (M+H) + .
Example 486
1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 467 (M+H) + .
Example 487
N-(3,4-difluorophenyl)-1-[(5-methyl-1,2-oxazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-methylisoxazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 420 (M+H) + .
Example 488
N-(3,4-difluorophenyl)-1-[(2,5-dimethylfuran-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,5-dimethylfuran-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 489
methyl 3-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)thiophene-2-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 3-(chlorosulfonyl)thiophene-2-carboxylate for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 479 (M+H) + .
Example 490
N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 491
methyl 5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-4-methoxythiophene-3-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 5-(chlorosulfonyl)-4-methoxythiophene-3-carboxylate for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 509 (M+H) + .
Example 492
N-(3,4-difluorophenyl)-1-[(5-ethylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-ethylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 449 (M+H) + .
Example 493
N-(3,4-difluorophenyl)-1-[(4-methylpiperidin-1-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 4-methylpiperidine-1-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 436 (M+H) + .
Example 494
N-(3,4-difluorophenyl)-1-{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-morpholinopyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 501 (M+H) +
Example 495
1-(1,3-benzodioxol-5-ylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting benzo[d][1,3]dioxole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 459 (M+H) + .
Example 496
N-(3,4-difluorophenyl)-1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 473 (M+H) + .
Example 497
N-(3,4-difluorophenyl)-1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 445 (M+H) + .
Example 498
N-(3,4-difluorophenyl)-4-phenyl-1-[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting (tetrahydro-2H-pyran-2-yl)methanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 437 (M+H) + .
Example 499
N-[5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-acetamidothiazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 479 (M+H) + .
Example 500
N-(3,4-difluorophenyl)-4-phenyl-1-{[6-(trifluoromethyl)pyridin-3-yl]sulfonyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-(trifluoromethyl)pyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 484 (M+H) + .
Example 501
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,4-dihydroquinoxaline-2,3-dione
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 502
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-pyrazole-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 419 (M+H) + .
Example 503
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-indole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 468 (M+H) + .
Example 504
methyl 5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1-methyl-1H-pyrrole-2-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 476 (M+H) + .
Example 505
1-(1,2-benzoxazol-5-ylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting benzo[d]isoxazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 456 (M+H) + .
Example 506
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-dihydro-2H-benzimidazol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 471 (M+H) + .
Example 507
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-dihydro-2H-indol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxoindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 470 (M+H) + .
Example 508
N-(3,4-difluorophenyl)-4-phenyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 447 (M+H) + .
Example 509
1-(cyclobutylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting cyclobutanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 393 (M+H) + .
Example 510
1-(cyclohexylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting cyclohexanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 421 (M+H) + .
Example 511
1-[(5-chlorothiophen-2-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-chlorothiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 455 (M+H) + .
Example 512
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-3,4-dihydroquinolin-2(1H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 484 (M+H) + .
Example 513
N-(3,4-difluorophenyl)-1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 3,5-dimethylisoxazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 434 (M+H) + .
Example 514
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-benzoxazol-2(3H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-2,3-dihydrobenzo[d]oxazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 472 (M+H) + .
Example 515
N-(3,4-difluorophenyl)-1-(isoquinolin-5-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting isoquinoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 466 (M+H) + .
Example 516
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-pyrazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 419 (M+H) + .
Example 517
N-(3,4-difluorophenyl)-1-[(2,5-dimethylthiophen-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,5-dimethylthiophene-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 449 (M+H) + .
Example 518
N-(3,4-difluorophenyl)-1-[(5-methylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-methylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 435 (M+H) + .
Example 519
N-(3,4-difluorophenyl)-1-(2,3-dihydro-1-benzo furan-5-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dihydrobenzofuran-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 457 (M+H) + .
Example 520
1-[(6-chloro imidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 495 (M+H) + .
Example 521
N-(3,4-difluorophenyl)-1-(morpholin-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting morpholine-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 424 (M+H) + .
Example 522
1-[5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-2,3-dihydro-1H-indol-1-yl]ethanone
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-acetylindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 498 (M+H) + .
Example 523
tert-butyl {trans-1-[(2-cyanophenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
Example 523A
Tert-butyl-trans-4-phenylpyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the procedures described in Example 2A-2D substituting (E)-(2-nitrovinyl)benzene for trans-4-methoxy-beta-nitrostyrene.
Example 523B
Tert-butyl {trans-1-[(2-cyanophenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 523A for Example 2D and substituting 2-cyanobenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride. MS (DCI) m/z 444.8 (M+NH4) + .
Example 524
tert-butyl [trans-1-[(2-cyanophenyl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]carbamate
Example 524A
Tert-butyl-trans-4-(4-fluorophenyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the procedures described in Example 2A-2D substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for trans-4-methoxy-beta-nitrostyrene.
Example 524 B
Tert-butyl [trans-1-[(2-cyanophenyl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 524A for Example 2D and substituting 2-cyanobenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride. MS (DCI) m/z 444.4 (M−H) − .
Example 525
2-{[trans-3-phenyl-4-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyrrolidin-1-yl]sulfonyl}benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 473.2 (M+H) + .
Example 526
2-{[trans-3-phenyl-4-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyrrolidin-1-yl]sulfonyl}benzamide
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 491.2 (M+H) + .
Example 527
2-(Trans-3-amino-4-phenylpyrrolidin-1-ylsulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 523 for Example 322B. MS (ESI) MS m/z 328.2 (M+H) + .
Example 528
2-({Trans-3-[(3-chlorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 438.2 (M+H) + .
Example 529
2-({Trans-3-[(4-fluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 1-bromo-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 422.2 (M+H) + .
Example 530
Trans-N-(3-chlorophenyl)-4-(cyclopropylmethoxy)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting (bromomethyl)cyclopropane for benzyl bromide. MS (ESI) m/z 411/413 (3:1) (M+H) + .
Example 531
N-{trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 425C substituting 4-bromo-6-trifluoromethylpyrimidine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 459.4 (M+H) + .
Example 532
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-2-methoxypyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 415.2 (M+H) + .
Example 533
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylthiazole-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418 (M+H) + .
Example 534
(3R,4S)—N-[(2-ethyl-1-benzofuran-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylbenzofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 465 (M+H) + .
Example 535
(3R,4S)—N-(imidazo[1,2-a]pyridin-8-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting imidazo[1,2-a]pyridine-8-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 536
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylpyridin-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylpicolinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 412 (M+H) + .
Example 537
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(pyrazolo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pyrazolo[1,5-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 538
N-{Trans-4-hydroxy-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 538A
Trans-tert-butyl 3-hydroxy-4-(4-(trifluoromethyl)benzamido)pyrrolidine-1-carboxylate
To a solution of trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (600 mg, 3 mmol) in dichloromethane (10 mL) at 0° C., was added triethylamine (350 mg, 3.5 mmol) and 4-(trifluoromethyl)benzoyl chloride (620 mg, 3 mmol). The mixture was allowed to stir for 16 hours. The mixture was concentrated and dissolved in methanol (5 mL). Sodium methoxide (21% in methanol, 0.5 mL) was added. The mixture was stirred for 6 hours, concentrated, and partitioned between ethyl acetate and water. The organic fractions were collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 538B
N-(trans-4-hydroxypyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 538A for Example 373A.
Example 538C
N-(trans-4-hydroxy-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 538B for Example 373B.
Example 538D
N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-oxopyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 382A substituting Example 538C for Example 379C.
Example 538E
N-{Trans-4-hydroxy-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 382B substituting Example 538D for Example 382A and phenylmagnesium bromide for benzylmagnesium bromide. MS (ESI) m/z 495 (M+H) + .
Example 539
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-phenyl-4-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-ol
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 538E for Example 404A. MS (ESI) m/z 481 (M+H) + .
Example 540
(3R,4S)—N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethoxy)benzene, but only heating for 1 hour. MS (ESI) m/z 503 (M+H) + .
Example 541
ethyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
To Example 396A (50 mg, 0.16 mmol) in dichloromethane (0.5 mL) was added triethylamine (20 mg, 0.2 mmol) and ethyl chloroformate (22 mg, 0.2 mmol). The mixture was stirred for 1 hour, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 379 (M+H) + .
Example 542
propyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting propyl chloroformate for ethyl chloroformate. MS (ESI) m/z 393 (M+H) + .
Example 543
2-methylpropyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting isobutyl chloroformate for ethyl chloroformate. MS (ESI) m/z 407 (M+H) + .
Example 544
butyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting butyl chloroformate for ethyl chloroformate. MS (ESI) m/z 407 (M+H) + .
Example 545
(3R,4S)—N-(2-cyclopropylethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 546 for Example 404A. MS (ESI) m/z 375 (M+H) + .
Example 546
2-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 2-cyclopropylacetic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 388 (M+H) + .
Example 547
(3R,4S)—N-[(2E)-hex-2-en-1-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (E)-hex-2-enal for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. Both Example 547 and Example 548 were isolated. MS (ESI) m/z 389 (M+H) + .
Example 548
(3R,4S)—N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (E)-hex-2-enal for 4-chlorobenzaldehyde and Example 396A for Example 354D. Both Example 547 and Example 548 were isolated. MS (ESI) m/z 391 (M+H) + .
Example 549
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and pentanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 391 (M+H) + .
Example 550
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}hexanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting hexanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 405 (M+H) + .
Example 551
(3R,4S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (tert-butyldimethylsilyloxy)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. MS (ESI) m/z 465.2 (M+H) + .
Example 552
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 6-(trifluoromethyl)picolinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 466 (M+H) + .
Example 553
(3R,4S)—N-[(3-chlorothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-chlorothiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 554
(3R,4S)—N-[(4,4-difluorocyclohexyl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,4-difluorocyclohexanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 439 (M+H) + .
Example 555
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(pyrazolo[1,5-a]pyridin-7-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pyrazolo[1,5-a]pyridine-7-carbaldehyde for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 556
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[4-(propan-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-isopropylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 446 (M+H) + .
Example 557
(3R,4S)—N-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (EST) m/z 433 (M+H) + .
Example 558
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(tetrahydro-2H-pyran-2-yl)thiophen-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-(tetrahydro-2H-pyran-2-yl)thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 487 (M+H) + .
Example 559
(3R,4S)—N-[(5-bromo-4-methyl-1,3-thiazol-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-bromo-4-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 497 (M+H) + .
Example 560
(3R,4S)—N-(imidazo[1,5-a]pyridin-5-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting imidazo[1,5-a]pyridine-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 561
(3R,4S)—N-(2,3-dimethylpentyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,3-dimethylpentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 405 (M+H) + .
Example 562
(3R,4S)—N-[(2-chloro-1,3-thiazol-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chlorothiazole-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 438 (M+H) + .
Example 563
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylimidazo[1,2-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 451 (M+H) + .
Example 564
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-phenylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-phenylcyclopropanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 565
(3R,4S)—N-[(4-chloro-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-chlorothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 438 (M+H) + .
Example 566
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(3,3,3-trifluoro-2-methylpropyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,3,3-trifluoro-2-methylpropanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417 (M+H) + .
Example 567
(3R,4S)—N-[(2-chloro-3-fluoropyridin-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-3-fluoroisonicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 450 (M+H) + .
Example 568
(3R,4S)—N-[(5-fluoro-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-fluorobenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 471 (M+H) + .
Example 569
(3R,4S)—N-[5-chloro-2-(difluoromethoxy)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-chloro-2-(difluoromethoxy)benzaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 497 (M+H) + .
Example 570
(3R,4S)—N-[(2,5-dichlorothiophen-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,5-dichlorothiophene-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 471 (M+H) + .
Example 571
(3R,4S)—N-{[2-(4-fluorophenyl)pyridin-3-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(4-fluorophenyl)nicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 492 (M+H) + .
Example 572
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[2-(4-methylphenyl)-1,3-thiazol-5-yl]methyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(p-tolyl)thiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 494 (M+H) + .
Example 573
(3R,4S)—N-(3-cyclopropylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 573A
3-cyclopropyl-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)propanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 3-cyclopropylpropanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 573B
(3R,4S)—N-(3-cyclopropylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 573A for Example 404A. MS (ESI) m/z 389 (M+H) + .
Example 574
5-fluoro-4-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
Example 574A
(3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and separating the enantiomers produced from the procedure of Example 2C via Chiral SFC separation (SFC 200 Column: Whelk-O1, 50×250 mm, 5 μm Column Temperature: 35° C. Mobile Phase: CO 2 /IPA/DEA=70300.1 Flow rate: 70 g/min Back Pressure: 100 Bar Wavelength: 214 nm Cycle time: 5.0 min Injection: 4.0 mL Sample solution: 41000 mg in 250 mL methanol) The enantiomer with a retention time of 4.41 minutes was used to make the title compound.
Example 574B
5-fluoro-4-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 2-bromo-4-methyl-5-fluoropyridine for 1-bromo-3-(trifluoromethoxy)benzene. MS (APCI) m/z 416 (M+H) + .
Example 575
1,5-dimethyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,4-triazol-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 3-bromo-1,5-dimethyl-1H-1,2,4-triazole for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 402 (M+H) + .
Example 576
1,5-dimethyl-4-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-1H-pyrrole-2-carbonitrile
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile for 1-bromo-3-(trifluoromethoxy)benzene. MS (APCI) m/z 425 (M+H) + .
Example 577
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yloxy)propyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-isopropoxypropylamine for aniline. MS (ESI) m/z 453.2 (M+H) + .
Example 578
(3S,4R)—N-(3-ethoxypropyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-ethoxypropylamine for aniline. MS (ESI) m/z 439.2 (M+H) + .
Example 579
(3S,4R)-4-(4-fluorophenyl)-N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-methoxyethylamine for aniline. MS (ESI) m/z 411.2 (M+H) + .
Example 580
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-propylpyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting propylamine for aniline. MS (ESI) m/z 395.2 (M+H) + .
Example 581
(3S,4R)—N-butyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting butylamine for aniline. MS (ESI) m/z 409.2 (M+H) + .
Example 582
(3S,4R)-4-(4-fluorophenyl)-N-[1-methoxypropan-2-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-methoxyisopropylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 583
(3R,4S)-4-(4-fluorophenyl)-N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-methoxypropylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 584
(3S,4R)—N-(2-ethoxyethyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-ethoxyethylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 585
(3R,4S)—N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene, but the reaction mixture was only heated for 1 hour. MS (APCI) m/z 519 (M+H) + .
Example 586
(3S,4R)—N-(cyclopropylmethyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting cyclopropylmethylamine for aniline. MS (ESI) m/z 407.1 (M+H) + .
Example 587
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(propan-2-yloxy)ethyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-isopropoxy-ethylamine for aniline. MS (ESI) m/z 439.1 (M+H) + .
Example 588
(3R,4S)—N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 588A
(3R,4S)—N-(3-(benzyloxy)propyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 396A for Example 354D and substituting 3-(benzyloxy)propanal for 4-chlorobenzaldehyde.
Example 588B
tert-butyl (3-(benzyloxy)propyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 588A for Example 337B.
Example 588C
tert-butyl (3-hydroxypropyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To Example 588B (200 mg, 0.36 mmol) in tetrahydrofuran (10 mL) was added 20% palladium hydroxide on carbon, (80 mg, 0.058 mmol). The mixture was allowed to stir under 30 psi of hydrogen at 50° C. for 16 hours. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.
Example 588D
(3R,4S)—N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To Example 588C (60 mg, 0.13 mmol) in tetrahydrofuran (0.5 mL) was added iodomethane (70 mg, 0.5 mmol) and sodium hydride (60%, 20 mg, 0.5 mmol). The mixture was stirred at 60° C. for 2 hours. Hydrochloric acid (4N in dioxane, 1 mL) was added. The mixture was stirred for 2 hours, concentrated, and partitioned between ethyl acetate and NaOH (1 M aq). The organic fraction was collected, concentrated, and purified HPLC to provide the title compound. MS (ESI) m/z 379 (M+H) + .
Example 589
(3R,4S)—N-(3-ethoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting iodoethane for iodomethane. MS (ESI) m/z 393 (M+H) + .
Example 590
(3R,4S)—N-{[1-(methoxymethyl)cyclopropyl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 590A
1-(methoxymethyl)-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 1-(methoxymethyl)cyclopropanecarboxylic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 590
(3R,4S)—N-{[1-(methoxymethyl)cyclopropyl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 590A for Example 404A. MS (ESI) m/z 405 (M+H) + .
Example 591
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(propan-2-yloxy)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 577 for Example 242E. MS (ESI) m/z 439.1 (M+H) + .
Example 592
3-ethoxy-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 578 for Example 242E. MS (ESI) m/z 425.1 (M+H) + .
Example 593
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-2-methoxyethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 579 for Example 242E. MS (ESI) m/z 397.1 (M+H) + .
Example 594
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 580 for Example 242E. MS (ESI) m/z 381.1 (M+H) + .
Example 595
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)butan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 581 for Example 242E. MS (ESI) m/z 394.1 (M+H) + .
Example 596
(2S)-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-1-methoxypropan-2-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 582 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 597
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-methoxypropan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 583 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 598
2-ethoxy-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 584 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 599
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-2-(propan-2-yloxy)ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 587 for Example 242E. MS (ESI) m/z 425.1 (M+H) + .
Example 600
(3R,4S)—N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 600A
Tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 551 (686 mg, 1.48 mmol) in ethyl acetate (7 mL), was added di-tert-butyldicarbonate (644 mg, 2.95 mmol). This solution was stirred at room temperature for 16 hours. The solution was then concentrated and purified by flash-chromatography (30-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI) m/z 565.0 (M+H) + .
Example 600 B
Tert-butyl 2-hydroxyethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 600A (626 mg, 1.11 mmol) in 8 mL of dichloromethane (5 mL) was added tetrabutylammonium fluoride hydrate (620 mg, 2.22 mmol). This solution was stirred at room temperature for 16 hours, concentrated, and purified by flash-chromatography (5% methanol/dichloromethane with 0.5% triethylamine added) to provide the title compound. MS (ESI) m/z 450.8 (M+H) + .
Example 600 C
(3R,4S)—N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Powdered potassium hydroxide (30 mg, 0.53 mmol) was added dimethylsulfoxide (7 mL) and the mixture was stirred for 2 minutes. To this solution was added Example 600 B (60 mg, 0.13 mmol) and iodomethane (66.2 mg, 0.47 mmol). This mixture was stirred at room temperature for 16 hours then partitioned between ethyl acetate and water, The organic fraction was collected, and the aqueous fraction was washed with ethyl acetate 3 times. All organic fractions were combined and concentrated. To this concentrate was added dichloromethane (1 mL) and trifluoroacetic acid (0.3 mL), and the solution stirred at room temperature for 2 hours. The mixture was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 365.1 (M+H) + .
Example 601
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 601A
(E)-2-(2-nitrovinyl)tetrahydrofuran
A solution of tetrahydrofuran-2-carboxaldehyde (2.0 g, 20.0 mmol) and nitromethane (3.66 g, 60.0 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature under nitrogen and 1,1,3,3-tetramethylguanidine (230 mg, 2.0 mmol) was added in one portion. The reaction mixture was stirred for thirty minutes. The mixture was then chilled in an ice bath to 0° C. Trifluoroacetic anhydride (5.25 g, 25 mmol) was added in one portion. The reaction mixture was stirred for thirty minutes after which time triethylamine (5.06 g, 50.0 mmol) was added dropwise. The reaction was stirred for 30 minutes and then partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic fraction was collected, and the aqueous portion was washed with additional ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and purified via flash column (1:2 ethyl acetate:heptanes) to afford the title compound.
Example 601B
1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 601A for trans-4-methoxy-beta nitrostyrene.
Example 601C
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A. Purification via flash chromatography (4:1 ethyl acetate:heptanes) provided the title compound. MS (ESI) m/z 461.1 (M+H) + .
Example 602
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A. Purification via flash chromatography (4:1 ethyl acetate:heptanes) provided the title compound. MS (ESI) m/z 461.1 (M+H) + .
Example 603
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 445.1 (M+H) + .
Example 604
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro furan-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 445.1 (M+H) + .
Example 605
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
Example 605A
N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine
To Example 396A (80 mg, 0.26 mmol) in dimethylsulfoxide (0.3 mL) was added 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (80 mg, 0.35 mmol) and cesium carbonate (120 mg, 0.37). The mixture was stirred at 120° C. for 4 hours and then partitioned between ethyl acetate and water. The organic fraction was dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 605B
N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine
To Example 605A in dichloromethane (1 mL) was added meta-chloroperbenzoic acid (<77%, 320 mg, 1.4 mmol). The mixture was allowed to stir for 3 days. Then the mixture was partition between sodium metabisulfite (aq.) and ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 605C
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
To a solution of Example 605B (0.19 g, 0.36 mmol) in methanol (1 mL) was added sodium methoxide (21% in methanol, 1 mL). The mixture was stirred at 100° C. for 2 hours and, partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by HPLC to provide the title compound. MS (EST) m/z 483 (M+H) + .
Example 606
6-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
To a solution of Example 574A (586 mg, 1.85 mmol) in methanol (10 mL) was added 4,6-dichloropyrimidine (829 mg, 5.6 mmol) and triethylamine (0.52 mL, 3.7 mmol). The reaction heated at 50 C for 1 hour. More 4,6-dichloropyrimidine (800 mg) was added and the reaction stirred for 18 hours. The reaction mixture was concentrated. Purification via flash chromatography (0-100% EtOAc/Hexanes) provided the title compound. MS (ESI) m/z 419 (M+H) + .
Example 607
1-cyclopropyl-N-({(3R,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)methanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 586 for Example 242E. MS (ESI) m/z 393.1 (M+H) + .
Example 608
(3R,4S)—N-(2-ethoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To a solution of Example 600B (70 mg, 0.16 mmol) in tetrahydrofuran (7 ml) under nitrogen was added iodoethane (43.6 mg, 0.28 mmol) and sodium hydride (18.6 mg, 0.47 mmol). This solution was stirred at 60° C. for 1 hour, and then it was cooled to room temperature. To the reaction mixture was added hydrochloric acid (4N in dioxane 0.7 mL) and the solution stirred at room temperature for 1 hour. The reaction mixture was then concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate (aq.). The organic fraction was collected, concentrated, and purified by HPLC to afford the title product. MS (ESI) m/z 379.1 (M+H) + .
Example 609
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-propoxyethyl)pyrrolidin-3-amine
Example 609A
Tert-butyl 2-(allyl oxy)ethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 600B (73 mg, 0.16 mmol) in dimethylformamide (0.5 mL) under nitrogen at 0° C. was added allyl bromide (98 mg, 0.81 mmol) and sodium hydride (19.44 mg, 0.49 mmol). This mixture was stirred at 0° C. for 30 minutes, partitioned between ethyl acetate and water. The organic fraction was collected and concentrated to afford the title compound. MS (ESI) m/z 491.3 (M+H) + .
Example 609B
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-prop oxyethyl)pyrrolidin-3-amine
To a solution of Example 609A (79 mg, 0.161 mmol) in tetrahydrofuran (15 ml) in a 50 ml pressure bottle was added 5% Pd/C, wet (8 mg, 1.879 μmol). The solution was stirred for 30 minutes under 50 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated. The concentrate was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.3 mL) was added. This solution was stirred at room temperature for 1 hour, concentrated, and purified via HPLC to afford the title compound. MS (ESI) m/z 393.1 (M+H) + .
Example 610
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 3,4-difluoro-1-bromobenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (100% ethyl acetate) provided the title compound. MS (ESI) m/z 413.0 (M+H) + .
Example 611
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 3,4-difluoro-1-bromobenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (100% ethyl acetate) provided the title compound. MS (ESI) m/z 413.0 (M+H) + .
Example 612
6-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-6-cyclopropylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 613
6-ethyl-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-ethylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 431.1 (M+H) + .
Example 614
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(propan-2-yl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-isopropylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 445.1 (M+H) + .
Example 615
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-methyl-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 485 (M+H) + .
Example 616
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-propylpyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 4-chloro-6-propylpyrimidine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 445 (M+H) + .
Example 617
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 2,5-dichloro-4-(trifluoromethyl)pyridine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 504506 (3:1) (M+H) + .
Example 618
(3S,4R)—N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-4-chloro-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 479.3 (M+H) + .
Example 619
(3R,4S)—N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-4-chloro-3-fluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 479.3 (M+H) + .
Example 620
6-ethoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
A microwave vial was charged with Example 606 (100 mg, 0.24 mmol), ethanol (2 mL), and sodium tert-butoxide (115 mg, 1.2 mmol). The reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) at 120° C. for 10 minutes. Purification via HPLC provided the title compound. MS (ESI) m/z 429 (M+H) + .
Example 621
6-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting methanol for ethanol. MS (ESI) m/z 415 (M+H) + .
Example 622
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-propoxypyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting propanol for ethanol. MS (ESI) m/z 443 (M+H) + .
Example 623
6-butoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting butanol for ethanol. MS (ESI) m/z 457 (M+H) + .
Example 624
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(2-methylpropoxy)pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting isobutanol for ethanol. MS (ESI) m/z 457 (M+H) + .
Example 625
4-{[(3S,4R)-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 625A
Trans-tert-butyl 3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidine-1-carboxylate
To Example 379A (140 mg, 0.5 mmol) in dimethylformamide (0.5 mL) was added sodium hydride (35 mg, 60%, 0.9 mmol) and 1-bromohexane (150 mg, 0.91 mmol). The mixture was stirred at 100° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic fraction was collected, and the aqueous fraction was washed with ethyl acetate 3 time. The organic fractions were combined, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 625B
Trans-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidine
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 625A for Example 373A.
Example 625C
4-{[Trans-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 625B for Example 373B. MS (ESI) m/z 410 (M+H) + .
Example 626
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting pentan-1-amine for aniline. MS (ESI) m/z 423.1 (M+H) + .
Example 627
Trans-4-(4-fluorophenyl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting hexan-1-amine for aniline. MS (ESI) m/z 437.1 (M+H) + .
Example 628
Trans-N-(3-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-chlorobenzylamine for aniline. MS (ESI) m/z 477.2 (M+H) + .
Example 629
Trans-N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-chlorobenzylamine for aniline. MS (ESI) m/z 477.2 (M+H) + .
Example 630
Trans-N-(4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluorobenzylamine for aniline. MS (ESI) m/z 461 (M+H) + .
Example 631
Trans-N-(3,4-difluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3,4-difluorophenyl)methanamine for aniline. MS (ESI) m/z 479.3 (M+H) + .
Example 632
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)benzyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-(trifluoromethyl)phenyl)methanamine for aniline. 45 mg (31%) of the product was obtained. MS (ESI) m/z 511.3 (M+H) + .
Example 633
Trans-N-[2-chloro-5-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (2-chloro-5-(trifluoromethyl)phenyl)methanamine for aniline. MS (ESI) m/z 545.3 (M+H) + .
Example 634
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting pyridin-2-ylmethanamine for aniline. MS (ESI) m/z 444.2 (M+H) + .
Example 635
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (4-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride for aniline. MS (ESI) m/z 512.2 (M+H) + .
Example 636
Trans-N,N-dibutyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting dibutylamine for aniline. MS (EST) m/z 465.2 (M+H) + .
Example 637
6-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-6-methylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 399 (M+H) + .
Example 638
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-methyl-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 639
4-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)-2-(trifluoromethyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-2-(trifluoromethyl)benzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 494 (M+H) + .
Example 640
4-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-propyl-1H-1,2,3-triazole
Example 640A
4-((trans-3-(2,2-dibromovinyl)-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole
To a solution of Example 332A (0.39 g, 1.2 mmol) in dichloromethane (10 mL) was added carbon tetrabromide (0.38 g, 1.2 mmol) and triphenylphosphine (0.61 g, 2.3 mmol) in portions. The mixture was stirred for 2 hours, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound.
Example 640B
4-(((3S,4S)-3-ethynyl-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole
To a solution of Example 640A (0.24 g, 0.49 mmol) in tetrahydrofuran (1 mL) at −78° C. was added butyllithium (2N, 0.5 mL, 1 mmol). The mixture was stirred for 1 hour and then warmed to room temperature. The mixture was stirred for 1 hour at room temperature, and then partitioned between ammonium chloride (aq.) and ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 640C
1-azidopropane
To a solution of 1-bromo propane (2.4 g, 20 mmol) in tetrahydrofuran (15 mL) was added sodium azide (1.3 g, 20 mmol) and water (1 mL). The mixture was stirred at 70° C. for 2 hours and this solution containing the title compound was used for Example 604D.
Example 640D
4-{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-propyl-1H-1,2,3-triazole
To Example 640B (0.18 g, 0.54 mmol) in half of Example 604C solution was added CuI (90 mg, 0.5 mmol). The mixture was heated at 70° C. for 5 hours, concentrated, and partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 419 (M+H) + .
Example 641
4-[-1-cyclopropyl)piperidin-3-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 641A
tert-Butyl (-1-benzyl-4-(pyridin-3-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared in similarly to the procedures described in Example 2A-2C substituting 3-(2-nitroethenyl)pyridine for trans-4-methoxy-beta-nitrostyrene. MS (DCI) m/z 354.2 (+H) + .
Example 641B
tert-butyl 1-benzyl-4-(piperidin-3-yl)pyrrolidin-3-ylcarbamate
A solution of Example 641A (3.9 g, 11.03 mmol) in acetic acid (80 mL) was added to 5% platinum on carbon (50% water, 1.1 g) in a stainless steel pressure bottle. The vessel was pressurized with 30 psi of hydrogen and shaken for 8 hours at room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.
Example 641C
tert-butyl 1-benzyl-4-(1-cyclopropylpiperidin-3-yl)pyrrolidin-3-ylcarbamate
641B (1.0 g, 2.78 mmol), 1-ethoxycyclopropoxy-trimethylsilane (1.16 g, 6.68 mmol) and sodium cyanoborohydride (327 mg, 5.2 mmol) in methanol (10 ml) was stirred and heated to 60° C. under nitrogen for six hours. The reaction was then concentrated and the residue was taken up in ethyl acetate. The organic solution was washed with water, brine, and dried over sodium sulfate. The organic mixture was filtered, concentrated, and purified via flash chromatography (97.5:2.5 dichloromethane:2N ammonia in methanol) to afford the title compound.
Example 641D
4-(1-cyclopropylpiperidin-3-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Examples 2D-2F substituting the 641C for Example 2C.
Example 641E
4-[-1-cyclopropylpiperidin-3-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 641D for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 514.2 (M+H) + .
Example 642
Trans-N-(3-chloro-4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-chloro-4-fluorophenyl)methanamine for aniline. MS (ESI) m/z 495.2 (M+H) + .
Example 643
Trans-4-(4-fluorophenyl)-N-(6-methylheptyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 6-methylheptan-1-amine for aniline. MS (ESI) m/z 465.2 (M+H) + .
Example 644
2-(4-fluorophenoxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}acetamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-fluorophenoxyacetic acid for Example 242D. MS (ESI) m/z 477.5 (M+H) + .
Example 645
(3R,4S)—N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 469 (M+H) + .
Example 646
(3R,4S)—N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 647
(3R,4S)—N-(4-methoxybutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 647A
methyl 4-(((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)amino)butanoate
The title compound was prepared similarly to the procedure described in Example 354E substituting methyl 4-oxobutanoate for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D.
Example 647B
methyl 4-((tert-butoxycarbonyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)amino)butanoate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 647A for Example 337B.
Example 647C
tert-butyl (4-hydroxybutyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 647B (140 mg, 0.28 mmol) in dichloromethane (1 mL) at −78° C. was added diisobutylaluminum hydride (0.5 mL, 1N in hexanes, 0.5 mmol). The mixture was allowed to stir for 45 minutes. The mixture was quenched and partitioned with ethyl acetate and sodium hydrideCO 3 (aq). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 647D
(3R,4S)—N-(4-methoxybutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 647C for Example 588C. MS (ESI) m/z 393 (M+H) + .
Example 648
(3R,4S)—N-(4-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 648A
tert-butyl ((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)(4-oxobutyl)carbamate
To a solution of Example 647B (140 mg, 0.28 mmol) in dichloromethane (1 mL) at −78° C. was added Diisobutylaluminum hydride (0.5 mL, 1N in hexanes, 0.5 mmol). The mixture was stirred for 45 minutes, and then quenched with ethyl acetate and sodium bicarbonate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 648B
tert-butyl (4-hydroxyhexyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 382B substituting Example 648A for Example 382A and substituting EtMgBr for BnMgBr.
Example 648C
(3R,4S)—N-(4-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 648B for Example 588C. MS (ESI) m/z 421 (M+H) + .
Example 649
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
Example 649A
Cis-2-propylcyclopropyl)methanol
To a solution of (Z)-hex-2-en-1-ol (200 mg, 2 mmol) in dichloromethane (4 mL) was added diiodomethane (0.66 g, 2.5 mmol), then diethylzinc (4 mL, 1N), 4 mmol) dropwise under nitrogen. The mixture was allowed to stir for 16 hours, and was then quenched with ammonium chloride (aq) hydrochloric acid (aq). Ethyl acetate was added and the mixture partitioned. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 649B
Cis-2-propylcyclopropanecarbaldehyde
To a solution of Example 649A (200 mg, 1.75 mmol) in dichloromethane (1 mL) was added Dess-Martin periodinane (424 mg, 1 mmol). The mixture was stirred for 1 hour, and then quenched with sodium bisulfate (aq), and extracted with dichloromethane. The organic extracts were dried over MgSO 4 , filtered, and concentrated to nearly dry to provide a concentrated dichloromethane solution of the title compound.
Example 649C
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 649B for 4-chlorobenzaldehyde and Example 396A for Example 354D. MS (ESI) m/z 403
Example 650
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
Example 650A
(Trans-2-propylcyclopropyl)methanol
The title compound was prepared similarly to the procedure described in Example 649A substituting (E)-hex-2-en-1-ol for (Z)-hex-2-en-1-ol.
Example 650B
Trans-2-propylcyclopropanecarbaldehyde
The title compound was prepared similarly to the procedure described in Example 649B substituting Example 650A for Example 649A.
Example 650C
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 650B for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. MS (ESI) m/z 403 (M+H) +
Example 651
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 503 (M+H) + .
Example 652
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 503 (M+H) + .
Example 653
(3R,4S)—N-[4-methoxy-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-methoxy-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 481 (M+H) + .
Example 654
(3R,4S)—N-(1-benzothiophen-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromobenzo[b]thiophene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439 (M+H) + .
Example 655
(3R,4S)—N-(2,3-dihydro-1H-inden-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromo-2,3-dihydro-1H-indene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 656
(3R,4S)—N-[3,4-bis(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-3,4-bis(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 519 (M+H) + .
Example 657
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 6-bromo-1,2,3,4-tetrahydronaphthalene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 437 (M+H) + .
Example 658
(3R,4S)—N-(3,4-dihydro-2H-chromen-6-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 6-bromochroman for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439 (M+H) + .
Example 659
4-({(3S,4R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-1-propyl-1H-1,2,3-triazole
Example 659A
1-benzyl-4-phenylpyrrolidin-2-one
To a solution of 4-phenylpyrrolidin-2-one (1 g, 6.2 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (60%, 280 mg, 7 mmol). Benzylbromide was added after 10 minutes. The mixture was allowed to stir at. 65° C. for 2 hours. The reaction mixture was, quenched with ammonium chloride (aq) and partitioned with ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 659B
Trans-1-benzyl-4-phenyl-3-(prop-2-yn-1-yl)pyrrolidin-2-one
To a solution of diisopropylamine (700 mg, 7 mmol) in tetrahydrofuran (7 mL) at −78° C. was added butyllithium (2N, 3.1 mL, 6.2 mmol). The mixture was allowed to stir for 10 minutes. Example 659A (1.56 g, 6.2 mmol) in tetrahydrofuran (5 mL) was added. The mixture was allowed to stir for 30 minutes. Propargyl bromide (0.7 mL, 80% toluene solution, 6.2 mmol) in tetrahydrofuran (3 mL) was added. The mixture was allowed to stir for 1 hour, quenched with ammonium chlorid (aq), and partitioned with ethyl acetate. The organic fraction was collected, concentrated, and purified via flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 659C
Trans-1-benzyl-4-phenyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-2-one
The title compound was prepared similarly to the procedure described in Example 640D substituting Example 659B for Example 640B.
Example 659D
4-((trans-1-benzyl-4-phenylpyrrolidin-3-yl)methyl)-1-propyl-1H-1,2,3-triazole
To a solution of Example 659C (0.32 g, 0.86 mmol) in tetrahydrofuran (3 mL) was added lithium aluminumhydride in tetrahydrofuran (2N, 1 mL, 2 mmol). The mixture was allowed to stir for 3 hours. It was then quenched with methanol, followed by sodium bicarbonate (aq). The mixture was partitioned with ethyl acetate. The organic fraction was dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 659E
4-((trans-4-phenylpyrrolidin-3-yl)methyl)-1-propyl-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 659D for Example 2C.
Example 659F
4-({Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-1-propyl-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 659E for Example 373B. MS (ESI) m/z 415 (M+H) + .
Example 660
(3R,4S)—N-(1-benzo furan-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromobenzofuran for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 661
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)benzyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-(trifluoromethoxy)phenyl)methanamine for aniline. MS (ESI) m/z 527.2 (M+H) + .
Example 662
methyl 5-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)-5-oxopentanoate
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline, methyl hydrogen glutarate for Example 242D. MS (ESI) m/z 453.3 (M+H) + .
Example 663
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (2-chloro-4-(trifluoromethyl)phenyl)methanamine for aniline. MS (ESI) m/z 545.3 (M+H) + .
Example 664
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting valeraldehyde for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 395.2 (M+H) + .
Example 665
(3R,4S)-4-(4-fluorophenyl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 409.2 (M+H) + .
Example 666
(3R,4S)—N-[2-(2-methoxyethoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 666A
2-(2-methoxyethoxy)-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 2-(2-methoxyethoxy)acetic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 666B
(3R,4S)—N-[2-(2-methoxyethoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 666A for Example 404A. MS (ESI) m/z 409 (M+H) + .
Example 667
(3R,4S)—N-[2-(4-fluorophenoxy)ethyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 644 for Example 242E. MS (ESI) m/z 463.1 (M+H) + .
Example 668
4-butyl-1-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-31)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,3-triazole
Example 668A
Ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)acetate
The title compound was prepared similarly to the procedure described in Example 640D substituting hex-1-yne for Example 640B and substituting ethyl 2-azidoacetate for Example 640C.
Example 668B
ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)-4-nitro-3-phenylbutanoate
The title compound was prepared similarly to the procedure described in Example 331A substituting Example 668A for methyl 3-(3-chlorophenyl)propanoate.
Example 668C
Trans-3-(4-butyl-1H-1,2,3-triazol-1-yl)-4-phenylpyrrolidin-2-one
To Example 668B (530 mg, 1.5 mmol) in ethanol (10 mL) was added Raney nickel, water slurry (616 mg, 10.5 mmol) in a 20 mL pressure bottle. The mixture was stirred under 60 psi of hydrogen at room temperature for 2 days. The mixture was filtered through a polypropylene membrane and concentrated to provide the title compound.
Example 668D
4-Butyl-1-(Trans-4-phenylpyrrolidin-3-yl)-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 668C for Example 404A.
Example 668E
4-butyl-1-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 668D for Example 373B. MS (ESI) m/z 375 (M+H) + . MS (ESI) m/z 415 (M+H) + .
Example 669
(3R,4S)—N-(4-chloro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-4-chloro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 431 (M+H) + .
Example 670
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 481 (M+H) + .
Example 671
(3R,4S)—N-(2,3-dihydro-1-benzofuran-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromo-2,3-dihydrobenzofuran for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 672
(3R,4S)—N-(4,4-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 6-bromo-4,4-dimethylchroman for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 673
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-hydroxyhexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting DL-alpha-hydroxycaproic acid for Example 242D. MS (ESI) m/z 439.2 (M+H) + .
Example 674
(3R,4S)—N-(3-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 674A
tert-butyl (3-hydroxyhexyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
A mixture of hex-1-en-3-one (38 mg, 0.4 mmol) and Example 396A (120 mg, 0.4 mmol) in methanol (0.5 mL) was allowed to stir overnight. Sodium borohydride (15 mg, 0.4 mmol) was added to the solution. The mixture was stirred for 30 minutes, di-tert-butyl dicarbonate (100 mg, 0.45 mmol) was added. The mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate). to afford the title compound.
Example 674B
(3R,4S)—N-(3-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 674A for Example 588C. MS (ESI) m/z 421 (M+H) + .
Example 675
(3R,4S)—N-[4-chloro-3-(propan-2-yl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-chloro-2-isopropylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 477 (M+H) + .
Example 676
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-methyl-4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-3-methyl-1-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 677
(3R,4S)—N-(1-benzothiophen-6-yl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 6-bromobenzo[b]thiophene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 457 (M+H) + .
Example 678
4-(1-cyclopropylpiperidin-4-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 678A
(E)-tert-butyl 4-(2-nitrovinyl)piperidine-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 601A substituting 4-formylpiperidine-1-carboxylic acid-t-butyl ester for tetrahydrofuran-2-carboxaldehyde. MS (DCI) m/z 274.1 (M+NH 4 ) +
Example 678B
4-(1-cyclopropylpiperidin-4-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 678A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 678C
4-(1-cyclopropylpiperidin-4-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 514.2 (M+H)+
Example 679
(3R,4S)—N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
Example 679A
tetrahydro-2H-pyran-2-carbaldehyde
To a solution of oxalyl chloride (1.3 g, 10 mmol) in dichloromethane (20 mL) at −78° C. was added dimethylsulfoxide (1.3 g, 17 mmol). The mixture was stirred for 10 minutes. A solution of (tetrahydro-2H-pyran-2-yl)methanol (1.2 g, 10 mmol) in dichloromethane (20 mL) was added. The mixture was stirred for 15 minutes at room temperature. The mixture was washed with water. The organic fraction was dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 679B
(E)-2-(2-nitrovinyl)tetrahydro-2H-pyran
To a solution of Example 679A (1.2 g, 10 mmol) in nitromethane (5 mL) was added pyrrolidine (100 mL). The mixture was allowed to stir overnight and concentrated to afford the title compound.
Example 679C
Trans-1-benzyl-3-nitro-4-(-tetrahydro-2H-pyran-2-yl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting Example 679B for 4-methoxy-beta-nitrostyrene.
Example 679D
Trans-1-benzyl-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 679C for Example 2A
Example 679E
tert-butyl (trans-1-benzyl-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 679D for Example 337B.
Example 679F
tert-butyl (trans-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 679E for 2C
Example 679G
tert-butyl (trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 679F for Example 373B
Example 679H
Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337F substituting Example 679G for Example 337E.
Example 679I
Trans-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 679H for Example 354D. MS (ESI) m/z 399 (M+H) + .
Example 680
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting Example 679H for Example 354D. MS (ESI) m/z 507509 (3:1) (M+H) + .
Example 681
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F. MS (ESI) m/z 459 (M+H) + .
Example 682
N-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 460 (M+H) + .
Example 683
N-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 460 (M+H) + .
Example 684
(3R,4S)—N-[4-(4,4-dimethyl-1,3-dioxan-2-yl)butyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5,5-dimethyl-2-(3′-formylpropyl)-1,3-dioxane for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 495.1 (M+H) + .
Example 685
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 686
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 687
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 461 (M+H) + .
Example 688
N-[2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]propan-1-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 689E for Example 404A. MS (ESI) m/z 411 (M+H) + .
Example 689
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-N-propylacetamide
Example 689A
Trans-tert-butyl 3-(4-fluorophenyl)-4-(2-methoxy-2-oxoethoxy)pyrrolidine-1-carboxylate
To a solution of Example 379A (0.56 g, 2 mmol) in dimethylformamide (2 mL) was added methyl 2-bromoacetate (0.38 g, 2.5 mmol) and sodium hydride (60%, 120 mg, 3 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was partitioned with water and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 689B
methyl 2-((trans-4-(4-fluorophenyl)pyrrolidin-3-yl)oxy)acetate
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 689A for Example 373A.
Example 689C
methyl 2-((trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 689B for Example 373B.
Example 689D
2-((Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetic acid
Example 689C (0.11 g, 0.28 mmol) was dissolved in a solution of lithium hydroxide (methanol:water. 5:3, 1N, 3 mL). The mixture was stirred for 2 hours. Hydrochloric acid (aq) was added to adjust the pH value to 2. The mixture was partitioned with ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 689E
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-N-propylacetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting propyl amine for Example 14A and Example 689D for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 690
6-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-methylpyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 606 substituting Example 322B for Example 574A and substituting 4,6-dichloro-2-methylpyrimidine for 4,6-dichloropyrimidine. MS (ESI) m/z 451 (M+H) + .
Example 691
6-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 606 substituting Example 322B for Example 574A but heated at 120° C. for 10 minutes in a microwave (Biotage Initiator™, maximum 400 Watts). MS (ESI) m/z 437 (M+H) + .
Example 692
1-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-phenylurea
A microwave vial was charged with Example 322B (50 mg, 0.15 mmol), isocyanatobenzene (20 mg, 0.17 mmol), triethylamine (65 μL, 0.46 mmol) and tetrahydrofuran (2 mL). The reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) at 100° C. for 10 minutes. Purification via HPLC provided the title compound. MS (ESI) m/z 444 (M+H) + .
Example 693
phenyl {(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}carbamate
The title compound was prepared similarly to Example 692 substituting phenyl carbonochloridate for isocyanatobenzene. MS (ESI) m/z 445 (M+H) + .
Example 694
1-(2-chlorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-2-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 478 (M+H) + .
Example 695
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-oxohexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-acetylbutyric acid for Example 242D. MS (ESI) m/z 437.1 (M+H) + .
Example 696
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)cyclohexanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-(trifluoromethyl)cyclohexanecarboxylic acid for Example 242D. MS (ESI) m/z 503.3 (M+H) + .
Example 697
butyl (3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl carbonate
Example 697A
Trans-tert-butyl 3-(butoxycarbonyloxy)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 699A substituting butyl carbonochloridate for 1-isocyanatobutane.
Example 697B
Butyl-trans-4-(4-fluorophenyl)pyrrolidin-3-yl carbonate
The title compound was prepared similarly to the procedure described in Example 699B substituting Example 697A for Example 699A.
Example 697C
Butyl-trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl carbonate
The title compound was prepared similarly to the procedure described in Example 699C substituting Example 697B for Example 699B. MS (ESI) m/z 426.0 (M+H) + .
Example 698
5,5,5-trifluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 5,5,5-trifluoropentanoic acid for Example 242D. MS (ESI) m/z 463.1 (M+H) + .
Example 699
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl butylcarbamate
Example 699A
Trans-tert-butyl 3-(butylcarbamoyloxy)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate
To a solution of Example 379A (155 mg, 0.55 mmol) in dichloromethane (1.5 mL) was added triethylamine (167 mg, 1.65 mmol) and 1-isocyanatobutane (109 mg, 1.10 mmol). The solution was stirred at room temperature for 16 hours. The mixture was partitioned between dichloromethane and water. The organic fraction was collected, dried over sodium sulfate, concentrated, and purified by flash chromatography (25% ethyl acetate/hexanes) to provide the title compound.
Example 699B
Trans-4-(4-fluorophenyl)pyrrolidin-3-yl butylcarbamate
To a solution of Example 699A (85.5 mg, 0.23 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at room temperature for 1 hour, and was then concentrated to afford title compound.
Example 699C
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl butylcarbamate
To a solution of Example 699B (63 mg, 0.23 mmol) in dichloromethane (1 mL) was added triethylamine (68.2 mg, 0.67 mmol) and 4-dimethylaminopyridine (1.4 mg, 0.011 mmol). The solution was cooled 0° C. To the chilled solution was added 1-methyl-1H-imidazole-4-sulfonyl chloride (42.6 mg, 0.24 mmol) portionwise. This mixture was slowly warmed up to room temperature over 1 hour and stirred at room temperature for 1 hour. The reaction mixture was partitioned with dichloromethane and water. The organic layer was collected, concentrated, and purified via HPLC to provide the title compound. MS (ESI) m/z 425.1 (M+H) + .
Example 700
2,2-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 2,2-difluorohexanoic acid for Example 242D. MS (ESI) m/z 459.2 (M+H) + .
Example 701
1-(4-chlorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-4-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 478 (M+H) + .
Example 702
1-(2-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-2-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 703
1-(3-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-3-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 704
1-(4-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-4-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 705
1-(2-chlorobenzyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-2-(isocyanatomethyl)benzene for isocyanatobenzene. MS (ESI) m/z 492 (M+H) + .
Example 706
4,5-dichloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
To a stirred solution of Example 322B (100 mg, 0.31 mmol) in dimethylsulfoxide (4 mL) was added 2,4,5-trichloropyridine (112 mg, 0.62 mmol) and sodium tert-butoxide (59 mg, 0.062 mmol). The reaction mixture was heated at 90° C. for 18 hours, then concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 470.5 (M+H) + .
Example 707
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[4-(trifluoromethyl)cyclohexyl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 696 for Example 242E. MS (ESI) m/z 489.1 (M+H) + .
Example 708
2,2-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}hexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 2,2-difluorohexanoic acid for Example 242D. MS (EST) m/z 459.2 (M+H) + .
Example 709
Trans-N-[3,4-difluorophenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
Example 709A
(E)-2-(2-nitrovinyl)oxazole
The title compound was prepared similarly to the procedure described in Example 601A substituting oxazole-2-carboxaldehyde for tetrahydrofuran-2-carboxaldehyde. MS (DCI) m/z 141.0 (M+H) +
Example 709B
(3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Examples 2A-2F substituting Example 709A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 709C
Trans-N-[3,4-difluorophenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 709C for Example 14A and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 410.1 (M+H) + .
Example 710
N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared as described in Example 709C substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3,4-difluorobenzene. MS (ESI) m/z 476.0 (M+H) +
Example 711
4-{[trans-3-[(4-fluorobenzyl)oxy]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-fluorobenzyl bromide for 1-bromohexane. MS (ESI) m/z 434 (M+H) + .
Example 712
4-{[trans-3-[(3-fluorobenzyl)oxy]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 3-fluorobenzyl bromide for 1-bromohexane. MS (ESI) m/z 434 (M+H) + .
Example 713
4-{[trans-3-(4-fluorophenyl)-4-{[4-(methylsulfonyl)benzyl]oxy}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-methylsulfonylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 494 (M+H) + .
Example 714
4-{[trans-3-(4-fluorophenyl)-4-{[3-(methylsulfonyl)benzyl]oxy}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 3-methylsulfonylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 494 (M+H) + .
