(en)The present invention relates to compounds of formula 1









that are useful for the preventive or therapeutic treatment of diseases caused by abnormal activation of CXCR3 chemokines. The invention relates furthermore to a process for the preparation of said compounds, to pharmaceutical compositions containing said compounds and to novel intermediates used in the preparation of said compounds.

1.ApplicationNumber: US-201414294885-A
1.PublishNumber: US-2014288106-A1
2.Date Publish: 20140925
3.Inventor: BATA IMRE
BUZDER-LANTOS PETER
VASAS ATTILA
BARTANE BODOR VERONIKA
FERENCZY GYORGY
TOMOSKOZI ZSUZSANNA
SZELECZKY GABOR
BATORI SANDOR
SMRCINA MARTIN
PATEK MARCEL
WEICHSEL ALEKSANDRA
THORPE DAVID SQUIRE

4.Inventor Harmonized: BATA IMRE(HU)
BUZDER-LANTOS PETER(HU)
VASAS ATTILA(HU)
BARTANE BODOR VERONIKA(HU)
FERENCZY GYORGY(HU)
TOMOSKOZI ZSUZSANNA(HU)
SZELECZKY GABOR(HU)
BATORI SANDOR(HU)
SMRCINA MARTIN(US)
PATEK MARCEL(US)
WEICHSEL ALEKSANDRA(US)
THORPE DAVID SQUIRE(US)

5.Country: US
6.Claims:
(en)The present invention relates to compounds of formula 1









that are useful for the preventive or therapeutic treatment of diseases caused by abnormal activation of CXCR3 chemokines. The invention relates furthermore to a process for the preparation of said compounds, to pharmaceutical compositions containing said compounds and to novel intermediates used in the preparation of said compounds.

7.Description:
(en)The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal activation of CXCR3 chemokines.
Chemokines are a large family of small soluble proteins of about 8 to 10 kDa in size. One of the major roles of chemokines is to direct the migration of immune cells. The mechanism by which the movement of cells is guided is the chemical attraction of the cells expressing the relevant chemokine receptor on their surface toward the concentration gradient of the corresponding chemokine.
Some chemokines are homeostatic in function as they regulate the trafficking of cells in a day to day manner. Such homeostatic chemokines, for example direct the homing of lymphocytes to the lymph nodes or they have effect on development by promoting or inhibiting the growth of new blood vessels—thus exerting angiogenic or angiostatic effects.
Other chemokines are expressed in response to inflammation or injury. These inflammatory chemokines regulate the recruitment of specific leukocyte populations into the inflamed tissue that in turn they can elicit the release of specific regulatory and enzymatic factors from the activated immune cells. The expression of these inflammatory chemokines is typically induced by interleukin-1 (IL-1) or interferon-γ (IFN-γ) from various types of cells.
Chemokines exert their function via binding to specific chemokine receptors that are expressed on the cell surface. The chemokine receptors are about 340-360 amino acids long, and they belong to the G-protein coupled receptor (GPCR) super family. To date, approximately 50 chemokines have been identified. Many of them can bind to the same receptor and particular chemokines can also bind to several chemokine receptors. Presently we know altogether 20 different chemokine receptors for these 50 known chemokines [Groom, J. R. and Luster, A. D. 2011. Immunology and Cell Biology, 1-9]. More recently different splice variants have also been described for some chemokine receptors that may have different expression patterns and different physiological or pathophysiological roles.
CXCR3 is an inflammatory chemokine receptor which is predominantly expressed on activated immune cells such as the CD4 + (Th1 helper) and CD8 + (CTL cytotoxic or Tc) T lymphocytes. CXCR3 is absent on naïve T lymphocytes, but its cell surface expression is rapidly induced following T cell activation by dendritic cells. CXCR3 is also expressed on innate lymphocytes such as natural killer cells (NK) and NKT cells, on plasmacytoid dendritic cells (pDC) [Groom, J. R. and Luster, A. D. 2011. Immunology and Cell Biology, 1-9], on inflammatory neutrophils and macrophages.
CXCR3 is selectively activated by three interferon-inducible chemokines, CXCL9 (also termed as Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Activation of CXCR3 by these endogenous agonists elicits intracellular Ca 2+ mobilization via phospholipases C (PLC) and, in addition, activation of both mitogen-activated protein kinase (MAP-kinase) and PI3-kinase [Liu, M; Guo, S; Hibbert, J. M; Jain, V; Sinh, N Wilson, N. O; and Stiles, JNK. 2011. Cytokine & Growth Factor Reviews, 22: 121-130.]. These intracellular events finally result in stimulation of lymphocyte migration and proliferation. CXCR3 plays a key role in selective recruitment of activated immune cells to the site of inflammation. Once recruited, cytotoxic T cells (CTL), through the release of perforin and granzyme B, induce apoptosis, thereby contributing to local tissue damage and subsequent remodelling. At the site of inflammation the recruited Th1 and CTL cells release IFN-gamma that stimulates epithelial cells and macrophages to further release of CXCR3 agonists that leads to a persistent inflammatory activation.
Strong Th1 and CTL responses are beneficial during acute infection, but these responses must be counterbalanced to prevent unwanted tissue destruction and chronic immunopathological changes [Groom, J. R. and Luster, A. D. 2011. Experimental Cell Research 317: 620-631]. In this respect CXCR3 antagonists are suggested to have significant therapeutic relevance.
More recent studies demonstrated that CXCR3 is also expressed on human CD25+ FOXP3+ regulatory CD4+ T cells (Treg) and the level of CXCR3 increases on Treg cells following activation [Vandercappellen, J et al, 2011. Cytokine & Growth Factor Reviews 22: 1-18.]. This observation suggests that CXCR3 may participate in mediation of trafficking of Treg cells. Treg cells migrate to the peripheral sites of inflammation, where they exert suppressive activity on CD4+ Th1 and CD8+ CTL cells [Hoerning, A et al 2011. Eur J Immunol, online manuscript, accepted: Apr. 26, 2011. DOI: 10.1002/eji.201041095]. Thus Treg cells are important for suppressing the immune responses, maintaining immune tolerance and preventing autoimmune responses.
For the time being little is known about the expression pattern of CXCR3 on Treg subsets or the association of CXCR3 with Treg immunoregulatory functions. However, this finding may explain some reported variable functional effects of CXCR3 blockade in different animal models [Hoerning, A et al 2011. Eur J Immunol, online manuscript, accepted: Apr. 26, 2011. DOI: 10.1002/eji.201041095] or the variable effects of CXCR3 blockade in different types of allograft rejection.
As of today, there are three splice variants for CXCR3 described in humans: CXCR3-A, CXCR3-B [Romagnani, P; Lasagni, L; Annunziato, F; Serio, M. and Romagnani, S. 2004. TRENDS in Immunology, 25: 201-209.] and CXCR3-alt. CXCR3-A is the most abundant variant, it couples to Gi/o type of G-proteins and it mediates chemotaxis and cell proliferation.
The splice variant CXCR3-B is thought to be expressed on endothelial and vascular smooth muscle cells and mediates angiostatic effects [Strider, R. M; Burdick, M. D; Gomperts, B. N; Belperio,. A; Keane, M. P. 2011. Cytokine & Growth Factor Reviews 16:593-609.]. CXCR3-B can bind not only the three well known CXCR3 agonists, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). but also a forth one, CXCL4 (PF-4), which is a selective, CXCR3-B specific chemokine agonist. Activation of CXCR3-B is supposed to mediate the activation of the Gs, the stimulatory type of G-proteins that in turn causes an intracellular cAMP rise, which finally results in angiostatic effects and inhibition of cell proliferation. More recent studies, however, showed that the alternative CXCR3-B splice variant does not exist in mice [Campanella, G. S. V; Colvin, R. A; and Luster, A. D. 2010. PLoS ONE 5(9): e12700. doi:10.1371/journal.pone.0012700] and, in addition to it, the same authors in their experiments with human endothelial cells also demonstrated that CXCL10 can inhibit endothelial cell proliferation independently of CXCR3 receptors. As of today, there are some controversial observations on the putative roles of the different alternative CXCR3 splice variants and thus further studies are still needed in order to clarify and understand their physiological and pathophysiological roles.
On the other hand, it is widely accepted that T lymphocytes play crucial regulatory function in the immune system [Wijtmans, M; Verzijl, D; Leurs, R; de Esch, I. J. P; and Smit, M. J. 2008. Chem Med Chem. 3:861-872.] and [Muller, M; Carter, M. J; Hofert, J; and Campbell, I. L. 2010. Neuropathology and Applied Neurobiology, 36:368-387.]. Their special roles are also indicated by the fact that 15 chemokine receptors out of the 20 known ones, are expressed among the different subpopulations of T lymphocytes [Pease and Williams, Br. J. Pharmacol. 2006. 147, S212]. T cells are implicated in many inflammatory diseases.
Clinical evidences showed significant overexpression of CXCR3 receptor and/or its endogenous agonists (CXCL10, CXCL11) in multiple autoimmune or inflammatory diseases, such as e.g.
(i) in peripheral airways of COPD patients [Donnelly, L. E. and Barnes, P. J. Trends in Pharmacol Sci 27(10): 564-553.],

(ii) in skin biopsies from patients with moderate to severe psoriasis [Chen, S-C; Groot, M.; Kinsley, D; Laverty, M; McClanahan, T; Arreaza, M; Gustafson, E. L; Teunissen, M. B. M; Rie, M. A; Jay, S. F; and Kraan, M. 2010. Arch. Dermatol. Rev. 302: 113-123],

(iii) in lymph nodes and islets of type 1 diabetic patients [Uno, S; Imagawa, A; Saisho, K; Okita, K; Iwahashi, H; Hanafusai, T; and Shimomura, I. 2010. Endocrine Journal. 57(11): 991-996.]

(iv) in acute allograft rejection (lung, heart, kidney and skin grafts) [Wenczel, J. Lucas, S; Zahn, S; Mikus, S; Metze, D; Stadter, S, et al, 2008. J. Am. Acad. Dermatol. 58:437-442.]

(v) in colon biopsies of patients with ulcerative colitis [Singh, U. P. Singh, R; Singh, S; Karls, R. K; Quinn, F. D; Taub, D. D; and Lillard Jr J. W. 2008. BMC Immunology 9:25]

and (vi) in thymus from myasthenia gravis patients [Pease, J. E and Horuk, R. 2009. Expert Opin Ther Patents, 19 (2): 199-221].

