English
Tiếng Việt
(en)The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases.
1.ApplicationNumber: US-201314385689-A
1.PublishNumber: US-10017481-B2
2.Date Publish: 20180710
3.Inventor: OBRECHT, DANIEL
ERMERT, PHILIPP
OUMOUCH, SAID
PIETTRE, ARNAUD
GOSALBES, Jean-François
THOMMEN, MARC
4.Inventor Harmonized: OBRECHT DANIEL(CH)
ERMERT PHILIPP(CH)
OUMOUCH SAID(FR)
PIETTRE ARNAUD(FR)
GOSALBES JEAN-FRANÇOIS(FR)
THOMMEN MARC(CH)
5.Country: US
6.Claims:
(en)The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases.
7.Description:
(en)Macrocyclic natural and synthetic products have played a crucial role in the development of new drugs, especially as anti-infectives (F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich, Angew. Chem. Int. Ed. Engl. 2006, 45, 5072-5129; D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. O. Gombert, Curr. Med. Chem. 2009, 16, 42-65), as anti-cancer drugs and in other therapeutic areas (C. E. Ballard, H. Yu, B. Wang, Curr. Med. Chem. 2002, 9, 471-498; F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309-1332). They often display remarkable biological activities, and many macrocycles or their derivatives have been successfully developed into drugs (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186; D. J. Newman, G. M. Gragg, K. M. Snader, J. Nat. Prod. 2003, 66, 1022-1037). The chemical diversity of macrocyclic natural products is immense and provides a tremendous source of inspiration for drug design.
Macrocyclic natural and synthetic products generally exhibit semi-rigid backbone conformations placing appended substituents into well-defined spatial orientation. Certain ring sizes are preferred (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186), e.g. 16-membered rings are frequently found in oxygen-containing macrocycles, such as polyketides (M. Q. Zhang, B. Wilkinson, Curr. Opin. Biotechnol. 2007, 18, 478-488). It is hypothesized that semi-rigid scaffolds possess some of the favorable binding properties of rigid molecules (entropy), yet still retaining enough flexibility to adapt suitable conformations in the binding event (induced fit).
Macrocyclic natural and synthetic products are generally classified according to the chemical nature of the backbone, e.g. cyclic peptides (Y. Hamady, T. Shioiri, Chem. Rev. 2005, 105, 4441-4482; N.-H. Tan, J. Zhou, Chem. Rev. 2006, 106, 840-895); cyclic depsipeptides (F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309-1332); macrocyclic lactones (macrolactones) and macrolides; macrocyclic lactams (macrolactams), macrocyclic amines, macrocyclic ethers, macrocyclic ureas and urethanes, and others. The conformational, physico-chemical, pharmacological and pharmacodynamic properties of macrocyclic natural and synthetic compounds depend largely on the ring size, the chemical nature of the backbone, and of appended groups (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186). By modifying these three parameters nature has created a virtually unlimited repertoire of molecular diversity. Despite their undisputed interesting biological properties, many natural products show limitations for drug development, such as low metabolic stability, i.e. short half lives, lack of or insufficient oral bioavailability as well as low tissue penetration and membrane permeability which renders them not amenable for intracellular targets. In addition, their high structural complexity imposes severe limitations to synthetic accessibility, often leaving fermentation or recombinant methods as sole options; thus making complex quality control and development processes necessary and leading to high production costs.
The present invention describes novel, fully synthetic, macrocyclic natural product-like molecules of type I (Scheme 1), accessible through a modular approach by connecting suitably protected building blocks A, B and C to a linear precursor followed by subsequent intramolecular cyclization.
Building blocks A serve as conformation-inducing templates (“Template”) and are based on appropriately substituted and protected divalent biaryl-derivatives. Biaryl as used in this context shall comprise all possible pairwise combinations of aromatic carbocyclic and/or aromatic heterocyclic ring systems connected by a C sp 2 -C sp 2 single bond, i.e. aryl-aryl, heteroaryl-heteroaryl, aryl-heteroaryl and heteroaryl-aryl.
Building blocks B are corresponding to appropriately substituted and protected primary, secondary or tertiary aminoalcohols and are functioning as conformational modulators (“Modulator”) by influencing the conformation of the macrocycle, e.g. through cis/trans-isomerization of amides.
Within the macrocycles backbone of I the building blocks A and B are connected via the “Bridge” C composed of one to three appropriately and independently substituted subunits c1, c2 and c3, which in turn are derived from suitably substituted and protected precursors, like, but not limited to, appropriately substituted and protected amino acids or amine derivatives.
The connectivity —X— between Template A and Modulator B is defined by an ether (X═O) or thioether (X═S) bond; while that between A and Bridge C is defined by the structural element —Y—Z— as detailed below. As sulfur atoms of such a thioether linkage can easily and selectively be oxidized to the corresponding sulfoxides (S═O) or sulfones (S(═O) 2 ), these higher oxidation states are also part of the invention.
The generic connection —Y—Z— between A and C corresponds in most exemplified cases to a secondary or tertiary amide bond (—C(═O)—NR 7 —). Alternative connectivities —Y—Z— are thioethers (—S—CHR 8 —) and its oxidation products, i.e. sulfoxides (—S(═O)—CHR 8 —) or sulfones (—S(═O) 2 —CHR 8 —), as well as olefinic moieties (—(CHR 9 ) t —CR 11 ═CR 10 —) and their reduced aliphatic analogs (—(CHR 9 ) t —CHR 11 —CHR 10 —). Furthermore, in case of Templates A carrying a thiophenolic Y-group (Y═S) an additional two carbon spacer can be easily introduced by reacting with β-halo carboxyl or β-halo carbonyl compounds prior to processing with the C building blocks; thus providing access to —Y—Z— groups of type —S—CHR 8 —C(═O)—NR 7 —, —S—CHR 8 —CHR 12 —NR 7 —, —S—CHR 8 —CHR 12 —NR 7 — and their corresponding S-oxidized congeners.
The functional moiety U connects Bridge C with the nitrogen atom of Modulator B. In most cases this is realized by an amide bond, in which case the moiety U corresponds to a carbonyl group (—C(═O)—). Alternatively, U can be defined as a carbamoyl moiety (—NR 7 —C(═O)—) leading to a urea (including the N-atom of B) as functional connection between B and C. Similarly, a carboxyl group (—O—C(═O)—) as U describes a carbamate linkage between B and C. In addition, U can represent an oxalyl group (—C(═O)—C(═O)—) or the corresponding acetal (—C(—OR 13 ) 2 —C(═O)—).
As mentioned before, the Bridge C itself comprises one to three (1-3) appropriately and independently substituted subunits c1, c2 and c3, which in turn are independently connected to each other by the generic groups V or W which can correspond to an amide bond (—C(═O)NR 7 —) and the corresponding inverse amide (—NR 7 C(═O)—), the methylene-heteroatom linkages —CHR 8 -Q- and -Q-CHR 8 —, an alkene[1,2]diyl moiety (—CHR 10 ═CHR 11 —) or its reduced form as alkane[1,2]diyl (—CHR 10 —CHR 11 —), an oxalyl group (—C(═O)—C(═O)—) or a disulfide bridge (—S—S—).
The spatial orientation of the substituents in macrocycles I is modulated by the ring size and the stereochemical connectivity within building blocks A, B and C. Therefore the macrocyclic backbone as well as the substituents contribute to the biological activity of compounds of type I.
Compounds of this invention are characterized by macrocyclic backbones containing an aromatic ether/thioether linkage and one or more tertiary amide bonds. In other cases secondary amide bonds, aliphatic ether linkages, ethylidene or ethylene moieties are exemplified as part of the backbone.
Ether linkages in macrocyclic molecules favorably influence physico-chemical and pharmacological properties, such as solubility in aqueous solutions, metabolic stability against proteolytic degradation, cell permeability and oral absorption (K. X. Chen et al., J. Med. Chem. 2006, 49, 995-1005). In addition, tertiary amide bonds containing macrocycles are well-known for increased proteolytic stability, cell permeability and oral bioavailability compared to the parent molecules with secondary amide bonds (E. Biron, J. Chatterjee, O. Ovadia, D. Langenegger, J. Brueggen, D. Hoyer, H. A. Schmid, R. Jelinek, C. Gilon, A. Hoffmann, H. Kessler, Angew. Chem. Int. Ed. 2008, 47, 1-6; J. Chatterjee, O. Ovadia, G. Zahn, L. Marinelli, A. Hoffmann, C. Gilon, H. Kessler, J. Med. Chem. 2007, 50, 5878-5881). For instance, the cyclic undecapeptide cyclosporin A (INN: Ciclosporin), which is used as immunosuppressant in organ transplants, contains seven N-methylated amino acids and possesses good oral bioavailability when formulated appropriately (P. R. Beauchesne, N. S. C. Chung, K. M. Wasan, Drug Develop. Ind. Pharm. 2007, 33, 211-220).
A well documented process in protein folding events is the peptidyl cis/trans isomerization of proline or pipecolic acid containing polypeptides and proteins. In vivo this process is mediated by peptidyl prolyl cis/trans isomerases such as the cyclophilins, the FK506-binding proteins and the parvulins (A. Bell, P. Monaghan, A. P. Page, Int. J. Parasitol. 2006, 36, 261-276). Besides their role in protein folding and in the immune system, peptidyl prolyl cis/trans isomerases have been implicated in cell cycle control (P. E. Shaw, EMBO Reports 2002, 3, 521-526) and therefore constitute interesting pharmaceutical targets. In the context of this invention it is worth mentioning that both FK506 and cyclosporin A are macrocyclic natural products interacting with the FK506-binding protein and cyclophilins, respectively.
An interesting structural motif found in several natural products consist of a macrocylic ring system with a biaryl moiety as backbone element. Such biaryls, which are composed of two aromatic or heteroaromatic rings connected via a single bond, are the outstanding characteristic of a number of antibacterial macrocyclic peptide classes, like the biphenomycins, arylomycins and aciculitins; not to mention the glycopeptide antibiotics with the vancomycins as most prominent representatives (L. Feliu, M. Planas, Int. J. Pept. Res. Ther. 2005, 11, 53-97).
For many extra- and intracellular biological targets the quest for small molecule hits has been disappointing; this is especially true if protein-protein interactions are involved (J. A. Robinson, S. DeMarco, F. Gombert, K. Moehle, D. Obrecht, Drug Disc. Today 2008, 13, 944-951). These so-called “difficult targets” include e.g. receptor tyrosine kinases, growth factor receptors, transcription modulators, and chaperones. Interestingly, several natural and synthetic macrocyclic compounds have been described as promising starting points for drug discovery programs around such difficult targets (D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. O. Gombert, Curr. Med. Chem. 2009, 16, 42-65).
The novel macrocycles of type I described in the embodiments of this invention are designed to combine unique features of natural macrocyclic compounds with beneficial physico-chemical and pharmacological properties of small molecules, e.g.:
Natural product-like structural complexity Good aqueous solubility High metabolic stability Improved oral bioavailability Enhanced membrane permeability Extra- and intracellular targets amenable Improved tissue penetration Small molecule-like pharmacokinetics Modular chemical synthesis Synthesis process well suited for parallelization Reasonable production costs Small molecule-like QC and development processes
The Main Embodiment of the current invention of novel and fully synthetic macrocyclic compounds I according Scheme 1 (detailed in Scheme 2 and Scheme 3) is defined by groups of selected building blocks A, B and C as shown in Table 1 to Table 3 and by the appending substituents R 1 -R 57 as detailed below.
As shortly indicated before, Template A exerts an important conformational constraint on products of type I. These structural effects of A depend on (i) the dihedral angle between the two C sp 2 -C sp 2 connected aromatic rings A B and A C that are defining the Template A entity; (ii) the relative orientation of the attachment vectors of —X— and —Y— and (iii) the spatial distance between the groups —X— and —Y—.
One possible general preparative access to the corresponding building blocks of type A consists of an C sp 2 -C sp 2 -coupling between appropriately functionalized arene and/or heteroarenes (R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A. de Meijere, F. Diederich (eds), Metal - Catalyzed Cross - Coupling Reactions, 2nd ed., Wiley-VCH 2004; especially for macrocyclic biaryls cf. Q. Wang, J. Zhu, Chimia 2011, 65, 168-174, and literature cited therein). Therefore the template A can be described by its two aryl/heteroaryl constituents A B and A C , wherein A B is defined as that structural half of A that is directly connected with building block B and A C as that half that is directly bound to building block C. In case of a biphenyl derivative as Template A such disconnection can be illustrated e.g. as:
In general, Template A of this invention is a divalent radical that is defined by the combinatorial connection of its two constituent aryl/heterorayl moieties A B and A C selected from Table 1 and Table 2.
TABLE 1
Constituents A B 1-A B 65 of Template A
A B 1
A B 2
A B 3
A B 4
A B 5
A B 6
A B 7
A B 8
A B 9
A B 10
A B 11
A B 12
A B 13
A B 14
A B 15
A B 16
A B 17
A B 18
A B 19
A B 20
A B 21
A B 22
A B 23
A B 24
A B 25
A B 26
A B 27
A B 28
A B 29
A B 30
A B 31
A B 32
A B 33
A B 34
A B 35
A B 36
A B 37
A B 38
A B 39
A B 40
A B 41
A B 42
A B 43
A B 44
A B 45
A B 46
A B 47
A B 48
A B 49
A B 50
A B 51
A B 52
A B 53
A B 54
A B 55
A B 56
A B 57
A B 58
A B 59
A B 60
A B 61
A B 62
A B 63
A B 64
A B 65
TABLE 2
Constituents A C 1-A C 66 of Template A
A C 1
A C 2
A C 3
A C 4
A C 5
A C 6
A C 7
A C 8
A C 9
A C 10
A C 11
A C 12
A C 13
A C 14
A C 15
A C 16
A C 17
A C 18
A C 19
A C 20
A C 21
A C 22
A C 23
A C 24
A C 25
A C 26
A C 27
A C 28
A C 29
A C 30
A C 31
A C 32
A C 33
A C 34
A C 35
A C 36
A C 37
A C 38
A C 39
A C 40
A C 41
A C 42
A C 43
A C 44
A C 45
A C 46
A C 47
A C 48
A C 49
A C 50
A C 51
A C 52
A C 53
A C 54
A C 55
A C 56
A C 57
A C 58
A C 59
A C 60
A C 61
A C 62
A C 63
A C 64
A C 65
A C 66
The Modulator B is a divalent radical selected from the groups of Table 3. B1-B10 are optionally substituted primary or secondary amines carrying a moiety of type —CHR 5 -LG, wherein LG is a suitable leaving group that can be replaced by the nucleophilic groups on Template A forming an ether (—O—) or a thioether (—S—) linkage (as well as its oxidized variations —S(═O)— and —S(═O) 2 —) between building blocks of type A and B. Examples of appropriate LGs include —OH, which is in situ transformed into the active LG during Mitsunobu reactions, or halogens, like —Br or —I, which are amenable to S N reactions.
For most examples of this invention, the amine nitrogen of Modulator B forms a secondary or tertiary amide bond with the carboxyl group of the Bridge C. By virtue of inducing peptidyl cis-trans isomerizations or stabilizing cis amide bonds, building blocks of type B can function as conformational modulators in macrocycles of type I.
TABLE 3
Radicals B1-B10
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
The Bridge C is a divalent radical selected from the groups of Table 4. This divalent moiety C may consist of one to three (1-3) subunits c1 to c3, i.e. (i) —Z-c1-U—, (ii) —Z-c1-V-c2-U— and (iii) —X-c1-V-c2-W-c3-U—. As a consequence Bridge C directly influences the ring size of the macrocycle and can therefore be regarded as spacer or linker. This Bridge C is joined to Template A via its terminal group Z (i.e. N-terminus in case of an amino acid) and to Modulator B via its terminal group U (i.e. C-terminus in case of an amino acid) to form the macrocyclic ring of type I. Thus C contributes to the backbone of macrocycle I with its carbon chains as well as with its functional groups Z, W, V and U (cf. Scheme 2 and 3).
TABLE 4
Generic Representations of Bridge C
C1
C2
C3
According to the preceding definitions, macrocycles I contain at least one amide bond or isosteric surrogate thereof. As emphasized in the introduction, tertiary amides generally show various ratios of cis and trans conformations in solution. In striking contrast secondary amides strongly prefer trans conformations. Such occurrence of cis and/or trans conformations in macrocyclic natural products containing tertiary amide groups is well documented. In some cases a rapid equilibration by peptidyl cis-trans isomerization is observed, whereas in other cases discrete cis and trans tertiary amide bonds are detected as two stable conformers in solution at room temperature. Consequently all possible stereoisomers, explicitly including atropisomers, conformers or rotamers of macrocycles of type I are part of this invention.
The substituents attached to the Main Embodiment of macrocycle I or its constituents A, B or C, are defined as follows:
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; C 1-12 -alkoxy or aryloxy; R 5 is H; CF 3 ; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 6 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; or —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or an N-protecting group; R 8 and R 9 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 10 , R 11 and R 12 are independently defined as H; C 1-24 -alkyl; or cycloalkyl; R 13 is C 1-24 -alkyl or cycloalkyl; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 17 , R 19 , R 21 , R 23 , R 25 , R 27 , R 29 and R 31 are independently defined as H; C 1-24 -alkyl; cycloalkyl; or heterocycloalkyl; R 16 , R 22 and R 28 are independently defined as H; CF 3 ; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 45 ; —(CR 51 R 53 ) q SR 45 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q OCONR 7 R 45 ; —(CR 51 R 53 ) q NR 74 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 37 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 37 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) q R 44 ; R 33 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 34 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) r OR 45 ; —(CR 51 R 53 ) r NR 7 R 45 ; —(CR 51 R 53 ) r OCONR 7 R 35 ; —(CR 51 R 53 ) r NR 7 COOR 36 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) q R 44 ; R 35 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 50 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) r NR 7 SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) q CONR 7 R 50 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or an O/S-protecting group; R 37 is C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 45 ; —(CR 51 R 53 ) q SR 45 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q OCONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) t COR 44 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) t R 39 ; —(CR 51 R 53 ) u R 40 ; —(CR 51 R 53 ) t R 41 ; or —(CR 51 R 53 ) t R 44 ; R 38 is C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 39 is aryl; heteroaryl; —C 6 H 2 R 3 R 4 R 46 ; or a group of one of the formulae H1-H34 listed in Table 5.
TABLE 5
Groups of Formulae H1-H34
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
H16
H17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
H30
H31
H32
H33
H34
R 40 is a group of one of formulae H35-H41 as shown in Table 6 below.
TABLE 6
Groups of Formulae H35-H41
H35
H36
H37
H38
H39
H40
H41
R 41 is a group of one of formulae H42-H50 as shown in Table 7 below.
TABLE 7
Groups of Formulae H42-H50
H42
H43
H44
H45
H46
H47
H48
H49
H50
R 42 and R 43 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl;
R 44 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 below.
TABLE 8
Groups of Formulae H51-H55
H51
H52
H53
H54
H55
R 45 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 51 R 53 ) r OR 36 ; —(CR 51 R 53 ) r NR 7 R 57 ; —(CR 51 R 53 ) r OCONR 7 R 57 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 57 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 SO 2 NR 7 R 57 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) s R 44 ;
R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 36 ; —(CR 51 R 53 ) q SR 36 ; —(CR 51 R 53 ) q NR 7 R 57 ; —(CR 51 R 53 ) q OCONR 7 R 57 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; or —(CR 51 R 53 ) q R 44 ;
R 47 is H; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or —NR 7 R 45 ;
R 48 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 51 R 53 ) r OR 45 ; —(CR 51 R 53 ) r SR 45 ; —(CR 51 R 53 ) r NR 7 R 45 ; —(CR 51 R 53 ) r OCONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 COOR 36 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) r SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; or —(CR 51 R 53 ) s R 44 ;
R 49 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 36 ; —(CR 51 R 53 ) q SR 36 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; or —(CR 51 R 53 ) q R 44 ;
R 50 is H; C 1-24 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group;
R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ;
R 52 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 COOR 36 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COOR 36 ; —CONR 7 R 57 ; —C(═NR 7 )NR 7 R 57 ; —NR 7 C(═NR 7 )NR 7 R 57 ; or a group of one of the formulae H56-H110 as shown in Table 9 below.
TABLE 9
Groups of Formulae H56-H110
H56
H57
H58
H59
H60
H61
H62
H63
H64
H65
H66
H67
H68
H69
H70
H71
H72
H73
H74
H75
H76
H77
H78
H79
H80
H81
H82
H83
H84
H85
H86
H87
H88
H89
H90
H91
H92
H93
H94
H95
H96
H97
H98
H99
H100
H101
H102
H103
H104
H105
H106
H107
H108
H109
H110
R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ;
R 55 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —COOR 36 ; or —CONR 7 R 45 ;
R 56 is H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ;
R 57 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; aryl; aryl-C 1-12 -alkyl; or an N-protecting group.
Taken together, the following pairs of substituents can form optionally substituted cycloalkyl or heterocycloalkyl moieties: (R 5 and R 6 ); (R 7 and R 14 ); (R 7 and R 16 ); (R 7 and R 18 ); (R 7 and R 20 ); (R 7 and R 22 ); (R 7 and R 24 ); (R 7 and R 26 ); (R 7 and R 28 ); (R 7 and R 30 ); (R 7 and R 35 ); (R 7 and R 45 ); (R 7 and R 57 ); (R 13 and R 13 ); (R 14 and R 16 ); (R 14 and R 18 ); (R 15 and R 51 ); (R 19 and R 51 ); (R 20 and R 22 ); (R 20 and R 24 ); (R 26 and R 28 ); (R 26 and R 30 ); (R 32 and R 33 ); (R 42 and R 43 ); or (R 51 and R 53 ).
In addition, the structural elements —NR 7 R 35 ; or —NR 44 R 45 can form one of the groups of formulae H111-H118 as shown in Table 10 below.
TABLE 10
Heterocyclic Groups Defined by Linking the Residues
of the Disubstituted Amino Groups —NR 7 R 35 or —NR 44 R 45 .
H111
H112
H113
H114
H115
H116
H117
H118
Generic atoms and connector groups in the aforementioned structures are:
Z, Y, X, W, V, U as defined by Scheme 3; T is CR 54 or N; Q is O; S; or NR 35 ; M is O; S; or NR 7 .
The indices in the aforementioned structures are defined as:
m is an integer of 0-8; n is an integer of 0-1; p is an integer of 0-4; q is an integer of 0-4; r is an integer of 2-4; s is an integer of 1-4; t is an integer of 0-2; u is an integer of 1-2.
For the avoidance of doubt, some of the aforementioned substituents, for example, but not limited to, R 7 , R 16 , R 17 , R 18 , R 19 , R 22 , R 23 , R 24 , R 25 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 42 , R 43 , R 45 , R 46 , and R 49 ; the indices as well as the generic atoms/connector groups (Z, Y, X, W, V, U, T, Q, M) can occur several times within the same molecular entity. In such a case each of them shall be selected independently from others specified by the same symbol.
“Salts” as understood herein are especially, but not limited to, the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, for example, as acid addition salts with organic or inorganic acids, from compounds of type I with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids; like acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzene-sulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
As used in this description, the term “alkyl”, taken alone or in combinations (i.e. as part of another group, such as “aryl-C 1-6 -alkyl”), designates saturated, straight-chain or branched hydrocarbon radicals and may be optionally substituted. The term “C x-y -alkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms. For example a C 1-6 -alkyl group contains one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
The term “alkenyl”, taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties are optionally substituted and can independently exist as E or Z configurations per double bond, which are all part of the invention. The term “C x-y -alkenyl” (x and y each being an integer) refers to an alkenyl group as defined before, containing x to y carbon atoms.
The term “alkynyl” designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four triple bonds. The term “C x-y -alkynyl” (x and y each being an integer) refers to an alkynyl group as defined before, containing x to y carbon atoms.
The term “cycloalkyl” refers to a saturated or partially unsaturated alicyclic moiety having from three to ten carbon atoms and may be optionally substituted. Examples of this moiety include, but are not limited to, cyclohexyl, norbornyl, decalinyl and the like.
The term “heterocycloalkyl” describes a saturated or partially unsaturated mono- or bicyclic moiety having from two to nine ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulphur. This term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1,7-diazaspiro[4.4]nonane and the like. Said heterocycloalkyl ring(s) might be optionally substituted.
The term “aryl”, taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted by up to three substituents such as F, Cl, Br, CF 3 , OH, OCF 3 , OCHF 2 , NH 2 , N(CH 3 ) 2 , NO 2 , CN, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, phenyl or phenoxy.
The term “heteroaryl”, taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for “aryl”.
The term “aryl-C x-y -alkyl”, as used herein, refers to an C x-y -alkyl group as defined above, substituted by an aryl group, as defined above. Representative examples of aryl-C x-y -alkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
The term “heteroaryl-C x-y -alkyl”, as used herein, refers to an C x-y -alkyl group as defined above, substituted by a heteroaryl group, as defined above. Examples of heteroaryl-C x-y -alkyl groups include pyridin-3-ylmethyl, (1H-pyrrol-2-yl)ethyl and the like.
The terms “alkoxy” and “aryloxy”, taken alone or in combinations, refer to the groups of —O-alkyl and —O-aryl respectively, wherein an alkyl group or an aryl group is as defined above. The term “C x-y -alkoxy” (x and y each being an integer) refers to an —O-alkyl group as defined before containing x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy and the like. Examples of aryloxy include e.g. phenoxy.
“Amino” designates primary, secondary or tertiary amines. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, arylalkyl-amines and diarylamines wherein the alkyl or aryl is as herein defined and optionally substituted.
The term “N-protecting group”, as use herein, refers to the following commonly known groups, suitable to protect a nitrogen atom: allyloxycarbonyl (Alloc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), 2- or 4-nitrobenzenesulfonyl (Ns), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-Trichloro-ethoxycarbonyl (Troc), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), triphenylmethyl (trityl, Tr), or 2-chlorotrityl (CTC).
The term “O/S-protecting group”, as use herein, refers to the following commonly known groups, suitable to protect either an oxygen and/or a sulfur atom: tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), tert-butyl, 2-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM), triphenylmethyl (trityl, Tr), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), or 2-(Trimethylsilyl)ethyl (TMSE).
A person skilled in the art might find easily corresponding equivalents for the above mentioned protecting groups which are considered to be as well comprised by the gist of the current invention. Examples of suitable protecting groups are as detailed in P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006.
The term “optionally substituted” is in general intended to mean that a group, such as, but not limited to C x-y -alkyl, C x-y -alkenyl, C x-y -alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C x-y -alkoxy and aryloxy may be substituted with one or more substituents independently selected from amino (—NH 2 ), dimethylamino, nitro (—NO 2 ), halogen (F, Cl, Br, I), CF 3 , cyano (—CN), hydroxy, methoxy, ethoxy, phenyloxy, benzyloxy, acetoxy, oxo (═O), carboxy, carboxamide, methyl, ethyl, n-propyl, iso-propyl, cyclo-propyl, phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate, or
—SR a , —S(O)R a , —S(O) 2 R a , —R a , —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(═NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R b , —NR a S(O) 2 R b , wherein R a , R b , R c , and R d are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl as described herein; or R b and R c may be taken together with the N-atom to which they are attached forming heterocycloalkyl or heteroaryl. These groups in turn can be substituted with one or more moieties selected from the group consisting of halogen (F, Cl, Br, or I), hydroxyl, amino, mono-, di- or tri-C 1-6 -alkylamino, mono-, di- or tri-arylamino, hydroxy, carboxy, C 1-6 -alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
As used herein, all groups that can be substituted in one embodiment are indicated to be “optionally substituted”, unless otherwise specified.
The embodiments of the present invention shall include so-called “prodrugs” of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds, which in vivo are readily convertible into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Hans Bundgaard, Design of Prodrugs , Elsevier, 1985; and in Valentino J. Stella et al., Prodrugs: Challenges and Rewards , Springer, 1st ed., 2007.
The term “isomer” comprises species of identical chemical formula, constitution and thus molecular mass, such as but not limited to C═C-double bond or amide cis/trans isomers, rotamers, conformers and diastereomers.
All possible stereoisomers—explicitly including atropisomers—conformers and rotamers as well as salts, solvates, clathrates, N-oxides, or isotopically enriched or enantiomerically enriched versions of the macrocycles of type I are part of this invention.
In a Preferred Embodiment of this invention, macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 . The connectivities between the building blocks of the preferred embodiment are defined as shown in Scheme 5.