Example 715
6-ethoxy-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606. MS (ESI) m/z 447 (M+H) + .
Example 716
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(propan-2-yloxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting isopropanol for ethanol. MS (ESI) m/z 461 (M+H) + .
Example 717
6-butoxy-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting n-butanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 718
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(2-methylpropoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting iso-butanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 719
6-(cyclobutyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclobutanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 720
6-(cyclopentyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclopentanol for ethanol. MS (ESI) m/z 487 (M+H) + .
Example 721
6-(cyclohexyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclohexanol for ethanol. MS (ESI) m/z 487 (M+H) + .
Example 722
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-phenylpyrimidin-4-amine
A microwave vial was charged with Example 722 (50 mg, 0.11 mmol), phenylboronic acid (14 mg, 0.12 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (4.7 mg, 11 μmol), potassium carbonate (2M, 57 μL, 0.14 mmol)), palladium(II) acetate (1.3 mg, 5.7 μmol), and 1,2-dimethoxyethane (2 mL). The reaction mixture was heated to 100° C. in a microwave (Biotage Initiator™, maximum 400 Watts) for 10 minutes. The reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 479 (M+H) + .
Example 723
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(2-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting o-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 724
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(3-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting m-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 725
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(4-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting p-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 726
6-(2-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 2-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 727
6-(3-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 3-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 728
6-(4-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 4-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 729
6-(3-chlorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 3-(chlorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 513 (M+H) + .
Example 730
6-(4-chlorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 4-(chlorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 513 (M+H) + .
Example 731
4-({(3S,4R)-3-(4-fluorophenyl)-4-[(4-methylbenzyl)oxy]pyrrolidin-1-yl}sulfonyl)-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-methylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 430 (M+H) + .
Example 732
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(5,5,5-trifluoropentyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 698 for Example 242E. MS (ESI) m/z 449.1 (M+H) + .
Example 733
(3R,4S)—N-(2,2-difluorohexyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 700 for Example 242E. MS (ESI) m/z 445.1 (M+H) + .
Example 734
(3R,4S)—N-(2,2-difluoropentyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 700 for Example 242E. MS (ESI) m/z 431.1 (M+H) + .
Example 735
5,5-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}hexanamide
To a solution of Example 695 (200 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was added diethylaminosulfur trifluoride (258 mg, 1.60 mmol). The reaction mixture stirred at 0° C. for 1 hour and then room temperature for 2 days. The reaction mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic fraction was collected, washed with water, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 459.1 (M+H) + .
Example 736
4-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-chloro-4-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (DCI) m/z 420.1 (M+H) + .
Example 737
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-chloro-5-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (DCI) m/z 420 (M+H) + .
Example 738
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-oxopentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-oxopentanoic acid for Example 242D. MS (ESI) m/z 423.0 (M+H) + .
Example 739
(3R,4S)—N-(5,5-difluorohexyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 735 for Example 242E. MS (ESI) m/z 445.2 (M+H) +
Example 740
4-chloro-N-[2-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]aniline
Example 740A
N-(4-fluorophenyl)-2-((trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting 4-fluoroaniline for Example 14A and substituting Example 689D for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 740B
4-chloro-N-[2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]aniline
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 740A for Example 404A. MS (ESI) m/z 479481 (3:1) (M+H) + .
Example 741
(3S,4R)—N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 493 (M+H) + .
Example 742
1-benzyl-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to the procedure described in Example 692 substituting (isocyanatomethyl)benzene for isocyanatobenzene. MS (ESI) m/z 458 (M+H) + .
Example 743
(3R,4S)—N-(4-chloro-3-methylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-4-chloro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 449 (M+H) + .
Example 744
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 499 (M+H) + .
Example 745
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyridin-3-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
A solution of Example 352 (100 mg, 0.22 mmol), pyridine-3-ylboronic acid (41 mg, 0.33 mmol), tricyclohexylphosphine (6.2 mg, 22 μmol), potassium phosphate (1.2 M (aq.), 0.36 mL, 442 mmol)) and palladium(II) acetate (10 mg, 11 μmol) in dioxane (2 mL) was stirred at 100° C. for 18 hours. The reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 496 (M+H) + .
Example 746
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyridin-4-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting pyridin-4-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 496 (M+H) + .
Example 747
(3R,4S)—N-(4-fluoro-3-methylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-fluoro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 433 (M+H) + .
Example 748
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-methylpyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 434 (M+H) + .
Example 749
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting pyrimidin-5-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 750
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3,4′-bipyridin-2′-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting Example 759 for Example 352. MS (ESI) m/z 479 (M+H) + .
Example 751
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4,4′-bipyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting Example 759 for Example 352 and substituting pyridin-4-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 479 (M+H) + .
Example 752
4-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-6-(trifluoromethyl)pyrimidine
The title compound was prepared similarly to the procedure described in Example 379D substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 2-fluoro-4-(trifluoromethyl)pyridine. MS (ESI) m/z 472 (M+H) + .
Example 753
N-[(3R,4S)-4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-4-yl)pyrrolidin-3-amine
Example 753A
(E)-4-(2-nitrovinyl) oxazole
The title compound was prepared similarly to the procedure described in Example 601A substituting 4-oxazolecarboxaldehyde for tetrahydrofuran-2-carboxaldehyde.
Example 753B
(trans)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(oxazol-4-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 753A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 753C
N-[(3R,4S)-4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-4-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 753B for Example 14a and substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 476.0 (M+H) + .
Example 754
4,4-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 735 substituting Example 738 for Example 695. MS (ESI) m/z 445.1 (M+H) + .
Example 755
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
Example 755 A
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 755 B
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 755 A for Example 322B. MS (ESI) m/z 339.1 (M+H) + .
Example 755 C
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 755B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 451.2 (M+H) + .
Example 756
(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 755B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 501.1 (M+H) + .
Example 757
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
Example 757 A
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-5-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 757 B
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-5-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 757A for Example 322B. MS (ESI) m/z 339.1 (M+H) + .
Example 757 C
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 757B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 451.2 (M+H) +
Example 758
(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 757B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 501.1 (M+H) +
Example 759
4-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-chloropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 436 (M+H) + .
Example 760
5-chloro-N-[(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 848 substituting Example 755B for Example 679H. MS (ESI) m/z 518.1 (M+H) +
Example 761
Trans-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 761A
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the procedures described in Examples 2A-2F substituting (E)-3-fluoro-2-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 761B
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 761A for Example 322B.
Example 761 C
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde, Example 761 A for 354D amine MS (ESI) m/z 517.9 (M+H) +
Example 762
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D amine. MS (ESI) m/z 410.1 (M+H) + .
Example 763
Trans-4-(3-fluoropyridin-2-yl)-N,N-dihexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 761A for 354D. MS (ESI) m/z 494.1 (M+H) +
Example 764
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,N-dipentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D. MS (ESI) m/z 466.1 (M+H) +
Example 765
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D. MS (ESI) m/z 396.1 (M+H) +
Example 766
Trans-N-(3,4-difluorophenyl)-4-(3-fluoropyridin-2-31)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761 B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 438.0 (M+H) +
Example 767
Trans-4-(3-fluoropyridin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 488.0 (M+H) +
Example 768
Trans-4-(3-fluoropyridin-2-yl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 504.0 (M+H) +
Example 769
5-fluoro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-methylpyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 435.1 (M+H) +
Example 770
N-{Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 472.0 (M+H) +
Example 771
Trans-N-(3-chloro-4-fluorophenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 453.9 (M+H) +
Example 772
6-chloro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
To a microwave vial charged with Example 761B (100 mg, 0.31 mmol) and methanol (1 mL) was added triethylamine (62.2 mg, 0.62 mmol) and 4,6-dichloropyrimidine (137 mg, 0.93 mmol). The reaction mixture was stirred in a microwave at 120° C. for 1 hour. The mixture was concentrated and purified via HPLC to afford the title compound. MS (ESI) m/z 438.0 (M+H) +
Example 773
(3R,4S)—N-[3-(benzyloxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-(benzyloxy)-3-bromobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 489 (M+H) + .
Example 774
6-(benzyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-(benzyloxy)-6-bromopyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 509 (M+H) + .
Example 775
Trans-N-(4-fluoro-3-methylphenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 434.0 (M+H) +
Example 776
4-(benzyloxy)-5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
Example 776A
4-(benzyloxy)-2-bromo-5-fluoropyridine
To a stirred solution of 2-bromo-5-fluoropyridin-4-ol (100 mg, 0.52 mmol) in dimethylformamide (4 mL) was added (bromomethyl)benzene (89 mg, 0.52 mmol) and potassium carbonate (144 mg, 1.0 mmol). The reaction mixture was stirred at 60° C. for 3 hours. Water and EtOAc were added. The organic fraction was collected and concentrated. Purification via flash chromatography (0-50% EtOAc/heptanes) provided the title compound.
Example 776B
4-(benzyloxy)-5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 776A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 508 (M+H) + .
Example 777
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(piperidin-4-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting tert-butyl 4-(3-bromophenyl)piperidine-1-carboxylate for 1-bromo-3-(trifluoromethyl)benzene followed by dissolving the crude mixture in dichloromethane (5 mL) and treating the crude mixture with HCl (4 M, 3 mL) and purifying via HPLC. MS (APCI) m/z 466 (M+H) + .
Example 778
6-(azetidin-3-ylmethoxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
Tert-butyl 3-((6-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylamino)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was prepared similarly to the procedure described in Example 691 substituting Example 606 for Example 691 and substituting tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (3 eq.) for ethanol and adding tert-butanol (5 mL). The reaction mixture was concentrated, dissolved in dichloromethane, and treated with HCl (4 M, 10 eq.). Purification via HPLC provided the title compound. MS (ESI) m/z 488 (M+H) + .
Example 779
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(pyrrolidin-3-ylmethoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 778 substituting tert-butyl-3-hydroxymethyl-pyrrolidine-1-carboxylate for tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate. MS (ESI) m/z 502 (M+H) + .
Example 780
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(pyrrolidin-2-ylmethoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 778 substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate. MS (ESI) m/z 502 (M+H) + .
Example 781
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
Example 781A
(E)-3-(2-nitrovinyl)tetrahydro-2H-pyran
The title compound was prepared similarly to the procedure described in Example 307A substituting tetrahydropyran-3-carbaldehyde for 2-pyridinecarboxaldeyde.
Example 781B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting Example 781A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 781C
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 405 (M+H) + .
Example 782
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B. MS (ESI) m/z 459 (M+H) + .
Example 783
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 784
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 785
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 489 (M+H) + .
Example 786
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-phenoxyphenyl)-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781 B for Example 322B and substituting 1-bromo-3-phenoxybenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 787
trans-N-(biphenyl-3-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 3-bromo-1,1′-biphenyl for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 467 (M+H) + .
Example 788
Trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2 H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 493 (M+H) + .
Example 789
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 443 (M+H) + .
Example 790
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 791
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 477 (M+H) + .
Example 792
Trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 509 (M+H) + .
Example 793
Trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-chloro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 497 (M+H) + .
Example 794
Trans-N-[3-(benzyloxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-(benzyloxy)-3-bromobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 497 (M+H) + .
Example 795
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To a solution of Example 368 (0.12 g, 0.26 mmol) in dimethylformamide (0.4 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (SelectFluo, 91 mg, 0.26 mmol). The mixture was stirred at room temperature for 16 hours. More 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (60 mg) was added. The mixture was stirred at room temperature for another 16 hours, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 488 (M+H) + .
Example 796
3-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To a solution of Example 368 (0.12 g, 0.26 mmol) in dimethylformamide (0.4 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (SelectFluo, 91 mg, 0.26 mmol). The mixture was stirred at room temperature for 16 hours. More 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (60 mg) was added. The mixture was stirred at room temperature for another 16 hours, concentrated, and purified by HPLC to afford the title compound. MS (EST) m/z 488 (M+H) + .
Example 797
N-(2,2-difluoroethyl)-2-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)acetamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2,2-difluoroethanamine for aniline and substituting Example 689D for Example 242D. MS (ESI) m/z 447.0 (M+H) +
Example 798
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761 B for Example 337F. MS (ESI) m/z 470.0 (M+H) +
Example 799
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 486.0 (M+H) +
Example 800
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500.0 (M+H) +
Example 801
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(pyridin-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 2-(3-bromophenyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 478 (M+H) + .
Example 802
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(pyridin-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting Example 574A for Example 322B and substituting 2-(3-bromophenyl)pyridine. MS (ESI) m/z 460 (M+H) + .
Example 803
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 803A
2-bromo-5-fluoro-4-(2,2,2-trifluoroethoxy)pyridine
A microwave vial was charged with 2-bromo-5-fluoropyridin-4-ol (1 g, 5.2 mmol), 1,1,1-trifluoro-2-iodoethane (3.3 g, 15.6 mmol), potassium carbonate (1.44 g, 10.4 mmol), and dimethylsulfoxide (10 mL). The reaction mixture was stirred in a microwave (Biotage Initiator™ maximum 400 Watts) at 150° C. for 1 hour. The reaction mixture was partitioned between water and EtOAc. The organic fraction was collected and concentrated. Flash chromatography (0-50% EtOAc/heptanes) provided the title compound.
Example 803B
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 803A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 804
5-Chloro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared as described in Example 848 substituting Example 761B for Example 679H. MS (ESI) m/z 505.0 (M+H) +
Example 805
Trans-N-(3-fluorophenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 420.0 (M+H) +
Example 806
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 806A
2-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)pyridine
The title compound was prepared similarly to Example 803A substituting 2-bromo-5-chloropyridin-4-ol for 2-bromo-5-fluoropyridin-4-ol.
Example 806B
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 806A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 534 (M+H) + .
Example 807
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 807A
2-bromo-4-(2,2,2-trifluoroethoxy)pyridine
The title compound was prepared similarly to the procedure described in Example 803A substituting 2-bromopyridin-4-ol for 2-bromo-5-fluoropyridin-4-ol.
Example 807B
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 807A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 808
5-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 806A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 516 (M+H) + .
Example 809
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 807A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 482 (M+H) + .
Example 810
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 803A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 518 (M+H) + .
Example 811
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 811 A
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-3-fluoro-2-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene and 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 811 B
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 811 A for 354D. MS (ESI) m/z 411.0 (M+H) +
Example 812
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(propan-2-yl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-isopropylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 444 (M+H) + .
Example 813
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(propan-2-yl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 2-bromo-4-isopropylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426 (M+H) + .
Example 814
2,2,2-trifluoro-N-[2-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 797 for Example 242E. MS (ESI) m/z 451.1 (M+H) +
Example 815
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 443.0 (M+H) +
Example 816
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 489.1 (M+H) +
Example 817
2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-4-(trifluoromethyl)pyridine
Example 817A
(E)-ethyl 3-(4-(trifluoromethyl)pyridin-2-yl)acrylate
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.45 g, 2 mmol) in tetrahydrofuran (3 mL) at −20° C. was added sodium hydride (100 mg, 60%, 2.5 mmol) followed by the addition of 4-(trifluoromethyl)picolinaldehyde in tetrahydrofuran (1 mL). The mixture was warmed to room temperature over 1 hour. Aqueous ammonium chloride was added and the solution was partitioned with ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (25% ethyl acetate/hexanes) to afford the title compound.
Example 817B
ethyl 3-(4-(trifluoromethyl)pyridin-2-yl)propanoate
To a solution of Example 817A (460 mg, 1.8 mmol) in ethanol (20 mL) in a 50 mL pressure bottle was added 5% palladium on carbon, (95 mg, 0.022 mmol). The mixture was stirred for 2 hours under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated to afford the title compound.
Example 817C
ethyl 4-nitro-3-phenyl-2-((4-(trifluoromethyl)pyridin-2-yl)methyl)butanoate
The title compound was prepared similarly to the procedure described in Example 331A substituting Example 817B for methyl 3-(3-chlorophenyl)propanoate.
Example 817D
4-phenyl-3-((4-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-2-one
The title compound was prepared similarly to the procedure described in Example 331B substituting Example 817C for Example 331A.
Example 817E
2-((4-phenylpyrrolidin-3-yl)methy 1)-4-(trifluoromethyl)pyridine
To a solution of Example 817D (450 mg, 1.4 mmol) in tetrahydrofuran (3 mL) was added lithiumaluminum hydride (2N, 1.5 mL, 3 mmol). The mixture was stirred for 16 hours. Aqueous sodium bicarbonate followed by ethyl acetate was added. The organic fraction was collected, dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 817F
2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-4-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 817E for Example 182B. MS (ESI) m/z 451 (M+H) + .
Example 818
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 811A for 354D. MS (ESI) m/z 519.0 (M+H) +
Example 819
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 475.1 (M+H) +
Example 820
N-Hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2R)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 385.2 (M+H) + .
Example 821
N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 385.2 (M+H) + .
Example 822
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 493.1 (M+H) + .
Example 823
N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 493.1 (M+H) + .
Example 824
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 429.1 (M+H) +
Example 825
N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 429.1 (M+H) +
Example 826
1-benzyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2,3-dihydro-1H-indol-6-amine
Example 826A
1-benzyl-6-bromoindoline
To a stirred solution of 6-bromoindoline (100 mg, 0.50 mmol) in dimethylformamide (5 mL) was added (bromomethyl)benzene (95 mg, 0.55 mmol) and potassium carbonate (140 mg, 1.0 mmol). The reaction was stirred at 60° C. for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was collected, washed with brine, dried with magnesium sulfate, and concentrated to provide the title compound.
Example 826B
1-benzyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2,3-dihydro-1H-indol-6-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 826A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 514 (M+H) + .
Example 827
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Example 827A
(E)-3-(2-nitrovinyl)tetrahydrofuran
To a solution of oxalyl chloride (5.1 mL, 60 mmol) in dichloromethane (100 mL) under a nitrogen atmosphere at −78° C. was added dropwise dimethylsulfoxide (4.6 mL, 65 mmol) in dichloromethane (10 mL). The reaction mixture stirred for 10 minutes. Tetrahydro-3-furan methanol (5.5 g, 54 mmol) was added in dichloromethane (20 mL) over several minutes, and the reaction mixture was stirred for 10 minutes. Triethylamine (17.4 mL, 125 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature. Diethyl ether was added and the solution was filtered. The filtrate was concentrated to provide crude tetrahydrofuran-3-carbaldehyde.
To a stirred solution of this crude tetrahydrofuran-3-carbaldehyde in tetrahydrofuran (50 mL) under a nitrogen atmosphere was added nitromethane (8.1 mL, 150 mmol), 1,1,2,2-tetramethyl guanidine (0.69 mL, 5.5 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and trifluoroacetic anhydride (6.3 mL, 100 mmol) was added. The reaction mixture stirred for 15 minutes. Triethylamine (13.9 mL, 100 mmol) was added dropwise and the reaction mixture stirred for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic fraction was collected, washed with brine, and concentrated. Purification via flash chromatography (40% EtOAc/heptanes) provided the title compound.
Example 827B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepare as an HCl salt similarly to the procedures described in Example 2A-2F substituting Example 827A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 827C
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B. MS (ESI) m/z 445 (M+H) + .
Example 828
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 391 (M+H) + .
Example 829
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 411 (M+H) + .
Example 830
trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but only stirring for 1 hour. MS (APCI) m/z 429 (M+H) + .
Example 831
trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 479 (M+H) + .
Example 832
trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro furan-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 463 (M+H) + .
Example 833
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 479 (M+H) + .
Example 834
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 835
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 461 (M+H) + .
Example 836
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
Example 836A
1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride
To an ice-cooled solution of sodium 1H-1,2,3-triazole-4-thiolate (34.5 g, 280 mmol) in ethanol (400 mL) was added benzylbromide (18.8 mL, 158 mmol) drop-wise. The mixture stirred at 25° C. for 2 hours, and was then diluted with EtOAc (600 mL), washed with water (500 mL), brine (500 mL), dried over sodium sulfate filtered, and concentrated under reduced pressure to afford 4-(benzylthio)-1H-1,2,3-triazole.
To a solution of 4-(benzylthio)-1H-1,2,3-triazole (55.0 g, 288 mmol) in dimethylformamide (550 mL) at 0° C. was added potassium carbonate (87.0 g, 630 mmol) followed by dimethyl sulfate (55.0 mL, 575 mmol) dropwise. Then the reaction mixture was stirred at 20° C. for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL) and washed with water (500 mL). The organic fraction was dried with sodium sulfate, and concentrated. The residue was purified via flash chromatography (Petroleum ether:EtOAc=1:0, 10:1, 5:1 to 3:1) to afford 4-(benzylthio)-1-methyl-1H-1,2,3-triazole.
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (40.3 g, 205 mmol) was added portion wise to a mixture of 4-(benzylthio)-1-methyl-1H-1,2,3-triazole (28.0 g, 137 mmol) in acetonitrile (1200 mL), AcOH (50 mL) and water (34 mL), which had been cooled to 0° C. The addition was slow enough to maintain the internal temperature of the reaction mixture below 5° C. Upon complete addition, the mixture stirred for an additional 2 hours at 0° C. The reaction mixture was then quenched slowly with aqueous sodium hydrideCO 3 solution (5%, 700 mL). The resulting mixture was stirred for 15 minutes and then diluted with dichloromethane (2000 mL). The organic fraction was collected, washed with brine (1000 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=1:0 to 5:1) to afford the title compound.
Example 836B
trans-4-(4-fluorophenyl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 836C
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 837
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 486 (M+H) + .
Example 838
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 504 (M+H) + .
Example 839
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470 (M+H) + .
Example 840
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 488 (M+H) + .
Example 841
(3R,4S)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 436 (M+H) + .
Example 842
(3R,4S)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but only stirring for 1 hour. MS (ESI) m/z 454 (M+H) + .
Example 843
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 463.1 (M+H) +
Example 844
5-Chloro-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure in Example 848 substituting Example 601B for Example 679H. MS (ESI) m/z 480.1 (M+H) +
Example 845
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 409.1 (M+H) +
Example 846
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 477.1 (M+H) +
Example 847
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 423.1 (M+H) +
Example 848
5-Chloro-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
To a microwave vial charged with Example 679H (80 mg, 0.254 mmol) and N-methyl-2-pyrrolidone (0.5 mL) was added cesium carbonate (141 mg, 0.43 mmol) and 2,5-dichloro-4-(trifluoromethyl)pyridine (71.4 mg, 0.33 mmol) under Argon. This mixture was stirred at 120° C. for 5 hours. The mixture was then partitioned between water and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography to provide the title compound. MS (ESI) m/z 494.1 (M+H) +
Example 849
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 425.1 (M+H) +
Example 850
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 1-bromo-3-chlorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 411.1 (M+H) +
Example 851
5-Fluoro-4-methyl-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 410.2 (M+H) +
Example 852
5-Fluoro-4-methyl-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 424.2 (M+H) +
Example 853
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 447.1 (M+H) +
Example 854
(3R,4S)—N-cyclohexyl-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting cyclohexanone for benzaldehyde. MS (ESI) m/z 407 (M+H) + .
Example 855
(3R,4S)—N-(3,3-dimethylcyclohexyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 3,3-dimethylcyclohexanone for benzaldehyde. MS (ESI) m/z 435 (M+H) + .
Example 856
(3R,4S)—N-(4,4-dimethylcyclohexyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 4,4-dimethylcyclohexanone for benzaldehyde. MS (ESI) m/z 435 (M+H) + .
Example 857
(3R,4S)—N-cyclopentyl-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting cyclopentanone for benzaldehyde. MS (ESI) m/z 393 (M+H) + .
Example 858
(3R,4S)—N-(3,3-dimethylcyclopentyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 3,3-dimethylcyclopentanone for benzaldehyde. MS (ESI) m/z 421 (M+H) + .
Example 859
(3R,4S)—N-(1-(2,4-dichlorophenyl)ethyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 1-(2,4-dichlorophenyl)ethanone for benzaldehyde. MS (ESI) m/z 497 (M+H) + .
Example 860
(3R,4S)—N-(2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-yl sulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 2,3-dihydro-1H-inden-1-one for benzaldehyde. MS (ESI) m/z 441 (M+H) + .
Example 861
(3R,4S)—N-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 5-chloro-2,3-dihydro-1H-inden-1-one for benzaldehyde. MS (ESI) m/z 475 (M+H) + .
Example 862
N-(4-chlorobenzyl)-N-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)acetamide
Example 862A
(3R,4S)—N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 4-chlorobenzaldehyde for benzaldehyde.
Example 862B
N-(4-chlorobenzyl)-N-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)acetamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 862A for Example 4B and substituting acetic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 491 (M+H) + .
Further exemplary compounds include:
1-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-3-yl)azepane; 4-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-3-yl)morpholine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(2-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(3-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(4-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(4-fluoropiperidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(4,4-difluoropiperidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(3-fluoroazetidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(piperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; Trans-1′-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4′-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)-1,3′-bipyrrolidine; Trans-3-((3-chlorophenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; Trans-3-((3-chloro-4-fluorophenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-3-((3-(trifluoromethyl)phenyl)amino)pyrrolidin-2-one; Trans-3-((4-fluoro-3-(trifluoromethoxy)phenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; 3-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole; 2-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazole; 5-(3-Chlorophenyl)-2-(trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1H-imidazole; 4-((Trans-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-N-(3-(trifluoromethyl)cyclohexyl)pyrrolidin-3-amine; N-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-isopropylpiperidin-4-amine; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-N-(2-methyltetrahydrofuran-3-yl)pyrrolidin-3-amine; 1-Ethyl-N-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)piperidin-3-amine.
Biological Testing
1. [ 3 H]-Glycine uptake into recombinant CHO cells expressing human GlyT1: Human GlyT1c expressing recombinant hGlyT1c_5_CHO cells were plated at 20,000 cells per well in 96 well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured to sub-confluency for 24 h. For glycine uptake assays the culture medium was aspirated and the cells were washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5 mM L-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10 μl inhibitor or vehicle (10% DMSO) and 10 μl [ 3 H]-glycine (TRK71, Amersham Biosciences) to a final concentration of 200 nM for initiation of glycine uptake.
The plates were placed in a Wallac Microbeta (PerkinElmer) and continuously counted by solid phase scintillation spectrometry during up to 3 hours. Nonspecific uptake was determined in the presence of 10 μM Org24598. IC 50 calculations were made by four-parametric logistic nonlinear regression analysis (GraphPad Prism) using determinations within the range of linear increase of [ 3 H]-glycine incorporation between 60 and 120 min.
2. Radioligand binding assays using recombinant CHO cell membranes expressing human GlyT1:
Radioligand binding to human GlyT1c transporter-expressing membranes was determined as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.
The following results were obtained with the compounds disclosed in the examples:
Ex.
Ki [μM]
1
—
2
≦1
3
≦0.1
4
≧10
13
≦1
14
≦1
15
≦10
16
≦1
17
≦10
18
≦10
19
≦10
20
≦10
21
≦10
22
≦10
23
≦10
24
≦10
25
≦10
26
≦1
27
≦1
29
≦1
30
≦10
31
≦1
32
≦10
33
≦10
34
≦10
35
≦10
36
≦1
37
≦1
38
≦10
39
≦10
40
≧10
41
≦10
42
≦10
43
≦10
44
≦10
45
≧10
46
≧10
47
≧10
48
≦10
49
≦10
50
≦10
51
≦0.1
52
≦10
53
≦10
54
≦1
55
≦1
56
≦1
57
≦10
58
≦0.1
59
≦10
60
≦0.1
61
≦1
62
≦0.1
63
≦0.1
64
≦0.1
65
≦1
66
≦10
67
≦0.01
68
≦1
69
≦10
70
≦1
71
≦1
72
—
73
≦10
74
≦0.1
75
≦1
76
≦10
77
≦1
78
≦1
79
≦1
80
≦1
81
≦10
82
≦10
83
≦1
84
≦1
85
≦0.01
86
≦1
87
≦10
88
≦0.01
89
≦0.1
90
≦1
91
≦0.1
92
≦0.1
93
≦1
94
≦0.01
95
≦1
100
≦10
101
≦1
102
≦1
115
≦0.1
122
≦10
123
≦10
124
≦10
125
>10
126
≦10
127
≦10
128
≦10
129
>10
130
>10
131
>10
132
≦10
133
≦10
134
≦10
135
>10
136
≦10
137
≦10
142
≦10
143
≦10
144
>10
145
≦0.1
148
≦10
149
≦0.1
150
≦0.001
151
≦0.1
152
≦1
153
≦1
154
≦0.1
155
≦0.1
156
≦0.1
157
≦10
158
≦0.1
159
≦0.01
160
≦0.01
161
≦1
162
≦1
163
≦1
164
≦10
165
≦1
166
≦1
167
≦0.1
168
≦0.1
169
≦10
170
≦0.1
171
≦0.1
172
≦0.1
173
≦1
174
≦1
175
≦1
176
≦0.01
177
≦10
178
≦1
179
≦10
180
≦1
181
≦10
182
≦0.1
183
≦10
184
≦10
185
≦10
186
≦1
187
≦10
188
≦0.1
189
≦0.1
190
≦1
191
≦10
192
≦1
193
≦10
194
≦0.1
195
≦10
196
≦10
197
≦1
198
≦1
199
≦1
200
≦1
201
≦0.1
202
≦1
203
≦10
204
≦0.1
205
≦1
206
≦10
207
≦10
208
≦10
209
≦10
210
≦10
211
≦1
212
≦0.10
213
≦1
214
≦0.1
215
≦0.1
216
≦1
217
≦1
218
≦1
219
≦10
220
≦0.01
221
≦1
222
≦1
223
≦0.1
224
≦1
225
≦10
226
≦0.01
227
≦10
228
≦10
229
≦10
230
≦10
231
≦1
232
≦10
233
≦10
234
≦1
235
≦10
236
≦10
237
≦10
238
≦10
239
≦10
240
≦0.1
241
≦10
242
≦10
243
≦1
244
≦1
245
≦0.1
246
≦0.1
247
≦0.01
248
≦1
249
≦1
250
≦10
251
≦0.1
252
≦1
253
≦1
254
≦10
255
≦0.1
256
≦1
257
≦0.1
258
≦1
259
≦1
260
≦0.1
261
≦1
262
≦0.01
263
≦0.1
264
≦1
265
≦1
266
≦1
267
≦0.01
268
≦10
269
≦10
270
≦10
271
≦1
272
≦1
273
≦1
274
≦0.1
275
≦1
276
≦1
277
≦10
278
≦0.1
279
≦10
280
≦0.01
281
≦0.01
282
≦0.1
283
≦0.1
284
≦0.1
285
≦0.1
286
≦10
287
≦0.01
288
≦1
289
≦1
290
≦10
291
≦0.1
292
≦1
293
≦0.1
294
≦0.01
295
≦0.1
296
≦0.1
297
≦0.01
298
≦0.01
299
≦1
300
≦1
301
≦1
302
≦0.1
303
≦10
304
≦1
305
≦0.01
306
≦0.1
307
≦0.1
308
≦1
309
≦1
310
≦0.1
311
≦1
312
≦0.1
313
≦1
314
≦1
315
≦1
316
≦1
317
≦1
318
≦1
319
≦0.1
320
≦0.01
321
≦1
322
≦0.01
323
≦1
324
≦10
325
≦1
326
≦1
327
≦0.01
328
≦0.1
329
≦0.01
329
≦0.01
330
≦0.1
330
≦0.1
331
≦1
332
≦0.1
333
≦1
334
≦1
335
≦1
336
≦1
337
≦1
338
≦1
339
≦10
340
≦1
341
≦10
342
≦10
343
≦10
344
≦0.1
345
≦0.1
346
≦1
347
≦10
348
≦0.1
349
≦0.1
350
>10
351
≦1
352
≦0.01
353
≦0.1
354
≦1
355
≦1
356
≦0.1
357
≦1
358
≦0.1
359
≦1
360
≦0.1
361
≦1
362
≦0.1
363
≦0.1
364
≦10
365
≦10
366
≦0.1
367
≦0.1
368
≦0.01
369
≦1
370
≦1
371
≦1
372
≦10
373
≦10
374
≧10
375
≧10
376
≦1
377
≦1
378
≦10
379
≦0.1
380
≦0.1
381
≦10
382
≦0.1
383
≦1
384
≦10
385
≦10
386
≦1
387
≦10
388
≦0.1
389
≦10
390
≦0.01
390
≦0.01
391
≦0.1
392
≦0.1
393
≦0.01
394
≦0.01
395
≦1
396
≦0.01
397
≦0.01
398
≦0.01
399
≦0.1
400
≦10
401
≦10
402
≦10
403
≦0.1
404
≦10
405
≦1
406
≦10
407
≦10
408
≦10
409
≦0.1
410
≦10
411
≦10
412
≦1
413
≦10
414
≦10
415
≦10
416
—
417
≦0.01
418
≦0.1
419
≧10
420
≦10
421
≦10
422
≦1
423
≦10
424
≦1
425
≦0.01
426
≦1
427
≦0.1
428
≦0.1
429
>10
430
>10
431
≦10
432
≦10
433
≦0.1
434
≦10
435
≦0.1
436
≦1
437
≦0.1
438
≦1
439
≦1
440
≦0.1
441
≦10
442
≦1
443
≦1
444
—
445
≦1
446
≦0.1
447
≦10
448
≦0.1
449
≦1
450
≦1
451
—
452
—
453
≦1
454
≦10
455
≦0.1
456
≦1
457
≦10
458
≦10
459
≦10
460
≦10
461
≦1
462
≦0.1
463
≦1
464
≦1
465
≦1
466
—
467
≦1
468
≦0.1
469
≦1
470
≦10
471
≦0.1
472
≦1
473
≦0.1
474
≦10
475
≦10
476
≦10
477
≦10
478
≦10
479
>10
480
>10
481
≦10
482
≦10
483
≦10
484
≦10
485
≦10
486
≦10
487
≦10
488
≦10
489
≦10
490
≦10
491
≦10
492
≧10
493
≦10
494
≦10
495
>10
496
≧10
497
≦10
498
≦10
499
≧10
500
≦10
501
≦10
502
≦10
503
≧10
504
≦10
505
—
506
≦10
507
≦10
508
≦10
509
≦10
510
≦10
511
≦10
512
≦10
513
>10
514
≦10
515
≦10
516
≦10
517
≦10
518
>10
519
>10
520
≦10
521
≦10
522
—
523
≦10
524
≦10
525
≦10
526
≦10
527
≦10
528
>10
529
≦10
530
≦1
531
≦0.1
532
≦10
533
≦10
534
≦1
535
≦10
536
≦1
537
≦10
538
≦10
539
≦10
540
≦0.1
540
≦0.1
541
≦10
542
≦10
543
≦10
544
≦10
545
≦1
546
≧10
547
≦0.1
548
≦0.01
549
≦10
550
≦10
551
≦10
552
≦10
553
≦1
554
≦1
555
≦10
556
≦10
557
≦10
558
≦10
559
≦1
560
≧10
561
≦1
562
≦10
563
≦10
564
≦1
565
≦10
566
≦10
567
≦1
568
≦0.1
569
≦1
570
≦0.01
571
≦10
572
≦1
573
≦0.1
574
≦0.1
575
≦10
576
—
577
>10
578
≦10
579
≦10
580
≦1
581
≦0.1
582
≦10
583
≦10
584
≦10
585
≦0.1
586
≦1
587
≦10
588
≦10
589
≦1
590
≦10
591
≦10
592
≦10
593
≦10
594
≦10
595
≦10
596
≦10
597
≦10
598
≦10
599
≦10
600
≦10
601
≦0.1
602
≦1
603
≦0.1
604
≦0.1
605
≦1
606
≦0.1
607
≦10
608
≦10
609
≦1
610
≦10
611
≦10
612
≦1
613
≦1
614
≦1
615
≦1
616
≦1
617
≦0.01
618
≦1
619
≦1
620
≦1
621
≦10
622
≦0.1
623
≦0.1
624
≦1
625
≦0.01
626
≦1
627
≦1
628
≦0.01
629
≦1
630
≦0.1
631
≦0.01
632
≦1
633
≦1
634
≦10
635
≦1
636
≦1
637
≦10
638
≦1
639
≦10
640
≦1
641
≦0.1
642
≦0.01
643
≦10
644
≦10
645
≦0.01
646
≦0.01
647
≦10
648
≦10
649
≦0.1
650
≦1
651
≦0.01
651
≦0.01
652
≦0.01
653
≦10
654
≦1
655
≦1
656
≦1
657
≦1
658
≦1
659
≦10
660
≦1
661
≦1
662
≦10
663
≦0.1
664
≦0.1
665
≦0.01
666
≦10
667
≦0.1
668
≦10
669
≦0.1
670
≦0.01
671
≦1
672
≦1
673
≦1
674
≦1
675
≦1
676
≦1
677
≦1
678
≦1
679
≦1
680
≦0.1
681
≦0.01
682
≦0.1
683
≦0.1
684
≦1
685
≦0.01
686
≦0.01
687
≦0.1
688
≦1
689
≦1
690
≦1
691
≦0.1
692
≦1
693
≦10
694
≦1
695
≦10
696
≦10
697
≦1
698
≦1
699
≦1
700
≦10
701
≦1
702
≦10
703
≦1
704
≦1
705
≦1
706
≦10
707
≦1
708
≦10
709
≦10
710
≦1
711
—
712
≦1
713
>10
714
≦10
715
≦1
716
≦0.1
717
≦0.1
718
≦0.1
719
≦0.1
720
≦0.1
721
≦0.1
722
≦0.01
723
≦0.1
724
≦0.1
725
≦0.01
726
≦0.1
727
≦0.01
728
≦0.01
729
≦0.01
730
≦0.01
731
≦0.1
732
≦0.1
733
≦0.01
734
≦0.1
735
≦10
736
≦1
737
≦0.1
738
>10
739
≦0.1
740
≦10
741
≦0.1
742
≦1
743
≦0.1
744
≦0.01
745
≦0.01
746
≦0.01
747
≦0.01
748
≦0.01
749
≦0.01
750
≦0.1
751
≦0.1
752
≦0.1
753
≦1
754
≦10
755
≧10
756
≦10
757
≦10
758
≦10
759
≦0.01
760
>10
761
≦0.1
762
≦0.1
763
≦1
764
≦1
765
≦1
766
≦1
767
≦0.1
768
≦0.1
769
≦1
770
≦1
771
≦0.1
772
≦10
773
≦0.1
774
≦0.1
775
≦1
776
≦0.01
777
≧10
778
≧10
779
≦10
780
≦10
781
≦10
782
≦1
783
≦1
784
≦0.1
785
≦0.1
786
≦1
787
≦1
788
≦1
789
≦1
790
≦1
791
≦1
792
≦10
793
≦10
794
≦1
795
≦0.01
796
≦0.1
797
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798
≦0.1
799
≦0.1
800
≦0.01
801
≦0.01
802
≦0.1
803
≦0.01
804
—
805
≦1
806
≦0.01
807
≦0.01
808
≦0.01
809
≦0.01
810
≦0.01
811
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812
—
813
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814
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815
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816
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817
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818
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819
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820
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821
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822
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823
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824
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825
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826
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827
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828
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829
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830
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831
≦1
832
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833
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834
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835
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836
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837
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838
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839
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840
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841
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842
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843
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845
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846
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848
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849
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850
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851
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852
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853
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855
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857
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858
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859
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860
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861
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862
—
1.PublishNumber: US-9656955-B2
2.Date Publish: 20170523
3.Inventor: AMBERG WILHELM
POHLKI FRAUKE
LANGE UDO
WANG YING X.
ZHAO HONGYU H.
LI HUAN-QIU
BREWER JASON T.
ZANZE IRINI
DIETRICH JUSTIN
VASUDEVAN ANIL
Djuric Stevan W.
LAO YANBIN
HUTCHINS CHARLES W.
4.Inventor Harmonized: AMBERG WILHELM(DE)
POHLKI FRAUKE(DE)
LANGE UDO(DE)
WANG YING X(US)
ZHAO HONGYU H(US)
LI HUAN-QIU(US)
BREWER JASON T(US)
ZANZE IRINI(US)
DIETRICH JUSTIN(US)
VASUDEVAN ANIL(US)
DJURIC STEVAN W(US)
LAO YANBIN(US)
HUTCHINS CHARLES W(US)
5.Country: US
6.Claims:
(en)The present invention relates to pyrrolidine derivatives of the formula (I),
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes. The pyrrolidine derivatives are GlyT1 inhibitors.
7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
This claims priority to U.S. Patent Application No. 61/789,382, filed on Mar. 15, 2013, the entire contents of which are fully incorporated herein by reference.
The present invention relates to pyrrolidine derivatives, pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes.
BACKGROUND OF THE INVENTION
The pyrrolidine motif is an important pharmacophore possessing biological activity against a number of different targets and thus has found use in various advanced pharmaceutical research compounds and clinical candidates (such as Factor Xa inhibitors, NK3 receptor antagonists, DPP-IV inhibitors, PDE-IV inhibitors, or MC4 receptorselective agonists).
A pyrrolidine compound already known in the art as type IV phosphodiesterase inhibitor (PDE-IV) is for example:
WO 9508534, US 2006074123, WO 2001047915, US 20020169196, WO 2001047879 and WO 2001047914 describe further PDE-IV inhibitors having related structures.
Further, the synthesis of certain trisubstituted pyrrolidine derivatives has been reported in Baumann Marcus, et al., ACS Comb. Sci. 2011, 13, 405-413.
Dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including but not limited to schizophrenia, cognitive deficits, dementia, Parkinson disease, Alzheimer disease and bipolar disorder. A large number of studies in animal models lend support to the NMDA hypofunction hypothesis of schizophrenia.
NMDA receptor function can be modulated by altering the availability of the co-agonist glycine. This approach has the critical advantage of maintaining activity-dependent activation of the NMDA receptor because an increase in the synaptic concentration of glycine will not produce an activation of NMDA receptors in the absence of glutamate. Since synaptic glutamate levels are tightly maintained by high affinity transport mechanisms, an increased activation of the glycine site will only enhance the NMDA component of activated synapses.
Two specific glycine transporters, GlyT1 and GlyT2 have been identified and shown to belong to the NaCl-dependent family of neurotransmitter transporters which includes taurine, gamma-aminobutyric acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2 have been isolated from different species and shown to have only 50% identity at the amino acid level. They also have a different pattern of expression in mammalian central nervous system, with GlyT2 being expressed in spinal cord, brainstem and cerebellum and GlyT1 present in these regions as well as forebrain areas such as cortex, hippocampus, septum and thalamus. At the cellular level, GlyT2 has been reported to be expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1 appears to be preferentially expressed by glial cells. These expression studies have led to the suggestion that GlyT2 is predominantly responsible for glycine uptake at glycinergic synapses whereas GlyT1 is involved in monitoring glycine concentration in the vicinity of NMDA receptor expressing synapses. Recent functional studies in rat have shown that blockade of GlyT1 with the potent inhibitor (N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS) potentiates NMDA receptor activity and NMDA receptor-dependent long-term potentiation in rat.
Molecular cloning has further revealed the existence of three variants of GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions.
The physiological effects of GlyT1 in forebrain regions together with clinical reports showing the beneficial effects of GlyT1 inhibitor sarcosine in improving symptoms in schizophrenia patients suggest that selective GlyT1 inhibitors represent a new class of antipsychotic drugs.
Glycine transporter inhibitors are already known in the art, for example:
(see also Hashimoto K., Recent patents on CNS Drug Discovery, 2006, 1, 43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13, 1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997; Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6, 771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6, 1883-1896).
Further glycine transporter inhibitors are known from the following documents.
WO 2009024611 describes 4-benzylaminoquinolines of formula:
WO 2009121872 describes tetrahydroisoquinoline of formula:
WO 2010092180 describes aminotetraline derivatives of formula:
WO 2010092181 describes heterocyclic compounds of formula:
WO 2012020131 describes aminoindane derivatives of formula:
WO 2012020130 describes phenalkylamine derivatives of formula:
WO 2012020133 describes tetraline and indane derivatives of formula:
WO 2012152915 describes benzazepine derivatives of formula:
WO 2012020134 describes phenalkylamine derivatives of formula:
and of formula:
US 20130035323 describes aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives of formula:
It was one object of the present invention to provide further glycine transporter inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to pyrrolidine derivatives of the formula (I)
wherein
R 1 is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 2a , R 2b
are independently hydrogen, halogen, or C 1 -C 3 -alkyl; or
R 2a , R 2b
together with the carbon atom to which they are bound may form a C═O;
R 3a
is C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, or optionally substituted C 3 -C 12 -heterocyclyl;
R 3b is hydrogen, C 1 -C 6 -alkyl, or hydroxy; Y 1 is >CR 6 — or >N—; R 6 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 6 -alkyl, or hydroxy; R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —NR 8e SO 2 R 17 , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl; R 7a , R 7b
are independently hydrogen or C 1 -C 6 -alkyl;
n1 is 1, 2, 3, or 4; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 7c , R 7d
are independently hydrogen or C 1 -C 6 -alkyl;
n2 is 1, 2, 3, or 4; R 11a is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 11b
is hydrogen or C 1 -C 6 -alkyl;
R 7e , R 7f
are independently hydrogen or C 1 -C 6 -alkyl;
n3 is 1, 2, 3, or 4; R 12
is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heterocyclyl;
R 8a , R 8b , R 8c , R 8d , R 8e
are independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -alkylcarbonyl, or
R 6 and one of R 8a , R 8b , R 8c , R 8d , or R 8e
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 9a , R 9b
are independently hydrogen, halogen, C 1 -C 6 -alkyl, hydroxy, or C 1 -C 6 -alkoxy;
n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, C 2 -C 6 -alkenyl, optionally substituted C 3 -C 6 -cycloalkenyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryloxy, optionally substituted C 3 -C 12 -heterocyclyloxy, optionally substituted C 3 -C 12 -heterocyclyl, or tri-(C 1 -C 4 -alkyl)-silyloxy; R 14 is C 1 -C 8 -alkyl, halogenated C 1 -C 6 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonyl-C 1 -C 4 -alkyl, optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 15 is C 1 -C 8 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 16b is hydrogen or C 1 -C 6 -alkyl; R 17 is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 9c , R 9d
are independently hydrogen, halogen, or C 1 -C 6 -alkyl;
n5 is 0, 1, 2, 3, or 4; R 18 is hydrogen, C 1 -C 8 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, optionally substituted C 6 -C 12 -aryl, C 1 -C 6 -alkylamine, (C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl)amino, (halogenated C 1 -C 6 -alkyl)amino, (C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl)amino, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)amino, C 1 -C 6 -dialkylamine, optionally substituted C 6 -C 12 -arylamine, or optionally substituted C 3 -C 12 -heterocyclyl; R 19 is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heterocyclyl; R 20a is C 1 -C 8 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; R 20b is hydrogen or C 1 -C 8 -alkyl; R 21 is optionally substituted C 6 -C 12 -aryl, or optionally substituted C 3 -C 12 -heterocyclyl; and R 5a , R 5b
are independently hydrogen, halogen, or C 1 -C 3 -alkyl, or
R 5a , R 5b
together with the carbon atom to which they are bound may form a C═O,
or a physiologically tolerated salt thereof.
Said compounds of formula (I), i.e., the pyrrolidine derivatives of formula (I) and their physiologically tolerated salts, are glycine transporter inhibitors and thus useful as pharmaceuticals.
The present invention thus further relates to the compounds of formula (I) for use in therapy.
The present invention also relates to pharmaceutical compositions which comprise a carrier and a compound of formula (I).
In particular, said compounds, i.e., the pyrrolidine derivatives and their physiologically tolerated salts, are inhibitors of the glycine transporter GlyT1.
The present invention thus further relates to the compounds of formula (I) for use in inhibiting the glycine transporter.
The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1 and corresponding methods of inhibiting the glycine transporter GlyT1.
Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are known to be useful in treating a variety of neurologic and psychiatric disorders.
The present invention thus further relates to the compounds of formula (I) for use in treating a neurologic or psychiatric disorder.
The present invention further relates to the compounds of formula (I) for use in treating pain.
The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating a neurologic or psychiatric disorder and corresponding methods of treating said disorders. The present invention also relates to the use of the compounds of formula (I) in the manufacture of a medicament for treating pain and corresponding methods of treating pain.
DETAILED DESCRIPTION OF THE INVENTION
Provided that the pyrrolidine derivatives of the formula (I) of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, the invention relates to the corresponding enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, as well as to the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formula (I) and/or of their salts.
According to one embodiment, an enantiomer of the pyrrolidine derivatives of the present invention has the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b are as defined herein.
According to another embodiment, an enantiomer of the pyrrolidine derivatives of the present invention has the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b are as defined herein.
If Y 1 is >CR 6 — it is preferred that R 3a and R 4 are in trans position.
Accordingly, the invention relates in particular to an enantiomer of the pyrrolidine derivatives having the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 6 , R 5a , R 5b are as defined herein.
Preferably, the invention relates to an enantiomer of the pyrrolidine derivatives having the following formula:
wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 6 , R 5a , R 5b are as defined herein.
The physiologically tolerated salts of the pyrrolidine derivatives of the formula (I) are especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C 1 -C 4 -alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other utilizable acids are described, e.g., in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of the isoindoline derivatives also include salts of a physiologically tolerated anion with an isoindoline derivatives wherein one or more than one nitrogen atom is quaternized, e.g. with an alkyl residue (e.g. methyl or ethyl).
The present invention moreover relates to compounds of formula (I) as defined herein, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 12 C by 13 C, 14 N by 15 N, 16 O by 18 O) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.
Of course, such compounds contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds (I).
Stable isotopes (e.g., deuterium, 13 C, 15 N, 18 O) are nonradioactive isotopes which contain one or more additional neutron than the normally abundant isotope of the respective atom. Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non-deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).
Incorporation of a heavy atom particularly substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This effect is usually insignificant if the label is placed at a metabolically inert position of the molecule.
Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.
Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to “kinetic isotope effect”. A reaction involving breaking a C—D bond can be up to 700 percent slower than a similar reaction involving breaking a C—H bond. If the C—D bond is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If a deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C—D bond is the rate limiting step. There is evidence to suggest that whenever cleavage of an aliphatic C—H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway a process called “metabolic switching”.
Deuterium tracers, such as deuterium-labeled drugs and doses, in some cases repeatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.
The weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).
Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
The hydrogens present on a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient. Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D 2 SO 4 /D 2 O. Alternatively, deuterium atoms may be incorporated in various combinations during the synthesis of compounds of the invention. Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.
Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471, the methods are hereby incorporated by reference.