In animals, CXCR3-KO mice display blocked T cell migration into bronchoalveolar space following noxious stimuli such as cigarette smoke (murine model of COPD). CXCL10-gene deficient or CXCR3-KO mice showed prolonged allograft survival in murine models of transplant rejection (cardiac and pancreatic island allografts).
Blocking the activation of CXCR3 by antagonists represents a possible approach for the treatment of diseases such as COPD [Hansel, T. T. and Barnes, P. J. 2009. Lancet, 374:744-755], psoriasis [Krueger, J. G. and Bowcock, A. 2005. Ann. Rheum. Dis. 64: Suppl. II.: ii30-ii36], graft/transplant rejection [Hancock, W. W; Lu, B; Gao, W; Cziszmadia, V; Faia, K; King, J. A; Smileey, S. T.; Ling, M; Gearad, N. P.; and Gerard, C. 2000. J Exp Med 192:1515-1519.], ophthalmological diseases [Sorensen, T. L.; Roed, H; Sellebjerg, F. 2004. Br. J. Ophthalmol. 88:1146-1148.], celiac disease [Lammers, K. M.; Khandelwal, S; Chaudhry, F; Kryszak, D; Puppa, E. L,; Casolaro; V; and Fasano, A. 2010. Immunology, 132:432-440.], inflammatory bowel disease (IBD) [Nishimura, M; Kuboi, Y; Muramato, K; Kawano, T; and Imai, T. 2009. Autoimmunity: Ann N.Y. Acad. Sci. 1173:350-356.], type 1 diabetes [Shimida, A; Oikawa, Y; Yamada, Y; Okubo, Y; and Narumi, S. 2009. Review of Diabetic Studies, 6(2): 81-84], myasthenia gravis (MG) [Pease, J. E. and Horuk, R. 2009. Expert Opin Ther Patents, 19 (2): 199-221], multiple sclerosis (MS) and other neuroinflammatory diseases [Muller, M; Carter, M. J.; Hofert, J; and Campbell, I. L. 2010. Neuropathology and Applied Neurobiology, 36:368-387.], lupus [Lacotte, S; Brun, S; Muller, S; and Dumortier, H. 2009. Autoimmunity: Ann N.Y. Acad. Sci. 1173:310-317.], rheumatoid arthritis (RA) [Brightling, C; Ammit, A. J.; Kaur, D; Black, J. L.; Wardlaw, A. J.; Hughes, J. M.; and Bradding, P. 2005. Am J Respir Crit Care Med. 171: 1103-1108.], lichen planus [Meller, S; Gillier, M; and Homey, B. 2009. J. Investigative Dermatology. 129: 315-319.].
Targeting CXCR3 appears a more straightforward way to treat the condition as this abrogates the effects of all three endogenous CXCR3 chemokines at the same time.
Assorted patent applications and granted patents disclose inhibitors of chemokines or CXCR3 receptor, such as WO2003087063, WO200604924, WO2009094168 and WO2009105435 but the known compounds are structurally very different from the compounds according to the present invention.
We aimed to prepare new CXCR3 receptor antagonist compounds, which have strong antagonistic effect and are selective to the CXCR3 receptor. We also aimed that the stability, bioavailability, metabolism, therapeutic index, toxicity and solubility of the new compounds allow their development into a drug substance. A further aim was that the compounds, due to their favorable enteric absorption, can be administered orally.
Thus, the inventors of the present invention have identified compounds represented by the following formula 1 possessing inhibitory activity against CXCR3 receptors.
The present invention thus provides a compound of formula 1









wherein
R represents hydrogen or C 1-4 alkyl group;

R 1 represents a group selected from the group consisting of










wherein
R 2 represents hydrogen or C 1-4 alkyl group; R 3 represents hydrogen, halogen, CF 3 , CN or C 1-4 alkyl; and R 4 represents hydrogen, halogen or C 1-4 alkyl-;

a=0, 1 or 2; b=0, 1, 2 or 3, c=1, 2 or 3, and

R a , R b , R c and R d represent independently from each other H or C 1-4 alkyl;

X represents a C 2 aliphatic hydrocarbon bridge optionally containing a double bond or a triple bond or a heteroatom selected from O and S, or —CH(CH 2 )CH—;

Y represents hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 hydroxyalkyl; and

Z represents a C 1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, NH and N(CH 3 ) or represents a C 2-4 aliphatic hydrocarbon bridge fused with a C 3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring or represents a C 1-4 aliphatic hydrocarbon bridge substituted with a spiro C 3-6 cycloalkyl ring optionally containing one or more double bond;

or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


According to another aspect of the present invention, there is provided a process for the preparation of a compound of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer, comprising the steps of reductive amination of a benzaldehyde of formula 4









—wherein X, Y and Z have the meaning as defined above—

with a primary amine of formula 5

R 1 —NH 2 5

—wherein R 1 has the meaning as defined above—

reacting the obtained secondary amine of formula 2










with a formyl- or oxocycloalkane carboxylic acid ester of formula 3









—wherein R, R a , R b , R c , R d , b, and c have the meaning as defined above and R′ represents —CHO or ═O—

and optionally hydrolyzing the obtained ester of formula 1.

According to another aspect of the present invention there is provided a pharmaceutical composition containing at least one compound of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer and at least one pharmaceutically acceptable excipient.
According to a further aspect the present invention is directed to the compounds of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer for use in the preventive and/or therapeutic treatment of a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) or lichen planus.
In addition the present invention is directed to a method of treating a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) or lichen planus comprising administering an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer to a patient in need thereof.
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, are to be understood to have the following meanings:
The C 1-4 alkyl group represents a straight or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and the like.
The C 1-4 alkoxy group represents an above identified alkyl group having 1 to 4 carbon atoms and attached through an oxygen atom, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like.
The C 1-4 hydroxyalkyl group represents an above identified alkyl group having 1 to 4 carbon atoms and bearing one or more hydroxy group, for example, hydroxymethyl group, 1-hydroxy-ethyl group, 2-hydroxy-ethyl group, 1-, 2- or 3-hydroxy- n-propyl group, 1- or 2-hydroxy-isopropyl group, and the like.
The halogen atom represents a fluorine, chlorine, bromine or iodine atom.
The C 2 aliphatic hydrocarbon bridge optionally containing a double or a triple bond or a heteroatom selected from O and S means an alkandiyl group having 2 carbon atoms and optionally containing a double or a triple bond or a heteroatom selected from O and S, for example, —CH 2 —CH 2 —, —CH═CH—, —C≡C—, —O—CH 2 —, —S—CH 2 —, and the like.
The C 1-4 aliphatic hydrocarbon bridge optionally containing one double bond and/or one or more heteroatom selected from O, S, NH and N(CH 3 ) means an alkandiyl group having 1 to 4 carbon atoms and optionally containing one double bond and/or one or more heteroatom selected from O, S, NH and N(CH 3 ), for example —CH 2 —CH 2 —, —CH 2 —O—, —CH 2 —S—, —CH 2 —NH—, —CH 2 —N(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —CH═CH—N(CH 3 )—, —N═CH—N(CH 3 )—, and the like.
The C 2-4 aliphatic hydrocarbon bridge fused with a C 3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring means an alkandiyl group having 2 to 4 carbon atoms and fused with a cycloalkyl ring having 3 to 6 carbon atoms and optionally containing one or more double bond or with a phenyl ring for example cyclopropandiyl,









The C 1-4 aliphatic hydrocarbon bridge substituted with a spiro C 3-6 cycloalkyl ring optionally containing one or more double bond means an alkandiyl group having 1 to 4 carbon atoms and substituted with a spiro cycloalkyl ring having 3 to 6 carbon atoms and optionally containing one or more double bond, means for example









In the formulae the bond crossed by dotted line









represents the attachment of the substituent with the other parts of the compound.
By salts of the compounds of the formula 1 we mean salts formed with inorganic and organic acids. Preferred salts are those given with pharmaceutically acceptable acids as for instance hydrochloric acid, and the like. The salts formed during purification or isolation are also subject of the invention.
The compounds represented by the aforementioned formula 1 may have one or more asymmetric carbon atoms. Thus, they can exist in the form of optical isomers, enantiomers or diastereoisomers.
The compounds of formula 1 can also exist in the form of cis (Z) or trans (E) stereoisomers. These stereoisomers, enantiomers and diastereoisomers as well as their mixtures, including the racemates, are also subject of the invention.
One of the embodiments of the present invention includes compounds of formula 1 wherein
R represents hydrogen or C 1-4 alkyl;

R 1 represents a group selected from the group consisting of










wherein
R 2 represents hydrogen or C 1-4 alkyl; R 3 represents hydrogen, halogen, CF 3 , CN or C 1-4 alkyl; and R 4 represents hydrogen, halogen or C 1-4 alkyl;

a=0 or 1; b=0, 1 or 2, c=1, 2 or 3; and











represents a cycloalkane carboxylic acid or ester thereof, selected from the group consisting of









wherein
R c and R d represent independently from each other H or C 1-4 alkyl;

X represents —O—CH 2 —, —S—CH 2 —, —CH═CH—, —CH 2 —CH 2 —, —C≡C— or cyclopropandiyl;

Y represents hydrogen, halogen; C 1-4 alkyl, C 1-4 alkoxy or C 1-4 hydroxyalkyl;

Z represents a C 1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, N and N(CH 3 ) or represents a C 2-4 aliphatic hydrocarbon bridge fused with a C 3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring or represents a C 1-4 aliphatic hydrocarbon bridge substituted with a spiro C 3-6 cycloalkyl ring optionally containing one or more double bond or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the present invention includes compounds of formula 1 wherein R represents hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein R 1 represents a group selected from the group consisting of









wherein
R 2 represents methyl or ethyl; R 3 represents Cl, F, CF 3 , CN, methyl or ethyl; and R 4 represents hydrogen, Cl, F or methyl;

or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the present invention includes compounds of formula 1 wherein R 1 represents a group selected from the group consisting of









wherein
R 2 represents methyl or ethyl; and R 4 represents hydrogen, Cl or F;

or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the present invention includes compounds of formula 1 wherein R 1 represents a group selected from the group consisting of









wherein
R 2 represents methyl or ethyl; and R 4 represents hydrogen, Cl or F;

or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the present invention includes compounds of formula 1 wherein X represents —O—CH 2 —, —S—CH 2 — or —CH 2 —CH 2 —, or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein Y represents hydrogen, Cl, F, methyl, ethyl, methoxy or —CH 2 —OH; or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein Y represents ethyl or methoxy; or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein Z represents —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 —O—, —CH 2 —S—, —CH 2 —N(CH 3 )—, —CH═CH—N(CH 3 )—, —N═CH—N(CH 3 )—, cyclopropandiyl, -,









or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein Z represents —(CH 2 ) 2 — or —CH 2 —N(CH 3 )—; or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the present invention includes compounds of formula 1 wherein
R represents hydrogen, methyl or ethyl;

R 1 represents a group selected from the group consisting of










wherein
R 2 represents hydrogen methyl or ethyl; R 3 represents hydrogen, chloro, fluoro, CF 3 , CN, methyl or ethyl; and R 4 represents hydrogen, chloro, fluoro, methyl or ethyl;

a=0 or 1; b=0, 1 or 2, c=1, 2 or 3; and











represents a cycloalkane carboxylic acid or ester thereof, selected from the group consisting of









wherein
R c and R d represent independently from each other H or methyl or ethyl;

X represents —O—CH 2 —, —S—CH 2 —, —CH═CH—, —CH 2 —CH 2 —, —C≡C— or cyclopropandiyl;

Y represents chloro, fluoro, methyl, ethyl, methoxy or —CH 2 —OH;