The biaryl Template A of the Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 2; A B 1-A C 3; A B 1-A C 4; A B 1-A C 5; A B 1-A C 6; A B 1-A C 8; A B 1-A C 9; A B 1-A C 11; A B 1-A C 12; A B 1-A C 13; A B 1-A C 19; A B 1-A C 22; A B 1-A C 24; A B 1-A C 49; A B 1-A C 51; A B 2-A C 1; A B 2-A C 2; A B 2-A C 3; A B 2-A C 4; A B 2-A C 5; A B 2-A C 11; A B 2-A C 12; A B 2-A C 51; A B 3-A C 1; A B 3-A C 2; A B 3-A C 3; A B 3-A C 4; A B 3-A C 5; A B 3-A C 11; A B 3-A C 12; A B 4-A C 1; A B 4-A C 2; A B 4-A C 3; A B 4-A C 4; A B 4-A C 5; A B 4-A C 6; A B 4-A C 11; A B 4-A C 12; A B 4-A C 19; A B 4-A C 22; A B 4-A C 24; A B 4-A C 49; A B 4-A C 51; A B 4-A C 59; A B 5-A C 1; A B 5-A C 2; A B 5-A C 3; A B 5-A C 4; A B 5-A C 5; A B 5-A C 11; A B 5-A C 12; A B 5-A C 51; A B 5-A C 59; A B 6-A C 1; A B 6-A C 4; A B 6-A C 8; A B 6-A C 9; A B 6-A C 11; A B 6-A C 13; A B 6-A C 16; A B 6-A C 18; A B 6-A C 19; A B 6-A C 20; A B 6-A C 30; A B 6-A C 31; A B 6-A C 49; A B 6-A C 51; A B 9-A C 6; A B 9-A C 49; A B 10-A C 6; A B 11-A C 6; A B 12-A C 2; A B 12-A C 5; A B 12-A C 11; A B 12-A C 12; A B 13-A C 2; A B 13-A C 5; A B 13-A C 11; A B 13-A C 12; A B 13-A C 5; A B 13-A C 11; A B 13-A C 12; A B 14-A C 49; A B 20-A C 2; A B 20-A C 6; A B 20-A C 49; A B 23-A C 4; A B 23-A C 49; A B 26-A C 2; A B 26-A C 5; A B 26-A C 11; A B 26-A C 12; A B 40-A C 2; A B 40-A C 5; A B 40-A C 11; A B 40-A C 12; A B 45-A C 49; A B 45-A C 52; A B 45-A C 57; A B 45-A C 58; A B 45-A C 65; A B 45-A C 66; A B 46-A C 57; A B 46-A C 58; A B 47-A C 58; A B 49-A C 49; A B 50-A C 57; A B 50-A C 58; A B 50-A C 61; A B 51-A C 49; A B 51-A C 61; A B 53-A C 2; A B 53-A C 5; A B 53-A C 11; A B 53-A C 12; A B 58-A C 2; A B 58-A C 5; A B 58-A C 11; A B 58-A C 12; A B 59-A C 2; A B 59-A C 5; A B 59-A C 11; A B 59-A C 12; or A B 59-A C 61.
The preferred Modulator B is selected from
B1; B4; B5; B6; B7; B8; B9 or B10;
and the preferred Bridge C from
C1; C2; or C3.
The substituents R 1 -R 57 attached to the Preferred Embodiment of macrocycle I are as defined as shown below.
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; cycloalkyl; C 1-6 -alkoxy or aryloxy; R 5 is H; CF 3 ; C 1-6 -alkyl; or cycloalkyl; R 6 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 8 and R 9 are independently defined as H; CF 3 ; C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; R 10 , R 11 and R 12 are independently defined as H; C 1-6 -alkyl; or cycloalkyl; R 13 is C 1-6 -alkyl; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 17 , R 19 , R 21 , R 23 , R 25 , R 27 , R 29 and R 31 are independently defined as H; or C 1-6 -alkyl; R 16 , R 22 and R 28 are independently defined as H; CF 3 ; or C 1-6 -alkyl; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 45 ; —(CR 42 R 51 ) q SR 45 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) q OCONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) q R 44 ; R 33 is H; or C 1-6 -alkyl; R 34 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) r OR 45 ; —(CR 42 R 51 ) r NR 7 R 45 ; —(CR 42 R 51 ) r OCONR 7 R 35 ; —(CR 42 R 51 ) r NR 7 COOR 36 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) q R 44 ; R 35 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 45 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-6 -alkyl; cycloalkyl; aryl; aryl-C 1 -alkyl; or an O/S-protecting group; R 37 is C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 45 ; —(CR 42 R 51 ) q SR 45 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) s OCONR 7 R 45 ; —(CR 42 R 51 ) s NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 44 ; —(CR 42 R 51 ) s NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) s NR 7 SO 2 R 38 ; —(CR 42 R 51 ) s R 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) t COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) t R 39 ; —(CR 42 R 51 ) u R 40 ; —(CR 42 R 51 ) t R 41 ; or —(CR 42 R 51 ) t R 44 ; R 38 is C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; or heteroaryl-C 1-6 -alkyl; R 42 and R 43 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; or heteroaryl-C 1-6 -alkyl; R 44 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 above. R 45 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 51 ) r OR 36 ; —(CR 42 R 51 ) r NR 7 R 57 ; —(CR 42 R 51 ) r OCONR 7 R 57 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 57 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) r NR 7 SO 2 NR 7 R 57 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 33 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) s R 44 ; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 36 ; —(CR 42 R 51 ) q SR 36 ; —(CR 42 R 51 ) q NR 7 R 57 ; —(CR 42 R 51 ) q OCONR 7 R 57 ; —(CR 42 R 51 ) q NR 44 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; or —(CR 42 R 51 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 ; R 48 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 51 ) r OR 45 ; —(CR 42 R 51 ) r SR 45 ; —(CR 42 R 51 ) r NR 7 R 45 ; —(CR 42 R 51 ) r OCONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 COOR 36 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) r SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; or —(CR 42 R 51 ) s R 44 ; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 36 ; —(CR 42 R 51 ) q SR 36 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) q NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; or —(CR 42 R 51 ) q R 44 ; R 50 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 COOR 36 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COOR 36 ; —CONR 7 R 57 ; —C(═NR 7 )NR 7 R 57 ; —NR 7 C(═NR 7 )NR 7 R 57 ; or a group of one of the formulae H56-H110 as shown in Table 9 above. R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl-C 1-6 -alkyl; or an N-protecting group.
Defined as for the Main Embodiment (vide supra) are i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) pairs of substituents that can be define additional cyclic structural elements.
In a Further Preferred Embodiment of this invention, the macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Further Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 4; A B 1-A C 6; A B 1-A C 8; A B 1-A C 9; A B 1-A C 11; A B 1-A C 13; A B 1-A C 19; A B 1-A C 22; A B 1-A C 24; A B 1-A C 49; A B 1-A C 51; A B 2-A C 4; A B 2-A C 51; A B 4-A C 1; A B 4-A C 4; A B 4-A C 6; A B 4-A C 19; A B 4-A C 22; A B 4-A C 24; A B 4-A C 49; A B 4-A C 51; A B 4-A C 59; A B 5-A C 51; A B 5-A C 59; A B 6-A C 1; A B 6-A C 4; A B 6-A C 8; A B 6-A C 9; A B 6-A C 11; A B 6-A C 13; A B 6-A C 16; A B 6-A C 18; A B 6-A C 19; A B 6-A C 20; A B 6-A C 30; A B 6-A C 31; A B 6-A C 49; A B 6-A C 51; A B 9-A C 6; A B 9-A C 49; A B 14-A C 49; A B 20-A C 6; A B 20-A C 49; A B 23-A C 4; A B 23-A C 49; A B 45-A C 49; A B 45-A C 52; A B 45-A C 57; A B 45-A C 58; A B 45-A C 65; A B 45-A C 66; A B 46-A C 57; A B 46-A C 58; A B 49-A C 49; A B 50-A C 57; A B 50-A C 58; A B 50-A C 61; A B 51-A C 49; A B 51-A C 61; or A B 59-A C 61.
The further preferred Modulator B is selected from
B1; B4; B5; B6; or B7;
and the further preferred Bridge of type C from
C1; C2; or C3.
The substituents R 1 -R 57 attached to the Further Preferred Embodiment of macrocycle I are as defined as described below.
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 . R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; or C 1-6 -alkoxy; R 5 is H; CF 3 ; or C 1-6 -alkyl; R 6 is H; C 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(R 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(R 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are defined as in the Preferred Embodiment; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 16 , R 17 , R 19 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 and R 31 are defined as in the Preferred Embodiment; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 37 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 45 ; —(CR 42 R 43 ) q SR 45 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 ) q NR 7 COOR 36 ; —(CR 42 R 43 ) q NR 7 COR 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 )COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) q R 44 ; R 33 is H; or C 1-6 -alkyl; R 34 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; —(CR 42 R 43 ) r OR 45 ; —(CR 42 R 43 ) r NR 7 R 45 ; —(CR 42 R 43 ) r OCONR 7 R 35 ; —(CR 42 R 43 ) r NR 7 COOR 36 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) q R 44 ; R 35 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 50 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 45 ; —(CR 32 R 33 ) q COR 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-6 -alkyl; cycloalkyl; aryl; aryl-C 1-6 -alkyl; or an O/S-protecting group; R 37 is C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 45 ; —(CR 42 R 43 ) q SR 45 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 ) s OCONR 7 R 45 ; —(CR 42 R 43 ) s NR 7 COOR 36 ; —(CR 42 R 43 ) s NR 7 COR 44 ; —(CR 42 R 43 ) s NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) s NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 )CONR 7 R 45 ; —(CR 42 R 43 ) t COR 38 ; —(CR 42 R 43 ) t R 39 ; —(CR 42 R 43 ) u R 40 ; —(CR 42 R 43 ) t R 41 ; or —(CR 42 R 43 ) t R 44 ; R 38 , R 42 , R 43 and R 44 are defined as in the Preferred Embodiment; R 39 , R 40 , and R 41 are as defined in the Main Embodiment; R 45 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 43 ) r OR 36 ; —(CR 42 R 43 ) r NR 7 R 57 ; —(CR 42 R 43 ) r OCONR 7 R 57 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 57 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) s R 44 ; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 36 ; —(CR 42 R 43 ) q NR 7 R 57 ; —(CR 42 R 43 ) q NR 7 COR 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q SO 2 NR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 . R 48 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 43 ) r OR 45 ; —(CR 42 R 43 ) r SR 45 ; —(CR 42 R 43 ) r NR 7 R 45 ; —(CR 42 R 43 ) r OCONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 COOR 36 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) s R 44 ; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 36 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 )NR 7 COR 38 ; —(CR 42 R 43 ) q NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) q R 44 ; R 50 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is defined as in the Preferred Embodiment; R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is defined as in the Preferred Embodiment;
as are (vide supra) i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In a Particularly Preferred Embodiment of this invention, the macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Particularly Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 4; A B 1-A C 19; A B 2-A C 4; A B 4-A C 1; A B 4-A C 4; A B 4-A C 19; A B 4-A C 59; A B 5-A C 51; A B 5-A C 59; A B 6-A C 31; A B 9-A C 6; or A B 46-A C 58.
The particularly preferred Modulator building block of type B and the Bridge of type C are selected as described in the Further Preferred Embodiment.
The substituents R 1 -R 57 attached to the Particularly Preferred Embodiment of macrocycle I are as defined as described below.
R 1 and R 2 are defined as in the Further Preferred Embodiment; R 3 and R 4 are independently defined as H; F; CF 3 ; OCF 3 ; OCHF 2 ; CN; or C 1-6 -alkoxy; R 5 is H; CF 3 ; or C 1-6 -alkyl; R 6 is defined as in the Further Preferred Embodiment; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are defined as in the Preferred Embodiment; R 14 , R 20 and R 26 are defined as in the Further Preferred Embodiment; R 15 , R 16 , R 17 , R 19 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 and R 31 are defined as in the Preferred Embodiment, R 18 , R 24 , R 30 and R 32 are defined as in the Further Preferred Embodiment; R 33 is H; or C 1-6 -alkyl; R 34 , R 35 , R 36 and R 37 are defined as in the Further Preferred Embodiment; R 38 , R 42 , R 43 and R 44 are defined as in the Preferred Embodiment; R 39 , R 40 , and R 41 are as defined in the Main Embodiment; R 45 is defined as in the Further Preferred Embodiment; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —(CR 42 R 43 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 ; R 48 is defined as in the Further Preferred Embodiment; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —(CR 42 R 43 ) q R 44 ; R 50 is defined as in the Further Preferred Embodiment; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is defined as in the Preferred Embodiment; R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is defined as in the Preferred Embodiment; as are (vide supra) i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In an Specific Representation of the Particularly Preferred Embodiment
the Bridge C is represented by
wherein
C AA is an amino acid selected from the readily accessible amino acids listed in Table 11. Even though only one stereoisomer, usually the L-enantiomer, is cited within Table 11, it is understood that the complementary enantiomer is also part to the embodiment. Also not listed explicitly, but part of the embodiment are the simple N-methyl derivatives of the listed amino acids.
TABLE 11
Structures representing subunits C AA of Bridge C (continued on the following pages)
Code
Chemical Name
Ala
L-Alanine
Arg
L-Arginine
Asn
L-Asparagine
Asp
L-Aspartic acid
Cys
L-Cysteine
Glu
L-Glutamic acid
Gln
L-Glutamine
Gly
Glycine
His
L-Histidine
Ile
L-Isoleucine
Leu
L-Leucine
Lys
L-Lysine
Met
L-Methionine
Phe
L-Phenylalanine
Pro
L-Proline
Ser
L-Serine
Thr
L-Threonine
Trp
L-Tryptophan
Tyr
L-Tyrosine
Val
L-Valine
Apa
3-Amino-propanoic acid
H-β 3 -HAla-OH
(3S)-3-Amino-butyric acid
H-β 3 -HVal-OH
(3R)-3-Amino-4-methyl-valeric acid
H-β 3 -HIle-OH
(3R,4S)-3-Amino-4-methyl-hexanoic acid
H-β 3 -HLeu-OH
(3S)-3-Amino-5-methyl-hexanoic acid
H-β 3 -HMet-OH
(3S)-3-Amino-5-methylthio pentanoic acid
H-β 3 -HTyr-OH
(3S)-3-Amino-4-(4′-hydroxyphenyl)-butyric acid
H-β 3 -HHis-OH
(3S)-3-Amino-4-(imidazole-4′-yl)-butyric acid
H-β 3 -HPhe-OH
(3S)-3-Amino-4-phenyl butyric acid
H-β 3 -HTrp-OH
(3S)-3-Amino-4-(indol-3′-yl)-butyric acid
H-β 3 -HSer-OH
(3R)-3-Amino-4-hydroxy-butyric acid
H-β 3 -HAsp-OH
3-Amino-pentanedioic acid
H-β 3 -HGlu-OH
(3S)-3-Amino-hexanedioic acid
H-β 3 -HLys-OH
(3S)-3,7-Diamino-heptanoic acid
H-β 3 -HArg-OH
(3S)-3-Amino-6-guanidino-hexanoic-acid
H-β 3 -HCys-OH
(3R)-3-Amino-4-mercapto-butyric acid
H-β 3 -HAsn-OH
(3S)-3-Amino-4-carbamoyl-butyric acid
H-β 3 -HGln-OH
(3S)-3-Amino-5-carbamoyl-pentanoic acid
H-β 3 -HThr-OH
(3R,4R)-3-Amino-4-hydroxy-pentanoic acid
Gaba
4-Amino-butyric acid
H-γ 4 -DiHAla-OH
(4S)-4-Amino-pentanoic acid
H-γ 4 -DiHVal-OH
(4R)-4-Amino-5-methyl-hexanoic acid
H-γ 4 -DiHIle-OH
(4R,5S)-4-Amino-5-methyl-heptanoic acid
H-γ 4 -DiHLeu-OH
(4R)-4-Amino-6-methyl-heptanoic acid
H-γ 4 -DiHMet-OH
(4R)-4-Amino-6-methylthio-hexanoic acid
H-γ 4 -DiHTyr-OH
(4R)-4-Amino-5-(4′-hydroxyphenyl)-pentanoic acid
H-γ 4 -DiHHis-OH
(4R)-4-Amino-5-(imidazole-4′-yl)-pentanoic acid
H-γ 4 -DiHPhe-OH
(4R)-4-Amino-5-phenyl-pentanoic acid
H-γ 4 -DiHTrp-OH
(4R)-4-Amino-5-(indol-3′-yl)-pentanoic acid
H-γ 4 -DiHSer-OH
(4R)-4-Amino-5-hydroxy-pentanoic acid
H-γ 4 -DiHAsp-OH
(4R)-4-Amino-hexanedioic acid
H-γ 4 -DiHGlu-OH
4-Amino-heptanedioic acid
H-γ 4 -DiHLys-OH
(4S)-4,8-Diamino-octanoic acid
H-γ 4 -DiHArg-OH
(4S)-4-Amino-7-guanidino-heptanoic-acid
H-γ 4 -DiHCys-OH
(4R)-4-Amino-5-mercapto-pentanoic acid
H-γ 4 -DiHAsn-OH
(4R)-4-Amino-5-carbamoyl-pentanoic acid
H-γ 4 -DiHGln-OH
(3S)-3-Amino-5-carbamoyl-hexanoic acid
H-γ 4 -DiHThr-OH
(4R,5R)-4-Amino-5-hydroxy-hexanoic acid
Cit
L-Citrulline
Orn
L-Ornithine
tBuA
L-t-Butylalanine
Sar
Sarcosine
Pen
L-Penicillamine
tBuG
L-tert-Butylglycine
4AmPhe
L-para-Aminophenylalanine
3AmPhe
L-meta-Aminophenylalanine
2AmPhe
L-ortho-Aminophenylalanine
Phe(mC(NH 2 )═NH)
L-meta-Amidinophenylalanine
Phe(pC(NH 2 )═NH)
L-para-Amidinophenylalanine
Phe(mNHC(NH 2 )═NH)
L-meta-Guanidinophenylalanine
Phe(pNHC(NH 2 )═NH)
L-para-Guanidinophenylalanine
2Pal
(2S)-2-Amino-3-(pyridine-2′-yl)-propionic acid
4Pal
(2S)-2-Amino-3-(pyridine-4′-yl)-propionic acid
Phg
L-Phenylglycine
Cha
L-Cyclohexylalanine
C 4 al
L-3-Cyclobutylalanine
C 5 al
L-3-Cyclopentylalanine
Nle
L-Norleucine
2-Nal
L-2-Naphthylalanine
1-Nal
L-1-Naphthylalanine
4ClPhe
L-4-Chlorophenylalanine
3ClPhe
L-3-Chlorophenylalanine
2ClPhe
L-2-Chlorophenylalanine
3,4Cl 2 Phe
L-3,4-Dichlorophenylalanine
4FPhe
L-4-Fluorophenylalanine
3FPhe
L-3-Fluorophenylalanine
2FPhe
L-2-Fluorophenylalanine
Thi
L-β-2-Thienylalanine
Tza
L-2-Thiazolylalanine
Mso
L-Methionine sulfoxide
AcLys
N-Acetyllysine
Dap
2,3-Diaminopropionic acid
Dab
2,4-Diaminobutyric acid
Dbu
(2S)-2,3-Diamino-butyric acid
Abu
γ-Aminobutyric acid (GABA)
Aha
ε-Aminohexanoic acid
Aib
α-Aminoisobutyric acid
ACC
1-Amino cyclopropane carboxylic acid
ACBC
1-Amino cyclobutane carboxylic acid
ACPC
1-Amino cyclopentane carboxylic acid
1-ACHC
1-Amino cyclohexane carboxylic acid
2-ACHC
2-Amino cyclohexane carboxylic acid
3-ACHC
3-Amino cyclohexane carboxylic acid
4-ACHC
4-Amino cyclohexane carboxylic acid
Y(Bzl)
L-O-Benzyltyrosine
H(Bzl)
(3S)-2-Amino-3-(1′-benzylimidazole-4′-yl)-propionic acid
Bip
L-(4-phenyl)phenylalanine
S(Bzl)
L-O-Benzylserine
T(Bzl)
L-O-Benzylthreonine
alloT
(2S,3S)-2-Amino-3-hydroxy-butyric acid
Leu3OH
(2S,3R)-2-Amino-3-hydroxy-4-methyl-pentanoic acid
hAla
L-Homo-alanine
hArg
L-Homo-arginine
hCys
L-Homo-cysteine
hGlu
L-Homo-glutamic acid
hGln
L-Homo-glutamine
hHis
L-Homo-histidine
hIle
L-Homo-isoleucine
hLeu
L-Homo-leucine
hNle
L-Homo-norleucine
hLys
L-Homo-lysine
hMet
L-Homo-Methionine
hPhe
L-Homo-phenylalanine
hSer
L-Homo-serine
hThr
L-Homo-threonine
hTrp
L-Homo-tryptophan
hTyr
L-Homo-tyrosine
hVal
L-Homo-valine
hCha
L-Homo-cyclohexylalanine
Bpa
L-4-Benzoylphenylalanine
OctG
L-Octylglycine
Tic
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid
Tiq
(1S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid
Oic
(2S,3aS,7aS)-1-Octahydro-1H-indole-2-carboxylic acid
4AmPyrr1
(2S,4S)-4-Amino-pyrrolidine-2-carboxylic acid
4AmPyrr2
(2S,4R)-4-Amino-pyrrolidine-2-carboxylic acid
4PhePyrr1
(2S,4R)-4-Phenyl-pyrrolidine-2-carboxylic acid
4PhePyrr2
(2S,4S)-4-Phenyl-pyrrolidine-2-carboxylic acid
5PhePyrr1
(2S,5R)-5-Phenyl-pyrrolidine-2-carboxylic acid
5PhePyrr2
(2S,5S)-5-Phenyl-pyrrolidine-2-carboxylic acid
4Hyp1
(4S)-L-Hydroxyproline
4Hyp2
(4R)-L-Hydroxyproline
4Mp1
(4S)-L-Mercaptoproline
4Mp2
(4R)-L-Mercaptoproline
Pip
L-Pipecolic acid
H-β 3 -HCit-OH
(3S)-3-Amino-6-carbamidyl-hexanoic acid
H-β 3 -HOrn-OH
(3S)-3,6-Diamino-hexanoic acid
H-β 3 -HtBuA-OH
(3S)-3-Amino-5,5-dimethyl-hexanoic acid
H-β 3 -HSar-OH
N-Methyl-3-amino-propionic acid
H-β 3 -HPen-OH
(3R)-3-Amino-4-methyl-4-mercapto-pentanoic acid
H-β 3 -HtBuG-OH
(3R)-3-Amino-4,4-dimethyl-pentanoic acid
H-β 3 -H4AmPhe-OH
(3S)-3-Amino-4-(4′-aminophenyl)-butyric acid
H-β 3 -H3AmPhe-OH
(3S)-3-Amino-4-(3′-aminophenyl)-butyric acid
H-β 3 -H2AmPhe-OH
(3S)-3-Amino-4-(2′-aminophenyl)-butyric acid
H-β 3 -HPhe(mC(NH 2 )═NH)—
(3S)-3-Amino-4-(3′-amidinophenyl)-butyric acid
OH
H-β 3 -HPhe(pC(NH 2 )═NH)—
(3S)-3-Amino-4-(4′-amidinophenyl)-butyric acid
OH
H-β 3 -HPhe(mNHC(NH 2 )═
(3S)-3-Amino-4-(3′-guanidinophenyl)-butyric acid
NH)—OH
H-β 3 -HPhe(pNHC(NH 2 )═
(3S)-3-Amino-4-(4′-guanidino-phenyl)-butyric acid
NH)—OH
H-β 3 -H2Pal-OH
(3S)-3-Amino-4-(pyridine-2′-yl)-butyric acid
H-β 3 -H4Pal-OH
(3S)-3-Amino-4-(pyridine-4′-yl)-butyric acid
H-β 3 -HPhg-OH
(3R)-3-Amino-3-phenyl-propionic acid
H-β 3 -HCha-OH
(3S)-3-Amino-4-cyclohexyl-butyric acid
H-β 3 -HC 4 al-OH
(3S)-3-Amino-4-cyclobutyl-butyric acid
H-β 3 -HC 5 al-OH
(3S)-3-Amino-4-cyclopentyl-butyric acid
H-β 3 -HNle-OH
(3S)-3-Amino-heptanoic acid
H-β 3 -H2Nal-OH
(3S)-3-Amino-4-(2′-naphthyl)-butyric acid
H-β 3 -H1Nal-OH
(3S)-3-Amino-4-(1′-naphthyl)-butyric acid
H-β 3 -H4ClPhe-OH
(3S)-3-Amino-4-(4′-chlorophenyl)-butyric acid
H-β 3 -H3ClPhe-OH
(3S)-3-Amino-4-(3′-chlorophenyl)-butyric acid
H-β 3 -H2ClPhe-OH
(3S)-3-Amino-4-(2′-chlorophenyl)-butyric acid
H-β 3 -H3,4Cl 2 Phe-OH
(3S)-3-Amino-4-(3′,4′-dichlorophenyl)-butyric acid
H-β 3 -H4FPhe-OH
(3S)-3-Amino-4-(4′-fluorophenyl)-butyric acid
H-β 3 -H3FPhe-OH
(3S)-3-Amino-4-(3′-fluorophenyl)-butyric acid
H-β 3 -H2FPhe-OH
(3S)-3-Amino-4-(2′-fluorophenyl)-butyric acid
H-β 3 -HThi-OH
(3R)-3-Amino-4-(2′-thienyl)-butyric acid
H-β 3 -HTza-OH
(3R)-3-Amino-4-(2′-thiazolyl)-butyric acid
H-β 3 -HMso-OH
(3R)-3-Amino-4-methylsulfoxyl-butyric acid
H-β 3 -HAcLys-OH
(3S)-7-Acetylamino-3-amino-heptanoic acid
H-β 3 -HDpr-OH
(3R)-3,4-diamino-butyric acid
H-β 3 -HA 2 Bu—OH
(3S)-3,5-Diamino-pentanoic acid
H-β 3 -HDbu-OH
(3R)-3,4-Diamino-pentanoic acid
H-β 3 -HAib-OH
Amino-dimethyl acetic acid
H-β 3 -HCyp-OH
1-Amino-cyclopentane-1-yl-acetic acid
H-β 3 -HY(Bzl)-OH
(3S)-3-Amino-4-(4′-benzyloxyphenyl)-butyric acid
H-β 3 -HH(Bzl)-OH
(3S)-3-Amino-4-(1′-benzylimidazole-4′-yl)-butyric acid
H-β 3 -HBip-OH
(3S)-3-Amino-4-biphenylyl-butyric acid
H-β 3 -HS(Bzl)-OH
(3S)-3-Amino-4-(benzyloxy)-butyric acid
H-β 3 -HT(Bzl)-OH
(3R,4R)-3-Amino-4-benzyloxy-pentanoic acid
H-β 3 -HalloT-OH
(3R,4S)-3-Amino-4-hydroxy-pentanoic acid
H-β 3 -HLeu3OH—OH
(3R,4R)-3-Amino-4-hydroxy-5-methyl-hexanoic acid
H-β 3 -HhAla-OH
(3S)-3-Amino-pentanoic acid
H-β 3 -HhArg-OH
(3S)-3-Amino-7-guanidino-heptanoic acid
H-β 3 -HhCys-OH
(3R)-Amino-5-mercapto-pentanoic acid
H-β 3 -HhGlu-OH
(3S)-3-Amino-heptanedioic acid
H-β 3 -HhGln-OH
(3S)-3-Amino-6-carbamoyl hexanoic acid
H-β 3 -HhHis-OH
(3S)-3-Amino-5-(imidazole-4′-yl)-pentanoic acid
H-β 3 -HhIle-OH
(3S,5S)-3-Amino-5-methyl-heptanoic acid
H-β 3 -HhLeu-OH
(3S)-3-Amino-6-methyl-heptanoic acid
H-β 3 -HhNle-OH
(3S)-3-Amino-octanoic acid
H-β 3 -DiAoc-OH
(3S)-3,8-Diamino-octanoic acid
H-β 3 -HhMet-OH
(3S)-3-Amino-6-methylthio-hexanoic acid
H-β 3 -HhPe-OH
(3S)-3-Amino-5-phenyl-pentanoic acid
H-β 3 -HhSer-OH
(3S)-3-Amino-5-hydroxy-pentanoic acid
H-β 3 -HhThr-OH
(3S,5R)-3-Amino-5-hydroxy-hexanoic acid
H-β 3 -HhTrp-OH
(3S)-3-Amino-5-(indol-3′-yl)-pentanoic acid
H-β 3 -HhThr-OH
(3S)-3-Amino-5-(4′-hydroxyphenyl)-pentanoic acid
H-β 3 -HhCha-OH
(3S)-3-Amino-5-cyclohexyl-pentanoic acid
H-β 3 -HBpa-OH
(3S)-3-Amino-4-(4′-benzoylphenyl)-butyric acid
H-β 3 -HOctG-OH
(3S)-3-Amino-undecanoic acid
H-β 3 -HNle-OH
(3S)-3-Amino-heptanoic acid
H-β 3 -HTic-OH
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-yl-acetic acid
H-β 3 -HTiq-OH
(1S)-1,2,3,4-Tetrahydroisoquinoline-1-acetic acid
H-β 3 -HOic-OH
(2S,3aS,7aS)-1-Octahydro-1H-indole-2-yl-acetic acid
H-β 3 -H4AmPyrr1-OH
(2S,4S)-4-Amino-pyrrolidine-2-acetic acid
H-β 3 -H4AmPyrr2-OH
(2S,4R)-4-Amino-pyrrolidine-2-acetic acid
H-β 3 -H4PhePyrr1-OH
(2S,4R)-4-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H4PhePyrr2-OH
(2S,4S)-4-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H5PhePyrr1-OH
(2S,5R)-5-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H5PhePyrr2-OH
(2S,5S)-5-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H4Hyp1-OH
(2S,4S)-4-Hydroxy-pyrrolidine-2-acetic acid
H-β 3 -H4Hyp2-OH
(2S,4R)-4-Hydroxy-pyrrolidine-2-acetic acid
H-β 3 -H4Mp1-OH
(2R,4S)-4-Mercapto-pyrrolidine-2-acetic acid
H-β 3 -H4Mp2-OH
(2R,4R)-4-Mercapto-pyrrolidine-2-acetic acid
H-β 3 -HPip-OH
(2S)-Piperidine-2-acetic acid
H-β 3 -HPro-OH
(2S)-Pyrrolidine-2-acetic acid
Ahb
4-Amino-2-hydroxy butyric acid
H-γ 4 -DiHCit-OH
(4S)-4-Amino-7-carbamidyl-heptanoic acid
H-γ 4 -DiHOrn-OH
(4S)-4,7-Diamino-heptanoic acid
H-γ 4 -DiHtBuA-OH
(4R)-4-Amino-6,6-dimethyl-heptanoic acid
H-γ 4 -DiHSar-OH
N-Methyl-4-amino-butyric acid
H-γ 4 -DiHPen-OH
(4R)-4-Amino-5-methyl-5-mercapto-hexanoic acid
H-γ 4 -DiHtBuG-OH
(4R)-4-Amino-5,5-dimethyl-hexanoic acid
H-γ 4 -DiH4AmPhe-OH
(4R)-4-Amino-5-(4′-aminophenyl)-pentanoic acid
H-γ 4 -DiH3AmPhe-OH
(4R)-4-Amino-5-(3′-aminophenyl)-pentanoic acid
H-γ 4 -DiH2AmPhe-OH
(4R)-4-Amino-5-(2′-aminophenyl)-pentanoic acid
H-γ 4 -DiHPhe(mC(NH 2 )═
(4R)-4-Amino-5-(3′-amidinophenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(pC(NH 2 )═
(4R)-4-Amino-5-(4′-amidinophenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(mNHC(NH 2 )═
(4R)-4-Amino-5-(3′-guanidino-phenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(pNHC(NH 2 )═
(4R)-4-Amino-5-(4′-guanidino-phenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiH2Pal-OH
(4R)-4-Amino-5-(pyridine-4′-yl)-pentanoic acid
H-γ 4 -DiH4Pal-OH
(4R)-4-Amino-5-(pyridine-4′-yl)-pentanoic acid
H-γ 4 -DiHPhg-OH
(4R)-4-Amino-4-phenyl-butyric acid
H-γ 4 -DiHCha-OH
(4R)-4-Amino-5-cyclohexyl-pentanoic acid
H-γ 4 -DiHC 4 al-OH
(4R)-4-Amino-5-cyclobutyl-pentanoic acid
H-γ 4 -DiHC 5 al-OH
(4R)-4-Amino-5-cyclopentyl-pentanoic acid
H-γ 4 -DiHNle-OH
(4S)-4-Amino-octanoic acid
H-γ 4 -DiH2Nal-OH
(4S)-4-Amino-5-(2′-naphthyl)-pentanoic acid
H-γ 4 -DiH1Nal-OH
(4S)-4-Amino-5-(1′-naphthyl)-pentanoic acid
H-γ 4 -DiH4ClPhe-OH
(4R)-4-Amino-5-(4′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH3ClPhe-OH
(4R)-4-Amino-5-(3′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH2ClPhe-OH
(4R)-4-Amino-5-(2′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH3,4Cl 2 Phe-OH
(4R)-4-Amino-5-(3′,4′-dichloro-phenyl)-pentanoic acid
H-γ 4 -DiH4FPhe-OH
(4R)-4-Amino-5-(4′-fluorophenyl)-pentanoic acid
H-γ 4 -DiH3FPhe-OH
(4R)-4-Amino-5-(3′-fluorophenyl)-pentanoic acid
H-γ 4 -DiH2FPhe-OH
(4R)-4-Amino-5-(2′-fluorophenyl)-pentanoic acid
H-γ 4 -DiHThi-OH
(4R)-4-Amino-5-(2′-thienyl)-pentanoic acid
H-γ 4 -DiHTza-OH
(4R)-4-Amino-5-(2′-thiazolyl)-pentanoic acid
H-γ 4 -DiHMso-OH
(4R)-4-Amino-5-methylsulfoxyl-pentanoic acid
H-γ 4 -DiHAcLys-OH
(4S)-8-Acetylamino-4-amino-ocatanoic acid
H-γ 4 -DiHDpr-OH
(4R)-4,5-diamino-pentanoic acid
H-γ 4 -DiHA 2 Bu—OH
(4R)-4,5-Diamino-hexanoic acid
H-γ 4 -DiHDbu-OH
(4R)-4,5-Diamion-hexanoic acid
H-γ 4 -DiHAib-OH
3-Amino-3,3-dimethyl propionic acid
H-γ 4 -DiHCyp-OH
(1′-Amino-cyclopentane-1′-yl)-3-propionic acid
H-γ 4 -DiHY(Bzl)-OH
(4R)-4-Amino-5-(4′-benzyloxyphenyl)-pentanoic acid
H-γ 4 -DiHH(Bzl)-OH
(4R)-4-Amino-5-(1′-benzylimidazole-4′-yl)-pentanoic
acid
H-γ 4 -DiHBip-OH
(4R)-4-Amino-5-biphenylyl-pentanoic acid
H-γ 4 -DiHS(Bzl)-OH
(4S)-4-Amino-5-(benzyloxy)-pentanoic acid
H-γ 4 -DiHT(Bzl)-OH
(4R,5R)-4-Amino-5-benzyloxy-hexanoic acid
H-γ 4 -DiHalloT-OH
(4R,5S)-4-Amino-5-hydroxy-hexanoic acid
H-γ 4 -DiHLeu3OH—OH
(4R,5R)-4-Amino-5-hydroxy-6-methyl-heptanoic acid
H-γ 4 -DiHhAla-OH
(4S)-4-Amino-hexanoic acid
H-γ 4 -DiHhArg-OH
(4S)-4-Amino-8-guanidino-octanoic acid
H-γ 4 -DiHhCys-OH
(4R)-Amino-6-mercapto-hexanoic acid
H-γ 4 -DiHhGlu-OH
(4S)-4-Amino-ocatanedioic acid
H-γ 4 -DiHhGln-OH
(4S)-4-Amino-7-carbamoyl-heptanoic acid
H-γ 4 -DiHhHis-OH
(4S)-4-Amino-6-(imidazole-4′-yl)-hexanoic acid
H-γ 4 -DiHhIle-OH
(4S,6S)-4-Amino-6-methyl-octanoic acid
H-γ 4 -DiHhLeu-OH
(4S)-4-Amino-7-methyl-ocatanoic acid
H-γ 4 -DiHhNle-OH
(4S)-4-Amino-nonanoic acid
H-γ 4 -DiHhLys-OH
(4S)-4,9-Diamino-nonanoic acid
H-γ 4 -DiHhMet-OH
(4R)-4-Amino-7-methylthioheptanoic acid
H-γ 4 -DiHhPhe-OH
(4S)-4-Amino-6-phenyl-hexanoic acid
H-γ 4 -DiHhSer-OH
(4R)-4-Amino-6-hydroxy-hexanoic acid
H-γ 4 -DiHhThr-OH
(4R,6R)-4-Amino-6-hydroxy-heptanoic acid
H-γ 4 -DiHhTrp-OH
(4S)-4-Amino-6-(indol-3′-yl)-hexanoi cacid
H-γ 4 -DiHhTyr-OH
(4S)-4-Amino-6-(4′-hydroxyphenyl)-hexanoic acid
H-γ 4 -DiHhCha-OH
(4R)-4-Amino-5-cyclohexyl-pentanoic acid
H-γ 4 -DihBpa-OH
(4R)-4-Amino-5-(4′-benzoylphenyl)-pentanoic acid
H-γ 4 -DiHOctG-OH
(4S)-4-Amino-dodecanoic acid
H-γ 4 -DiHNle-OH
(4S)-4-Amino-octanoic acid
H-γ 4 -DiHTic-OH
(3R)-1′,2′,3′,4′-Tetrahydroisoquinoline-3′-yl-3-propionic
acid
H-γ 4 -DiHTiq-OH
(1′R)-1′,2′,3′,4′-Tetrahydroisoquinoline-1′-yl-3-propionic
acid
H-γ 4 -DiHOic-OH
(2′S,3′aS,7′aS)-1′-Octahydro-1H-indole-2′-yl-3-
propionic acid
H-γ 4 -DiH4AmPyrr1-OH
(2′R,4′S)-4′-Amino-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4AmPyrr2-OH
(2′R,4′R)-4′-Amino-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4PhePyrr1-OH
(2′R,4′R)-4′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4PhePyrr2-OH
(2′R,4′S)-4′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH5PhePyrr1-OH
(2′S,5′R)-5′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH5PhePyrr2-OH
(2′S,5′S)-5′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Hyp1-OH
(2′R,4′S)-4′-Hydroxy-pyrrolidine-2′-yl-2-propionic acid
H-γ 4 -DiH4Hyp2-OH
(2′R,4′R)-4′-Hydroxy-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Mp1-OH
(2′R,4′S)-4′-Mercapto-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Mp2-OH
(2′R,4′R)-4′-Mercapto-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiHPip-OH
(2′S)-Piperidine-2′-yl-3-propionic acid
H-γ 4 -DiHPro-OH
(2′S)-Pyrrolidine-2′-yl-3-propionic acid
(AEt)G
N-(2-Aminoethyl)glycine
(APr)G
N-(3-Amino-n-propyl)glycine
(ABu)G
N-(4-Amino-n-butyl)glycine
(APe)G
N-(5-Amino-n-pentyl)glycine
(GuEt)G
N-(2-Guanidinoethyl)glycine
(GuPr)G
N-(3-Guanidino-n-propyl)glycine
(GuBu)G
N-(4-Guanidino-n-butyl)glycine
(GuPe)G
N-(5-Guanidino-n-pentyl)glycine
(PEG 3 -NH 2 )G
N—[H 2 N—(CH 2 ) 3 —(OCH 2 —CH 2 ) 2 —O(CH 2 ) 3 ]glycine
(Me)G
N-Methylglycine
(Et)G
N-Ethylglycine
(Bu)G
N-Butylglycine
(Pe)G
N-Pentylglycine
(Ip)G
N-Isopropylglycine
(2MePr)G
N-(2-Methylpropyl)glycine
(3MeBu)G
N-(3-Methylbutyl)glycine
(1MePr)G
(1S)-N-(1-Methylpropyl)glycine
(2MeBu)G
(2S)-N-(2-Methylbutyl)glycine
(MthEt)G
N-(Methylthioethyl)glycine
(MthPr)G
N-(Methylthiopropyl)glycine
(Ben)G
N-(Benzyl)glycine
(PhEt)G
N-(2-Phenylethyl)glycine
(HphMe)G
N-([4′-hydroxyphenyl]methyl)glycine
(HphEt)G
N-(2-[4′-hydroxyphenyl]ethyl)glycine
(ImMe)G
N-(Imidazol-5-yl-methyl)glycine
(ImEt)G
N-(2-(Imidazol-5′-yl)ethyl)glycine
(InMe)G
N-(Indol-2-yl-methyl)glycine
(InEt)G
N-(2-(Indol-2′-yl)ethyl)glycine
(CboMe)G
N-(Carboxymethyl)glycine
(CboEt)G
N-(2-Carboxyethyl)glycine
(CboPr)G
N-(3-Carboxypropyl)glycine
(CbaMe)G
N-(Carbamoylmethyl)glycine
(CbaEt)G
N-(2-Carbamoylethyl)glycine
(CbaPr)G
N-(3-Carbamoylpropyl)glycine
(HyEt)G
N-(2-Hydroxyethyl)glycine
(HyPr)G
(2R)-N-(2-Hydroxypropyl)glycine
(Mcet)G
N-(2-Mercaptoethyl)glycine
Nip
(S)-Nipecotic acid/(S)-3-Piperidinecarboxylic acid
INip
Isonipecotic acid/4-Piperidinecarboxylic acid
PCA
(S)-2-Piperazinecarboxylic acid
(S)betaPro
(S)-β-Proline/(S)-Pyrrolidine-3-carboxylic acid
In a Specific Embodiment of this invention, the macrocycles of formula I are selected from the following list (Table 12).