The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
Unless indicated otherwise, the term “substituted” means that a radical is substituted with 1, 2 or 3, especially 1, substituent which, according to a particular embodiment of the invention, are independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 3 -C 6 -aryl-C 1 -C 4 -alkyl, halogenated-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, C 2 -C 4 -alkenyl, —CN, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, alkylamino)carbonyl, C 6 -C 12 -arylaminocarbonyl, C 3 -C 12 -heterocyclylaminocarbonyl, C 6 -C 12 -aryl, oxo (═O), OH, C 1 -C 4 -alkoxy, halogenated-C 1 -C 4 -alkoxy, C 3 -C 7 -cycloalkoxy, carboxy-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, SH, alkylthio, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylaminosulfonyl, di-C 1 -C 4 -alkylaminosulfonyl, C 3 -C 6 -arylsulfonyl, aminosulfonyl, C 3 -C 6 -arylaminosulfonyl, C 3 -C 12 -heterocyclylaminosulfonyl, NH 2 , C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, C 6 -C 12 -aryl-C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonylamino, C 3 -C 6 -arylcarbonylamino, C 3 -C 12 -heterocyclylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, C 3 -C 6 -arylsulfonylamino, C 3 -C 12 -heterocyclylsulfonylamino and C 3 -C 12 -heterocyclyl, wherein aryl and heterocyclyl may be unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy.
The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.
C 1 -C 4 -Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, C 2 -C 4 -alkyl such as ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl or tert-butyl. C 1 -C 2 -Alkyl is methyl or ethyl, C 1 -C 3 -alkyl is additionally n-propyl or iso-propyl.
C 1 -C 6 -Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include methyl, C 2 -C 4 -alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
C 1 -C 8 -Alkyl is a straight-chain or branched alkyl group having from 1 to 8 carbon atoms. Examples include methyl, C 2 -C 4 -alkyl as mentioned herein and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,2,3-trimethylbutyl 1-ethyl-2-methylbutyl, 1-methyl-2-ethylbutyl, octyl, 1-methyl-heptyl, 2-methylheptyl, 3-methyl-heptyl, 4-methyl-heptyl, 5-methylheptyl, 6-methylheptyl, 1-methyl-2-ethylpentyl, 1,1-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 3,3-dimethylhexyl, 4,5-dimethylhexyl, 1,2,3-trimethylpentyl, 1,2-dimethyl-3-ethylbutyl, 1-ethyl-2-ethylbutyl and 1,3-dimethyl-2-ethylbutyl.
Halogenated C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethyl, dihalogenomethyl, trihalogenomethyl, (R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl, 1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl, (R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl, 3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl, 3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl, (R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl, (R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl, (R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl, (R)-2,2,2-trihalogeno-1-methylethyl, (S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl, 1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl, (S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl, 1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl, 4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, 1,1-dihalogenopentyl, 4,4-dihalogenopentyl etc. Particular examples include the fluorinated C 1 -C 4 alkyl groups as defined, such as trifluoromethyl.
C 3 -C 12 -Cycloalkyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a cycloaliphatic radical having from 3 to 12 carbon atoms such as in cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
C 1 -C 6 -Alkylcarbonyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or 2 carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylcarbonyl group, in particular by a C 1 -C 4 -alkylcarbonyl group, such as in methylcarbonylmethyl, methylcarbonylethyl, methylcarbonylpropyl, ethylcarbonylmethyl, n-propylcarbonylmethyl, iso-propylcarbonylmethyl, n-butylcarbonylmethyl, 2-butylcarbonylmethyl or iso-butylcarbonylmethyl.
C 1 -C 6 -Alkoxycarbonyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkoxycarbonyl group, in particular by a C 1 -C 4 -alkoxycarbonyl group, such as in methoxycarbonylmethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, n-butoxycarbonylmethyl, 2-butoxycarbonylmethyl or iso-butoxycarbonylmethyl.
C 6 -C 12 -Aryl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 6 -C 12 -aryl, such as in benzyl.
Hydroxy-C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl, (S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl, (S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl, (S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, (R)-1-hydroxypentyl, (S)-1-hydroxypentyl, 2-hydroxypentyl and 4-hydroxypentyl.
Hydroxy-(halogenated C 1 -C 4 -alkyl) is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, wherein at least two, e.g. 2, 3, 4 or all of the hydrogen atoms are replaced by a number of identical or different halogen atoms and by one or two hydroxyl groups, such as in hydroxyhalogenomethyl, hydroxydihalogenomethyl, (R)-1-hydroxy-1-halogenoethyl, (S)-1-hydroxy-1-halogenoethyl, (R) 2,2-dihalogeno-1-hydroxyethyl, (S) 2,2-dihalogeno-1-hydroxyethyl, (R) 2,2,2-trihalogeno-1-hydroxyethyl, (S) 2,2,2-trihalogeno-1-hydroxyethyl (R)-1-hydroxy-1-halogenopropyl, (S)-1-hydroxy-1-halogenopropyl, (R)-2-halogeno-2-hydroxypropyl, (S)-2-halogeno-2-hydroxypropyl, 3-halogeno-2-hydroxypropyl, 1,1-dihalogeno-1-hydroxypropyl, 2,2-dihalogeno-1-hydroxypropyl, 3,3,3-trihalogeno-1-hydroxypropyl, (R)-2-halogeno-1-methyl-1-hydroxyethyl, (S)-2-halogeno-1-methyl-1-hydroxyethyl, (R)-2,2-dihalogeno-1-methyl-1-hydroxyethyl, (S)-2,2-dihalogeno-1-methyl-1-hydroxyethyl, (R)-2,2,2-trihalogeno-1-methyl-1-hydroxyethyl, (S)-2,2,2-trihalogeno-1-methyl-1-hydroxyethyl, (R)-1-(halogenomethyl)-1-hydroxyethyl, (S)-1-(halogenomethyl)-1-hydroxyethyl, (R)-1-(dihalogenomethyl)-1-hydroxyethyl, (S)-1-(dihalogenomethyl)-1-hydroxyethyl, (R)-1-(trihalogenomethyl)-1-hydroxyethyl, (S)-1-(trihalogenomethyl)-1-hydroxyethyl, etc. Particular examples include the hydroxyfluorinated C 1 -C 4 alkyl groups as defined, such as 1-(trifluoromethyl)-1-hydroxyethyl.
C 1 -C 6 -Alkoxy-C 1 -C 6 -alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are replaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4, in particular 1 or 2 carbon atoms, such as in methoxymethyl, (R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl, (R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, (R)-2-methoxy-1-methylethyl, (S)-2-methoxy-1-methyl ethyl, 2-methoxy-1-(methoxymethyl)ethyl, (R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, (R)-1-methoxypentyl, (S)-1-methoxypentyl, 2-methoxypentyl, 3-methoxypentyl, 4-methoxypentyl, (R)-1-methoxyhexyl, (S)-1-methoxyhexyl, 2-methoxyhexyl, 3-methoxyhexyl, 4-methoxyhexyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl, 2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl, 3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methyl ethyl, 2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl, 2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl, (R)-1-ethoxypentyl, (S)-1-ethoxypentyl, 2-ethoxypentyl, 3-ethoxypentyl, 4-ethoxypentyl, 5-ethoxypentyl, (R)-1-ethoxyhexyl, (S)-1-ethoxyhexyl, 2-ethoxyhexyl, 3-ethoxyhexyl and 6-ethoxybutyl.
C 6 -C 12 -Aryloxy-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a radical of the formula R—O—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxymethyl, (4-F-phenoxy)methyl.
Amino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by an amino group, such as in aminomethyl, 2-aminoethyl.
C 1 -C 6 -Alkylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylamino group, in particular by a C 1 -C 4 -alkylamino group, such as in methylaminomethyl, ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl, n-butylaminomethyl, 2-butylaminomethyl, isobutylaminomethyl or tert-butylaminomethyl.
Di-C 1 -C 6 -Alkylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-C 1 -C 6 -Alkylamino group, in particular by a di-C 1 -C 4 -alkylamino group, such as in dimethylaminomethyl.
C 1 -C 6 -Alkylcarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylcarbonylamino group, in particular by a C 1 -C 4 -alkylcarbonylamino group, such as in methylcarbonylaminomethyl, ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl, 2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl or tert-butylcarbonyl aminomethyl.
C 1 -C 6 -Alkylaminocarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylaminocarbonylamino group, in particular by a C 1 -C 4 -alkylaminocarbonylamino group, such as in methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl, n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl, n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl, iso-butylaminocarbonylaminomethyl or tertbutylaminocarbonylaminomethyl.
Di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a di-C 1 -C 6 -alkylaminocarbonylamino group, in particular by a di-C 1 -C 4 -alkylaminocarbonylamino group, such as in dimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl, dimethylaminocarbonylamino-propyl.
C 1 -C 6 -Alkylsulfonylamino-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a C 1 -C 6 -alkylsulfonylamino group, in particular by a C 1 -C 4 -alkylsulfonylamino group, such as in methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl, iso-propylsulfonylaminomethyl, n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl, iso-butylsulfonylaminomethyl or tertbutylsulfonylaminomethyl.
(C 6 -C 12 -Aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by a (C 6 -C 17 -aryl-C 1 -C 6 -alkyl)amino group, in particular a (C 6 -C 12 -aryl-C 1 -C 2 -alkyl)amino group, such as in benzylaminomethyl.
C 3 -C 12 -Heterocyclyl-C 1 -C 4 -alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is replaced by C 3 -C 12 -heterocyclyl, such as in N-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl, tetrahydropyran-2-yl-methyl.
C 3 -C 12 -Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4 C 1 -C 4 alkyl radicals, preferably one or more methyl radicals.
Carbonyl is >C═O.
C 1 -C 6 -Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.
Halogenated C 1 -C 6 -alkylcarbonyl is C 1 -C 6 -alkylcarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms. Examples include fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are 1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.
C 6 -C 12 -Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include benzoyl.
C 1 -C 6 -Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methoxycarbonyl and tert-butoxycarbonyl.
Halogenated C 1 -C 6 -alkoxycarbonyl is a C 1 -C 6 -alkoxycarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenoxycarbonyl.
Cyano is —C≡N.
Aminocarbonyl is NH 2 C(O)—.
C 1 -C 6 -Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined herein. Examples include methylaminocarbonyl.
(Halogenated C 1 -C 4 -alkyl)aminocarbonyl is a C 1 -C 4 -alkylaminocarbonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different hydrogen atoms.
C 6 -C 12 -Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylaminocarbonyl.
C 2 -C 6 -Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like. C 3 -C 5 -Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl, 2-hexen-1-yl.
C 3 -C 6 -Cycloalkenyl is a carbocyclic radical having at least one carbon-carbon double bond and from 3 to 6 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic structure, such as 2-cyclopenten-1-yl, 2-cyclohexen-1-yl. The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4 C 1 -C 4 alkyl radicals, preferably one or more methyl radicals.
C 2 -C 6 -Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl, 2-propyn-2-yl and the like. C 3 -C 5 -Alkynyl is, in particular, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl.
C 1 -C 5 -Alkylene is straight-chain or branched alkylene group having from 1 to 5 carbon atoms. Examples include methylene and ethylene. A further example is propylene.
C 2 -C 4 -Alkenylene is straight-chain or branched alkenylene group having from 2 to 4 carbon atoms.
C 2 -C 4 -Alkynylene is straight-chain or branched alkynylene group having from 2 to 4 carbon atoms. Examples include propynylene.
C 6 -C 12 -Aryl is a 6- to 12-membered, in particular 6- to 10-membered, aromatic cyclic radical which can be a monocyclic aromatic ring, for example, phenyl etc., or a fused polycyclic aromatic ring comprising a first monocyclic aromatic ring and one or more carbocycles which are saturated, partially unsaturated or aromatic, for example, naphthyl, indenyl, tetrahydronaphthyl, indanyl.
C 3 -C 12 -Arylene is an aryl diradical. Examples include phen-1,4-ylene and phen-1,3-ylene.
Hydroxy is —OH.
Oxo is ═O.
C 1 -C 6 -Alkoxy is a radical of the formula R—O—, wherein R is a straight-chain or branched alkyl group having from 1 to 6, in particular 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy), tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.
Halogenated C 1 -C 6 -alkoxy is a straight-chain or branched alkoxy group having from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms, such as in halogenomethoxy, dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy, (S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy, 2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy, (S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy, 1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy, 3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy, (S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy, (S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy, (S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy, (S)-2,2,2-trihalogeno-1-methylethoxy, 2-halogeno-1-(halogenomethyl)ethoxy, 1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy, (S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy, 4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy, 3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy, etc. Particular examples include the fluorinated C 1 -C 4 alkoxy groups as defined, such as trifluoromethoxy.
C 1 -C 6 -Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by hydroxy. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and the like.
C 1 -C 6 -Alkoxy-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as defined herein, wherein one or two hydrogen atoms are replaced by one or two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.
Amino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an amino group. Examples include 2-aminoethoxy.
C 1 -C 6 -Alkylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy, iso-propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy, iso-butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy, 2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy, 2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy, 2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy, 2-(tertbutylamino)ethoxy.
Di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a di-alkylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy, 2-(N-methyl-N-ethylamino)ethoxy.
C 1 -C 6 -Alkylcarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylcarbonylamino group wherein the alkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylcarbonylaminomethoxy, ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy, iso-propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy, 2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy, tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy, 2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonylamino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.
C 6 -C 12 -Arylcarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -arylcarbonylamino group as defined herein. Examples include 2-(benzoylamino)ethoxy.
C 1 -C 6 -Alkoxycarbonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy, iso-propoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy, 2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy, tertbutoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy, 2-(isobutoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.
C 2 -C 6 -Alkenyloxy is a radical of the formula R—O—, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy (2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy (2-methylprop-2-en-1-yloxy) and the like. C 3 -C 5 -Alkenyloxy is, in particular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy, 3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy, 4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.
C 6 -C 12 -Aryl-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -aryl group as defined herein. Examples include benzyloxy.
C 1 -C 6 -Alkylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy, 2-[(2-methylpropyl)sulfonylamino]ethoxy.
(Halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein, wherein the alkyl group is halogenated. Examples include 2-(trifluoromethylsulfonylamino)ethoxy.
C 6 -C 12 -Arylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 6 -C 12 -arylsulfonylamino group as defined herein. Examples include 2-(phenylsulfanylamino)ethoxy, 2-(naphthylsulfonylamino)ethoxy.
(C 6 -C 12 -Aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino group, preferably by a (C 6 -C 12 -aryl-C 1 -C 2 -alkyl)sulfonylamino group. Examples include 2-(benzylsulfonylamino)ethoxy.
C 3 -C 12 -Heterocyclylsulfonylamino-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -C 12 -heterocyclylsulfonylamino group as defined herein. Examples include 2-(pyridin-3-ylsulfonylamino)ethoxy.
C 3 -C 12 -Heterocyclyl-C 1 -C 4 -alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen atom is replaced by a C 3 -C 12 -heterocyclyl group as defined herein. Examples include 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.
C 1 -C 2 -Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is a straight-chain or branched alkylene group having from 1 or 2 carbon atoms as defined herein. Examples include methylenedioxo.
C 6 -C 12 -Aryloxy is a radical of the formula R—O—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenoxy.
C 3 -C 12 -Heterocyclyloxy is a radical of the formula R—O—, wherein R is a C 3 -C 12 -heterocyclyl group having from 3 to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples include pyridin-2-yloxy.
C 1 -C 6 -Alkylthio is a radical of the formula R—S—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
Halogenated C 1 -C 6 -alkylthio is a radical of the formula R—S—, wherein R is a halogenated alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include halogenomethylthio, dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio, (S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio, 2,2-dihalogenoethylthio, 2,2,2-trihalogeno ethylthio, (R)-1-halogenopropylthio, (S)-1-halogenopropylthio, 2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio, 2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio, 3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio, (S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio, (S)-2,2-dihalogeno-1-methylethylthio, (R)-1,2-dihalogeno-1-methylethylthio, (S)-1,2-dihalogeno-1-methylethylthio, (R)-2,2,2-trihalogeno-1-methylethylthio, (S)-2,2,2-trihalogeno-1-methylethylthio, 2-halogeno-1-(halogenomethyl)ethylthio, 1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio, (S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio, 4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio, 3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio, 4,4,4-trihalogenobutylthio, etc. Particular examples include the fluorinated alkylthio groups as defined, such as trifluoromethylthio.
C 1 -C 6 -Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
C 1 -C 6 -Alkylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexyl sulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
(Halogenated C 1 -C 6 -alkyl)sulfonyl is a C 1 -C 6 -alkylsulfonyl as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonyl.
(C 6 -C 12 -Aryl-C 1 -C 4 -alkyl)sulfonyl is a radical of the formula R—S(O) 2 —, wherein R is a C 6 -C 12 -aryl-C 1 -C 4 -alkyl radical, in particular a C 6 -C 12 -aryl-C 1 -C 2 -alkyl radical as defined herein. Examples include benzylsulfonyl.
C 3 -C 12 -Heterocyclylsulfonyl is a radical of the formula R—S(O) 2 —, wherein R is C 3 -C 12 -heterocyclyl as defined herein.
Aminosulfonyl is NH 2 —S(O) 2 —.
C 1 -C 6 -Alkylaminosulfonyl is a radical of the formula R—NH—S(O) 2 — wherein R is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, iso-propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl, tert-butylaminosulfonyl.
Di-C 1 -C 6 -alkylaminosulfonyl is a radical of the formula RR′N—S(O) 2 — wherein R and R′ are independently of each other an alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as defined herein. Examples include dimethylaminosulfonyl, diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl.
C 6 -C 12 -Arylaminosulfonyl is a radical of the formula R—NH—S(O) 2 — wherein R is an aryl radical having from 6 to 12, preferably 6 carbon atoms as defined herein.
Amino is NH 2 .
C 1 -C 6 -Alkylamino is a radical of the formula R—NH— wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino, tertbutylamino.
(Halogenated C 1 -C 6 -alkyl)amino is a C 1 -C 6 -alkylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
Di-C 1 -C 6 -alkylamino is a radical of the formula RR′N— wherein R and R′ are independently of each other an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.
Di-(halogenated C 1 -C 6 -alkyl)amino is a di-C 1 -C 6 -alkylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 1 -C 6 -Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include acetamido (methylcarbonylamino), propionamido, n-butyramido, 2-methylpropionamido (iso-propylcarbonylamino), 2,2-dimethylpropionamido and the like.
(Halogenated C 1 -C 6 -alkyl)carbonylamino is a C 1 -C 6 -alkylcarbonylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylcarbonylamino is a radical of the formula R—C(O)—NH—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylcarbonylamino.
C 2 -C 6 -Alkenylamino is a radical of the formula R—NH—, wherein R is a straight-chain or branched alkenyl group having from 2 to 6, in particular 2 to 4 carbon atoms. Examples include vinylamino, allylamino (2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino, methallylamino (2-methylprop-2-en-1-ylamino) and the like. C 3 -C 5 -Alkenylamino is, in particular, allylamino, 1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino, methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino, 4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or 2-ethylprop-2-en-1-ylamino.
C 6 -C 12 -Arylamino is a radical of the formula R—NH—, wherein R is an aryl group having from 6 to 12, in particular 6 carbon atoms as defined herein. Examples include phenylamine.
C 1 -C 6 -Alkylsulfonylamino is a radical of the formula R—S(O) 2 —NH—, wherein R is an alkyl radical having from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein. Examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, iso-propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino, iso-butylsulfonylamino, tert-butylsulfonylamino.
(Halogenated C 1 -C 6 alkyl)sulfonylamino is a C 1 -C 6 -alkylsulfonylamino as defined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number of identical or different halogen atoms.
C 6 -C 12 -Arylsulfonylamino is a radical of the formula R—S(O) 2 —NH—, wherein R is an aryl radical having from 6 to 12 carbon atoms as defined herein. Examples include phenylsulfonylamino.
Nitro is —NO 2 .
C 3 -C 12 -Heterocyclyl is a 3- to 12-membered heterocyclic radical including a saturated heterocyclic radical, which generally has 3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring forming atoms, and a heteroaromatic radical (heteroaryl), which generally has 5, 6 or 7 ring forming atoms. The heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclic radicals comprise 1 nitrogen atom as ring member atom and optionally 1, 2 or 3 further heteroatoms as ring members, which are selected, independently of each other from O, S and N. Likewise preferred heterocyclic radicals comprise 1 heteroatom as ring member, which is selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms as ring members.
Examples of C 3 -C 12 -heterocyclyl include:
C- or N-bound 3-4-membered, saturated rings, such as 2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl;
C-bound, 5-membered, saturated rings, such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl, tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl, 1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, 1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;
C-bound, 6-membered, saturated rings, such as tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl, 1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl, tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl, tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl, tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl, tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl, tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl, tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl, tetrahydro-1,2-oxazin-6-yl;
N-bound, 5-membered, saturated rings, such as tetrahydropyrrol-1-yl(pyrrolidin-1-yl), tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;
N-bound, 6-membered, saturated rings, such as piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl(morpholin-1-yl), tetrahydro-1,2-oxazin-2-yl;
C-bound, 5-membered, partially unsaturated rings, such as 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl, 2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl, 4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl, 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl, 2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl, 2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;
C-bound, 6-membered, partially unsaturated rings, such as 2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl, 2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl, 2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl, 2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-, 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl, 4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl, 1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl, 1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl, 1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl, 1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl, 1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or 3,4-dihydropyrimidin-6-yl;
N-bound, 5-membered, partially unsaturated rings, such as 2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;
N-bound, 6-membered, partially unsaturated rings, such as 1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl, 2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl, 1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;
C-bound, 5-membered, heteroaromatic rings, such as 2-furyl, 3-furyl, 5-furyl, 2-thienyl, 3-thienyl, 5-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrrol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-imidazol-4-yl, 4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl;
C-bound, 6-membered, heteroaromatic rings, such as pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;
N-bound, 5-membered, heteroaromatic rings, such as pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl.
Heterocyclyl also includes bicyclic heterocycles, which comprise one of the described 5- or 6-membered heterocyclic rings and a further anellated, saturated or unsaturated or aromatic carbocycle, such as a benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a further anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring being saturated or unsaturated or aromatic. These include quinolinyl, isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl, benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[b]thiazolyl, thieno[b]pyridyl, imidazo[a]pyridyl, pyrazo[a]pyridyl and pyrrol[d]pyrimidyl. Examples of 5- or 6-membered heteroaromatic compounds comprising an anellated cycloalkenyl ring include dihydroindolyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzofuryl, chromanyl, chromanyl, dihydropyrrolo[a]imidazolyl and tetrahydro benzothiazolyl.
C 3 -C 12 -Heteroarylene is a heteroaryl diradical. Examples include pyrid-2,5-ylene and pyrid-2,4-ylene.
With respect to the compounds' capability of inhibiting glycine transporter 1, the variables R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y 1 , R 5a , R 5b , R 6 , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8a , R 8d , R 8e , R 9a , R 9b , R 9c , R 9d , R 10 , R 11a , R 11b , R 12 , R 13 , R 14 , R 15 , R 16a , R 16b , R 17 , R 18 , R 19 , R 20a , R 20b , R 21 , n1, n2, n3, n4 and n5 preferably have the following meanings which, when taken alone or in combination, represent particular embodiments of the pyrrolidine derivatives of the formula (I) or any other formula disclosed herein.
R 1 is C 1 -C 8 -alkyl (e.g. methyl; ethyl, or n-propyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl, (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. tetrahydropyran-2-yl-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclobutyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 2,4-dichlorophenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-CN-phenyl, 2-aminocarbonyl-phenyl, or 4-OMe-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2,5-dimethyl-furan-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-ethyl-thiophen-2-yl, 2,5-dimethyl-thiophen-3-yl, 5-Cl-thiophen-2-yl, 2-methoxycarbonyl-thiophen-3-yl, 3-methoxy-4-methoxycarbonyl-thiophen-2-yl, 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, 2-methylcarbonylamino-1,3-thiazol-5-yl, 3-pyridyl, 2-CF 3 -pyrid-5-yl, 2-(morpholin-1-yl)-pyrid-5-yl, 2-OMe-pyrid-5-yl, 1-methylcarbonyl-indolin-5-yl, 1,2-benzoxazol-5-yl, 1,4-dihydroquinoxaline-2,3-dion-6-yl, 6-chloro-imidazo[2,1-b]thiazol-5-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 3H-1,3-benzoxazol-2-on-5-yl, 3,3-dimethylindolin-2-on-5-yl, indolin-2-on-5-yl, 1,3-dihydrobenzimidazol-2-on-5-yl, 1H-quinazoline-2,4-dion-6-yl, 6-Me-4H-1,4-benzoxazin-3-on-7-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzodioxol-5-yl, isoquinoline-5-yl, 3,4-dihydro-1H-quinolin-2-on-6yl, 1-Me-indol-5yl, pyrrolidin-1-yl, 4-Me-piperidin-1-yl, morpholin-1-yl).
Preferably, R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl).
According to one embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to an alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 , substituted 5-membered heterocyclic rings containing at least 1 N atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular include 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 6 -alkylcarbonylamino.
Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl.
In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl).
According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
According to a further particular embodiment, 1,2,3-triazolyl is substituted with C 1 -C 6 -alkyl as described herein. According to a further specific embodiment, R 1 is 1-methyl-1,2,3-triazol-4-yl.
R 2a , R 2b are independently hydrogen, halogen (e.g. F), or C 1 -C 3 -alkyl (e.g. methyl, ethyl, n-propyl, or iso-propyl), or R 2a , R 2b together with the carbon atom to which they are bound may form a C═O.
According to one particular embodiment R 2a is hydrogen, halogen (e.g. F) or C 1 -C 3 -alkyl (e.g. methyl or ethyl), and R 2b is hydrogen. Preferably, R 2a , R 2b are both hydrogen.
R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy) halogenated C 1 -C 6 -alkoxy (e.g OCF 3 ), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy, or 2-(N-imidazolyl)ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
In particular, R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
According to one preferred embodiment, R 3a is optionally substituted C 6 -C 12 -aryl wherein C 6 -C 12 -aryl is phenyl, in particular phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-F-phenyl, 2-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, or 2,4,5-trifluoro-phenyl).
According to a further preferred embodiment, R 3a is optionally substituted C 3 -C 12 -heterocyclyl wherein C 3 -C 12 -heterocyclyl is in particular tetrahydrofuranyl or tetrahydropyranyl, preferably unsubstituted tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl) or unsubstituted tetrahydropyranyl (e.g. tetrahydropyran-2-yl).
According to an additional aspect, R 3a is not 3,4-di-O-substituted phenyl if R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl). According to a further additional aspect, there is not more than one O-bound substituent on the aryl group if R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
In connection with R 3a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.
Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a , substituted C 6 -C 12 -aryloxy in particular includes C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
Preferably, the substituent(s) on C 6 -C 12 -aryloxy are independently selected from the group consisting of halogen.
In connection with R 3a , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, piperidinyl, isoxazolyl, diazolyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 3 -C 6 -cycloalkyl.
Preferably, the substituent(s) on C 3 -C 12 -heterocyclyl are independently selected from the group consisting of halogen.
R 3b is hydrogen, C 1 -C 6 -alkyl, or hydroxy. Preferably, R 3b is hydrogen.
Y 1 is >CR 6 — or >N—.
Preferably, Y 1 is >CR 6 —.
R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, or iso-butyl), halogenated C 1 -C 6 -alkyl (e.g. CF 3 or CF 2 H), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH or —(CH 2 ) 2 OH), C 1 -C 4 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxymethyl, 2-ethoxypropyl, or 3-ethoxypropyl), or hydroxy.
In particular, R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl or ethyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl or phenethyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH, or —(CH 2 ) 2 OH), or hydroxy, i.e., R 6 is, e.g., hydrogen, methyl, benzyl, hydroxymethyl, or hydroxy.
Preferably, R 6 is hydrogen.
According to some embodiments, Y 1 is >N—. In particular, Y 1 is >N— if R 4 is —(CR 7e R 7f ) n3 R 12 .
R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 - aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —NR 8e SO 2 R 17 , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl).
In particular, R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , (CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b ), —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, or 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl).
Preferably, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 or —O(CR 9c R 9d ) n5 R 18 . More preferably, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 .
In connection with R 4 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 4 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, isoxazolyl, diazolyl, 1,2,3-triazolyl, dihydroquinazolyn, or isoindolinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl and hydroxy.
In particular, R 5a , R 5b are independently hydrogen, halogen, or C 1 -C 3 — alkyl (e.g. methyl, ethyl, n-propyl, or iso-propyl) or R 5a , R 5b together with the carbon atom to which they are bound may form a C═O.
Preferably, R 5a is hydrogen, halogen or C 1 -C 3 -alkyl (e.g. methyl or ethyl), and R 5b is hydrogen. More preferably, R 5a , R 5b are both hydrogen.
According to a one embodiment, R 4 is —(CR 7a R 7b ) n1 OR 10 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ia):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7a , R 7b
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n1 is 1, 2, 3 or 4, in particular 1; and R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl).
In connection with R 10 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
In connection with R 10 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, pyrimidyl, or pyridazyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ia)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ia)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ia)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ia)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ia)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula—(Ia) are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ia) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7a , R 7b
are hydrogen;
n1 is 1; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl); and R 5a , R 5b
are hydrogen.
According to a particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to an alternative particular embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further particular alternative embodiment, R 1 is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-iso-propyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ia)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ia), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ia), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ia)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ia) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7a , R 7b
are hydrogen;
n1 is 1; R 10 is hydrogen, C 6 -C 12 -aryl (e.g. phenyl) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy, or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —(CR 7c R 2d ) n2 NR 11a R 11b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ib):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7c , R 7d
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n2 is 1, 2, 3, or 4, in particular, 1; R 11a is C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-propyl, or n-butyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxypropyl, 3-ethoxy-propyl, or 3-isopropoxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl; and R 11b is hydrogen or (e.g. methyl, ethyl, n-propyl or n-butyl).
In particular, R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)phenyl).
In connection with R 11a substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, amino-carbonyl and halogenated C 1 -C 4 -alkoxy.
In particular, R 11b is hydrogen.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ib)—are, in particular, both hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ib)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4 Cl phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ib)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ib)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ib)—is, in particular, hydrogen.
R 5a , R 5b in the pyrrolidine derivatives of formula (Ib)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ib) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7c , R 7d
are hydrogen;
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; and R 5a , R 5b are
hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ib)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ib)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ib), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ib), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ib)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ib) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 7c , R 7d
are hydrogen;
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. n-propyl or n-butyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropylmethyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, aminocarbonyl and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —(CR 7e R 7f ) n3 R 12 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ic):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 7e , R 7f
are independently hydrogen or C 1 -C 6 -alkyl (e.g. methyl or ethyl), in particular, hydrogen;
n3 is 1, 2, 3, or 4, in particular, 1; and R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl).
In connection with R 12 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 12 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl or triazolyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
R 2a , R 2b —in pyrrolidine derivatives of formula (Ic)—are, in particular, hydrogen.
R 3a —in pyrrolidine derivatives of formula (Ic)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ic)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ic)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ic)—is, in particular, hydrogen or hydroxy.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ic)—are, in particular, hydrogen or together with the carbon atom to which they are bound may form a C═O.
If Y 1 —in the pyrrolidine derivatives of formula (Ic)—is >N—R 5a , R 5b together with the carbon atom to which they are bound form, in particular, a C═O.
Particular embodiments of pyrrolidine derivatives of formula (Ic) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 or >N—; R 6 is hydrogen or hydroxy; R 7e , R 7f
are hydrogen;
n3 is 1; R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); and R 5a , R 5b
are hydrogen or together with the carbon atom to which they are bound may form a C═O.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ic)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ic)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ic), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ic), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ic)—is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of pyrrolidine derivatives of formula (Ic) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl and preferably 1-methyl-1,3-diazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl) or C 6 -C 12 -aryl optionally substituted with halogen (e.g. phenyl, 2-Br-phenyl, or 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 or >N—; R 6 is hydrogen or hydroxy; R 7e , R 7f
are hydrogen;
n3 is 1; R 12 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); and R 5a , R 5b
are hydrogen or together with the carbon atom to which they are bound may form a C═O.
According to a further embodiment, R 4 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
In connection with R 4 being optionally substituted C 6 -C 12 -aryl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
R 2a , R 2b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1 methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; R 4 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl, substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkylcarbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl).
Further preferred embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 6 -C 12 -aryl result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl and preferably 1-methyl-1,3-diazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; R 4 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —NR 8a (CR 9a R 9b ) n4 R 13 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Id):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O (e.g. —C(O)OCH 2 —);
R 9a , R 9b
are independently hydrogen, halogen (e.g. F, Cl, or Br), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), hydroxy, or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy);
n4 is 0, 1, 2, 3, or 4; and R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl or cyclohexyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propyloxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-iso-propyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-yl 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-8-yl, 5-methyl-imidazo[1,2-a]pyridine-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-iso-propyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri(C 1 -C 4 -alkyl)-silyloxy.
In particular, R 9a , R 9b are independently hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy).
In particular, R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propyloxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tert-butyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-iso-propyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)silyloxy.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Id)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Id)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy), halogenated C 1 -C 6 -alkoxy (e.g OCF 3 ), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. 2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), C 3 -C 12 -heterocyclyloxy (e.g. pyridin-2-yloxy), or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl). Preferably, R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy) or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl).
R 3b —in the pyrrolidine derivatives of formula (Id)—is, in particular, hydrogen or hydroxy.
Y 1 —in the pyrrolidine derivatives of formula (Id)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Id)—is, in particular, hydrogen, C 1 -C 6 -alkyl (e.g. methyl), or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH).
R 5a , R 5b —in the pyrrolidine derivatives of formula (Id)—are, in particular, hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Id) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy) or optionally substituted C 3 -C 12 -heterocyclyl (tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 ; R 6 is hydrogen, C 1 -C 6 -alkyl, or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH); R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
are together optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O e.g. —C(O)OCH 2 —);
R 9a is hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy); R 9b is hydrogen; n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutoxy-pyrimid-4-yl, 6-cyclopentoxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; and R 5a , R 5b
are hydrogen.
According to a particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 O (e.g. 5-methyl-1,2-oxazol-4-yl or 3,5-dimethyl-1,2-oxazol-4-yl). According to a further particular embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1 or 2 N and 1 S (e.g. 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl). According to a further particular embodiment, R 11 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 1, 2 or 3 N (e.g. 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, or 1-Me-1,2,3-triazol-4-yl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 2 N and, in particular, R 1 is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Id)—is an optionally substituted 5-membered heterocyclic ring containing 3 N and, in particular, R 1 is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Id), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl. According to a further particular embodiment, 1,2,3-triazolyl is substituted with C 1 -C 6 -alkyl as described herein. According to a further specific embodiment, R 1 is 1-methyl-1,2,3-triazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 6 -C 12 -aryloxy in particular includes is C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
In connection with R 3a and the pyrrolidine derivatives of formula (Id), substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, piperidinyl, isoxazolyl, diazolyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Id)—is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, or cyclohexyl), C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl), or hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl, in particular tetrahydrofuranyl or tetrahydropyranyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 3 -C 6 -cycloalkyl (tetrahydropyran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl).
According to a preferred embodiment, R 9a , R 9b —in the pyrrolidine derivatives of formula (Id)—are independently hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy).
More preferably, R 9a is hydrogen, halogen (e.g. F), C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy) and R 9b is hydrogen.
In connection with R 13 , substituted C 3 -C 12 -cycloalkyl in particular includes C 3 -C 12 -cycloalkyl, such as cyclopropyl, cyclopentyl, or cyclohexyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl.
In connection with R 13 , substituted C 3 -C 6 -cycloalkenyl in particular includes C 3 -C 6 -cycloalkenyl, such as cyclohexenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl.
In connection with R 13 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-carbonylamino and C 3 -C 12 -heterocyclyl.
In connection with R 13 , substituted C 6 -C 12 -aryloxy in particular includes C 6 -C 12 -aryloxy, such as phenoxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
In connection with R 13 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as furanyl, pyrrolyl, thiophenyl, oxazolyl, diazolyl, thiazolyl, triazolyl, pyridyl pyrimidyl, pyrazyl, pyridazyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl or isoquinolinyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl.
According to a preferred embodiment, R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), or C 2 -C 6 -alkenyl (e.g. hex-2-enyl), C 3 -C 6 -cycloalkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-carbonylamino and C 3 -C 12 -heterocyclyl, (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), or C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), C 6 -C 12 -aryloxy optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl (e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-ylmethoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)silyloxy.
Further preferred embodiments of the pyrrolidine derivatives of formula (Id) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl), or 1,2,3-triazolyl optionally substituted with C 1 -C 4 -alkyl (e.g. 1-methyl-1,2,3-triazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, or cyclohexyl) C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, or 2,4,5-trifluoro-phenyl), or hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, or iso-butoxy), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen or C 3 -C 6 -cycloalkyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropyl-piperidin-3-yl, 2-pyridyl, 3-pyridyl, 3-F-pyrid-2-yl, 1,3-oxazol-4-yl, or 1,3-oxazol-2-yl); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 ; R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl), or hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH); R 8a is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, pentyl, or hexyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8a
are together optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O e.g. —C(O)OCH 2 —);
R 9a is hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, or 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy); R 9b is hydrogen; n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 6 -C 12 -aryl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxy-methyl)cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, cyclopentyl, 3,3-dimethylcyclopentyl, cyclohexyl, 3,3-dimethyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, 3-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), or C 2 -C 6 -alkenyl (e.g. hex-2-enyl), C 3 -C 6 -cycloalkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 4 -alkyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-(halogenated C 1 -C 4 -alkyl), CN, C 6 -C 12 -aryl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 1 -C 4 alkyl sulfonyl, C 1 -C 4 -alkylcarbonylamino and C 3 -C 12 -heterocyclyl, (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, 2-chlor-indan-5-yl, or tetralin-6-yl), or C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), C 6 -C 12 -aryloxy optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, hydroxy, CN, C 6 -C 12 -aryl optionally substituted with halogen and C 1 -C 1 -alkyl, C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy and C 3 -C 12 -heterocyclyl (e.g. e.g. n-propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2,4-diMe-1,3-thiazol-5-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, 2-Cl-1,3-thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl, 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 4-CF 3 -pyrimid-2-yl, 6-CF 3 -pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)-pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, 2,3-dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, 2-Me-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, 1-ethyl-piperidin-3-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; and R 5a , R 5b
are hydrogen.
According to a particularly preferred embodiment of the pyrrolidine derivatives of the formula (Id), R 3a is phenyl, 4-F-phenyl, tetrahydrofuran-2-yl or tetrahydropyran-2-yl.
According to a further particularly preferred embodiment of the pyrrolidine derivatives of the formula (Id), R 13 is a group of the formula (Id1):
wherein
X is >CH— or >N—;
Z is >C—R 13c or >N—;
R 13b is halogen (e.g. fluoro or chloro), C 1 -C 4 -alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, tert-butyl), halogenated C 1 -C 4 -alkyl (e.g. CHF 2 , CF 3 ), hydroxy-(halogenated C 1 -C 4 -alkyl) (e.g. 1-OH-1-CF 3 -Et), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), C 3 -C 6 -cycloalkyl (e.g. cyclopropyl), CN, C 6 -C 12 -aryl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl), C 1 -C 4 -alkoxy (e.g. methoxy, ethoxy, n-propoxy, iso-propoxy), halogenated C 1 -C 4 -alkoxy (e.g. —OCHF 2 , —OCH 2 CF 3 , —OCF 3 ), C 3 -C 6 -cycloalkoxy (e.g. cyclobutoxy, cyclopentyloxy, cyclohexyloxy), C 6 -C 12 aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy (e.g. pyrrolid-3-yl-methoxy, pyrrolid-2-yl-methoxy, azetid-3-yl-methoxy), C 6 -C 12 -aryloxy (e.g. phenoxy), C 1 -C 4 -alkyl-sulfonyl (e.g. methylsulfonyl), C 1 -C 4 -alkyl-carbonylamino (e.g. 2-methylcarbonylamino) or C 3 -C 12 -heterocyclyl (e.g. piperidin-4-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimid-5-yl); and
R 13c is hydrogen or halogen (e.g. fluoro, chloro).
Especially preferred among the pyrrolidine derivatives of the formula (Id) wherein R 13 is a group of the formula (Id1) are those wherein X is >CH— or >N—, and Z is >C—R 13c . According this embodiment it is particularly preferred if X is >CH—, Z is >C—R 13c and R 13c is hydrogen or fluoro, especially fluoro, or X is >N—, Z is >C—R 13c and R 13c is hydrogen or fluoro, especially fluoro.
In the pyrrolidine derivatives of the formula (Id) wherein R 13 is a group of the formula (Id1), R 8a , n4, R 9a and R 9b are as defined herein. Preferably, R 8a is hydrogen n4 is, in particular, 0 or 1, with n4=0 being particularly preferred. R 9a and R 9b are preferably both hydrogen if n4 is 1.
According to a further embodiment, R 4 is —NR 8b COR 14 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ie):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8b is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8b
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O; and
R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxyl-methyl or 1-hydroxy-pentyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl, ethoxy-methyl, or ethoxy-ethyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), C 1 -C 6 -alkylaminocarbonyl-C 1 -C 4 -alkyl (e.g. 3-methylaminocarbonyl-propyl), optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. 2-pyridyl-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
In particular, R 8b is hydrogen.
In particular, R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
R 2a , R 2b —in pyrrolidine derivatives of formula (Ie)—are hydrogen.
R 3a —in pyrrolidine derivatives of formula (Ie)—is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
R 3b —in pyrrolidine derivatives of formula (Ie)—is hydrogen or hydroxy. Preferably, R 3b is hydrogen.
Y 1 —in pyrrolidine derivatives of formula (Ie)—is >CR 6 .
R 6 —in pyrrolidine derivatives of formula (Ie)—is hydrogen.
R 5a , R 5b —in pyrrolidine derivatives of formula (Ie)—are hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Ie) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8b is hydrogen; R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ie)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ie)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ie), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ie), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ie)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkoxy (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl).
In connection with R 14 , substituted C 6 -C 12 -aryloxy-C 1 -C 4 -alkyl in particular includes C 6 -C 12 -aryloxy-C 1 -C 4 -alkyl, such as benzyloxy, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 14 , substituted C 3 -C 12 -cycloalkyl in particular includes C 3 -C 12 -cycloalkyl, such as cyclopropyl or cyclohexyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
In connection with R 14 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy. Preferably the substituents on C 6 -C 12 -aryl are independently selected from the group consisting of C 1 -C 4 -alkyl and CN.
In connection with R 14 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridazyl or pyrazyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxyl-methyl or 1-hydroxy-pentyl), (halogenated C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. 4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, 3-CN-phenyl, or 4-CN-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ie) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkoxy (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl)yl; R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8b is hydrogen; R 14 is C 1 -C 8 -alkyl (e.g. pentyl or n-butyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (halogenated C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. 4-F-phenoxy)methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonylpropyl), C 3 -C 12 -cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and C 1 -C 4 -alkoxy (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and halogenated C 1 -C 4 -alkyl(e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); and R 5a , R 5b
are hydrogen.
According to a particularly preferred embodiment, R 3a is phenyl, or halogenated phenyl (e.g. 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl), 4-OMe-phenyl, or pyrid-2-yl.
According to a further embodiment, R 4 is —NR 8c COOR 15 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (If):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8c is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8c
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O. Preferably R 8c is hydrogen; and
R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 2-Cl-4-F-phenyl or 2-Me-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-pyridazyl or 5-pyrazyl).
In particular, R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl), or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 2-Cl-4-F-phenyl or 2-Me-phenyl). Preferably, R 15 is C 1 -C 6 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl) or C 6 -C 12 -aryl (e.g. phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (If)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (If)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4 Cl phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (If)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (If)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (If)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (If)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (If) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8c is hydrogen; R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-bu) or C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (If)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (If)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (If), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (If), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a particular embodiment, R 3a —in the pyrrolidine derivatives of formula (If)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
Further preferred embodiments of pyrrolidine derivatives of formula (If) result if:
R 1 is 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, or 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8c is hydrogen; R 15 is C 1 -C 8 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-butyl) or C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen;
According to a further embodiment, R 4 is —NR 8d CONR 16a R 16b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ig):
wherein R 1 , R 2a R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 8d is hydrogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl), or C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), or R 6 , R 8d
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl), optionally substituted (C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. 2-pyridyl-methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (2-pyridyl, 5-pyrazyl, or 6-pyridazyl); and R 16b is hydrogen or C 1 -C 6 -alkyl (e.g. methyl, ethyl, iso-propyl, or n-butyl).
In particular, R 8d is hydrogen.
In particular, R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
In particular, R 16b is hydrogen.
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ig)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ig)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 3 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 3 -C 12 -aryloxy (e.g. phenyloxy or 4-F-phenyloxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ig)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ig)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ig)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ig)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (If) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8d is hydrogen; R 16a is (optionally substituted C 3 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ig)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ig)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ig), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ig), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ig)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 16a , substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl in particular includes C 3 -C 12 -aryl-C 1 -C 4 -alkyl, such as benzyl, wherein C 6 -C 12 -aryl, such as phenyl, is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 16a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
According to a preferred embodiment, R 16a is C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 6 -C 12 -aryl, with C 6 -C 12 -aryl being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. benzyl or (2-Cl-phenyl)-methyl and phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl).
Preferred embodiments of the pyrrolidine derivatives of formula (Ig) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 26
are hydrogen;
R 3a is C 6 -C 12 aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 8d is hydrogen; R 16a is C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 6 -C 12 -aryl, with C 6 -C 12 -aryl being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. benzyl or (2-Cl-phenyl)-methyl and phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —O(CR 9e R 9d ) n5 R 18 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ih):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 9c , R 9d
are independently hydrogen, halogen (e.g. F), or C 1 -C 6 -alkyl (e.g. methyl or ethyl);
n5 is 0, 1, 2, 3, or 4; and R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl or pentyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl or cyclohexyl), C 1 -C 6 -alkylcarbonyl (e.g. methylcarbonyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), halogenated C 1 -C 6 -alkoxycarbonyl (e.g. —C(O)OCF 3 ), C 6 -C 12 -aryloxycarbonyl (e.g. phenoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -arylaminocarbonyl (e.g. phenylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl)amino (e.g. cyclopropylmethyl-amino), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), (C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl)amino (e.g. 2-methoxyethylamine), (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)amino (e.g. benzylamine), C 1 -C 6 -dialkylamine (e.g. dimethylamino), optionally substituted C 6 -C 12 -arylamino (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
In particular, R 9c , R 9d are hydrogen.
In particular, n5 is 0, 1, or 2.
In particular, R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, isopropyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 6 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
R 2a , R 2b in pyrrolidine derivatives of formula (Ih) are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ih)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1-yl, 3-Me-piperidin-1-yl, 4-Me-piperidin-1-yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1-yl, or azepan-1-yl).
R 3b —in the pyrrolidine derivatives of formula (Ih)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ih)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ih)—is, in particular, hydrogen or C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl). According to a particular embodiment, R 6 is hydrogen or benzyl. Preferably, R 6 is hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ih)—are, in particular, hydrogen.
Particular embodiments of pyrrolidine derivatives of formula (Ih) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ih)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ih)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ih), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ih), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives of formula (Ih), substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl, or azepanyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 3 -C 12 -heterocyclyl are independently selected from the group consisting of halogen and C 1 -C 4 -alkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ih)—is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1yl, or azepan-1-yl).
In connection with R 18 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl.
In connection with R 18 , substituted C 6 -C 12 -arylamine in particular includes C 6 -C 12 -arylamine, such as phenylamine, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.
In connection with R 18 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as 2-pyridyl or 4-pyrimidyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 18 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), or C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), C 6 -C 12 -arylamine optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-Cl-phenylamine), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ih) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1 -C 4 -alkyl (e.g. 3-F-azetidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 2-Me-piperidin-1yl, 3-Me-piperidin-1yl, 4-Me-piperidin-1yl, 4-F-piperidin-1-yl, 4,4-diF-piperidin-1-yl, or azepan-1-yl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkyl-sulfonyl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), or C 1 -C 6 -alkylamine (e.g. n-propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), C 6 -C 12 -arylamine optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-Cl-phenylamine), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —COR 19 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Ii):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 6b are as defined herein, and
R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl or 6-pyrimidyl).
In particular, R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Ii)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Ii)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Ii)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Ii)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Ii)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Ii)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Ii) result if
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Ii)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Ii)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Ii), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Ii), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Ii)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 19 , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
According to a preferred embodiment, R 19 is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Ii) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 19 C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); and R 5a , R 5b
are hydrogen.
According to a further particular embodiment R 4 is —CONR 20a R 20b . Thus, the present invention relates to the pyrrolidine derivatives of the formula (II):
wherein R 1 , R 2a , R 2b , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methy 1, (3,4-diF-phenyl)methy 1, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl); and R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl).
In particular, R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Il)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Il)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Il)—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives of formula (Il)—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives of formula (Il)—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives of formula (Il)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Il) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl); R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl); and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives of formula (Il)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Il)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Il), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives of formula (Il), substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Il)—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl).
In connection with R 20a , substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl in particular includes C 6 -C 12 -aryl-C 1 -C 4 -alkyl, such as benzyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy.
In connection with R 20a , substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl in particular includes C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, such as pyridyl-methyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
In connection with R 20a , substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy.
In connection with R 20a , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl wherein C 6 -C 12 -aryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), or C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl wherein C 3 -C 12 -heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Il) result if
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. 4-F-phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl wherein C 6 -C 12 -aryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, halogenated C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkoxy (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), or C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl wherein C 3 -C 12 -heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), or C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, CN and halogenated C 1 -C 4 -alkoxy (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or C 3 -C 12 -heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenated C 1 -C 4 -alkyl (e.g. 4-CF 3 -pyrid-2-yl); R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. n-butyl); and R 5a , R 5b
are hydrogen.
According to a further embodiment, R 4 is —SO 2 R 21 . Thus, the present invention relates to the pyrrolidine derivatives of the formula (Im):
wherein R 1 , R 2a , R 3a , R 3b , Y 1 , R 5a and R 5b are as defined herein, and
R 21 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, or 4-Me-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 2-pyridyl).
In particular, R 21 is C 6 -C 12 -aryl (e.g. phenyl).
R 2a , R 2b —in the pyrrolidine derivatives of formula (Im)—are, in particular, hydrogen.
R 3a —in the pyrrolidine derivatives of formula (Im)—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl).
R 3b —in the pyrrolidine derivatives of formula (Im)—is, in particular, hydrogen. Y 1 —in the pyrrolidine derivatives of formula (Im)—is, in particular, >CR 6 . R 6 —in the pyrrolidine derivatives of formula (Im)—is, in particular, hydrogen. R 5a , R 5b —in the pyrrolidine derivatives of formula (Im)—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of formula (Im) result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl);
R 3b is hydrogen;
Y 1 is >CR 6 ; R 6 is hydrogen; R 5a , R 5b
are hydrogen; and
R 21 is C 6 -C 12 -aryl (e.g. phenyl).