Z represents —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 —O—, —CH 2 —S—, —CH 2 —N(CH 3 )—, —CH═CH—N(CH 3 )—, —N═CH—N(CH 3 )—, CH(CH 2 )CH—, -,











or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Particularly compounds of the present invention represented by formula 1 include compounds selected from the group consisting of:
1. trans-4-[([1-(2,3-Dihydro-1-benzofuran-5-yl)ethyl]{4-[2-(2,5-dioxo-pyrrolidin-1-yl)ethoxy]-3-methoxybenzyl}amino)methyl]-cyclohexanecarboxylic acid 1.1 trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid ethyl ester 2. cis-4-[([1-(2,3-Dihydro-1-benzofuran-5-yl)ethyl]{4-[2-(2,5-dioxo-pyrrolidin-1-yl)ethoxy]-3-methoxybenzyl}amino)methyl]-cyclohexanecarboxylic acid 3. trans-4-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 4. trans-4-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 5. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]cyclohexanecarboxylic acid 6. trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 7. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 8. cis-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 9. trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 10. trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 11. trans-4-[(((R)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 12. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 13. cis-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 14. trans-4-[(((S)-4,5-Dichloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid hydrochloride 15. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 16. trans-4-({{3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 17. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 18. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 19. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-oxazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 20. trans-4-[((5-Chloro-indan-1-yl)-{3-chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 21. trans-4-{[{3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-(5-chloro-indan-1-yl)-amino]-methyl}-cyclohexanecarboxylic acid 22. trans-4-({{3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 23. trans-4-({{3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-[(S)-1-(4-chloro-phenyl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 24. trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 25. trans-4-[([1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 26. trans-4-[([(S)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 27. trans-4-[([(R)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 28. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 29. trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 30. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 31. trans-4-[(((R)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 32. trans-4-({{3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-[(S)-1-(4-chloro-phenyl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 33. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 34. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 35. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[(E)-3-(2,5-dioxo-pyrrolidin-1-yl)-propenyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 36. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,4-dioxo-oxazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 37. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 38. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,6-dioxo-piperidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 39. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 40. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 41. 3-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 42. trans-4-[((5-Chloro-6-methyl-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 43. trans-4-[((5-Chloro-4-methyl-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 44. trans-4-[((5-Chloro-indan-1-yl)-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 45. trans-4-[(((R)-5-Chloro-indan-1-yl)-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 46. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 47. trans-4-({{3-Chloro-4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-benzyl}-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 48. trans-4-[((5-Chloro-indan-1-yl)-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 49. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-ylmethyl)-cyclopropyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 50. trans-4-[((5-Chloro-indan-1-yl)-{3-methoxy-4-[3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-propyl]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 51. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methoxy-4-[3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-propyl]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 52. trans-4-[((5-Chloro-indan-1-yl)-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 53. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 54. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 55. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 56. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 57. trans-4-[((5-Chloro-indan-1-yl)-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 58. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 59. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 60. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 61. trans-4-[([1-(4-Cyano-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 62. trans-4-[([1-(4-Cyano-phenyl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 63. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 64. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 65. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 66. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 67. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 68. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 69. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 70. trans-4-[([1-(4-Chloro-phenyl)-propyl]-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 71. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 72. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 73. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 74. trans-4-[(((S)-5,6-Dichloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 75. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 76. trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 77. trans-4-[([1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 78. trans-4-[([1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 79. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 80. trans-4-[([1-(3,4-Dichloro-phenyl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 81. trans-4-({{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-[1-(4-ethyl-phenyl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 82. trans-4-[([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 83. trans-4-{[{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(1-p-tolyl-ethyl)-amino]-methyl}-cyclohexanecarboxylic acid 84. trans-4-{[{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-(1-p-tolyl-ethyl)-amino]-methyl}-cyclohexanecarboxylic acid 85. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-hydroxymethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 86. trans-4-[(((S)-4,5-Dichloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 87. trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 88. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 89. trans-4-[([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 90. trans-4-[([(R)-1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 91. trans-4-[([(S)-1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 92. trans-4-[([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 93. trans-4-[((4-Chloro-5-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 94. trans-4-[((6-Chloro-5-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 95. trans-4-[((6-Chloro-5-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 96. trans-4-[((4-Chloro-5-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 97. trans-4-[((6-Chloro-5-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 98. trans-4-[((5-Chloro-6-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 99. (1R,3R)-3-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 100. (1S,3S)-3-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 101. (1R,3S)-3-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 102. (1S,3R)-3-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 103. (1R,3S)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 104. (1R,3R)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 105. (1R,3R)-3-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 106. (1S,3R)-3-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 107. (1R,3S)-3-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 108. (1S,3R)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 109. (1S,3S)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 110. (1S,3S)-3-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid 111. (1R,2R)-2-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopropanecarboxylic acid ethyl ester 112. (1R,2R)-2-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopropanecarboxylic acid 113. (1S,2R)-2-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopropanecarboxylic acid ethyl ester 114. (1S,2R)-2-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopropanecarboxylic acid 115. (1R,3R)-3-[([1-(4-Chloro-phenyl)-propyl]-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-2,2-dimethyl-cyclopropanecarboxylic acid 116. (1S,3S)-3-[([1-(4-Chloro-phenyl)-propyl]-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-2,2-dimethyl-cyclopropanecarboxylic acid 117. (1S,3S)-3-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-2,2-dimethyl-cyclopropanecarboxylic acid 118. (1R,3R)-3-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-2,2-dimethyl-cyclopropanecarboxylic acid 119. 1-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopropanecarboxylic acid 120. trans-3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 121. cis-3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 122. cis-3-([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 123. cis-3-([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 124. trans-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 125. cis-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 126. 3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 127. 3-((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 128. trans-3-([(R)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 129. cis-3-([(R)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 130. trans-34[(S)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 131. cis-3-([(S)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 132. cis-3-([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 133. cis-3-((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 134. cis-3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 135. cis-3-([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 136. cis-3-([(R)-1-(4-Chloro-phenyl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 137. cis-3-([1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 138. cis-3-([1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 139. cis-3-([1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-cyclobutanecarboxylic acid 140. cis-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-cyclobutanecarboxylic acid 141. cis-3-([1-(3,4-Dichloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 142. cis-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 143. cis-3-([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid 144. trans-4-{[{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-(1-indan-5-yl-ethyl)-amino]-methyl}-cyclohexanecarboxylic acid 145. trans-4-[((1-Indan-5-yl-ethyl)-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 146. -4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,4-dioxo-3-aza-bicyclo[3.1.0]hex-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 147. 4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(7,9-dioxo-8-aza-spiro[4.5]dec-8-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 148. trans-4-[(((S)-5-Chloro-4-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 149. trans-4-[(((S)-5-Chloro-4-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 150. cis-3-([(R)-1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 151. cis-3-([(R)-1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-cyclobutanecarboxylic acid 152. cis-3-([(R)-1-(3,4-Dichloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid 153. cis-3-([(R)-1-(4-Chloro-phenyl)-ethyl]-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 154. trans-4-({{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-[1-(4-trifluoromethyl-phenyl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid 155. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-((3aS,7aR)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid; hydrochloride 156. trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid; hydrochloride 157. trans-4-[(((S)-5-Chloro-4-fluoro-indan-1-yl)-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid 158. 3-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclobutanecarboxylic acid 159. cis-3-(((R)-1-Indan-5-yl-ethyl)-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid 160. trans-3-(((R)-1-Indan-5-yl-ethyl)-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid

or a pharmaceutically acceptable salt thereof or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


A particular group of the compounds of the present invention represented by formula 1 include compounds selected from the group consisting of:
trans-4-[([1-(2,3-Dihydro-1-benzofuran-5-yl)ethyl]{4-[2-(2,5-dioxo-pyrrolidin-1-yl)ethoxy]-3-methoxybenzyl}amino)methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]cyclohexanecarboxylic acid trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[(((S)-4,5-Dichloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid hydrochloride trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-({{3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amino}-methyl)-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-oxazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-3-methyl-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,4-dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,4-dioxo-oxazolidin-3-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(4-Chloro-phenyl)-propyl]-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid trans-4-[([(S)-1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid (1R,3R)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid (1R,3R)-3-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid (1S,3S)-3-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclopentanecarboxylic acid (1S,3S)-3-[([1-(4-Chloro-phenyl)-propyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-2,2-dimethyl-cyclopropanecarboxylic acid
cis-3-([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid
3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-cyclobutanecarboxylic acid trans-4-[(((S)-5-Chloro-4-fluoro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid

or a pharmaceutically acceptable salt thereof or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


A further embodiment of the invention includes compounds of formula 4,









wherein
X represents a C 2 aliphatic hydrocarbon bridge optionally containing a double bond or a triple bond or a heteroatom selected from O and S, or —CH(CH 2 )CH—;

Y represents hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 hydroxyalkyl; and

Z represents a C 1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, N and N(CH 3 ) or represents a C 2-4 aliphatic hydrocarbon bridge fused with a C 3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring or represents a C 1-4 aliphatic hydrocarbon bridge substituted with a spiro C 3-6 cycloalkyl ring optionally containing one or more double bond.

Particularly compounds represented by formula 4 include compounds selected from the group consisting of
4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzaldehyde 3-Chloro-4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-hydroxymethyl-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-benzaldehyde 3-Methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzaldehyde 3-Methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzaldehyde 3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzaldehyde 4-[2-(2,4-Dioxo-thiazolidin-3-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-(2,4-Dioxo-thiazolidin-3-yl)-ethoxy]-3-methyl-benzaldehyde 4-[2-(2,4-Dioxo-oxazolidin-3-yl)-ethoxy]-3-methoxy-benzaldehyde 3-Methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzaldehyde 3-Methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzaldehyde 4-[2-(2,6-Dioxo-piperidin-1-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzaldehyde 4-[(E)-3-(2,5-Dioxo-pyrrolidin-1-yl)-propenyl]-3-methoxy-benzaldehyde 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methyl-benzaldehyde 3-Methyl-4-[3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-prop-1-ynyl]-benzaldehyde 3-Methoxy-4-[3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-prop-1-ynyl]-benzaldehyde 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzaldehyde 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzaldehyde 3-Chloro-4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-benzaldehyde 3-Methoxy-4-[3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-propyl]-benzaldehyde 4-[2-(2,5-Dioxo-pyrrolidin-1-ylmethyl)-cyclopropyl]-3-methoxy-benzaldehyde 4-[2-(2,4-Dioxo-3-aza-bicyclo[3.1.0]hex-3-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-((3aS,7aR)-1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-methoxy-benzaldehyde 4-[2-(7,9-Dioxo-8-aza-spiro[4.5]dec-8-yl)-ethoxy]-3-methoxy-benzaldehyde.

A further embodiment of the invention includes compounds of formula 2









wherein
R 1 represents a group selected from the group consisting of









wherein
R 2 represents hydrogen or C 1-4 alkyl group; R 3 represents hydrogen, halogen, CF 3 , CN or C 1-4 alkyl; and R 4 represents hydrogen, halogen or C 1-4 alkyl;

X represents a C 2 aliphatic hydrocarbon bridge optionally containing a double bond or a triple bond or a heteroatom selected from O and S, or —CH(CH 2 )CH—;

Y represents hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 hydroxyalkyl; and

Z represents a C 1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, N and N(CH 3 ) or represents a C 2-4 aliphatic hydrocarbon bridge fused with a C 3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring or represents a C 1-4 aliphatic hydrocarbon bridge substituted with a spiro C 3-6 cycloalkyl ring optionally containing one or more double bond;

or a salt thereof.