TABLE 12 IUPAC Names of the Examples (continued on the following pages) Example IUPAC Name Ex. 1 benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 2 tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]carbamate Ex. 3 benzyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]carbamate Ex. 4 tert-butyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]carbamate Ex. 5 N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]-2-(1-naphthyl)acetamide Ex. 6 methyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]carbamate Ex. 7 N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]-2-(1-naphthyl)acetamide Ex. 8 N-[(12R,16S,18S)-16-(dimethylamino)-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]-2-(1-naphthyl)acetamide Ex. 9 (12R,16S,18S)-12,16-diamino-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaene- 8,13-dione Ex. 10 benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 11 N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(2-naphthyl)acetamide Ex. 12 2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}- 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide Ex. 13 3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]butanamide Ex. 14 benzyl N-[(12R,16S,18S)-8,13-dioxo-16-[(phenoxycarbonyl)amino]-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 15 benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]carbamate Ex. 16 tert-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate Ex. 17 benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]carbamate Ex. 18 benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]carbamate Ex. 19 N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]-2-(2-naphthyl)acetamide Ex. 20 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2- naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 21 N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 22 N-[(10S,12S,16S)-20-methyl-16-{[(methylamino)carbonyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 23 2-methoxy-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide Ex. 24 3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]butanamide Ex. 25 N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)amino]-8- oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 26 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]benzamide Ex. 27 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]butanamide Ex. 28 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]pentanamide Ex. 29 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]amino}acetic acid Ex. 30 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- {[(methylamino)carbothioyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 31 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-[(2- sulfanylacetyl)amino]-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 32 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-{[2- (tritylsulfanyl)acetyl]amino}-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 33 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- {[(methylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 34 2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3- (dimethylamino)anilino]carbonyl}amino)-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide Ex. 35 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(2- naphthylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 36 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- [(methylsulfonyl)amino]-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 37 N-[(10S,12S,16S)-12-[(benzylsulfonyl)amino]-20-methyl-15,21-dioxo-8- oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]-2-(dimethylamino)acetamide Ex. 38 tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20- methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate Ex. 39 N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]-2-(dimethylamino)acetamide Ex. 40 ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]amino}acetate Ex. 41 benzyl (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate Ex. 42 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid Ex. 43 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 44 (10R,15S)-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 45 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-phenyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 46 (10R,15S)-4-methoxy-10,16-dimethyl-15-(1-pyrrolidinylcarbonyl)-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17- dione Ex. 47 (10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-10,16-dimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide Ex. 48 tert-butyl N-[3-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)propyl]carbamate Ex. 49 (10R,15S)-N-(3-aminopropyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 50 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 51 (10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 52 (10R,15S)-N-cyclopropyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 53 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(2,2,2-trifluoroethyl)- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 54 (10R,15S)-N-isobutyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 55 (10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 56 tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetate Ex. 57 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetic acid Ex. 58 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-[(1S)-1-phenylethyl]- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 59 (10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-N,10,16-trimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide Ex. 60 (10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 61 (10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 62 (10R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 63 (10R,15S)-4-methoxy-10,16-dimethyl-15-[(3-pyridinyloxy)methyl]-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17- dione Ex. 64 (10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 65 (10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 66 N-{[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl}-2- phenylacetamide Ex. 67 [(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N- phenylcarbamate Ex. 68 benzyl (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxylate Ex. 69 (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxylic acid Ex. 70 (9S,14S)-N,9,15-trimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 71 (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 72 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 73 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenethyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 74 (9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 75 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 76 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-[(1S)-1-phenylethyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 77 (9S,14S)-N-(2-methoxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 78 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 79 (9S,14S)-N-cyclopropyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 80 (9S,14S)-N-isobutyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 81 (9S,14S)-N-(2-hydroxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 82 tert-butyl 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14- yl]carbonyl}amino)acetate Ex. 83 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14- yl]carbonyl}amino)acetic acid Ex. 84 (9S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethyl-11,16-dioxo-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 85 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-[3-(1-pyrrolidinyl)propyl]-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 86 (9S,14S)-14-(1-azetanylcarbonyl)-9,15-dimethyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16- dione Ex. 87 (9S,14S)-9,15-dimethyl-14-(morpholinocarbonyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16- dione Ex. 88 (9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16- dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19- hexaene-14-carboxamide Ex. 89 (9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 90 benzyl (9S,11R)-11-[(tert-butoxycarbonyl)amino]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 91 tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 92 benzyl (9S,11R)-11-amino-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxylate Ex. 93 (9S,11R)-11-amino-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 94 tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 95 (9S,11R)-11-amino-16-methyl-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 96 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 97 tert-butyl N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 98 (9S,11R)-11-amino-16-(3-fluorobenzyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 99 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide Ex. 100 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide Ex. 101 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(1-naphthyl)acetamide Ex. 102 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-phenylurea Ex. 103 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]benzenesulfonamide Ex. 104 tert-butyl N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 105 (9S,11R)-11-amino-16-[2-(dimethylamino)acetyl]-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 106 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-phenylacetamide Ex. 107 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]cyclopropanesulfonamide Ex. 108 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-methylurea Ex. 109 tert-butyl N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 110 (9S,11R)-11-amino-16-(cyclopropylsulfonyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 111 N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]benzamide Ex. 112 tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 113 (9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxamide Ex. 114 (95,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxamide Ex. 115 allyl N-[(135,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 116 (135,16R)-13-amino-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 117 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 118 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 119 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- pyrrolidinyl)acetamide Ex. 120 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide Ex. 121 3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide Ex. 122 methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 123 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 124 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 125 N-methyl-N′-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 126 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 127 (13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 128 (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 129 allyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 130 (13S,16R)-13-amino-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 131 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 132 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 133 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- pyrrolidinyl)acetamide Ex. 134 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide Ex. 135 3-methyl-N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide Ex. 136 methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 137 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 138 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 139 N-methyl-N′-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 140 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 141 (13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 142 (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 143 allyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 144 (10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 145 (10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 146 (10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 147 (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 148 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 149 2-methoxy-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 150 2-(dimethylamino)-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 151 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]nicotinamide Ex. 152 3-methyl-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]butanamide Ex. 153 tert-butyl N-(3-{[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3- oxopropyl)carbamate Ex. 154 3-amino-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 155 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 156 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 157 3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 158 3-fluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide Ex. 159 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 160 N-methyl-N′-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 161 tert-butyl 3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate Ex. 162 3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid Ex. 163 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide Ex. 164 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 165 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 166 methyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 167 2-methoxyethyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 168 allyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 169 (10R,13S)-13-amino-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 170 (10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 171 (10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 172 (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 173 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 174 2-methoxy-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 175 2-(dimethylamino)-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 - thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]acetamide Ex. 176 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]nicotinamide Ex. 177 3-methyl-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]butanamide Ex. 178 tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}-3-oxopropyl)carbamate Ex. 179 3-amino-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 180 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 181 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 182 3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 183 3-fluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide Ex. 184 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 185 N-methyl-N′-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 186 tert-butyl 3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate Ex. 187 3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid Ex. 188 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide Ex. 189 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 190 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 191 methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 192 2-methoxyethyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]carbamate Ex. 193a (9S,16S,19R)-16-benzyl-19,20-dimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193c (9S,19S)-19-benzyl-20-methyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193d (9S,19S)-19-benzyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193e (9S,16R,19S)-19-benzyl-16,17,20-trimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193f (9S,16R)-16,17,20-trimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193g (9S,16R,19S)-19-benzyl-16,17-dimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193h (9S,16S)-16-benzyl-21-methyl-7-oxa-13,17,21,25- tetraazatetracyclo[21.3.1.1 2,6 .0 9,13 ]octacosa-1(27),2(28),3,5,23,25- hexaene-14,18,22-trione Ex. 194b 3-[(9S,16R,19S)-16,17,20-trimethyl-14,18,21-trioxo-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaen-19-yl]propanoic acid Ex. 195a (9S,16R,22S)-16,17,20,22,23-pentamethyl-7-oxa-13,17,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,18,21,24-tetrone Ex. 195b (9S,16R,22S)-16,17,22-trimethyl-7-oxa-13,17,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,18,21,24-tetrone Ex. 195e (9S,19R,22S)-16,19,20,22,23-pentamethyl-7-oxa-13,16,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,17,21,24-tetrone Ex. 195f (9S,18S,22R)-16,18,19,22,23-pentamethyl-7-oxa-13,16,19,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,17,20,24-tetrone Ex. 195g (9S,18S,21R)-18-benzyl-21,22-dimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 195h (9S,18S,21R)-18-benzyl-16,21-dimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 195j (9S,18S,21R)-18-benzyl-16,21,22-trimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 196c 3-[(9S,16R,19S,22S)-16,17,19,23-tetramethyl-14,18,21,24-tetraoxo-7- oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta- 1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid Ex. 196i 3-[(9S,15S,18R,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7- oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa- 1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid Ex. 196k 3-[(9S,15R,18S,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7- oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa- 1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid Ex. 197d (9S,16R,19S,22R)-19-(4-aminobutyl)-16,17,22-trimethyl-7-oxa- 13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta- 1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone Ex. 198 benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate Ex. 199 benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxylate Ex. 200 tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]carbamate Ex. 201 tert-butyl N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]carbamate Ex. 202 (10S,12S)-12-amino-17-methyl-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 15,21-dione Ex. 203 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-2-(1-naphthyl)acetamide Ex. 204 3-methyl-N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]butanamide Ex. 205 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-N′-(3-pyridinyl)urea Ex. 206 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]benzenesulfonamide Ex. 207 tert-butyl N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate Ex. 208 (10S,12S)-12-amino-17-[2-(dimethylamino)acetyl]-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 15,21-dione Ex. 209 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-2-phenylacetamide Ex. 210 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-N′-methylurea Ex. 211 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]cyclopropanesulfonamide Ex. 212 benzyl (10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxylate Ex. 213 N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 214 N-[(10S,12S)-17-(3-fluorobenzyl)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 215 N-[(10S,12S)-15,21-dioxo-17-[2-(1-pyrrolidinyl)acetyl]-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 216 (10S,12S)-12-(acetylamino)-15,21-dioxo-N-phenyl-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxamide Ex. 217 N-[(10S,12S)-15,21-dioxo-17-(phenylsulfonyl)-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 218 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 17-yl]carbonyl}amino)propanoic acid Ex. 219 tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 17-yl]carbonyl}amino)propanoate Ex. 220 methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),12,22,24-hexaene-8-carboxylate Ex. 221 methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate Ex. 222 methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia- 7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa-1(26),2,5(27),22,24- pentaene-8-carboxylate Ex. 223 methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate Ex. 224 (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylic acid Ex. 225 (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide Ex. 226 (8S,17S,19S)-24-fluoro-N-isobutyl-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide Ex. 227 methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 228 (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 229 methyl (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4- thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 230 methyl (8S,12E,18S,20S)-25-fluoro-18-[2-(2-naphthyl)acetyl]amino-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 231 tert-butyl N-[(8S,12E,18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]- 6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen- 18-yl]carbamate Ex. 232 (8S,12E,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa- 4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide Ex. 233 (8S,12E,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide Ex. 234 tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaen-18-yl]carbamate Ex. 235 (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa- 4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide Ex. 236 methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2- phenylacetyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxylate Ex. 237 (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 238 methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 239 (8S,12E 18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 240 (8S,12E,18S,20S)-25-fluoro-N-isobutyl-18-{[2-(2-naphthyl)acetyl]amino}- 6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide Ex. 241 (8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 242 methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 243 (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 244 methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxylate Ex. 245 methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 246 tert-butyl N-[(8S,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 247 (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 248 methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 249 (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 250 methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 251 (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 252 (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 253 tert-butyl N-[(8S,18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 254 (8S,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa-4- thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 255 (8S,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxamide Ex. 256 tert-butyl N-[(8S,18S,20S)-8-[(4-chloroanilino)carbonyl]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 257 (8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide Ex. 258 tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidinocarbonyl)- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 259 (8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide Ex. 260 tert-butyl N-[(8S,18S,20S)-8-[(benzylamino)carbonyl]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 261 (8S,18S,20S)-18-amino-N-benzyl-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 262 benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethyl-14,19- dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate Ex. 263 (9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethyl-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraene-14,19-dione Ex. 264 (9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethyl-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraene-14,19-dione Ex. 265 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(2-naphthyl)acetamide Ex. 266 N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]acetamide Ex. 267 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(1-naphthyl)acetamide Ex. 268 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-3-methylbutanamide Ex. 269 3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzamide Ex. 270 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]benzenesulfonamide Ex. 271 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]methanesulfonamide Ex. 272 methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate Ex. 273 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-methylurea Ex. 274 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-(3-pyridinyl)urea Ex. 275 N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(2-naphthyl)acetamide Ex. 276 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-(2-naphthyl)urea Ex. 277 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-phenylacetamide Ex. 278 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-3-methoxybenzamide Ex. 279 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-naphthalenesulfonamide Ex. 280 3-(4-fluorophenyl)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19- dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]propanamide Ex. 281 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(1H-indol-3-yl)acetamide Ex. 282 (9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl]amino}- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione Ex. 283 (9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21-dimethyl-7- oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione Ex. 284a benzyl N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate EX. 284b benzyl N-[(13R,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate Ex. 285 (13S,19S)-13-amino-4,8-dimethyl-23-nitro-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaene-7,14-dione Ex. 286 benzyl N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate Ex. 287 benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 288 N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]acetamide Ex. 289 N-(2-chlorophenyl)-N′-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]urea Ex. 290 N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]-N′-(2-chlorophenyl)urea Ex. 291 N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino}-4,8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide Ex. 292 N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]cyclopropanecarboxamide Ex. 293 N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]cyclopropanecarboxamide Ex. 294 N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]cyclopropanecarboxamide Ex. 295 N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]methanesulfonamide Ex. 296 benzyl N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo- 21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 297 benzyl N-[(13S,19S)-4,8-dimethyl-7,14-dioxo-23-(2-pyrimidinylamino)-21- oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 298 (13S,19S)-13-amino-4,8-dimethyl-23-(2-pyrimidinylamino)-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaene-7,14-dione Ex. 299 N-[(13S,19S)-13-(dimethylamino)-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 300 N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]-2-phenylacetamide Ex. 301 N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino}-4.8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 302 N-[(13S,19S)-13-{[(isobutylamino)carbonyl]amino}-4,8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 303 N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]-4-fluorobenzamide Ex. 304 N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide Ex. 305 benzyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]carbamate Ex. 306 (15R,16aS)-15-amino-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione Ex. 307 (15R,16aS)-15-(dimethylamino)-10-methyl-10,11,15,16,16a,17- hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine- 9,12-dione Ex. 308 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]acetamide Ex. 309 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- methylbutanamide Ex. 310 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(2- naphthyl)acetamide Ex. 311 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(1- naphthyl)acetamide Ex. 312 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2- (dimethylamino)acetamide Ex. 313 tert-butyl N-(3-[(15R,16aS)-10-methyl-9,12-dioxo- 9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1- c][1,4,7]oxadiazacyclododecin-15-yl]amino-3-oxopropyl)carbamate Ex. 314 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- aminopropanamide Ex. 315 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- fluorobenzamide Ex. 316 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]isonicotinamide Ex. 317 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′- methylurea Ex. 318 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′-(3- pyridinyl)urea Ex. 319 2-methoxyethyl N-[(15R,16aS)-10-methyl-9,12-dioxo- 9,10,11,12,15,16,163,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1- c][1,4,7]oxadiazacyclododecin-15-yl]carbamate Ex. 320 tert-butyl 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]amino}carbonyl)amino]propanoate Ex. 321 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]amino}carbonyl)amino]propanoic acid Ex. 322 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]methanesulfonamide Ex. 323 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]benzenesulfonamide Ex. 324 (15R,16aS)-15-[(3-fluorobenzyl)amino]-10-methyl-10,11,15,16,16a,17- hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine- 9,12-dione Ex. 325 (15R,16aS)-15-(isobutylamino)-10-methyl-10,11,15,16,16a,17-hexahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione Ex. 326 N″-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]- N,N,N′,N′-tetramethylguanidine Ex. 327 benzyl (16S,18S)-16-[(tert-butoxycarbonyl)amino]-7,13-dioxo-4- (trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23- pentaene-11-carboxylate Ex. 328 tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa- 3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa- 1(25),2(6),3,21,23-pentaen-16-yl]carbamate Ex. 329 benzyl (165,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa- 3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa- 1(25),2(6),3,21,23-pentaene-11-carboxylate Ex. 330 allyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 331 allyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]carbamate Ex. 332 2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}- 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]acetamide Ex. 333 N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]-2-(1-naphthyl)acetamide Ex. 334 2-(3-chlorophenyl)-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide Ex. 335 2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide Ex. 336 N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide Ex. 337 N-[(12R,16S,18S)-12-[(benzylsulfonyl)amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(1-pyrrolidinyl)acetamide Ex. 338 benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 339 N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(1-pyrrolidinyl)acetamide Ex. 340 N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyl]amino}-8,13-dioxo-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide Ex. 341 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(1-naphthyl)acetamide Ex. 342 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 343 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-(2-naphthyl)urea Ex. 344 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-naphthalenesulfonamide Ex. 345 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-3-(2-naphthyl)propanamide Ex. 346 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-3-phenylpropanamide Ex. 347 2-(dimethylamino)-N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide Ex. 348 benzyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 349 N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 350 N-[(9S,11R)-16-(3-fluorobenzoyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 351 N-[(9S,11R)-16-benzyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 352 N-[(9S,11R)-14,20-dioxo-16-phenethyl-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 353 N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 354 N-[(9S,11R)-16-isopentyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 355 N-[(9S,11R)-16-isobutyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 356 2-(dimethylamino)ethyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 357 N-[(9S,11R)-16-[2-(dimethylamino)ethyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 358 3,3-dimethyl-N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]butanamide
Synthesis of the Building Blocks
Readily available examples of amino acids representing subunits of the Bridge C are detailed to the level of fully-defined structures in Table 11. Additional analogs can be accessed smoothly, and a plethora of literature precedents are published. Therefore this section focuses on synthetic approaches towards building blocks of the Template A and the Modulator B.