Preferably, R 1 —in the pyrrolidine derivatives of formula (Im)—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives of formula (Im)—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives of formula (Im), substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives of formula (Im)—is C 6 -C 12 -aryl (e.g. phenyl).
Further preferred embodiments of the pyrrolidine derivatives of formula (Im) result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl (e.g. phenyl); R 3b is hydrogen; Y 1 is >CR 6 ; R 6 is hydrogen; R 21 is C 6 -C 12 -aryl (e.g. phenyl); and R 5a , R 5b
are hydrogen.
According to a further embodiment R 4 is optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl).
R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 3 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (e.g. cyclopropylmethoxy or cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy or 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy or 4-F-phenoxy), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl). Preferably, R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
R 3b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, hydrogen.
Y 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, >CR 6 .
R 6 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is, in particular, hydrogen.
R 5a , R 5b —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—are, in particular, hydrogen.
Particular embodiments of the pyrrolidine derivatives of the invention result if:
R 1 is an optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-2-methoxycarbonyl-pyrrol-5-yl, 1-methyl-pyrrol-3-yl, 5-methyl-1,2-oxazol-4-yl, 3,5-dimethyl-1,2-oxazol-4-yl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-methyl-1,2-diazol-3-yl, 1-methyl-1,3-diazol-4-yl, 1-methyl-1,2-diazol-5-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-4-yl, 1,5-dimethyl-1,2-diazol-4-yl, 1,3-dimethyl-1,2-diazol-5-yl, 1,3-dimethyl-5-Cl-1,2-diazol-4-yl, 1-isopropyl-3-methyl-1,2-diazol-4-yl, 1-Me-3-CF 3 -1,2-diazol-4-yl, 1-cyclopentyl-3-Me-1,2-diazol-4-yl, 1,3,5-trimethyl-1,2-diazol-4-yl, 1-CHF 2 -3,5-dimethyl-1,2-diazol-4-yl, 1,2-dimethyl-1,3-diazol-4-yl, 1,2-dimethyl-1,3-diazol-5-yl, 1-methyl-5-Cl-1,3-diazol-4-yl, 1-Me-1,2,3-triazol-4-yl, 2,4-dimethyl-1,3-thiazol-5-yl, or 2-methylcarbonylamino-1,3-thiazol-5-yl); R 2a , R 2b
are hydrogen;
R 3a is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl) or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; R 4 is optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
Preferably, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is an optionally substituted 5-membered heterocyclic ring containing 2 N which, in particular, is optionally substituted 1,3-diazolyl.
According to a further preferred embodiment, R 1 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is an optionally substituted 5-membered heterocyclic ring containing 3 N which, in particular, is optionally substituted 1,2,3-triazolyl.
In connection with R 1 and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S in particular includes 5-membered heterocyclic rings, such as pyrrolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl, which are substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy-carbonyl and C 1 -C 6 -alkyl-carbonylamino. Preferably, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of halogen and C 1 -C 6 -alkyl. In particular, the substituent(s) on the heterocyclic ring are independently selected from the group consisting of C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl (e.g. methyl). According to a particular embodiment, 1,3-diazolyl is substituted with halogen or C 1 -C 6 -alkyl as described herein. According to a specific embodiment, R 1 is 1-methyl-1,3-diazol-4-yl.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted C 6 -C 12 -aryl in particular includes C 6 -C 12 -aryl, such as phenyl or naphthyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy. Preferably, the substituent(s) on C 6 -C 12 -aryl are independently selected from the group consisting of halogen.
In connection with R 3a and the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl, substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as pyridyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 3a —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is C 6 -C 12 -aryl, in particular phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen (e.g. phenyl, 4-F-phenyl), or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl).
In connection with R 4 , substituted C 3 -C 12 -heterocyclyl in particular includes C 3 -C 12 -heterocyclyl, such as triazolyl or isoindolinonyl, which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and halogenated C 1 -C 4 -alkyl.
According to a preferred embodiment, R 4 —in the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl—is C 3 -C 12 -heterocyclyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-chloroisoindolin-1-onyl, 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, or 1-propyl-1,2,3-triazol-4-yl).
Further preferred embodiments of the pyrrolidine derivatives wherein R 4 is optionally substituted C 3 -C 12 -heterocyclyl result if:
R 1 is 1,3-diazolyl optionally substituted with halogen or C 1 -C 4 -alkyl (e.g. 1-methyl-1,3-diazol-4-yl); R 2a , R 2b
are hydrogen;
R 3a is C 6 -C 12 -aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, or C 3 -C 12 -heterocyclyl (e.g. pyrid-2-yl); R 3b is hydrogen; R 4 is C 3 -C 12 -heterocyclyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl and halogenated C 1 -C 4 -alkyl (e.g. 4-chloroisoindolin-1-one; 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl, 4-butyl-1,2,3-triazol-1-yl, 1-propyl-1,2,3-triazol-4-yl, 5-(4-CF 3 -phenyl)-4,5-dihydroisooxazol-3-yl, 5-(4-CF 3 -phenyl)-oxazol-2-yl, or 5-(3-Cl-phenyl)-imidazol-2-yl); Y 1 is >CR 6 ; R 6 is hydrogen; and R 5a , R 5b
are hydrogen.
Particular embodiments of pyrrolidine derivatives of the invention result if
R 1 is optionally substituted 5-membered heterocyclic ring containing at least 1 N ring atom and optionally 1 or 2 further heteroatoms selected from N, O and S (e.g. 1-methyl-1,3-diazol-4-yl or 1-methyl-1,2,3-triazol-4-yl; R 2a , R 2b
are hydrogen;
R 3a is C 3 -C 12 -cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-Cl-phenyl, 2-Br-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-OMe-phenyl, or 2,4,5-trifluoro-phenyl)hydroxy, C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, n-propyloxy, iso-propoxy, or iso-butoxy) C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkoxy (cyclopropylmethoxy, cyclohexylmethoxy), C 2 -C 6 -alkenyloxy (e.g. allyloxy, 2-methylprop-2-en-1-oxy), C 6 -C 12 -aryl-C 1 -C 4 -alkoxy (e.g. benzyloxy), optionally substituted C 6 -C 12 -aryloxy (e.g. phenoxy, 4-F-phenoxy); R 3b is hydrogen or hydroxy; Y 1 is >CR 6 — or >N—; R 6 is hydrogen, C 1 -C 6 -alkyl (e.g. methyl or ethyl), C 3 -C 12 -aryl-C 1 -C 21 -alkyl (e.g. benzyl or phenethyl), hydroxy-C 1 -C 6 -alkyl (e.g. —CH 2 OH, or —(CH 2 ) 2 OH), or hydroxy; R 4 is —(CR 7a R 7b ) n1 OR 10 , —(CR 7c R 7d ) n2 NR 11a R 11b , —(CR 7e R 7f ) n3 R 12 , optionally substituted C 6 -C 12 -aryl, —NR 8a (CR 9a R 9b ) n4 R 13 , —NR 8b COR 14 , —NR 8c COOR 15 , —NR 8d CONR 16a R 16b , —O(CR 9c R 9d ) n5 R 18 , —COR 19 , —CONR 20a R 20b , —SO 2 R 21 , or optionally substituted C 3 -C 12 heterocyclyl (e.g. 1-propyl-1,2,3-triazol-4-yl, 4-butyl-1,2,3-triazolyl-1-yl, 4-chloroisoindolin-1-one, or 7-(trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-on-1-yl); R 7a , R 7b
are hydrogen, or
n1 is 1; R 10 is hydrogen, optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, or 3-OCF 3 -phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 6-CF 3 -pyrimid-4-yl, 4-CF 3 -pyrid-2-yl, or 2-CF 3 -pyrid-4-yl); R 7c , R 7d
are hydrogen, or
n2 is 1; R 11a is C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, or n-heptyl), C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl) C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropyloxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropyloxy-propyl), C 6 -C 12 -aryl-C 1 -C 4 -alkyl (e.g. benzyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-(aminomethyl)-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, or 3-(aminocarbonyl)-phenyl); R 11b is hydrogen; R 7e , R 7f
are hydrogen, or
n3 is 1; R 12 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-Cl-phenyl, or 3-Br-phenyl) or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 1-propyl-1,2,3-triazol-4-yl); R 8a , R 8b , R 8c , R 8d , R 8e
are independently hydrogen or C 1 -C 6 -alkyl (e.g. pentyl or hexyl), or
R 6 and one of R 8a , R 8b , R 8c , R 8d , or R 8e
together are optionally substituted C 1 -C 5 -alkylene, wherein one or more —CH 2 — of C 1 -C 5 -alkylene may be independently replaced by a an oxygen atom or C═O;
R 9a , R 9b
are independently hydrogen, halogen, C 1 -C 6 -alkyl (e.g. methyl, ethyl, tert-butyl, 2,3-dimethyl-propyl), or C 1 -C 6 -alkoxy (e.g. methoxy or ethoxy);
n4 is 0, 1, 2, 3, or 4; R 13 is hydrogen, C 1 -C 8 -alkyl (e.g. methyl, ethyl, n-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. —CF 3 or —CF 2 Me), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. methoxy-methyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. cyclopropyl, 2-propyl-cyclopropyl, 1-(methoxymethyl)-cyclopropyl, 2-phenyl-cyclopropyl, cyclopentyl, 1-methyl-cyclohexyl, 1-CF 3 -cyclopropyl, 4-CF 3 -cyclohexyl, or 4,4-diF-cyclohexyl), C 2 -C 6 -alkenyl (e.g. hex-2-enyl), optionally substituted C 3 -C 6 -cycloalkenyl (e.g. 1,3,3-trimethylcyclohexen-2-yl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 4-F-phenyl, 3-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 3,4-diF-phenyl, 2,3,4-triF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 3-F-4-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-5-F-phenyl, 3,4-diF-5-Cl-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-iPr-phenyl, 3-tBu-phenyl, 3-Me-4-F-phenyl, 3-Me-4-Cl-phenyl, 3-iPr-4 Cl-phenyl, 3-(1-OH-1-CF 3 -Et)-phenyl, 3-CHF 2 -4-F-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-F-3-CF 3 -phenyl, 2-F-5-CF 3 -phenyl, 3-F-5-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CF 3 -4-Cl-phenyl, 3-Me-4-CF 3 -phenyl, 3-CF 3 -4-Me-phenyl, 3,4-diCF 3 -phenyl, 4-OMe-phenyl, 3-OiPr-phenyl, 3-CF 3 -4-OMe-phenyl, 3-OCH 2 CF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -5-Cl-phenyl, 3-OCF 3 -4-F-phenyl, 3-OCF 3 -4-Cl-phenyl, 3-OBn-phenyl, 3-OPh-phenyl, 3-CN-phenyl, 4-CN-phenyl, 2-F-3-CN-phenyl, 2-F-4-CN-phenyl, 3-F-4-CN-phenyl, 2-F-5-CN-phenyl, 3-F-5-CN-phenyl, 3-Cl-4-CN-phenyl, 2-Cl-5-CN-phenyl, 3-Cl-5-CN-phenyl, 3-CN-4-Cl-phenyl, 2-Me-3-CN-phenyl, 2-Me-5-CN-phenyl, 3-Me-5-CN-phenyl, 3-CF 3 -4-CN-phenyl, 3-CN-4-OMe-phenyl, 3-CN-4-OCF 3 -phenyl, 3-phenyl-phenyl, 3-MeSO 2 -phenyl, 3-(piperidin-4-yl)-phenyl, 2-methylcarbonylamino-5-Cl-phenyl, 3-(pyrid-2-yl)-phenyl, 3-(pyrid-3-yl)-4F-phenyl, 3-(pyrid-4-yl)-4F-phenyl, 3-(pyrimid-5-yl)-4F-phenyl, indan-5-yl, or tetralin-6-yl), C 1 -C 6 -alkoxy (e.g. methoxy, ethoxy, or n-propoxy), C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy (e.g. 2-methoxy-ethoxy), optionally substituted C 6 -C 12 -aryloxy (e.g. 4-F-phenoxy or 4-tertbutyl-phenoxy), optionally substituted C 3 -C 12 -heterocyclyl (e.g. e.g. propyl-furan-2-yl, 2-CF 3 -furan-5-yl, 1,2-dimethyl-5-CN-pyrrol-3-yl, 2,3-diMe-thiophen-5-yl, 2-Me-thiophen-5-yl, 2-Cl-thiophen-5-yl, 3-Cl-thiophen-2-yl, 2,5-diCl-thiophen-3-yl, 2-tetrahydropyranyl-thiophen-5-yl, 1,3-thiazol-5-yl, 4-Me-1,3-thiazol-2-yl, 2-Me-1,3-thiazol-5-yl, 5-Me-1,3-thiazol-2-yl, 4-Me-1,3-thiazol-5-yl, 2-Me-1,3-thiazol-4-yl, 4-isopropyl-1,3-thiazol-2-yl, 2-phenyl-4-Me-1,3-thiazol-5-yl, 4-phenyl-1,3-thiazol-5-yl, 2-(4-Me-phenyl)-1,3-thiazol-5-yl, 4-(4-F-phenyl)-1,3-thiazol-2-yl, thiazol-4-yl, 4-Cl-1,3-thiazol-5-yl, 2-Br-1,3-thiazol-5-yl, 4-Br-1,3-thiazol-2-yl, 4-Me-5-Br-1,3-thiazol-2-yl, 2,4-dichloro-1,3-thiazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-F-pyrid-2-yl, 5-F-pyrid-2-yl, 6-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 5-F-pyrid-3-yl, 2-F-pyrid-4-yl, 3,5-diCl-pyrid-4-yl, 4,5-diCl-pyrid-2-yl, 2-Cl-3F-pyrid-4-yl, 5-Me-pyrid-2-yl, 4-iPr-pyrid-2-yl, 4-Me-5-F-pyrid-2-yl, 4-CF 3 -pyrid 2-yl-5-CF 3 -pyrid-2-yl, 6-CF 3 -pyrid-2-yl, 5-CF 3 -pyrid-3-yl, 2-CF 3 -pyrid-4-yl, 3-F-4-CF 3 -pyrid-2-yl, 4-CF 3 -5-F-pyrid-2-yl 4-CF 3 -5-Cl-pyrid-2-yl, 3,5-diF-4-CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -pyrid-2-yl, 4-OCH 2 CF 3 -5-F-pyrid-2-yl, 4-OCH 2 CF 3 -5-Cl-pyrid-2-yl, 4-OBn-5-F-pyrid-2-yl, 3-(4-F-phenyl)-pyrid-5-yl, 2-(4-F-phenyl)-pyrid-3-yl, 4-(pyrid-4-yl)-pyrid-2-yl, 4-(pyrid-3-yl)-pyrid-2-yl, 5-cyclopropyl-pyraz-2-yl, 5-cyclobutyl-pyraz-2-yl, 5-pyrrolidin-pyraz-2-yl, pyridaz-3-yl, 4-CF 3 -pyridaz-3-yl, 5-CF 3 -pyridaz-3-yl, 5-F-pyrimid-2-yl, 6-Cl-pyrimid-4-yl, 6-Me-pyrimid-4-yl, 6-Et-pyrimid-4-yl, 6-Pr-pyrimid-4-yl, 6-iPr-pyrimid-4-yl, 2-Me-6-Cl-pyrimid-4-yl, 2-Me-6-CF 3 -pyrimid-4-yl, 2-OMe-6-CF 3 -pyrimid-4-yl, 2-OMe-pyrimid-4-yl, 6-OMe-pyrimid-4-yl, 6-OEt-pyrimid-4-yl, 6-OPr-pyrimid-4-yl, 6-OiPr-pyrimid-4-yl, 6-OiBu-pyrimid-4-yl, 6-OBu-pyrimid-4-yl, 6-OBn-pyrimid-4-yl, 6-cyclobutyloxy-pyrimid-4-yl, 6-cyclopentyloxy-pyrimid-4-yl, 6-cyclohexyloxy-pyrimid-4-yl, 6-cyclopropyl-pyrimid-4-yl, 6-phenyl-pyrimid-4-yl, 6-(2-F-phenyl)-pyrimid-4-yl, 6-(3-F-phenyl)-pyrimid-4-yl, 6-(4-F-phenyl)-pyrimid-4-yl, 6-Cl-pyrimid-4-yl, 6-(2-Me-phenyl)pyrimid-4-yl, 6-(3-Me-phenyl)-pyrimid-4-yl, 6-(4-Me-phenyl)-pyrimid-4-yl, 6-(3-Cl-phenyl)-pyrimid-4-yl, 6-(4-Cl-phenyl)-pyrimid-4-yl, 2-(morpholin-1-yl)-pyrimid-4-yl, 6-(azetidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-3-yl-methoxy)-pyrimid-4-yl, 6-(pyrrolidin-2-yl-methoxy)-pyrimid-4-yl, benzofuran-5-yl, 2-Me-benzofuran-3-yl, 2-Et-benzofuran-3-yl, benzothiophen-5-yl, benzothiophen-6-yl, 5-Me-benzothiophen-2-yl, 5-F-benzothiophen-2-yl, 3-Cl-benzothiophen-2-yl, benzothiazol-2-yl, isoquinolin-6-yl, isoquinolin-7-yl, quinolin-6-yl, quinolin-7-yl, 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, dihydrobenzofuran-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrazolo[1,5-a]pyridine-3-yl, pyrazolo[1,5-a]pyridine-7-yl, imidazo[1,2-a]pyridin-8-yl, 5-methyl-imidazo[1,2-a]pyridin-3-yl, 6-chloro-2-methyl-imidazo[1,2-a]pyridin-3-yl, 6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl, thieno[2,3-b]pyridin-2-yl, N-benzyl-indolin-6-yl, indolinon-4-yl, chroman-6-yl, 4,4-dimethylchroman-6-yl, 4,4-dimethyl-1,3-dioxan-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-Me-tetrahydropyran-4-yl, 2,2-diMe-tetrahydropyran-4-yl, 1-isopropyl-piperidin-4-yl, or 2-CF 3 -piperazin-5-yl), or tri-(C 1 -C 4 -alkyl)-silyloxy; R 14 is C 1 -C 8 -alkyl (e.g. pentyl, n-butyl, or hexyl), halogenated C 1 -C 6 -alkyl (e.g. 1,1-diF-butyl, 3,3-diF-butyl, 4,4,4-triF-butyl, 1,1-diF-pentyl, or 4,4-diF-pentyl), (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), hydroxy-C 1 -C 6 -alkyl (e.g. hydroxylmethyl or 1-hydroxy-pentyl), (optionally substituted C 6 -C 12 -aryloxy)-C 1 -C 4 -alkyl (e.g. phenoxy-methyl or (4-F-phenoxy)-methyl), C 1 -C 6 -alkylcarbonyl-C 1 -C 4 -alkyl (e.g. 2-methylcarbonyl-ethyl or 3-methylcarbonyl-propyl), C 1 -C 6 -alkoxycarbonyl-C 1 -C 4 -alkyl (e.g. 3-methoxycarbonyl-propyl), optionally substituted C 3 -C 12 -cycloalkyl (e.g. 1-CF 3 -cyclopropyl or 4-CF 3 -cyclohexyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diCl-phenyl, 3,5-diCl-phenyl, 2-Cl-4-F-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-CF 3 -phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 2-Cl-4-CF 3 -phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 2-CN-phenyl, or 3-CN-phenyl, 4-CN-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 3-Cl-pyridazin-6-yl, 2-Cl-pyrazin-5-yl, or 2-CF 3 -pyrazin-5-yl); R 15 is C 1 -C 6 -alkyl (e.g. ethyl, n-propyl, n-butyl, iso-butyl, or tert-bu) or C 6 -C 12 -aryl (e.g. phenyl); R 16a is (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl or (2-Cl-phenyl)-methyl) or optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-F-phenyl, 2F-phenyl, 4-Cl-phenyl, or 2-Cl-phenyl); R 16b is hydrogen; R 9c , R 9d
are hydrogen;
n5 is 0, 1, or 2; R 18 is hydrogen, optionally substituted C 1 -C 8 -alkyl (e.g. methyl, ethyl, iso-propyl, or pentyl), C 1 -C 6 -alkoxycarbonyl (e.g. methoxycarbonyl or n-butoxycarbonyl), C 1 -C 6 -alkylaminocarbonyl (e.g. n-propylaminocarbonyl or n-butylaminocarbonyl), (halogenated C 1 -C 4 -alkyl)aminocarbonyl (e.g. 2,2-diF-ethylaminocarbonyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 4-Me-phenyl, 3-MeSO 2 -phenyl, or 4-MeSO 2 -phenyl), C 1 -C 6 -alkylamine (e.g. propylamine), (halogenated C 1 -C 6 -alkyl)amino (e.g. 2,2,2-triF-ethylamine), optionally substituted C 6 -C 12 -arylamine (e.g. 4-Cl-phenylamine), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl or 6-CF 3 -pyrimid-4-yl); R 19 is optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,4-diF-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 3-OCF 3 -phenyl, or 4-OCF 3 -phenyl); R 20a is C 1 -C 8 -alkyl (e.g. n-propyl, n-butyl, hexyl, pentyl, or 6-Me-heptyl), (C 3 -C 12 -cycloalkyl)-C 1 -C 4 -alkyl (e.g. cyclopropyl-methyl), C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl (e.g. 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxy-ethyl, 1-methyl-2-methoxy-ethyl, 3-methoxy-propyl, 3-ethoxy-propyl, or 3-isopropoxy-propyl), (optionally substituted C 6 -C 12 -aryl)-C 1 -C 4 -alkyl (e.g. benzyl, (4-F-phenyl)methyl, (3-Cl-phenyl)methyl, (4-Cl-phenyl)methyl, (3,4-diF-phenyl)methyl, (3-Cl-4-F-phenyl)methyl, (3-CF 3 -phenyl)methyl, (2-Cl-4-CF 3 -phenyl)methyl, (2-Cl-5-CF 3 -phenyl)methyl, or (3-OCF 3 -phenyl)methyl)), (optionally substituted C 3 -C 12 -heterocyclyl)-C 1 -C 4 -alkyl (e.g. (pyrid-2-yl)-methyl or (4-CF 3 -pyrid-2-yl)methyl), optionally substituted C 6 -C 12 -aryl (e.g. phenyl, 4-F-phenyl, 3-Cl-phenyl, 3,5-diCl-phenyl, 3-Cl-4-F-phenyl, 3-Me-phenyl, 3-CF 3 -phenyl, 4-CF 3 -phenyl, 2-Cl-3-CF 3 -phenyl, 3-Cl-4-CF 3 -phenyl, 3-CF 3 -4-F-phenyl, 3-CN-phenyl, 3-OCF 3 -phenyl, 3-OCF 3 -4-F-phenyl, or 3-OCF 3 -4-Cl-phenyl), or optionally substituted C 3 -C 12 -heterocyclyl (e.g. 4-CF 3 -pyrid-2-yl). R 20b is hydrogen or C 1 -C 8 -alkyl (e.g. methyl, ethyl, or n-butyl); R 21 is C 6 -C 12 -aryl (e.g phenyl); and R 5a , R 5b
are hydrogen; or
R 5a , R 5b
together with the carbon atom to which they are bound may form a C═O.
Further particular compounds of the present invention are the individual pyrrolidine derivatives of the formula (Id2) as listed in the following tables 1 to 8 and physiologically tolerated salts thereof:
Table 1 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is H and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 2 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is F and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 3 Compounds of the formula (Id2) wherein X is ═CH—, Z is ═CR 13c —, R 13c is Cl and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 4 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is H and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 5 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is F and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
Table 6 Compounds of the formula (Id2) wherein X is ═N—, Z is ═CR 13c —, R 13c is Cl and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-44).
Table 7 Compounds of the formula (Id2) wherein X is ═N—, Z is ═N— and the combination of R 1 , R 3a and R 13b for a compound in each case corresponds to one line of Table A (A-1 to A-344).
R 1
R 3a
R 13b
A-1.
1-methyl-1,3-diazol-4-yl
Ph
H
A-2.
1-methyl-1,3-diazol-4-yl
4-F—Ph
H
A-3.
1-methyl-1,3-diazol-4-yl
2-THP
H
A-4.
1-methyl-1,3-diazol-4-yl
2-THF
H
A-5.
1-methyl-1,2,3-triazol-4-yl
Ph
H
A-6.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
H
A-7.
1-methyl-1,2,3-triazol-4-yl
2-THP
H
A-8.
1-methyl-1,2,3-triazol-4-yl
2-THF
H
A-9.
1-methyl-1,3-diazol-4-yl
Ph
F
A-10.
1-methyl-1,3-diazol-4-yl
4-F—Ph
F
A-11.
1-methyl-1,3-diazol-4-yl
2-THP
F
A-12.
1-methyl-1,3-diazol-4-yl
2-THF
F
A-13.
1-methyl-1,2,3-triazol-4-yl
Ph
F
A-14.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
F
A-15.
1-methyl-1,2,3-triazol-4-yl
2-THP
F
A-16.
1-methyl-1,2,3-triazol-4-yl
2-THF
F
A-17.
1-methyl-1,3-diazol-4-yl
Ph
Cl
A-18.
1-methyl-1,3-diazol-4-yl
4-F—Ph
Cl
A-19.
1-methyl-1,3-diazol-4-yl
2-THP
Cl
A-20.
1-methyl-1,3-diazol-4-yl
2-THF
Cl
A-21.
1-methyl-1,2,3-triazol-4-yl
Ph
Cl
A-22.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
Cl
A-23.
1-methyl-1,2,3-triazol-4-yl
2-THP
Cl
A-24.
1-methyl-1,2,3-triazol-4-yl
2-THF
Cl
A-25.
1-methyl-1,3-diazol-4-yl
Ph
—CH 3
A-26.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 3
A-27.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 3
A-28.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 3
A-29.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 3
A-30.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 3
A-31.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 3
A-32.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 3
A-33.
1-methyl-1,3-diazol-4-yl
Ph
—CH 2 CH 3
A-34.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 2 CH 3
A-35.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 2 CH 3
A-36.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 2 CH 3
A-37.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 2 CH 3
A-38.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 2 CH 3
A-39.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 2 CH 3
A-40.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 2 CH 3
A-41.
1-methyl-1,3-diazol-4-yl
Ph
—CH 2 CH 2 CH 3
A-42.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH 2 CH 2 CH 3
A-43.
1-methyl-1,3-diazol-4-yl
2-THP
—CH 2 CH 2 CH 3
A-44.
1-methyl-1,3-diazol-4-yl
2-THF
—CH 2 CH 2 CH 3
A-45.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH 2 CH 2 CH 3
A-46.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH 2 CH 2 CH 3
A-47.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH 2 CH 2 CH 3
A-48.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH 2 CH 2 CH 3
A-49.
1-methyl-1,3-diazol-4-yl
Ph
—CH(CH 3 ) 2
A-50.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH(CH 3 ) 2
A-51.
1-methyl-1,3-diazol-4-yl
2-THP
—CH(CH 3 ) 2
A-52.
1-methyl-1,3-diazol-4-yl
2-THF
—CH(CH 3 ) 2
A-53.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH(CH 3 ) 2
A-54.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH(CH 3 ) 2
A-55.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH(CH 3 ) 2
A-56.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH(CH 3 ) 2
A-57.
1-methyl-1,3-diazol-4-yl
Ph
—C(CH 3 ) 3
A-58.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—C(CH 3 ) 3
A-59.
1-methyl-1,3-diazol-4-yl
2-THP
—C(CH 3 ) 3
A-60.
1-methyl-1,3-diazol-4-yl
2-THF
—C(CH 3 ) 3
A-61.
1-methyl-1,2,3-triazol-4-yl
Ph
—C(CH 3 ) 3
A-62.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—C(CH 3 ) 3
A-63.
1-methyl-1,2,3-triazol-4-yl
2-THP
—C(CH 3 ) 3
A-64.
1-methyl-1,2,3-triazol-4-yl
2-THF
—C(CH 3 ) 3
A-65.
1-methyl-1,3-diazol-4-yl
Ph
—CF 3
A-66.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CF 3
A-67.
1-methyl-1,3-diazol-4-yl
2-THP
—CF 3
A-68.
1-methyl-1,3-diazol-4-yl
2-THF
—CF 3
A-69.
1-methyl-1,2,3-triazol-4-yl
Ph
—CF 3
A-70.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CF 3
A-71.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CF 3
A-72.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CF 3
A-73.
1-methyl-1,3-diazol-4-yl
Ph
—CHF 2
A-74.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CHF 2
A-75.
1-methyl-1,3-diazol-4-yl
2-THP
—CHF 2
A-76.
1-methyl-1,3-diazol-4-yl
2-THF
—CHF 2
A-77.
1-methyl-1,2,3-triazol-4-yl
Ph
—CHF 2
A-78.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CHF 2
A-79.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CHF 2
A-80.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CHF 2
A-81.
1-methyl-1,3-diazol-4-yl
Ph
—CH(OH)(CF 3 )CH 3
A-82.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CH(OH)(CF 3 )CH 3
A-83.
1-methyl-1,3-diazol-4-yl
2-THP
—CH(OH)(CF 3 )CH 3
A-84.
1-methyl-1,3-diazol-4-yl
2-THF
—CH(OH)(CF 3 )CH 3
A-85.
1-methyl-1,2,3-triazol-4-yl
Ph
—CH(OH)(CF 3 )CH 3
A-86.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CH(OH)(CF 3 )CH 3
A-87.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CH(OH)(CF 3 )CH 3
A-88.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CH(OH)(CF 3 )CH 3
A-89.
1-methyl-1,3-diazol-4-yl
Ph
cyclopropyl
A-90.
1-methyl-1,3-diazol-4-yl
4-F—Ph
cyclopropyl
A-91.
1-methyl-1,3-diazol-4-yl
2-THP
cyclopropyl
A-92.
1-methyl-1,3-diazol-4-yl
2-THF
cyclopropyl
A-93.
1-methyl-1,2,3-triazol-4-yl
Ph
cyclopropyl
A-94.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
cyclopropyl
A-95.
1-methyl-1,2,3-triazol-4-yl
2-THP
cyclopropyl
A-96.
1-methyl-1,2,3-triazol-4-yl
2-THF
cyclopropyl
A-97.
1-methyl-1,3-diazol-4-yl
Ph
phenyl
A-98.
1-methyl-1,3-diazol-4-yl
4-F—Ph
phenyl
A-99.
1-methyl-1,3-diazol-4-yl
2-THP
phenyl
A-100.
1-methyl-1,3-diazol-4-yl
2-THF
phenyl
A-101.
1-methyl-1,2,3-triazol-4-yl
Ph
phenyl
A-102.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
phenyl
A-103.
1-methyl-1,2,3-triazol-4-yl
2-THP
phenyl
A-104.
1-methyl-1,2,3-triazol-4-yl
2-THF
phenyl
A-105.
1-methyl-1,3-diazol-4-yl
Ph
4-Cl-phenyl
A-106.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-Cl-phenyl
A-107.
1-methyl-1,3-diazol-4-yl
2-THP
4-Cl-phenyl
A-108.
1-methyl-1,3-diazol-4-yl
2-THF
4-Cl-phenyl
A-109.
1-methyl-1,2,3-triazol-4-yl
Ph
4-Cl-phenyl
A-110.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-Cl-phenyl
A-111.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-Cl-phenyl
A-112.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-Cl-phenyl
A-113.
1-methyl-1,3-diazol-4-yl
Ph
3-Cl-phenyl
A-114.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-Cl-phenyl
A-115.
1-methyl-1,3-diazol-4-yl
2-THP
3-Cl-phenyl
A-116.
1-methyl-1,3-diazol-4-yl
2-THF
3-Cl-phenyl
A-117.
1-methyl-1,2,3-triazol-4-yl
Ph
3-Cl-phenyl
A-118.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-Cl-phenyl
A-119.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-Cl-phenyl
A-120.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-Cl-phenyl
A-121.
1-methyl-1,3-diazol-4-yl
Ph
4-F-phenyl
A-122.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-F-phenyl
A-123.
1-methyl-1,3-diazol-4-yl
2-THP
4-F-phenyl
A-124.
1-methyl-1,3-diazol-4-yl
2-THF
4-F-phenyl
A-125.
1-methyl-1,2,3-triazol-4-yl
Ph
4-F-phenyl
A-126.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-F-phenyl
A-127.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-F-phenyl
A-128.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-F-phenyl
A-129.
1-methyl-1,3-diazol-4-yl
Ph
3-F-phenyl
A-130.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-F-phenyl
A-131.
1-methyl-1,3-diazol-4-yl
2-THP
3-F-phenyl
A-132.
1-methyl-1,3-diazol-4-yl
2-THF
3-F-phenyl
A-133.
1-methyl-1,2,3-triazol-4-yl
Ph
3-F-phenyl
A-134.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-F-phenyl
A-135.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-F-phenyl
A-136.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-F-phenyl
A-137.
1-methyl-1,3-diazol-4-yl
Ph
2-F-phenyl
A-138.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-F-phenyl
A-139.
1-methyl-1,3-diazol-4-yl
2-THP
2-F-phenyl
A-140.
1-methyl-1,3-diazol-4-yl
2-THF
2-F-phenyl
A-141.
1-methyl-1,2,3-triazol-4-yl
Ph
2-F-phenyl
A-142.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-F-phenyl
A-143.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-F-phenyl
A-144.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-F-phenyl
A-145.
1-methyl-1,3-diazol-4-yl
Ph
2-Me-phenyl
A-146.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-Me-phenyl
A-147.
1-methyl-1,3-diazol-4-yl
2-THP
2-Me-phenyl
A-148.
1-methyl-1,3-diazol-4-yl
2-THF
2-Me-phenyl
A-149.
1-methyl-1,2,3-triazol-4-yl
Ph
2-Me-phenyl
A-150.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-Me-phenyl
A-151.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-Me-phenyl
A-152.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-Me-phenyl
A-153.
1-methyl-1,3-diazol-4-yl
Ph
3-Me-phenyl
A-154.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-Me-phenyl
A-155.
1-methyl-1,3-diazol-4-yl
2-THP
3-Me-phenyl
A-156.
1-methyl-1,3-diazol-4-yl
2-THF
3-Me-phenyl
A-157.
1-methyl-1,2,3-triazol-4-yl
Ph
3-Me-phenyl
A-158.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-Me-phenyl
A-159.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-Me-phenyl
A-160.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-Me-phenyl
A-161.
1-methyl-1,3-diazol-4-yl
Ph
4-Me-phenyl
A-162.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-Me-phenyl
A-163.
1-methyl-1,3-diazol-4-yl
2-THP
4-Me-phenyl
A-164.
1-methyl-1,3-diazol-4-yl
2-THF
4-Me-phenyl
A-165.
1-methyl-1,2,3-triazol-4-yl
Ph
4-Me-phenyl
A-166.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-Me-phenyl
A-167.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-Me-phenyl
A-168.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-Me-phenyl
A-169.
1-methyl-1,3-diazol-4-yl
Ph
—CN
A-170.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—CN
A-171.
1-methyl-1,3-diazol-4-yl
2-THP
—CN
A-172.
1-methyl-1,3-diazol-4-yl
2-THF
—CN
A-173.
1-methyl-1,2,3-triazol-4-yl
Ph
—CN
A-174.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—CN
A-175.
1-methyl-1,2,3-triazol-4-yl
2-THP
—CN
A-176.
1-methyl-1,2,3-triazol-4-yl
2-THF
—CN
A-177.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 3
A-178.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 3
A-179.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 3
A-180.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 3
A-181.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 3
A-182.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 3
A-183.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 3
A-184.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 3
A-185.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 CH 3
A-186.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 CH 3
A-187.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 CH 3
A-188.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 CH 3
A-189.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 CH 3
A-190.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 CH 3
A-191.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 CH 3
A-192.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 CH 3
A-193.
1-methyl-1,3-diazol-4-yl
Ph
—O(CH 2 ) 2 CH 3
A-194.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O(CH 2 ) 2 CH 3
A-195.
1-methyl-1,3-diazol-4-yl
2-THP
—O(CH 2 ) 2 CH 3
A-196.
1-methyl-1,3-diazol-4-yl
2-THF
—O(CH 2 ) 2 CH 3
A-197.
1-methyl-1,2,3-triazol-4-yl
Ph
—O(CH 2 ) 2 CH 3
A-198.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O(CH 2 ) 2 CH 3
A-199.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O(CH 2 ) 2 CH 3
A-200.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O(CH 2 ) 2 CH 3
A-201.
1-methyl-1,3-diazol-4-yl
Ph
—O(CH 2 ) 3 CH 3
A-202.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O(CH 2 ) 3 CH 3
A-203.
1-methyl-1,3-diazol-4-yl
2-THP
—O(CH 2 ) 3 CH 3
A-204.
1-methyl-1,3-diazol-4-yl
2-THF
—O(CH 2 ) 3 CH 3
A-205.
1-methyl-1,2,3-triazol-4-yl
Ph
—O(CH 2 ) 3 CH 3
A-206.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O(CH 2 ) 3 CH 3
A-207.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O(CH 2 ) 3 CH 3
A-208.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O(CH 2 ) 3 CH 3
A-209.
1-methyl-1,3-diazol-4-yl
Ph
—OCH(CH 3 ) 2
A-210.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH(CH 3 ) 2
A-211.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH(CH 3 ) 2
A-212.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH(CH 3 ) 2
A-213.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH(CH 3 ) 2
A-214.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH(CH 3 ) 2
A-215.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH(CH 3 ) 2
A-216.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH(CH 3 ) 2
A-217.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (CH 3 ) 2
A-218.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (CH 3 ) 2
A-219.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (CH 3 ) 2
A-220.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (CH 3 ) 2
A-221.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (CH 3 ) 2
A-222.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (CH 3 ) 2
A-223.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (CH 3 ) 2
A-224.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (CH 3 ) 2
A-225.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (pyrrolyd-3yl)
A-226.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-3yl)
A-227.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (pyrrolyd-3yl)
A-228.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (pyrrolyd-3yl)
A-229.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (pyrrolyd-3yl)
A-230.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-3yl)
A-231.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (pyrrolyd-3yl)
A-232.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (pyrrolyd-3yl)
A-233.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (pyrrolyd-2yl)
A-234.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-2yl)
A-235.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (pyrrolyd-2yl)
A-236.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (pyrrolyd-2yl)
A-237.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (pyrrolyd-2yl)
A-238.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (pyrrolyd-2yl)
A-239.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (pyrrolyd-2yl)
A-240.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (pyrrolyd-2yl)
A-241.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 (azetid-3yl)
A-242.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 (azetid-3yl)
A-243.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 (azetid-3yl)
A-244.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 (azetid-3yl)
A-245.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 (azetid-3yl)
A-246.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 (azetid-3yl)
A-247.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 (azetid-3yl)
A-248.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 (azetid-3yl)
A-249.
1-methyl-1,3-diazol-4-yl
Ph
—OCF 3
A-250.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCF 3
A-251.
1-methyl-1,3-diazol-4-yl
2-THP
—OCF 3
A-252.
1-methyl-1,3-diazol-4-yl
2-THF
—OCF 3
A-253.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCF 3
A-254.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCF 3
A-255.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCF 3
A-256.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCF 3
A-257.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 CF 3
A-258.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 CF 3
A-259.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 CF 3
A-260.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 CF 3
A-261.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 CF 3
A-262.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 CF 3
A-263.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 CF 3
A-264.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 CF 3
A-265.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclobutyl
A-266.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclobutyl
A-267.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclobutyl
A-268.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclobutyl
A-269.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclobutyl
A-270.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclobutyl
A-271.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclobutyl
A-272.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclobutyl
A-273.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclopentyl
A-274.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclopentyl
A-275.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclopentyl
A-276.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclopentyl
A-277.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclopentyl
A-278.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclopentyl
A-279.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclopentyl
A-280.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclopentyl
A-281.
1-methyl-1,3-diazol-4-yl
Ph
—O-cyclohexyl
A-282.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—O-cyclohexyl
A-283.
1-methyl-1,3-diazol-4-yl
2-THP
—O-cyclohexyl
A-284.
1-methyl-1,3-diazol-4-yl
2-THF
—O-cyclohexyl
A-285.
1-methyl-1,2,3-triazol-4-yl
Ph
—O-cyclohexyl
A-286.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—O-cyclohexyl
A-287.
1-methyl-1,2,3-triazol-4-yl
2-THP
—O-cyclohexyl
A-288.
1-methyl-1,2,3-triazol-4-yl
2-THF
—O-cyclohexyl
A-289.
1-methyl-1,3-diazol-4-yl
Ph
—OCH 2 Ph
A-290.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—OCH 2 Ph
A-291.
1-methyl-1,3-diazol-4-yl
2-THP
—OCH 2 Ph
A-292.
1-methyl-1,3-diazol-4-yl
2-THF
—OCH 2 Ph
A-293.
1-methyl-1,2,3-triazol-4-yl
Ph
—OCH 2 Ph
A-294.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—OCH 2 Ph
A-295.
1-methyl-1,2,3-triazol-4-yl
2-THP
—OCH 2 Ph
A-296.
1-methyl-1,2,3-triazol-4-yl
2-THF
—OCH 2 Ph
A-297.
1-methyl-1,3-diazol-4-yl
Ph
—SO 2 Me
A-298.
1-methyl-1,3-diazol-4-yl
4-F—Ph
—SO 2 Me
A-299.
1-methyl-1,3-diazol-4-yl
2-THP
—SO 2 Me
A-300.
1-methyl-1,3-diazol-4-yl
2-THF
—SO 2 Me
A-301.
1-methyl-1,2,3-triazol-4-yl
Ph
—SO 2 Me
A-302.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
—SO 2 Me
A-303.
1-methyl-1,2,3-triazol-4-yl
2-THP
—SO 2 Me
A-304.
1-methyl-1,2,3-triazol-4-yl
2-THF
—SO 2 Me
A-305.
1-methyl-1,3-diazol-4-yl
Ph
2-pyridyl
A-306.
1-methyl-1,3-diazol-4-yl
4-F—Ph
2-pyridyl
A-307.
1-methyl-1,3-diazol-4-yl
2-THP
2-pyridyl
A-308.
1-methyl-1,3-diazol-4-yl
2-THF
2-pyridyl
A-309.
1-methyl-1,2,3-triazol-4-yl
Ph
2-pyridyl
A-310.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
2-pyridyl
A-311.
1-methyl-1,2,3-triazol-4-yl
2-THP
2-pyridyl
A-312.
1-methyl-1,2,3-triazol-4-yl
2-THF
2-pyridyl
A-313.
1-methyl-1,3-diazol-4-yl
Ph
3-pyridyl
A-314.
1-methyl-1,3-diazol-4-yl
4-F—Ph
3-pyridyl
A-315.
1-methyl-1,3-diazol-4-yl
2-THP
3-pyridyl
A-316.
1-methyl-1,3-diazol-4-yl
2-THF
3-pyridyl
A-317.
1-methyl-1,2,3-triazol-4-yl
Ph
3-pyridyl
A-318.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
3-pyridyl
A-319.
1-methyl-1,2,3-triazol-4-yl
2-THP
3-pyridyl
A-320.
1-methyl-1,2,3-triazol-4-yl
2-THF
3-pyridyl
A-321.
1-methyl-1,3-diazol-4-yl
Ph
4-pyridyl
A-322.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-pyridyl
A-323.
1-methyl-1,3-diazol-4-yl
2-THP
4-pyridyl
A-324.
1-methyl-1,3-diazol-4-yl
2-THF
4-pyridyl
A-325.
1-methyl-1,2,3-triazol-4-yl
Ph
4-pyridyl
A-326.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-pyridyl
A-327.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-pyridyl
A-328.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-pyridyl
A-329.
1-methyl-1,3-diazol-4-yl
Ph
5-pyrimidyl
A-330.
1-methyl-1,3-diazol-4-yl
4-F—Ph
5-pyrimidyl
A-331.
1-methyl-1,3-diazol-4-yl
2-THP
5-pyrimidyl
A-332.
1-methyl-1,3-diazol-4-yl
2-THF
5-pyrimidyl
A-333.
1-methyl-1,2,3-triazol-4-yl
Ph
5-pyrimidyl
A-334.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
5-pyrimidyl
A-335.
1-methyl-1,2,3-triazol-4-yl
2-THP
5-pyrimidyl
A-336.
1-methyl-1,2,3-triazol-4-yl
2-THF
5-pyrimidyl
A-337.
1-methyl-1,3-diazol-4-yl
Ph
4-piperidyl
A-338.
1-methyl-1,3-diazol-4-yl
4-F—Ph
4-piperidyl
A-339.
1-methyl-1,3-diazol-4-yl
2-THP
4-piperidyl
A-340.
1-methyl-1,3-diazol-4-yl
2-THF
4-piperidyl
A-341.
1-methyl-1,2,3-triazol-4-yl
Ph
4-piperidyl
A-342.
1-methyl-1,2,3-triazol-4-yl
4-F—Ph
4-piperidyl
A-343.
1-methyl-1,2,3-triazol-4-yl
2-THP
4-piperidyl
A-344.
1-methyl-1,2,3-triazol-4-yl
2-THF
4-piperidyl
Further particular compounds of the present invention are the pyrrolidine derivatives disclosed in preparation examples and physiologically tolerated salts thereof. These include for each preparation example the exemplified compound as well as the corresponding free base and any other physiologically tolerated salts of the free base (if the exemplified compound is a salt), or any physiologically tolerated salt of the free base (if the exemplified compound is a free base). These further include enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
It is noted that the following compounds of formula (Il)
wherein R 1 , R 3a and R 14 are as defined in the following table
R 1 R 3a R 14 4-F—Ph 4-CF 3 —Ph 2-OMe—Ph 2-OMe-4-OCF 3 —Ph 4-F-phenyl 4-CF 3 -phenyl 2-OMe-phenyl 2-OMe-4-OCF 3 -phenyl 4-F-phenyl 4-CF 3 -phenyl 4-F-phenyl 4-F-phenyl 2-OMe-phenyl 4-F-phenyl 4-OMe-phenyl 4-F-phenyl 2-furyl 4-F-phenyl
are described in Baumann Marcus, et al., ACS Comb. Sci. 2011, 13, 405-413 and therefore the present invention does not encompass these compounds and physiologically tolerated salts thereof per se. However, the present invention does encompass pharmaceutical compositions comprising such pyrrolidine derivatives, and the use of such pyrrolidine derivatives for therapeutic purposes, as described herein.
The compounds of the formula (I) can be prepared by analogy to methods which are well known in the art. Suitable methods for the preparation of compounds of formula (I) are outlined in the following schemes.
The process depicted in scheme 1 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —N(CR 9a R 9b ) n4 R 13 , —NHCOR 14 or —NHCONHR 16a .
In scheme 1, the variables R 1 , R 3a , R 13 , R 14 , R 16a are as defined herein.
As shown in the above scheme 1, the intermediate of general formula 1 can be alkylated to give compounds of formula 2. Alternatively, 1 can be transformed to compounds 3 via reductive amination or can yield amides of formula 4 by coupling reaction with the corresponding acid. Reaction with isocyanates of formula 5 affords compounds of formula 6.
The process depicted in scheme 2 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —(CR 7c R 7d ) n2 NR 11a R 11b or —CONR 20a R 20b .
As shown in the above scheme 2, cycloaddition followed by benzyl deprotection afford pyrrolidine 7. Sulfonylation, methylester hydrolysis and coupling with amines yield compounds of formula 8. Reduction of compounds of formula 8 affords the corresponding amines 9.
The process depicted in scheme 3 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —(CR 7a R 7b ) n1 NR 10 .
As shown in the above scheme 3, reduction with LiAlH 4 of intermediate 10 affords the corresponding alcohol which then can be transformed in the alkoxy derivatives of formula 11 via Mitsunobu coupling.
The process depicted in scheme 4 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —COR 19 .
As shown in the above scheme 4, the pyrrolidine intermediate 12 can be converted in the corresponding Weinreb amide. Treatment of the Weinreb amide with Grignard reagents affords the ketones of formula 13.
The process depicted in scheme 5 is useful for obtaining pyrrolidine derivatives, wherein Y 1 is >CH— and R 4 is —O(CR 9c R 9d ) n5 R 18 .
As shown in the above scheme 5, alkylation of alcohol 14 affords the compounds of formula 15.
Schemes 1 to 5 refer also to the preparation of the enantiomers, diastereomers, tautomers and any other isomeric forms of said compounds, be they explicitly or implicitly disclosed.
The acid addition salts of the pyrrolidine derivatives of formula (I) are prepared in a customary manner by mixing the free base with a corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
The compounds of the formula (I) are capable of inhibiting the activity of glycine transporter, in particular glycine transporter 1 (GlyT1).
The utility of the compounds in accordance with the present invention as inhibiting the glycine transporter activity, in particular GlyT1 activity, may be demonstrated by methodology known in the art. For instance, human GlyT1c expressing recombinant hGlyT1c_5_CHO cells can be used for measuring glycine uptake and its inhibition (IC 50 ) by a compound of formula (I).
Amongst the compounds of the formula (I) those are preferred which achieve effective inhibition at low concentrations. In particular, compounds of the formula (I) are preferred which inhibit glycine transporter 1 (GlyT1) at a level of IC 50 <1 μMol, more preferably at a level of IC 50 <0.5 μMol, particularly preferably at a level of IC 50 <0.2 μMol and most preferably at a level of IC 50 <0.1 μMol.
The compounds of formula (I) display good to moderate metabolic stability.
The metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (R S Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved. The stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver. The slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the compounds of the invention is increased. Increased and/or longer-lasting active levels may lead to a better activity of the compound in therapeutic treatment. In addition, an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degradation in the liver (so-called first pass effect). An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.
Amongst the compounds of the formula (I) those are particularly preferred which display good to moderate metabolic stability towards human liver microsomes. In particular, compounds of the formula (I) are preferred which display a microsomal clearance at a level of mCl <1000 μl/min/mg, more preferably at a level of mCl <500 μl/min/mg, particularly preferably at a level of mCl <100 μl/min/mg and most preferably at a level of mCl <50 μl/min/mg.
The compounds of the formula (I) according to the present invention are thus useful as pharmaceuticals.
The present invention therefore also relates to pharmaceutical compositions which comprise an inert carrier and a compound of the formula (I).
The present invention also relates to the use of the compounds of the formula (I) in the manufacture of a medicament for inhibiting the glycine transporter GlyT1, and to corresponding methods of inhibiting the glycine transporter GlyT1.