Particularly compounds represented by formula 2 include compounds selected from the group consisting of
1. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione naphthalene-1,5-disulfonic acid salt 2. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 3. 1-[2-(4-{[(R)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 4. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 5. 1-[2-(4-{[(R)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 6. 1-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 7. 1-(2-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 8. 1-(2-{4-[((S)-4,5-Dichloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 9. 1-(2-{4-[((S)-5-Chloro-4-fluoro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 10. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-thiazolidine-2,4-dione 11. 1-[2-(2-Chloro-4-{[1-(2,3-dihydro-benzofuran-5-yl)-ethylamino]-methyl}-phenoxy)-ethyl]-pyrrolidine-2,5-dione 12. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 13. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 14. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-oxazolidine-2,4-dione 15. 3-(2-{2-Chloro-4-[(5-chloro-indan-1-ylamino)-methyl]-phenoxy}-ethyl)-1-methyl-imidazolidine-2,4-dione 16. 1-(2-{2-Chloro-4-[(5-chloro-indan-1-ylamino)-methyl]-phenoxy}-ethyl)-pyrrolidine-2,5-dione 17. 3-[2-(2-Chloro-4-{[1(2,3-dihydro-benzofuran-5-yl)-ethylamino]-methyl}-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 18. 3-[2-(2-Chloro-4-{[(S)-1-(4-chloro-phenyl)-ethylamino]-methyl}-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 19. 3-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-thiazolidine-2,4-dione 20. 1-[2-(4-{[1-(4-Chloro-3-methyl-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 21. 1-[2-(4-{[(S)-1-(4-Chloro-3-methyl-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 22. 1-[2-(4-{[(R)-1-(4-Chloro-3-methyl-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 23. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 24. 1-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 25. 1-(2-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-methyl-phenoxy}-ethyl)-pyrrolidine-2,5-dionel-(2-{4-[((R)-5-Chloro-indan-1-ylamino)-methyl]-2-methyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 26. 1-[2-(2-Chloro-4-{[(S)-1-(4-chloro-phenyl)-ethylamino]-methyl}-phenoxy)-ethyl]-pyrrolidine-2,5-dione 27. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-thiazolidine-2,4-dione 28. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-thiazolidine-2,4-dione 29. 1-[(E)-3-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenyl)-allyl]-pyrrolidine-2,5-dione 30. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-oxazolidine-2,4-dione 31. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 32. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-piperidine-2,6-dione 33. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 34. 1-[3-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenyl)-propyl]-pyrrolidine-2,5-dione 35. 1-(2-{4-[(5-Chloro-6-methyl-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 36. 1-(2-{4-[(5-Chloro-4-methyl-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 37. 1-(3-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenyl}-propyl)-pyrrolidine-2,5-dione 38. 1-(3-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenyl}-propyl)-pyrrolidine-2,5-dione 39. 1-(3-{4-[((R)-5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenyl}-propyl)-pyrrolidine-2,5-dione 40. 1-[3-(2-Chloro-4-{[1-(2,3-dihydro-benzofuran-5-yl)-ethylamino]-methyl}-phenyl)-propyl]-pyrrolidine-2,5-dione 41. 3-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-1-methyl-1H-pyrimidine-2,4-dione 42. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenyl)-cyclopropylmethyl]-pyrrolidine-2,5-dione 43. 3-(3-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenyl}-propyl)-1-methyl-imidazolidine-2,4-dione 44. 3-[3-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenyl)-propyl]-1-methyl-imidazolidine-2,4-dione 45. 3-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-1-methyl-imidazolidine-2,4-dione 46. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 47. 1-[3-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenyl)-propyl]-pyrrolidine-2,5-dione 48. 1-[3-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenyl)-prop-2-ynyl]-pyrrolidine-2,5-dione 49. 1-[3-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenyl)-propyl]-pyrrolidine-2,5-dione 50. 3-(2-{4-[(5-Chloro-indan-1-ylamino)-methyl]-2-methyl-phenoxy}-ethyl)-1-methyl-imidazolidine-2,4-dione 51. 3-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 52. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 53. 3-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 54. 4-(1-{4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzylamino}-ethyl)-benzonitrile 55. 4-(1-{3-Methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzylamino}-ethyl)-benzonitrile 56. 1-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 57. 3-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 58. 3-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 59. 1-[3-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-propylamino]-methyl}-2-methoxy-phenyl)-propyl]-pyrrolidine-2,5-dione 60. 3-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 61. 3-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-1-methyl-1H-pyrimidine-2,4-dione 62. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-propylamino]-methyl}-2-methyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 63. 3-[2-(4-{[1-(4-Chloro-phenyl)-propylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 64. 1-(2-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-ethyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 65. 1-(2-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-fluoro-phenoxy}-ethyl)-pyrrolidine-2,5-dione 66. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-fluoro-phenoxy)-ethyl]-pyrrolidine-2,5-dione 67. 1-(2-{4-[((S)-5,6-Dichloro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 68. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-ethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 69. 1-[2-(4-{[1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-ethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 70. 1-[2-(4-{[1-(3,4-Dichloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 71. 1-[2-(4-{[1-(3,4-Dichloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 72. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-phenoxy)-ethyl]-pyrrolidine-2,5-dione 73. 3-[2-(4-{[1-(3,4-Dichloro-phenyl)-ethylamino]-methyl}-2-methyl-phenoxy)-ethyl]-1-methyl-imidazolidine-2,4-dione 74. 1-[2-(4-{[1-(4-Ethyl-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 75. 1-[2-(4-{[1-(4-Chloro-3-fluoro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 76. 1-(2-{2-Methyl-4-[(1-p-tolyl-ethylamino)-methyl]-phenoxy}-ethyl)-pyrrolidine-2,5-dione 77. 1-(2-{2-Methoxy-4-[(1-p-tolyl-ethylamino)-methyl]-phenoxy}-ethyl)-pyrrolidine-2,5-dione 78. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-hydroxymethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 79. -(2-{4-[((S)-4,5-Dichloro-indan-1-ylamino)-methyl]-2-ethyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 80. 1-[2-(4-{[(S)-1-(4-Chloro-phenyl)-ethylamino]-methyl}-2-methoxy-phenylsulfanyl)-ethyl]-pyrrolidine-2,5-dione 81. 1-(2-{4-[((S)-5-Chloro-indan-1-ylamino)-methyl]-2-methoxy-phenylsulfanyl}-ethyl)-pyrrolidine-2,5-dione 82. 1-[2-(4-{[1-(4-Chloro-3-fluoro-phenyl)-ethylamino]-methyl}-2-ethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 83. 1-[2-(4-{[(R)-1-(4-Chloro-3-fluoro-phenyl)-ethylamino]-methyl}-2-ethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 84. 1-[2-(4-{[(S)-1-(4-Chloro-3-fluoro-phenyl)-ethylamino]-methyl}-2-ethyl-phenoxy)-ethyl]-pyrrolidine-2,5-dione 85. 1-[2-(4-{[1-(4-Chloro-3-fluoro-phenyl)-ethylamino]-methyl}-2-fluoro-phenoxy)-ethyl]-pyrrolidine-2,5-dione 86. 1-(2-{4-[(4-Chloro-5-fluoro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 87. 1-(2-{4-[(6-Chloro-5-fluoro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 88. 1-(2-{4-[(6-Chloro-5-fluoro-indan-1-ylamino)-methyl]-2-ethyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 89. 1-(2-{4-[(4-Chloro-5-fluoro-indan-1-ylamino)-methyl]-2-ethyl-phenoxy}-ethyl)-pyrrolidine-2,5-dione 90. 1-(2-{4-[(6-Chloro-5-fluoro-indan-1-ylamino)-methyl]-2-fluoro-phenoxy}-ethyl)-pyrrolidine-2,5-dione 91. 1-(2-{4-[(5-Chloro-6-fluoro-indan-1-ylamino)-methyl]-2-methoxy-phenoxy}-ethyl)-pyrrolidine-2,5-dione 92. 1-[2-(4-{[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione 93. 1-[2-(4-{[(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-methyl}-2-methoxy-phenoxy)-ethyl]-pyrrolidine-2,5-dione.

General Procedures:
Starting materials and solvents used in the synthesis are obtained from chemical vendors such as ABCR, Aldrich, Acros, Apollo, Fluka, Netchem, Lancaster and others.
The crude product is purified by column chromatography or flash chromatography.
In first step the appropriate benzaldehydes (4=4a-f) are synthesized in different way depending on the side chain of dioxoamide derivatives as described on Scheme 1.
The synthesis of compound formula 4a, wherein X represents —O—CH 2 — or —S—CH 2 —, is done by alkylation of 4-hydroxy- or 4-mercapto-benzaldehydes 6a with dibromoethane and dioxoamide (route via 6a′, 7a′) or bromo-ethyldioxoamide derivatives (route via 7a) in the presence of a base, preferably K 2 CO 3 , TEA or sodium hydride using acetonitrile, DMF or MEK as solvent. Compounds of formula 4f, wherein X represents —CH 2 —O— or —CH 2 —S—, can be prepared analogously by alkylation of the corresponding benzyl alcohols or benzyl thiols of formula 6d with dibromomethane and dioxoamide (route via 6d′, 7c′) or bromo-methyldioxoamide derivatives (route via 7c) in the presence of a base, preferably K 2 CO 3 , TEA or sodium hydride using acetonitrile, DMF or MEK as solvent
An unsaturated compound of formula 4b, wherein X represents —C≡C—, can be synthesized in a Sonogashira reaction (Sonogashira, K. et al. Tetrahedron Lett. 1975, 16 (50), 4467) and an unsaturated compound of formula 4d, wherein X represents —CH═CH—, can be synthesized in a Suzuki coupling (Suzuki, A. Tetrahedron Lett. 1979, 20 (36), 3437) followed by hydrolysis of the resulted compound of formula 4d′. A compound of formula 4c, wherein X represents —CH 2 —CH 2 —, can be prepared by hydrogenation of the corresponding compound of formula 4b or 4d′. A compound of formula 4e, wherein X represents —CH(CH 2 )CH— can be synthesized from the corresponding protected allylic derivative of formula 4d′ using diazomethane (Scheme 1).
















Then the benzaldehydes 4 are reacted with different primary amines 5 in mild reductive amination conditions (NaBH(OAc) 3 in THF or 2-picoline borane complex in EtOH). The resulted secondary amines 2 are reacted with different formyl- (R′: —CHO) or oxo- (R′: ═O) cycloalkane carboxylic acid esters 3 in a repeated reductive amination step. The resulted esters (1, R=Me, Et) are optionally hydrolyzed in acidic conditions. The crude 1 is purified by chromatography, crystallization or via salt formation (Scheme 2).









Starting materials of formula 3, 5 and 7 are commercially available or can be prepared by known methods. Compounds of formula 6 are commercially available (6a) or can be prepared by known methods. Compounds of formula 6b can be synthesized with triflation of the corresponding alcohol. A compound of formula 6c is a protected derivative of an aldehyde of formula 6a with ethyleneglycol. A compound of formula 6d can be synthesized from commercially available benzoic acid derivatives by known method (Scheme 3).