Functional groups not involved in ring connections of the macrocyclic backbone can be diversified by standard methods of organic synthesis, preferably by parallel/combinatorial chemistry introducing so-called high variation substituents. These derivatization methods are well-known to those skilled in the art and do not require further exemplification (selected references: A. R. Katritzky et al. (eds), Comprehensive Functional Group Transformations , Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups , Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; D. Obrecht, J. M. Villalgordo (eds), Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Pergamon, 1998; W. Bannwarth et al. (eds), Combinatorial Chemistry: From Theory to Application, 2 ed., Wiley-VCH 2006).
a) Synthesis of Template a Building Blocks
Over the last decades the coupling to suitably functionalized aromatic or heteroaromatic compounds has reached a highly mature status providing an easy and reliable route to biaryl derivatives of nearly any substitution pattern (cf. leading reviews covering several types of coupling reactions and the references cited therein: R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A. de Meijere, F. Diederich (eds), Metal - Catalyzed Cross - Coupling Reactions, 2nd ed., Wiley-VCH 2004; with focus on heteroaromatic substrates: G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644-4680; especially for macrocyclic biaryls: Q. Wang, J. Zhu, Chimia 2011, 65, 168-174). Most prominent among these coupling reactions is definitely the Suzuki-Miyaura cross coupling of aryl boronic acid derivatives with aryl halides under palladium catalysis (N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; S. Kotha et al., Tetrahedron 2002, 58, 9633-9695; S. L. Buchwald et al., J. Am. Chem. Soc. 2005, 127, 4685-4696). Special catalysts, especially the Nolan's catalysts make the Suzuki-Miyaura reaction also amenable to highly sterically hindered substrates (S. P. Nolan et al., J. Am. Chem. Soc. 2003, 125, 16194-16195; S. P. Nolan et al., Org. Lett. 2005, 7, 1829-1832). More recent developments broadened the scope of the Suzuki coupling from aryl halides to other substrates like aryl mesylates (F. Y. Kwong et al., Angew. Chem. Int. Ed. 2008, 47, 8059-8063) or aryl carbamates, carbonates and sulfamates (N. K. Garg et al., J. Am. Chem. Soc. 2009, 131, 17748-17749).
The biaryl compounds obtained by such coupling protocols might require further functional group transformations as described below.
General Functional Group Interconversions
The majority of the Templates A are carrying an aromatic or heteroaromatic hydroxy (—OH) or sulfanyl (thiol) group (—SH) in the A B substructure and a carboxylic acid group (—COOH) or sulfanyl moiety (—SH) or its respective oxidation products in the Ac substructure.
As more phenolic precursors are commercially available than the corresponding thiophenols, a transformation of a phenol into a thiophenol might be required. Alternatively thiophenols might be derived from the corresponding aryl halides or diazonium salts. Selected functional group transformations for introducing a sulfanyl group (—SH), i.e. Ar/Hetar-X→Ar/Hetar-SH (X═OH, F, Cl, Br, I, N 2 + ), are the compiled below (T-I to T-VII):
T-I: A sequence of broad applicability is the transformation of a phenol into a thiocarbamate with N,N-dimethylthiocarbamoyl chloride, followed by Newman-Kwart rearrangement and subsequent hydrolysis (A. Gallardo-Godoy et al., J. Med. Chem. 2005, 48, 2407-2419; P. Beaulieu et al., Bioorg. Med. Chem. Lett. 2006, 16, 4987-4993; H. Sugiyama et al., Chem. Pharm. Bull. 2007, 55, 613-624; S. Lin et al., Org. Prep. Proced. Int. 2000; 547-556).
T-II: The direct transformation of an —OH adjacent to a pyridinic nitrogen (i.e. equivalent to the pyridone tautomer) can be accomplished by heating with P 2 S 5 (K. Hirai et al., Heterocycles 1994, 38, 277-280).
T-III: As an alternative to phenols, halogen-substituted (esp. with F or Cl) aromatic ring systems might serve as precursors. In case the halogen is in a position activated by an electron withdrawing group in ortho- or para-position the —SH moiety or a protected surrogate can be introduced under mild conditions by nucleophilic aromatic substitution reactions (S N Ar) (G. J. Atwell et al., J. Med. Chem. 1994, 37, 371-380). Especially in the field of heterocyclic compounds, where the electron withdrawing effect is exerted by pyridine-like nitrogen atoms, this type of substitution is often utilized (S. McCombie et al., Heterocycles, 1993, 35, 93-97).
T-IV: Similarly, in Sandmeyer-type reactions a diazonium group (—N 2 + ) can be replaced (C. Mukherjee, E. Biehl, Heterocycles 2004, 63, 2309-2318).
T-V: In positions not activated for an S N Ar the substitution of halogen atoms (esp. Br or I) can be accomplished via the corresponding organolithium or Grignard reagents (J. L. Kice, A. G. Kutateladze, J. Org. Chem. 1993, 58, 917-923; P. C. Kearney et al., J. Am. Chem. Soc. 1993, 115, 9907-9919). Alternatively, transition metal-catalyzed transformations are feasible for this type of reaction, e.g. Cu-catalyzed substitution with benzothioic S-acid (N. Sawada et al., Tetrahedron Lett. 2006, 47, 6595-6597), or Pd-catalyzed substitution with KS—Si(i-Pr) 3 followed by desilylation of the introduced —SSi(i-Pr) 3 group (A. M. Rane et al., Tetrahedron Lett. 1994, 35, 3225-3226).
The thus introduced —SH moieties constitute a thia-bridge —S— in the later macrocyclic products and can be selectively transformed into higher oxidation states. Therefore the building blocks with sulfanyl moieties are also regarded as building blocks for the introduction of sulfinyl (—S(═O)—; i.e. sulfoxide) and sulfonyl (—S(═O) 2 —; i.e. sulfone) moieties. Suitable oxidation methods are:
T-VI: The selective oxidation of a thioether (—S—) to a sulfoxide (—S(═O)—) can be highly selectively and mildly achieved with hexamethylenetetramine-bromine HMTAB (K. Choudhary et al.; J. Phys. Org. Chem. 2000, 13, 283-292); under these conditions primary hydroxyl groups for example are not affected. In a number of related reactions chlorotrimethylsilane showed high selectivity, too (Y.-J. Chen et al., Tetrahedron Lett. 2000, 41, 5233-5236).
T-VII: Stronger oxidants directly transfer the sulfanyl (—S—) into the sulfonyl group (—S(═O) 2 —). Among the many reagents mentioned in literature the system periodic acid/chromium(VI)oxide for example can be applied in the presence of C═C-double bonds (US2007/293548 A1).
Hydroxyl groups attached to aromatic rings (Ar—OH or Heteroaryl-OH) in turn, if not already part of a synthesized or commercially available biaryl, can be introduced by various methods, e.g. H-I to H-IV:
H-I: Analogously to T-III) the hydroxy group or its surrogate can be introduced by an S N Ar reaction of halogen atoms, esp. Cl or F, ortho or para to an electron withdrawing substituent (W. Cantrell, Tetrahedron Lett. 2006, 47, 4249-4251) or to a pyridinic nitrogen atom (S. D. Taylor et al., J. Org. Chem. 2006, 71, 9420-9430).
H-II: Sandmeyer-type hydroxylations of aromatic amines via intermediate diazonium salts (P. Madsen et al., J. Med. Chem. 2002, 45, 5755-5775).
H-III: The substitution of halogen atoms (esp. Br and I), which are not activated for an S N Ar, can be achieved by transition metal-catalyzed C—O-couplings. Predominant are Pd-catalysts (K. W. Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695; B. J. Gallon et al., Angew. Chem., Int. Ed. 2007, 46, 7251-7254), but also others find application, like Cu-catalysts (J. E. Ellis, S. R. Lenger, Synth. Commun. 1998, 28, 1517-1524).
H-IV: Of broad scope is also a two-step process which first transforms halogen atoms (Cl, Br and I) into a boronate and then oxidatively cleaves the carbon-boron bond to the phenol (J. R. Vyvyan et al., J. Org. Chem. 2004, 69, 2461-2468).
The carboxylic acid group of the biaryl A building blocks, if not already present in commercially available coupling precursors, can be introduced by standard procedures like C-I to C-IV:
C-I: The oxidation of functional groups like hydroxymethyl (—CH 2 —OH) or aldehyde (—C(═O)H) can be achieved under mild conditions (G. V. M. Sharma et al., Synth. Commun. 2000, 30, 397-406; C. Wiles et al., Tetrahedron Lett. 2006, 47, 5261-5264). Also methyl groups on benzene rings can be oxidized; however, as harsh reaction conditions are usually required, its applicability is limited. In contrast, the relatively acidic methyl groups ortho or para to a pyridine nitrogen can be oxidized under milder conditions; making this the method of choice for many pyridine analogs (T. R. Kelly, F. Lang, J. Org. Chem. 1996, 61, 4623-4633).
C-II: Halogen atoms can easily be replaced by a carboxyl group or surrogate thereof, e.g. by halogen metal exchange and subsequent carboxylation of the intermediate Grignard or organolithium species (C. G. Screttas, B. R. Steele, J. Org. Chem. 1989, 54, 1013-1017), or by utilizing Mander's reagent (methyl cyanoformate) (A. Lepretre et al., Tetrahedron 2000, 56, 265-274).
C-III: In the case that acidified ring positions are to be carboxylated, a viable method is deprotonation with a strong base (usually tert-butyl lithium) followed by carboxylation of the intermediate organolithium species in analogy to C-II).
C-IV: Hydrolysis of ester, amide or nitrile groups. The CN group in turn can easily be introduced by treating organic halides with CuCN (Rosenmund-von Braun reaction: C. F. Koelsch, A. G. Whitney, J. Org. Chem., 1941, 6, 795-803).
Applied to commercially available starting materials or biarlys obtained by coupling route, these general transformations offer a tool box for accessing a huge variety of Templates A. Additional literature examples are cited below within the sections on specific derivatives.
b) Synthesis of Modulator B Building Blocks
The Modulator B moieties of macrocycle I are derived from appropriately substituted aminoalcohols, wherein the amino and alcohol group, which contribute to the ring connectivity, are separated by 2-4 C-atoms.
If not already present in a commercial building block, the substituent R 6 can be introduced by standard nucleophilic addition of organometallic reagents to carbonyl or carboxyl derivatives. Alkyl (as R 6 ) substituted analogs of B1 and derivatives of B2-B10 with no additional C-substituent on their ring system are commercially available, as are many derivatives with an amino (—NH 2 ) or alcohol (—OH) substituent as R 6 . In the such cases the diversification of the substitution pattern can be easily achieved by standard transformations of the free amine or hydroxy functionalities.
Possible pathways to more complex pyrrolidine derivatives of type B4-B6 or piperidine derivatives of type B7-B9 rely on the same strategy: Intramolecular cyclization reactions are the predominant route applicable to diversely substituted substrates. Amines carrying a residue with a leaving group in the ω-position lead directly to the desired saturated ring systems by intramolecular nucleophilic substitution (G. Ceulemans et al., Tetrahedron 1997, 53, 14957-14974; S. H. Kang, D. H. Ryu, Tetrahedron Lett. 1997, 38, 607-610; J. L. Ruano et al., Synthesis 2006, 687-691). Also N-haloamines can be directly transformed into the desired compounds by a Hofmann-Löffler-Freytag reaction (M. E. Wolff, Chem. Rev. 1963, 63, 55-64). Alternatively, amines carrying two substituents, each with an alkene or alkyne bond, can be subjected to a ring closing metathesis (RCM) reaction (Y. Coquerel, J. Rodriguez, Eur. J. Org. Chem. 2008, 1125-1132) and subsequent reduction of the partially unsaturated ring to the saturated heterocycle.
Another possible access, reduction of aromatic five- or six-membered heterocycles to their saturated analogs, is described in the literature. Due to the large number of commercially available pyridines this approach is especially useful for the synthesis of the piperidine system (J. Bolos et al., J. Heterocycl. Chem. 1994, 31, 1493-1496; A. Solladie-Cavallo et al., Tetrahedron Lett. 2003, 44, 8501-8504; R. Naef et al., J. Agric. Food Chem. 2005, 53, 9161-9164).
General Processes for the Synthesis of Macrocyclic Compounds I
General procedures for the synthesis of libraries of macrocyclic compounds of general structure I are described below. It will be immediately apparent to those skilled in the art how these procedures have to be modified for the synthesis of individual macrocyclic compounds of type I.
The macrocyclic compounds of this invention are obtained by cyclization of suitable linear precursors which are derived from optionally substituted bifunctional hydroxy- or mercapto biaryls/heteroaryls X-A B -A C -Y (Template A B -A C ), substituted amino alcohols B (Modulator), and one to three building blocks forming Bridge C.
Hydroxy- or mercapto biaryls/heteroaryls X-A B -A C -Y consist of two optionally substituted building blocks X-A B and A C -Y. Building blocks X-A B comprise hydroxyaryl, hydroxyheteroaryl-, mercaptoaryl- and mercaptoheteroaryl compounds. Building blocks A c -Y comprise carboxyaryl-, carboxyheteroaryl-, mercaptoaryl-, mercaptoheteroaryl, alkenylaryl, and alkenylheteroaryl compounds. X-A B and A C -Y are six-membered aromatic or five- or six-membered heteroaromatic rings. Templates X-A B -A C -Y can be obtained by combination of two six-membered rings, two five-membered rings or a five- and a six-membered ring. The building blocks X-A B and A C -Y are connected by a carbon-carbon bond to form the biaryls X-A B -A C -Y.
Variable substituents are introduced by pre- or postcyclative derivatization of one or more orthogonally protected functional group (e.g. amino groups, carboxyl groups, hydroxyl groups) attached to B, C or A. Variable R-groups may also be introduced as side chain motifs of the subunits of Bridge C.
The macrocyclic products of this invention can be prepared either in solution or on solid support.
The essential ring closure reaction is possible between any of the building blocks; and macrocycles I are obtained by e.g.
Macrolactamization between C and B; Macrolactamization between A B -A C and C; Macrolactamization between any two subunits of Bridge C; Arylether or arylthioether formation between A B -A C and B; Arylthioether formation between A B -A C and C; Biaryl synthesis by coupling reaction (e.g. Suzuki coupling) between A B and A C ; Ring closing metathesis (RCM) reaction between any two subunits of C or upon formation of such a subunit; Ring closing metathesis reaction between A B -A C and C.
SW-1: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
Macrocycles of structure I with orthogonally protected exocyclic functional groups (attachment points for derivatizations) are prepared in solution by the process outlined below. Throughout all steps the orthogonal protection of the side chains stays intact and is not affected by protecting group manipulations of the main chain.
a1) Condensation of an appropriately protected hydroxy- or mercapto-biaryl/heteroaryl carboxylic acid PG 1 -X-A B -A C -CO 2 H and a suitable C-terminally and side-chain protected C-subunit building block H—NR 7 -c1-CO—OPG 2 to form PG 1 -X-A B -A C -CONR 7 -c1-CO—OPG 2 ;
b1) If required, deprotection of the aryl/heteroaryl hydroxy or mercapto group;
c1) Aryl/heteroaryl ether or thioether formation with a suitably N-protected amino alcohol PG 3 -B-OH leading to the fully protected linear precursor PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 ;
d1) Cleavage of the “main chain” protective groups affording the free amino acid H—B—X-A B -A C -CONR 7 -c1-CO—OH, which is subjected to macrocyclization
e1) Intramolecular amide coupling to cyclo(B—X-A B -A C -CONR 7 -c1-CO—) as macrocyclic product.
In addition to the steps described above, chain elongation by one or two additional C-subunits (c2, c3) and subsequent macrolactamization starts with coupling of a second suitably C-protected amino acid to the free carboxylic acid functionality of the product obtained by N-reprotection of the product of step d1. Cleavage of the main chain protective groups and either macrolactamization or repetition of the chain elongation steps and macrolactamization provides either cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—) or cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CONR 7 -c3-CO—).
The free carboxylic acid functionality of the N-reprotected product derived from any of the three linear macrolactamization precursors (product of step d1, or corresponding product after coupling of one or two additional C-subunits) can be further elaborated by chain extensions/homologizations (e.g. Arndt-Eistert reaction) or functional group interconversions like Curtius rearrangement ultimately affording homologous macrocycles or those where the connection between Modulator B and Bridge C corresponds to a urea moiety.
SW-2: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
As an alternative to SW-1 the intermediate H—X-A B -A C -Y-Z-c1-CO—OPG 2 (product of step b1) can be prepared by
a2) S-alkylation of a suitable mercapto-substituted haloaryl/heteroaryl compound Hal-A C -SH (Hal represents a halogen atom) with a C-terminally and side-chain protected C-subunit building block LG-CHR 8 -c1-CO—OPG 2 (LG represents a leaving group like halide, alkyl-, arylsulfonate or activated OH like e.g. under Mitsunobu conditions);
b2) Suzuki coupling reaction between the product of step a2) and a suitable hydroxyl-substituted boronic acid or boronic ester HX-A B -B(OR) 2 leading to HX-A B -A C -S—CHR 8 -c1-CO—OPG 2 .
In analogy, amide coupling of a suitable C-terminally and side-chain protected C-subunit building block H—NR 7 -c1-CO—OPG 2 to a haloaryl/heteroaryl carboxylic acid Hal-A C -CO—OH and subsequent Suzuki biaryl coupling reaction with a suitable hydroxyl-substituted boronic acid or boronic ester would provide H—X-A B -A C -CONR 7 -c1-CO—OPG 2 .
Possible subsequent steps are as described in SW-1, providing cyclo(B—X-A B -A C -Y-Z-c1-CO—) with Y—Z═CONR 7 , S—CHR 8 .
Oxidation of cyclo(B—X-A B -A C -S—CHR 8 -c1-CO—) leads to the corresponding sulfoxides cyclo(B—X-A B -A C -SO—CHR 8 -c1-CO—) or sulfone cyclo(B—X-A B -A C -SO 2 —CHR 8 -c1-CO—).
SW-3: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
As an alternative to SW-1 the protected cyclization precursor PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 can also be synthesized by an inverted order of reaction steps:
a3) Arylether or arylthioether formation between a hydroxyl or mercapto-aryl/heteroaryl ester H—X-A B -A C -CO—OPG 4 and a suitably protected amino alcohol PG 3 -B-OH to afford PG 3 -B-X-A B -A C -CO—OPG 4 .
Further more, PG 3 -B-X-A B -A C -CO—OPG 4 can also be obtained by arylether or arylthio ether formation between a suitably protected aminoalcohol PG 3 -B-OH and an optionally substituted hydroxyl- or mercaptoaryl halide or heteroaryl halide HX-A B -Hal leading to PG 3 -B-X-A B -Hal and subsequent coupling of an optionally substituted alkoxycarbonyl aryl or heteroaryl boronic acid or boronic ester (RO) 2 B-A C -CO—OPG 4 .
b3) Deprotection of the carboxylic acid group to PG 3 -B-X-A B -A C -CO—OH;
c3) Condensation with a C-terminally and side-chain protected building block H—NR 7 -c1-CO—OPG 2 to PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 .
Possible subsequent steps are as described in SW-1.
In analogy to step c3), PG 3 -B-X-A B -A C -CO 2 H can be coupled to a previously formed di- or tripeptide leading to protected cyclization precursors such as PG 3 -B-X-A B A C -CONR 7 -c1-CONR 7 -c2-CO—OPG 2 or PG 3 -B-X-A B -A C -CONR 7 -c1-CONR 7 -c2-CONR 7 -c3-CO—OPG 2 . If applying this approach for the synthesis of macrocycles I, the synthesis is best performed by preparation of the linear N-terminal deprotected cyclization precursor on solid support, followed by release from resin and cyclization as well as cleavage of side chain protective groups in solution, as detailed in SW4.
SW-4: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Combined Solid Phase and Solution Phase Chemistry
Macrocyclic compounds of general formula I with highly variable side chain motifs in Bridge C can advantageously be prepared in parallel array synthesis applying a combination of solid phase and solution phase synthesis methodologies.
The solid support (polymer, resin) is preferably a trityl resin e.g. chlorotrityl chloride resin (cross-linked with 1-5% divinylbenzene), which is useful as polymer-bound protective group for carboxylic acids (D. Obrecht, J.-M. Villalgordo, Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998; K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520; K. Barlos et al., Angew. Chem. Int. Ed. 1991, 30, 590-593).
a4) The suitably side-chain protected C-subunit PG 5 NR 7 -c2-CO—OH is attached to the solid support;
b4) The N-terminal protective group is cleaved;
c4) The suitably side-chain protected C-subunit PG 5 NR 7 -c1-CO—OH is coupled; subsequent N-terminal deprotection leads to HNR 7 -c1-CO—NR 7 -c2-CO—O-chlorotrityl resin;
d4) Coupling of a suitably side chain protected building block PG 3 -B-X-A B -A C -CO—OH (cf. SW-3, product of step b3) and cleavage of the N-terminal protective group;
e4) Release of the linear main-chain deprotected macrolactamization precursor H—B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—OH from the resin;
f4) Macrolactamization to cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—).
g4) Optional: Cleavage of protective groups of side-chain functions.
Immobilization of an amino acid PG 5 NR 7 -c3-CO—OH and two additional amino acid coupling/deprotection cycles would lead to HNR 7 -c1-CO—NR 7 -c2-CO—NR 7 -c3-CO—O-chlorotrityl resin. Possible subsequent steps are as described above, providing cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—NR 7 -c3-CO—).
The ring closure of linear precursors like H—B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—OH may be achieved using soluble coupling reagents as described below or by engaging polymer-supported coupling reagents such as N-cyclohexyl-carbodiimide-N′-methylpolystyrene or N-alkyl-2-chloro pyridinium triflate resin (S. Crosignani et al, Org. Lett. 2004, 6, 4579-4582).
Further viable alternatives for the synthesis of macrocycles I by combined application of solid phase and solution phase conditions could involve macrolactamization in other positions, e.g. between two subunits in Bridge C. Alternative cyclization precursors like H—NR 7 -c2-CO—B—X-A B -A C -CONR 7 -c1-CO—OH can be obtained from the same building blocks (as described for SW4) by changing the sequence of coupling/deprotection steps.
SW-5: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Ring-Closing Metathesis in Solution
Ring-closing metathesis (RCM) of olefinic precursors was applied for the synthesis of subunits of Bridge C, wherein e.g. c2=c2′−c2″:
a5) Coupling of an optionally substituted alkenyl amine building block H—NR 7 -c1-V-c2′=CH 2 with suitably protected carboxylic acid derivatives PG 1 -X-A B -A C -CO 2 H to afford PG 1 -X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 ;
b5) if required release of the aryl/heteroaryl hydroxyl or mercapto group;
c5) Arylether or arylthioether formation between H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 and PG 3 -B-OH leading to PG 3 -B-X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2
d5) Cleavage of the N-terminal protective group leading to H—B—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2
e5) Coupling of a suitable (optionally substituted and suitably protected) enoic acid to H 2 C=c2″-CO—B—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 ;
f5) Ring-closing metathesis to cyclo(c2″-CO—B—X-A B -A C -CO—NR 7 -c1-V-c2′) [=cyclo(B—X-A B -A C -CO—NR 7 -c1-V-c2-CO—)]
g5) Optional: Hydrogenation of the newly formed C—C double bond of the metathesis product.
In addition, it is also feasible to prepare olefinic macrocycles with modified Bridges C such as cyclo(B—X-A B -A C -Y-Z-c1-V-c2-CO—NR 7 -c3-CO—), or cyclo(B—X-A B -A C -Y-Z-c1-CO—), and subsequently the respective hydrogenated analogs.
General Procedures for Synthetic Steps Utilized in SW-1 to SW-5
In all general procedures below Y—Z represents CONR n or SCHR n .
Amidation Reactions (Steps a1, c3, a5, e5)
An appropriately protected (preferably as acetyloxy or acetylmercapto) and optionally substituted biaryl/heteroaryl carboxylic acid (PG 3 -X-A B -A C -CO 2 H) or a more advanced intermediate like PG 3 -B-X-A B -A C -CO 2 H is condensed with a suitably protected amino acid ester H—NR 7 -c1-CO—OPG 2 or an amine H—NR 7 -c1-V-c2′=CH 2 in the presence of a coupling reagent (e.g. benzotriazole derivatives like HBTU, HCTU, BOP, PyBOP; their aza analogs like HATU; or carbodiimides like EDC; others like PyClu, T3P), an auxiliary base (e.g. i-Pr 2 NEt, Et 3 N, pyridine, collidine) in solvents like CH 2 Cl 2 , DMF, pyridine. Benzotriazole-based coupling reagents and carbodiimides can be used together with suitable auxiliary reagents HOBt or HOAt.
Hydroxybiaryl/heteroaryl carboxylic acids H—X-A B -A C -CO 2 H do not necessarily require protection of the phenolic OH-group and can directly be coupled with the H—NR 7 -c1-CO—OPG 2 to the free phenol derivative H—X-A B -A C -CONR 7 -c1-CO—OPG 2 .
As an alternative, the amidation can also be accomplished with the corresponding acid derivatives like acid chlorides, anhydrides, or active esters.
Deprotection of Aromatic Hydroxy or Mercapto Groups (Steps b1, b5)
Deacylation of PG 1 -X-A B -A C -CONR 7 -c1-CO—OPG 2 or PG 1 -X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 to the corresponding free hydroxyl or mercapto aryl/heteroaryl amide H—X-A B -A C -CONR 7 -c1-CO—OPG 2 or H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 is achieved by aminolysis, which is advantageously carried out with a dialkylaminoalkyl amine in solvents like degassed THF at 0-25° C. Acyl amine side products formed in the course of the reaction are easily removed by extraction with acidic aqueous solutions.
Arylether or Arylthioether Formation Between A and B (Steps c1, a3, c5)
Alkylation of the phenol or thiophenol like H—X-A B -A C -Y-Z-c1-CO—OPG 2 , H—X-A B -A C -CO—OPG 4 , or H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 with a suitably N-protected amino alcohol PG 3 -B-OH to the ether or thioether PG 3 -B-X-A B -A C -Y-Z-c1-CO—OPG 2 , PG 3 -B-X-A B -A C -CO—OPG 4 , or PG 3 -B-X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 is accomplished with azodicarboxylic acid derivatives such as DEAD, DIAD, TMAD or ADDP in the presence of trialkyl or triaryl phosphines in solvents like benzene, toluene, CH 2 Cl 2 , CHCl 3 or THF at 0° C. to room temperature. As a variation, the reaction is performed with CMBP in toluene at temperatures of 20-110° C.
In an alternative approach, the alcohol PG 3 -B-OH is converted into the corresponding sulfonate (e.g. mesylate, tosylate or triflate) or halide (e.g. chloride, bromide or iodide) and subsequently treated with the phenol/thiophenol H—X-A B -A C -CO—OPG 4 in the presence of an auxiliary base such as NaH or K 2 CO 3 in solvents like DMF, DMSO, NMP, HMPA, or THF, to yield PG 3 -B-X-A B -A C -CO—OPG 4 .
Cleavage of the Main Chain Protective Groups (Step d1)
Simultaneous or stepwise cleavage of the main chain protective groups provides the linear amino acids as cyclization precursors. The preferred protecting groups are Alloc as PG 3 and/or allylester as PG 2 , which can be cleaved simultaneously by palladium catalysts (e.g. Pd(PPh 3 ) 4 ) in the presence of 1,3-dimethyl barbituric acid in solvents like CH 2 Cl 2 or EtOAc or mixtures thereof.
Also applied were Boc as PG 3 and methyl, ethyl or tert-butyl ester as PG 2 . Boc and groups and t-Bu esters are cleaved either with TFA in CH 2 Cl 2 or with HCl-dioxane. Methyl or ethyl esters are best saponified with aq. LiOH in mixtures of MeOH and THF.
Macrolactamization (Steps e1, f4)
Macrolactamization occurs upon treatment of the cyclization precursor with coupling reagents like T3P or FDPP (if required in the presence of an auxiliary base such as i-Pr 2 NEt) in solvents like CH 2 Cl 2 or DMF under high dilution conditions and at temperatures ranging from 20 to 100° C.
Due to their synthetic importance, macrolactamizations are a well-investigated class of transformations. The favorable application of FDPP as cyclization mediator is described e.g. by J. Dudash et al., Synth. Commun. 1993, 23, 349-356; and R. Samy et al., J. Org. Chem. 1999, 64, 2711-2728. Many other coupling reagents were successfully utilized in related head to tail cyclizations and might be applied instead; examples include benzotriazole derivatives like HBTU, HCTU, PyBOP; or their aza analogs such as HATU, as well as DPPA, and carbodiimides like EDC or DIC (P. Li, P. P. Roller, Curr. Top. Med. Chem. 2002, 2, 325-341; D. L. Boger et al., J. Am. Chem. Soc. 1999, 121, 10004-10011). Still another route to macrolactams relies on the intramolecular reaction of an active ester with an in situ released amino group (e.g. by carbamate deprotection or azide reduction) as demonstrated in the synthesis of peptide alkaloids and vancomycin model systems (U. Schmidt et al., J. Org. Chem. 1982, 47, 3261-3264; K. C. Nicolaou et al., Chem. Commun. 1997, 1899-1900).