The NMDA receptor is central to a wide range of CNS processes, and its role in a variety of diseases in humans or other species has been described. GlyT1 inhibitors slow the removal of glycine from the synapse, causing the level of synaptic glycine to rise. This in turn increases the occupancy of the glycine binding site on the NMDA receptor, which increases activation of the NMDA receptor following glutamate release from the presynaptic terminal Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus known to be useful in treating a variety of neurologic and psychiatric disorders. Further, glycine A receptors play a role in a variety of diseases in humans or other species. Increasing extracellular glycine concentrations by inhibiting glycine transport may enhance the activity of glycine A receptors. Glycine transport inhibitors and in particular inhibitors of the glycine transporter GlyT1 are thus useful in treating a variety of neurologic and psychiatric disorders.
The present invention thus further relates to the use of the compounds of the formula (I) for the manufacture of a medicament for treating a neurologic or psychiatric disorder, and to corresponding methods of treating said disorders.
According to a particular embodiment, the disorder is associated with glycinergic or glutamatergic neurotransmission dysfunction.
According to a further particular embodiment, the disorder is one or more of the following conditions or diseases: schizophrenia or a psychotic disorder including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder, including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or cognitive impairment including age related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including attention-deficit hyperactivity disorder (ADHD) and conduct disorder; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias [including tremor (such as rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia)]; urinary incontinence; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders including insomnia and narcolepsy.
According to a further particular embodiment, the disorder is pain, in particular chronic pain and especially neuropathic pain.
Pain can be classified as acute and chronic pain. Acute pain and chronic pain differ in their etiology, pathophysiology, diagnosis and treatment.
Acute pain, which occurs following tissue injury, is self-limiting, serves as an alert to ongoing tissue damage and following tissue repair it will usually subside. There are minimal psychological symptoms associated with acute pain apart from mild anxiety. Acute pain is nociceptive in nature and occurs following chemical, mechanical and thermal stimulation of A-delta and C-polymodal pain receptors.
Chronic pain, on the other hand, serves no protective biological function. Rather than being the symptom of tissue damage it is a disease in its own right. Chronic pain is unrelenting and not self-limiting and can persist for years, perhaps decades after the initial injury. Chronic pain can be refractory to multiple treatment regimes. Psychological symptoms associated with chronic pain include chronic anxiety, fear, depression, sleeplessness and impairment of social interaction. Chronic non-malignant pain is predominantly neuropathic in nature and involves damage to either the peripheral or central nervous systems.
Acute pain and chronic pain are caused by different neuro-physiological processes and therefore tend to respond to different types of treatments. Acute pain can be somatic or visceral in nature. Somatic pain tends to be a well localised, constant pain and is described as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing or colicky in nature. Examples of acute pain include post-operative pain, pain associated with trauma and the pain of arthritis. Acute pain usually responds to treatment with opioids or non-steroidal anti-inflammatory drugs.
Chronic pain, in contrast to acute pain, is described as burning, electric, tingling and shooting in nature. It can be continuous or paroxysmal in presentation. The hallmarks of chronic pain are chronic allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus that normally does not ellicit a painful response, such as a light touch. Hyperalgesia is an increased sensitivity to normally painful stimuli. Primary hyperalgesia occurs immediately within the area of the injury. Secondary hyperalgesia occurs in the undamaged area surrounding the injury. Examples of chronic pain include complex regional pain syndrome, pain arising from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension-type headache, pain arising from mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic disease, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain arising as a consequence of or associated with stress or depressive illness.
Although opioids are cheap and effective, serious and potentially life-threatening side effects occur with their use, most notably respiratory depression and muscle rigidity. In addition the doses of opioids which can be administered are limited by nausea, emesis, constipation, pruritis and urinary retention, often resulting in patients electing to receive sub-optimal pain control rather than suffer these distressing side-effects. Furthermore, these side-effects often result in patients requiring extended hospitalisation. Opioids are highly addictive and are scheduled drugs in many territories.
The compounds of formula (I) are particularly useful in the treatment of schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorder including autistic disorder, attention deficit disorders including Attention-Deficit/Hyperactivity Disorder, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.
Particular cognitive disorders are dementia, delirium, amnestic disorders and cognitive impairment including age-related cognitive decline.
Particular anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder and panic attack.
Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
Particular neurologic disorders that can be treated with the compounds of the formula (I) include in particular a cognitive disorder such as dementia, cognitive impairment, attention deficit hyperactivity disorder.
Particular psychiatric disorders that can be treated with the compounds of the formula (I) include in particular an anxiety disorder, a mood disorder such as depression or a bipolar disorder, schizophrenia, a psychotic disorder.
Within the context of the treatment, the use according to the invention of the compounds of the formula (I) involves a method. In this method, an effective quantity of one or more compounds or the formula (I), as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other drugs or drug-containing preparations.
The invention also relates to the manufacture of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being. Thus, the compounds of the formula (I) are customarily administered in the form of pharmaceutical compositions which comprise an inert carrier (e.g. a pharmaceutically acceptable excipient) together with at least one compound according to the invention and, where appropriate, other drugs. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.
When producing the compositions, the compounds according to the invention are optionally mixed or diluted with one or more carriers (excipients). Carriers (excipients) can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
Suitable carriers (excipients) are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.
The compounds of formula (I) may also be suitable for combination with other therapeutic agents.
Thus, the present invention also provides:
i) a combination comprising a compound of formula (I) with one or more further therapeutic agents;
ii) a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient;
iii) the use of a combination as defined in i) above in the manufacture of a medicament for treating or preventing a disorder, disease or condition as defined herein;
iv) a combination as defined in i) above for use in treating or preventing a disorder, disease or condition as defined herein;
v) a kit-of-parts for use in the treatment of a disorder, disease or condition as defined herein, comprising a first dosage form comprising a compound of formula (I) and one or more further dosage forms each comprising one or more further therapeutic agents for simultaneous therapeutic administration,
vi) a combination as defined in i) above for use in therapy;
vii) a method of treatment or prevention of a disorder, disease or condition as defined herein comprising administering an effective amount of a combination as defined in i) above;
viii) a combination as defined in i) above for treating or preventing a disorder, disease or condition as defined herein.
The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) and at least one further therapeutic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component.
The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides a combination of compounds of formula (I) and at least one antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder. The invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a psychotic disorder.
In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
Antipsychotic agents include both typical and atypical antipsychotic drugs. Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldlinc, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from OrthoMcNeil); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE®, from Pfizer); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman); perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE (D; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used. Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease.
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by adjunctive therapeutic administration of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for adjunctive therapeutic administration for the treatment of a neurodegenerative disorder such as Alzheimer Disease in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of a neurodegenerative disorder such as Alzheimer Disease by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides the use of at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease. The invention further provides at least one agent suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease for simultaneous therapeutic administration with compounds of formula (I) in the treatment of a neurodegenerative disorder such as Alzheimer Disease.
Examples of agents suitable for the treatment of a neurodegenerative disorder such as Alzheimer Disease that are useful in the present invention include, but are not limited to: cholinesterase inhibitors, agents targeting nicotinic or muscarinic acethylcholine receptors, NMDA receptors, amyloid formation, mitochondrial dysfunctions, disease associated calpain activity, neuroinflamation, tumor necrosis factor receptors, NF-kappaB, peroxisome proliferator activator receptor gamma, Apolipoprotein E variant 4 (ApoE4), disease-associated increase of the HPA axis, epileptic discharges, vascular dysfunction, vascular risk factors, and oxidative stress.
Suitable cholinesterase inhibitors which may be used in combination with the compounds of the inventions include for example tacrine, donepezil, galantamine and rivastigmine.
Suitable NMDA receptors targeting agents which may be used in combination with the compounds of the inventions include for example memantine.
Suitable agents affecting increased HPA axis activity which may be used in combination with the compounds of the inventions include for example CRF1 antagonists or V1b antagonists.
In a further aspect therefore, the invention provides a method of treatment of pain by adjunctive therapeutic administration of compounds of formula (I) to a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. In a further aspect, the invention provides the use of compounds of formula (I) in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain. The invention further provides compounds of formula (I) for use for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of at least one agent suitable for the treatment of pain.
In a further aspect, the invention provides a method of treatment of pain by adjunctive therapeutic administration of at least one agent suitable for the treatment of pain to a patient receiving therapeutic administration of compounds of formula (I). In a further aspect, the invention provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I). The invention further provides at least one agent suitable for the treatment of pain for adjunctive therapeutic administration for the treatment of pain in a patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides a method of treatment of pain by simultaneous therapeutic administration of compounds of formula (I) in combination with at least one agent suitable for the treatment of pain. The invention further provides the use of a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of pain. The invention further provides a combination of compounds of formula (I) and at least one agent suitable for the treatment of pain for simultaneous therapeutic administration in the treatment of pain. The invention further provides the use of compounds of formula (I) in the manufacture of a medicament for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides compounds of formula (I) for use for simultaneous therapeutic administration with at least one agent suitable for the treatment of pain in the treatment of pain. The invention further provides the use of at least one agent suitable for the treatment of pain in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain. The invention further provides at least one agent suitable for the treatment of pain for simultaneous therapeutic administration with compounds of formula (I) in the treatment of pain.
Examples of agents suitable for the treatment of pain that are useful in the present invention include, but are not limited to: NSAIDs (Nonsteroidal Antiinflammatory Drugs), anticonvulsant drugs such as carbamazepine and gabapentin, sodium channel blockers, antidepressant drugs, cannabinoids and local anaesthetics.
Suitable agents used in combination with the compounds of the inventions include for example celecoxib, etoricoxib, lumiracoxib, paracetamol, tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion, gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam, remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil, pethidine, diamorphine and butorphanol.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as cognitive enhancers.
Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
The following examples serve to explain the invention without limiting it.
The compounds were characterized by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
Preparation Examples
Abbreviations:
APCI for atmospheric pressure chemical ionization; AcOH for acetic acid; Boc for tert-butoxy carbonyl; Bu for butyl; DCI for desorption chemical ionization; DCM for dichloromethane; dimethylsulfoxide for dimethyl sulfoxide; eq for equivalent(s); ESI for electrospray ionization; EtOAc for ethyl acetate; HATU for [o-(azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate]; HCl for hydrochloric acid; HPLC for high performance liquid chromatography; id for internal diameter; LCMS for liquid chromatography/mass spectrometry; MeOH for methanol; MgSO4 for magnesium sulfate; MP for macroporous resin; NaOAc for sodium acetate; PS for polymer supported; psi for pounds per square inch; SFC for supercritical fluid chromatography; SPE for solid phase extraction, and tBu for tert-butyl.
Definitions:
Similarly indicates that that reactants may be substituted for other the reactants described, the temperature may vary by 50° C., the equivalents may differ by upto 2 fold, or any combination thereof.
Preparative HPLC Procedure:
Samples were purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm) A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). With specified samples, ammonium acetate was used instead of trifluoroacetic acid. A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SATIN module, Alltech Varex III evaporative light-scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software, automated using an Abbott developed Visual Basic application for fraction collector control and fraction tracking. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan LCQ using 70:30 methanol:10 mM NH 4 OH(aqueous) at a flow rate of 0.8 mL/minute. Loop-injection mass spectra were acquired using a Finnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquid handler for fraction injection controlled by an Abbott developed Visual Basic application.
For chiral compounds the absolute configuration is indicated in their chemical names. A chemical name with “trans” or no stereochemistry information does not refer to a chiral compound (even if the corresponding formula depicts a chiral compound).
Example 1
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 1A
To a solution of trans-tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate (0.305 g, 1.163 mmol) and 2-chloro-3-(trifluoromethyl)benzoic acid (0.261 g, 1.163 mmol) in dichloromethane (4.65 ml) was added triethylamine (0.486 ml, 3.49 mmol) and HATU (0.663 g, 1.744 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned with water, the organic fraction was collected, and the aqueous fraction was washed with dichloromethane. The organic fractions were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (Anal ogix IntelliFlash 280, SF15-12) eluting with 30% ethyl acetate hexanes to afford the title compound. MS (ESI) m/z 469.3 [M+H] +
Example 1B
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide hydrochloride
To a solution of Example 1A (0.32 g, 0.682 mmol) in dioxane (0.682 ml) was added HCl in dioxane (4M, 1.706 ml, 6.82 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the solid was triturated twice with dichloromethane and the solvent was evaporated to afford the title compound. MS (ESI) m/z 369.2 [M+H]+
Example 1C
2-chloro-N-(trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
To a solution of Example 1B (0.075 g, 0.185 mmol) in dichloromethane (0.740 ml) was added triethylamine (0.077 ml, 0.555 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.033 g, 0.185 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. The crude product was purified by HPLC to afford the title compound. MS (ESI) m/z 513.1 [M+H]+
Example 2
2-chloro-N-{trans-4-(4-methoxyphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 2A trans-1-benzyl-3-(4-methoxyphenyl)-4-nitropyrrolidine
To a solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (5.09 g, 28.4 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (8.07 g, 34.0 mmol) in 75 mL of dichloromethane at 0° C. under nitrogen was added trifluoroacetic acid (388 mg, 3.4 mmol) in one portion. The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was then partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic fraction was collected. The aqueous portion was washed with additional dichloromethane and the combined organic fractions were washed with water, brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (7:3 hexane:ethyl acetate) to afford the title compound. MS (DCI) m/z 313.1 (M+H) + .
Example 2B
trans-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine
Example 2A (4.85 mg, 15.5 mmol) and tetrahydrofuran (100 mL) were added to a Raney nickel water slurry (Grace 2800, 5.00 g) in a stainless steel reactor. The vessel was pressurized with 30 psi of hydrogen and shaken at room temperature for 16 hours. The mixture was filtered through a nylon membrane concentrated and purified on a silica gel flash column (95:5 dichloromethane: 2N ammonia in methanol) to afford the title compound as colorless oil. MS (DCI) m/z 283.1 (M+H) + .
Example 2C
tert-Butyl trans-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-ylcarbamate
To a solution of 2.5 g (8.86 mmol) of Example 2B in tetrahydrofuran (20 ml) was added saturated sodium bicarbonate solution (20 ml) followed by di-tert-butyl dicarbonate (1.0 M solution in tetrahydrofuran, 10 ml, 10.0 mmol) at room temperature under nitrogen. The reaction was stirred for 1 hour and then partitioned between ethyl acetate and water. The organic fraction was collected. The aqueous portion was washed several additional times with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (3:2 ethyl acetate hexane) to afford the title compound. MS (DCI) m/z 383.2 (M+H) + .
Example 2D
tert-butyl (3S,4R)-4-(4-methoxyphenyl)pyrrolidin-3-ylcarbamate
Example 2C (2.65 mg, 6.93 mmol) and 2,2,2-trifluoroethanol or tetrahydrofuran (40 mL) were added to 20% Pd(OH) 2 /C (50% water, 0.530 g) in a stainless steel reactor. The vessel was pressurized with 30 psi of hydrogen and shaken at 50° C. for 30 minutes. The mixture was filtered through a nylon membrane, and the product was purified on a silica gel column (95:5 dichloromethane:2N ammonia in methanol) to afford the title compound. MS (DCI) m/z 293.1 (M+H) + .
Example 2E
tert-butyl (trans-4-(4-methoxyphenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)carbamate
To a solution of the product from Example 2D (154 mg, 0.53 mmol), and triethylamine (152 mg, 1.5 mmol) in dichloromethane (8 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (108 mg, 0.60 mmol) in one portion at room temperature. 4-(dimethylamino)-pyridine (4 mg, 0.03 mmol) was added and the reaction stirred for two hours at room temperature. The reaction was concentrated and purified on a silica gel flash column (97:3 dichloromethane: 2N ammonia in methanol) to afford the title compound. MS (DCI) m/z 425.1 (M+H) + .
Example 2F
trans-4-(4-methoxyphenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-amine
The product from Example 2E (195 mg, 0.46 mmol) was stirred with 1,4-dioxane (4 ml) and hydrogen chloride in 1,4-dioxane (4M, 4 ml, 16.0 mmol) at room temperature under nitrogen overnight. The reaction was concentrated and concentrated to afford the title compound as the hydrochloride salt. MS (DCI) m/z 325.0 (M+H) + .
Example 2G
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
A mixture of Example 2F, 2-chloro-3-(trifluoromethyl)benzoic acid (101 mg, 0.45 mmol), and N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) was stirred in a 1:1 solution of pyridine and N,N-dimethylformamide (5 ml) at room temperature under nitrogen for 16 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic fraction was collected and the aqueous portion was washed with additional ethyl acetate. The combined organic fractions were washed with water, brine and dried over sodium sulfate. The mixture was filtered, concentrated and purified on a silica gel flash column (95:5 dichloromethane 2N ammonia in methanol) to afford the title compound. MS (ESI) m/z 543.2 (M+H) + .
Example 3
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 3A
trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 3B
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 2G substituting Example 3A for Example 2F. MS (ESI) m/z 531 (M+H) + .
Example 4
2-chloro-N-[trans-1-(methylsulfonyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
Example 4A
(E)-1,2,4-trifluoro-5-(2-nitrovinyl)benzene
A stirred solution containing 2,4,5-trifluorobenzaldehyde (16.2 g, 80.1 mmol), ammonium acetate (17.3 g, 225 mmol), nitromethane (12.2 mL, 225 mmol), and acetic acid (75 mL) was heated to 100° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic fraction was collected and the aqueous fraction was washed with dichloromethane. The organic fractions were combined and washed with sodium bicarbonate (aq.), brine, and water. The organic fraction was dried with sodium sulfate and purified via flash chromatography (0-100% EtOAc/hexanes) to provide the title compound.
Example 4B
trans-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Examples 2A-2B substituting Example 4A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 4C
N-(trans-1-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)-2-chloro-3-(trifluoromethyl)benzamide
To a stirred solution of Example 4B (3.3 g, 10.7 mmol) in a 1:1 dimethylformamide:pyridine solution (20 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (2.9 g, 12.9 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.85 g, 15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrate. The reaction mixture was partitioned between, EtOAc (100 mL) and 1 M HCl (200 mL). The organic layer was collected. The aqueous fraction was washed with EtOAc (100 mL). The organic fractions were combined. Purification via flash chromatography (0-100% EtOAc/hexanes) provided the title compound.
2-chloro-3-(trifluoromethyl)-N-(trans-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)benzamide
To a stirred solution of Example 4C (3.4 g, 6.63 mmol) in dichloroethane was added 1-chloroethyl carbonochloridate (1.0 g, 7.29 mmol). The reaction mixture was stirred at 80° C. for 2 hours. Some precipitate was collected via filtration to provide the title compound. The filtrate was concentrated and purified via flash chromatography (0-30% methanol/DCM) to provide the title compound.
Example 4E
2-chloro-N-[(trans-1-(methylsulfonyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
To a stirred solution of Example 4D (50 mg, 0.18 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction mixture stirred at 60° C. for 18 hours. The reaction mixture was then concentrated and purified via HPLC. MS (ESI) m/z 501 (M+H) + .
Example 13
2-chloro-N-{trans-4-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-chloro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene. MS (DCI) m/z 547.0 (M+H) +
Example 14
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
Example 14A
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 14B
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 15
3-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 16
4-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-chloro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 445 (M+H) + .
Example 17
2-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 18
3-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 19
4-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-fluoro-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 429 (M+H) + .
Example 20
2-methoxy-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-methoxy-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 21
3-methoxy-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-methoxy-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 22
2-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 23
3-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 24
4-methyl-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-methyl-benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 25
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 411 (M+H) + .
Example 26
2,4-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2,4-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 27
2-chloro-4-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-4-fluorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 463 (M+H) + .
Example 29
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,4-diphenylpyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 14A (50 mg, 0.15 mmol), bromobenzene (23 mg, 0.15 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (5.0 mg, 0.02 mmol), tris(dibenzylidene-acetone)dipalladium(0) (6.7 mg, 7.3 μmol), sodium tert-butoxide (18 mg, 0.19 mmol), and toluene (1 mL). The reaction mixture was stirred at 80° C. for 3 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 383 (M+H) + .
Example 30
3,5-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 31
2,3-dichloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2,3-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 32
2-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 33
3-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 34
4-cyano-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-cyanobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 436 (M+H) + .
Example 35
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 36
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 37
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 479 (M+H) + .
Example 38
2-chloro-N-([trans-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
Example 38A
(trans)-1-benzyl-4-phenylpyrrolidin-3-amine
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Examples 2A-2B substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 38B
2-chloro-N-(trans-4-phenylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C-4D substituting Example 38A for Example 4B.
Example 38C
2-chloro-N-[trans-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4E substituting Example 38B for Example 4D and substituting 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 581 (M+H) + .
Example 39
2-chloro-N-[trans-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (EST) m/z 577 (M+H) + .
Example 40
2-chloro-N-{trans-1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tort-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 561 (M+H) + .
Example 41
2-chloro-N-{trans-1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 527 (M+H) + .
Example 42
2-chloro-N-{trans-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 527 (M+H) + .
Example 43
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 44
2-chloro-N-{trans-1-[(6-methoxypyridin-3-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 6-methoxypyridine-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 540 (M+H) + .
Example 45
2-chloro-N-[trans-4-phenyl-1-(pyridin-3-ylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting pyridine-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 510 (M+H) + .
Example 46
2-chloro-N-[trans-4-phenyl-1-(1-pyrazol-4-ylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1H-pyrazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 47
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-5-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 48
2-chloro-N-{trans-1-[(5-chloro-1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 5-chloro-1-methyl-1H-imidazole-4-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 547 (M+H) + .
Example 49
2-chloro-N-{trans-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4E substituting Example 38B for tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and substituting 1-methyl-1H-pyrazole-3-sulfonyl chloride for methanesulfonyl chloride. MS (ESI) m/z 513 (M+H) + .
Example 50
trans-N-(4-methoxyphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 29 substituting 1-bromo-4-methoxybenzene for bromobenzene. MS (ESI) m/z 413 (M+H) + .
Example 51
3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 3-bromobenzenenitrile for bromobenzene. MS (EST) m/z 408 (M+H) + .
Example 52
4-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 4-bromobenzenenitrile for bromobenzene. MS (ESI) m/z 408 (M+H) + .
Example 53
3-fluoro-4-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 29 substituting 4-bromo-3-fluorobenzonitrile for bromobenzene. MS (ESI) m/z 426 (M+H) + .
Example 54
2-chloro-N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 530.9 (M+H) +
Example 55
2-chloro-N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures as described in Example 2 substituting (E)-1-fluoro-3-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 531.2 (M+H) +
Example 56
2-chloro-N-{trans-4-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to procedures described in Example 2 substituting (E)-1-chloro-3-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 547.5 (M+H) +
Example 57
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylphenyl)-4-phenylpyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 14A as a hydrochloric salt (100 mg, 0.30 mmol), 1-bromo-2-methylbenzene (55 mg, 0.32 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (10 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.02 mmol), sodium tert-butoxide (70 mg, 0.729 mmol), and toluene (2 mL). The reaction mixture was stirred at 80° C. for 6 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 397 (M+H) + .
Example 58
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 397 (M+H) + .
Example 59
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(4-methylphenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 397 (M+H) + .
Example 60
2-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 2-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 513 (M+H) + .
Example 61
3-chloro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 14A for Example 4B and substituting 3-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 513 (M+H) + .
Example 62
2-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 2-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 531 (M+H) + .
Example 63
3-chloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 3-chloro-4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 531 (M+H) + .
Example 64
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 497 (M+H) + .
Example 65
3,5-dichloro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the conditions described in Example 4C substituting Example 3A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 497 (M+H) + .
Example 66
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 67
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 68
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 69
trans-N-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 70
trans-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (APCI) m/z 401 (M+H) + .
Example 71
trans-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 72
3-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromo-benzenonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 73
trans-N-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-2-chlorobenzene for 1-bromo-2-methylbenzene. MS (APCI) m/z 418 (M+H) + .
Example 74
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 417 (M+H) + .
Example 75
trans-N-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 417 (M+H) + .
Example 76
4-fluoro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (APCI) m/z 426 (M+H) + .
Example 77
2-fluoro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-2-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 78
3-fluoro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-fluorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 426 (M+H) + .
Example 79
2-chloro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 80
3-chloro-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 81
4-chloro-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-chlorobenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 442 (M+H) + .
Example 82
4-methyl-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-4-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 83
2-methyl-3-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-2-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 84
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A. MS (ESI) m/z 415 (M+H) + .
Example 85
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 415 (M+H) + .
Example 86
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(4-methylphenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-methylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 415 (M+H) + .
Example 87
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 88
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 89
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 90
trans-N-(2-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 91
trans-N-(3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 92
trans-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 93
trans-N-(2-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 94
trans-N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 95
trans-N-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 100
2-methoxy-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-methoxybenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 438 (M+H) + .
Example 101
3-methyl-5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 3-bromo-5-methylbenzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 422 (M+H) + .
Example 102
5-({trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-2-(trifluoromethoxy)benzonitrile
The title compound was prepared similarly to the conditions described in Example 57 substituting 5-bromo-2-(trifluoromethoxy)benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 476 (M-CH 3 ) + .
Example 115
2-chloro-N-{trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedures described in Example 2 substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene in Example 2A. MS (DCI) m/z 547.2 (M+H) + .
Example 122
N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
Example 122A
trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting ethanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 122B
N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 427 (M+H) + .
Example 123
3,5-dichloro-N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 427 (M+H) + .
Example 124
2-chloro-N-[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 122A for Example 4B. MS (ESI) m/z 461 (M+H) + .
Example 125
N-[trans-4-phenyl-1-(propyl sulfonyl)pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
Example 125A
The title compound was prepared as an HCl salt similarly to the procedures described for Examples 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting propanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 125B
N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 125A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 126
3,5-dichloro-N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]benzamide
The title compound was prepared similarly to Example 4C substituting Example 125A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 441 (M+H) + .
Example 127
2-chloro-N-[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 125A for Example 4B. MS (ESI) m/z 475 (M+H) + .
Example 128
N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 128A
trans-1-(cyclopropylmethylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2A-2F substituting (E)-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting cyclopropylmethanesulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 128B
N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (EST) m/z 453 (M+H) + .
Example 129
3,5-dichloro-N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 453 (M+H) + .
Example 130
2-chloro-N-{trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to Example 4C substituting Example 128A for Example 4B. MS (ESI) m/z 487 (M+H) + .
Example 131
3-{[trans-1-(ethylsulfonyl)-4-phenylpyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 122A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 356 (M+H) + .
Example 132
3-{[trans-4-phenyl-1-(propylsulfonyl)pyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 125A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 370 (M+H) + .
Example 133
3-({trans-1-[(cyclopropylmethyl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 128A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 382 (M+H) + .
Example 134
N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 134A
trans-1-(4-methoxyphenylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 4-methoxybenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 134B
N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B and substituting 4-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 505 (M+H) + .
Example 135
3,5-dichloro-N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 505 (M+H) + .
Example 136
2-chloro-N-{trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 134A for Example 4B. MS (ESI) m/z 539 (M+H) + .
Example 137
3-({trans-1-[(4-methoxyphenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 134A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 142
3,5-dichloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]benzamide
Example 142A
trans-4-phenyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to Example 2A-2F substituting (E)(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 142B
3,5-dichloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 142A for Example 4B and substituting 3,5-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 543 (M+H) + .
Example 143
2-chloro-N-[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 142A for Example 4B. MS (ESI) m/z 577 (M+H) + .
Example 144
3-{[trans-4-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-3-yl]amino}benzonitrile
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 142A for Example 14A and substituting 3-bromo-benzonitrile for 1-bromo-2-methylbenzene. MS (ESI) m/z 472 (M+H) + .
Example 145
4-{[trans-3-benzyl-4-phenylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 145A
(1-benzyl-4-phenylpyrrolidin-3-yl)(phenyl)methanone
A solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (5.9 g, 0.025 mole) in dichloromethane (30 mL) was stirred under nitrogen, in an ice/methanol bath. Chalcone (4.16 g, 0.02 mole) was added dropwise and the mixture was stirred in the cold bath overnight. The reaction mixture was washed with aqueous sodium bicarbonate, brine, and dried over sodium sulfate. The solvent was evaporated to provide the title compound. MS (ESI) m/z 342 [M+H] + .
Example 145B
3-benzyl-4-phenylpyrrolidine hydrochloride
Example 145A (8.5 g, 0.025 mole) was hydrogenated with 10% Pd/C (0.25 g) in methanol (200 mL). The reaction mixture was filtered, dissolved in methanol (100 mL) and passed through Amberlite resin. The filtrate was concentrated, redissolved in toluene and concentrated. This procedure was repeated several times until the residue was dry. MS (ESI) m/z 338 [M+H] + .
Example 145C
4-(trans-3-benzyl-4-phenylpyrrolidin-1-ylsulfonyl)-1-methyl-1H-imidazole
To a solution of Example 145B (0.0767 g, 0.280 mmol) in dichloromethane (1.121 ml) was added triethylamine (0.156 ml, 1.121 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.051 g, 0.280 mmol), The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated. The crude material was purified by HPLC to afford the title compound. MS (ESI) m/z 382.2 [M+H] + .
Example 148
trans-N-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a stirred solution of Example 3A (100 mg, 0.28 mmol) in a buffer 4 pH solution (5 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added benzaldehyde (24 mg, 0.22 mmol) and MgSO 4 (334 mg, 2.77 mmol). The reaction was allowed to stir for 1 hour at room temperature before MgSO 4 was removed via filtration. To the filtrate was added MP-cyanoborohydride (2.19 mmol/g, 380 mg, 0.83 mmol) and the reaction was allowed to stir for 24 hours. The resin was removed via filtration and purification via HPLC provided the title compound. MS (ESI) m/z 415 (M+H) + .
Example 149
trans-N-[2-chloro-3-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chloro-3-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 150
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 151
trans-N-[3-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 152
3-[({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)methyl]benzonitrile
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-cyanobenzaldehyde for benzaldehyde. MS (ESI) m/z 440 (M+H) + .
Example 153
trans-4-(4-fluorophenyl)-N-(2-methylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 154
trans-4-(4-fluorophenyl)-N-(3 ethylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 155
trans-4-(4-fluorophenyl)-N-(4-methylbenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-methylbenzaldehyde for benzaldehyde. MS (ESI) m/z 429 (M+H) + .
Example 156
trans-N-(4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 157
(cis)-N-benzyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 157A
1-benzyl-3-(benzylamino)-4-chloro-1H-pyrrole-2,5-dione
To a stirred solution of 3,4-dichlorofuran-2,5-dione (5 g, 30 mmol) in acetic acid (17 mL) was added benzylamine (3.2 g, 30 mmol) and the reaction was stirred at room temperature for 1 hour. More benzylamine (3.2 g, 30 mmol) was added and the reaction was heated to 100° C. for 2 hours. The reaction mixture was concentrated. The mixture was neutralized with aqueous sodium hydroxide and partitioned with ethyl acetate. The organic fraction was collected and concentrated. Purification via flash chromatography (0-60% EtOAc/hexanes) provided the title compound.
Example 157B
1-benzyl-3-(benzylamino)-4-chloro-1H-pyrrole-2,5-dione
To a solution of Example 157A (5.5 g, 16.8 mmol) in 1,2-dimethoxyethane (60 mL) was added phenylboronic acid (2.46 g, 20.2 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (691 mg, 1.68 mmol), palladium(II) acetate (189 mg, 0.848 mmol), and potassium carbonate (2 M, 16.8 mL, 33.7 mmol). The reaction mixture was refluxed for 2 hours. The reaction was partitioned between water and EtOAc. The organic layer was collected and concentrated. Purification via flash chromatography (0-80% EtOAc/hexanes) provided the title compound.
Example 157C
tert-butyl benzyl (1-benzyl-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-3-yl)carbamate
To a stirred solution of Example 157B (4.13 g, 11.2 mmol) and triethylamine (113 mg, 1.12 mmol) in dichloromethane (50 mL) at 0° C. was added di-tert-butyl dicarbonate (1 M in tetrahydrofuran, 12.3 mL, 12.3 mmol) and N,N-dimethylpyridin-4-amine (137 mg, 1.12 mmol). The reaction was allowed to warm to room temperature after 1 hour and stirred at room temperature for 24 hours. More di-tert-butyl dicarbonate (1 M in tetrahydrofuran, 3 mL, 3 mmol) was added and the reaction mixture stirred for 2 more hours. The reaction mixture was then concentrated. Purification via flash chromatography (0-10% methanol/DCM) provided the title compound.
Example 157D
tert-butyl benzyl(cis-1-benzyl-2,5-dioxo-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 157C (25 mg, 0.053 mmol) in trifluoroethane (4 ml) in a 50 ml pressure bottle was added 20% Pd(OH) 2 /C, wet (6.25 mg, 0.045 mmol). The reaction mixture stirred for 16 hours at 30 psi hydrogen and 50° C. The mixture was filtered through a nylon membrane and the filtrate was concentrated to provide the title compound.
Example 157E
tert-butyl benzyl((cis)-1-benzyl-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 157D (2.5 g, 5.3 mmol) in tetrahydrofuran (50 mL) was added borane (1 M in tetrahydrofuran, 21.3 mL, 21.3 mmol). The reaction mixture was heated to 70° C. for 18 hours. The reaction was cooled to 50° C. and methanol (20 mL) was added slowly. The reaction mixture stirred for 1 hour. The reaction mixture was concentrated. Purification via flash chromatography (0-100% EtOAc/hexanes) provided the title compound.
Example 157F
tert-butyl benzyl((cis)-4-phenylpyrrolidin-3-yl)carbamate
To a pressure vial was added Example 157E (801 mg, 1.810 mmol), tetrahydrofuran (20 ml) and Pd(OH) 2 /C, (20%, wet, 160 mg, 1.141 mmol) and the reaction mixture was stirred for 16 hours at 30 psi of hydrogen at 50° C. The mixture was filtered through a nylon membrane and the filtrate was concentrated to provide the title compound.
Example 157G
(cis)-N-benzyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2E-2F substituting Example 157F for Example 2D. MS (ESI) m/z 397 (M+H) + .
Example 158
trans-N-(3,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 159
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 160
trans-N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 161
trans-N-(3,4-dichlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1,2-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 162
trans-N-(4-chloro-3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-chloro-2-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 163
trans-N-(2,3-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 164
trans-N-(2,5-di fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 165
trans-N-(2,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 166
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2,3,4-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2,3,4-trifluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 455 (M+H) + .
Example 167
trans-4-(4-fluorophenyl)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 168
trans-4-(4-fluorophenyl)-N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 169
trans-4-(4-fluorophenyl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-2-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 487 (M+H) + .
Example 170
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-isopropylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 443 (M+H) + .
Example 171
trans-N-(3-tert-butylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-tert-butylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 457 (M+H) + .
Example 172
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 173
trans-N-[3-chloro-4-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-chloro-1-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 174
trans-N-(3-chloro-5-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chloro-5-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 175
trans-N-(3-chloro-4,5-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-chloro-4,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 471 (M+H) + .
Example 176
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 177
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromopyridine hydrochloride for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 178
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 179
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 180
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 181
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 182
4-{[3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 182A
2-(3-chlorobenzyl)-3-(4-fluorophenyl)-4-nitrobutanal
To a solution of (E)-1-fluoro-4-(2-nitrovinyl)benzene (1 g, 6.0 mmol) in dichloromethane (10 mL) was added 3-(3-chlorophenyl)propanal (1 g, 5.9 mmol), triethylamine (50 mL), and L-proline (50 mg, 0.43 mmol). The mixture was allowed to stir for 16 hours and the crude material was purified by silica gel column chromatography e(25% ethyl acetate/hexanes) to provide the title compound (4:1 mixture of 2 diastereomers).
Example 182B
3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidine
To a solution of Example 182A (0.92 g, 2.7 mmol) in methanol (5 mL) was added 50% acetic acid (aq) (5 mL) followed by zinc (6×200 mg, 19 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol). The mixture was allowed to stir for 30 minutes. Sodium hydroxide (1 M) was added to adjust the pH value to 8. Ethyl acetate was added and the solution partitioned. The organic fraction was collected and concentrated to provide the crude title compound.
Example 182C
4-{[3-(3-chlorobenzyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
To a solution of Example 182B (289 mg, 1.0 mmol) in dichloromethane (5 mL) was added triethylamine (130 mg, 1.3 mmol), and 1-methyl-1H-imidazole-4-sulfonyl chloride (180 mg, 1.0 mmol). The mixture was allowed to stir for 20 minutes and purified by silica gel column chromatography (100% ethyl acetate). The product was recrystallized in ethyl acetate to provide the title compound. MS (ESI) m/z 434/436 (3:1) (M+H) + .
Example 183
2-chloro-N-{(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
Example 183A
A 20 mL pressure vial was charged with Example 157 (891.1 mg, 2.247 mmol), ethanol (6 mL) and dihydroxypalladium (60.2 mg, 0.429 mmol). The mixture was stirred under 60 psi of hydrogen at 50° C. for 1.5 hours. Another 60 mg of catalyst was added, and the hydrogenation was continued for 2 hours more. The mixture was filtered through a polypropylene membrane and concentrated to provide the title compound.
Example 183B
2-chloro-N-{(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-3-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 183A for Example 4B. MS (ESI) m/z 513 (M+H) + .
Example 184
(cis)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,4-diphenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 183A for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 383 (M+H) + .
Example 185
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
Example 185A
(E)-1-fluoro-3-(2-nitrovinyl)benzene
A stirred solution containing 3-fluorobenzaldehyde (9.95 g, 80.1 mmol), ammonium acetate (17.3 g, 225 mmol), nitromethane (12.2 mL, 225 mmol), and acetic acid (75 mL) was heated to 100° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic fraction was collected and the aqueous fraction was washed with dichloromethane. The organic fractions were combined and washed with sodium bicarbonate (aq.), brine, and water. The organic fraction was dried with sodium sulfate and purification via flash chromatography (10% EtOAc/hexanes) provided the title compound.
Example 185B
trans-4-(3-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as the HCl salt similarly to the procedures described in Example 2A-2F substituting Example 185A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 185C
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 186
trans-N,4-bis(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 187
trans-4-(3-fluorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 188
trans-N-(3-chlorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 189
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-(trifluoromethane)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 190
trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-(trifluoromethane)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 191
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 4-bromopyridine hydrochloride for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 192
trans-N-(3,4-dichlorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3,4-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 193
trans-N-(4-chloro-3-fluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-4-chloro-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 194
trans-N-(3-chloro-4-fluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 195
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 196
N-{trans-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 197
trans-N-(3,4-difluorophenyl)-4-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 185B for Example 14A and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 198
trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl) sulfonyl]-N-phenylpyrrolidin-3-amine
Example 198A
trans-4-(2-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-(2-nitrovinyl)benzene.
Example 198B
trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting bromobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 401 (M+H) + .
Example 199
trans-4-(2-fluorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 200
trans-4-(2-fluorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 201
trans-N-(3-chlorophenyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 202
trans-N-(4-chlorophenyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 203
N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 204
N-{trans-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 198A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 205
4-{[3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 205A
2-(2-bromobenzyl)-3-(2-bromophenyl)-4-nitrobutanal
The title compound was prepared using the conditions described in Example 182A substituting (E)-1-bromo-2-(2-nitrovinyl)benzene for (E)-1-fluoro-4-(2-nitrovinyl)benzene and 3-(2-bromophenyl)propanal for 3-(3-chlorophenyl)propanal.
Example 205B
3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidine
The title compound was prepared using the conditions described in Example 182B substituting Example 205A for Example 182A.
Example 205C
4-{[3-(2-bromobenzyl)-4-(2-bromophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the conditions described in Example 182C substituting Example 205B for Example 182B. MS (ESI) m/z 537/539/541 (1:2:1) (M+H) + .
Example 206
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanol
To a solution of Example 242C (620 mg, 1.69 mmol) in 6 mL of tetrahydrofuran at −30° C. was added lithium aluminum hydride (2N in tetrahydrofuran, 0.93 mL, 1.86 mmol). The reaction mixture stirred at −30° C. for 30 min. The reaction mixture was quenched with a saturated sodium bicarbonate solution, and the solution was partitioned with EtOAc. The organic fraction was collected, washed with water dried over sodium sulfate, and concentrated to give the title compound. MS (ESI) m/z 340.0 (M+H) + .
Example 207
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 208
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 209
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromopyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 384 (M+H) + .
Example 210
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-6-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 211
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 212
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 213
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(trifluoromethyl)pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromo-5-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 214
trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 215
trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 216
trans-N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1,2-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 217
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 218
trans-N-(3,4-dichlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-1,2-dichlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 219
trans-N-(3-chloro-4,5-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 5-bromo-1-chloro-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 220
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(propan-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-isopropylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 425 (M+H) + .
Example 221
trans-N-(3-tert-butylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-tert-butyl-benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 439 (M+H) + .
Example 222
trans-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 223
trans-N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 224
trans-N-[2-fluoro-5-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2-fluoro-5-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 225
trans-N-(3-chloro-5-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-chloro-5-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 226
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 467 (M+H) + .
Example 227
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyrimidin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-4-(trifluoromethyl)pyrimidine for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 228
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}quinolin-7-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 7-bromoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 229
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}quinolin-6-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 6-bromoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 230
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}isoquinolin-6-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 6-bromoisoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 231
trans-N-(2,3-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,3-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 232
trans-N-(2,5-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,5-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 233
trans-N-(2,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 419 (M+H) + .
Example 234
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2,3,4-trifluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-2,3,4-trifluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 437 (M+H) + .
Example 235
6-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-6-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 236
2-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-2-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 237
5-fluoro-N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 3-bromo-5-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 402 (M+H) + .
Example 238
6-fluoro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-6-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 420 (M+H) + .
Example 239
2-fluoro-N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-fluoropyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 420 (M+H) + .
Example 240
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-2-methylbenzene. MS (ESI) m/z 453 (M+H) + .
Example 241
N-{trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}isoquinolin-7-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 7-bromoisoquinoline for 1-bromo-2-methylbenzene. MS (ESI) m/z 434 (M+H) + .
Example 242
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidine-3-carboxamide
Example 242A
A solution of (E)-methyl 3-(4-fluorophenyl)acrylate (10.52 g, 58.4 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (19.41 g, 81.8 mmol) in 110 mL of dichloromethane was cooled to 0° C. Trifluoroacetic acid (0.495 ml, 6.42 mmol) was slowly added under N 2 . The reaction mixture was stirred at 0° C. for 1 hour, then stirred at room temperature for 18 hours. The reaction mixture was partitioned with saturated sodium bicarbonate. The organic fraction was collected, concentrated, and purified by flash-chromatography on silica gel (20-30% ethyl acetate in hexane) to provide the title compound. MS (ESI) m/z 314.3 (M+H) +
Example 242B
Trans-methyl 4-(4-fluorophenyl)pyrrolidine-3-carboxylate
Example 242A (17.98 g, 57.4 mmol) and tetrahydrofuran (10 ml) were added to 20% Pd(OH) 2 /C, wet (3.60 g, 25.6 mmol) in a 250 mL SS pressure bottle and stirred for 16 hours under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound. MS (ESI) m/z 224.0 (M+H) + .
Example 242C
Trans-methyl 4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxylate
To Example 242 B (12.74 g, 57.1 mmol) in 15 mL of dichloromethane were added triethylamine (12.13 g, 120 mmol) and 4-dimethylaminopyridine (0.35 g, 2.85 mmol). The reaction mixture was cooled to 0° C. 1-methyl-1H-imidazole-4-sulfonyl chloride (10.82 g, 59.9 mmol) was added portion wise at 0° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hour. The reaction mixture was partitioned with dichloromethane, and water. The organic fraction was collected, washed with water, concentrated, and purified by flash-chromatography on silica gel (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 368.0 (M+H) + .
Example 242D
Trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxylic acid
To Example 242C (3.67 g, 9.99 mmol) was added 4 mL of methanol. To this solution was added lithium hydroxide (1 M, methanol:water=5:3, 15 mL, 15 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was then treated with hydrochloric acid (1 M, aq.) until pH=5. The reaction mixture was partitioned with ethyl acetate and the organic fraction was collected. The aqueous fraction was washed with ethyl acetate (3×), and the organic fractions were combined and concentrated to provide the title product. MS (ESI) m/z 354.0 (M+H) + .
Example 242E
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-phenylpyrrolidine-3-carboxamide
To solution of Example 242D (150 mg, 0.42 mmol) in dimethylformamide/pyridine (1:1. 15 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.45 mmol) and aniline (41.5 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated purified by HPLC to provide the title product. MS (ESI) m/z 429.1 (M+H) + .
Example 243
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the same sequence of steps described in Example 242 substituting 4-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 497.0 (M+H) + .
Example 244
Trans-N-(3,5-dichlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedures described in Example 242 substituting 3,5-dichloroaniline for aniline. MS (ESI) m/z 497.1 (M+H) + .
Example 245
4-{[trans-3-(4-fluorophenyl)-4-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
To a solution of Example 206 (52 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added phenol (21.6 mg, 0.23 mmol), PS-triphenylphosphine (105 mg, 0.34 mmol, 3.2 mmol/g), and di-tert-butylazodicarboxylate (70.6 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and washed with methanol. The filtrate was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 416.1 (M+H) + .
Example 246
4-{[trans-3-[(2,4-dichlorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 2,4-dichlorophenol for phenol. MS (ESI) m/z 484.1 (M+H) + .
Example 247
4-{[trans-3-(4-fluorophenyl)-4-{[3-(trifluoromethoxy)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-(trifluoromethoxy)phenol for phenol. MS (ESI) m/z 500.1 (M+H) + .
Example 248
4-{[trans-3-[(3-chlorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-chlorophenol for phenol. MS (ESI) m/z 450.1 (M+H) + .
Example 249
4-{[trans-3-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedures described in Example 245 substituting 4-chloro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 518.2 (M+H) + .
Example 250
4-{[trans-3-{[2-chloro-3-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedures as in Example 245 substituting 2-chloro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 518.1 (M+H) + .
Example 251
4-{[trans-3-[(3-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the procedure described in Example 245 substituting 3-fluorophenol for phenol. MS (ESI) m/z 434.1 (M+H) + .
Example 252
trans-4-(2-chlorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 252A
trans-4-(2-chlorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 252B
trans-4-(2-chlorophenyl)-N-(3-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 252A for Example 14A and substituting 1-bromo-3-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 253
trans-4-(2-chlorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 253A
trans-4-(2-chlorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 3A substituting (E)-1-chloro-2-(2-nitrovinyl)benzene for (E)-(2-nitrovinyl)benzene.
Example 253B
trans-4-(2-chlorophenyl)-N-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 435 (M+H) + .
Example 254
trans-4-(2-chlorophenyl)-N-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 255
trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 256
trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 257
trans-N-(3-chloro-4-fluorophenyl)-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 469 (M+H) + .
Example 258
trans-4-(2-chlorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 503 (M+H) + .
Example 259
N-{trans-4-(2-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 253A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 486 (M+H) + .
Example 260
trans-N-(2-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 261
trans-N-(3-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 262
trans-N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-chlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 449 (M+H) + .
Example 263
trans-N-(2-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 264
trans-N-(3-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-fluorobenzaldehyde for benzaldehyde. MS (ESI) m/z 433 (M+H) + .
Example 265
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 266
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 3-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 267
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 268
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting picolinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 269
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting nicotinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 270
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-4-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting isonicotinaldehyde for benzaldehyde. MS (ESI) m/z 416 (M+H) + .
Example 271
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(phenyl)methanone
Example 271A
Trans-4-(4-fluorophenyl)-N-methoxy-N-methyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carboxamide
To a solution of Example 242D (610 mg, 1.73 mmol) in dimethylformamide (5 mL) was added triethylamine (0.52 mL, 3.71 mmol), N,O-dimethylhydroxylamine hydrochloride (236 mg. 2.42 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (665 mg, 2.07 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was collected. The aqueous fraction was washed with ethyl acetate 3 more times. The combined organic fractions were dried over sodium sulfate, concentrated, and purified by flash-chromatography on silica gel (5-10% methanol in dichloromethane (with 0.5% volume triethylamine added)) to afford the title compound. MS (ESI) m/z 397.0 (M+H) + .
Example 271B
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(phenyl)methanone
To a solution of Example 271A (113 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) was added phenylmagnesium bromide (0.57 mL, 0.57 mmol, 1.0 M in tetrahydrofuran) slowly at room temperature. The solution stirred for 1 hour. The reaction mixture was partitioned with saturated ammonium chloride (aq.) and the organic fraction was collected. The organic fraction was dried over sodium sulfate, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 414.1 (M+H) + .
Example 272
Trans-N-[2-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 2-chloro-3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 273
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 513.1 (M+H) + .
Example 274
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoro-3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 515.1 (M+H) + .
Example 275
trans-N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-chloro-4-fluoroaniline for aniline. MS (ESI) m/z 481.1 (M+H) + .
Example 276
trans-N-[3-chloro-4-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-chloro-4-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 277
1-methyl-4-[(3-phenoxy-4-phenylpyrrolidin-1-yl)sulfonyl]-1H-imidazole
To a stirred solution of tert-butyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate (200 mg, 0.76 mmol) in tetrahydrofuran (5 mL) was added (Z)-di-tert-butyl diazene-1,2-dicarboxylate (262 mg, 1.1 mmol), phenol (72 mg, 0.76 mmol), and polystyrene triphenylphosphine resin (2.37 mmol/g, 961 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 18 hours before the resin was filtered off. The filtrate was concentrated. The concentrate was dissolved in dichloromethane (2 mL) and HCl (4M in dioxane, 2 mL, 8 mmol) was added. When LCMS showed that the reaction was complete the reaction mixture was concentrated. To a stirred solution of the concentrate in pyridine (4 mL) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (165 mg, 0.91 mmol). The reaction mixture was warmed to 60° C. for 18 hours. The reaction was then concentrated. Purification via HPLC provided the title compound.
Example 278
trans-4-(2-chlorophenyl)-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 252A for Example 14A and substituting 1-bromo-3-chlorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 451 (M+H) + .
Example 279
trans-N-(2,4-dichlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 280
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 14A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 465 (M+H) + .
Example 281
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 14A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 499 (M+H) + .
Example 282
trans-N-(2,4-dichlorobenzyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 282A
trans-4-(2-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as the HCl salt similarly to the procedure described in Example 2A-2F substituting (E)-1-fluoro-2-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 282B
trans-N-(2,4-dichlorobenzyl)-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 282A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 483 (M+H) + .
Example 283
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(2-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 282A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 284
trans-4-(2-chlorophenyl)-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 252A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 501 (M+H) + .
Example 285
trans-4-(2-chlorophenyl)-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 252A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 533 (M+H) + .