As mentioned above the compounds of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer can be used as active ingredient of a medicament in the preventive and/or therapeutic treatment of a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) or lichen planus.
As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula 1 and pharmacologically acceptable salts, or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer. The substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substances may be used in combination. The type of pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline.
Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content ratios of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.
The dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like. Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.
The present invention will be explained more specifically with reference to the following examples, however, the scope of the present invention is not limited to these examples.
Unless otherwise stated, the following abbreviations have the stated meanings in the examples below:
abs.=absolute

AcOH=Acetic acid

[(C 6 H 5 ) 3 P] 2 PdCl 2 =Bis(triphenylphosphine)palladium(II) dichloride

cc. HCl=concentrated hydrogen chloride solution

CuI=copper1 iodide

DCM=dichloromethane

Diazald=N-methyl-N-nitroso-p-toluenesulfonamide
DMF=N,N-dimethylformamide
equiv.=equivalent

Et=ethyl

EtOH=ethanol

Et 2 O=diethyl ether

EtOAc=ethyl acetate

HCCOH=formic acid

HPLC=high performance liquid chromatography

Ipam=isopropyl amine

K 2 CO 3 =potassium carbonate

K 3 PO 4 =potassium phosphate

KBr=potassium bromide

KOH=potassium hydroxide

LC/MS=liquid chromatography—mass spectrometry

MEK=methyl-ethyl ketone

Me=methyl

MeOH=methanol

NaHCO 3 =sodium bicarbonate

Na 2 SO 4 =sodium sulfate

NaBH(OAc) 3 =sodium triacetoxy borohydride

nM=nanomole

NaOH=sodium hydroxide

NMR=nuclear magnetic spectroscopy

Pd(OAc) 2 =palladium(II) acetate

r.t.=room temperature

TBAB=tetrabutylammonium bromide

TEA=triethylamine

THF=tetrahydrofuran

TsOH=p-toluenesulfonic acid monohydrate

Analytical LC/MS is performed using Waters Alliance 2695+2996 PDA at 220 nm.
A system) MS: Waters LCT Premier XE; Column: Atlantis dC18 (3 μm) 2.1×50 mm; flow 0.7 ml/min of acetonitrile/water/0.05% TFA gradient in ESI+mode

B system) MS: Micromass ZQ; Column: Purospher-STAR RP18e (3 μm) 4.6×55 mm; flow 1.6 ml/min of water/acetonitrile/20 mM NH 4 OH gradient or Xterra MS-C18 (3.5 μM) 2.1×50 mm; flow: 1.0 ml/min of water/acetonitrile/20 mM NH 4 OH gradient in ESI+mode.

Preparative chiral HPLC is performed using Berger Prep SFC at 210 nm;
C system) Column: Chiralpack IC 250×21 mm (5 μm) Flow: 50 ml/min; CO2/[Ethanol/+0.5% Ipam] 60%/40% (other circumstances are detailed in examples).
For structural confirmation NMR spectra are measured for all compounds as well. The NMR spectra are recorded on a Bruker Advance II 400 MHz spectrometer at ambient temperature in DMSO-d 6 solution. The chemical shifts are referred to tetramethylsilane (6, ppm). In some cases not only 1 H but 13 C, ed-HSQC, zqs-TOCSY and HMBC spectra are also recorded.
Precursor Preparations
Intermediate 4.1 4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzaldehyde









A Method:
6.85 g (45 mmol) of vanillin (6.1) and 10.2 g (49.5 mmol) 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione (7.1) is heated with 8.28 g (60 mmol) K 2 CO 3 in 200 ml of acetonitrile under reflux for 15 h. Precipitated KBr is filtered off, the filtrate is evaporated, the residue is dissolved in 200 ml of dichloromethane, washed with water and 2N NaOH solution, dried with Na 2 SO 4 and evaporated. The remaining oil is triturated with n-hexane to result the desired 4.1 in white crystals. Yield: 6.88 g (55%). (M+H) + =278, R t (A)=1.90 min, purity 97.6%.
1 H-NMR: 2.64 (s, 4H), 3.77 (t, 2H), 2.75 (s, 3H), 4.21 (t, 3H), 7.17 (d, 1H), 7.40 (d, 1H), 7.53 (dd, 1H), 9.84 (s, 1H).









B Method:
11.66 g (45 mmol) of 4-(2-bromo-ethoxy)-3-methoxy-benzaldehyde (6.2) and 4.46 g (45 mmol) pyrrolidine-2,5-dione (7.2) is heated with 8.28 g (60 mmol) K 2 CO 3 in 200 ml of acetonitrile for 8 h. After same isolation procedure as in A method 4.1 is given with same purity.
Following the procedure as outlined for intermediate 4.1, the intermediates of general formula 4a listed in Table 1 are prepared.









TABLE 1






R t
Purity

Intermediate
Structure
(M + H) +
min. (system)
(%)



4.2









262
2.25 (A)
98.2



4.3









276
2.45 (A)
98.3



4.4









282
2.26 (A)
98.3



4.5









266
3.36 (B)
99.3



4.6









278
1.69 (A)
86.7



4.7









248
1.98 (A)
95.9



4.8









293
1.86 (A)
98.7



4.9









277
2.28 (A)
98.3



4.10









297
2.19 (A)
95.3



4.11









296
2.32 (A)
86.1



4.12









280
2.67 (A)
93.7



4.13









280
2.05 (A)
91.7



4.14









305
2.08 (A)
97.9



4.15









289
2.35 (A)
99.6



4.16









292
2.22 (A)
88.2



4.17









294
2.34 (A)
97.2



4.28









290
2.07 (A)
94.0



4.29









330
2.78 (A)
98.0



4.30









326
3.06 (A)
99.0



4.32









346
2.86 (A)
99.3
























































Intermediate 4.18 4-[(E)-3-(2,5-Dioxo-pyrrolidin-1-yl)-propenyl]-3-methoxy-benzaldehyde









Step 1:
6.85 g (45 mmol) vanillin (6.1) is cooled in a 100 ml of a mixture of DCM-pyridine 4:1, then 9.1 ml (54 mmol) of trifluoromethanesulfonic anhydride in 10 ml DCM is dropped in. The mixture is stirred at r.t. for 2 hours, after evaporated and the residue is triturated with 3×10 ml of EtOAc, the collected organic layer is dried and evaporated. The crude material (6.1a) is used for next step without further purification.









Step 2:
The formed crude trifluoro-methanesulfonic acid 4-formyl-2-methoxy-phenyl ester (6.1a), 2.52 ml (45 mmol) of ethylene glycol and 0.77 g (4.5 mmol) TsOH are refluxed in 180 ml of benzene. After evaporation the residue is purified by column chromatography. The desired intermediate is 11 g (80%) of trifluoro-methanesulfonic acid 4-[1,3]dioxolan-2-yl-2-methoxy-phenyl ester (6.1b), as a yellow oil. (M+H) + =329, R t (A)=3.44 min, purity 93.4%.
Step 3:
A mixture of 1.76 g (5 mmol) triflate (6.1a), 2.1 g (15 mmol) of 1-allyl-pyrrolidine-2,5-dione (7.3; Bull. Chem. Soc. Japan, 1984, 57(10), 3021), 0.067 g (0.3 mmol) of Pd(OAc) 2 , 0.373 g (5 mmol) KCl, 3.22 g (10 mmol) TBAB and 2.12 g (10 mmol) K 3 PO 4 is heated in 10 ml DMF under nitrogen at 120° C. for 8 h. The mixture is diluted with water, extracted with 3×50 ml of EtOAc, the collected organic phase is evaporated and purified by column chromatography (EtOAc-n-hexane 1:1). The desired intermediate (4.18a) is 1.8 g of 1-[(E)-3-(4-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-allyl]-pyrrolidine-2,5-dione, as an oil. (M+H) + =318, R t (A)=2.58 min, R t (B)=4.15 min, purity 71%.
Step 4:
1.8 g (4 mmol) of protected aldehyde (4.18a) and 5 ml (30 mmol) of cc. HCl in 15 ml of dioxane are stirred at r.t. for 3 h. After evaporation and purification by flash chromatography the desired 4-[(E)-3-(2,5-dioxo-pyrrolidin-1-yl)-propenyl]-3-methoxy-benzaldehyde (Intermediate 4.18) is 0.5 g (46%) as an oil. (M+H) + =274, R t =2.56 min (A), purity 91.2%.
1 H-NMR: 2.67 (s, 4H), 3.90 (s, 3H), 4.16 (d, 2H), 6.37 (dt, 1H), 6.79 (d, 1H), 7.47-7.50 (m, 2H), 7.67 (d, 1H), 9.95 (s, 1H).
Intermediate 4.19 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde









A mixture of 4.26 g (15 mmol) triflate (6.1b), 2.47 g (18 mmol) of 1-prop-2-ynyl-pyrrolidine-2,5-dione (7.4), 0.067 g (0.3 mmol) of [(C 6 H 5 ) 3 P] 2 PdCl 2 , 0.143 g (0.75 mmol) CuI, 0.32 g (0.75 mmol) of 1,4-bis(diphenyl-phosphino)butane and 7 ml (50.5 mmol) of TEA in 40 ml DMF under nitrogen at 100° C. for 3 h. The inorganic salts are removed and DMF is evaporated. The residue is treated with water, extracted 3×50 ml of EtOAc, the collected organic phase is evaporated and purified by flash chromatography (toluene-MeOH 9:1). The desired intermediate 4.19 is 1.9 g (44%) of 4-[3-(2,5-dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde, as a dark yellow solid. (M+H) + =272, R t =2.15 min (A), purity: 98.9%.
1 H-NMR: 2.71 (s, 4H), 3.89 (s, 3H), 4.44 (s, 2H), 7.47-7.50 (m, 2H), 7.55 (d, 1H), 9.98 (s, 1H).
Following procedures outlined for intermediate 4.19 the intermediates of general formula 4b listed in Table 2 are prepared.









TABLE 2






R t
Purity

Intermediate
Structure
(M + H) +
min (system)
(%)



4.20









256
2.60 (A)
94.8



4.21









271
2.40 (A)
96.7



4.22









287
1.98 (A)
95.3






















Intermediate 4.23 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzaldehyde









A Method:
Using 3.02 g (9.2 mmol) of triflate (6.1b) a crude protected allyl derivative (4.18a) is formed (as described in step 2 and 3 of Intermediate 4.18), which is hydrogenated by H-Cube equipment in full-H 2 mode in EtOAc. After evaporation the residue is dissolved in 50 ml of dioxane and stirred with 10 ml of cc. HCl at r.t. for 0.5 h. The mixture is evaporated, the residue is diluted with water, extracted with ethyl acetate, dried and removed the solvent. The crude material is purified by flash chromatography. The desired product (Intermediate 4.23) is 1.65 g (65.3%). (M+H) + =276, R t =2.57 min (A), purity: 97.7%.
1 H-NMR: 1.75 (qv, 2H), 2.59-2.62 (m, 6H), 3.38 (t, 2H), 3.86 (s, 3H), 7.40 (d, 2H), 7.47 (dd, 1H), 9.94 (s, 1H).
B Method:
Hydrogenation of 4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde (Intermediate 4.19) in same circumstances as described in A method is resulted Intermediate 4.23 in one step. The yield and purity is same as in A method.
Following procedures outlined for intermediate 4.23 the intermediate compounds of general formula 4c listed in Table 3 are prepared.