Ring-Closing Metathesis (RCM) (Step f5)
Ring-closing metathesis (RCM) of olefinic precursors to macrocyclic compounds is well documented (e.g. A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811-4820) and supplements the macrocyclization strategies described above.
The ring-closing metathesis is conveniently performed in solvents like CH 2 Cl 2 or toluene at temperatures of 20-100° C. in the presence of indenylidene-ruthenium complexes such as [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(II); dichloro-(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexyl-phosphine)-ruthenium(II); [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene(tri-cyclohexylphosphine)-ruthenium(II); or [1,3-bis(2,4,6-tri-methylphenyl)-2-imidazolidinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene)(pyridyl)ruthenium(II) (S. Monsaert et al., Eur. J. Inorg. Chem. 2008, 432-440 and references cited therein).
In addition to ring closing transformations described above, biaryl coupling reactions such as intramolecular Suzuki coupling and Suzuki-Miyaura conditions have been applied to prepare macrocyclic compounds with biaryl motifs (M. Kaiser et al., Org. Lett. 2003, 5, 3435-3437; R. Lépine et al., Org. Lett. 2005, 7, 2981-2984).
The coupling of arylboronato-carboxylic acids to amines is also described (cf ref. above, M. Kaiser et al., R. Lépine et al.); therefore the synthesis of linear precursors Hal-A B -X-B—CO-c1-NR 7 —CO-A C -B(OR) 2 (Hal represents a halogen atom or a triflate, B(OR) 2 a boronic acid or boronic ester functionality) an their cyclization in a Pd-catalyzed coupling reaction is a feasible alternative.
General Procedures for Synthetic Steps in SW-4
Synthesis of Linear Cyclization Precursors on Solid Support (Steps a4 to e4)
Chlorotrityl resins are frequently used in solid phase peptide synthesis. Therefore, attachment of Fmoc- or Alloc-protected amino acids to these resins as well as subsequent deprotection steps and coupling/deprotection of additional amino acids are well described (K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520; K. Barlos et al., Angew. Chem. Int. Ed. 1991, 30, 590-593). For the examples of the present invention, chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB) is treated with an N-terminally Fmoc-protected amino acid in CH 2 Cl 2 in the presence of an auxiliary base like i-Pr 2 NEt. Fmoc deprotection (DBU, DMF) and coupling/deprotection of Fmoc- or Alloc-protected amino acids provides a linear, N-terminally deprotected cyclization precursor, still attached to the resin. Fmoc- or Alloc-protected amino acids are coupled in the presence of reagents like HATU or PyBOP in DMF in the presence of i-Pr 2 NEt. Alloc protective groups were removed by treatment of the carbamate with Pd(PPh 3 ) 4 and phenylsilane in CH 2 Cl 2 . The linear cyclization precursor is then released by treatment of the resin with HFIP in CH 2 Cl 2 (R. Bollhagen et al. J. Chem. Soc. Chem. Commun. 1994, 2559-2560). It is well known, that peptides can also be cleaved from the resin using TFA in CH 2 Cl 2 or mixtures of acetic acid, 2,2,2-trifluoroethanol and CH 2 Cl 2 (K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520). The subsequent macrolactaminzation step is described above.
SW-6: Synthesis Workflow for Derivatizations of Attachment Points in Solution
The macrocyclic compounds obtained according to SW-1 to SW-3 and SW-5 can be further modified by transformations involving functional groups like, but not limited to, amino, carboxyl or hydroxyl groups. In addition, aromatic halides or sulfonates can be subjected to transition-metal catalyzed C—C or C-heteroatom-coupling reactions. The orthogonal protection of the attachment points allows stepwise deprotections and derivatizations which are carried out in a parallel fashion to generate substance libraries:
a6) Cleavage of the first protective group;
b6) Derivatization of the unmasked functional group;
c6) Cleavage of the second protective group;
d6) Derivatization of the liberated functional group; etc.
General Procedures for Synthetic Steps Utilized in SW-6
Protecting Group Cleavage (Steps a6 and c6)
The utilized amine protecting groups (e.g. Boc, Cbz, Teoc, Alloc, Fmoc, etc.), carboxylic acid protecting groups (e.g. tert-butyl, benzyl, allyl, methyl, etc.) or alcohol protecting groups (e.g. tert-butyl, benzyl, allyl, acetyl, benzoyl, pivaloyl) are removed under standard conditions (P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006; P. J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005).
Aryl nitro groups are reduced to anilines.
Attachment Point Derivatizations (Steps b6 and d6)
Derivatizations of the liberated functional groups are based on standard synthesis procedures (A. R. Katritzky et al. (eds), Comprehensive Functional Group Transformations , Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups , Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; leading reviews for Mitsunobu reaction: O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. Reactions ; Wiley, 1992, Vol. 42; leading reviews for reductive amination/alkylation: A. F. Abdel-Magid et al., J. Org. Chem. 1996, 61, 3849; E. W. Baxter, A. B. Reitz, Org. Reactions , Wiley, 2002, Vol. 59).
Such prototypical transformations include, but are not limited to:
(i) Amino group derivatizations such as
Amidations with carbonyl chlorides, carboxylic acid anhydrides, active esters; or with carboxylic acids in the presence of coupling reagents (cf. the general procedures);
Formation of sulfonamides with sulfonyl chlorides;
Reductive alkylation with carbonyl compounds; or alkylation with alkyl halides, alkylsulfonates or Michael acceptors;
Formation of ureas by reacting with isocyanates or their equivalents like carbamoyl chlorides or hydroxysuccinimidyl esters;
Transformation into thioureas with isothiocyanates or their equivalents;
Carbamate formation by reacting with chloroformates or their surrogates such as hydroxysuccinimidyl carbonates;
N-arylation to the corresponding N-aryl or N-heteroaryl derivatives with activated aromatic or heteroaromatic halides or sulfonates in the presence of an auxiliary base and/or transition metal catalyst like Pd or Cu catalyst (e.g. Buchwald-Hartwig coupling).
(ii) Carboxyl group derivatizations like
Amidation with amines in the presence of a coupling reagent;
Esterification with alcohols.
Reduction to alcohols (also obtained by reduction of the corresponding esters)
(iii) Alcoholic hydroxyl group derivatizations such as
Alkylation to alkyl ethers with alkyl halides or alkylsulfonates, trialkyloxonium tetrafluoroborates;
Transformation into aryl or heteroaryl ethers by reaction with (a) phenols in the presence of azodicarboxylic acid derivatives and triaryl or trialkyl phosphines (Mitsunobu type reactions); or (b) suitably activated aryl or heteroaryl halides or sulfonates;
Conversion into carbamates by reaction with isocyanates;
Conversion into primary amines (obtained e.g. by hydrogenation of azides, which in turn are prepared by the reaction of an alcohol with DPPA, PPh 3 , and DEAD) and derivatization of these amines as described above;
Oxidation to carbonyl compounds, which in turn can be further elaborated by e.g. reductive amination, Wittig reaction or related olefination reactions, etc.;
Esterification with carboxylic acids or their activated surrogates.
(iv) Aryl halide or sulfonate derivatizations by e.g. Suzuki, Sonogashira, Buchwald, Negishi or Kumada coupling reactions etc.
SW-7: Synthesis Workflow for Derivatizations of Functional Groups at the Solid Phase
As a possible alternative to SW-6, macrocyclic compounds I with one or more orthogonally protected exocyclic functional groups and one free primary amino group can be converted into fully derivatized products on solid support as previously described for related macrocyclic compounds (WO2011/014973) by:
a7) Attachment of the macrocyclic amine to an appropriately functionalized solid support by reductive amination;
b7) Acylation, carbamoylation, or sulfonylation, of the secondary amine functionality generated in the previous step a7 or conversion of this secondary amine functionality into carbamates;
c7) Removal of the protecting group from the second attachment point;
d7) Derivatization of the liberated second functional group whereby e.g. amino groups can be alkylated or converted into amides, ureas, thioureas carbamates, or sulfonamides; and carboxylic acid moieties can be transformed into amides or esters;
e7) Repetitions of steps c7 and d7 if a third, fourth etc. attachment point is available;
f7) Release of the final product from the solid support.
In case of macrocyclic carboxylic acids the attachment to a polymer-supported amine is followed by derivatizations and release in analogy to c7 to f7:
a8) Attachment of an amine to an appropriately functionalized solid support by reductive amination;
b8) Coupling of the macrocyclic carboxylic acid to the polymer-supported amine of step a8;
c8-f8) Derivatizations and release in analogy to steps c7-f7.
General Procedures for Synthetic Steps Utilized in SW-7
The Functionalized Solid Support
The solid support (polymer, resin) is preferably a derivative of polystyrene cross-linked with 1-5% divinylbenzene, of polystyrene coated with polyethyleneglycol (Tentagel™), or of polyacrylamide (D. Obrecht, J.-M. Villalgordo, Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998). It is functionalized by means of a linker, i.e. an α,ω-bifunctional spacer molecule with an anchoring group for the solid support on one end, and on the other end by means of a selectively cleavable functional group that is used for subsequent transformations and finally for release of the product. For the examples of the present invention linkers are used that release an N-acyl (amide, urea, carbamate) or an N-sulfonyl (sulfonamide) derivative under acidic conditions. These kinds of linkers have been applied in the backbone amide linker (BAL) strategy for solid-phase synthesis of linear and cyclic peptides (K. J. Jensen et al., J. Am. Chem. Soc. 1998, 120, 5441-5452; J. Alsina et al., Chem. Eur. J. 1999, 5, 2787-2795) and heterocyclic compounds as well (T. F. Herpin et al., J. Comb. Chem. 2000, 2, 513-521; M. del Fresno et al., Tetrahedron Lett. 1998, 39, 2639-2642; N. S. Gray et al., Tetrahedron Lett. 1997, 38, 1161-1164).
Examples of such functionalized resins include DFPE polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene), DFPEM polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene), FMPB resins (4-(4-formyl-3-methoxy-phenoxy)butyryl AM-resin), FMPE polystyrene HL (2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL), FMPB NovaGel™ (4-(4-formyl-3-methoxyphenoxy)butyryl NovaGel; a PEG PS resin).
Attachment of the Macrocyclic Amine to the Functionalized Resin (Steps a7 and b7) and Subsequent N-Acylation or N-Sulfonylation
The macrocyclic primary amine is attached to the functionalized solid support by reductive amination preferably with NaBH(OAc) 3 as reducing agent in 1,2-dichloroethane and in the presence of trimethyl orthoformate or i-Pr 2 NEt.
The use of reductive aminations for such processes as well as the subsequent N-acylation or N-sulfonylation are well-documented; for example NaBH 3 CN in DMF or in methanol, or NaBH(OAc) 3 in DMF/acetic acid or in dichloromethane/acetic acid have been used (cf. references cited for the functionalized solid support). The N-acylation is favorably conducted with carboxylic acids in the presence of coupling reagents like PyBOP, PyBroP, or HATU or with carboxylic acid fluorides/chlorides or carboxylic acid anhydrides.
Deprotection (steps c7)
The second attachment point is an Alloc or Fmoc protected amino group or a carboxyl group protected as allyl ester. Standard methods (cf. SW-6) are applied for their deprotection and derivatization.
Release from the Resin (Step f7)
The final products are detached from the solid support by acids dissolved in organic solvents and/or H 2 O. The use of TFA in dichloromethane, of TFA in dichloromethane in the presence of a scavenger such as H 2 O or dimethyl sulfide, or of TFA/H 2 O and TFA/H 2 O/dimethylsulfide has been described (cf. references cited for the functionalized solid support).
Attachment of the Macrocyclic Carboxylic Acid to the Functionalized Resin (Steps a8 and b8)
A primary amine is attached to the functionalized solid support by reductive amination preferably using NaBH(OAc) 3 in 1,2-dichloroethane in the presence of trimethyl orthoformate.
Subsequent acylation with the macrocyclic carboxylic acids is favorably conducted in the presence of coupling reagents like HATU, PyBOP, or PyBroP.
It is worth mentioning that the initially attached primary amine corresponds to an attachment point derivatization of the carboxylic acid.
Properties and Usefulness
The macrocycles of type I of the present invention interact with specific biological targets. In particular, they show i) inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1), ii) inhibitory activity on the cysteine protease cathepsin S (CatS), iii) antagonistic activity on the oxytocin (OT) receptor), iv) antagonistic activity on the thyrotropin-releasing hormone (TRH) receptor), v) agonistic activity on the bombesin 3 (BB3) receptor, vi) antagonistic activity on the leukotriene B4 (LTB4) receptor, and/or vii) antimicrobial activity against at least one bacterial strain, in particular Staphylococcus aureus or Streptococcus pneumoniae.
Accordingly, these compounds are useful for the prevention or treatment of i) diseases resulting from abnormally high plasma or tissue levels of the potent vasoconstrictive peptide endothelin-1 (ET-1), like systemic and pulmonary hypertension, cerebral vasospasm and stroke, asthma, cardiac and renal failure, atherosclerosis, preeclampsia, benign prostatic hyperplasia, and carcinogenesis (S. De Lombaert et al., J. Med. Chem. 2000, 43, 488-504); ii) a wide range of diseases related to Cathepsin S, including neuropathic hyperalgesia, obesity, and in particular diseases of the immune system, like rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis, transplant rejection, diabetes, Sjøgrens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, and chronic obstructive pulmonary disease (COPD) (O. Irie et al., J. Med. Chem. 2008, 51, 5502-5505; WO2009/1112826); iii) diseases and conditions associated to an overexpression of oxytocin (OT), like preterm delivery (P. D. Williams, D. J. Pettibone, Curr. Pharm. Des. 1996, 2, 41-58; A. D. Borthwick, J. Med. Chem. 2010, 53, 6525-6538); iv) diseases related to a dysfunction in the homoestatic system of the thyrotropin-releasing hormone (TRH), such as infantile spasms, generalized and refractory partial seizures, edematous and destructive forms of acute pancreatitis, and certain inflammatory disorders (e.g. autoimmune diseases, inflammatory bowel diseases, cancer-related fatigue or depression, and Alzheimer's disease) (P.-Y. Deng et al., J. Physiol. 2006, 497-511; J. Kamath et al., Pharmacol. Ther. 2009, 121, 20-28); v) diseases related to a dysfunction of the bombesin 3 (BB3) receptor, like obesity and impairment of glucose metabolism, disorders of lung development, pulmonary diseases, CNS disorders and carcinogenesis (R. T. Jensen, Pharmacol. Rev. 2008, 60, 1-42); vi) diseases potentially treatable by blockade of the leukotriene B4 (LTB4) receptor, especially inflammatory and allergic diseases like asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, obliterative bronchiolitis after lung transplantation, or interstitial lung diseases (R. A. Goodnow, Jr., et al., J. Med. Chem. 2010, 53, 3502-3516; E. W. Gelfand et al., H. Ohnishi et., Allergol. Int. 2008, 57, 291-298); and/or vii) a wide range of infections caused by microorganisms, in particular strains of Staphylococcus aureus or Streptococcus pneumonia , comprising infections related to: a) respiratory diseases like cystic fibrosis, emphysema, asthma or pneumonia, b) skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles, c) gastrointestinal diseases including epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis, d) eye diseases such as keratitis and endophthalmitis, e) ear diseases, e.g. otitis, f) CNS diseases including brain abscess and meningitis or encephalitis, g) bone diseases such as osteochondritis and osteomyelitis, h) cardiovascular diseases like endocartitis and pericarditis, or i) genitourinal diseases such as epididymitis, prostatitis and urethritis (R. P. Rennie, Handb. Exp. Pharmacol. 2012, 211, 45-65; W. Bereket et al., Eur. Rev. Med. Pharmacol. Sci. 2012, 16, 1039-1044; D. P. Calfee, Curr. Opin. Infect. Dis. 2012, 25, 385-394). Additional uses of antimicrobial macrocycles of type I comprise the treatment or prevention of microbial infections in plants and animals or as disinfectants or preservatives for materials such as foodstuff, cosmetics, medicaments and other nutrient-containing materials.
The macrocycles, as such or after further optimization, may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well-known in the art.
When used to treat or prevent the diseases mentioned above the macrocycles can be administered singly, as mixtures of several macrocycles, or in combination with other pharmaceutically active agents. The macrocycles can be administered per se or as pharmaceutical compositions.
Pharmaceutical compositions comprising macrocycles of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active macrocycles into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
For topical administration the macrocycles of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
For injections, the macrocycles of type I may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the macrocycles of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
For oral administration, the compounds can be readily formulated per se or by combining the active macrocycles of the invention with pharmaceutically acceptable carriers well known in the art. Such carriers enable the macrocycles of type I to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, (e.g. lactose, sucrose, mannitol or sorbitol) or such as cellulose preparations (e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose); and/or granulating agents; and/or binding agents such as polyvinylpyrrolidone (PVP). If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. Solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.
For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.
For administration by inhalation, the macrocycles of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. hydrofluoroalkanes (HFA) such as HFA 134a (1,1,1,2,-tetrafluoroethane); carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocycles of the invention and a suitable powder base such as lactose or starch.
The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases like cocoa butter or other glycerides.
In addition to the formulations described above, the macrocycles of the invention may also be formulated as depot preparations. Such slow release, long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the macrocycles of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble salts.
Furthermore, other pharmaceutical delivery systems may be employed such as liposomes and emulsions. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the macrocycles of type I may be delivered using a sustained-release system, such as semi-permeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well-known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds over a period of a few days up to several months. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for stabilization may be employed.
As the macrocycles of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base or acid forms.
The macrocycles of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is understood that the amount used will depend on a particular application.
For example, the therapeutically effective dose for systemic administration can be estimated initially from in vitro assays: A dose can be formulated in animal models to achieve a circulating macrocycle concentration range that includes the IC 50 or EC 50 as determined in the cell culture (i.e. the concentration of a test compound that shows half maximal inhibitory concentration in case of antagonists or half maximal effective concentration in case agonists). Such information can be used to more accurately determine useful doses in humans.
Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art.
Dosage amounts for applications such as gastroparesis or schizophrenia etc. may be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.
In cases of local administration or selective uptake, the effective local concentration of the macrocycles of the invention may not be related to plasma concentration.
Those having the ordinary skill in the art will be able to optimize therapeutically effective dosages without undue experimentation.
The amount of macrocycle administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the method of administration and the judgment of the prescribing physician.
Normally, a therapeutically effective dose of the macrocycles described herein will provide therapeutic benefit without causing substantial toxicity.
Toxicity of the macrocycles can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LD 100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the macrocycles of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form and the route of administration. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (cf. E. Fingl et al. in L. Goodman und A. Gilman (eds), The Pharmacological Basis of Therapeutics, 5 th ed. 1975, Ch. 1, p. 1).
Another embodiment of the present invention may also include compounds, which are identical to the compounds of formula I, except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2 H (D), 3 H, 11 C, 14 C, 125 I etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and/or diagnostics, for example, but not limited to, fine-tuning of in vivo half-life.
EXAMPLES
The following examples illustrate the invention in more detail but are not intended to limit its scope in any way. Before specific examples are described in detail the used abbreviations and applied general methods are listed.
Ac: acetyl
addn: addition
ADDP: azodicarboxylic dipiperidide
Alloc: allyloxycarbonyl
AllocCl: allyl chloroformate
AllocOSu: allyloxycarbonyl-N-hydroxysuccinimide
AM-resin: aminomethyl resin
AM-PS: aminomethyl polystyrene
aq.: aqueous
arom.: aromatic
Bn: benzyl
BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
Boc: tert-butoxycarbonyl
br.: broad
Cbz: benzyloxycarbonyl
CbzCl: benzyl chloroformate
CbzOSu: N-(benzyloxycarbonyloxy)succinimide
Cl-HOBt: 6-chloro-1-hydroxybenzotriazole
CMBP: cyanomethylenetributyl-phosphorane
m-CPBA: 3-chloroperbenzoic acid
d: day(s) or doublet (spectral)
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCE: 1,2-dichloroethane
DEAD: diethyl azodicarboxylate
DFPE polystyrene: 2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene
DIAD: diisopropyl azodicarboxylate
DIC: N,N′-diisopropylcarbodiimide
DMAP: 4-(dimethylamino)pyridine
DME: 1,2-dimethoxyethane
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
DPPA: diphenyl phosphoryl azide
DVB: divinylbenzene
EDC: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
equiv.: equivalent
Et: ethyl
Et 3 N: triethylamine
Et 2 O: diethyl ether
EtOAc: ethyl acetate
EtOH: ethanol
exp.: experimental
FC: flash chromatography
FDPP: pentafluorophenyl diphenylphosphinate
FI-MS: flow injection mass spectrometry
Fmoc: 9-fluorenylmethoxycarbonyl
Fmoc-Cl: Fmoc chloride, 9-fluorenylmethyl chloroformate
Fmoc-OSu: (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (or 9-fluorenylmethyl-succinimidyl carbonate)
h: hour(s)
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
HBTU: O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
mCPBA: 3-chloroperbenzoic acid
HCTU: O-(6-chlorobenoztriazol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate
HFIP: Hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol)
HL: high loading
HOAt: 1-hydroxy-7-azabenzotriazole
HOBt.H 2 O: 1-hydroxybenzotriazole hydrate
HMPA: hexamethylphosphoramide
i.v.: in vacuo
m: multiplet (spectral)
MeCN: acetonitrile
MeOH: methanol
Me: methyl
NMP: 1-methyl-2-pyrrolidinone
Ns: 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl
PdCl 2 (PPh 3 ) 2 : bis(triphenylphosphine)palladium (II) dichloride
Pd(dppf)Cl 2 .CH 2 Cl 2 : [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane
Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium(0)
PEG PS resin: polyethyleneglycol coated polystyrene resin
PG: protective group
Ph: phenyl
PPh 3 : triphenylphosphine
prep.: preparative
i-Pr: isopropyl
i-Pr 2 NEt: N-ethyl-N,N-diisopropylamine
i-PrOH: isopropanol
PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
PyBroP: bromotripyrrolidinophosphonium hexafluorophosphate
PyClu: N,N,N′,N′-bis-(tetramethylene)-chloroforamidinium hexafluorophosphate
q: quartet (spectral)
quant.: quantitative
quint: quintet (spectral)
rt: room temperature
s: singlet (spectral)
sat.: saturated
soln: solution
TBAF: tetrabutylammonium fluoride
t: triplet (spectral)
Teoc: 2-(trimethylsilyl)ethoxycarbonyl
tert.: tertiary
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TLC: thin layer chromatography
TMAD: tetramethylazodicarboxamide
T3P=T3P™: propanephosphonic acid cyclic anhydride
p-TsOH: p-toluenesulfonic acid
Umicore M72 SIMes (RD): [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(II)
General Methods
TLC: Merck (silica gel 60 F254, 0.25 mm).
Flash chromatography (FC): Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm).
I. Analytical HPLC-MS methods:
R t in min (purity at 220 nm in %), m/z [M+H] +
UV wave length 220 nm, 254 nm
MS: Electrospray Ionization
Volume of injection: 5 μL
Method 1
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 3×50 mm (53811U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 1a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 1b: MS scan range: 95-800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 1c: MS scan range: 95-1800 Da; centroid mode, positive mode 20V, scan time: 1 sec
Method 1d: MS scan range: 95-1800 Da; profile mode, positive mode 40V, scan time: 1 sec
Method 1e: MS scan range: 95-1800 Da; profile mode, positive mode 80V, scan time: 1 sec
Method 1f: MS scan range: 95-1800 Da; profile mode, positive mode 20V, scan time: 1 sec
Method 1g: MS scan range: 95-1800 Da; centroid mode, positive mode 80V, scan time: 1 sec
Method 2
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 3×50 mm (53811U—Supelco Inc.)
Mobile Phases: A: Ammonium Bicarbonate 1 mM in Water—pH=10 in Water; B: MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 2a: MS scan range: 95-800 Da; centroid mode, negative mode 40V scan time: 1 sec
Method 2b: MS scan range: 95-1800 Da; centroid mode, negative mode 40V scan time: 1 sec
Method 2c: MS scan range: 95-1800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 2d: MS scan range: 95-1800 Da; centroid mode, positive mode 20V scan time: 1 sec
Method 2e: MS scan range: 95-800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 2f: MS scan range: 95-1800 Da; profile mode, positive mode 40V scan time: 1 sec
Method 3
LC-MS: Dionex Ultimate 3000 RS (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 2.1×50 mm (53822-U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.4 97 3 0.05 1.4 97 3 1.95 1.4 3 97 2.15 1.4 3 97 2.18 1.4 97 3 2.3 1.4 97 3
Method 3a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 3b: MS scan range: 95-1800 Da; profile mode, positive mode 40V scan time: 1 sec
Method 4
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ F5 2.7 μm, 3×50 mm (53576-U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Method 4a and method 4b
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 70 30 0.05 1.3 70 30 2.95 1.3 30 97 3.15 1.3 30 97 3.17 1.3 70 30 3.2 1.3 70 30
Method 4a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 4b: MS scan range: 95-1800 Da; profile mode, positive mode 40V, scan time: 1 sec
Method 4c
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 4c: MS scan range: 95-1800 Da; centroid mode, positive mode 20V, scan time: 1 sec
Method 5
LC-MS: Agilent HP1100 (DAD detector)
Column: Atlantis™ T3 3 μm, 2.1×50 mm (186003717—Waters AG)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 0.8 100 0 0.1 0.8 100 0 2.9 0.8 50 50 2.95 0.8 3 97 3.2 0.8 3 97 3.22 0.8 100 100 3.3 0.8 100 100
Method 5a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
II. Preparative HPLC methods:
1. Reverse Phase—Acidic Conditions
Method 1a
Column: XBridge™ C18 5 μm, 30×150 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1b
Column: XBridge™ C18 5 μm, 30×100 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1c
Column: Gemini-NX™ C18 5 μm, 30×100 mm (Phenomenex Inc.)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1d
Column: XBridge™ Prep C18 10 μm, 50×250 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: Acetonitrile
Flow rate: 150 mL/min
2. Reverse Phase—Basic conditions
Method 2a
Column: XBridge™ C18 5 μm, 30×150 mm (Waters AG)
Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v
B: Acetonitrile
Method 2b
Column: XBridge™ C18 5 μm, 30×100 mm (Waters AG)
Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v
B: Acetonitrile
3. Normal Phase
Method 3
Column: VP 100/21 NUCLEOSIL™ 50-10, 21×100 mm (Macherey-Nagel AG)
Mobile phases:
A: Hexane B: Ethylacetate C: Methanol
FI-MS: Agilent HP1100; m/z [M+H] +
NMR Spectroscopy: Bruker Avance 300, 1 H-NMR (300 MHz) in the indicated solvent at ambient temperature. Chemical shifts δ in ppm, coupling constants J in Hz.
SPECIFIC EXAMPLES
In the examples below and if no other sources are cited, leading reference for standard conditions of protecting group manipulations (protection and deprotection) are 1) P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006; 2) P. J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005; and 3) M. Goodman (ed.), Methods of Organic Chemistry (Houben-Weyl), Vol E22a, Synthesis of Peptides and Peptidomimetics, Georg Thieme Verlag 2004.
Starting Materials
Template A Building Blocks (Scheme 5):
3′-Hydroxybiphenyl-2-carboxylic acid (1) is commercially available.
Methyl 3′-hydroxybiphenyl-2-carboxylate (2)
Thionyl chloride (7.7 mL, 105 mmol) was added at 0° C. to a soln of 1 (4.5 g, 21.0 mmol) in MeOH (55 mL). The mixture was stirred for 10 min at 0° C. and then heated to reflux for 4 h. Evaporation of the volatiles, aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 5:1) afforded the ester 2 (4.34 g, 90%).
Data of 2: C 14 H 12 O 3 (228.2). 1 H-NMR (DMSO-d 6 ): 9.52 (br. s, OH); 7.68 (dd, J=1.1, 7.6, 1H); 7.59 (dt, J=1.5, 7.6, 1H); 7.47 (dt, J=1.3, 7.5, 1H); 7.40 (dd, J=0.9, 7.6, 1H); 7.20 (t-like m, J=8.0, 1H); 6.75 (m, 1H); 6.70-6.67 (m, 2H); 3.59 (s, 3H).
2′-Hydroxybiphenyl-3-carboxylic acid (3) is commercially available.
Methyl 2′-hydroxybiphenyl-3-carboxylate (4)
Thionyl chloride (6.8 mL, 93 mmol) was added at 0° C. to a soln of 3 (4.0 g, 18.6 mmol) in MeOH (60 mL). The mixture was stirred for 10 min at 0° C. and then heated to reflux for 3 h. Evaporation of the volatiles and aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded the ester 4 (3.68 g, 86%).
Data of 4: C 14 H 12 O 3 (228.2). LC-MS (method 2a): R t =1.95 (98), 226.9 ([M−H] − ). 1 H-NMR (DMSO-d 6 ): 9.66 (s, 1H); 8.16 (t, J=1.6, 1H); 7.89 (d-like m, 1H); 7.81 (d-like m, 1H); 7.56 (t, J=7.7, 1H); 7.29 (dd, J=1.7, 7.6, 1H); 7.20 (t-like m, 1H); 6.98-6.88 (m, 2H); 3.87 (s, 3H).
2′-Hydroxy-5′-methoxybiphenyl-3-carboxylic acid (5) is commercially available.