Example 286
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)pyrrolidin-3-amine
Example 286A
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(pyridin-3-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-3-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 286B
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting 286A for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 466 (M+H) + .
Example 287
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 288
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-(trifluoromethyl)pyridin-4-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 3A for Example 14A and substituting 4-bromo-2-(trifluoromethyl)pyridine for 1-bromo-2-methylbenzene. MS (ESI) m/z 470 (M+H) + .
Example 289
Trans-N-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting phenylmethanamine for aniline. MS (ESI) m/z 443.1 (M+H) + .
Example 290
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
To a solution of Example 242E (106.7 mg, 0.25 mmol) in dry tetrahydrofuran (0.7 mL) under argon, was added borane dimethyl sulfide complex (0.5 mL, 1.0 mmol, 2M in tetrahydrofuran). The reaction mixture was stirred at 60° C. for 5 hours and stirred at room temperature for 18 hours. Hydrochloric acid (0.5 mL of 0.5 N HCl) was carefully added. The reaction mixture was refluxed for 2 hours, then treated with sodium hydroxide (1N) to pH=8-9. The reaction mixture was portioned with ethyl acetate. The organic fraction was collected. The aqueous fraction was washed with dichloromethane. The organic fractions were combined, dried over sodium sulfate, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 415.1 (M+H) + .
Example 291
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
The title compound was prepared using the procedure described in Example 290 substituting Example 243 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 292
3,5-dichloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared using the procedure described in Example 290 substituting Example 244 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 293
4-{[trans-3-(4-fluorophenyl)-4-{[3-(trifluoromethyl)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 484.1 (M+H) +
Example 294
4-{[trans-3-{[2-chloro-4-(trifluoromethyl)phenoxy]methyl}-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-chloro-4-hydroxybenzotrifluoride for phenol. MS (ESI) m/z 518.1 (M+H) +
Example 295
4-{[trans-3-(4-fluorophenyl)-4-{[4-fluoro-3-(trifluoromethyl)phenoxy]methyl}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-fluoro-3-(trifluoromethyl)phenol for phenol. MS (ESI) m/z 502.1 (M+H) + .
Example 296
4-({trans-3-(4-fluorophenyl)-4-[(3-methylphenoxy)methyl]pyrrolidin-1-yl}sulfonyl)-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting m-cresol for phenol. MS (ESI) m/z 430.1 (M+H) + .
Example 297
(3-chlorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-chlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 448.1 (M+H) + .
Example 298
trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 485 (M+H) + .
Example 299
trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 501 (M+H) + .
Example 300
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}(3-methylphenyl)methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting m-tolylmagnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 428.0 (M+H) + .
Example 301
(3-fluorophenyl){(trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 432.1 (M+H) + .
Example 302
{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[3-(trifluoromethyl)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-(trifluoromethyl)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 303
(4-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methasone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 432.1 (M+H) + .
Example 304
trans-N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-chloro aniline for aniline. MS (ESI) m/z 463.0 (M+H) + .
Example 305
trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A For Example 14A and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (EST) m/z 503 (M+H) + .
Example 306
trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the conditions described in Example 57 substituting Example 3A For Example 14A and substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 519 (M+H) + .
Example 307
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
Example 307A
(E)-2-(2-nitrovinyl)pyridine
To a stirred solution of nitromethane (15.2 mL, 280 mmol) and 2-pyridinecarboxaldeyde (8.9 mL, 93 mmol) in toluene (100 mL) at room temperature was added 1,1,2,2,-tetramethylguanidine (1.2 mL, 9.3 mmol) followed by methanesulfonyl chloride (14.5 mL, 187 mmol). The reaction mixture was stirred for 5 minutes before triethylamine (26.1 mL, 187 mmol) was added. The reaction mixture was stirred for 30 minutes, then quenched with sodium bicarbonate (aq.) The organic fraction was collected. The aqueous fraction was washed with dichloromethane. All organic fractions were combined. Purification via flash chromatography provided the title compound.
Example 307B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Example 2A-2F substituting Example 307A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 307C
trans-N-(2,4-dichlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 307B for Example 3A and substituting 2,4-dichlorobenzaldehyde for benzaldehyde. MS (ESI) m/z 466 (M+H) + .
Example 308
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 286A for Example 14A and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 452 (M+H) + .
Example 309
4-{[3-(3-chlorobenzyl)-4-cyclopropylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 309A
2-(3-chlorobenzyl)-3-cyclopropyl-4-nitrobutanal
The title compound was prepared using the conditions described in Example 182A substituting (E)-(2-nitrovinyl)cyclopropane for (E)-1-fluoro-4-(2-nitrovinyl)benzene.
Example 309B
3-(3-chlorobenzyl)-4-cyclopropylpyrrolidine
The title compound was prepared using the conditions described in Example 182B substituting Example 309A for Example 182A.
Example 309
4-{[3-(3-chlorobenzyl)-4-cyclopropylpyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared using the conditions described in Example 182C substituting Example 309B for Example 182B. MS (ESI) m/z 380/382 (3:1) (M+H) + .
Example 310
N-[3-(difluoromethyl)-4-fluorophenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a 10 mL microwave vial was added 4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride (100 mg, 0.277 mmol) and premixed tris(dibenzylidene-acetone)dipalladium(0)sodium tert-butoxide 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (100 mg, 0.05:0.15:2), aldrich 715530). The solids were suspended in 1,2-dimethoxyethane, and 4-bromo-2-(difluoromethyl)-1-fluorobenzene (74.8 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) for 15 min at 130° C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% methanol/dimethylsulfoxide, and purified by HPLC to provide the title compound. MS (ESI) m/z 469 (M+H) + .
Example 311
3-chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 276 for Example 242E. MS (ESI) m/z 517.0 (M+H) + .
Example 312
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 273 for Example 242E. MS (ESI) m/z 499 (M+H) + .
Example 313
4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 274 for Example 242E. MS (ESI) m/z 501.1 (M+H) + .
Example 314
3-chloro-4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 275 for Example 242E. MS (ESI) m/z 467.1 (M+H) + .
Example 315
N-benzyl-1-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 289 for Example 242E. MS (ESI) m/z 429.1 (M+H) + .
Example 316
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting m-toluidine for aniline. MS (ESI) m/z 443.0 (M+H) +
Example 317
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide
The title compound was prepared using the procedure described in Example 242E substituting 3-(trifluoromethyl)aniline for aniline. MS (ESI) m/z 497.0 (M+H) + .
Example 318
4-{[Trans-3-[(3-chloro-4-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 3-chloro-4-fluorophenol for phenol. MS (ESI) m/z 468.1 (M+H) + .
Example 319
(4-Chloro-3-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-chloro-3-fluorophenyl) magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 466.1 (M+H) + .
Example 320
trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 286A for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 500 (M+H) + .
Example 321
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 321A
tert-butyl (3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the conditions described in Example 2A-2E substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene. A Chiral SFC separation provided the title compound. (Instrument: SFC200 Column: AD-H, 50×250 mm, 5 μm; Column Temperature: 35° C.; Mobile Phase: CO 2 /methanol/diethylamine=80200.1; Flow rate: 180 g/min; Back Pressure: 100 Bar; Wavelength: 214 nm; Cycle time: 5.1 min; Injection: 2.0 mL Sample solution: 55 g in 500 mL methanol). Retention Time=4.03 minutes.
Example 321B
(3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2F substituting Example 321A for Example 2E.
Example 321C
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 321B for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 322
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 322A
tert-butyl (3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to Example 321A. RT=5.73 minutes.
Example 322B
(3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedure described in Example 2F substituting Example 322A for Example 2E.
Example 322C
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for benzaldehyde. MS (ESI) m/z 517 (M+H) + .
Example 323
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 321B (100 mg, 0.27 mmol), 1-bromo-3-(trifluoromethoxy)benzene (67 mg, 0.27 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (9.5 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.014 mmol), sodium tert-butoxide (107 mg, 1.1 mmol), and dioxane (4 mL). The reaction mixture was stirred at 80° C. for 2 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 485 (M+H) + .
Example 324
(3S,4R)—N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-4-fluorobenzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 419 (M+H) + .
Example 325
(3S,4R)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-3-chlorobenzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 435 (M+H) + .
Example 326
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 323 substituting 1-bromo-3-(trifluoromethyl)benzene for bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 469 (M+H) + .
Example 327
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Under nitrogen, a pressure vial was charged with Example 322B (100 mg, 0.28 mmol), 1-bromo-3-(trifluoromethyl)benzene (62 mg, 0.28 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (9.5 mg, 0.03 mmol), tris(dibenzylidene-acetone)dipalladium(0) (13 mg, 0.014 mmol), sodium tert-butoxide (107 mg, 1.1 mmol), and dioxane (4 mL). The reaction mixture was stirred at 80° C. for 2 hours. Then, the reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 469 (M+H) + .
Example 328
(3R,4S)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but the reaction only stirred for 1 hour. MS (ESI) m/z 435 (M+H) + .
Example 329
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 330
(3R,4S)-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-fluorobenzene for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 419 (M+H) + .
Example 331
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-2-one
Example 331A
methyl 2-(3-chlorobenzyl)-4-nitro-3-phenylbutanoate
To a solution of diisopropylamine (210 mg, 2 mmol) in tetrahydrofurane (1 mL) at −78° C. was added butyllithium (1 mL, 2N, 2 mmol). The mixture was allowed to stir for 10 minutes. Then methyl 3-(3-chlorophenyl)propanoate in tetrahydrofurane (1 mL) was added. The mixture was allowed to stir for 30 minutes. (E)-(2-nitrovinyl)benzene in tetrahydrofuran (1 mL) was added. The mixture was allowed to stir for 1 hour, and partitioned with ammonium chloride (aq) and ethyl acetate. The organic fraction was collected and concentrated to provide the crude title compound.
Example 331B
3-(3-chlorobenzyl)-4-phenylpyrrolidin-2-one
To a solution of Example 331A in methanol (2 mL) was added an acetic acid solution (2 mL. 50% aq.), and zinc (6×130 mg, 12 mmol). The reaction mixture stirred for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and enough NaOH (1M aq.) to adjust the pH value to 10. The insoluble material was filtered off through celite. The organic fraction was collected, and dried over sodium hydroxide pellets for 16 hours. The mixture was washed with HCl(aq) and purified by silica gel flash chromatography (100% ethyl acetate) to afford the title compound.
Example 331C
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-2-one
To a solution of Example 331B (150 mg, 0.53 mmol) in tetrahydrofuran (1 mL) at −78° C. was added butyllithium (0.3 mL, 2 N, 0.6 mmol). The mixture was allowed to stir for 10 minutes. 1-Methyl-1H-imidazole-4-sulfonyl chloride (95 mg, 0.53 mmol) was added. The reaction stirred for 2 hours. The mixture was warmed to 20° C. and quenched with ammonium chloride (aq.) The mixture was extracted with ethyl acetate and purified by flash chromatography (10% methanol/ethyl acetate) followed by trituration in methanol. The precipitates were collected to afford the title compound. MS (ESI) m/z 430432 (3:1) (M+H) + .
Example 332
2-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
Example 332A
Trans-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidine-3-carb aldehyde
To a solution of Example 206 (180 mg, 0.53 mmol) in dichloromethane (2 mL) was added Dess-MartinPeriodinane (450 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated to afford the title compound. MS (EST) m/z 338.0 (M+H) + .
Example 332B
2-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-4-(trifluoromethyl)aniline
To Example 332A (150 mg, 0.45 mmol) in methanol acetate buffer (2 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added 2-chloro-4-(trifluoromethyl)aniline (104 mg, 0.53 mmol) and sodium cyanoborohydride (42 mg, 0.67 mmol). The mixture was allowed to stir overnight. It was partitioned between dichloromethane and saturated sodium bicarbonate. Purification via HPLC afford the title compound. MS (ESI) m/z 517.0 (M+H) + .
Example 333
3-Chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 304 for Example 242E. MS (EST) m/z 449.1 (M+H) + .
Example 334
N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-methylaniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 316 for Example 242E. MS (ESI) m/z 429.1 (M+H) + .
Example 335
N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethyl)aniline
The title compound was prepared using the procedure as described in Example 290 substituting Example 317 for Example 242E. MS (ESI) m/z 483.1 (M+H) + .
Example 336
4-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-6-(trifluoromethyl)pyrimidine
The title compound was prepared using the procedure as described in Example 245 substituting 6-(trifluoromethyl)pyrimidin-4-ol for phenol. MS (ESI) m/z 486.1 (M+H) + .
Example 337
Trans-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Example 337A
Trans-1-benzyl-3-cyclopropyl-4-nitropyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting (E)-(2-nitrovinyl)cyclopropane for trans-4-methoxy-beta-nitrostyrene.
Example 337B
Trans-1-benzyl-4-cyclopropylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 337A for Example 2A.
Example 337C
tert-butyl (trans-1-benzyl-4-cyclopropylpyrrolidin-3-yl)carbamate
To a solution of Example 337B (1.0 g, 4.6 mmol) in ethyl acetate (10 mL) was added di-tert-butyl dicarbonate (1.4 g, 6.4 mmol). The mixture was allowed to stir for 1 hour. The mixture was concentrated and purified by silica gel column chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 337D
tert-butyl ((trans-4-cyclopropylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 337C for 2C.
Example 337E
tert-butyl ((trans-4-cyclopropyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 337D for Example 2D.
Example 337F
Trans-4-cyclopropyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-amine
To Example 337E (0.82 g, 2.2 mmol) in dioxane (5 mL), was added hydrochloric acid (4N in dioxane, 3 mL). The mixture was stirred overnight, concentrated, and partitioned between ethyl acetate and sodium hydroxide (1M). The organic fraction was dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 337G
Trans-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
To a solution of Example 337F (135 mg, 0.5 mmol) in dioxane (1 mL) was added 1-bromo-3-(trifluoromethyl)benzene (101 mg, 0.5 mmol), tris(dibenzylidene-acetone)dipalladium(0) (46 mg, 0.05 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48 gm, 0.1 mmol), and sodium 2-methylpropan-2-olate (48 mg, 0.5 mmol). The mixture was heated at 110° C. for 2 hours, partitioned between ethyl acetate and ammonium chloride (aq), and purified by HPLC to give the title compound. MS (ESI) m/z 415 (M+H) + .
Example 338
Trans-N-(3-chlorophenyl)-4-cyclopropyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 381/383 (3:1) (M+H) + .
Example 339
4-{[3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 339A
2-(2-chlorophenyl)acetaldehyde
To 2-(2-chlorophenyl)ethanol (1 g, 6.39 mmol) in 10 mL of dichloromethane was added Dess-MartinPeriodinane (3.52 g, 8.3 mmol) at 0° C. This mixture was stirred at 0° C. for 1 hour. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated to afford the title product.
Example 339B
2-(2-Chlorophenyl)-3-(4-fluorophenyl)-4-nitrobutanal
The title compound was prepared similarly to the procedure described in Example 182A substituting Example 339A for 3-(3-chlorophenyl)propanal.
Example 339C
Trans-3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 182B substituting Example 339B for Example 182A.
Example 339D
4-{[3-(2-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 339C for Example 182 B. MS (ESI) m/z 420.3 (M+H) + .
Example 340
4-{[3-(4-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 340A
2-(4-Chlorophenyl)acetaldehyde
The title compound was prepared similarly to the procedure described in Example 339A substituting 2-(4-chlorophenyl)ethanol for 2-(2-chlorophenyl)ethanol.
Example 340B
2-(4-Chlorophenyl)-3-(4-fluorophenyl)-4-nitrobutanal
The title compound was prepared similarly to the procedure described in Example 182A substituting Example 340A for 3-(3-chlorophenyl)propanal.
Example 340C
The title compound was prepared similarly to the procedure described in Example 182B substituting Example 340B for Example 182A.
Example 340D
4-{[3-(4-chlorophenyl)-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 340C for Example 182B. MS (ESI) m/z 420.2 (M+H) + .
Example 341
2-chloro-4-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
A 10 mL microwave vial was charged with Example 322B (100 mg, 0.277 mmol) and 100 mg of premixed tris(dibenzylidene-acetone)dipalladium(0)sodium tert-butoxide/2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05:0.15:2), aldrich 715530). The solids were suspended in 1,2-dimethoxyethane and 4-bromo-2-chlorobenzonitrile (72.1 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture heated under microwave conditions for 15 min at 130° C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% MeOH/dimethylsulfoxide, and purified by reverse phase HPLC to obtain the title compound. MS (ESI) m/z 460 (M+H) + .
Example 342
2-fluoro-4-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 341 substituting 4-bromo-2-fluorobenzonitrile for 4-bromo-2-(difluoromethyl)benzonitrile. MS (ESI) m/z 444 (M+H) + .
Example 343
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylimidazolidin-2-one
Example 343A
N1-(3-chlorobenzyl)-1-phenylethane-1,2-diamine
To (3-chlorophenyl)methanamine (0.28 g, 2 mmol) in methanol (5 mL) was added (E)-(2-nitrovinyl)benzene (0.30 g, 2 mmol). The mixture was allowed to stir for 4 hours. A solution of acetic acid in water (50%, 2 mL) was added, followed by zinc (5×130 mg, 10 mmol). The mixture was allowed to stir for 1 hour and concentrated. NaOH (1 M) was added to adjust the pH to 10. Ethyl acetate was added and the solution partitioned. The organic fraction was collected, dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 343B
1-(3-chlorobenzyl)-5-phenylimidazolidin-2-one
To a solution of Example 343A in dichloromethane (5 mL) at −78° C. was added triethylamine (100 mg, 1 mmol) and triphosgene (60 mg, 0.2 mmol). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. The crude material was purified by flash chromatography (100% ethyl acetate) to afford the title compound.
Example 343C
3-(3-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylimidazolidin-2-one
To a solution of Example 343B (60 mg, 0.2 mmol) in tetrahydrofuran (1 mL) at 0° C. was added sodium hydride (40 mg, 60%, 1 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (38 mg, 0.2 mmol). The mixture was stirred for 18 hours, quenched with ammonium chloride (aq). Ethyl acetate was added then the solution partitioned. The organic fraction was collected and concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 431433 (3:1) (M+H) + .
Example 344
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 307B for Example 337F. MS (ESI) m/z 452 (M+H) + .
Example 345
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 307B for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 418420 (3:1) (M+H) + .
Example 346
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-4-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-(trifluoromethyl)pyridin-2-ol for phenol. MS (ESI) m/z 485.1 (M+H) + .
Example 347
Trans-N-(3-cyanophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-aminobenzonitrile for aniline. MS (ESI) m/z 454.1 (M+H) + .
Example 348
4-{[Trans-3-[(4-fluorophenoxy)methyl]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 245 substituting 4-fluorophenol for phenol. MS (ESI) m/z 434.1 (M+H) + .
Example 349
4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yloxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 1-bromo-3-isopropoxybenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 459 (M+H) +
Example 350
N-[4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl]pyridazin-3-amine
Example 350A
6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)pyridazin-3-amine
4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine (100 mg, 0.308 mmol), 3,6-dichloro-pyridazine (46 mg, 0.308 mmol), N,N-diisopropylethyl amine (53.8 μl, 0.308 mmol), and 4 mL ethanol were placed in a 2-5 mL microwave vial and irradiated in a microwave (Biotage Initiator™, maximum 400 Watts) for 1 hour at 175° C. The reaction contents were concentrated, redissolved in 2 mL 50% dimethylsulfoxide/methanol and purified via reverse phase HPLC to yield the title compound.
Example 350B
N-{4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridazin-3-amine
Example 350A (18 mg, 0.041 mmol) and methanol (4 ml) were added to 5% Pd/C, wet (4 mg, 0.940 μmol) and triethyl amine (8 mg, 0.082 mmol) in a 50 ml pressure bottle. The mixture stirred for 2 hours under 30 psi of hydrogen until HPLC indicated complete conversion. The mixture was filtered through a nylon membrane. Purification via HPLC provided the title compound. MS (ESI) m/z 459 (M+H) + .
Example 351
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 2-bromo-6-(trifluoromethyl)pyridine for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 470 (M+H) + .
Example 352
(3R,4S)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 4-bromo-2-chloro-1-fluorobenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 453 (M+H) + .
Example 353
(3R,4S)—N-(3-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 341 substituting 1-bromo-3-fluorobenzene for 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI) m/z 419 (M+H) + .
Example 354
Trans-N-(4-chlorobenzyl)-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 354A
Trans-1-benzyl-3-methyl-3-nitro-4-phenylpyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting Example (E)-(2-nitroprop-1-en-1-yl)benzene for 4-methoxy-beta-nitrostyrene.
Example 354B
Trans-1-benzyl-3-methyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 354A for Example 2A.
Example 354C
Trans-3-methyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 354B for 2C.
Example 354D
Trans-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 354C for Example 182B.
Example 354E
Trans-N-(4-chlorobenzyl)-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To a solution of Example 354D (100 mg, 0.28 mmol) in methanol acetate buffer (pH4, 1M, 1 mL, made from 48 g AcOH and 30.5 g NaOAc in 1 L methanol) was added 4-chlorobenzaldehyde (40 mg, 0.28 mmol) and sodium cyanoborohydride (40 mg, 0.65 mmol). The mixture was stirred for 18 hours and partitioned between ethyl acetate and NaOH (1 M). The organic fraction was collected, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 445447 (3:1) (M+H) + .
Example 355
Trans-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 479 (M+H) + .
Example 356
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 514/516 (3:1) (M+H) + .
Example 357
(3,4-Difluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,4-difluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 450.2 (M+H) + .
Example 358
Trans-N,4-bis(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoroaniline for aniline. MS (ESI) m/z 447.1 (M+H) + .
Example 359
(3,4-Dichlorophenyl) {trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,4-dichlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 360
(3,5-Dichlorophenyl) {trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3,5-dichlorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 482.1 (M+H) + .
Example 361
(3-Chloro-5-fluorophenyl){trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-chloro-5-fluorophenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 466.2 (M+H) + .
Example 362
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[3-(trifluoromethoxy)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (3-(trifluoromethoxy)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 498.1 (M+H) + .
Example 363
{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}[4-(trifluoromethoxy)phenyl]methanone
The title compound was prepared similarly to the procedure described in Example 271B substituting (4-(trifluoromethoxy)phenyl)magnesium bromide for phenylmagnesium bromide. MS (ESI) m/z 498.1 (M+H) + .
Example 364
3-[({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)amino]benzamide
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 347 for Example 242E. MS (ESI) m/z 458.1 (M+H) + .
Example 365
3-(Aminomethyl)-N-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 347 for Example 242E. MS (ESI) m/z 444.1 (M+H) + .
Example 366
4-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methoxy)-2-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 245 substituting 2-(trifluoromethyl)pyridin-4-ol for phenol. MS (ESI) m/z 485.1 (M+H) + .
Example 367
4-Fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 358 for Example 242E. MS (ESI) m/z 433.1 (M+H) + .
Example 368
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 470 (M+H) + .
Example 369
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-(trifluoromethyl)pyridin-2-amine for aniline. MS (ESI) m/z 498.1 (M+H) + .
Example 370
Trans-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluoro-3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 531.1 (M+H) + .
Example 371
Trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-chloro-3-(trifluoromethoxy)aniline for aniline. MS (ESI) m/z 547.1 (M+H) + .
Example 372
N-[4-chloro-2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]acetamide
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 3A for Example 337F and N-(2-bromo-4-chlorophenyl)acetamide for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 492/494 (3:1) (M+H) + .
Example 373
Trans-4-[(3-chlorophenyl)amino]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-ol
Example 373A
(trans)-tert-butyl 3-((3-chlorophenyl)amino)-4-hydroxypyrrolidine-1-carboxylate
A mixture of 3-chloroaniline (0.38 g, 3 mmol) and tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.56 g, 3 mmol) in ethanol (3 mL) was heated at 100° C. for 3 days. The mixture was concentrated and purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 373B
Trans-4-((3-chlorophenyl)amino)pyrrolidin-3-ol
To a solution of Example 373A (0.97 g, 3.1 mmol) in dioxane (3 mL) at 0° C. was added hydrochloric acid (4N in dioxane, 5 mL). The mixture was allowed to stir for 5 hours. Concentration provided the title compound as the hydrochloride salt.
Example 373C
Trans-4-[(3-chlorophenyl)amino]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin
To a solution of Example 373B in dichloromethane (5 mL) was added triethylamine (1 g, 10 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (540 mg, 3.0 mmol). The mixture was allowed to stir for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and NaOH (1 M). The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 357359 (3:1) (M+H) + .
Example 374
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 307B for 242D and substituting 1-(trifluoromethyl)cyclopropanecarboxylic acid for aniline. MS (ESI) m/z 444.0 (M+H) +
Example 375
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-(trifluoromethyl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 322B for Example 242D and substituting 1-(trifluoromethyl)cyclopropanecarboxylic acid for aniline. MS (ESI) m/z 461.1 (M+H) + .
Example 376
4-fluoro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 370 for Example 242E. MS (ESI) m/z 517.2 (M+H) + .
Example 377
4-chloro-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(trifluoromethoxy)aniline
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 371 for Example 242E. MS (ESI) m/z 533.2 (M+H) + .
Example 378
Trans-N-(3-chlorophenyl)-4-(4-fluorophenoxy)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a solution of Example 373 (142 mg, 0.4 mmol) in dimethylformamide (0.2 mL) was added copper(I) iodide (40 mg, 0.2 mmol), cesium carbonate (300 mg, 0.92 mmol), and 1-fluoro-4-iodobenzene (88 mg, 0.4 mmol). The mixture was stirred at 110° C. for 16 hours, then partitioned between ethyl acetate and water. The organic fraction was collected, concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 452/454 (3:1) (M+H) + .
Example 379
2-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-4-(trifluoromethyl)pyridine
Example 379A
Trans-tert-butyl 3-(4-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate
To a solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.93 g, 5 mmol) in tetrahydrofuran (5 mL) at −78° C. was added copper(I) iodide (85 mg, 0.5 mmol) then (4-fluorophenyl)magnesium bromide (7 mL, 1 M, 7 mol). The mixture was warmed to room temperature and, allowed to stir for 3 hours. The reaction mixture was partitioned with ammonium chloride (aq). The organic fraction was collected dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 379B
Trans-4-(4-fluorophenyl)pyrrolidin-3-ol
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 379A for Example 373A.
Example 379C
Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-ol
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 379B for Example 373B.
Example 379D
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-4-(trifluoromethyl)pyridine
To a solution of Example 379C (110 mg, 0.34 mmol) in dimethylsulfoxide (0.3 mL) was added potassium 2-methylpropan-2-olate (50 mg, 0.45 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (70 mg, 0.43 mmol). The mixture was stirred at 100° C. for 16 hours, then partitioned between ethyl acetate and water. Purification by HPLC provided the title compound. MS (ESI) m/z 471 (M+H) + .
Example 380
3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-amino)benzonitrile
Example 380A
(3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
Example 322B (2.53 g, 7.03 mmol) was partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate (aq. 10 mL). The organic fraction was collected. The aqueous fraction was washed with ethyl acetate 3 times. The combined organic fractions were dried over sodium sulfate and concentrated to give the title compound. MS (EST) m/z 325.3 (M+H) + .
Example 380B
3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 3-bromobenzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426.1 (M+H) + .
Example 381
6-chloro-2-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-2,3-dihydro-1H-isoindol-1-one
Example 381A
Trans-N-(2-bromo-4-chlorobenzyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(pyridin-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 307B for Example 354D and 2-bromo-4-chlorobenzaldehyde for 4-chlorobenzaldehyde.
Example 381B
6-chloro-2-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(pyridin-2-yl)pyrrolidin-3-yl]-2,3-dihydro-1H-isoindol-1-one
To a solution of Example 381A (500 mg, 0.98 mmol) in methanol (5 mL) in a 50 mL pressure bottle was added 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), (36 mg, 0.048 mmol) and triethylamine (0.27 mL, 2 mmol). The mixture was pressurized with Carbon Monoxide (60 psi), and stirred for 4 hours at 80° C. The insoluble materials were filtered off and the filtrate was purified by HPLC to provide the title compound. MS (ESI) m/z 458460 (3:1) (M+H) + .
Example 382
3-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-ol
Example 382A
4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-one
To a solution of Example 379C (0.43 g, 1.3 mmol) in dichloromethane (3 mL) was added Dess-Martin periodinane (0.67 g, 1.6 mmol). The mixture was stirred overnight and partitioned between ethyl acetate and sodium hydroxide (1M aq.). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 382B
3-benzyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-
To a solution of Example 382A (50 mg) in tetrahydrofuran (0.5 mL) at −78° C. was added benzylmagnesiumbromide (1 M, 1 mL, 1 mmol). The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was partitioned between Ammonium chloride (aq) and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound. MS (ESI) m/z 416 (M+H) + .
Example 383
N-{trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridazin-3-amine
Example 383A
Trans-6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyridazin-3-amine
Example 3A (100 mg, 0.308 mmol), 3,6-dichloro-4-(trifluoromethyl)pyridazine (67 mg, 0.308 mmol), diisopropylethylamine (53.8 μl, 0.308 mmol), and ethanol (4 mL) were placed in a 2-5 mL microwave vial and irradiated for 1 hr at 175° C. The reaction contents were concentrated, redissolved in 2 mL 50% dimethylsulfoxide/methanol and purified via HPLC to provide the title compound. MS (ESI) m/z 505 (M+H) + .
Example 383B
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-(trifluoromethyl)pyridazin-3-amine
The title compound was prepared similarly to the procedure described in Example 350B substituting 6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-5-yl)-4-(trifluoromethyl)pyridazin-3-amine for 6-chloro-N-(4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)pyridazin-3-amine. MS (ESI) m/z 471 (M+H)+
Example 384
N-{4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridazin-3-amine
The title compound was prepared similarly to the procedure described in Example 350A-350B As both isomers are formed in 350A. MS (ESI) m/z 471 (M+H)+
Example 385
1-methyl-4-{[trans-3-phenyl-4-(phenylsulfonyl)pyrrolidin-1-yl]sulfonyl}-1H-imidazole
Example 385A
Trans-1-benzyl-3-phenyl-4-(phenylsulfonyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting phenyl trans-styryl sulfone for 4-methoxy-beta-nitrostyrene. MS (ESI) m/z 378.1 (M+H) + .
Example 385B
Trans-3-phenyl-4-(phenylsulfonyl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 385A for 2C. MS (ESI) m/z 288.1 (M+H) + .
Example 385C
1-Methyl-4-{trans-3-phenyl-4-(phenylsulfonyl)pyrrolidin-1-yl]sulfonyl}-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 385B for Example 2D. MS (ESI) m/z 432.1 (M+H) + .
Example 386
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 375 for Example 242E. MS (ESI) m/z 447.1 (M+H) + .
Example 387
(3S,4R)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 389A for Example 337F and 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 453.2 (M+H) + .
Example 388
N-{Trans-3-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 354D for Example 337F and 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 466 (M+H) + .
Example 389
3-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
Example 389A
(3S,4R)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 321B for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 389B
3-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting 389A for Example 337F and substituting 3-bromobenzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426.3 (M+H) + .
Example 390
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 471.2 (M+H) + .
Example 391
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[5-(trifluoromethyl)furan-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 5-(trifluoromethyl)furan-2-carbaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 473.1 (M+H) + .
Example 392
1,1,1-trifluoro-2-[3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]propan-2-ol
Example 392A
2-(3-Bromophenyl)-1,1,1-trifluoropropan-2-ol
To 1-(3-bromophenyl)ethanone (364 mg, 1.83 mmol) and (trifluoromethyl)trimethylsilane (3 mL, 1.46 mmol, 0.5 M in tetrahydrofuran) was added tetrabutylammonium fluoride (1 M in tetrahydrofurane, 2.0 mL, 2.0 mmol) at 0° C. The reaction mixture stirred at room temperature for 3 hours. The reaction mixture was partitioned with saturated sodium carbonate (aq.) and dichloromethane. The organic fraction was collected. The aqueous fraction was washed with dichloromethane 3 times. The combined organic fractions were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by flash chromatography (5:1 EtOAc/hexanes) to afford the title compound.
Example 392B
1,1,1-trifluoro-2-[3-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)phenyl]propan-2-ol
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting Example 392A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 513.3 (M+H) + .
Example 393
(3R,4S)—N-[(5-chlorothiophen-2-yl)methyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 5-chlorothiophene-2-carbaldehyde for 4-chlorobenzaldehyde and. MS (ESI) m/z 455.3 (M+H) + .
Example 394
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 380A for Example 354D and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 455.3 (M+H) + .
Example 395
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 395A
(3S,4R)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and separating the enantiomers produced from the procedure of Example 2C via Chiral SFC separation (SFC 200 Column: Whelk-O1, 50×250 mm, 5 μm Column Temperature: 35° C. Mobile Phase: CO 2 /IPA/DEA=70/30/0.1 Flow rate: 70 g/min Back Pressure: 100 Bar Wavelength: 214 nm Cycle time: 5.0 min Injection: 4.0 mL Sample solution: 41000 mg in 250 mL methanol) RT=6.00 minutes.
Example 395B
(3S,4R)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 395A for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 395 C
(3S,4R)—N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 395B for Example 354D and substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 499.2 (M+H) + .
Example 396
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
Example 396A
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 574A for Example 322B. MS (ESI) m/z 307.1 (M+H) + .
Example 396B
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 452.2 (M+H) + .
Example 397
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F. MS (ESI) m/z 452.2 (M+H) + .
Example 398
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[4-(trifluoromethyl)benzyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and Example 396A Example 354D. MS (ESI) m/z 465.1 (M+H) + .
Example 399
1,1,1-trifluoro-2-[3-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)phenyl]propan-2-ol
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and Example 392A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 495.1 (M+H) + .
Example 400
Trans-4-(benzyloxy)-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
To a solution of Example 373C (71 mg, 0.2 mmol) in tetrahydrofuran (0.5 mL) was added potassium tert-butoxide (22 mg, 0.2 mmol) and benzyl bromide (40 mg, 0.23 mmol). The mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was then partitioned with water and ethyl acetate. The organic fraction was collected, concentrate, and purified by HPLC to provide the title compound. MS (ESI) m/z 447/449 (3:1) (M+H) + .
Example 401
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-3-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-yl]methanol
Example 401A
(E)-2-nitro-3-phenylprop-2-en-1-ol
To (E)-(2-nitrovinyl)benzene (1.5 g, 10 mmol) in tetrahydrofuran (10 mL) was added formaldehyde (37%, aq., 10 mL), imidazole (0.68 g, 10 mmol), and anthranilic acid (14 mg, 0.1 mmol). The mixture was allowed to stir for 16 hours. The reaction mixture was partitioned between ethyl acetate and hydrochloric acid (1N). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 401B
(E)-((2-nitro-3-phenylallyl)oxy)methyl acetate
To a solution of Example 401A (900 mg, 5 mmol) in dichloromethane (5 mL) was added triethylamine (600 mg, 6 mmol) and acetyl chloride (400 mg, 5.1 mmol) at 0° C. The mixture was allowed to stir for 1 hour. Water was added and the solution partitioned. The organic fraction was collected, concentrated, and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the title compound.
Example 401C
((1-benzyl-3-nitro-4-phenylpyrrolidin-3-yl)methoxy)methyl acetate
The title compound was prepared similarly to the procedure described in Example 2A substituting Example 401B for 4-methoxy-beta-nitrostyrene.
Example 401D
7-benzyl-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 401C for Example 2A.
Example 401E
tert-butyl 7-benzyl-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 401D for Example 337B.
Example 401F
tert-butyl 9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 401E for 2C.
Example 401G
tert-butyl 7-((1-methyl-1H-imidazol-4-yl)sulfonyl)-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 401F for Example 373B.
Example 401H
7-((1-methyl-1H-imidazol-4-yl)sulfonyl)-9-phenyl-3-oxa-1,7-diazaspiro[4.4]nonane
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 401G for Example 373A
Example 401I
[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-3-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-yl]methanol
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and Example 401H for Example 354D MS (ESI) m/z 495 (M+H) + .
Example 402
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(prop-2-en-1-yloxy)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting allyl bromide for benzyl bromide. MS (ESI) m/z 397/399 (3:1) (M+H) + .
Example 403
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2-methylprop-2-en-1-yl)oxy]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting 3-bromo-2-methylprop-1-ene for benzyl bromide. MS (ESI) m/z 411413 (3:1) (M+H) + .
Example 404
3-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
Example 404A
N-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-nitro-5-(trifluoromethyl)benzamide
To Example 14A (140 mg, 0.4 mmol) in dimethylformamide (0.5 mL) was added 2-nitro-5-(trifluoromethyl)benzoic acid (96 mg, 0.4 mmol), triethylamine (100 mg, 1 mmol), and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (160 mg, 0.5 mmol). The mixture was allowed to stir overnight. Water was added and the precipitates were collected to provide the title compound.
Example 404B
Trans-N-(2-amino-5-(trifluoromethyl)benzyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
To a solution of Example 404A (110 mg, 0.21 mmol) in tetrahydrofuran (1 mL) was added borane dimethyl sulfide complex (2N, 1.4 mL, 2.8 mmol). The mixture was stirred at 60° C. for 2 days and quenched with hydrochloric acid (1 M aq.). The mixture was allowed to stir for 30 minutes. Sodium hydroxide (1 M, aq.) was added to adjust the pH value to 10. The mixture was partitioned with ethyl acetate. The organic fraction was collected and dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 404C
3-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
To a solution of Example 404B (130 mg, 0.27 mmol) in dichloromethane (10 mL) was added triethylamine (100 mg, 1 mmol) and triphosgene (28 mg, 0.094 mmol). The mixture was allowed to stir for 1 hour, and then methanol was added. The mixture was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 506 (M+H) + .
Example 405
4-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-4-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 402.1 (M+H) + .
Example 406
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-7H-pyrrolo[2,3-D]pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 424.2 (M+H) + .
Example 407
Trans-7-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-9-phenyl-1-[4-(trifluoromethyl)benzyl]-3-oxa-1,7-diazaspiro[4.4]nonan-2-one
The title compound was prepared similarly to the procedure described in Example 404C substituting Example 401I for Example 404B. MS (ESI) m/z 521 (M+H) + .
Example 408
3,5-difluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To Example 396A (100 mg, 0.33 mmol) in dimethylsulfoxide (0.5 mL) was added potassium tert-butoxide (50 mg, 0.45 mmol) and 2,3,5-trifluoro-4-(trifluoromethyl)pyridine (80 mg, 0.4 mmol). The mixture was stirred at 80° C. for 2 hours, and then partitioned between water and ethyl acetate. The organic fraction was collected, dried over potassium carbonate, filtered, concentrated, and purified by reversed phase HPLC to provide the title compound. MS (ESI) m/z 488 (M+H) + .
Example 409
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 574A for Example 354D and substituting 5-(trifluoromethyl)picolinaldehyde for 4-chlorobenzaldehyde. MS (ESI) m/z 466.1 (M+H) + .
Example 410
5-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-5-cyclopropyl-pyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425.3 (M+H) + .
Example 411
5-cyclobutyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and 2-bromo-5-cyclobutylpyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439.3 (M+H) + .
Example 412
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(2-methylprop oxy)pyrrolidin-3-amine
To Example 403 (17 mg, 0.041 mmol) in tetrahydrofuran (4 mL) was added 5% Pt/C (20 mg, 0.041 mmol). The mixture was stirred for 45 minutes under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and purified by reversed phase HPLC to provide the title compound. MS (ESI) m/z 413415 (3:1) (M+H) + .
Example 413
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(pyrrolidin-1-yl)pyrazin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 2-bromo-5-(pyrrolidin-1-yl)pyrazine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 454.3 (M+H) + .
Example 414
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-5-(trifluoromethyl)pyrazine-2-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and 5-(trifluoromethyl)pyrazine-2-carboxylic acid for Example 242D. MS (ESI) m/z 481.2 (M+H) + .
Example 415
5-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrazine-2-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and 5-chloropyrazine-2-carboxylic acid for Example 242D. MS (ESI) m/z 447.1 (M+H) + .
Example 416
(3R,4S)—N-(4-chlorobenzyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 574A for Example 354D. MS (ESI) m/z 431.1 (M+H) +
Example 417
(3R,4S)—N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene MS (ESI) m/z 435.1 (M+H) + .
Example 418
(3R,4S)—N-(3,4-difluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 437.1 (M+H) + .
Example 419
6-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridazine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 574A for aniline and substituting 6-chloropyridazine-3-carboxylic acid for Example 242D. MS (ESI) m/z 447.2 (M+H) + .
Example 420
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2-(morpholin-4-yl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-(4-bromopyrimidin-2-yl)morpholine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470.2 (M+H) + .
Example 421
4-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-2,3-dihydro-1H-isoindol-1-one
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-(4-bromopyrimidin-2-yl)morpholine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470.2 (M+H) + .
Example 422
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(methylsulfonyl)phenyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 1-bromo-3-(methylsulfonyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 461.2 (M+H) + .
Example 423
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(trifluoromethyl)piperazin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared using the same procedures as described in Example 290 substituting Example 414 for Example 242E. MS (ESI) m/z 473.2 (M+H) + .
Example 424
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-2-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 2-bromo-5-fluoropyrimidine for 1-bromo-2-methylbenzene MS (ESI) m/z 403.2 (M+H) +
Example 425
Trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 425A
(E)-(2-nitrovinyl)cyclohexane
A solution of cyclohexane carboxaldehyde (5.0 g, 44.6 mmol) and nitromethane (4.1 g, 66.9 mmol) in tetrahydrofuran (25 ml) and tert butanol (25 ml) was stirred and chilled in an ice bath under nitrogen. Potassium-t-butoxide (1.0 g, 9.0 mmol) was added as a solid in one portion and the reaction was allowed to stir and warm to room temperature over one hour. The reaction was stirred for an additional four hours and was then partitioned with a saturated solution of ammonium chloride. The organic fraction was collected, and the aqueous portion was washed with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting liquid was dissolved in dichloromethane (100 ml) and chilled in an ice bath. Trifluoroacetic anhydride (9.8 g, 46.7 mmol) was added in one portion, and the solution stirred for five minutes. Triethylamine (9.5 g, 93.5 mmol) was added dropwise. Stirring was continued for one hour, and then the reaction was allowed to warm to room temperature and stir for two hours. The reaction was partitioned with a solution of saturated ammonium chloride. The organic fraction was collected. The aqueous portion was washed with dichloromethane. The organic fractions were combined and washed with water and brine, and dried over sodium sulfate. The mixture was filtered, concentrated and chromatographed on a silica gel flash column eluting with 98:2 heptane:ethyl acetate to afford 5.1 g of a slightly tinted liquid. MS (DCI) m/z 173.1 (M+NH 4 ) +
Example 425B
trans-4-cyclohexyl-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting Example 425A for trans-4-methoxy-beta-nitrostyrene in Example 2A. MS (DCI) m/z 313.1 (M+H) +
Example 425C
trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 57 substituting Example 425B for Example 14A and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 473.2 (M+H) + .
Example 426
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(4,4,4-trifluorobutyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,4,4-trifluorobutanol for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) +
Example 427
(3R,4S)—N-(2-cyclopentylethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-cyclopentylacetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 403.0 (M+H) +
Example 428
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(5-propylfuran-2-yl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-propylfuran-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 429.0 (M+H) + .
Example 429
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyltetrahydro-2H-pyran-4-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methyltetrahydro-2H-pyran-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) + .
Example 430
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(4-phenyl-1,3-thiazol-5-yl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-phenylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 480.0 (M+H) +
Example 431
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) +
Example 432
(3R,4S)—N-[(3,5-dichloropyridin-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,5-dichloroisonicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 467.0 (M+H) +
Example 433
(3R,4S)—N-(2-ethylhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylhexanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) +
Example 434
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) +
Example 435
(3R,4S)—N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,4-dichlorothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 473.0 (M+H) +
Example 436
(3R,4S)—N-(2,2-dimethylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pivalaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) +
Example 437
(3R,4S)—N-[(5-methyl-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylbenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 467.0 (M+H) + .
Example 438
(3R,4S)—N-[(2-bromo-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-bromothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 483.0 (M+H) + .
Example 439
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylpropyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting isobutyraldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 363.0 (M+H) + .
Example 440
(3R,4S)—N-[(3-chloro-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-chlorobenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 487.0 (M+H) + .
Example 441
(3R,4S)—N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,4-dimethylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 432.0 (M+H) + .
Example 442
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(thieno[2,3-b]pyridin-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting thieno[2,3-b]pyridine-2-carbaldehyde for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 454.0 (M+H) + .
Example 443
(3R,4S)—N-[(2-methyl-1-benzofuran-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylbenzofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 451.0 (M+H) + .
Example 444
(3R,4S)—N-[(6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 6-chloro-2-methylimidazo[1,2-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 485.0 (M+H) + .
Example 445
(3R,4S)—N-{[5-(4-fluorophenyl)pyridin-3-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-(4-fluorophenyl)nicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 492.0 (M+H) + .
Example 446
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(2-methylpentyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylpentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 447
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(tetrahydro furan-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting tetrahydrofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 448
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentyl-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) + .
Example 449
(3R,4S)—N-(2-ethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) +
Example 450
(3R,4S)—N-(2,2-dimethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,2-dimethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) + .
Example 451
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(2-methyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) + .
Example 452
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 419.0 (M+H) + .
Example 453
(3R,4S)—N-(1,3-benzothiazol-2-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting benzo[d]thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 454.0 (M+H) + .
Example 454
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418.0 (M+H) + .
Example 455
(3R,4S)—N-[(4,5-dimethylthiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,5-dimethylthiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 431.0 (M+H) + .
Example 456
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,5,6,7-tetrahydrobenzo[d]thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 458.0 (M+H) + .
Example 457
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(1,3-thiazol-5-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting thiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 404.0 (M+H) + .
Example 458
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 457.0 (M+H) + .
Example 459
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[1-(propan-2-yl)piperidin-4-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 1-isopropylpiperidine-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 446.0 (M+H) + .
Example 460
(3R,4S)—N-{[4-(4-fluorophenyl)-1,3-thiazol-2-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-(4-fluorophenyl)thiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 498.0 (M+H) + .
Example 461
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(4-methylphenyl)ethyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(p-tolyl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 425.0 (M+H) + .
Example 462
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylthiophen-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylthiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) + .
Example 463
(3R,4S)—N-(3-methylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-methylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 377.0 (M+H) + .
Example 464
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(3,5,5-trimethylhexyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,5,5-trimethylhexanal for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 433.0 (M+H) + .
Example 465
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-phenylpropyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-phenylpropanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 425.0 (M+H) + .
Example 466
(3R,4S)—N-(3,3-dimethylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,3-dimethylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 391.0 (M+H) + .
Example 467
(3R,4S)—N-[(1-methylcyclohexyl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 1-methylcyclohexanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417.0 (M+H) + .
Example 468
(3R,4S)—N-[2-(3-chlorophenyl)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(3-chlorophenyl)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 445.0 (M+H) + .
Example 469
(3R,4S)—N-[2-(4-tert-butylphenoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(4-(tert-butyl)phenoxy)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 483.0 (M+H) + .
Example 470
(3R,4S)—N-(2-ethyl-3-methylbutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethyl-3-methylbutanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 405.0 (M+H) + .
Example 471
(3R,4S)—N-[3-(3-chlorophenyl)propyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-(3-chlorophenyl)propanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 459.0 (M+H) + .
Example 472
(3R,4S)—N-[(4-bromo-1,3-thiazol-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-bromothiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 482 (M+H) + .
Example 473
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-methyl-2-phenylthiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 494 (M+H) + .
Example 474
N-(3,4-difluorophenyl)-1-[(2,4-dim ethyl-1,3-thiazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 474A
N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
To a 100 mL round bottom flask with magnetic stir bar under argon was added cesium carbonate (28.7 g, 88 mmol)], 4-bromo-1,2-difluorobenzene (5.66 g, 29.3 mmol), 1-benzyl-4-phenylpyrrolidin-3-amine (7.4 g, 29.3 mmol), and Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), (0.928 g, 1.173 mmol). 1,2-dimethoxyethane (25 mL) was added and the reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled, concentrated onto celite, and purified via flash chromatography (5-50% EtOAc/Hex, 220 g column) to provide the title compound.
Example 474B
N-(3,4-difluorophenyl)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
A 4 mL vial with a magnetic stir bar was charged with Example 474A (40 mg, 0.146 mmol) and a solution of diisopropylethylamine in dichloromethane (1 mL of a 5 wt % diisopropylethylamine). A solution of 2,4-dimethylthiazole-5-sulfonyl chloride (972 μl, 0.292 mmol, 0.3 mM in 5% diisopropylethylamine in dichloromethane) was added and the reaction mixture was allowed to stir for 4 hours. The reaction was concentrated, redissolved in 2 mL of 50% dimethylsulfoxide/methanol and purified via HPLC to provide the title compound. MS (ESI) m/z 450 (M+H) + .
Example 475
N-(3,4-difluorophenyl)-1-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-isopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 461 (M+H) + .
Example 476
N-(3,4-difluorophenyl)-1-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 487 (M+H) + .
Example 477
N-(3,4-difluorophenyl)-4-phenyl-1-(pyridin-3-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting pyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 416 (M+H) + .
Example 478
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 3,3-dimethyl-2-oxoindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 498 (M+H) + .
Example 479
1-[(1-cyclopentyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-cyclopentyl-3-methyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 487 (M+H) + .
Example 480
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)quinazoline-2,4(1H,3H)-dione
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 481
7-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-6-methyl-2H-1,4-benzoxazin-3(4H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 500 (M+H) + .
Example 482
N-(3,4-difluorophenyl)-1-[(1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,3-dimethyl-1H-pyrazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 483
N-(3,4-difluorophenyl)-1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 484
N-(3,4-difluorophenyl)-1-[(4-methylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 4-methylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 435 (M+H) + .
Example 485
N-(3,4-difluorophenyl)-4-phenyl-1-(pyrrolidin-1-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting pyrrolidine-1-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 408 (M+H) + .
Example 486
1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 467 (M+H) + .
Example 487
N-(3,4-difluorophenyl)-1-[(5-methyl-1,2-oxazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-methylisoxazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 420 (M+H) + .
Example 488
N-(3,4-difluorophenyl)-1-[(2,5-dimethylfuran-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,5-dimethylfuran-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 489
methyl 3-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)thiophene-2-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 3-(chlorosulfonyl)thiophene-2-carboxylate for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 479 (M+H) + .
Example 490
N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 433 (M+H) + .
Example 491
methyl 5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-4-methoxythiophene-3-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 5-(chlorosulfonyl)-4-methoxythiophene-3-carboxylate for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 509 (M+H) + .