TABLE 3






Rt
Purity

Intermediate
Structure
(M + H) +
min. (system)
(%)



4.24









260
2.60 (A)
96.0



4.25









280
2.58 (A)
96.2



4.26









291
2.31 (A)
86.0






















Intermediate 4.27 4-[2-(2,5-Dioxo-pyrrolidin-1-ylmethyl)-cyclopropyl]-3-methoxy-benzaldehyde









Diazomethane is generated with a diazomethane-generating kit (Aldrich): a solution of 3.846 g (17.9 mmol) of Diazald in 24 ml of Et 2 O is added drop wise to a mixture of 3.018 g (53.78 mmol) of KOH in 18 ml of water, 4 ml of diethyl ether and 18 ml of 2-(2-ethoxyethoxy)-ethanol at 70° C. The ethereal solution of diazomethane is continuously distilled into a stirred solution of 575 mg (1.81 mmol) of protected aldehydes (4.18a; as described in step 3 of Intermediate 4.19) and 3.6 mg (0.016 mmol) Pd(OAc) 2 in a mixture of DCM and Et 2 O (28 ml/20 ml) kept at 70° C. After the addition of diazomethane is complete the solution is stirred at r.t. for 30 min. The excess of diazomethane is quenched with AcOH. The resulted mixture is washed with AcOH, saturated Na 2 CO 3 solution, dried and evaporated. The yield is 514 (95%) mg of titled compound. (M+H) + =276, R t =2.58 min (A), purity: 99.9%,


EXAMPLES
Example 1
trans-4-[([1-(2,3-Dihydro-1-benzofuran-5-yl)ethyl]{4-[2-(2,5-dioxo-pyrrolidin-1-yl)ethoxy]-3-methoxybenzyl}amino)methyl]cyclohexanecarboxylic acid









Step 1:
3.59 g (22 mmol) of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (5.1), 5.54 g (20 mmol) of intermediate 4.1 and 1.60 ml (28 mmol) of AcOH are dissolved in 200 mL of THF, then 12.7 g (60 mmol) of NaHB(OAc) 3 is added in small portions into the solution at room temperature. The formed suspension is stirred overnight, and then diluted with 200 ml of EtOAc and 400 mL of water. After separation the aqueous phase is washed EtOAc, the combined organic phase is dried and evaporated. The crude oil is purified with flash chromatography (up 10% MeOH in DCM). The intermediate (2.1) is 7.05 g pale yellow oil (83%); (M+H) + =425, R t =2.1 min (A), purity: 96.4%.
Salt Formation:
118 mg (0.28 mmol) of 2.1 and 100 mg (0.28 mmol) of 1.5-naphthalenedisulfonic acid tetrahydrate is dissolved in 2 ml of EtOH, then evaporated, the residue is treated with Et 2 O and the formed white solid filtrated, and washed with Et 2 O. Yield is 80 mg (48%) 2.1 with 0.6 moles 1,5-naphthalenedisulfonic acid. (M+H) + =425, R t =2.1 min (A), purity: 98.6%.









Step 2:
950 mg (2.24 mmol) of free amine (2.1) and 1.14 g (6.72 mmol) of trans-4-formyl-cyclohexanecarboxylic acid ethyl ester (3.1) are dissolved in THF and 0.19 mL (3.36 mmol) of AcOH is added followed by the addition 2.37 g (11.19 mmol) of NaHB(OAc) 3 and the reaction is stirred overnight at room temperature. Then the reaction is diluted EtOAc (75 ml) and water (50 ml) and 2 ml 1N HCl is added. The aqueous phase is separated, the organic phase is extracted two times with the same amounts of water and 1N HCl solution. The aqueous phases are combined, the pH adjusted to 8-9 by the addition of 1N NaOH and extracted two times with EtOAc. The combined organic phase is washed with brine, dried and evaporated. The crude product is used for next step without purification. Yield is 1.21 g of 1.1 (93.4%) as an oil. (M+H) + =593; R t =2.78 min (A), purity: 91.1%.
Salt Formation:
250 mg (0.44 mmol) of 1.1 is dissolved 1 ml of THF and acidified with HCl in Et 2 O. The precipitated HCl salt is filtrated, washed Et 2 O and dried. Yield is 185 mg (66.4%) as a white foam. (M+H) + =593; R t =2.78 min (A), purity 93.3%.
Step 3:
1.21 g (2.1 mmol) of ester (1.1) is dissolved in 5 ml of dioxane, 5.23 ml (10.5 mmol) of 2N HCl is added in and the mixture was stirred at 60° C. for 3 hours. Then the mixture is diluted with water, the pH value is adjusted to 7 with 1N NaOH and the aqueous phase is extracted 3 times with DCM. Organic phases were combined, dried and evaporated. The title compound is isolated as a white foam after HPLC purification using 4% MeOH in DCM. Yield 615 mg (52%); Molecular Formula=C 32 H 40 N 2 O 7 ; (M+H) + =565, R t =2.35 min (A), purity 98.1%.
1 H-NMR: 0.6 (dddd, 1H), 0.7 (dddd, 1H), 1.23 (ddd, 2H), 1.28 (d, 3H), 1.4 (br, 1H), 1.82 (d, 1H), 1.83 (d, 1H), 1.84 (d, 1H), 1.85 (d, 1H), 2.00 (dd, 1H), 2.04 (dddd, 1H), 2.25 (dd, 1H), 2.63 (s, 4H), 3.16 (t, 2H), 3.27 (d, 1H), 3.42 (d, 1H), 3.70 (t, 2H), 3.71 (s, 3H), 3.79 (q, 1H), 4.03 (t, 2H), 4.49 (t, 2H), 6.70 (d, 1H), 6.78 (dd, 1H), 6.84 (d, 1H), 6.90 (d, 1H), 7.04 (dd, 1H), 7.20 (d, 1H), 11.90 (s, 1H).
Example 2
cis-4-[([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1:
is undertaking as in Example 1, step 2 is accomplished with cis-4-formyl-cyclohexanecarboxylic acid methyl ester (3.2) in same conditions, after acidic hydrolysis and purification the title compound is isolated as a white foam. Molecular Formula=C 32 H 40 N 2 O 7 ; (M+H) + =565; R t =2.45 min (A), purity 99.5%.
1 H-NMR: 1.05-1.07 (m, 2H), 1.28 (d, 3H), 1.36-1.38 (m, 3H), 1.55 (m, 3H), 1.68 (m, 1H), 2.07 (dd, 1H), 2.25 (dd, 1H), 2.35 (qi, 1H), 2.63 (s, 4H), 3.15 (t, 2H), 3.28 (d, 1H), 3.42 (d, 1H), 3.70 (t, 2H), 3.71 (s, 3H), 3.78 (q, 1H), 4.02 (t, 2H), 4.49 (t, 2H), 6.69 (d, 1H), 6.78 (dd, 1H), 6.86 (d, 1H), 6.90 (d, 1H), 7.03 (dd, 1H), 7.20 (d, 1H), 11.89 (s, 1H).
Example 3
trans-4-[([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









611 mg of Example 1 is separated by preparative chiral column chromatography. The first eluted enantiomer has (R)-configuration, yield is 290 mg (95%). (M+H) + =565, R t =11.0 min. (C), purity: 98.1%.
Example 4
trans-4-[([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









611 mg of Example 1 is separated by preparative chiral column chromatography. The second eluted enantiomer has (S)-configuration, yield is 240 mg (79%). (M+H) + =565, R t =12.2 min (C), purity: 99.2%.
Example 5
trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1 is undertaking as in Example 1 using (S)-1-(4-chloro-phenyl)-ethylamine (5.2), further steps are occurred analogously as in Example 1 and the desired compound is resulted. (M+H) + =557, R t =2.51 min (A), purity: 97.6%.
Example 6
trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1 is undertaking as in Example 5 using (R)-1-(4-chloro-phenyl)-ethylamine (5.3), further steps are occurred analogously as in Example 1 and the desired compound is resulted. (M+H) + =557, R t =2.59 min (A), purity: 96.8%.
Example 7
trans-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1 is undertaking as in Example 1 using (S)-1-(4-chloro-phenyl)-ethylamine (5.2) and Intermediate 4.2, further steps are occurred analogously as in Example 1 and the desired compound is resulted. (M+H) + =541, R t =2.66 min (A), purity: 95.5%.
Example 8
cis-4-[([(S)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1 is undertaking as in Example 7, step 2 is accomplished with cis-4-formyl-cyclohexanecarboxylic acid methyl ester (3.2) in same conditions, after acidic hydrolysis and purification the title compound is isolated. (M+H) + =541, R t =2.64 min (A), purity 98.0%.
Example 9
trans-4-[([(R)-1-(4-Chloro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Step 1 is undertaking as in Example 6 using (R)-1-(4-chloro-phenyl)-ethylamine (5.3) and Intermediate 4.2, further steps are occurred analogously as in Example 6 and the desired compound is resulted. (M+H) + =541, R t =2.61 min (A), purity: 96.8%.
Example 10
trans-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexane-carboxylic acid









Following procedures outlined in Example 1 using 5-chloro-indan-1-ylamine (5.4) and Intermediate 4.1 in the first reductive amination step, the desired compound is resulted. (M+H) + =569, R t =2.57 min (A), purity 89.9%.
Example 11
trans-4-[(((R)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]cyclohexanecarboxylic acid









643 mg of Example 10 is separated by preparative chiral column chromatography. The first eluted enantiomer has (R)-configuration, yield is 250 mg (77.8%). (M+H) + =569, R t =6.6 min. (C), purity: 98.2%.
Example 12
trans-4-[(((S)-5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid









Method A:
Following chiral separation procedures outlined in Example 11 using 643 mg of Example 10, 270 mg (84%) of the titled compound is isolated as a second eluted material. (M+H) + =569, R t =9.0 min. (C), purity: 97.4%.
Method:
Following procedures outlined in Example 1 using 400 mg (2.39 mmol) of (S)-5-chloro-indan-1-ylamine (5.5) and 661 mg (2.39 mmol) of Intermediate 4.1 the titled compound is isolated: 652 mg (48%) (M+H) + =569, R t =2.69 min (A), purity 99.5%.
Example 13
cis-4-[((5-Chloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexane-carboxylic acid









Following procedures outlined in Example 2 using 5-chloro-indan-1-ylamine (5.4) and Intermediate 4.1 and 3.2 ester in reductive amination steps the desired compound is resulted. (M+H) + =569, R t =6.31 min (B), purity 85.6%.
Example 14
trans-4-[(((S)-4,5-Dichloro-indan-1-yl)-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-methyl]-cyclohexanecarboxylic acid hydrochloride









Step 1 and 2:
3.70 g (15.5 mmol) of (S)-4,5-dichloro-indan-1-ylamine hydrochloride (5.6) is dissolved in DCM, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated at reduced pressure. The residue is dissolved in THF and placed into a water bath (bath temperature: 15° C.). 4.29 g (15.5 mmol) of Intermediate 4.1 is added followed by the addition of acetic acid (1.33 ml; 23.3 mmol). 8.21 g (38.7 mmol) of NaBH(OAc) 3 is added in four portions at 10 minutes intervals. Water bath is removed and the reaction is stirred one hour at room temperature. 2.63 g (15.5 mmol) of trans-4-formyl-cyclohexanecarboxylic acid methyl ester (3.3) is added and the reaction is stirred another hour at room temperature. Then the mixture is diluted with water, pH is adjusted to 7 by the addition of saturated NaHCO 3 and extracted with DCM three times. Organic phases are combined, dried over Na 2 SO 4 and evaporated at reduced pressure. The residue is purified by silica gel flash chromatography using 50% EtOAc in hexane. Evaporation of pure fractions resulted in a pale yellow oil. Yield: 6.40 g (67%), (M+H) + =317, R t =2.91 min (A). Purity: 98.6%
Step 3:
6.40 g (10.4 mmol) of methyl ester is dissolved in 20 ml of dioxane. 25.9 ml (51.8 mmol) of 2N HCl solution is added and the reaction was stirred for 5 hours at 80° C. Then the mixture is diluted with water, pH is adjusted to 7 by the addition of saturated NaHCO 3 and extracted with DCM three times. Organic phases are combined, dried over sodium sulfate and evaporated at reduced pressure. The residue is purified by silica gel flash chromatography using a gradient of 3 to 6% of MeOH in DCM. Pure fractions are combined and evaporation resulted in a white solid foam of desired compound: 3.82 g (61.1%). (M+H) + =603, R t =2.66 min (A). Purity: 99.6%
Following the procedures as outlined in Example 1 using different amines (5), benzaldehydes (4) and formyl-cycloalkane carboxylic acid esters (3, R′═CHO) the compounds listed in Table 4 are prepared.