Methyl 2′-hydroxy-5′-methoxybiphenyl-3-carboxylate (6)
Thionyl chloride (5.14 mL, 71 mmol) was added at 0° C. to a soln of 5 (5.74 g, 23.5 mmol) in MeOH (100 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 4:1) afforded the ester 6 (5.1 g, 84%).
Data of 6: C 15 H 14 O 4 (258.3). 1 H-NMR (DMSO-d 6 ): 9.18 (s, OH); 8.17 (t, J=1.7, 1H); 7.89 (td, J=1.4, 7.8, 1H); 7.82 (td, J=1.5, 8.0, 1H); 7.56 (t, J=7.8, 1H); 6.91-6.78 (m, 3H); 3.87 (s, 3H); 3.72 (s, 3H).
3′-Hydroxybiphenyl-3-carboxylic acid (7) is commercially available.
Methyl 3′-hydroxybiphenyl-3-carboxylate (8)
Thionyl chloride (4.1 mL, 56 mmol) was added at 0° C. to a soln of 7 (4.0 g, 18.6 mmol) in MeOH (160 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, filtration of the residue through a pad of silica gel (EtOAc) and FC (hexane/EtOAc 93:7 to 0:100) afforded the ester 8 (4.0 g, 94%).
Data of 8: C 14 H 12 O 3 (228.2). LC-MS (method 2a): R t =1.90 (98), 227.3 ([M−H] − ). 1 H-NMR (DMSO-d 6 ): 9.63 (br. s, OH); 8.13 (t, J=1.6, 1H); 7.96-7.88 (m, 2H), 7.61 (t, J=7.7, 1H); 7.29 (t, J=7.8, 1H); 7.10 (m, 1H); 7.06 (t, J=2.0, 1H); 6.81 (m, 1H); 3.89 (s, 3H).
5-(3-Hydroxyphenyl)nicotinic acid (9) is commercially available.
5-(3-Acetoxyphenyl)nicotinic acid (10)
At 0° C. acetic anhydride (18.8 mL, 0.2 mol) was added dropwise to a soln of 5-(3-hydroxyphenyl)nicotinic acid (9; 7.13 g, 0.033 mol) in 4 M aq. NaOH soln (41.4 mL, 0.166 mol). The mixture was stirred for 1 h. A precipitate was formed. The mixture was diluted with 4 M aq. NaOH soln (41.4 mL, 0.166 mol). More acetic anhydride (18.8 mL, 0.2 mol) was added and stirring was continued for 2 h followed by the addition of H 2 O (50 mL). The mixture was acidified to pH 1 by addition of 3 M aq. HCl soln. The solid was filtered, washed (H 2 O) and dried i.v. to afford 10.HCl (8.22 g, 84%).
Data of 10.HCl: C 14 H 11 NO 4 .HCl (257.2, free base). LC-MS (method 1b): R t =1.22 (99), 258.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.62 (very br. s, 1H); 9.12 (d, J=2.0, 1H); 9.07 (d, J=1.3, 1H); 8.46 (s, 1H); 7.71 (d, J=7.7, 1H); 7.63 (s, 1H); 7.57 (t, J=7.9, 1H); 7.23 (d, J=8.0, 1H); 2.31 (s, 3H).
2-Bromothiophenol (11) is commercially available.
3-Hydroxyphenylboronic acid (12) is commercially available.
5-Bromopyridine-3-thiol (13) was prepared as described in the literature (S. A. Thomas et al. Bioorg. Med. Chem. Lett. 2006, 16, 3740-3744).
2-Hydroxyphenylboronic acid (14) is commercially available.
4-(3-Hydroxypyridin-2-yl)benzoic acid (92) is commercially available.
Methyl 4-(3-hydroxypyridin-2-yl)benzoate (93)
Thionyl chloride (7.6 mL, 104 mmol) was added at 4° C. to a soln of 92 (4.5 g, 21.0 mmol) in MeOH (130 mL). The mixture was heated to 70° C. for 14 h and concentrated. The residue was dissolved in CHCl 3 (200 mL) and EtOH (20 mL) and treated with aq. NaHCO 3 soln (100 mL). The organic phase was separated, the aq. phase was extracted repeatedly with CHCl 3 . The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated to afford the ester 93 (4.45 g, 92%).
Data of 93: C 13 H 11 NO 3 (229.2). LC-MS (method 1a): R t =1.07 (90), 230.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 10.40 (br. s, OH), 8.32-8.18 (m, 3H); 8.02 (d, J=8.6, 2 H), 7.38 (dd, J=1.4, 8.2, 1H); 7.26 (dd, J=4.4, 8.2, 1H); 3.88 (s, 3H).
4-(3-Fluoro-5-hydroxyphenyl)thiophene-2-carboxylic acid (98)
At rt, a solution of tert-butyl 2,2,2-trichloroacetimidate (27.7 mL, 155 mmol) in CH 2 Cl 2 (50 mL) was added dropwise to a soln of 4-bromothiophene-2-carboxylic acid (94; 16.0 g, 77.3 mmol) in CH 2 Cl 2 (150 mL). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%).
Sat. aq. NaHCO 3 soln (183 mL) was added to a soln of 95 (17.2 g, 65.2 mmol), 3-fluoro-5-hydroxyphenylboronic acid (96; 15.3 g, 97.9 mmol) and Pd(PPh 3 ) 4 (3.77 g, 3.26 mmol) in dioxane (517 mL). The mixture was heated to reflux for 2 h. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 90:10) afforded 97 (12.55 g, 65%).
TFA (150 mL) was added at rt to a mixture of 97 (12.5 g, 42.6 mmol) in CH 2 Cl 2 (150 mL). The soln was stirred for 2.5 h and concentrated to give 98 (10.3 g, quant. yield).
Data of 98: C 11 H 7 FO 3 S (238.2). 1 H-NMR (DMSO-d 6 ): 13.23 (br. s, 1H); 10.03 (br. s, 1H); 8.21 (d, J=1.6, 1H); 8.05 (d, J=1.6, 1H); 7.05 (m, 1H); 6.95 (t, J=1.7, 1H), 6.53 (td, J=2.2, 10.7, 1H).
3-(Allyloxy)-N-methoxy-N-methylthiophene-2-carboxamide (102)
At 0° C., allyl bromide (18.1 mL, 209 mmol) was added dropwise to a mixture of 3-hydroxythiophene-2-carboxylic acid (99; 10.0 g, 69.8 mmol) and K 2 CO 3 (48.2 g, 349 mmol) in DMF (255 mL). The mixture was allowed to stir for 2 h at 0° C. to rt. The mixture was filtered and the residue was washed with EtOAc. The filtrate was concentrated, followed by an aqueous workup (Et 20 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, H 2 O; Na 2 SO 4 ) to give ester 100 (15.5 g).
At rt, 2 M aq. LiOH soln (346 mL, 691 mmol) was added to a soln of the crude ester 100 (15.5 g) in DME (315 mL). The mixture was heated to 50° C. for 16 h and concentrated. The residue was distributed between H 2 O and EtOAc. The aqueous phase was acidified with 1 M aq. HCl soln and repeatedly extracted with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to afford the acid 101 (11.5 g, 90%).
At 5° C., i-Pr 2 NEt (42.3 mL, 249 mmol) was added dropwise to a mixture of 101 (11.45 g, 62.2 mmol), N,O-dimethylhydroxylamine hydrochloride (7.28 g, 74.6 mmol), EDC-HCl (14.3 g, 74.6 mmol), HOBt.H 2 O (11.4 g, 74.6 mmol) and DMAP (1.52 g, 12.4 mmol) in DMF (116 mL). The mixture was allowed to warm to rt over 5 h followed by an aqueous workup (EtOAc, 1 M aq. HCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1) to afford 102 (9.69 g, 69%).
Data of 102: C 10 H 13 NO 3 S (227.3). LC-MS (method 1c): R t =1.59 (92), 228.1 ([M+H] + ).
tert-Butyl 3-(3-hydroxythiophen-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (106)
n-Butyllithium (1.6 M in hexane; 41.9 mL, 67.0 mmol) was added dropwise within 10 min at −55 to −50° C. to a soln of tert-butyl propiolate (103; 8.76 mL, 63.8 mmol) in dry THF (200 mL). The mixture was allowed to stir at −40° C. for 1.5 h. The mixture was cooled to −78° C. A soln of 102 (7.25 g, 31 9 mmol) in THF (66 mL) was added within 10 min with the temperature not exceeding −64° C. The mixture was stirred for 0.5 h at −78° C., then warmed to −40° C. and allowed to slowly warm to 0° C. over 3 h. The mixture was poured into 1 M aq. KHSO 4 soln and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and concentrated. FC (hexane/EtOAc 90:10 to 70:30) afforded the ketone 104 (8.34 g, 89%).
Methylhydrazine (1.0 mL, 18.8 mmol) was added at rt to a soln of 104 (4.6 g, 16 mmol) in EtOH (62 mL). Stirring was continued for 1 h and the volatiles were evaporated. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 90:10) gave pyrazole 105 (4.25 g, 84%).
Data of 105: C 16 H 20 N 2 O 3 S (320.4). LC-MS (method 4a): R t =1.80 (96), 321.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.08 (s, 1H); 7.07 (d, J ca 5.9, 1H); 6.06 (m, 1H); 5.43 (qd, J=1.7, 17.3, 1H); 5.29 (qd, J=1.6, 10.6, 1H); 4.69 (td, J=1.6, 5.0, 2 H); 4.05 (s, 3H); 1.55 (s, 9H).
Phenylsilane (15.0 mL, 121 mmol) was added to a soln of 105 (7.75 g, 24 mmol) and Pd(PPh 3 ) 4 (1.4 g, 1.2 mmol) in THF (78 mL). The mixture was stirred at rt for 16 h. More Pd(PPh 3 ) 4 (0.8 g, 0.7 mmol) and phenylsilane (6.0 mL, 48 mmol) were added and stirring was continued for 24 h. The volatiles were evaporated followed by an aqueous workup (EtOAc, 1 M NH 4 Cl soln) and FC (hexane/EtOAc 90:10) to yield 106 (5.75 g, 84%).
Data of 106: C 13 H 16 N 2 O 3 S (280.3). LC-MS (method 1a): R t =2.40 (94), 281.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 10.01 (br. s, 1H); 7.24 (d, J=5.3, 1H); 7.04 (s, 1H); 6.72 (d, J=5.3, 1H); 4.04 (s, 3H); 1.55 (s, 9H).
2-(4-Hydroxy-3-nitrophenyl)-6-methylpyrimidine-4-carboxylic acid (110)
Sat. aq. Na 2 CO 3 soln (52.5 mL) was added to a soln of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (107; 5.0 g, 26.8 mmol), 4-methoxy-3-nitrophenylboronic acid (108; 6.86 g, 34.8 mmol) and PdCl 2 (PPh 3 ) 2 (0.94 g, 1.3 mmol) in dioxane (175 mL). The mixture was heated to reflux for 4 h and partially concentrated, followed by an aqueous workup (EtOAc, 1 M aq. HCl soln; sat. aq. NaCl soln; Na 2 SO 4 ). The crude product was suspended in CH 2 Cl 2 /MeOH 2:1; the solid was filtered, washed (MeOH) and dried i.v to afford 109.HCl (3.7 g, 42%). The filtrate was concentrated and purified by FC(CH 2 Cl 2 /MeOH 100:0 to 70:30) to give 109.HCl (3.87 g, 44%).
A mixture of 109.HCl (7.5 g, 23.1 mmol) and LiCl (4.9 g, 11.5 mmol) in DMF (100 mL) was heated to 145° C. for 18 h. The volatiles were mostly evaporated. The residue was cooled to 0° C. and treated with 1 M aq. HCl soln (250 mL). The resulting suspension was sonicated and filtered. The solid material was washed (Et 2 O) and dried. The solid material was suspended in CH 2 Cl 2 /Et 2 O 1:4, filtered and dried to give 110.HCl (6.5 g, 80%).
Data of 110.HCl: C 12 H 9 N 3 O 5 .HCl (free base, 275.2). LC-MS (method 1a): R t =1.73 (83), 276.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.91 (d, J=1.9, 1H); 8.56 (dd, J=1.9, 8.8, 1H); 7.80 (s, 1H); 7.30 (d, J=8.8, 1H); 2.63 (s, 3H).
2-Iodophenol (111) is commercially available.
2-(Ethoxycarbonyl)phenylboronic acid (112) is commercially available.
Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (113) is commercially available.
4-(3-Hydroxyphenyl)-2-(trifluoromethyl)oxazole-5-carboxylic acid (117)
The aminoacrylic acid ester 115 was prepared according to J. H. Lee et al, J. Org. Chem. 2007, 72, 10261.
The 2-(trifluoromethyl)oxazole 116 was prepared as described by F. Zhao et al. J. Org. Chem. 2011, 76, 10338 for similar compounds:
A degassed soln of 115 (2.15 g, 9.72 mmol) in DCE (500 mL) was warmed to 45° C. [Bis(trifluoroacetoxy)iodo]benzene (5.02 g, 11.67 mmol) was added in one portion, and stirring at 45° C. was continued for 16 h. Evaporation of the volatiles and FC (hexane/EtOAc 98:2) afforded 116 (1.55 g, 50%).
Data of 116: C 14 H 12 F 3 NO 4 (315.2). 1 H-NMR (DMSO-d 6 ): 7.62-7.57 (m, 2H); 7.45 (t, J=8.0, 1H); 7.11 (m, 1H); 4.38 (q, J=7.1, 2 H); 3.81 (s, 3H); 1.31 (t, J=7.1, 3 H). At 0° C., BBr 3 (1 M in THF; 24.2 mL, 24.2 mmol) was added dropwise to a soln of 116 (1.5 g, 4.85 mmol) in CH 2 Cl 2 (3.5 mL). The mixture was stirred for 16 h at 0° C. to rt, slowly added onto ice-cold water (500 mL) and extracted with EtOAc. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 75:25 to 0:100, then CH 2 Cl 2 /MeOH 90:10) afforded 117 (1.24 g, 95%).
Data of 117: C 11 H 6 F 3 NO 4 (273.2). 1 H-NMR (DMSO-d 6 ): 9.54 (br. s, 1H), 7.71-7.65 (m, 2H); 7.23 (t, J=7.9, 1H); 6.80 (m, 1H).
Modulator B Building Blocks (Scheme 6):
tert-Butyl (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (15.HCl) is commercially available.
(2S,4S)-Allyl 4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (16) was prepared by Alloc protection of the secondary amino group of 15.HCl with allyl chloroformate in CH 2 Cl 2 in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 16: C 14 H 24 N 2 O 5 (300.4). 1 H-NMR (DMSO-d 6 ): 7.12 (br. d, J=6.1, 1H); 5.91 (m, 1H); 5.27 (m, 1H); 5.18 (m, 1H); 4.49 (m, 2H); ca 3.9 (br. m, 1H); 3.89-3.57 (several m, 4H); 3.48 (dd, J=3.1, 10.6, 1H); 2.95 (br. m, 1H); 2.21 (br. m, 1H); 1.75 (br. m, 1H); 1.38 (s, 9H).
tert-Butyl (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (17.HCl) is commercially available.
(2S,4R)-Allyl 4-(tert-butoxycarbonylamino)-2-(hydroxylmethyl)-pyrrolidin-1-carboxylate (18) was prepared by Alloc protection of the secondary amino group of 17.HCl with allyl chloroformate in CH 2 Cl 2 in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 18: C 14 H 24 N 2 O 5 (300.4). 1 H-NMR (DMSO-d 6 ): 7.08 (br. d, J=7.1, 1H); 5.91 (m, 1H); 5.26 (br. m, 1H); 5.18 (br. d, J ca 10.4, 1H); 4.52 (br. m, 2H), ca 4.1 (br. m, 2H); 3.82 (br. m, 1H); ca 3.5-3.35 (br. s-like m, 3H); 3.19 (br. m, 1H); 2.05 (br. m, 1H); 1.79 (br. m, 1H); 1.38 (s, 9H).
N-Boc-L-alaninol (19) is commercially available.
N-Boc-D-alaninol (20) is commercially available.
(S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21) is commercially available.
(2S,4S)-Allyl 4-(4-bromobenzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (118) was prepared as described in the preceding patent application (WO 2011/014973 A2).
(S)-(+)-Prolinol (119) is commercially available.
(S)-Allyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (120) was prepared by Alloc protection of the secondary amino group of (S)-(+)-prolinol (119) with allyl chloroformate in dioxane in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 120: C 9 H 15 NO 3 (185.2). FI-MS: 186.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 5.92 (m, 1H); 5.28 (br. dd-like m, 1H); 5.18 (br. dd-like m, 1H); 4.72 (br. not resolved m, 1H); 4.60-4.45 (br. not resolved m, 2H); 3.73 (br. not resolved m, 1H); 3.50 (br. not resolved m, 1H); 3.35-3.25 (br. not resolved m, 3H); 2.0-1.75 (br. not resolved m, 4H).
(2S,4R)-tert-Butyl 4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate hydrochloride (121.HCl) is commercially available.
(2S,4R)-tert-Butyl 4-(benzyloxycarbonylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (122) was prepared by Cbz protection of the primary amino group of 121.HCl with benzyl chloroformate in CH 2 Cl 2 in the presence of aq. Na 2 CO 3 soln applying standard conditions.
Data of 122: C 18 H 26 N 2 O 5 (350.4). LC-MS (method 1c): R t =1.89 (95), 351.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.49 (d, J=6.8, 1H); 7.42-7.28 (m, 5H); 5.02 (s, 2H); 4.76 (br. s, 1H); 4.13 (br. not resolved m, 1H), 3.76 (br. not resolved m, 1H); 3.40 (m, 3 H; partially superimposed by H 2 O signal); 3.11 (dd; J=6.4, 10.6, 1H); 2.07 (br. not resolved m, 1H); 1.82 (br. not resolved m, 1H); 1.38 (s, 9H).
Building Blocks for Subunits of Bridge C (Scheme 7):
(R)-Allyl 4-amino-2-(benzyloxycarbonylamino)butanoate toluene-4-sulfonate (22.pTsOH) was prepared as described for the (S)-enantiomer in the preceding patent application (WO 2011/014973 A2).
(S)-Allyl 2-(benzyloxycarbonylamino)-(5-methylamino)pentanoate hydrochloride (23.HCl), (S)-5-allyl 1-benzyl 2-(methylamino)pentanedioate hydrochloride (24.HCl) and (S)-5-allyl 1-benzyl 2-aminopentanedioate hydrochloride (25.HCl) were prepared as described in the preceding patent application (WO 2011/014973 A2).
Ethyl 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (28.HCl)
Ethyl 2-(2-(tert-butoxycarbonylamino)ethylamino)acetate hydrochloride (26.HCl; 25.0 g, 88 mmol) was added to a mixture of dioxane (250 mL) and 1 M aq. Na 2 CO 3 soln (250 mL). After 5 min, CbzCl (17.0 g, 98 mmol) was slowly added and the mixture was stirred for 2 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 ; Na 2 SO 4 ) and FC (hexane/EtOAc 8:2 to 1:1) afforded 27 (29.0 g, 85%). A solution of 27 (29.5 g, 77.5 mmol) in 4 M HCl-dioxane (300 mL) was stirred at rt for 2 h and concentrated. The residue was washed with Et 2 O to give 28.HCl (24.3 g, 99%).
Data of 28.HCl: C 14 H 20 N 2 O 4 .HCl (280.3, free base). LC-MS (method 1a): R t =1.33 (99), 281.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.05 (br. s, NH 3 + ); 7.39-7.28 (m, 5 arom. H); 5.12, 5.07 (2 s; 2H); 4.16-4.04 (m, 4H); 3.54 (m, 2H); 2.97 (br m, 2H); 1.19, 1.32 (2 t, J=7.1, 3 H).
(S)-Methyl 2-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (30)
At 0° C., iodomethane (8.18 mL, 131 mmol) was added to a suspension of Boc-L-6-hydroxynorleucine (29; 25 g, 101 mmol) and NaHCO 3 (42.5 g, 505 mmol) in DMF (790 mL). The mixture was stirred at 0° C. to rt for 16 h. The mixture was filtered. The filtrate was distributed between EtOAc and 1 M aq. HCl soln. The organic layer was subsequently washed with H 2 O, sat. aq. NaHCO 3 soln and sat. aq. NaCl soln. The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated to afford 30 (24.54 g, 92%).
Data of 30: C 12 H 23 NO 5 (261.3). FI-MS: 262.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.21 (d, J=7.8, 1H); 4.36 (t, J=5.2, 1H); 3.92 (m, 1H); 3.61 (s, 3H); 3.36 (q, J=5.8, 2 H); 1.59 (m, 2H); 1.44 (s, 9H); 1.44-1.26 (m, 4H).
(S)-3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid (31; Fmoc-β 3 -homoPhe-OH) is commercially available.
3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanoic acid (33; Fmoc-NMe-β-Ala-OH) was prepared from 3-(methylamino)propanoic acid hydrochloride (32.HCl) applying Fmoc-OSu and Na 2 CO 3 in H 2 O and dioxane.
Data of 33: C 19 H 19 NO 4 (325.3). LC-MS (method 1a): R t =1.95 (96), 326.0 ([M+H] + ).
3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)propanoic acid (34; Fmoc-β-Ala-OH) is commercially available.
Synthesis of (R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)butanoic acid (40; Fmoc-NMe-β 3 -homoDAla-OH)
At 0° C., 4 M HCl-dioxane (37.8 mL, 151 mmol) was added dropwise to a mixture of (R)-homo-β-alanine (35; 13.0 g, 126 mmol) in CH 2 Cl 2 (170 mL). PCl 5 (31.5 g, 151 mmol) was added to the suspension. The mixture was stirred at 0° C. to rt for 15 h. A clear solution resulted. The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 (150 mL). Allyl alcohol (10.3 mL, 151 mmol) was added slowly and the mixture was stirred for 2 h at rt. The volatiles were evaporated to afford crude 36.HCl (25.6 g).
Pyridine (115 mL) was added to a soln of crude 36.HCl (25.5 g) in CH 2 Cl 2 (275 mL). The mixture was cooled to 0° C., followed by the addition of 4-nitrobenzenesulfonyl chloride (63 g, 284 mmol). The mixture was stirred at 0° C. to rt for 16 h. Aq. workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 9:1 to 1:1) yielded 37 (26.7 g, 64%).
K 2 CO 3 (56 g, 404 mmol) was added to a solution of 37 (26.5 g, 81 mmol) in DMF (295 mL). Iodomethane (50 mL, 807 mmol) was added at 0° C. and the mixture was allowed to warm to rt over 3 h. Aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) gave crude 38 (27.6 g).
K 2 CO 3 (16.7 g, 121 mmol) was added to a soln of crude 38 (13.8 g, ca 40 mmol) in CH 3 CN (275 mL). The mixture was degassed, cooled to 0° C. and treated with thiophenol (6.15 mL, 60 mmol). The mixture was stirred at 0° C. to rt for 15 h. H 2 O (115 mL) and (in portions) Fmoc-Cl (10.5 g, 40.3 mmol) were added. Stirring was continued for 3 h followed by an aq. workup (EtOAc, sat. aq. Na 2 CO 3 ; Na 2 SO 4 ) and FC (hexane/EtOAc 95:5 to 70:30). The material obtained (11.5 g) was purified again by FC (hexane/CH 2 Cl 2 8:2, then CH 2 Cl 2 , then CH 2 Cl 2 /EtOAc) to give 39 (9.2 g, 60%). A degassed soln of 39 (18.3 g, 48.2 mmol) in CH 2 Cl 2 (175 mL)/EtOAc (210 mL) was treated with Pd(PPh 3 ) 4 (0.9 g, 0.77 mmol) and 1,3-dimethylbarbituric acid (9.04 g, 57.9 mmol) for 3 h at rt. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded 40 (7.55 g, 46%) and impure material which was further purified by prep. HPLC (method 1d) to give more 40 (5.61 g, 34%).
Data of 40: C 20 H 21 NO 4 (339.4). LC-MS (method 1a): R t =2.03 (96), 340.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 12.2 (br. s, 1H); 7.89 (d, J=7.4, 2 H); 7.65 (br. s, 2H); 7.41 (t, J=7.4, 2 H); 7.33 (t, J=7.3, 2 H); 4.40-4.24 (m, 4H), 2.67 (s, 3H); 2.45-2.30 (br. m, 2H); 1.37 (br. d, 3H).
Allyl 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (125.HCl)
At 4° C., LiOH.H 2 O (6.36 g, 152 mmol) was added to a soln of 27 (28.82 g, 75.8 mmol) in MeOH (86 mL), H 2 O (85 mL) and THF (270 mL). The mixture was stirred for 18 h at rt, acidified with 1 M aq. HCl soln (500 mL) and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to give 123 (26.5 g, 99%). NaHCO 3 (17.7 g, 210 mmol) was added to a soln of 123 (37.1 g, 105.4 mmol) in DMF (530 mL). The mixture was stirred for 5 min followed by the addn of allyl bromide (18.0 mL; 208 mmol). The mixture was stirred at rt for 18 h. More NaHCO 3 (2.0 g, 24 mmol) and allyl bromide (2.0 mL; 23.1 mmol) were added and stirring was continued for 4 h. Aq. Workup (EtOAc, 1 M aq. HCl soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 99.5:0.5 to 98:2) afforded 124 (38.8 g, 94%).
A soln of 124 (22.5 g, 53.3 mmol) in dioxane (23 mL) was treated at rt with 4 M HCl in dioxane (80 mL) for 3 h. Dioxane (50 mL) was added and stirring was continued for 1 h. The volatiles were evaporated and the residue was washed (Et 2 O) and dried i.v. to yield 125.HCl (17.0 g, 97%).
Data of 125.HCl: C 15 H 20 N 2 O 4 .HCl (free base, 292.3). FI-MS: 292.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.03 (br s, 3H); 7.39-7-28 (m, 5H); 5.87 (m, 1H); 5.35-5.17 (m, 2H); 5.12, 5.07 (2 s, 2H); 4.59 (m, 2H); 4.16 (d, J=7.5, 2 H); 3.54 (q-like m, 2H); 2.97 (br m, 2H).
All Fmoc-α-amino acids and Fmoc-N-methyl-α-amino acids applied in the synthesis of Core 10 and Core 11 are commercially available:
Fmoc-L-alanine (Fmoc-Ala-OH)
Fmoc-N-methyl-L-alanine (Fmoc-NMe-Ala-OH)
Fmoc-D-alanine (Fmoc-DAla-OH)
Fmoc-N-methyl-D-alanine (Fmoc-NMe-DAla-OH)
Fmoc-N-methyl-L-glutamic acid 5 tert.-butyl ester (Fmoc-NMe-Glu(OtBu)-OH)
Fmoc-glycine (Fmoc-Gly-OH)
N-α-Fmoc-N-ε-Boc-L-lysine (Fmoc-Lys(Boc)-OH)
Fmoc-L-phenylalanine (Fmoc-Phe-OH)
Fmoc-N-methyl-L-phenylalanine (Fmoc-NMe-Phe-OH)
Fmoc-D-phenylalanine (Fmoc-DPhe-OH)
Fmoc-N-methyl-D-phenylalanine (Fmoc-NMe-DPhe-OH)
Fmoc-sarcosine (Fmoc-Sar-OH)
(S)-Methyl 3-(allyloxy)-2-aminopropanoate hydrochloride (129)
A soln of Boc-serine (126; 14.0 g, 68.2 mmol) in DMF (143 mL) was cooled to 0° C. NaHCO 3 (17.2 g 205 mmol) was added and the mixture was stirred for 15 min. Iodomethane (8.5 mL, 136 mmol) was added dropwise. The mixture was stirred at 0° C. to rt for 16 h and again cooled to 0° C. More iodomethane (4.2 mL, 67 mmol) was slowly added and stirring was continued for 3 h. The mixture was diluted with H 2 O and extracted with EtOAc. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give crude 127 (14.2 g).
A soln of crude 127 (14.2 g) and Pd(PPh 3 ) 4 (0.64 g) in THF (416 mL) was degassed. Carbonic acid allyl methyl ester (9.6 g, 82.8 mmol) was added and the mixture was heated to 60° C. for 2 h. The volatiles were evaporated. FC (hexane/EtOAc 9:1) afforded 128 (11.4 g, 79%)
A soln of 128 (11.4 g, 43.9 mmol) in dioxane (110 mL) was treated with 4 M HCl in dioxane (110 mL) for 4 h at rt. Additional 4 M HCl in dioxane (30 mL) was added and stirring was continued for 30 min. The volatiles were evaporated and the residue was washed with Et 2 O to give 129.HCl (8.3 g, 96%).
Data of 129.HCl: C 7 H 13 NO 3 .HCl (159.2, free base). FI-MS: 160.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.70 (br. s, 3H); 5.85 (m, 1H); 5.29 (qd, J=1.7, 17.3, 1H), 5.19 (qd, J=1.5, 10.4, 1H); 4.33 (t, J=3.6, 1H); 4.07-3.93 (m, 2H); 3.86-3.78 (m, 2H); 3.76 (s, 3H).
(S)-Allyl 2-(benzyloxycarbonylamino)-4-(methylamino)butanoate hydrochloride (130.HCl) and
(S)-Allyl 2-(benzyloxycarbonylamino)-6-(methylamino)hexanoate hydrochloride (131.HCl) were prepared described in the preceding patent application (WO 2011/014973 A2).
Sarcosine tert-butylester hydrochloride (132.HCl) is commercially available.