Example 492
N-(3,4-difluorophenyl)-1-[(5-ethylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-ethylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 449 (M+H) + .
Example 493
N-(3,4-difluorophenyl)-1-[(4-methylpiperidin-1-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 4-methylpiperidine-1-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 436 (M+H) + .
Example 494
N-(3,4-difluorophenyl)-1-{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-morpholinopyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 501 (M+H) +
Example 495
1-(1,3-benzodioxol-5-ylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting benzo[d][1,3]dioxole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 459 (M+H) + .
Example 496
N-(3,4-difluorophenyl)-1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 473 (M+H) + .
Example 497
N-(3,4-difluorophenyl)-1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 445 (M+H) + .
Example 498
N-(3,4-difluorophenyl)-4-phenyl-1-[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting (tetrahydro-2H-pyran-2-yl)methanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 437 (M+H) + .
Example 499
N-[5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-acetamidothiazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 479 (M+H) + .
Example 500
N-(3,4-difluorophenyl)-4-phenyl-1-{[6-(trifluoromethyl)pyridin-3-yl]sulfonyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-(trifluoromethyl)pyridine-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 484 (M+H) + .
Example 501
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,4-dihydroquinoxaline-2,3-dione
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 499 (M+H) + .
Example 502
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-pyrazole-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 419 (M+H) + .
Example 503
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-indole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 468 (M+H) + .
Example 504
methyl 5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1-methyl-1H-pyrrole-2-carboxylate
The title compound was prepared similarly to the procedure described in Example 474B substituting methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 476 (M+H) + .
Example 505
1-(1,2-benzoxazol-5-ylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting benzo[d]isoxazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 456 (M+H) + .
Example 506
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-dihydro-2H-benzimidazol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 471 (M+H) + .
Example 507
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-dihydro-2H-indol-2-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxoindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 470 (M+H) + .
Example 508
N-(3,4-difluorophenyl)-4-phenyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 447 (M+H) + .
Example 509
1-(cyclobutylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting cyclobutanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 393 (M+H) + .
Example 510
1-(cyclohexylsulfonyl)-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting cyclohexanesulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 421 (M+H) + .
Example 511
1-[(5-chlorothiophen-2-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-chlorothiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 455 (M+H) + .
Example 512
6-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-3,4-dihydroquinolin-2(1H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 484 (M+H) + .
Example 513
N-(3,4-difluorophenyl)-1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 3,5-dimethylisoxazole-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 434 (M+H) + .
Example 514
5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-1,3-benzoxazol-2(3H)-one
The title compound was prepared similarly to the procedure described in Example 474B substituting 2-oxo-2,3-dihydrobenzo[d]oxazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 472 (M+H) + .
Example 515
N-(3,4-difluorophenyl)-1-(isoquinolin-5-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting isoquinoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 466 (M+H) + .
Example 516
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-methyl-1H-pyrazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 419 (M+H) + .
Example 517
N-(3,4-difluorophenyl)-1-[(2,5-dimethylthiophen-3-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,5-dimethylthiophene-3-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 449 (M+H) + .
Example 518
N-(3,4-difluorophenyl)-1-[(5-methylthiophen-2-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 5-methylthiophene-2-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 435 (M+H) + .
Example 519
N-(3,4-difluorophenyl)-1-(2,3-dihydro-1-benzo furan-5-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 2,3-dihydrobenzofuran-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 457 (M+H) + .
Example 520
1-[(6-chloro imidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N-(3,4-difluorophenyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 495 (M+H) + .
Example 521
N-(3,4-difluorophenyl)-1-(morpholin-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 474B substituting morpholine-4-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 424 (M+H) + .
Example 522
1-[5-({3-[(3,4-difluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)-2,3-dihydro-1H-indol-1-yl]ethanone
The title compound was prepared similarly to the procedure described in Example 474B substituting 1-acetylindoline-5-sulfonyl chloride for 2,4-dimethylthiazole-5-sulfonyl chloride. MS (ESI) m/z 498 (M+H) + .
Example 523
tert-butyl {trans-1-[(2-cyanophenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
Example 523A
Tert-butyl-trans-4-phenylpyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the procedures described in Example 2A-2D substituting (E)-(2-nitrovinyl)benzene for trans-4-methoxy-beta-nitrostyrene.
Example 523B
Tert-butyl {trans-1-[(2-cyanophenyl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 523A for Example 2D and substituting 2-cyanobenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride. MS (DCI) m/z 444.8 (M+NH4) + .
Example 524
tert-butyl [trans-1-[(2-cyanophenyl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]carbamate
Example 524A
Tert-butyl-trans-4-(4-fluorophenyl)pyrrolidin-3-ylcarbamate
The title compound was prepared similarly to the procedures described in Example 2A-2D substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for trans-4-methoxy-beta-nitrostyrene.
Example 524 B
Tert-butyl [trans-1-[(2-cyanophenyl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]carbamate
The title compound was prepared similarly to the procedure described in Example 2E substituting Example 524A for Example 2D and substituting 2-cyanobenzene-1-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride. MS (DCI) m/z 444.4 (M−H) − .
Example 525
2-{[trans-3-phenyl-4-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyrrolidin-1-yl]sulfonyl}benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 473.2 (M+H) + .
Example 526
2-{[trans-3-phenyl-4-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyrrolidin-1-yl]sulfonyl}benzamide
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 491.2 (M+H) + .
Example 527
2-(Trans-3-amino-4-phenylpyrrolidin-1-ylsulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 523 for Example 322B. MS (ESI) MS m/z 328.2 (M+H) + .
Example 528
2-({Trans-3-[(3-chlorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 438.2 (M+H) + .
Example 529
2-({Trans-3-[(4-fluorophenyl)amino]-4-phenylpyrrolidin-1-yl}sulfonyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 527 for Example 337F and substituting 1-bromo-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 422.2 (M+H) + .
Example 530
Trans-N-(3-chlorophenyl)-4-(cyclopropylmethoxy)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 400 substituting (bromomethyl)cyclopropane for benzyl bromide. MS (ESI) m/z 411/413 (3:1) (M+H) + .
Example 531
N-{trans-4-cyclohexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 425C substituting 4-bromo-6-trifluoromethylpyrimidine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 459.4 (M+H) + .
Example 532
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 396A for Example 337F and substituting 4-bromo-2-methoxypyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 415.2 (M+H) + .
Example 533
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-methylthiazole-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 418 (M+H) + .
Example 534
(3R,4S)—N-[(2-ethyl-1-benzofuran-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-ethylbenzofuran-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 465 (M+H) + .
Example 535
(3R,4S)—N-(imidazo[1,2-a]pyridin-8-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting imidazo[1,2-a]pyridine-8-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 536
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylpyridin-2-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylpicolinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 412 (M+H) + .
Example 537
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(pyrazolo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pyrazolo[1,5-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 538
N-{Trans-4-hydroxy-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
Example 538A
Trans-tert-butyl 3-hydroxy-4-(4-(trifluoromethyl)benzamido)pyrrolidine-1-carboxylate
To a solution of trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (600 mg, 3 mmol) in dichloromethane (10 mL) at 0° C., was added triethylamine (350 mg, 3.5 mmol) and 4-(trifluoromethyl)benzoyl chloride (620 mg, 3 mmol). The mixture was allowed to stir for 16 hours. The mixture was concentrated and dissolved in methanol (5 mL). Sodium methoxide (21% in methanol, 0.5 mL) was added. The mixture was stirred for 6 hours, concentrated, and partitioned between ethyl acetate and water. The organic fractions were collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 538B
N-(trans-4-hydroxypyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 538A for Example 373A.
Example 538C
N-(trans-4-hydroxy-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 538B for Example 373B.
Example 538D
N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-oxopyrrolidin-3-yl)-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 382A substituting Example 538C for Example 379C.
Example 538E
N-{Trans-4-hydroxy-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(trifluoromethyl)benzamide
The title compound was prepared similarly to the procedure described in Example 382B substituting Example 538D for Example 382A and phenylmagnesium bromide for benzylmagnesium bromide. MS (ESI) m/z 495 (M+H) + .
Example 539
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-phenyl-4-{[4-(trifluoromethyl)benzyl]amino}pyrrolidin-3-ol
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 538E for Example 404A. MS (ESI) m/z 481 (M+H) + .
Example 540
(3R,4S)—N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethoxy)benzene, but only heating for 1 hour. MS (ESI) m/z 503 (M+H) + .
Example 541
ethyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
To Example 396A (50 mg, 0.16 mmol) in dichloromethane (0.5 mL) was added triethylamine (20 mg, 0.2 mmol) and ethyl chloroformate (22 mg, 0.2 mmol). The mixture was stirred for 1 hour, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 379 (M+H) + .
Example 542
propyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting propyl chloroformate for ethyl chloroformate. MS (ESI) m/z 393 (M+H) + .
Example 543
2-methylpropyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting isobutyl chloroformate for ethyl chloroformate. MS (ESI) m/z 407 (M+H) + .
Example 544
butyl {(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}carbamate
The title compound was prepared similarly to the procedure described in Example 541 substituting butyl chloroformate for ethyl chloroformate. MS (ESI) m/z 407 (M+H) + .
Example 545
(3R,4S)—N-(2-cyclopropylethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 546 for Example 404A. MS (ESI) m/z 375 (M+H) + .
Example 546
2-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 2-cyclopropylacetic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 388 (M+H) + .
Example 547
(3R,4S)—N-[(2E)-hex-2-en-1-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (E)-hex-2-enal for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. Both Example 547 and Example 548 were isolated. MS (ESI) m/z 389 (M+H) + .
Example 548
(3R,4S)—N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (E)-hex-2-enal for 4-chlorobenzaldehyde and Example 396A for Example 354D. Both Example 547 and Example 548 were isolated. MS (ESI) m/z 391 (M+H) + .
Example 549
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and pentanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 391 (M+H) + .
Example 550
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}hexanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting hexanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 405 (M+H) + .
Example 551
(3R,4S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting (tert-butyldimethylsilyloxy)acetaldehyde for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. MS (ESI) m/z 465.2 (M+H) + .
Example 552
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[6-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 6-(trifluoromethyl)picolinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 466 (M+H) + .
Example 553
(3R,4S)—N-[(3-chlorothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3-chlorothiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 554
(3R,4S)—N-[(4,4-difluorocyclohexyl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4,4-difluorocyclohexanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 439 (M+H) + .
Example 555
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(pyrazolo[1,5-a]pyridin-7-ylmethyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pyrazolo[1,5-a]pyridine-7-carbaldehyde for 4-chlorobenzaldehyde and Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 556
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[4-(propan-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-isopropylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 446 (M+H) + .
Example 557
(3R,4S)—N-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (EST) m/z 433 (M+H) + .
Example 558
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-{[5-(tetrahydro-2H-pyran-2-yl)thiophen-2-yl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-(tetrahydro-2H-pyran-2-yl)thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 487 (M+H) + .
Example 559
(3R,4S)—N-[(5-bromo-4-methyl-1,3-thiazol-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-bromo-4-methylthiazole-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 497 (M+H) + .
Example 560
(3R,4S)—N-(imidazo[1,5-a]pyridin-5-ylmethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting imidazo[1,5-a]pyridine-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 561
(3R,4S)—N-(2,3-dimethylpentyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,3-dimethylpentanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 405 (M+H) + .
Example 562
(3R,4S)—N-[(2-chloro-1,3-thiazol-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chlorothiazole-4-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 438 (M+H) + .
Example 563
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-methylimidazo[1,2-a]pyridine-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 451 (M+H) + .
Example 564
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-phenylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-phenylcyclopropanecarbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 437 (M+H) + .
Example 565
(3R,4S)—N-[(4-chloro-1,3-thiazol-5-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 4-chlorothiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 438 (M+H) + .
Example 566
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(3,3,3-trifluoro-2-methylpropyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 3,3,3-trifluoro-2-methylpropanal for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 417 (M+H) + .
Example 567
(3R,4S)—N-[(2-chloro-3-fluoropyridin-4-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-3-fluoroisonicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 450 (M+H) + .
Example 568
(3R,4S)—N-[(5-fluoro-1-benzothiophen-2-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-fluorobenzo[b]thiophene-2-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 471 (M+H) + .
Example 569
(3R,4S)—N-[5-chloro-2-(difluoromethoxy)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5-chloro-2-(difluoromethoxy)benzaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 497 (M+H) + .
Example 570
(3R,4S)—N-[(2,5-dichlorothiophen-3-yl)methyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2,5-dichlorothiophene-3-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 471 (M+H) + .
Example 571
(3R,4S)—N-{[2-(4-fluorophenyl)pyridin-3-yl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(4-fluorophenyl)nicotinaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 492 (M+H) + .
Example 572
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[2-(4-methylphenyl)-1,3-thiazol-5-yl]methyl}-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-(p-tolyl)thiazole-5-carbaldehyde for 4-chlorobenzaldehyde and substituting Example 574A for Example 354D. MS (ESI) m/z 494 (M+H) + .
Example 573
(3R,4S)—N-(3-cyclopropylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 573A
3-cyclopropyl-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)propanamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 3-cyclopropylpropanoic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 573B
(3R,4S)—N-(3-cyclopropylpropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 573A for Example 404A. MS (ESI) m/z 389 (M+H) + .
Example 574
5-fluoro-4-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
Example 574A
(3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the conditions described in Example 2A-2F substituting (E)-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and separating the enantiomers produced from the procedure of Example 2C via Chiral SFC separation (SFC 200 Column: Whelk-O1, 50×250 mm, 5 μm Column Temperature: 35° C. Mobile Phase: CO 2 /IPA/DEA=70300.1 Flow rate: 70 g/min Back Pressure: 100 Bar Wavelength: 214 nm Cycle time: 5.0 min Injection: 4.0 mL Sample solution: 41000 mg in 250 mL methanol) The enantiomer with a retention time of 4.41 minutes was used to make the title compound.
Example 574B
5-fluoro-4-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 2-bromo-4-methyl-5-fluoropyridine for 1-bromo-3-(trifluoromethoxy)benzene. MS (APCI) m/z 416 (M+H) + .
Example 575
1,5-dimethyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,4-triazol-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 3-bromo-1,5-dimethyl-1H-1,2,4-triazole for 1-bromo-3-(trifluoromethoxy)benzene. MS (ESI) m/z 402 (M+H) + .
Example 576
1,5-dimethyl-4-({(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}amino)-1H-pyrrole-2-carbonitrile
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile for 1-bromo-3-(trifluoromethoxy)benzene. MS (APCI) m/z 425 (M+H) + .
Example 577
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(propan-2-yloxy)propyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-isopropoxypropylamine for aniline. MS (ESI) m/z 453.2 (M+H) + .
Example 578
(3S,4R)—N-(3-ethoxypropyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-ethoxypropylamine for aniline. MS (ESI) m/z 439.2 (M+H) + .
Example 579
(3S,4R)-4-(4-fluorophenyl)-N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-methoxyethylamine for aniline. MS (ESI) m/z 411.2 (M+H) + .
Example 580
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-propylpyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting propylamine for aniline. MS (ESI) m/z 395.2 (M+H) + .
Example 581
(3S,4R)—N-butyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting butylamine for aniline. MS (ESI) m/z 409.2 (M+H) + .
Example 582
(3S,4R)-4-(4-fluorophenyl)-N-[1-methoxypropan-2-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-methoxyisopropylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 583
(3R,4S)-4-(4-fluorophenyl)-N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-methoxypropylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 584
(3S,4R)—N-(2-ethoxyethyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-ethoxyethylamine for aniline. MS (ESI) m/z 425.2 (M+H) + .
Example 585
(3R,4S)—N-[4-chloro-3-(trifluoromethoxy)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-4-chloro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene, but the reaction mixture was only heated for 1 hour. MS (APCI) m/z 519 (M+H) + .
Example 586
(3S,4R)—N-(cyclopropylmethyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting cyclopropylmethylamine for aniline. MS (ESI) m/z 407.1 (M+H) + .
Example 587
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[2-(propan-2-yloxy)ethyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2-isopropoxy-ethylamine for aniline. MS (ESI) m/z 439.1 (M+H) + .
Example 588
(3R,4S)—N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 588A
(3R,4S)—N-(3-(benzyloxy)propyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 396A for Example 354D and substituting 3-(benzyloxy)propanal for 4-chlorobenzaldehyde.
Example 588B
tert-butyl (3-(benzyloxy)propyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 588A for Example 337B.
Example 588C
tert-butyl (3-hydroxypropyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To Example 588B (200 mg, 0.36 mmol) in tetrahydrofuran (10 mL) was added 20% palladium hydroxide on carbon, (80 mg, 0.058 mmol). The mixture was allowed to stir under 30 psi of hydrogen at 50° C. for 16 hours. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.
Example 588D
(3R,4S)—N-(3-methoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To Example 588C (60 mg, 0.13 mmol) in tetrahydrofuran (0.5 mL) was added iodomethane (70 mg, 0.5 mmol) and sodium hydride (60%, 20 mg, 0.5 mmol). The mixture was stirred at 60° C. for 2 hours. Hydrochloric acid (4N in dioxane, 1 mL) was added. The mixture was stirred for 2 hours, concentrated, and partitioned between ethyl acetate and NaOH (1 M aq). The organic fraction was collected, concentrated, and purified HPLC to provide the title compound. MS (ESI) m/z 379 (M+H) + .
Example 589
(3R,4S)—N-(3-ethoxypropyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting iodoethane for iodomethane. MS (ESI) m/z 393 (M+H) + .
Example 590
(3R,4S)—N-{[1-(methoxymethyl)cyclopropyl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 590A
1-(methoxymethyl)-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)cyclopropanecarboxamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 1-(methoxymethyl)cyclopropanecarboxylic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 590
(3R,4S)—N-{[1-(methoxymethyl)cyclopropyl]methyl}-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 590A for Example 404A. MS (ESI) m/z 405 (M+H) + .
Example 591
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-(propan-2-yloxy)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 577 for Example 242E. MS (ESI) m/z 439.1 (M+H) + .
Example 592
3-ethoxy-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 578 for Example 242E. MS (ESI) m/z 425.1 (M+H) + .
Example 593
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-2-methoxyethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 579 for Example 242E. MS (ESI) m/z 397.1 (M+H) + .
Example 594
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)propan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 580 for Example 242E. MS (ESI) m/z 381.1 (M+H) + .
Example 595
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)butan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 581 for Example 242E. MS (ESI) m/z 394.1 (M+H) + .
Example 596
(2S)-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-1-methoxypropan-2-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 582 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 597
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-3-methoxypropan-1-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 583 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 598
2-ethoxy-N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 584 for Example 242E. MS (ESI) m/z 411.1 (M+H) + .
Example 599
N-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)-2-(propan-2-yloxy)ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 587 for Example 242E. MS (ESI) m/z 425.1 (M+H) + .
Example 600
(3R,4S)—N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 600A
Tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 551 (686 mg, 1.48 mmol) in ethyl acetate (7 mL), was added di-tert-butyldicarbonate (644 mg, 2.95 mmol). This solution was stirred at room temperature for 16 hours. The solution was then concentrated and purified by flash-chromatography (30-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI) m/z 565.0 (M+H) + .
Example 600 B
Tert-butyl 2-hydroxyethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 600A (626 mg, 1.11 mmol) in 8 mL of dichloromethane (5 mL) was added tetrabutylammonium fluoride hydrate (620 mg, 2.22 mmol). This solution was stirred at room temperature for 16 hours, concentrated, and purified by flash-chromatography (5% methanol/dichloromethane with 0.5% triethylamine added) to provide the title compound. MS (ESI) m/z 450.8 (M+H) + .
Example 600 C
(3R,4S)—N-(2-methoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Powdered potassium hydroxide (30 mg, 0.53 mmol) was added dimethylsulfoxide (7 mL) and the mixture was stirred for 2 minutes. To this solution was added Example 600 B (60 mg, 0.13 mmol) and iodomethane (66.2 mg, 0.47 mmol). This mixture was stirred at room temperature for 16 hours then partitioned between ethyl acetate and water, The organic fraction was collected, and the aqueous fraction was washed with ethyl acetate 3 times. All organic fractions were combined and concentrated. To this concentrate was added dichloromethane (1 mL) and trifluoroacetic acid (0.3 mL), and the solution stirred at room temperature for 2 hours. The mixture was concentrated and purified by HPLC to provide the title compound. MS (ESI) m/z 365.1 (M+H) + .
Example 601
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 601A
(E)-2-(2-nitrovinyl)tetrahydrofuran
A solution of tetrahydrofuran-2-carboxaldehyde (2.0 g, 20.0 mmol) and nitromethane (3.66 g, 60.0 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature under nitrogen and 1,1,3,3-tetramethylguanidine (230 mg, 2.0 mmol) was added in one portion. The reaction mixture was stirred for thirty minutes. The mixture was then chilled in an ice bath to 0° C. Trifluoroacetic anhydride (5.25 g, 25 mmol) was added in one portion. The reaction mixture was stirred for thirty minutes after which time triethylamine (5.06 g, 50.0 mmol) was added dropwise. The reaction was stirred for 30 minutes and then partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic fraction was collected, and the aqueous portion was washed with additional ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and purified via flash column (1:2 ethyl acetate:heptanes) to afford the title compound.
Example 601B
1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 601A for trans-4-methoxy-beta nitrostyrene.
Example 601C
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A. Purification via flash chromatography (4:1 ethyl acetate:heptanes) provided the title compound. MS (ESI) m/z 461.1 (M+H) + .
Example 602
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A. Purification via flash chromatography (4:1 ethyl acetate:heptanes) provided the title compound. MS (ESI) m/z 461.1 (M+H) + .
Example 603
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 445.1 (M+H) + .
Example 604
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro furan-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 445.1 (M+H) + .
Example 605
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
Example 605A
N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine
To Example 396A (80 mg, 0.26 mmol) in dimethylsulfoxide (0.3 mL) was added 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (80 mg, 0.35 mmol) and cesium carbonate (120 mg, 0.37). The mixture was stirred at 120° C. for 4 hours and then partitioned between ethyl acetate and water. The organic fraction was dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 605B
N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine
To Example 605A in dichloromethane (1 mL) was added meta-chloroperbenzoic acid (<77%, 320 mg, 1.4 mmol). The mixture was allowed to stir for 3 days. Then the mixture was partition between sodium metabisulfite (aq.) and ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 605C
2-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
To a solution of Example 605B (0.19 g, 0.36 mmol) in methanol (1 mL) was added sodium methoxide (21% in methanol, 1 mL). The mixture was stirred at 100° C. for 2 hours and, partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by HPLC to provide the title compound. MS (EST) m/z 483 (M+H) + .
Example 606
6-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
To a solution of Example 574A (586 mg, 1.85 mmol) in methanol (10 mL) was added 4,6-dichloropyrimidine (829 mg, 5.6 mmol) and triethylamine (0.52 mL, 3.7 mmol). The reaction heated at 50 C for 1 hour. More 4,6-dichloropyrimidine (800 mg) was added and the reaction stirred for 18 hours. The reaction mixture was concentrated. Purification via flash chromatography (0-100% EtOAc/Hexanes) provided the title compound. MS (ESI) m/z 419 (M+H) + .
Example 607
1-cyclopropyl-N-({(3R,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}methyl)methanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 586 for Example 242E. MS (ESI) m/z 393.1 (M+H) + .
Example 608
(3R,4S)—N-(2-ethoxyethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
To a solution of Example 600B (70 mg, 0.16 mmol) in tetrahydrofuran (7 ml) under nitrogen was added iodoethane (43.6 mg, 0.28 mmol) and sodium hydride (18.6 mg, 0.47 mmol). This solution was stirred at 60° C. for 1 hour, and then it was cooled to room temperature. To the reaction mixture was added hydrochloric acid (4N in dioxane 0.7 mL) and the solution stirred at room temperature for 1 hour. The reaction mixture was then concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate (aq.). The organic fraction was collected, concentrated, and purified by HPLC to afford the title product. MS (ESI) m/z 379.1 (M+H) + .
Example 609
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-propoxyethyl)pyrrolidin-3-amine
Example 609A
Tert-butyl 2-(allyl oxy)ethyl((3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 600B (73 mg, 0.16 mmol) in dimethylformamide (0.5 mL) under nitrogen at 0° C. was added allyl bromide (98 mg, 0.81 mmol) and sodium hydride (19.44 mg, 0.49 mmol). This mixture was stirred at 0° C. for 30 minutes, partitioned between ethyl acetate and water. The organic fraction was collected and concentrated to afford the title compound. MS (ESI) m/z 491.3 (M+H) + .
Example 609B
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(2-prop oxyethyl)pyrrolidin-3-amine
To a solution of Example 609A (79 mg, 0.161 mmol) in tetrahydrofuran (15 ml) in a 50 ml pressure bottle was added 5% Pd/C, wet (8 mg, 1.879 μmol). The solution was stirred for 30 minutes under 50 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated. The concentrate was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.3 mL) was added. This solution was stirred at room temperature for 1 hour, concentrated, and purified via HPLC to afford the title compound. MS (ESI) m/z 393.1 (M+H) + .
Example 610
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 3,4-difluoro-1-bromobenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (100% ethyl acetate) provided the title compound. MS (ESI) m/z 413.0 (M+H) + .
Example 611
N-(3,4-difluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 3,4-difluoro-1-bromobenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (100% ethyl acetate) provided the title compound. MS (ESI) m/z 413.0 (M+H) + .
Example 612
6-cyclopropyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-6-cyclopropylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 613
6-ethyl-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-ethylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 431.1 (M+H) + .
Example 614
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(propan-2-yl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 380A for Example 337F and substituting 4-bromo-6-isopropylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 445.1 (M+H) + .
Example 615
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-methyl-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 485 (M+H) + .
Example 616
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-propylpyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 4-chloro-6-propylpyrimidine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 445 (M+H) + .
Example 617
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 605A substituting Example 380A for Example 396A and substituting 2,5-dichloro-4-(trifluoromethyl)pyridine for 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine. MS (ESI) m/z 504506 (3:1) (M+H) + .
Example 618
(3S,4R)—N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-4-chloro-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 479.3 (M+H) + .
Example 619
(3R,4S)—N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 601B for Example 14A and substituting 1-bromo-4-chloro-3-fluoromethylbenzene for 1-bromo-2-methylbenzene. Purification via flash chromatography (3:1 ethyl acetate:heptane) provided the title compound. MS (ESI) m/z 479.3 (M+H) + .
Example 620
6-ethoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
A microwave vial was charged with Example 606 (100 mg, 0.24 mmol), ethanol (2 mL), and sodium tert-butoxide (115 mg, 1.2 mmol). The reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) at 120° C. for 10 minutes. Purification via HPLC provided the title compound. MS (ESI) m/z 429 (M+H) + .
Example 621
6-methoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting methanol for ethanol. MS (ESI) m/z 415 (M+H) + .
Example 622
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-propoxypyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting propanol for ethanol. MS (ESI) m/z 443 (M+H) + .
Example 623
6-butoxy-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting butanol for ethanol. MS (ESI) m/z 457 (M+H) + .
Example 624
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-6-(2-methylpropoxy)pyrimidin-4-amine
The title compound was prepared similarly to Example 620 substituting isobutanol for ethanol. MS (ESI) m/z 457 (M+H) + .
Example 625
4-{[(3S,4R)-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
Example 625A
Trans-tert-butyl 3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidine-1-carboxylate
To Example 379A (140 mg, 0.5 mmol) in dimethylformamide (0.5 mL) was added sodium hydride (35 mg, 60%, 0.9 mmol) and 1-bromohexane (150 mg, 0.91 mmol). The mixture was stirred at 100° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic fraction was collected, and the aqueous fraction was washed with ethyl acetate 3 time. The organic fractions were combined, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 625B
Trans-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidine
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 625A for Example 373A.
Example 625C
4-{[Trans-3-(4-fluorophenyl)-4-(hexyloxy)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 625B for Example 373B. MS (ESI) m/z 410 (M+H) + .
Example 626
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting pentan-1-amine for aniline. MS (ESI) m/z 423.1 (M+H) + .
Example 627
Trans-4-(4-fluorophenyl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting hexan-1-amine for aniline. MS (ESI) m/z 437.1 (M+H) + .
Example 628
Trans-N-(3-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 3-chlorobenzylamine for aniline. MS (ESI) m/z 477.2 (M+H) + .
Example 629
Trans-N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-chlorobenzylamine for aniline. MS (ESI) m/z 477.2 (M+H) + .
Example 630
Trans-N-(4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 4-fluorobenzylamine for aniline. MS (ESI) m/z 461 (M+H) + .
Example 631
Trans-N-(3,4-difluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3,4-difluorophenyl)methanamine for aniline. MS (ESI) m/z 479.3 (M+H) + .
Example 632
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)benzyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-(trifluoromethyl)phenyl)methanamine for aniline. 45 mg (31%) of the product was obtained. MS (ESI) m/z 511.3 (M+H) + .
Example 633
Trans-N-[2-chloro-5-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (2-chloro-5-(trifluoromethyl)phenyl)methanamine for aniline. MS (ESI) m/z 545.3 (M+H) + .
Example 634
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting pyridin-2-ylmethanamine for aniline. MS (ESI) m/z 444.2 (M+H) + .
Example 635
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (4-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride for aniline. MS (ESI) m/z 512.2 (M+H) + .
Example 636
Trans-N,N-dibutyl-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting dibutylamine for aniline. MS (EST) m/z 465.2 (M+H) + .
Example 637
6-methyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-6-methylpyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 399 (M+H) + .
Example 638
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-methyl-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 639
4-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)-2-(trifluoromethyl)benzonitrile
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-2-(trifluoromethyl)benzonitrile for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 494 (M+H) + .
Example 640
4-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-propyl-1H-1,2,3-triazole
Example 640A
4-((trans-3-(2,2-dibromovinyl)-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole
To a solution of Example 332A (0.39 g, 1.2 mmol) in dichloromethane (10 mL) was added carbon tetrabromide (0.38 g, 1.2 mmol) and triphenylphosphine (0.61 g, 2.3 mmol) in portions. The mixture was stirred for 2 hours, concentrated, and purified by flash chromatography (100% ethyl acetate) to afford the title compound.
Example 640B
4-(((3S,4S)-3-ethynyl-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole
To a solution of Example 640A (0.24 g, 0.49 mmol) in tetrahydrofuran (1 mL) at −78° C. was added butyllithium (2N, 0.5 mL, 1 mmol). The mixture was stirred for 1 hour and then warmed to room temperature. The mixture was stirred for 1 hour at room temperature, and then partitioned between ammonium chloride (aq.) and ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 640C
1-azidopropane
To a solution of 1-bromo propane (2.4 g, 20 mmol) in tetrahydrofuran (15 mL) was added sodium azide (1.3 g, 20 mmol) and water (1 mL). The mixture was stirred at 70° C. for 2 hours and this solution containing the title compound was used for Example 604D.
Example 640D
4-{Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-1-propyl-1H-1,2,3-triazole
To Example 640B (0.18 g, 0.54 mmol) in half of Example 604C solution was added CuI (90 mg, 0.5 mmol). The mixture was heated at 70° C. for 5 hours, concentrated, and partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 419 (M+H) + .
Example 641
4-[-1-cyclopropyl)piperidin-3-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 641A
tert-Butyl (-1-benzyl-4-(pyridin-3-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared in similarly to the procedures described in Example 2A-2C substituting 3-(2-nitroethenyl)pyridine for trans-4-methoxy-beta-nitrostyrene. MS (DCI) m/z 354.2 (+H) + .
Example 641B
tert-butyl 1-benzyl-4-(piperidin-3-yl)pyrrolidin-3-ylcarbamate
A solution of Example 641A (3.9 g, 11.03 mmol) in acetic acid (80 mL) was added to 5% platinum on carbon (50% water, 1.1 g) in a stainless steel pressure bottle. The vessel was pressurized with 30 psi of hydrogen and shaken for 8 hours at room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.
Example 641C
tert-butyl 1-benzyl-4-(1-cyclopropylpiperidin-3-yl)pyrrolidin-3-ylcarbamate
641B (1.0 g, 2.78 mmol), 1-ethoxycyclopropoxy-trimethylsilane (1.16 g, 6.68 mmol) and sodium cyanoborohydride (327 mg, 5.2 mmol) in methanol (10 ml) was stirred and heated to 60° C. under nitrogen for six hours. The reaction was then concentrated and the residue was taken up in ethyl acetate. The organic solution was washed with water, brine, and dried over sodium sulfate. The organic mixture was filtered, concentrated, and purified via flash chromatography (97.5:2.5 dichloromethane:2N ammonia in methanol) to afford the title compound.
Example 641D
4-(1-cyclopropylpiperidin-3-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Examples 2D-2F substituting the 641C for Example 2C.
Example 641E
4-[-1-cyclopropylpiperidin-3-yl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 641D for Example 14A and substituting 1-bromo-3-trifluoromethylbenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 514.2 (M+H) + .
Example 642
Trans-N-(3-chloro-4-fluorobenzyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-chloro-4-fluorophenyl)methanamine for aniline. MS (ESI) m/z 495.2 (M+H) + .
Example 643
Trans-4-(4-fluorophenyl)-N-(6-methylheptyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 6-methylheptan-1-amine for aniline. MS (ESI) m/z 465.2 (M+H) + .
Example 644
2-(4-fluorophenoxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}acetamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-fluorophenoxyacetic acid for Example 242D. MS (ESI) m/z 477.5 (M+H) + .
Example 645
(3R,4S)—N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 469 (M+H) + .
Example 646
(3R,4S)—N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 647
(3R,4S)—N-(4-methoxybutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 647A
methyl 4-(((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)amino)butanoate
The title compound was prepared similarly to the procedure described in Example 354E substituting methyl 4-oxobutanoate for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D.
Example 647B
methyl 4-((tert-butoxycarbonyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)amino)butanoate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 647A for Example 337B.
Example 647C
tert-butyl (4-hydroxybutyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
To a solution of Example 647B (140 mg, 0.28 mmol) in dichloromethane (1 mL) at −78° C. was added diisobutylaluminum hydride (0.5 mL, 1N in hexanes, 0.5 mmol). The mixture was allowed to stir for 45 minutes. The mixture was quenched and partitioned with ethyl acetate and sodium hydrideCO 3 (aq). The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 647D
(3R,4S)—N-(4-methoxybutyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 647C for Example 588C. MS (ESI) m/z 393 (M+H) + .
Example 648
(3R,4S)—N-(4-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 648A
tert-butyl ((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)(4-oxobutyl)carbamate
To a solution of Example 647B (140 mg, 0.28 mmol) in dichloromethane (1 mL) at −78° C. was added Diisobutylaluminum hydride (0.5 mL, 1N in hexanes, 0.5 mmol). The mixture was stirred for 45 minutes, and then quenched with ethyl acetate and sodium bicarbonate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the crude title compound.
Example 648B
tert-butyl (4-hydroxyhexyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 382B substituting Example 648A for Example 382A and substituting EtMgBr for BnMgBr.
Example 648C
(3R,4S)—N-(4-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 648B for Example 588C. MS (ESI) m/z 421 (M+H) + .
Example 649
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
Example 649A
Cis-2-propylcyclopropyl)methanol
To a solution of (Z)-hex-2-en-1-ol (200 mg, 2 mmol) in dichloromethane (4 mL) was added diiodomethane (0.66 g, 2.5 mmol), then diethylzinc (4 mL, 1N), 4 mmol) dropwise under nitrogen. The mixture was allowed to stir for 16 hours, and was then quenched with ammonium chloride (aq) hydrochloric acid (aq). Ethyl acetate was added and the mixture partitioned. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 649B
Cis-2-propylcyclopropanecarbaldehyde
To a solution of Example 649A (200 mg, 1.75 mmol) in dichloromethane (1 mL) was added Dess-Martin periodinane (424 mg, 1 mmol). The mixture was stirred for 1 hour, and then quenched with sodium bisulfate (aq), and extracted with dichloromethane. The organic extracts were dried over MgSO 4 , filtered, and concentrated to nearly dry to provide a concentrated dichloromethane solution of the title compound.
Example 649C
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 649B for 4-chlorobenzaldehyde and Example 396A for Example 354D. MS (ESI) m/z 403
Example 650
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
Example 650A
(Trans-2-propylcyclopropyl)methanol
The title compound was prepared similarly to the procedure described in Example 649A substituting (E)-hex-2-en-1-ol for (Z)-hex-2-en-1-ol.
Example 650B
Trans-2-propylcyclopropanecarbaldehyde
The title compound was prepared similarly to the procedure described in Example 649B substituting Example 650A for Example 649A.
Example 650C
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[(2-propylcyclopropyl)methyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting Example 650B for 4-chlorobenzaldehyde and substituting Example 396A for Example 354D. MS (ESI) m/z 403 (M+H) +
Example 651
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 503 (M+H) + .
Example 652
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 503 (M+H) + .
Example 653
(3R,4S)—N-[4-methoxy-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 4-bromo-1-methoxy-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 481 (M+H) + .
Example 654
(3R,4S)—N-(1-benzothiophen-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromobenzo[b]thiophene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439 (M+H) + .
Example 655
(3R,4S)—N-(2,3-dihydro-1H-inden-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromo-2,3-dihydro-1H-indene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 656
(3R,4S)—N-[3,4-bis(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-3,4-bis(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 519 (M+H) + .
Example 657
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 6-bromo-1,2,3,4-tetrahydronaphthalene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 437 (M+H) + .
Example 658
(3R,4S)—N-(3,4-dihydro-2H-chromen-6-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 6-bromochroman for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 439 (M+H) + .
Example 659
4-({(3S,4R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-1-propyl-1H-1,2,3-triazole
Example 659A
1-benzyl-4-phenylpyrrolidin-2-one
To a solution of 4-phenylpyrrolidin-2-one (1 g, 6.2 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (60%, 280 mg, 7 mmol). Benzylbromide was added after 10 minutes. The mixture was allowed to stir at. 65° C. for 2 hours. The reaction mixture was, quenched with ammonium chloride (aq) and partitioned with ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 659B
Trans-1-benzyl-4-phenyl-3-(prop-2-yn-1-yl)pyrrolidin-2-one
To a solution of diisopropylamine (700 mg, 7 mmol) in tetrahydrofuran (7 mL) at −78° C. was added butyllithium (2N, 3.1 mL, 6.2 mmol). The mixture was allowed to stir for 10 minutes. Example 659A (1.56 g, 6.2 mmol) in tetrahydrofuran (5 mL) was added. The mixture was allowed to stir for 30 minutes. Propargyl bromide (0.7 mL, 80% toluene solution, 6.2 mmol) in tetrahydrofuran (3 mL) was added. The mixture was allowed to stir for 1 hour, quenched with ammonium chlorid (aq), and partitioned with ethyl acetate. The organic fraction was collected, concentrated, and purified via flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 659C
Trans-1-benzyl-4-phenyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-2-one
The title compound was prepared similarly to the procedure described in Example 640D substituting Example 659B for Example 640B.
Example 659D
4-((trans-1-benzyl-4-phenylpyrrolidin-3-yl)methyl)-1-propyl-1H-1,2,3-triazole
To a solution of Example 659C (0.32 g, 0.86 mmol) in tetrahydrofuran (3 mL) was added lithium aluminumhydride in tetrahydrofuran (2N, 1 mL, 2 mmol). The mixture was allowed to stir for 3 hours. It was then quenched with methanol, followed by sodium bicarbonate (aq). The mixture was partitioned with ethyl acetate. The organic fraction was dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 659E
4-((trans-4-phenylpyrrolidin-3-yl)methyl)-1-propyl-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 659D for Example 2C.
Example 659F
4-({Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-1-propyl-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 659E for Example 373B. MS (ESI) m/z 415 (M+H) + .
Example 660
(3R,4S)—N-(1-benzo furan-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromobenzofuran for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 661
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)benzyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (3-(trifluoromethoxy)phenyl)methanamine for aniline. MS (ESI) m/z 527.2 (M+H) + .
Example 662
methyl 5-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}amino)-5-oxopentanoate
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline, methyl hydrogen glutarate for Example 242D. MS (ESI) m/z 453.3 (M+H) + .
Example 663
(3R,4S)—N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidine-3-carboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting (2-chloro-4-(trifluoromethyl)phenyl)methanamine for aniline. MS (ESI) m/z 545.3 (M+H) + .
Example 664
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting valeraldehyde for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 395.2 (M+H) + .
Example 665
(3R,4S)-4-(4-fluorophenyl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 409.2 (M+H) + .
Example 666
(3R,4S)—N-[2-(2-methoxyethoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 666A
2-(2-methoxyethoxy)-N-((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting Example 396A for Example 14A and substituting 2-(2-methoxyethoxy)acetic acid for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 666B
(3R,4S)—N-[2-(2-methoxyethoxy)ethyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 666A for Example 404A. MS (ESI) m/z 409 (M+H) + .
Example 667
(3R,4S)—N-[2-(4-fluorophenoxy)ethyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 644 for Example 242E. MS (ESI) m/z 463.1 (M+H) + .
Example 668
4-butyl-1-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-31)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,3-triazole
Example 668A
Ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)acetate
The title compound was prepared similarly to the procedure described in Example 640D substituting hex-1-yne for Example 640B and substituting ethyl 2-azidoacetate for Example 640C.
Example 668B
ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)-4-nitro-3-phenylbutanoate
The title compound was prepared similarly to the procedure described in Example 331A substituting Example 668A for methyl 3-(3-chlorophenyl)propanoate.
Example 668C
Trans-3-(4-butyl-1H-1,2,3-triazol-1-yl)-4-phenylpyrrolidin-2-one
To Example 668B (530 mg, 1.5 mmol) in ethanol (10 mL) was added Raney nickel, water slurry (616 mg, 10.5 mmol) in a 20 mL pressure bottle. The mixture was stirred under 60 psi of hydrogen at room temperature for 2 days. The mixture was filtered through a polypropylene membrane and concentrated to provide the title compound.
Example 668D
4-Butyl-1-(Trans-4-phenylpyrrolidin-3-yl)-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 668C for Example 404A.
Example 668E
4-butyl-1-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-1H-1,2,3-triazole
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 668D for Example 373B. MS (ESI) m/z 375 (M+H) + . MS (ESI) m/z 415 (M+H) + .
Example 669
(3R,4S)—N-(4-chloro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-4-chloro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 431 (M+H) + .
Example 670
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 481 (M+H) + .
Example 671
(3R,4S)—N-(2,3-dihydro-1-benzofuran-5-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 5-bromo-2,3-dihydrobenzofuran for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 672
(3R,4S)—N-(4,4-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 6-bromo-4,4-dimethylchroman for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 485 (M+H) + .
Example 673
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-hydroxyhexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting DL-alpha-hydroxycaproic acid for Example 242D. MS (ESI) m/z 439.2 (M+H) + .
Example 674
(3R,4S)—N-(3-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
Example 674A
tert-butyl (3-hydroxyhexyl)((3R,4S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenylpyrrolidin-3-yl)carbamate
A mixture of hex-1-en-3-one (38 mg, 0.4 mmol) and Example 396A (120 mg, 0.4 mmol) in methanol (0.5 mL) was allowed to stir overnight. Sodium borohydride (15 mg, 0.4 mmol) was added to the solution. The mixture was stirred for 30 minutes, di-tert-butyl dicarbonate (100 mg, 0.45 mmol) was added. The mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic fraction was collected, concentrated, and purified by flash chromatography (100% ethyl acetate). to afford the title compound.
Example 674B
(3R,4S)—N-(3-methoxyhexyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 588D substituting Example 674A for Example 588C. MS (ESI) m/z 421 (M+H) + .
Example 675
(3R,4S)—N-[4-chloro-3-(propan-2-yl)phenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-1-chloro-2-isopropylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 477 (M+H) + .
Example 676
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-methyl-4-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-bromo-3-methyl-1-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 677
(3R,4S)—N-(1-benzothiophen-6-yl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 6-bromobenzo[b]thiophene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 457 (M+H) + .
Example 678
4-(1-cyclopropylpiperidin-4-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
Example 678A
(E)-tert-butyl 4-(2-nitrovinyl)piperidine-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 601A substituting 4-formylpiperidine-1-carboxylic acid-t-butyl ester for tetrahydrofuran-2-carboxaldehyde. MS (DCI) m/z 274.1 (M+NH 4 ) +
Example 678B
4-(1-cyclopropylpiperidin-4-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 678A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 678C
4-(1-cyclopropylpiperidin-4-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 514.2 (M+H)+
Example 679
(3R,4S)—N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
Example 679A
tetrahydro-2H-pyran-2-carbaldehyde
To a solution of oxalyl chloride (1.3 g, 10 mmol) in dichloromethane (20 mL) at −78° C. was added dimethylsulfoxide (1.3 g, 17 mmol). The mixture was stirred for 10 minutes. A solution of (tetrahydro-2H-pyran-2-yl)methanol (1.2 g, 10 mmol) in dichloromethane (20 mL) was added. The mixture was stirred for 15 minutes at room temperature. The mixture was washed with water. The organic fraction was dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 679B
(E)-2-(2-nitrovinyl)tetrahydro-2H-pyran
To a solution of Example 679A (1.2 g, 10 mmol) in nitromethane (5 mL) was added pyrrolidine (100 mL). The mixture was allowed to stir overnight and concentrated to afford the title compound.
Example 679C
Trans-1-benzyl-3-nitro-4-(-tetrahydro-2H-pyran-2-yl)pyrrolidine
The title compound was prepared similarly to the procedure described in Example 2A substituting Example 679B for 4-methoxy-beta-nitrostyrene.
Example 679D
Trans-1-benzyl-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 2B substituting Example 679C for Example 2A
Example 679E
tert-butyl (trans-1-benzyl-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 337C substituting Example 679D for Example 337B.
Example 679F
tert-butyl (trans-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 2D substituting Example 679E for 2C
Example 679G
tert-butyl (trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl)carbamate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 679F for Example 373B
Example 679H
Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337F substituting Example 679G for Example 337E.
Example 679I
Trans-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 679H for Example 354D. MS (ESI) m/z 399 (M+H) + .
Example 680
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting Example 679H for Example 354D. MS (ESI) m/z 507509 (3:1) (M+H) + .
Example 681
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F. MS (ESI) m/z 459 (M+H) + .
Example 682
N-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 460 (M+H) + .
Example 683
N-{Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-4-(trifluoromethyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 460 (M+H) + .
Example 684
(3R,4S)—N-[4-(4,4-dimethyl-1,3-dioxan-2-yl)butyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 5,5-dimethyl-2-(3′-formylpropyl)-1,3-dioxane for 4-chlorobenzaldehyde and substituting Example 380A for Example 354D. MS (ESI) m/z 495.1 (M+H) + .
Example 685
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 686
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[tetrahydro-2H-pyran-2-yl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 687
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 461 (M+H) + .
Example 688
N-[2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]propan-1-amine
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 689E for Example 404A. MS (ESI) m/z 411 (M+H) + .
Example 689
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-N-propylacetamide
Example 689A
Trans-tert-butyl 3-(4-fluorophenyl)-4-(2-methoxy-2-oxoethoxy)pyrrolidine-1-carboxylate
To a solution of Example 379A (0.56 g, 2 mmol) in dimethylformamide (2 mL) was added methyl 2-bromoacetate (0.38 g, 2.5 mmol) and sodium hydride (60%, 120 mg, 3 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was partitioned with water and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound.
Example 689B
methyl 2-((trans-4-(4-fluorophenyl)pyrrolidin-3-yl)oxy)acetate
The title compound was prepared as the hydrochloride salt similarly to the procedure described in Example 373B substituting Example 689A for Example 373A.
Example 689C
methyl 2-((trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetate
The title compound was prepared similarly to the procedure described in Example 373C substituting Example 689B for Example 373B.
Example 689D
2-((Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetic acid
Example 689C (0.11 g, 0.28 mmol) was dissolved in a solution of lithium hydroxide (methanol:water. 5:3, 1N, 3 mL). The mixture was stirred for 2 hours. Hydrochloric acid (aq) was added to adjust the pH value to 2. The mixture was partitioned with ethyl acetate. The organic fraction was collected, dried over MgSO 4 , filtered, and concentrated to provide the title compound.
Example 689E
2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-N-propylacetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting propyl amine for Example 14A and Example 689D for 2-nitro-5-(trifluoromethyl)benzoic acid. MS (ESI) m/z 425 (M+H) + .
Example 690
6-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-2-methylpyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 606 substituting Example 322B for Example 574A and substituting 4,6-dichloro-2-methylpyrimidine for 4,6-dichloropyrimidine. MS (ESI) m/z 451 (M+H) + .
Example 691
6-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 606 substituting Example 322B for Example 574A but heated at 120° C. for 10 minutes in a microwave (Biotage Initiator™, maximum 400 Watts). MS (ESI) m/z 437 (M+H) + .
Example 692
1-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3-phenylurea
A microwave vial was charged with Example 322B (50 mg, 0.15 mmol), isocyanatobenzene (20 mg, 0.17 mmol), triethylamine (65 μL, 0.46 mmol) and tetrahydrofuran (2 mL). The reaction mixture was heated in a microwave (Biotage Initiator™, maximum 400 Watts) at 100° C. for 10 minutes. Purification via HPLC provided the title compound. MS (ESI) m/z 444 (M+H) + .
Example 693
phenyl {(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}carbamate
The title compound was prepared similarly to Example 692 substituting phenyl carbonochloridate for isocyanatobenzene. MS (ESI) m/z 445 (M+H) + .
Example 694
1-(2-chlorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-2-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 478 (M+H) + .
Example 695
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-5-oxohexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-acetylbutyric acid for Example 242D. MS (ESI) m/z 437.1 (M+H) + .
Example 696
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)cyclohexanecarboxamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-(trifluoromethyl)cyclohexanecarboxylic acid for Example 242D. MS (ESI) m/z 503.3 (M+H) + .
Example 697
butyl (3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl carbonate
Example 697A
Trans-tert-butyl 3-(butoxycarbonyloxy)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate
The title compound was prepared similarly to the procedure described in Example 699A substituting butyl carbonochloridate for 1-isocyanatobutane.
Example 697B
Butyl-trans-4-(4-fluorophenyl)pyrrolidin-3-yl carbonate
The title compound was prepared similarly to the procedure described in Example 699B substituting Example 697A for Example 699A.
Example 697C
Butyl-trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl carbonate
The title compound was prepared similarly to the procedure described in Example 699C substituting Example 697B for Example 699B. MS (ESI) m/z 426.0 (M+H) + .
Example 698
5,5,5-trifluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 5,5,5-trifluoropentanoic acid for Example 242D. MS (ESI) m/z 463.1 (M+H) + .