TABLE 4






Rt
Purity

Examples
Structure
(M + H) +
min. (system)
(%)



15.









583
2.53 (A)
92.3



16.









569
2.48 (A)
97.8



17.









549
2.51 (A)
92.8



18.









579
2.61 (A)
89.3



19.









567
2.41 (A)
97.9



20.









589
2.65 (A)
96.9



21.









573
2.70 (A)
92.0



22.









584
2.42 (A)
93.4



23.









576
2.58 (A)
92.7



24.









587
2.74 (A)
86.9



25.









571
2.67 (A)
95.6



26.









571
2.73 (A)
94.5



27.









571
2.73 (A)
94.9



28.









594
2.47 (A)
87.0



29.









553
2.73 (A)
97.6



30.









553
5.4 (C)
99.8



31.









553
7.1 (C)
100



32.









561
2.63 (A)
92.3



33.









567
2.72 (A)
92.7



34.









575
2.80 (A)
93.6



35.









561
2.61 (A)
91.7



36.









559
2.63 (A)
90.9



37.









584
2.53 (A)
96.5



38.









579
2.50 (A)
81.0



39.









556
2.68 (A)
96.3



40.









550
2.74 (A)
95.2



41.









565
5.5-8.6 (C) no separation
97.0



42.









583
2.68 (A)
91.7



43.









583
2.67 (A)
91.0



44.









567
6.68 (B)
87.5



45.









567
4.8 (C)
99.0



46.









567
5.8 (C)
99.0



47.









567
2.38 (A)
91.0



48.









596
2.70 (A)
95.2



49.









575
2.38 (A)
98



50.









582
2.70 (A)
91



51.









570
2.63 (A)
92



52.









584
2.54 (A)
96.8



53.









572
2.48 (A)
96.8



54.









539
2.57 (A)
91.3



55.









551
2.74 (A)
95.0



56.









555
2.71 (A)
92.0



57.









568
2.64 (A)
96.5



58.









568
2.41 (A)
89.5



59.









592
2.55 (A)
96.9



60.









576
2.43 (A)
94.0



61.









532
2.26 (A)
95.9



62.









575
2.57 (A)
96.6



63.









571
2.30 (A)
95.0



64.









582
2.35 (A)
92.0



65.









555
2.38 (A)
90.0



66.









577
2.62 (A)
89.2



67.









586
2.25 (A)
92.0



68.









598
2.35 (A)
93.0



69.









563
2.60 (A)
98.7



70.









570
2.35 (A)
93.0



71.









567
2.72 (A)
95.0



72.









557
2.56 (A)
96.4



73.









545
2.49 (A
97.3



74.









603
2.61 (A)
93.1



75.









555
2.69 (A)
98.2



76.









563
2.54 (A)
98.5



77.









591
2.58 (A)
94.6



78.









575
2.71 (A)
96.8



79.









527
2.48 (A)
99.2



80.









591
2.67 (A)
94.5



81.









551
2.55 (A)
98.5



82.









575
2.48 (A)
98.8



83.









521
2.56 (A)
99.4



84.









537
2.39 (A)
96.4



85.









557
2.33 (A)
94.6



86.









601
2.88 (A)
99.4



87.









573
2.59 (A)
98.8



88.









585
2.64 (A)
96.9



89.









573
2.71 (A)
98.7



90.









573
2.71 (A)
99.4



91.









5.73
2.71 (A)
96.5



92.









563
2.54 (A)
95.3



93.









587
2.54 (A)
97.3



94.









587
2.46 (A)
98.2



95.









585
2.68 (A)
97.6



96.









585
2.75 (A)
99.4



97.









575
2.51 (A)
98.8



98.









587
2.49 (A)
95.0



99.









543
9.9 (C)
98.5



100.









543
11.1 (C)
99.8



101.









543
13.4 (C)
97.6



102.









543
14.7 (C)
97.4



103.









551
7.8 (C)
85.4



104.









551
9.2 (C)
99.2



105.









551
11.7 (C)
97.6



106.









551
12.3 (C)
97.3



107.









551
13.3 (C)
99.8



108.









551
14.7 (C)
94.8



109.









551
21.8 (C)
93.8



110.









551
22.8 (C)
91.6



111.









551
2.50 (A)
92.2



112.









523
2.19 (A)
93.1



113.









551
2.56 (A)
95.1



114.









523
2.19 (A)
81.6



115.









556
2.30 (A)
96.5



116.









572
2.25 (A)
97.5



117.









557
2.63 (A)
97.5



118.









541
2.35 (A)
94.0



119.









527
2.60 (A)
96.0


































































































































































































































Example 120
trans-3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid









Step 1:
0.37 g (2.24 mmol) of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (5.1) and 0.62 g (2.054 mmol) of Intermediate 4.13 are dissolved in 10 ml of THF. 0.17 ml (3.06 mmol) of AcOH and 1.08 g (5.09 mmol) of NaHB(OAc) 3 are added in and the reaction is stirred overnight. Then the mixture is diluted with water, pH adjusted to 8-9 with NaHCO 3 and it is extracted with EtOAc, the combined organic phase is washed water and brine, dried Na 2 SO 4 and evaporated. The intermediate of 2.2 is 0.88 g (95.6%).
(M+H) + =452, R t =2.24 min (A), purity: 86.7%.
Step 2:
0.88 g (1.95 mmol) of formed secondary amine is dissolved in 15 ml of abs. EtOH, 0.334 g (2.92 mmol) of 3-oxo-cyclobutanecarboxylic acid (3.4), 0.17 ml (2.92 mmol) of AcOH and 0.313 g (2.92 mmol) of 2-picoline borane complex are added in. The mixture is stirred at 55° C. overnight, then is cooled, evaporated, diluted with water and extracted with DCM. The combined organic phases is dried, evaporated and purified by column chromatography (CHCl 3 -MeOH 19/1). The first eluted is the titled compound. 110 mg (10.3%); (M+H) + =550, R t =3.16 min(B), purity: 93.2%.
Example 121
cis-3-([1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid









During the column chromatography of Example 120 the second eluted is the titled compound: 510 mg (47.6%); (M+H) + =550, R t =3.26 min (B), purity: 95.6%.
Example 122
cis-3-([(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid









375 mg (0.68 mmol) of Example 121 is separated by preparative chiral column chromatography (Berger SFC systems; Chiralcel OJ-H 250×21 mm column (5 μM); 50 ml/min flow rate; CO2/80%/20%; EtOH+0.5% IPA). The first eluted enantiomer has (R)-configuration, yield is 124 mg (68%). (M+H) + =550, R t =10.7 min, purity: 100%.
Example 123
cis-3-([(S)-1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-cyclobutanecarboxylic acid









375 mg (0.68 mmol) of Example 121 is separated by preparative chiral column chromatography (Berger SFC systems; Chiralcel OJ-H 250×21 mm column (5 μM); 50 ml/min flow rate; CO2/80%/20%; EtOH+0.5% IPA). The second eluted enantiomer has (S)-configuration, yield is 125 mg (68%). (M+H) + =550, R t =12.6 min, purity: 99.9%.
Example 124
trans-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid









Step 1
is undertaking as in Example 120 using 1-(4-chloro-3-fluoro-phenyl)-ethyl-amine (5.7) and (4.2) for the first reductive amination step. (M+H) + =419, R t =2.44 min (A), purity: 93.9%.
Step 2:
2.73 g (6.5 mmol) of formed secondary amine is dissolved in 108 ml of THF, 1.487 g (2 equiv.) of 3-oxo-cyclobutanecarboxylic acid (3.4), 0.56 g (1.5 equiv.) of AcOH and 4.14 g (3 equiv.) of NaBH(OAc) 3 are added in. The mixture is stirred at 35° C. for 48 h, then is cooled, diluted with water and extracted with EtOAc. The combined organic layer is purified by column chromatography (CHCl 3 -MeOH 19/1). The first eluted material is the titled compound. 180 mg (5.3%). (M+H) + =517, R t =4.69 min (B), purity: 96.5%.
Example 125
cis-3-([1-(4-Chloro-3-fluoro-phenyl)-ethyl]-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-cyclobutanecarboxylic acid









From Example 124 after the column chromatography the second eluted material is the titled compound: 310 mg (9.2%). (M+H) + =517, R t =4.70 min (B), purity: 99%.
Following the procedures as outlined in Example 121 using different amines (5), benzaldehydes (4) and oxo-cycloalkane carboxylic acid esters (3, R′═O), or as outlined in Example 1 using different amines (5), benzaldehydes (4) and formyl-cycloalkane carboxylic acid esters (3, R′═CHO) the compounds listed in Table 5 are prepared.









TABLE 5






Rt





min.
Purity

Examples
Structure
(M + H) +
(system)
(%)



126.









583
2.16 and 2.20 trans/ cis = 36/61 (A)
92.3



127.









527
2.40 and 2.43 trans/ cis = 29/54 (A)
83.0



128.









513
4.35 (B)
96.5



129.









513
4.43 (B)
97.7



130.









513
4.37 (B)
98.9



131.









513
4.44 (B)
97.1



132.









499
4.28 (B)
97.4



133.









511
4.31 (B)
92.8



134.









534
3.52 (B)
93.6



135.









521
3.81 (B)
98.7



136.









526
4.16 (B)
97.7



137.









549
4.68 (B)
99.4



138.









533
4.91 (B)
100



139.









547
2.63 (A)
99.7



140.









531
2.57 (A)
97.8



141.









563
4.98 (B)
98.3



142.









533
4.37 (B)
96.7



143.









497
2.69 (B)
97.4



144.









563
2.81 (A)
95.6



145.









578
2.56 (A)
97.4



146.









581
2.57 (A)
97.9



147.









637
2.99 (A)
97.4



148.









587
2.53 (A)
96.5



149.









585
2.76 (A)
94.5



150.









533
4.43 (B)
98.7



151.









531
2.57 (A)
99.3



152.









549
4.65 (B)
99.8



153.









514
3.92 (B)
98.0



154.









591
2.51 (A)
95.8



155.









621
5.34 (B)
92.4



156.









617
5.65 (B)
96.4



157.









586
2.62 (A)
93.7



158.









541
2.35 and 2.38; trans/ cis: 67/21; (A)
88.0



159.









548
3.15 (B)
92.5



160.