Core 01: Synthesis of Ex. 1, Ex. 2 and Ex. 3 (Scheme 8)
Synthesis of the Mitsunobu Product 41
At 0° C., ADDP (7.08 g, 28.1 mmol) was added in portions to a mixture of phenol 2 (4.27 g, 18.7 mmol), alcohol 16 (6.18 g, 20.6 mmol) and PPh 3 (7.36 g, 28.1 mmol) in CHCl 3 (110 mL). The stirred mixture was allowed to warm to rt over 15 h.
The volatiles were evaporated. The residue was suspended in CH 2 Cl 2 and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1) to yield 41 (5.98 g, 62%).
Data of 41: C 28 H 34 N 2 O 7 (510.6). LC-MS (method 1a): R t =2.58 (94), 511.2 ([M+H] + ).
Synthesis of the Acid 42
Aq. LiOH soln (2 M; 11 mL, 22.0 mmol) was added to a solution of ester 41 (5.65 g, 11.1 mmol) in MeOH (11 mL) and THF (19 mL). The mixture was heated to 65° C. for 4 h, partially concentrated, acidified with 1 M aq. HCl soln to pH 1 and extracted twice with EtOAc. The combined organic layer was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 42 (4.46 g, 81%).
Data of 42: C 27 H 32 N 2 O 7 (496.6). LC-MS (method 1a): R t =2.28 (90), 497.2 ([M+H] + ).
Synthesis of the Amide 43
A solution of acid 42 (4.46 g, 9.0 mmol), amine 22.pTsOH (5.6 g, 11 mmol), HATU (5.1 g, 13 mmol), HOAt (1.8 g, 13 mmol) in DMF (70 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (6.2 mL, 36 mmol). The mixture was allowed to warm to rt over 15 h. The mixture was diluted with 0.5 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:1) of the crude product afforded 43 (5.56 g, 80%).
Data of 43: C 42 H 50 N 4 O 10 (770.9). LC-MS (method 1a): R t =2.55 (95), 771.3 ([M+H] + ).
Synthesis of Amino Acid 44
A degassed solution of amide 43 (5.55 g, 7.2 mmol) and 1,3-dimethylbarbituric acid (2.5 g, 16 mmol) in CH 2 Cl 2 (40 mL) and EtOAc (40 mL) was treated with Pd(PPh 3 ) 4 (0.41 g, 0.36 mmol) at rt. After 2 h, more CH 2 Cl 2 (40 mL) and Pd(PPh 3 ) 4 (0.41 g, 0.36 mmol) were added and stirring was continued for 1 h. The volatiles were evaporated. The solid was suspended in EtOAc, filtered, washed (EtOAc) and dried i.v. to afford 44 (3.94 g, 83%).
Data of 44: C 35 H 42 N 4 O 8 (646.7). LC-MS (method 1a): R t =1.75 (97), 647.2 ([M+H] + ).
Synthesis of Ex. 1
The amino acid 44 (2.77 g, 4.28 mmol) was added in portions over 2 h to a solution of T3P (50% in EtOAc; 13 mL, 22.1 mmol) and i-Pr 2 NEt (5.8 mL, 34.3 mmol) in dry CH 2 Cl 2 (800 mL). Stirring was continued for 30 min. The mixture was washed (sat. aq. NaHCO 3 soln.), dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /THF 9:1) of the crude product yielded Ex. 1 (2.35 g, 87%).
Data of Ex. 1: C 35 H 40 N 4 O 7 (628.7). LC-MS (method 1a): R t =2.17 (94), 629.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.18 (br. t, 1H); 7.67 (d, J=7.2, 1H); 7.52-7.23 (m, 11H); 7.11-7.06 (m, 2H); 6.98 (d, J=8.1, 1H); 4.98 (s, 2H); 4.64 (br. m, 1H); ca 4.3-4.0 (several br. m, 4H); 3.85 (br. m, 1H); 3.10 (br. m, 1H); 2.98 (m, 1H); 2.31 (br. m, 1H); ca 2.0-1.75 (br. m, 2H); 1.53 (br. m, 1H); 1.41 (s, 9H); 0.83 (br. m, 1H).
Synthesis of Ex. 2
A soln of Ex. 1 (300 mg, 0.477 mmol) in MeOH (6.0 mL) was hydrogenated for 16 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 63 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 80:20) gave Ex. 2 (206 mg, 87%).
Data of Ex. 2: C 27 H 34 N 4 O 5 (494.6). LC-MS (method 1a): R t =1.60 (99), 495.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.21 (t-like m, 1H); 7.52-7.36 (m, 5H); 7.21 (br. d, 1H), 7.15-7.00 (m, 2H); 7.00 (s, 1H), 4.43 (br. not resolved m, 1H); 4.24-4.01 (m, 3H); 3.89 (q-like m, 1H); 3.58-3.12 (several br. m, 3H); 2.98 (dd, J=6.2, 12.1, 1H); 2.33 (m, 1H); 1.89 (m, 1H); 1.65-1.55 (br. not resolved m, 2H); 1.41 (s, 9H).
Synthesis of Ex. 3
A soln of Ex. 1 (750 mg, 1.19 mmol) in CH 2 Cl 2 (5 mL) was cooled to 0° C. TFA (2.0 mL) was slowly added and the mixture was stirred at 0° C. to rt for 4 h. The volatiles were evaporated. The residue was taken up in CHCl 3 and concentrated.
The residue was taken up in CH 2 Cl 2 (6 mL), treated with 4 M HCl in dioxane (2 mL) to give a precipitate. The volatiles were evaporated. The treatment with CH 2 Cl 2 /4 M HCl in dioxane was repeated. The residue was suspended in Et 2 O, filtered, washed (Et 2 O) and dried i.v. to afford Ex. 3.HCl (613 mg, 90%).
Data of Ex. 3.HCl: C 30 H 32 N 4 O 5 .HCl (528.6, free base). LC-MS (method 1a): R t =1.55 (99), 529.1 ([M+H] + ).
Core 01: Synthesis of Ex. 330, Ex. 331 and the Resin 133 (Scheme 8)
Synthesis of Ex. 330
Sat. aq. NaHCO 3 soln (131 mL) and H 2 O (53.5 mL) were added to a soln of Ex. 2 (14.4 g, 29 mmol) in dioxane (131 mL) and THF (78 mL). The mixture was cooled to 0° C. Allyl chloroformate (3.71 mL, 34.9 mmol) was slowly added. Stirring was continued for 2 h at 0° C. to rt. The mixture was diluted with sat. aq. Na 2 CO 3 soln and extracted with CH 2 Cl 2 . The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to give Ex. 330 (16.18 g, 96%).
Data of Ex. 330: C 31 H 38 N 4 O 7 (578.6). LC-MS (method 1c): R t =2.06 (97), 578.9 ([M+H] + ).
Synthesis of Ex. 331
At 0° C., TFA (40.6 mL) was added to a soln of Ex. 330 (15.8 g, 27.3 mmol) in CH 2 Cl 2 (160 mL). The cooling bath was removed and stirring was continued for 2 h. The volatiles were evaporated. The residue was dissolved in CHCl 3 (76 mL) and 4 M HCl in dioxane (14.0 mL) was added. The volatiles were evaporated. The residue was again taken up in CHCl 3 (76 mL), treated with 4 M HCl in dioxane (14.0 mL) and concentrated. The residue was distributed between sat. aq. Na 2 CO 3 soln and EtOAc. The organic layer was separated, the aqueous layer repeatedly extracted with EtOAc. The combined organic phases were concentrated. The residue was dissolved in CH 2 Cl 2 (200 mL). Then 4 M HCl in dioxane (17.7 mL) was slowly added to give a thick precipitate. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered, washed (Et 2 O) and dried i.v. to afford Ex. 331.HCl (12.5 g, 89%).
Data of Ex. 331.HCl: C 26 H 30 N 4 O 5 .HCl (free base, 478.5). LC-MS (method 1a): R t =1.36 (96), 479.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.43 (br. s, 3H); 8.27 (br. t, J ca 5.3, 1H); 7.67 (d, J=6.9, 1H); 7.52-7.37 (m, 5H); 7.12-7.09 (m, 2H); 7.02 (d, J=8.8, 1H); 5.88 (m, 1H); 5.26 (dd, J=1.2, 17.2, 1H); 5.17 (dd, J=1.1, 10.4, 1H); 4.67 (br. m, not resolved, 1H); 4.43 (d, J=5.2, 2 H); 4.31-4.11 (m, 4H); 3.56 (br. m, not resolved, 1H); 3.31-3.16 (br. m, 2H); 3.19 (dd, J=8.1, 12.1, 1H); 2.60 (m, 1H); 2.12 (m, 1H); 1.83 (br. m, 1H); 1.47 (br. m, 1H).
Synthesis of the Resin 133
Under Ar, DFPE polystyrene (1% DVB, 100-200 mesh, loading 0.87 mmol/g; 11.1 g, 9.6 mmol) was swollen in DCE (110 mL) for 1 h. Ex. 331.HCl (5.7 g, 10.6 mmol) and i-Pr 2 NEt (4.9 mL, 28.9 mmol) were added. The mixture was shaken at rt for 1 h. NaBH(OAc) 3 (4.09 g, 19.3 mmol) was added and the mixture was shaken for 20 h. The resin was filtered and successively washed with MeOH twice, then three times each with DCE, 10% i-Pr 2 NEt in DMF, DMF, CH 2 Cl 2 and MeOH. The resin was dried i.v. to give 133 (15.73 g; loading 0.6 mmol/g).
Procedure D:
Core 01: Synthesis of Final Products on Solid Support
Synthesis of Resin 134
1) First Derivatization Step
Resin 133 (loading 0.6 mmol/g; 96 mg, 0.055 mmol) was swollen in DMF (1 mL) for 60 min and filtered. The resin was resuspended in DMF/CH 2 Cl 2 1:1 (1 mL). i-Pr 2 NEt (8 equiv.) the carboxylic acid R III CO 2 H (4 equiv.) and HATU (4 equiv.) or the succinimidyl carbamate R III NHCO 2 Su (4 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was washed with DMF. The coupling step was repeated. The resin was washed three times with DMF.
2) Cleavage of the Alloc Group
The resin was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (10 equiv.) and Pd(PPh 3 ) 4 (0.2 equiv.) were added, then the mixture was shaken for 15 min and filtered. The deprotection step was repeated. The resin was filtered, washed three times each with CH 2 Cl 2 , DMF, twice with MeOH and three times with CH 2 Cl 2 .
3) Second Derivatization Step
The resin was resuspended in DMF/CH 2 Cl 2 1:1 (1 mL). i-Pr 2 NEt (8 equiv.) and the carboxylic acid R IV CO 2 H (4 equiv.) and PyBOP (4 equiv.) or the isocyanate R IV NCO (4 equiv) or the sulfonyl chlorides R IV SO 2 Cl (4 equiv) and DMAP (1 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was filtered, washed three times with DMF to afford resin 134.
Release of the Final Products
The resin 134 was treated with 20% TFA in CH 2 Cl 2 (1 mL) for 30 min, filtered and washed with CH 2 Cl 2 . The cleavage step was repeated once. The combined filtrates and washings were concentrated. The residue was treated with CH 3 CN, evaporated and dried i.v. Purification of the crude product by normal phase or reverse phase prep. HPLC afforded Ex. 7 and Ex. 332-Ex. 337.
Core 01: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 8)
Synthesis on Solid Support:
Ex. 7.CF 3 CO 2 H (6.6 mg, 15%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 7.CF 3 CO 2 H: cf. Table 13b.
1 H-NMR (DMSO-d 6 ): 9.94 (br. s, 1H); 8.77 (d, J=5.3, 1H); 8.65 (d, J=7.7, 1H); 8.06 (t, J=5.4, 1H); 8.01 (m, 1H); 7.92 (m, 1H); 7.81 (d, J=7.9, 1H); 7.55-7.37 (m, 8H); 7.34 (t, J=8.0, 1H); 7.09-7.05 (m, 2H); 6.91 (dd, J=2.0, 8.2, 1H); 4.58 (br. not resolved m, 1H); 4.44 (br. not resolved m, 1H); 4.19 (dd, J=4.9, 11.5, 1H); 4.12-4.00 (m, 5H); 3.94 (d, J=14.9, 1H); 3.87 (d, J=14.9, 1H); ca 3.6-3.5 (br m, 2H), 3.30 (1H, superimposed by H 2 O signal); 3.07-3.02 (br. m, 4H); 2.15-1.84 (br. m, 7H); 1.67 (br. m, 1H).
Ex. 332.CF 3 CO 2 H (21 mg, 48%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with imidazol-1-yl acetic acid (in total 55 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 332.CF 3 CO 2 H: cf. Table 13b.
Ex. 333.CF 3 CO 2 H (29 mg, 65%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 2,5-dioxopyrrolidin-1-yl pyridine-3-ylcarbamate (in total 103 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 333.CF 3 CO 2 H: cf. Table 13b.
Ex. 334.CF 3 CO 2 H (16 mg, 38%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 3-chlorophenylacetic acid (37 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 334.CF 3 CO 2 H: cf. Table 13b.
Ex. 335.CF 3 CO 2 H (11 mg, 26%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with cyclohexylacetic acid (31 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 335.CF 3 CO 2 H: cf. Table 13b.
Ex. 336.CF 3 CO 2 H (6 mg, 13%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 1-naphthyl isocyanate (0.031 mL, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 336.CF 3 CO 2 H: cf. Table 13b.
1 H-NMR (DMSO-d 6 ): 9.94 (br. s, 1H); 8.81 (d, J=4.9, 1H); 8.63 (s, 1H); 8.27 (t, J=5.6, 1H); 8.06 (d, J=8.0, 1H); 7.96 (dd, J=1.0, 7.6, 1H); 7.89 (d, J ca 9.3, 1H); 7.59-7.38 (m, 9H); 7.16-7.13 (m, 2H); 7.04-6.99 (t-like m, 2H); 4.82 (br. not resolved m, 1H); 4.45 (t-like m, 1H); 4.29 (dd, J=5.9, 11.5, 1H); 4.22-4.13 (br. m, 3H); 4.01 (s, 2H); 3.65-3.45 (br. m, 3H); 3.25-3.0 (br. m, 4H); 2.45 (m, 1H); 2.10-1.70 (br. m, 7H).
Synthesis in Solution:
Synthesis of Ex. 4
At rt, i-Pr 2 NEt (0.27 mL, 1.57 mmol) was added to a soln of Ex. 2 (258 mg, 0.52 mmol), 1-naphthaleneacetic acid (117 mg, 0.63 mmol), HATU (298 mg, 0.78 mmol) and HOAt (107 mg, 0.78 mmol) in DMF (4.3 mL). The mixture was stirred at rt for 15 h and distributed between CH 2 Cl 2 and 1 M aq. Na 2 CO 3 soln. The organic phase was separated, washed (H 2 O), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 34:66 to 0:100) afforded Ex. 4 (267 mg, 77%).
Data of Ex. 4: cf. Table 13b
Synthesis of Ex. 5
A soln of Ex. 4 (220 mg, 0.33 mmol) in dioxane (4.0 mL) was treated with 4 M HCl-dioxane (1.0 mL) for 2 h. The volatiles were evaporated to afford Ex. 5.HCl (208 mg, quant.)
Data of Ex. 5.HCl: cf. Table 13b
Synthesis of Ex. 7
At rt, i-Pr 2 NEt (0.057 mL, 0.33 mmol) was added to a soln of Ex. 5.HCl (50 mg, 0.08 mmol), 1-Pyrrolidineacetic acid (22 mg, 0.17 mmol), HATU (63 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (1.2 mL). The mixture was stirred at rt for 4 h and distributed between EtOAc and sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 7 (40 mg, 71%).
Data of Ex. 7: C 40 H 43 N 5 O 5 (673.8). LC-MS (method 1a): R t =1.70 (96), 674.2 ([M+H] + ).
Synthesis of Ex. 14
At 0° C., phenyl chloroformate (87 mg, 0.55 mmol) was slowly added to a mixture of Ex. 3 (285 mg, 0.50 mmol) in CH 2 Cl 2 (5 mL) and sat. aq. Na 2 CO 3 soln (1.7 mL). Stirring was continued for 2 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln., Na 2 SO 4 ) and FC (EtOAc) afforded Ex. 14 (315 mg, 96%)
Data of Ex. 14: cf. Table 13b
Core 02: Synthesis of Ex. 15, Ex. 16 and Ex. 17 (Scheme 9)
Synthesis of the Mitsunobu Product 45
At 0° C., a solution of TMAD (7.57 g, 43.9 mmol) in benzene (80 mL) was added dropwise to a degassed solution of the phenol 4 (3.68 g, 16.1 mmol), alcohol 16 (4.40 g, 14.65 mmol) and PPh 3 (11.5 g, 43.9 mmol) in benzene (80 mL). The stirred mixture was allowed to warm to rt over 15 h.
The volatiles were evaporated. The residue was suspended in hexane and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 5:1) to yield 45 (5.45 g, 73%).
Data of 45: C 28 H 34 N 2 O 7 (510.6). LC-MS (method 1c): R t =2.67 (97), 511.2 ([M+H] + ).
Synthesis of the Acid 46
At 0° C., aq. LiOH soln (2 M; 10.6 mL, 21.1 mmol) was added to a solution of ester 45 (5.4 g, 10.6 mmol) in MeOH (10 mL) and THF (20 mL). The mixture was allowed to warm to rt over 16 h. The volatiles were evaporated. The residue was taken up in 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1 to 0:100 then EtOAc/MeOH 100:0 to 90:10 gave 46 (4.48 g, 85%).
Data of 46: C 27 H 32 N 2 O 7 (496.6). LC-MS (method 1c): R t =2.29 (99), 497.2 ([M+H] + ).
Synthesis of the Amide 47
A solution of acid 46 (4.28 g, 8.6 mmol), amine 23.HCl (4.6 g, 10.3 mmol), HATU (4.9 g, 12.9 mmol) and HOAt (1.76 g, 12.9 mmol) in DMF (80 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (5.9 mL, 34.5 mmol). The mixture was allowed to warm to rt over 15 h. The mixture was diluted with H 2 O and EtOAc. The organic layer was washed (aq. 1 M HCl soln, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:1) of the crude product afforded 47 (6.1 g, 89%).
Data of 47: C 44 H 54 N 4 O 10 (798.9). LC-MS (method 1a): R t =2.72 (97), 799.4 ([M+H] + ).
Synthesis of Amino Acid 48
A degassed solution of 47 (6.14 g, 7.7 mmol) and 1,3-dimethylbarbituric acid (2.64 g, 16.9 mmol) in CH 2 Cl 2 (70 mL) and EtOAc (42 mL) was treated with Pd(PPh 3 ) 4 (0.44 g, 0.38 mmol) at rt for 1 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 98:2 to 80:20) afforded 48 (4.64 g, 89%).
Data of 48: C 37 H 46 N 4 O 8 (674.8). LC-MS (method 1a): R t =1.86 (97), 675.3 ([M+H] + ).
Synthesis of Ex. 15
A soln of the amino acid 48 (1.12 g, 1.66 mmol) in CH 2 Cl 2 (60 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 2.45 mL, 4.15 mmol) and i-Pr 2 NEt (1.14 mL, 6.64 mmol) in dry CH 2 Cl 2 (770 mL). Evaporation of the volatiles, aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) yielded Ex. 15 (0.96 g, 88%).
Data of Ex. 15: C 37 H 44 N 4 O 7 (656.7). LC-MS (method 1d): R t =2.29 (97), 657.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.6-7.0 (br. m, 13H); 7.13 (d, J=7.9, 1H); 7.03 (t, J=7.3, 1H); 5.01 (br. s, 2H); 4.37 (br. d, J ca 9.7, 1H); ca 4.25-3.7 (several br. m, 4H); 3.25 (br. m, 1H); 2.95 (br. s, 3H); 2.64 (br. m, 1H); 2.40 (br. m, 1H); 2.18 (br. m, 1H); ca. 1.85-1.0 (several br. m, 6H); 1.37 (s, 9H).
Synthesis of Ex. 16
A soln of Ex. 15 (1.3 g, 2.0 mmol) in MeOH (60 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 240 mg). The mixture was filtered through a pad of celite and Na 2 SO 4 . The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 16 (1.03 g, 99%).
Data of Ex. 16: C 29 H 38 N 4 O 5 (522.6). LC-MS (method 1a): R t =1.68 (97), 523.1 ([M+H] + ).
Synthesis of Ex. 17
A soln of Ex. 15 (600 mg, 0.91 mmol) in dioxane (6 mL) was treated with 4 M HCl in dioxane (6 mL) at rt for 1 h followed by evaporation of the volatiles. The residue was taken up in CHCl 3 and concentrated to afford Ex. 17 (571 mg, quant. yield).
Data of Ex. 17.HCl: C 32 H 36 N 4 O 5 .HCl (556.6, free base). LC-MS (method 1a): R t =1.65 (96), 557.2 ([M+H] + ).
Core 02: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 9)
Synthesis of Ex. 18
At 0° C., i-Pr 2 NEt (0.635 mL, 3.71 mmol) was added dropwise to a soln of Ex. 17.HCl (550 mg, 0.93 mmol), 2-naphthaleneacetic acid (207 mg, 1.11 mmol), HATU (529 mg, 1.39 mmol) and HOAt (189 mg, 1.39 mmol) in DMF (10 mL). The mixture was stirred at 0° C. for 4 h and distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was separated, washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (EtOAc) afforded Ex. 18 (530 mg, 79%).
Data of Ex. 18: cf. Table 14b
Synthesis of Ex. 19
A soln of Ex. 18 (520 mg, 0.72 mmol) in MeOH (5 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 94 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 19 (412 mg, 97%).
Data of Ex. 19: cf. Table 14b
Synthesis of Ex. 20
i-Pr 2 NEt (0.043 mL, 0.25 mmol) was added to a soln of Ex. 19 (50 mg, 0.085 mmol), 2-(dimethylamino)acetic acid (17 mg, 0.17 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol). The mixture was stirred at rt for 15 h and distributed between CH 2 Cl 2 and sat. aq. Na 2 CO 3 soln. The organic phase was separated, dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 20 (17 mg, 30%).
Data of Ex. 20: cf. Table 14b
Synthesis of Ex. 25
Phenylacetyl chloride (0.013 mL, 0.098 mmol) was added at 0° C. to a soln of Ex. 19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at 0° C. for 2 h followed by the addition of more phenylacetyl chloride (0.006 mL, 0.045 mmol). Stirring was continued for 1 h. Evaporation of the volatiles and prep. HPLC (method 1a) afforded Ex. 25 (36 mg, 60%).
Data of Ex. 25: cf. Table 14b
Synthesis of Ex. 26
Benzoyl chloride (0.012 mL, 0.10 mmol) was added at 0° C. to a soln of Ex. 19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at 0° C. for 2 h followed by evaporation of the volatiles and prep. HPLC (method 1a) to afford Ex. 26 (40 mg, 67%).
Data of Ex. 26: cf. Table 14b
Core 03: Synthesis of Ex. 41, Ex. 42, Ex. 50 and Ex. 62-Ex. 67 (Scheme 10)
Synthesis of the Mitsunobu Product 49
At 0° C., ADDP (7.32 g, 29.0 mmol) was added in portions to a mixture of phenol 6 (5.0 g, 19.4 mmol), alcohol 20 (5.08 g, 29.0 mmol) and PPh 3 (7.62 g, 29.0 mmol) in CHCl 3 (82 mL). The stirred mixture was allowed to warm to rt over 15 h.
More 20 (5.08 g, 29.0 mmol), PPh 3 (7.62 g, 29.0 mmol) and finally ADDP (7.32 g, 29.0 mmol) were added at 0° C. Stirring was continued at rt for 6 h. The mixture was filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 90:10 to 80:20) to yield 49 (7.57 g, 94%).
Data of 49: C 23 H 29 NO 6 (415.5). LC-MS (method 1a): R t =2.54 (99), 416.2 ([M+H] + ).
Synthesis of the Acid 50
At 0° C., aq. LiOH soln (2 M; 27 mL, 54.0 mmol) was added dropwise to a solution of ester 49 (7.44 g, 17.9 mmol) in MeOH (27 mL) and THF (50 mL). The mixture was stirred at rt for 5 h, partially concentrated, acidified with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give 50 (7.1 g, 98%).
Data of 50: C 22 H 27 NO 6 (401.4). LC-MS (method 1a): R t =2.20 (98), 402.1 ([M+H] + ).
Synthesis of the Amide 51
A solution of acid 50 (7.0 g, 17.4 mmol), amine 24.HCl (6.86 g, 20.9 mmol), HATU (9.95 g, 26.2 mmol) and HOAt (3.56 g, 26.2 mmol) in DMF (180 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (11.9 mL, 69.7 mmol). The mixture was allowed to warm to rt over 7 h. More 24.HCl (6.86 g, 20.9 mmol) was added and stirring continued for 15 h. The mixture was diluted with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1) of the crude product afforded 51 (10.05 g, 85%).
Data of 51: C 38 H 46 N 2 O 9 (674.8). LC-MS (method 1a): R t =2.69 (97), 675.2 ([M+H] + ).
Synthesis of the Amino Ester 52
A soln of 51 (10.0 g, 14.8 mmol) in dioxane (10 mL) was treated at rt with 4 M HCl in dioxane (40 mL) for 5 h. The volatiles were evaporated. The residue was taken up in CH 2 Cl 2 and concentrated to afford 52.HCl (9.2 g, quant. yield).
Data of 52.HCl: C 33 H 38 N 2 O 7 .HCl (574.6, free base). LC-MS (method 1a): R t =1.94 (94), 575.2 ([M+H] + ).
Synthesis of Amino Acid 53
A degassed solution of ester 52 (9.2 g, 15 mmol) and 1,3-dimethylbarbituric acid (2.8 g, 18 mmol) in CH 2 Cl 2 (30 mL) and EtOAc (60 mL) was treated with Pd(PPh 3 ) 4 (1.8 g, 1.5 mmol) at rt for 2 h. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 98:2 to 70:30) afforded 53 (8.2 g, quant.).
Data of 53: C 30 H 34 N 2 O 7 (534.6). LC-MS (method 1a): R t =1.70 (94), 535.2 ([M+H] + ).
Synthesis of Ex. 41
A soln of the amino acid 53 (4.0 g, 7.5 mmol) in CH 2 Cl 2 (80 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 11.0 mL, 18.7 mmol) and i-Pr 2 NEt (5.12 mL, 29.9 mmol) in dry CH 2 Cl 2 (1360 mL). Evaporation of the volatiles, aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 20:80 to 0:100) yielded Ex. 41 (3.0 g, 77%).
Data of Ex. 41: C 30 H 32 N 2 O 6 (516.5). LC-MS (method 1d): R t =2.14 (96), 517.0 ([M+H] + ). 1 H-NMR (CDCl 3 ): 7.78 (s, 1H); 7.50-7.35 (m, 7H); 7.25 (m, 1H), 6.92-6.82 (m, 3H); 5.59 (d, J=8.4, 1H); 5.32 (d, J=12.2, 1H); 5.26 (d, J=12.2, 1H); 4.78 (d, J=11.9, 1H); 4.16 (q-like m, 1H); 3.81 (s, 3H); 3.71 (d, J=9.0, 1H); 3.38 (t-like m, 1H); 2.98 (s, 3H); 2.64 (br. t, J ca. 12.7, 1H); 2.37 (dd, J=5.6, 16.2, 1H); 2.01-1.90 (m, 2H); 1.24 (d, J=6.8, 3 H).
Synthesis of Ex. 42
A soln of Ex. 41 (2.0 g, 3.87 mmol) in MeOH (30 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 220 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 42 (1.77 g, quant. yield).
Data of Ex. 42: C 23 H 26 N 2 O 6 (426.5). LC-MS (method 1d): R t =1.55 (93), 427.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.2 (br. s, 1H); 8.03 (d, J=8.2, 1H); 7.59 (s, 1H); 7.46-7.41 (m, 2H); 7.16 (m, 1H); 7.04 (d, J=8.9, 1H); 6.90 (dd, J=3.0, 8.8, 1H); 6.83 (d, J=3.0, 1H); 4.13 (dd, J=3.0, 12.2, 1H); 4.03-3.91 (m, 2H); 3.74 (s, 3H); 3.52 (t, J=9.2, 1H); 2.86 (s, 3H); 2.39 (br. t, J ca 13.2, 1H); 2.19 (br. dd, J ca 4.9, 15.9, 1H); 1.99 (d-like m, 1H); 1.86 (m, 1H); 1.03 (d, J=6.6, 3 H).
Core 03: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 10)
Synthesis of Ex. 62
A soln of Ex. 41 (50 mg, 0.1 mmol) in THF (1 mL) was cooled to 0° C. LiBH 4 (5 mg, 0.213 mmol) and MeOH (3.9 μL, 0.1 mmol) in THF (0.5 mL) were added. The mixture was stirred at rt for 20 h followed by the addition of acetone (0.1 mL). Aqueous workup (CHCl 3 , 1 M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 90:10) yielded Ex. 62 (25 mg, 61%).
Data of Ex. 62: C 23 H 28 N 2 O 5 (412.5). LC-MS (method 1a): R t =1.49 (97), 413.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.90 (d, J=8.2, 1H); 7.56-7.53 (m, 2H); 7.41-7.32 (m, 2H); 7.00 (d, J=8.9, 1H); 6.89 (dd, J=3.1, 8.9, 1H); 6.80 (d, J=3.1, 1H); 5.05 (t, J=5.3, 1H); 4.01-3.87 (m, 2H); 3.74 (s, 3H); 3.74 (m, 1H); 3.61-3.38 (m, 3H); 2.78 (s, 3H); 2.11 (dd, J=5.6, 15.9, 1H); 1.99 (br. t, 1H); 1.85 (br. t, 1H); 1.45 (dt, J=6.1, 12.7, 1H); 1.00 (d, J=6.7, 3 H).