Example 699
(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl butylcarbamate
Example 699A
Trans-tert-butyl 3-(butylcarbamoyloxy)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate
To a solution of Example 379A (155 mg, 0.55 mmol) in dichloromethane (1.5 mL) was added triethylamine (167 mg, 1.65 mmol) and 1-isocyanatobutane (109 mg, 1.10 mmol). The solution was stirred at room temperature for 16 hours. The mixture was partitioned between dichloromethane and water. The organic fraction was collected, dried over sodium sulfate, concentrated, and purified by flash chromatography (25% ethyl acetate/hexanes) to provide the title compound.
Example 699B
Trans-4-(4-fluorophenyl)pyrrolidin-3-yl butylcarbamate
To a solution of Example 699A (85.5 mg, 0.23 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at room temperature for 1 hour, and was then concentrated to afford title compound.
Example 699C
Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl butylcarbamate
To a solution of Example 699B (63 mg, 0.23 mmol) in dichloromethane (1 mL) was added triethylamine (68.2 mg, 0.67 mmol) and 4-dimethylaminopyridine (1.4 mg, 0.011 mmol). The solution was cooled 0° C. To the chilled solution was added 1-methyl-1H-imidazole-4-sulfonyl chloride (42.6 mg, 0.24 mmol) portionwise. This mixture was slowly warmed up to room temperature over 1 hour and stirred at room temperature for 1 hour. The reaction mixture was partitioned with dichloromethane and water. The organic layer was collected, concentrated, and purified via HPLC to provide the title compound. MS (ESI) m/z 425.1 (M+H) + .
Example 700
2,2-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 2,2-difluorohexanoic acid for Example 242D. MS (ESI) m/z 459.2 (M+H) + .
Example 701
1-(4-chlorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-4-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 478 (M+H) + .
Example 702
1-(2-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-2-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 703
1-(3-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-3-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 704
1-(4-fluorophenyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-fluoro-4-isocyanatobenzene for isocyanatobenzene. MS (ESI) m/z 462 (M+H) + .
Example 705
1-(2-chlorobenzyl)-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to Example 692 substituting 1-chloro-2-(isocyanatomethyl)benzene for isocyanatobenzene. MS (ESI) m/z 492 (M+H) + .
Example 706
4,5-dichloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
To a stirred solution of Example 322B (100 mg, 0.31 mmol) in dimethylsulfoxide (4 mL) was added 2,4,5-trichloropyridine (112 mg, 0.62 mmol) and sodium tert-butoxide (59 mg, 0.062 mmol). The reaction mixture was heated at 90° C. for 18 hours, then concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 470.5 (M+H) + .
Example 707
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-{[4-(trifluoromethyl)cyclohexyl]methyl}pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 696 for Example 242E. MS (ESI) m/z 489.1 (M+H) + .
Example 708
2,2-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}hexanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 2,2-difluorohexanoic acid for Example 242D. MS (EST) m/z 459.2 (M+H) + .
Example 709
Trans-N-[3,4-difluorophenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
Example 709A
(E)-2-(2-nitrovinyl)oxazole
The title compound was prepared similarly to the procedure described in Example 601A substituting oxazole-2-carboxaldehyde for tetrahydrofuran-2-carboxaldehyde. MS (DCI) m/z 141.0 (M+H) +
Example 709B
(3R,4S)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Examples 2A-2F substituting Example 709A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 709C
Trans-N-[3,4-difluorophenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 709C for Example 14A and substituting 1-bromo-3,4-difluorobenzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 410.1 (M+H) + .
Example 710
N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-2-yl)pyrrolidin-3-amine
The title compound was prepared as described in Example 709C substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3,4-difluorobenzene. MS (ESI) m/z 476.0 (M+H) +
Example 711
4-{[trans-3-[(4-fluorobenzyl)oxy]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-fluorobenzyl bromide for 1-bromohexane. MS (ESI) m/z 434 (M+H) + .
Example 712
4-{[trans-3-[(3-fluorobenzyl)oxy]-4-(4-fluorophenyl)pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 3-fluorobenzyl bromide for 1-bromohexane. MS (ESI) m/z 434 (M+H) + .
Example 713
4-{[trans-3-(4-fluorophenyl)-4-{[4-(methylsulfonyl)benzyl]oxy}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-methylsulfonylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 494 (M+H) + .
Example 714
4-{[trans-3-(4-fluorophenyl)-4-{[3-(methylsulfonyl)benzyl]oxy}pyrrolidin-1-yl]sulfonyl}-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 3-methylsulfonylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 494 (M+H) + .
Example 715
6-ethoxy-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606. MS (ESI) m/z 447 (M+H) + .
Example 716
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(propan-2-yloxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting isopropanol for ethanol. MS (ESI) m/z 461 (M+H) + .
Example 717
6-butoxy-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting n-butanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 718
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(2-methylpropoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting iso-butanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 719
6-(cyclobutyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclobutanol for ethanol. MS (ESI) m/z 473 (M+H) + .
Example 720
6-(cyclopentyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclopentanol for ethanol. MS (ESI) m/z 487 (M+H) + .
Example 721
6-(cyclohexyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 620 substituting Example 691 for Example 606 and substituting cyclohexanol for ethanol. MS (ESI) m/z 487 (M+H) + .
Example 722
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-phenylpyrimidin-4-amine
A microwave vial was charged with Example 722 (50 mg, 0.11 mmol), phenylboronic acid (14 mg, 0.12 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (4.7 mg, 11 μmol), potassium carbonate (2M, 57 μL, 0.14 mmol)), palladium(II) acetate (1.3 mg, 5.7 μmol), and 1,2-dimethoxyethane (2 mL). The reaction mixture was heated to 100° C. in a microwave (Biotage Initiator™, maximum 400 Watts) for 10 minutes. The reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 479 (M+H) + .
Example 723
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(2-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting o-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 724
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(3-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting m-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 725
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(4-methylphenyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting p-tolylboronic acid for phenylboronic acid. MS (ESI) m/z 493 (M+H) + .
Example 726
6-(2-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 2-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 727
6-(3-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 3-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 728
6-(4-fluorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 4-(fluorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 729
6-(3-chlorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 3-(chlorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 513 (M+H) + .
Example 730
6-(4-chlorophenyl)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 722 substituting 4-(chlorophenyl)boronic acid for phenylboronic acid. MS (ESI) m/z 513 (M+H) + .
Example 731
4-({(3S,4R)-3-(4-fluorophenyl)-4-[(4-methylbenzyl)oxy]pyrrolidin-1-yl}sulfonyl)-1-methyl-1H-imidazole
The title compound was prepared similarly to the procedure described in Example 625A substituting Example 379C for Example 379A and substituting 4-methylbenzyl bromide for 1-bromohexane. MS (ESI) m/z 430 (M+H) + .
Example 732
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(5,5,5-trifluoropentyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 698 for Example 242E. MS (ESI) m/z 449.1 (M+H) + .
Example 733
(3R,4S)—N-(2,2-difluorohexyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 700 for Example 242E. MS (ESI) m/z 445.1 (M+H) + .
Example 734
(3R,4S)—N-(2,2-difluoropentyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 700 for Example 242E. MS (ESI) m/z 431.1 (M+H) + .
Example 735
5,5-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}hexanamide
To a solution of Example 695 (200 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was added diethylaminosulfur trifluoride (258 mg, 1.60 mmol). The reaction mixture stirred at 0° C. for 1 hour and then room temperature for 2 days. The reaction mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic fraction was collected, washed with water, concentrated, and purified by HPLC to provide the title compound. MS (ESI) m/z 459.1 (M+H) + .
Example 736
4-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-chloro-4-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (DCI) m/z 420.1 (M+H) + .
Example 737
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-chloro-5-fluoropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (DCI) m/z 420 (M+H) + .
Example 738
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-oxopentanamide
The title compound was prepared similarly to the procedure described in Example 242E substituting Example 380A for aniline and substituting 4-oxopentanoic acid for Example 242D. MS (ESI) m/z 423.0 (M+H) + .
Example 739
(3R,4S)—N-(5,5-difluorohexyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 735 for Example 242E. MS (ESI) m/z 445.2 (M+H) +
Example 740
4-chloro-N-[2-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]aniline
Example 740A
N-(4-fluorophenyl)-2-((trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)acetamide
The title compound was prepared similarly to the procedure described in Example 404A substituting 4-fluoroaniline for Example 14A and substituting Example 689D for 2-nitro-5-(trifluoromethyl)benzoic acid.
Example 740B
4-chloro-N-[2-({Trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]aniline
The title compound was prepared similarly to the procedure described in Example 404B substituting Example 740A for Example 404A. MS (ESI) m/z 479481 (3:1) (M+H) + .
Example 741
(3S,4R)—N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 493 (M+H) + .
Example 742
1-benzyl-3-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}urea
The title compound was prepared similarly to the procedure described in Example 692 substituting (isocyanatomethyl)benzene for isocyanatobenzene. MS (ESI) m/z 458 (M+H) + .
Example 743
(3R,4S)—N-(4-chloro-3-methylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-4-chloro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 449 (M+H) + .
Example 744
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 499 (M+H) + .
Example 745
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyridin-3-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
A solution of Example 352 (100 mg, 0.22 mmol), pyridine-3-ylboronic acid (41 mg, 0.33 mmol), tricyclohexylphosphine (6.2 mg, 22 μmol), potassium phosphate (1.2 M (aq.), 0.36 mL, 442 mmol)) and palladium(II) acetate (10 mg, 11 μmol) in dioxane (2 mL) was stirred at 100° C. for 18 hours. The reaction mixture was concentrated. Purification via HPLC provided the title compound. MS (ESI) m/z 496 (M+H) + .
Example 746
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyridin-4-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting pyridin-4-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 496 (M+H) + .
Example 747
(3R,4S)—N-(4-fluoro-3-methylphenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 1-bromo-4-fluoro-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 433 (M+H) + .
Example 748
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-methylpyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 434 (M+H) + .
Example 749
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting pyrimidin-5-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 497 (M+H) + .
Example 750
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-3,4′-bipyridin-2′-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting Example 759 for Example 352. MS (ESI) m/z 479 (M+H) + .
Example 751
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4,4′-bipyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 745 substituting Example 759 for Example 352 and substituting pyridin-4-ylboronic acid for pyridine-3-ylboronic acid. MS (ESI) m/z 479 (M+H) + .
Example 752
4-({(3S,4R)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)-6-(trifluoromethyl)pyrimidine
The title compound was prepared similarly to the procedure described in Example 379D substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 2-fluoro-4-(trifluoromethyl)pyridine. MS (ESI) m/z 472 (M+H) + .
Example 753
N-[(3R,4S)-4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-4-yl)pyrrolidin-3-amine
Example 753A
(E)-4-(2-nitrovinyl) oxazole
The title compound was prepared similarly to the procedure described in Example 601A substituting 4-oxazolecarboxaldehyde for tetrahydrofuran-2-carboxaldehyde.
Example 753B
(trans)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-(oxazol-4-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting Example 753A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 753C
N-[(3R,4S)-4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(1,3-oxazol-4-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 57 substituting Example 753B for Example 14a and substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-2-methylbenzene. MS (ESI) m/z 476.0 (M+H) + .
Example 754
4,4-difluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pentanamide
The title compound was prepared similarly to the procedure described in Example 735 substituting Example 738 for Example 695. MS (ESI) m/z 445.1 (M+H) + .
Example 755
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
Example 755 A
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the procedures described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 755 B
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 755 A for Example 322B. MS (ESI) m/z 339.1 (M+H) + .
Example 755 C
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 755B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 451.2 (M+H) + .
Example 756
(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 755B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 501.1 (M+H) + .
Example 757
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
Example 757 A
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-5-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 757 B
(3R,4S)-1-(1,2-dimethyl-1H-imidazol-5-ylsulfonyl)-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 757A for Example 322B. MS (ESI) m/z 339.1 (M+H) + .
Example 757 C
(3R,4S)—N-(3,4-difluorophenyl)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 757B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 451.2 (M+H) +
Example 758
(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 757B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 501.1 (M+H) +
Example 759
4-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-chloropyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 436 (M+H) + .
Example 760
5-chloro-N-[(3R,4S)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-(4-fluorophenyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 848 substituting Example 755B for Example 679H. MS (ESI) m/z 518.1 (M+H) +
Example 761
Trans-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 761A
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the procedures described in Examples 2A-2F substituting (E)-3-fluoro-2-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 761B
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 380A substituting Example 761A for Example 322B.
Example 761 C
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde, Example 761 A for 354D amine MS (ESI) m/z 517.9 (M+H) +
Example 762
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D amine. MS (ESI) m/z 410.1 (M+H) + .
Example 763
Trans-4-(3-fluoropyridin-2-yl)-N,N-dihexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 761A for 354D. MS (ESI) m/z 494.1 (M+H) +
Example 764
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N,N-dipentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D. MS (ESI) m/z 466.1 (M+H) +
Example 765
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-pentylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting pentanal for 4-chlorobenzaldehyde and substituting Example 761 A for 354D. MS (ESI) m/z 396.1 (M+H) +
Example 766
Trans-N-(3,4-difluorophenyl)-4-(3-fluoropyridin-2-31)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761 B for Example 337F and substituting 4-bromo-1,2-difluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 438.0 (M+H) +
Example 767
Trans-4-(3-fluoropyridin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 488.0 (M+H) +
Example 768
Trans-4-(3-fluoropyridin-2-yl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 504.0 (M+H) +
Example 769
5-fluoro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-methylpyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 435.1 (M+H) +
Example 770
N-{Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 472.0 (M+H) +
Example 771
Trans-N-(3-chloro-4-fluorophenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 453.9 (M+H) +
Example 772
6-chloro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
To a microwave vial charged with Example 761B (100 mg, 0.31 mmol) and methanol (1 mL) was added triethylamine (62.2 mg, 0.62 mmol) and 4,6-dichloropyrimidine (137 mg, 0.93 mmol). The reaction mixture was stirred in a microwave at 120° C. for 1 hour. The mixture was concentrated and purified via HPLC to afford the title compound. MS (ESI) m/z 438.0 (M+H) +
Example 773
(3R,4S)—N-[3-(benzyloxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 1-(benzyloxy)-3-bromobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 489 (M+H) + .
Example 774
6-(benzyloxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 4-(benzyloxy)-6-bromopyrimidine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 509 (M+H) + .
Example 775
Trans-N-(4-fluoro-3-methylphenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 434.0 (M+H) +
Example 776
4-(benzyloxy)-5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
Example 776A
4-(benzyloxy)-2-bromo-5-fluoropyridine
To a stirred solution of 2-bromo-5-fluoropyridin-4-ol (100 mg, 0.52 mmol) in dimethylformamide (4 mL) was added (bromomethyl)benzene (89 mg, 0.52 mmol) and potassium carbonate (144 mg, 1.0 mmol). The reaction mixture was stirred at 60° C. for 3 hours. Water and EtOAc were added. The organic fraction was collected and concentrated. Purification via flash chromatography (0-50% EtOAc/heptanes) provided the title compound.
Example 776B
4-(benzyloxy)-5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 776A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 508 (M+H) + .
Example 777
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(piperidin-4-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting tert-butyl 4-(3-bromophenyl)piperidine-1-carboxylate for 1-bromo-3-(trifluoromethyl)benzene followed by dissolving the crude mixture in dichloromethane (5 mL) and treating the crude mixture with HCl (4 M, 3 mL) and purifying via HPLC. MS (APCI) m/z 466 (M+H) + .
Example 778
6-(azetidin-3-ylmethoxy)-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}pyrimidin-4-amine
Tert-butyl 3-((6-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-ylamino)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was prepared similarly to the procedure described in Example 691 substituting Example 606 for Example 691 and substituting tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (3 eq.) for ethanol and adding tert-butanol (5 mL). The reaction mixture was concentrated, dissolved in dichloromethane, and treated with HCl (4 M, 10 eq.). Purification via HPLC provided the title compound. MS (ESI) m/z 488 (M+H) + .
Example 779
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(pyrrolidin-3-ylmethoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 778 substituting tert-butyl-3-hydroxymethyl-pyrrolidine-1-carboxylate for tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate. MS (ESI) m/z 502 (M+H) + .
Example 780
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-6-(pyrrolidin-2-ylmethoxy)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 778 substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate. MS (ESI) m/z 502 (M+H) + .
Example 781
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
Example 781A
(E)-3-(2-nitrovinyl)tetrahydro-2H-pyran
The title compound was prepared similarly to the procedure described in Example 307A substituting tetrahydropyran-3-carbaldehyde for 2-pyridinecarboxaldeyde.
Example 781B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting Example 781A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 781C
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 405 (M+H) + .
Example 782
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B. MS (ESI) m/z 459 (M+H) + .
Example 783
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 425 (M+H) + .
Example 784
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 785
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 489 (M+H) + .
Example 786
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-phenoxyphenyl)-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781 B for Example 322B and substituting 1-bromo-3-phenoxybenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 483 (M+H) + .
Example 787
trans-N-(biphenyl-3-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 3-bromo-1,1′-biphenyl for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 467 (M+H) + .
Example 788
Trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2 H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 493 (M+H) + .
Example 789
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 443 (M+H) + .
Example 790
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 423 (M+H) + .
Example 791
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 477 (M+H) + .
Example 792
Trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-chloro-2-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 509 (M+H) + .
Example 793
Trans-N-[4-chloro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 4-bromo-1-chloro-2-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 497 (M+H) + .
Example 794
Trans-N-[3-(benzyloxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3S)-tetrahydro-2H-pyran-3-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 781B for Example 322B and substituting 1-(benzyloxy)-3-bromobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 497 (M+H) + .
Example 795
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To a solution of Example 368 (0.12 g, 0.26 mmol) in dimethylformamide (0.4 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (SelectFluo, 91 mg, 0.26 mmol). The mixture was stirred at room temperature for 16 hours. More 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (60 mg) was added. The mixture was stirred at room temperature for another 16 hours, concentrated, and purified by HPLC to afford the title compound. MS (ESI) m/z 488 (M+H) + .
Example 796
3-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
To a solution of Example 368 (0.12 g, 0.26 mmol) in dimethylformamide (0.4 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (SelectFluo, 91 mg, 0.26 mmol). The mixture was stirred at room temperature for 16 hours. More 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (60 mg) was added. The mixture was stirred at room temperature for another 16 hours, concentrated, and purified by HPLC to afford the title compound. MS (EST) m/z 488 (M+H) + .
Example 797
N-(2,2-difluoroethyl)-2-({(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)acetamide
The title compound was prepared similarly to the procedure described in Example 242E substituting 2,2-difluoroethanamine for aniline and substituting Example 689D for Example 242D. MS (ESI) m/z 447.0 (M+H) +
Example 798
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761 B for Example 337F. MS (ESI) m/z 470.0 (M+H) +
Example 799
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 486.0 (M+H) +
Example 800
Trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500.0 (M+H) +
Example 801
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-[3-(pyridin-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting 2-(3-bromophenyl)pyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 478 (M+H) + .
Example 802
(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-N-[3-(pyridin-2-yl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to Example 327 substituting Example 574A for Example 322B and substituting 2-(3-bromophenyl)pyridine. MS (ESI) m/z 460 (M+H) + .
Example 803
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 803A
2-bromo-5-fluoro-4-(2,2,2-trifluoroethoxy)pyridine
A microwave vial was charged with 2-bromo-5-fluoropyridin-4-ol (1 g, 5.2 mmol), 1,1,1-trifluoro-2-iodoethane (3.3 g, 15.6 mmol), potassium carbonate (1.44 g, 10.4 mmol), and dimethylsulfoxide (10 mL). The reaction mixture was stirred in a microwave (Biotage Initiator™ maximum 400 Watts) at 150° C. for 1 hour. The reaction mixture was partitioned between water and EtOAc. The organic fraction was collected and concentrated. Flash chromatography (0-50% EtOAc/heptanes) provided the title compound.
Example 803B
5-fluoro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 803A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 804
5-Chloro-N-{trans-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared as described in Example 848 substituting Example 761B for Example 679H. MS (ESI) m/z 505.0 (M+H) +
Example 805
Trans-N-(3-fluorophenyl)-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 761B for Example 337F and substituting 1-bromo-3-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 420.0 (M+H) +
Example 806
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 806A
2-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)pyridine
The title compound was prepared similarly to Example 803A substituting 2-bromo-5-chloropyridin-4-ol for 2-bromo-5-fluoropyridin-4-ol.
Example 806B
5-chloro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 806A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 534 (M+H) + .
Example 807
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
Example 807A
2-bromo-4-(2,2,2-trifluoroethoxy)pyridine
The title compound was prepared similarly to the procedure described in Example 803A substituting 2-bromopyridin-4-ol for 2-bromo-5-fluoropyridin-4-ol.
Example 807B
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 807A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 808
5-chloro-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 806A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 516 (M+H) + .
Example 809
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 807A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 482 (M+H) + .
Example 810
5-fluoro-N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(2,2,2-trifluoroethoxy)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 803A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 518 (M+H) + .
Example 811
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
Example 811 A
Trans-4-(3-fluoropyridin-2-yl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine hydrochloride
The title compound was prepared similarly to the conditions described in Example 2A-2F substituting (E)-3-fluoro-2-(2-nitrovinyl)pyridine for (E)-1-methoxy-4-(2-nitrovinyl)benzene and 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 811 B
Trans-4-(3-fluoropyridin-2-yl)-N-hexyl-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting Example 811 A for 354D. MS (ESI) m/z 411.0 (M+H) +
Example 812
N-{(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}-4-(propan-2-yl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting 2-bromo-4-isopropylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 444 (M+H) + .
Example 813
N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-4-(propan-2-yl)pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting 2-bromo-4-isopropylpyridine for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 426 (M+H) + .
Example 814
2,2,2-trifluoro-N-[2-({trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-yl}oxy)ethyl]ethanamine
The title compound was prepared similarly to the procedure described in Example 290 substituting Example 797 for Example 242E. MS (ESI) m/z 451.1 (M+H) +
Example 815
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 443.0 (M+H) +
Example 816
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 489.1 (M+H) +
Example 817
2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-4-(trifluoromethyl)pyridine
Example 817A
(E)-ethyl 3-(4-(trifluoromethyl)pyridin-2-yl)acrylate
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.45 g, 2 mmol) in tetrahydrofuran (3 mL) at −20° C. was added sodium hydride (100 mg, 60%, 2.5 mmol) followed by the addition of 4-(trifluoromethyl)picolinaldehyde in tetrahydrofuran (1 mL). The mixture was warmed to room temperature over 1 hour. Aqueous ammonium chloride was added and the solution was partitioned with ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography (25% ethyl acetate/hexanes) to afford the title compound.
Example 817B
ethyl 3-(4-(trifluoromethyl)pyridin-2-yl)propanoate
To a solution of Example 817A (460 mg, 1.8 mmol) in ethanol (20 mL) in a 50 mL pressure bottle was added 5% palladium on carbon, (95 mg, 0.022 mmol). The mixture was stirred for 2 hours under 30 psi of hydrogen at room temperature. The mixture was filtered through a nylon membrane and concentrated to afford the title compound.
Example 817C
ethyl 4-nitro-3-phenyl-2-((4-(trifluoromethyl)pyridin-2-yl)methyl)butanoate
The title compound was prepared similarly to the procedure described in Example 331A substituting Example 817B for methyl 3-(3-chlorophenyl)propanoate.
Example 817D
4-phenyl-3-((4-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-2-one
The title compound was prepared similarly to the procedure described in Example 331B substituting Example 817C for Example 331A.
Example 817E
2-((4-phenylpyrrolidin-3-yl)methy 1)-4-(trifluoromethyl)pyridine
To a solution of Example 817D (450 mg, 1.4 mmol) in tetrahydrofuran (3 mL) was added lithiumaluminum hydride (2N, 1.5 mL, 3 mmol). The mixture was stirred for 16 hours. Aqueous sodium bicarbonate followed by ethyl acetate was added. The organic fraction was collected, dried over potassium carbonate, filtered, and concentrated to provide the title compound.
Example 817F
2-({1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}methyl)-4-(trifluoromethyl)pyridine
The title compound was prepared similarly to the procedure described in Example 182C substituting Example 817E for Example 182B. MS (ESI) m/z 451 (M+H) + .
Example 818
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-4-(3-fluoropyridin-2-yl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 811A for 354D. MS (ESI) m/z 519.0 (M+H) +
Example 819
Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 475.1 (M+H) +
Example 820
N-Hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2R)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 385.2 (M+H) + .
Example 821
N-hexyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting hexanal for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 385.2 (M+H) + .
Example 822
Trans-N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 493.1 (M+H) + .
Example 823
N-[2-chloro-4-(trifluoromethyl)benzyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 354E substituting 2-chloro-4-(trifluoromethyl)benzaldehyde for 4-chlorobenzaldehyde and substituting example 601B for 354D. MS (ESI) m/z 493.1 (M+H) + .
Example 824
Trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 429.1 (M+H) +
Example 825
N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(2S)-tetrahydrofuran-2-yl]pyrrolidin-3-amine
The title compound was prepared as described in Example 603 substituting 4-bromo-2-chloro-1-fluorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 429.1 (M+H) +
Example 826
1-benzyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2,3-dihydro-1H-indol-6-amine
Example 826A
1-benzyl-6-bromoindoline
To a stirred solution of 6-bromoindoline (100 mg, 0.50 mmol) in dimethylformamide (5 mL) was added (bromomethyl)benzene (95 mg, 0.55 mmol) and potassium carbonate (140 mg, 1.0 mmol). The reaction was stirred at 60° C. for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic fraction was collected, washed with brine, dried with magnesium sulfate, and concentrated to provide the title compound.
Example 826B
1-benzyl-N-{(3R,4S)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenylpyrrolidin-3-yl}-2,3-dihydro-1H-indol-6-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 574A for Example 322B and substituting Example 826A for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 514 (M+H) + .
Example 827
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
Example 827A
(E)-3-(2-nitrovinyl)tetrahydrofuran
To a solution of oxalyl chloride (5.1 mL, 60 mmol) in dichloromethane (100 mL) under a nitrogen atmosphere at −78° C. was added dropwise dimethylsulfoxide (4.6 mL, 65 mmol) in dichloromethane (10 mL). The reaction mixture stirred for 10 minutes. Tetrahydro-3-furan methanol (5.5 g, 54 mmol) was added in dichloromethane (20 mL) over several minutes, and the reaction mixture was stirred for 10 minutes. Triethylamine (17.4 mL, 125 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature. Diethyl ether was added and the solution was filtered. The filtrate was concentrated to provide crude tetrahydrofuran-3-carbaldehyde.
To a stirred solution of this crude tetrahydrofuran-3-carbaldehyde in tetrahydrofuran (50 mL) under a nitrogen atmosphere was added nitromethane (8.1 mL, 150 mmol), 1,1,2,2-tetramethyl guanidine (0.69 mL, 5.5 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and trifluoroacetic anhydride (6.3 mL, 100 mmol) was added. The reaction mixture stirred for 15 minutes. Triethylamine (13.9 mL, 100 mmol) was added dropwise and the reaction mixture stirred for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic fraction was collected, washed with brine, and concentrated. Purification via flash chromatography (40% EtOAc/heptanes) provided the title compound.
Example 827B
trans-1-(1-methyl-1H-imidazol-4-ylsulfonyl)-4-((S)-tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepare as an HCl salt similarly to the procedures described in Example 2A-2F substituting Example 827A for (E)-1-methoxy-4-(2-nitrovinyl)benzene.
Example 827C
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B. MS (ESI) m/z 445 (M+H) + .
Example 828
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-N-(3-methylphenyl)-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-methylbenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 391 (M+H) + .
Example 829
trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 411 (M+H) + .
Example 830
trans-N-(3-chloro-4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but only stirring for 1 hour. MS (APCI) m/z 429 (M+H) + .
Example 831
trans-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 479 (M+H) + .
Example 832
trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro furan-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (APCI) m/z 463 (M+H) + .
Example 833
trans-N-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-4-chloro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 479 (M+H) + .
Example 834
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 475 (M+H) + .
Example 835
trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-3-yl)-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 827B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (EST) m/z 461 (M+H) + .
Example 836
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
Example 836A
1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride
To an ice-cooled solution of sodium 1H-1,2,3-triazole-4-thiolate (34.5 g, 280 mmol) in ethanol (400 mL) was added benzylbromide (18.8 mL, 158 mmol) drop-wise. The mixture stirred at 25° C. for 2 hours, and was then diluted with EtOAc (600 mL), washed with water (500 mL), brine (500 mL), dried over sodium sulfate filtered, and concentrated under reduced pressure to afford 4-(benzylthio)-1H-1,2,3-triazole.
To a solution of 4-(benzylthio)-1H-1,2,3-triazole (55.0 g, 288 mmol) in dimethylformamide (550 mL) at 0° C. was added potassium carbonate (87.0 g, 630 mmol) followed by dimethyl sulfate (55.0 mL, 575 mmol) dropwise. Then the reaction mixture was stirred at 20° C. for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL) and washed with water (500 mL). The organic fraction was dried with sodium sulfate, and concentrated. The residue was purified via flash chromatography (Petroleum ether:EtOAc=1:0, 10:1, 5:1 to 3:1) to afford 4-(benzylthio)-1-methyl-1H-1,2,3-triazole.
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (40.3 g, 205 mmol) was added portion wise to a mixture of 4-(benzylthio)-1-methyl-1H-1,2,3-triazole (28.0 g, 137 mmol) in acetonitrile (1200 mL), AcOH (50 mL) and water (34 mL), which had been cooled to 0° C. The addition was slow enough to maintain the internal temperature of the reaction mixture below 5° C. Upon complete addition, the mixture stirred for an additional 2 hours at 0° C. The reaction mixture was then quenched slowly with aqueous sodium hydrideCO 3 solution (5%, 700 mL). The resulting mixture was stirred for 15 minutes and then diluted with dichloromethane (2000 mL). The organic fraction was collected, washed with brine (1000 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=1:0 to 5:1) to afford the title compound.
Example 836B
trans-4-(4-fluorophenyl)-1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared as an HCl salt similarly to the procedures described in Examples 2A-2F substituting (E)-1-fluoro-4-(2-nitrovinyl)benzene for (E)-1-methoxy-4-(2-nitrovinyl)benzene and substituting 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride for 1-methyl-1H-imidazole-4-sulfonyl chloride.
Example 836C
trans-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(2,2,2-trifluoroethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 500 (M+H) + .
Example 837
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 486 (M+H) + .
Example 838
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethoxy)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 504 (M+H) + .
Example 839
(3R,4S)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-N-[3-(trifluoromethyl)phenyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 470 (M+H) + .
Example 840
(3R,4S)-4-(4-fluorophenyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-4-fluoro-3-(trifluoromethyl)benzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 488 (M+H) + .
Example 841
(3R,4S)—N-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-(trifluoromethyl)benzene. MS (ESI) m/z 436 (M+H) + .
Example 842
(3R,4S)—N-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 327 substituting Example 836B for Example 322B and substituting 1-bromo-3-chloro-4-fluorobenzene for 1-bromo-3-(trifluoromethyl)benzene, but only stirring for 1 hour. MS (ESI) m/z 454 (M+H) + .
Example 843
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 463.1 (M+H) +
Example 844
5-Chloro-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
The title compound was prepared similarly to the procedure in Example 848 substituting Example 601B for Example 679H. MS (ESI) m/z 480.1 (M+H) +
Example 845
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 409.1 (M+H) +
Example 846
Trans-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-(trifluoromethyl)benzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 477.1 (M+H) +
Example 847
Trans-N-(4-fluoro-3-methylphenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 4-bromo-1-fluoro-2-methylbenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 423.1 (M+H) +
Example 848
5-Chloro-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-amine
To a microwave vial charged with Example 679H (80 mg, 0.254 mmol) and N-methyl-2-pyrrolidone (0.5 mL) was added cesium carbonate (141 mg, 0.43 mmol) and 2,5-dichloro-4-(trifluoromethyl)pyridine (71.4 mg, 0.33 mmol) under Argon. This mixture was stirred at 120° C. for 5 hours. The mixture was then partitioned between water and ethyl acetate. The organic fraction was collected, concentrated, and purified by flash chromatography to provide the title compound. MS (ESI) m/z 494.1 (M+H) +
Example 849
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 1-bromo-3-chlorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 425.1 (M+H) +
Example 850
Trans-N-(3-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 1-bromo-3-chlorobenzene for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 411.1 (M+H) +
Example 851
5-Fluoro-4-methyl-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 410.2 (M+H) +
Example 852
5-Fluoro-4-methyl-N-[trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydro-2H-pyran-2-yl)pyrrolidin-3-yl]pyridin-2-amine
The title compound was prepared similarly to the procedure described in Example 337G substituting Example 679H for Example 337F and substituting 2-bromo-5-fluoro-4-methylpyridine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 424.2 (M+H) +
Example 853
N-[Trans-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(tetrahydrofuran-2-yl)pyrrolidin-3-yl]-6-(trifluoromethyl)pyrimidin-4-amine
The title compound was prepared similarly to the procedure described in Example 603 substituting 4-bromo-6-(trifluoromethyl)pyrimidine for 1-bromo-3-trifluoromethylbenzene. MS (ESI) m/z 447.1 (M+H) +
Example 854
(3R,4S)—N-cyclohexyl-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting cyclohexanone for benzaldehyde. MS (ESI) m/z 407 (M+H) + .
Example 855
(3R,4S)—N-(3,3-dimethylcyclohexyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 3,3-dimethylcyclohexanone for benzaldehyde. MS (ESI) m/z 435 (M+H) + .
Example 856
(3R,4S)—N-(4,4-dimethylcyclohexyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 4,4-dimethylcyclohexanone for benzaldehyde. MS (ESI) m/z 435 (M+H) + .
Example 857
(3R,4S)—N-cyclopentyl-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting cyclopentanone for benzaldehyde. MS (ESI) m/z 393 (M+H) + .
Example 858
(3R,4S)—N-(3,3-dimethylcyclopentyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 3,3-dimethylcyclopentanone for benzaldehyde. MS (ESI) m/z 421 (M+H) + .
Example 859
(3R,4S)—N-(1-(2,4-dichlorophenyl)ethyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 1-(2,4-dichlorophenyl)ethanone for benzaldehyde. MS (ESI) m/z 497 (M+H) + .
Example 860
(3R,4S)—N-(2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-yl sulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 2,3-dihydro-1H-inden-1-one for benzaldehyde. MS (ESI) m/z 441 (M+H) + .
Example 861
(3R,4S)—N-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 5-chloro-2,3-dihydro-1H-inden-1-one for benzaldehyde. MS (ESI) m/z 475 (M+H) + .
Example 862
N-(4-chlorobenzyl)-N-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)acetamide
Example 862A
(3R,4S)—N-(4-chlorobenzyl)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-amine
The title compound was prepared similarly to the procedure described in Example 148 substituting Example 322B for Example 3A and substituting 4-chlorobenzaldehyde for benzaldehyde.
Example 862B
N-(4-chlorobenzyl)-N-((3R,4S)-4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yl)acetamide
The title compound was prepared similarly to the procedure described in Example 4C substituting Example 862A for Example 4B and substituting acetic acid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) m/z 491 (M+H) + .
Further exemplary compounds include:
1-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-3-yl)azepane; 4-(Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-3-yl)morpholine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(2-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(3-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(4-methylpiperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(4-fluoropiperidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(4,4-difluoropiperidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-4-(3-fluoroazetidin-1-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; 4-((Trans-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-(piperidin-1-yl)pyrrolidin-3-yl)oxy)-6-(trifluoromethyl)pyrimidine; Trans-1′-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4′-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)-1,3′-bipyrrolidine; Trans-3-((3-chlorophenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; Trans-3-((3-chloro-4-fluorophenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-3-((3-(trifluoromethyl)phenyl)amino)pyrrolidin-2-one; Trans-3-((4-fluoro-3-(trifluoromethoxy)phenyl)amino)-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-one; 3-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole; 2-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazole; 5-(3-Chlorophenyl)-2-(trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1H-imidazole; 4-((Trans-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-4-(4-fluorophenyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-imidazole; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-N-(3-(trifluoromethyl)cyclohexyl)pyrrolidin-3-amine; N-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-isopropylpiperidin-4-amine; Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-N-(2-methyltetrahydrofuran-3-yl)pyrrolidin-3-amine; 1-Ethyl-N-(Trans-4-(4-fluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)piperidin-3-amine.
Biological Testing
1. [ 3 H]-Glycine uptake into recombinant CHO cells expressing human GlyT1: Human GlyT1c expressing recombinant hGlyT1c_5_CHO cells were plated at 20,000 cells per well in 96 well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured to sub-confluency for 24 h. For glycine uptake assays the culture medium was aspirated and the cells were washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5 mM L-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10 μl inhibitor or vehicle (10% DMSO) and 10 μl [ 3 H]-glycine (TRK71, Amersham Biosciences) to a final concentration of 200 nM for initiation of glycine uptake.
The plates were placed in a Wallac Microbeta (PerkinElmer) and continuously counted by solid phase scintillation spectrometry during up to 3 hours. Nonspecific uptake was determined in the presence of 10 μM Org24598. IC 50 calculations were made by four-parametric logistic nonlinear regression analysis (GraphPad Prism) using determinations within the range of linear increase of [ 3 H]-glycine incorporation between 60 and 120 min.
2. Radioligand binding assays using recombinant CHO cell membranes expressing human GlyT1:
Radioligand binding to human GlyT1c transporter-expressing membranes was determined as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.
The following results were obtained with the compounds disclosed in the examples:
Ex.
Ki [μM]
1
—
2
≦1
3
≦0.1
4
≧10
13
≦1
14
≦1
15
≦10
16
≦1
17
≦10
18
≦10
19
≦10
20
≦10
21
≦10
22
≦10
23
≦10
24
≦10
25
≦10
26
≦1
27
≦1
29
≦1
30
≦10
31
≦1
32
≦10
33
≦10
34
≦10
35
≦10
36
≦1
37
≦1
38
≦10
39
≦10
40
≧10
41
≦10
42
≦10
43
≦10
44
≦10
45
≧10
46
≧10
47
≧10
48
≦10
49
≦10
50
≦10
51
≦0.1
52
≦10
53
≦10
54
≦1
55
≦1
56
≦1
57
≦10
58
≦0.1
59
≦10
60
≦0.1
61
≦1
62
≦0.1
63
≦0.1
64
≦0.1
65
≦1
66
≦10
67
≦0.01
68
≦1
69
≦10
70
≦1
71
≦1
72
—
73
≦10
74
≦0.1
75
≦1
76
≦10
77
≦1
78
≦1
79
≦1
80
≦1
81
≦10
82
≦10
83
≦1
84
≦1
85
≦0.01
86
≦1
87
≦10
88
≦0.01
89
≦0.1
90
≦1
91
≦0.1
92
≦0.1
93
≦1
94
≦0.01
95
≦1
100
≦10
101
≦1
102
≦1
115
≦0.1
122
≦10
123
≦10
124
≦10
125
>10
126
≦10
127
≦10
128
≦10
129
>10
130
>10
131
>10
132
≦10
133
≦10
134
≦10
135
>10
136
≦10
137
≦10
142
≦10
143
≦10
144
>10
145
≦0.1
148
≦10
149
≦0.1
150
≦0.001
151
≦0.1
152
≦1
153
≦1
154
≦0.1
155
≦0.1
156
≦0.1
157
≦10
158
≦0.1
159
≦0.01
160
≦0.01
161
≦1
162
≦1
163
≦1
164
≦10
165
≦1
166
≦1
167
≦0.1
168
≦0.1
169
≦10
170
≦0.1
171
≦0.1
172
≦0.1
173
≦1
174
≦1
175
≦1
176
≦0.01
177
≦10
178
≦1
179
≦10
180
≦1
181
≦10
182
≦0.1
183
≦10
184
≦10
185
≦10
186
≦1
187
≦10
188
≦0.1
189
≦0.1
190
≦1
191
≦10
192
≦1
193
≦10
194
≦0.1
195
≦10
196
≦10
197
≦1
198
≦1
199
≦1
200
≦1
201
≦0.1
202
≦1
203
≦10
204
≦0.1
205
≦1
206
≦10
207
≦10
208
≦10
209
≦10
210
≦10
211
≦1
212
≦0.10
213
≦1
214
≦0.1
215
≦0.1
216
≦1
217
≦1
218
≦1
219
≦10
220
≦0.01
221
≦1
222
≦1
223
≦0.1
224
≦1
225
≦10
226
≦0.01
227
≦10
228
≦10
229
≦10
230
≦10
231
≦1
232
≦10
233
≦10
234
≦1
235
≦10
236
≦10
237
≦10
238
≦10
239
≦10
240
≦0.1
241
≦10
242
≦10
243
≦1
244
≦1
245
≦0.1
246
≦0.1
247
≦0.01
248
≦1
249
≦1
250
≦10
251
≦0.1
252
≦1
253
≦1
254
≦10
255
≦0.1
256
≦1
257
≦0.1
258
≦1
259
≦1
260
≦0.1
261
≦1
262
≦0.01
263
≦0.1
264
≦1
265
≦1
266
≦1
267
≦0.01
268
≦10
269
≦10
270
≦10
271
≦1
272
≦1
273
≦1
274
≦0.1
275
≦1
276
≦1
277
≦10
278
≦0.1
279
≦10
280
≦0.01
281
≦0.01
282
≦0.1
283
≦0.1
284
≦0.1
285
≦0.1
286
≦10
287
≦0.01
288
≦1
289
≦1
290
≦10
291
≦0.1
292
≦1
293
≦0.1
294
≦0.01
295
≦0.1
296
≦0.1
297
≦0.01
298
≦0.01
299
≦1
300
≦1
301
≦1
302
≦0.1
303
≦10
304
≦1
305
≦0.01
306
≦0.1
307
≦0.1
308
≦1
309
≦1
310
≦0.1
311
≦1
312
≦0.1
313
≦1
314
≦1
315
≦1
316
≦1
317
≦1
318
≦1
319
≦0.1
320
≦0.01
321
≦1
322
≦0.01
323
≦1
324
≦10
325
≦1
326
≦1
327
≦0.01
328
≦0.1
329
≦0.01
329
≦0.01
330
≦0.1
330
≦0.1
331
≦1
332
≦0.1
333
≦1
334
≦1
335
≦1
336
≦1
337
≦1
338
≦1
339
≦10
340
≦1
341
≦10
342
≦10
343
≦10
344
≦0.1
345
≦0.1
346
≦1
347
≦10
348
≦0.1
349
≦0.1
350
>10
351
≦1
352
≦0.01
353
≦0.1
354
≦1
355
≦1
356
≦0.1
357
≦1
358
≦0.1
359
≦1
360
≦0.1
361
≦1
362
≦0.1
363
≦0.1
364
≦10
365
≦10
366
≦0.1
367
≦0.1
368
≦0.01
369
≦1
370
≦1
371
≦1
372
≦10
373
≦10
374
≧10
375
≧10
376
≦1
377
≦1
378
≦10
379
≦0.1
380
≦0.1
381
≦10
382
≦0.1
383
≦1
384
≦10
385
≦10
386
≦1
387
≦10
388
≦0.1
389
≦10
390
≦0.01
390
≦0.01
391
≦0.1
392
≦0.1
393
≦0.01
394
≦0.01
395
≦1
396
≦0.01
397
≦0.01
398
≦0.01
399
≦0.1
400
≦10
401
≦10
402
≦10
403
≦0.1
404
≦10
405
≦1
406
≦10
407
≦10
408
≦10
409
≦0.1
410
≦10
411
≦10
412
≦1
413
≦10
414
≦10
415
≦10
416
—
417
≦0.01
418
≦0.1
419
≧10
420
≦10
421
≦10
422
≦1
423
≦10
424
≦1
425
≦0.01
426
≦1
427
≦0.1
428
≦0.1
429
>10
430
>10
431
≦10
432
≦10
433
≦0.1
434
≦10
435
≦0.1
436
≦1
437
≦0.1
438
≦1
439
≦1
440
≦0.1
441
≦10
442
≦1
443
≦1
444
—
445
≦1
446
≦0.1
447
≦10
448
≦0.1
449
≦1
450
≦1
451
—
452
—
453
≦1
454
≦10
455
≦0.1
456
≦1
457
≦10
458
≦10
459
≦10
460
≦10
461
≦1
462
≦0.1
463
≦1
464
≦1
465
≦1
466
—
467
≦1
468
≦0.1
469
≦1
470
≦10
471
≦0.1
472
≦1
473
≦0.1
474
≦10
475
≦10
476
≦10
477
≦10
478
≦10
479
>10
480
>10
481
≦10
482
≦10
483
≦10
484
≦10
485
≦10
486
≦10
487
≦10
488
≦10
489
≦10
490
≦10
491
≦10
492
≧10
493
≦10
494
≦10
495
>10
496
≧10
497
≦10
498
≦10
499
≧10
500
≦10
501
≦10
502
≦10
503
≧10
504
≦10
505
—
506
≦10
507
≦10
508
≦10
509
≦10
510
≦10
511
≦10
512
≦10
513
>10
514
≦10
515
≦10
516
≦10
517
≦10
518
>10
519
>10
520
≦10
521
≦10
522
—
523
≦10
524
≦10
525
≦10
526
≦10
527
≦10
528
>10
529
≦10
530
≦1
531
≦0.1
532
≦10
533
≦10
534
≦1
535
≦10
536
≦1
537
≦10
538
≦10
539
≦10
540
≦0.1
540
≦0.1
541
≦10
542
≦10
543
≦10
544
≦10
545
≦1
546
≧10
547
≦0.1
548
≦0.01
549
≦10
550
≦10
551
≦10
552
≦10
553
≦1
554
≦1
555
≦10
556
≦10
557
≦10
558
≦10
559
≦1
560
≧10
561
≦1
562
≦10
563
≦10
564
≦1
565
≦10
566
≦10
567
≦1
568
≦0.1
569
≦1
570
≦0.01
571
≦10
572
≦1
573
≦0.1
574
≦0.1
575
≦10
576
—
577
>10
578
≦10
579
≦10
580
≦1
581
≦0.1
582
≦10
583
≦10
584
≦10
585
≦0.1
586
≦1
587
≦10
588
≦10
589
≦1
590
≦10
591
≦10
592
≦10
593
≦10
594
≦10
595
≦10
596
≦10
597
≦10
598
≦10
599
≦10
600
≦10
601
≦0.1
602
≦1
603
≦0.1
604
≦0.1
605
≦1
606
≦0.1
607
≦10
608
≦10
609
≦1
610
≦10
611
≦10
612
≦1
613
≦1
614
≦1
615
≦1
616
≦1
617
≦0.01
618
≦1
619
≦1
620
≦1
621
≦10
622
≦0.1
623
≦0.1
624
≦1
625
≦0.01
626
≦1
627
≦1
628
≦0.01
629
≦1
630
≦0.1
631
≦0.01
632
≦1
633
≦1
634
≦10
635
≦1
636
≦1
637
≦10
638
≦1
639
≦10
640
≦1
641
≦0.1
642
≦0.01
643
≦10
644
≦10
645
≦0.01
646
≦0.01
647
≦10
648
≦10
649
≦0.1
650
≦1
651
≦0.01
651
≦0.01
652
≦0.01
653
≦10
654
≦1
655
≦1
656
≦1
657
≦1
658
≦1
659
≦10
660
≦1
661
≦1
662
≦10
663
≦0.1
664
≦0.1
665
≦0.01
666
≦10
667
≦0.1
668
≦10
669
≦0.1
670
≦0.01
671
≦1
672
≦1
673
≦1
674
≦1
675
≦1
676
≦1
677
≦1
678
≦1
679
≦1
680
≦0.1
681
≦0.01
682
≦0.1
683
≦0.1
684
≦1
685
≦0.01
686
≦0.01
687
≦0.1
688
≦1
689
≦1
690
≦1
691
≦0.1
692
≦1
693
≦10
694
≦1
695
≦10
696
≦10
697
≦1
698
≦1
699
≦1
700
≦10
701
≦1
702
≦10
703
≦1
704
≦1
705
≦1
706
≦10
707
≦1
708
≦10
709
≦10
710
≦1
711
—
712
≦1
713
>10
714
≦10
715
≦1
716
≦0.1
717
≦0.1
718
≦0.1
719
≦0.1
720
≦0.1
721
≦0.1
722
≦0.01
723
≦0.1
724
≦0.1
725
≦0.01
726
≦0.1
727
≦0.01
728
≦0.01
729
≦0.01
730
≦0.01
731
≦0.1
732
≦0.1
733
≦0.01
734
≦0.1
735
≦10
736
≦1
737
≦0.1
738
>10
739
≦0.1
740
≦10
741
≦0.1
742
≦1
743
≦0.1
744
≦0.01
745
≦0.01
746
≦0.01
747
≦0.01
748
≦0.01
749
≦0.01
750
≦0.1
751
≦0.1
752
≦0.1
753
≦1
754
≦10
755
≧10
756
≦10
757
≦10
758
≦10
759
≦0.01
760
>10
761
≦0.1
762
≦0.1
763
≦1
764
≦1
765
≦1
766
≦1
767
≦0.1
768
≦0.1
769
≦1
770
≦1
771
≦0.1
772
≦10
773
≦0.1
774
≦0.1
775
≦1
776
≦0.01
777
≧10
778
≧10
779
≦10
780
≦10
781
≦10
782
≦1
783
≦1
784
≦0.1
785
≦0.1
786
≦1
787
≦1
788
≦1
789
≦1
790
≦1
791
≦1
792
≦10
793
≦10
794
≦1
795
≦0.01
796
≦0.1
797
≦10
798
≦0.1
799
≦0.1
800
≦0.01
801
≦0.01
802
≦0.1
803
≦0.01
804
—
805
≦1
806
≦0.01
807
≦0.01
808
≦0.01
809
≦0.01
810
≦0.01
811
≦0.1
812
—
813
≦0.1
814
≦1
815
≦0.1
816
≦0.01
817
≦1
818
≦0.01
819
≦0.1
820
≦10
821
≦10
822
≦1
823
≦1
824
≦1
825
≦1
826
≦10
827
≦1
828
≦10
829
≦10
830
≦10
831
≦1
832
≦1
833
≦10
834
≦1
835
≦1
836
≦0.01
837
≦0.01
838
≦0.01
839
≦0.01
840
≦0.01
841
≦0.01
842
≦0.01
843
≦0.1
844
≦1
845
≦1
846
≦0.1
847
≦0.1
848
≦1
849
≦0.1
850
≦1
851
≦10
852
≦1
853
≦1
854
—
855
—
856
—
857
—
858
—
859
—
860
—
861
—
862
—
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