548
3.05 (B)
81.5























































































Biological Methods
Compounds according to the invention as described are useful to block the interaction of CXCR3-A and CXCL10 in a radiolabelled binding assay.
Competition radioligand binding assays were performed to determine the in vitro potency of the newly synthesized, unlabeled test compounds to displace the specific binding of the radiolabelled endogenous chemokine, 125I-CXCL10, from the human CXCR3-A receptor. IC 50 values were determined for the test compounds and used to explore the structure-activity relationships (SAR). The established SAR was used to feed back the molecular design and to suggest some suitable modifications for groups and structural elements by which the affinity of test compounds for the human CXCR3 receptor would be improved.
Cell Line and Membrane Preparation
CHO cells stably expressing human recombinant CXCR3-A receptors were generated in Sanofi-Aventis (LIT Frankfurt) by transfection of Flp-In-CHO host cells with a plasmid construct of pCDA5-FRT-TO_IRES-Gai4qi4_DEST. This cell line was registered in Sanofi-Aventis cell line bank. Cells were grown in Ham's F12 (PAA) medium supplemented with 10% FCS (PAA, Cat No. E15-898) and 0.6% Hygromycin (PAA) in T175 flasks at 37° C. in a humidified incubator under 5% CO 2, 95% air. Cells were harvested from the culture flasks by a short treatment (8-10 minutes) with Versene (Gibco, Cat No. 15040). Cell suspension was diluted with PBS and cells were collected with centrifugation at 230 g for 10 minutes at 10° C. with a Juan centrifuge. Pellets containing approximately 1×10 8 cells were resuspended in 15 ml of 20 mM HEPES pH=7.4, 10 mM EDTA buffer supplemented with complete protease inhibitor (Roche, Cat No. 11 697 498 001). This suspension was homogenized with a Teflon/glass homogenizer (Sartorius potter S) with 3×10 sec pulses in ice cold water bath, and then centrifuged at 300×g for 10 min at 4° C. with a Sigma centrifuge. The supernatant was carefully collected and centrifuged at 100,000×g for 60 min at 4° with a Beckman Avanti J30 centrifuge. The resulting pellet was washed once with 15 ml of fresh preparation buffer. The final membrane pellet was resuspended in storage buffer (20 mM HEPES pH=7.4, 0.1 mM EDTA, 250 mM sucrose supplemented with complete protease inhibitor) in a volume ratio of approximately 1×10 8 cells/1 ml, which gave a protein concentration of 2 to 4 mg/ml. Protein concentration was determined with Bio-Rad protein assay (Cat No 500-0006). Membrane aliquots were stored at −80° C. No degradation was observed until a storage period of approximately 5 months.
125I-CXCL10 Radioligand Binding Study
The composition of the binding assay buffer was determined in a course of detailed optimization procedure. This resulted in a binding assay buffer constituted by the following components: 25 mM HEPES (pH=7.4), 5 mM MgCl 2 , 1 mM CaCl 2 , 100 mM NaCl, supplemented with 0.1% of protease free BSA (as a final concentration). Competition binding assay was performed using 125I-CXCL10 (PerkinElmer, NEX348, specific activity 2200 Ci/mmol) radioligand in a final concentration of 50-70 pM. The nonspecific binding was defined by 150 pM of hr-CXCL10 (R&D Systems, Cat No 266-IP). The total assay volume was equal to 150 μl and contained 0.1% of DMSO (final concentration). Binding reaction was initiated by adding of membranes (10-20 μg proteins, approximately 5×10 5 cell equivalents) to the reaction mixture. After 60 minutes of incubation at 25° C. the reaction was terminated by rapid filtration over GF/B glass fiber filters that were pre-soaked with 0.5% polyethyleneimine (Fluka Analytical, P3143) for 1 hour, using a Skatron cell harvester device. Filters then were washed with 8 ml of ice-cold wash buffer (modified binding buffer in which BSA was omitted and the concentration of NaCl was adjusted to 500 mM concentration). The radioactivity retained on the filters was measured by a Wizard 1470 Automatic Gamma counter.
Test compounds were dissolved prior to the binding assay at a concentration of 10 mM in DMSO. Stock solutions were stored at −20° C. for not longer than 3 months. On the day of binding assay serial dilutions of test compounds ranging from 10 mM up to 3×10 −7 M (or 3×10 −9 M) were generated by 8 (or 12) consecutive steps using DMSO as solvent. Before adding these solutions of test compound to the binding reaction mixture, an intermediate dilution procedure was applied, in which 30 μL of each solution sample was transferred into a dilution tube containing 970 μL of binding assay buffer. Then 50 μL of these second dilution series was added to the test tubes and a concentration range of test compounds between 1×10 −5 M and 3×10 −9 M (or 3×10 −11 M).
The IC 50 values and Hill slopes for competition binding data were obtained using nonlinear four-parametric curve fitting method.
The exemplified compounds of the present invention have activities in the above binding assay of less than 20 micromolar, more particular compound have activities of less than 1 micromolar, and further particular compounds have activities of less than 200 nanomolar IC50.








TABLE 6





Example #
IC50 (nM)











1.1
177


1
60


2
760


3
60


4
37


5
19


6
20


7
38


8
3810


9
32


10
64


11
200


12
13


13
1660


14
25


15
37


16
35


17
44


18
64


19
55


20
1200


21
633


22
112


23
116


24
58


25
25


26
64


27
80


28
81


29
150


30
53


31
360


32
123


33
42


34
22


35
1430


36
28


37
76


38
163


39
99


40
81


41
131


42
87


43
68


44
410


45
160


46
1000


47
800


48
409


49
746


50
1240


51
157


52
177


53
789


54
482


55
6600


56
215


57
200


58
169


59
195


60
345


61
102


62
200


63
62


64
487


65
121


66
85


67
77


68
143


69
56


70
180


71
176


72
825


73
154


74
350


75
45


76
45


77
182


78
270


79
154


80
431


81
245


82
46


83
146


84
107


85
71


86
85


87
19


88
23


89
52


90
494


91
121


92
220


93
84


94
630


95
4040


96
443


97
4640


98
155


99
223


100
108


101
1810


102
154


103
260


104
15


105
53


106
144


107
5130


108
190


109
73


110
525


111
646


112
145


113
82


114
180


115
244


116
160


117
71


118
190


119
3200


120
2900


121
152


122
70


123
7000


124
24% at 10 μM


125
465


126
58


127
1090


128
37% at 10 μM


129
105


130
5300


131
6500


132
170


133
1640


134
240


136
347


137
104


138
670


139
1200


140
260


141
200


142
120


143
3000


144
167


145
146


146
254


147
7000


148
26


149
165


150
98


151
457


152
149


153
294


154
70


155
2870


156
79


157
71


158
1060


159
544


160
26% at 10 μM





















































































































































































Cyclic AMP Accumulation Assay
An in vitro functional assay measuring the changes in the intracellular cyclic adenosine 3′,5′-monophosphate (cyclic AMP, or also called as cAMP) level following either stimulation or activation of CXCR3-A receptor was used to demonstrate the antagonistic functionality of the selected compounds.
Cyclic AMP is one of the most important intracellular second messenger molecules whose level is regulated principally by the G-protein coupled adenylyl cyclase effector enzyme located in the inner surface of the cellular plasma membrane. Receptor dependent, G-protein mediated changes in the cyclic AMP concentration elicit then complex regulatory processes within the cell such as activation of multiple protein kinases and phospholipases, generation of inositol triphosphate and transient rise in the intracellular calcium ion (Ca2+) concentration, ion channel gating, effects on different gene transcriptions.
Upon agonist stimulation, CXCR3-A receptor activates the pertussis toxin (PTX) sensitive G-proteins of the Gi class that mediates a reduction in the intracellular cAMP levels, an increase in the intracellular Ca2+ mobilization and actin polymerization, that finally lead to cytoskeletal rearrangement and directed cell migration (chemotaxis). [Sauty A et al, 2001. J. Immunol. 167: 7084-7093.]
Cyclic AMP accumulation assay was performed with a homogeneous time-resolved fluorescence (HTRF) cAMP femto 2 kit from CisBio International. The measurement was basically carried out by following the manufacturer's instructions.
Since CXCR3-A receptor is coupled to Gi-protein, thus an agonist activation of the receptor will lead to a decrease in the intracellular cAMP level [Crosignani S. et al, 2010. Bioorg. Med. Chem Letters, 20:3614-3617]. Therefore, the cells have to be preactivated by forskolin, a direct activator of the cell adenylyl cyclase enzyme, in order to reach a sufficient cellular basal cAMP level. The agonist induced decrease in cAMP level will be measured by an increase of the Fluorescence Resonance Energy Transfer signal, as the signal is inversely proportional to the concentration of cAMP in the cell.
For the assay, the adherent hr-CXCR3-Flp-In-CHO— IRES-Gai4qi4 cells (the same cell line as used for binding assay) were washed with Ca2+-Mg2+ free PBS and harvested by a short treatment with Acutase (Sigma, A6964). At a time point of 2 min after adding Acutase (3 ml/T175 flask) 7 ml of culture medium was added to the detached cells. Cell suspension was collected and centrifuged at 1,700 rpm for 10 min. (Sigma 2-S table centrifuge). The resulting cell pellet was resuspended in PBS with Ca2+/Mg2+ (Invitrogen 14080-048) and subjecting to a second centrifugation step as above. The final cell pellet was resuspended in assay buffer (PBS with Ca2+/Mg2+, supplemented with fatty acid free BSA (Sigma A6003) at a final concentration of 1 mg/ml and with the phosphodiesterase inhibitor Rolipram (Calbiochem 557330) at a final concentration of 10 μM. Cells were transferred to a 96-well microplate (Costar 3694, Half Area flat bottom, non-treated, black polystyrene plate) at a density of 16,000 cells/well.
The cells were incubated in the presence of different concentrations of antagonist compounds (within the range of 1004 and 0.1 nM) for 10 min at room temperature (R.T.) under continuous shaking the microplate in a plate shaker (Heidolph Titramax 100, at 600 rpm). The final concentration of DMSO in reaction mixture was 0.1%. Then CXCL10 at a final concentration of 20 nM was added and the cells were further incubated for 10 min at R.T., as above. After that forskolin (Sigma F-6886) at 1 μM final concentration was added and an additional incubation period (30 min, R.T., shaking) followed. The final reaction volume was 40 μl. The reaction was stopped by adding the lysis buffer containing the HTRF reagents.
Plates were then incubated for 60 min at R.T. under shaking, and time-resolved FRET signals were measured after excitation at 337 nm. Both the emission signal from the europium cryptate-labelled anti-cAMP antibody (620 nm) and the FRET signal resulting from the labelled cAMP-d2 (665 nm) were recorded using a RubyStar instrument (BMG Labtechnologies).
The results were calculated as a fluorescence ratio (Em.665 nm/Em.620 nm)×10000 and were analyzed by calculating the Delta F value which corresponded to the following formula:
Delta F =(Standard or Sample Ratio−Negative Control Ratio)/(Negative Control Ratio)×100.

The negative control corresponded to the background signal obtained with the cryptate conjugate alone.
The compounds tested in the above functional cAMP assay displayed an 1050 value of less than 2 micromolar and particularly less than 20 nanomolar.
Formulation Examples
(1) Tablets
The ingredients below are mixed by an ordinary method and compressed by using a conventional apparatus.











Compound of Example 1
30 mg


Crystalline cellulose
60 mg


Corn starch
100 mg


Lactose
200 mg


Magnesium stearate
4 mg



















(2) Soft Capsules
The ingredients below are mixed by an ordinary method and filled in soft capsules.











Compound of Example 1
30 mg


Olive oil
300 mg


Lecithin
20 mg

















(1) Parenteral Preparations
The ingredients below are mixed by an ordinary method to prepare injections contained in a 1 ml ampoule.











Compound of Example 1
3 mg


Sodium chloride
4 mg


Distilled water for injection
1 ml

















The compounds of the present invention have CXCR3 inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) or lichen planus.