Synthesis of Ex. 63
At 0° C., DEAD (40% in toluene; 0.05 mL, 0.109 mmol) was slowly added to a soln of Ex. 62 (30 mg, 0.073 mmol), 3-hydroxypyridine (8.3 mg, 0.087 mmol) and PPh 3 (29 mg, 0.109 mmol) in degassed benzene/THF 1:1 (2 mL). The mixture was stirred at rt for 16 h and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 90:10) afforded Ex. 63 (26 mg, 73%).
Data of Ex. 63: C 28 H 31 N 3 O 5 (489.5). LC-MS (method 1a): R t =1.44 (95), 490.1 ([M+H] + ).
Synthesis of Ex. 64
At 0° C., DEAD (40% in toluene; 0.83 mL, 1.82 mmol) was slowly added to a soln of Ex. 62 (250 mg, 0.61 mmol), PPh 3 (477 mg, 1.82 mmol) and DPPA (0.394 mL; 1.82 mmol) in degassed benzene (10 mL). The mixture was stirred for 30 min at rt and for 1 h at 50° C. The volatiles were evaporated. The residue was suspended in Et 2 O. The solid was collected to afford Ex. 64 (169 mg, 63%).
Data of Ex. 64: C 23 H 27 N 5 O 4 (437.5). LC-MS (method 1a): R t =1.86 (94), 438.2 ([M+H] + ).
Synthesis of Ex. 65
A soln of Ex. 64 (166 mg, 0.38 mmol) in MeOH/CH 2 Cl 2 2:1 (3 mL) was hydrogenated at rt for 4 h in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 71 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. The residue was dissolved in CHCl 3 and evaporated. The residue was dissolved in CH 2 Cl 2 (3 mL), treated with 4 M HCl-dioxane (0.285 mL, 1.1 mmol). A precipitate was obtained which was filtered and washed (EtOAc) to afford Ex. 65.HCl (149 mg, 87%).
Data of Ex. 65.HCl: C 23 H 29 N 3 O 4 (411.5). LC-MS (method 1a): R t =1.35 (86), 412.2 ([M+H] + ).
Synthesis of Ex. 66
At 0° C., i-Pr 2 NEt (0.076 mL, 0.45 mmol) was added dropwise to a soln of Ex. 65.HCl (50 mg, 0.11 mmol), phenylacetic acid (18 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.167 mmol) in DMF (0.5 mL). The mixture was stirred at 0° C. for 2 h. Aq. workup (EtOAc, 0.2 M HCl soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and prep. HPLC (method 3) afforded Ex. 66 (33 mg, 55%).
Data of Ex. 66: C 31 H 35 N 3 O 5 (529.6). LC-MS (method 1a): R t =1.89 (91), 530.2 ([M+H] + ).
Synthesis of Ex. 67
i-Pr 2 NEt (0.031 mL, 0.18 mmol) was added to a soln of Ex. 62 (50 mg, 0.12 mmol) and phenyl isocyanate (17 mg, 0.15 mmol) in THF/DMF 1:1 (1.0 mL). The mixture was stirred at rt for 16 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and prep. HPLC (method 3) to afford Ex. 67 (46 mg, 72%).
Data of Ex. 67: C 30 H 33 N 3 O 6 (531.6). LC-MS (method 1a): R t =2.06 (90), 532.2 ([M+H] + ).
Synthesis of Ex. 50
3-Picolylamine (0.014 mL, 0.141 mmol) and i-Pr 2 NEt (0.06 mL, 0.352 mmol) were slowly added to a cold solution of Ex. 42 (50 mg, 0.117 mmol), HATU (67 mg, 0.176 mmol) and HOAt (24 mg, 0.176 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 4° C., followed by an aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) and purification by prep HPLC (method 1c) to give Ex. 50.CF 3 CO 2 H (28 mg, 37%).
Data of Ex. 50.CF 3 CO 2 H: cf. Table 15b.
1 H-NMR (DMSO-d 6 and D 2 O): 8.90 (br. s, 1H); 8.50 (very br. s, 1H); 7.56 (s, 1H); 7.40 (br. s, 1H); 7.30 (very br. s, 1H); 7.01 (m, 2H); 6.88 (dd, J=2.9, 8.9, 1H); 6.78 (d, J=2.7, 1H); 4.60 (br. not resolved m, 2H); 4.08 (br. d, J=9.8, 1H); 3.98-3.89 (br. m, 2H); 3.71 (s, 3H); 3.51 (t, J=9.2, 1H); 2.84 (s, 3H); 2.43 (br. not resolved m, 1H), 2.21 (br. m, 1H); 1.96-1.76 (m, 2H); 1.00 (d, J=6.5, 3 H).
An analytical sample of Ex. 50.CF 3 CO 2 H was dissolved in CH 2 Cl 2 and washed with sat. aq. Na 2 CO 3 soln. The organic phase was separated, dried (Na 2 SO 4 ) and concentrated to give Ex. 50.
Data of Ex. 50: 1 H-NMR (DMSO-d 6 ): 8.88 (t, J=6.0, 1H); 8.59 (d, J=1.6, 1H); 8.56 (dd, J=1.5, 4.8, 1H); 8.09 (d, J=8.2, 1H); 7.82 (td, J=1.9, 7.9, 1H); 7.67 (s, 1H); 7.50-7.44 (m, 2H); 7.32 (t, J=7.6, 1H); 7.13-7.08 (m, 2H); 6.95 (dd; J=3.1, 8.9, 1H); 6.87 (d, J=3.1, 1H); 4.43-4.40 (m, 2H); 4.15-3.96 (m, 3H); 3.80 (s, 3H); 3.57 (t, J ca 9.0, 1H); 2.91 (s, 3H); ca 2.5 (1H, superimposed by DMSO-d signal); 2.26 (br. dd, 1H); 1.98 (br. dd, 1H), 1.81 (dt; J=5.3, 10.0, 1H); 1.08 (d, J=6.7, 3 H).
Core 04: Synthesis of Ex. 68 and Ex. 69 (Scheme 11)
Synthesis of the Mitsunobu Product 54
ADDP (6.61 g, 26.2 mmol) was added to a mixture of the phenol 8 (3.98 g, 17.5 mmol), the alcohol 19 (4.59 g, 26.2 mmol) and PPh 3 (6.87 g, 26.2 mmol) in CHCl 3 (160 mL). The mixture was stirred at rt for 15 h. Silica gel (20 g) was added. The volatiles were evaporated and the residue was purified by FC (hexane/EtOAc 5:1) to give 54 (3.2 g, 48%).
Data of 54: C 22 H 27 NO 5 (385.5). LC-MS (method 2b): R t =2.56 (90), 384.0 ([M−H] − ).
Synthesis of the Acid 55
LiOH.H 2 O (1.6 g, 38 mmol) was added to a solution of ester 54 (4.89 g, 12.7 mmol) in THF (72 mL), MeOH (24 mL) and H 2 O (24 mL). The mixture was stirred at rt for 4.5 h, partially concentrated, diluted with H 2 O (30 mL), acidified with 1 M aq. HCl soln (ca 40 mL) and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give 55 (4.67 g, 99%).
Data of 55: C 21 H 25 NO 5 (371.4). LC-MS (method 2a): R t =1.32 (98), 369.9 ([M−H] − ).
Synthesis of the Amide 56
PyClu (2.2 g, 6.62 mmol) and i-Pr 2 NEt (2.95 mL, 17.3 mmol) were successively added to a solution of acid 55 (2.14 g, 5.76 mmol) and amine 24.HCl (2.52 g, 7.7 mmol), in DMF (50 mL). The mixture was stirred at rt for 1 h followed by an aq. workup (Et 2 O, 0.5 M aq. HCl soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ). FC (hexane/EtOAc 7:3 to 4:6) afforded 56 (2.29 g, 61%).
Data of 56: C 37 H 44 N 2 O 8 (644.8). LC-MS (method 1a): R t =2.69 (95), 645.3 ([M+H] + ).
Synthesis of the Amino Ester 57
A soln of 56 (5.6 g, 8.66 mmol) in dry CH 2 Cl 2 (75 mL) was treated with TFA (15 mL) at rt for 1 h. The volatiles were evaporated. Aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) of the residue gave 57 (4.93 g, quant. yield).
Data of 57: C 32 H 36 N 2 O 6 (544.6). LC-MS (method 1a): R t =1.88 (93), 545.2 ([M+H] + ).
Synthesis of Amino Acid 58
A degassed solution of ester 57 (4.7 g, 8.66 mmol) and 1,3-dimethylbarbituric acid (1.62 g, 10.4 mmol) in CH 2 Cl 2 (73 mL) and EtOAc (73 mL) was treated with Pd(PPh 3 ) 4 (0.3 g, 0.26 mmol) at rt for 1.5 h. The volatiles were evaporated. The solid was suspended in EtOAc (200 mL), filtered and washed (EtOAc). The solid was suspended in CH 2 Cl 2 . The volatiles were evaporated. The residue was dried i.v. to yield 58 (3.94 g, 90%).
Data of 58: C 29 H 32 N 2 O 6 (504.6). LC-MS (method 1a): R t =1.61 (91), 505.2 ([M+H] + ).
Synthesis of Ex. 68
A soln of the amino acid 58 (3.45 g, 6.8 mmol) in CH 2 Cl 2 (150 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 10 mL, 17.1 mmol) and i-Pr 2 NEt (4.7 mL, 27.4 mmol) in dry CH 2 Cl 2 (1250 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 98.5:1.5) yielded Ex. 68 (2.57 g, 78%).
Data of Ex. 68: C 29 H 30 N 2 O 5 (486.5). LC-MS (method 1d): R t =2.23 (95), 486.9 ([M+H] + ).
Synthesis of Ex. 69
A soln of Ex. 68 (2.5 g, 5.2 mmol) in MeOH (50 mL) and CH 2 Cl 2 (25 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium on activated charcoal (moistened with 50% H 2 O; 1.9 g). The mixture was filtered through a pad of celite. The solid was washed with MeOH/CH 2 Cl 2 2:1. The combined filtrate and washings were concentrated to give Ex. 69 (2.0 g, 98%).
Data of Ex. 69: C 22 H 24 N 2 O 5 (396.4). LC-MS (method 1a): R t =1.58 (98), 397.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.05 (br. s, 1H); 8.21 (br. s, 1H); 7.86-7.17 (several m, 6.33H); 7.06 (s, 0.66H); 6.96 (d, J=8.2, 0.66H); 6.90 (dd, J=1.9, 8.2, 0.33H); 4.49-4.31 (m, 1.66H); 4.15 (s, 2H); 3.57 (t, J=11.8, 0.33H); 2.91, 2.86 (2 br. s, 3H); 2.45-2.20 (m, 2.33H); 2.2-2.0 (m, 1.66H); 1.15-1.12 (2 d, 3H).
Core 05: Synthesis of Ex. 90, Ex. 91 and Ex. 92 (Scheme 12)
Synthesis of Amide 59
A mixture of acid 10.HCl (9.34 g, 31.8 mmol), amine 28.HCl (13.1 g, 41.3 mmol), HATU (19.3 g, 51 mmol) and HOAt (6.93 g, 51 mmol) in DMF (75 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (21.6 mL, 127 mmol). The mixture was stirred for 4 h and concentrated to ca 50% of its volume. The mixture was diluted with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (H 2 O, sat. aq. NaHCO 3 soln,), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 50:50 to 20:80) of the crude product afforded 59 (13.4 g, 80%).
Data of 59: C 28 H 29 N 3 O 7 (519.5). LC-MS (method 1a): R t =1.89 (98), 520.0 ([M+H] + ).
Synthesis of Phenol 60
At 0° C. 3-(dimethylamino)propylamine (12.0 mL, 95.4 mmol) was slowly added to a soln of 59 (16.53 g, 31.8 mmol) in THF (110 mL). The soln was allowed to warm to rt over 2 h. Aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) yielded 60 (14.45 g, 95%).
Data of 60: C 26 H 27 N 3 O 6 (477.5). LC-MS (method 1a): R t =1.67 (97), 478.1 ([M+H] + ).
Synthesis of the Mitsunobu Product 61
The phenol 60 (4.35 g, 9.1 mmol) and the alcohol 18 (3.56 g, 11.8 mmol) were dissolved in toluene (39 mL). CMBP (3.0 mL, 11.4 mmol) was added and the mixture was heated to reflux for 0.5 h. More CMBP (0.31 mL, 1.2 mmol) was added and the mixture was refluxed for 0.5 h followed by evaporation of the volatiles and FC (hexane/EtOAc 50:50 to 0:100) to afford 61 (5.25 g, 77%).
Data of 61: C 40 H 49 N 5 O 10 (759.8). LC-MS (method 1a): R t =2.24 (92), 760.2 ([M+H] + ).
Synthesis of the Amino Acid 63
A soln of 61 (11.8 g, 16 mmol) in THF (59 mL) and MeOH (30 mL) was treated with 2 M aq. LiOH soln (31 mL, 62 mmol) at rt for 2 h. The volatiles were partially evaporated. The remaining mixture was acidified to pH ca 1 by addition of 3 M aq. HCl soln and repeatedly extracted with EtOAc. The combined organic phase was dried (Na 2 SO 4 ) and concentrated to afford crude acid 62 (12.6 g).
1,3-Dimethylbarbituric acid (3.2 g, 20.5 mmol) and acid 62 (12.5 g) were dissolved in CH 2 Cl 2 /EtOAc 1:1 (300 mL). The mixture was degassed, treated with Pd(PPh 3 ) 4 (1.98 g, 1.71 mmol) and stirred at rt for 2 h. The volatiles were evaporated. The residue was suspended in EtOAc and filtered to give 63 (9.80 g, 97%).
Data of 63: C 34 H 41 N 5 O 8 (647.7). LC-MS (method 1c): R t =1.51 (83), 648.1 ([M+H] + ).
Synthesis of Ex. 90
A soln of the amino acid 63 (2.0 g, 3.1 mmol) in DMF (50 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 9.1 mL, 15 mmol) and i-Pr 2 NEt (4.2 mL, 25 mmol) in dry CH 2 Cl 2 (600 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 97:3) yielded Ex. 90 (1.18 g, 60%).
Data of Ex. 90: C 34 H 39 N 5 O 7 (629.7). LC-MS (method 1d): R t =2.00 (99), 630.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 9.68, 9.62 (2 s, 1H); 9.18 (s, 1H); 9.11 (s, 1H); 8.97 (s, 1H); 8.41 (br. s, 1H); 7.58 (d, J=7.5, 1H); 7.40 (t, J=7.9, 1H); 7.40-7.20 (m, 5H); 7.17 (m, 1H); 6.94 (d, J=8.0, 1H); 5.15 (d, J=12.1, 0.5H); 5.12 (s, 1H); 5.01 (d, J=12.9, 0.5H); 4.55-4.15 (m, 4H); 4.15-3.5 (several m, 5H); 3.5-3.1 (several m, 3H); 2.11 (m, 1H); 1.91 (m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 91
A soln of Ex. 90 (200 mg, 0.32 mmol) in MeOH (5 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 50 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 91 (150 mg, 95%).
Data of Ex. 91: C 26 H 33 N 5 O 5 (495.6). LC-MS (method 1a): R t =1.48 (97), 496.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 9.73 (br. s, 1H); 9.26 (t, J=1.9, 1H); 9.18 (d, J=1.9, 1H); 8.94 (d, J=1.9, 1H); 8.51 (s, 1H); 7.59 (d, J=7.7, 1H); 7.40 (t, J=7.9, 1H); 7.26 (d, J=6.5, 1H); 6.94 (dd; J=1.9, 8.1, 1H); 4.5-4.4 (m, 2H); 4.26 (m, 1H); 3.89 (t, J ca. 11.5, 1H); 3.67 (dd, J=7.2, 9.7, 1H); 3.53 (d, J=17.9, 1H); 3.39 (d, J=17.8, 1H); 3.21-3.08 (m, 3H); 2.55 (m, 1H); ca 2.45 (m, 1H); 2.11 (m, 1H); 1.89 (m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 92
A soln of Ex. 90 (200 mg, 0.32 mmol) in dioxane (2 mL) was treated with 4 M HCl in dioxane (2 mL) for 15 h. The volatiles were evaporated. Purification by prep. HPLC (method 1c) afforded Ex. 92.2CF 3 CO 2 H (89 mg, 37%) and Ex. 93.3CF 3 CO 2 H (34 mg, 17%).
Data of Ex. 92.2 CF 3 CO 2 H: C 29 H 31 N 5 O 5 (529.6, free base). LC-MS (method 1a): R t =1.38 (98), 530.1 ([M+H] + ).
Data of Ex. 93.3 CF 3 CO 2 H: Cf Table 17b
Core 05: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 12)
Synthesis of Ex. 94
A soln of Ex. 91 (137 mg, 0.28 mmol) in DCE (4.0 mL) was cooled to 0° C. Aq. formaldehyde soln. (36.5%; 0.104 mL, 1.38 mmol) was added followed by acetic acid (0.019 mL, 0.332 mmol) and NaBH(OAc) 3 (234 mg, 1.106 mmol). The mixture was stirred at 0° C. for 4 h followed by an aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln). FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 94 (119 mg, 84%).
Data of Ex. 94: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.60 (br. s, 1H); 9.21 (t, J=1.9, 1H); 9.17 (d, J=1.9, 1H); 8.93 (d, J=1.9, 1H), 8.48 (s, 1H); 7.58 (d, J=7.7, 1H); 7.39 (t, J=8.0, 1H); 7.28 (d, J=6.4, 1H); 6.94 (dd, J=1.9, 8.1, 1H); 4.45-4.41 (br, m, 2H); 4.26 (m, 1H); 3.88 (br. t, J ca 11.5, 1H); 3.68 (dd, J=7.2, 9.7, 1H); 3.45 (d, J=17.6, 1H); 3.89-3.21 (m, 3H, signal partially superimposed by H 2 O signal); 3.15 (t-like m, J ca 9, 1H); 2.62 (br. not resolved m, 2H), 2.37 (s, 3H); 2.11 (m, 1H); 1.90 (m, 1H); 1.41 (s, 9H).
Synthesis of Ex. 95
A soln of Ex. 94 (100 mg, 0.196 mmol) in dioxane (1.0 mL) was treated with 4 M HCl-dioxane (1.0 mL) for 2 h. The volatiles were evaporated to afford Ex. 95.3HCl (116 mg, quant.).
Data of Ex. 95.3HCl: cf. Table 17b
Synthesis of Ex. 96
At 0° C., i-Pr 2 NEt (0.11 mL, 0.65 mmol) was slowly added to a soln of Ex. 95.3HCl (97 mg, 0.19 mmol), 2-naphthaleneacetic acid (49 mg, 0.26 mmol), HATU (124 mg, 0.326 mmol) and HOAt (44 mg, 0.323 mmol) in DMF (1.0 mL). The mixture was stirred at at 0° C. for 2 h and distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) and prep. HPLC (method 1b) afforded Ex. 96.2CF 3 CO 2 H (62 mg, 41%).
Data of Ex. 96: cf. Table 17b
1 H-NMR (DMSO-d 6 ): Ca. 9.7 (very br. s, 1H); 9.28 (very br. s, 1H); 9.14 (br. s, 1H); 8.96 (very br. s, 1H); 8.62 (d, J=5.4, 1H); 8.54 (br. s, 1H); 8.30 (br. s, 1H); 7.90-7.85 (m, 3H); 7.77 (s, 1H); 7.65 (d, J=7.6, 1H); 7.53-7.41 (m, 4H); 6.98 (d, J=8.3, 1H); 4.55-4.33 (2 br. not resolved m, 5H); 4.01 (t, J=11.2, 1H); 3.85 (br. t, J ca 8.4, 1H); 3.65 (br. not resolved m, 2H); 3.63 (s, 2H); 3.39 (br. not resolved m, 2H); 3.11 (t, J=9.0, 1H); 2.89 (s, 3H); 2.26 (m, 1H); 2.04 (m, 1H).
Synthesis of Ex. 101
A soln of 1-naphthaleneacetic acid (43 mg, 0.23 mmol) and T3P (50% in DMF; 0.17 mL; 0.29 mmol) in DMF (0.3 mL) was added dropwise to a suspension of Ex. 95.3HCl (50 mg, 0.096 mmol) in DMF (0.2 mL). The mixture was stirred at rt for 15 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 101.2 CF 3 CO 2 H (38 mg, 49%).
Data of Ex. 101.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.71 (very br. s, 1H); 9.26 (d, J=1.9, 1H); 9.13 (br. s, 1H); 8.93 (d, J=1.5, 1H); 8.68 (d, J=5.6, 1H); 8.52 (br. s, 1H); 8.30 (s, 1H); 8.10 (m, 1H), 7.93 (m, 1H); 7.84 (dd, J=1.9, 7.3, 1H); 7.66 (d, J=7.7, 1H); 7.57-7.41 (m, 5H); 6.98 (dd, J=1.8, 8.3, 1H); 4.55-4.39 (2 br. not resolved m, 5H); 4.04-3.94 (m, 3H); 3.83 (br. t, J ca 8.5, 1H); 3.68 (br. not resolved m, 2H); 3.41 (br. not resolved m, 2H); 3.12 (t, J=9.0, 1H); 2.89 (s, 3H); 2.26 (m, 1H); 2.03 (m, 1H).
Synthesis of Ex. 103
At 4° C., Et 3 N (0.04 mL, 0.29 mmol) and then benzenesulfonyl chloride (17 mg, 0.096 mmol) were added to a soln of Ex. 95.3HCl (50 mg, 0.096 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at rt for 15 h; i-Pr 2 NEt (0.049 mL, 0.29 mmol) and more benzenesulfonyl chloride (17 mg, 0.096 mmol) were added. Stirring was continued for 1 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln, Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 103.2 CF 3 CO 2 H (33 mg, 44%).
Data of Ex. 103.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.69 (br. s, 1H); 9.24 (d, J=1.9, 1H); 9.09 (br. s, 1H); 8.92 (d, J=1.6, 1H); 8.47 (br. s, 1H); 8.30 (br. s, 1H); 8.22 (br. s, 1H); 7.90-7.88 (m, 2H); 7.74-7.63 (m, 4H); 7.41 (t, J=7.9, 1H); 6.93 (dd; J=1.9, 8.2, 1H); ca. 4.5-4.2 (m, 4H); 4.00 (br. not resolved m, 1H); 3.89 (t, J ca. 11.4, 1H); 3.69-3.63 (m, 3H); 3.42 (br. not resolved m, 2H); 3.23 (dd, J=8.4, 9.7; 1H); 2.91 (s, 3H); 2.02 (m, 1H); 1.88 (m, 1H).
Synthesis of Ex. 97
3-Fluorobenzaldehyde (50 mg, 0.40 mmol) was added to a soln of Ex. 91 (120 mg, 0.24 mmol) in THF (1.5 mL). The soln was stirred at rt for 1 h followed by the addn of acetic acid (0.015 mL, 0.27 mmol) and NaBH(OAc) 3 (154 mg, 0.73 mmol). The mixture was stirred at rt for 16 h. More 3-fluorobenzaldehyde (15 mg, 0.12 mmol) was added and stirring continued. Aq. workup (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH) afforded Ex. 97 (117 mg, 80%).
Data of Ex. 97: cf. Table 17b
Synthesis of Ex. 98
A soln of Ex. 97 (94 mg, 0.156 mmol) in dioxane (0.8 mL) was treated with 4 M HCl-dioxane (0.8 mL) for 2 h. The volatiles were evaporated to afford Ex. 98.3HCl (91 mg, 95%).
Data of Ex. 98.3HCl: cf. Table 17b
Synthesis of Ex. 100
A soln of Ex. 98.3HCl (62 mg, 0.10 mmol) in CH 2 Cl 2 (0.6 mL) was treated with pyridine (0.041 mL, 0.51 mmol) and acetyl chloride (16 mg, 0.2 mmol) at rt for 16 h. i-Pr 2 NEt (0.052 mL, 0.3 mmol) and more acetyl chloride (16 mg, 0.2 mmol) were added and stirring was continued for 24 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 100.2 CF 3 CO 2 H (50 mg, 64%).
Data of Ex. 100.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): Ca. 9.5 (br. s, 1H); 9.23 (s, 2H); 8.96 (d, J=1.0, 1H); 8.45 (br. s, 1H); 8.17 (d, J=6.5, 1H); 7.62 (d, J=7.7, 1H); 7.42 (t, J=7.9, 1H); ca 7.4 (br. not resolved m, 1H); ca 7.35-7.25 (br. not resolved m, 2H); 7.15 (br. t-like m, 1H); 6.97 (dd; J=1.9, 8.2, 1H); 4.52-4.39 (m, 4H); ca 4.2-3.8 (br. not resolved m, 3H); 3.90 (t, J=11.3, 1H); 3.71 (t-like m, 2H); 3.49 (m, 1H); 3.33 (br. t-like m, 1H); 3.07 (t, J=9.0, 1H); 2.95 (br. not resolved m, 2H); 2.14 (m, 1H); 1.89 (m, 1H); 1.81 (s, 3H).
Core 06/07: Synthesis of Ex. 115, Ex. 116 and Ex. 129, Ex. 130 (Scheme 13)
Synthesis of the Arylbromide 65
2-Bromothiophenol (11; 2.71 mL, 23 mmol) was added to a soln of 30 (5.0 g, 19.1 mmol) and CMBP (6.02 mL, 23 mmol) in toluene (50 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/EtOAc 4:1) afforded 65 7.31 g, 88%)
Data of 65: C 18 H 26 BrNO 4 S (432.3). LC-MS (method 1c): R t =2.58 (97), 434.0/431.9 ([M+H] + ).
Synthesis of the Biphenyl 66
Sat. aq. NaHCO 3 soln (37.8 mL) was added dropwise to a soln of 65 (5.0 g, 11.6 mmol), 3-hydroxyphenylboronic acid (12, 4.79 g, 34.7 mmol) and Pd(PPh 3 ) 4 (1.34 g, 1.16 mmol) in DME (150 mL). The mixture was heated to reflux for 4 h. The volatiles were evaporated and the residue was distributed between EtOAc and sat. aq. Na 2 CO 3 soln. The organic phase was repeatedly washed (sat. aq. Na 2 CO 3 soln), dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /EtOAc 100:0 to 95:5) afforded 66 (3.91 g, 75%).
Data of 66: C 24 H 31 NO 5 S (445.5). LC-MS (method 1a): R t =2.46 (94), 446.1 ([M+H] + ).
Synthesis of the Phenol 68
At 0° C., TFA (11.9 mL) was slowly added to a soln of 66 (2.38 g, 5.34 mmol) in CH 2 Cl 2 (24 mL). Stirring was continued for 1 h followed by evaporation of the volatiles. The residue was dissolved in CHCl 3 and concentrated to afford 67-CF 3 CO 2 H as a brown oil which was dissolved in CH 2 Cl 2 (12 mL) and cooled to 0° C. i-Pr 2 NEt (2.73 mL, 16.0 mmol) was slowly added. Allyl chloroformate (0.63 mL, 5.88 mmol) in CH 2 Cl 2 (12 mL) was added over 30 min. The mixture was stirred for 2 h followed by evaporation of the volatiles. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 9:1 to 7:3) yielded 68 (2.02 g, 88%).
Data of 68: C 23 H 27 NO 5 S (429.5). LC-MS (method 1a): R t =2.29 (92), 430.1 ([M+H] + ).
Synthesis of the Ether 69
A soln of ADDP (1.34 g, 5.31 mmol) in degassed CHCl 3 (5.0 mL) was added at 0° C. to a soln of 68 (1.52 g, 3.54 mmol), Boc-D-alaminol (20; 0.93 g, 5.31 mmol) and PPh 3 (1.39 g, 5.31 mmol) in CHCl 3 (20 mL). The mixture was stirred at 0° C. to rt for 16 h. More Boc-D-alaminol (20; 0.93 g, 5.31 mmol) and PPh 3 (1.39 g, 5.31 mmol) were added. The mixture was cooled to 0° C. followed by the slow addition of ADDP (1.34 g, 5.31 mmol) in CHCl 3 (5.0 mL). The mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1 to 3:1) to afford 69 (1.6 g, 77%). Data of 69: C 31 H 42 N 2 O 7 S (586.7). LC-MS (method 1a): R t =2.78 (97), 587.1 ([M+H] + ).
Synthesis of the Amino Acid 71
A soln of 69 (3.2 g, 5.5 mmol) in THF (17 mL) and MeOH (17 mL) was treated at 0° C. with 1 M aq. LiOH soln (6.5 mL, 6.5 mmol). The mixture was allowed to stir at 0° C. to rt for 16 h. The volatiles were evaporated. The residue was distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ) and concentrated to afford crude acid 70 (3.02 g) which was dissolved in dioxane (12.5 mL) and treated with 4 M HCl-dioxane (7.9 mL) for 4 h. The volatiles were evaporated. The residue was taken up in CHCl 3 and concentrated to afford crude 71.HCl (2.84 g, quant. yield) which was used without further purification.
Data of 71.HCl: C 25 H 32 N 2 O 5 S.HCl (472.6, free base). LC-MS (method 1a): R t =1.76 (89), 473.1 ([M+H] + ).
Synthesis of Ex. 115
A soln of crude 71.HCl (0.94 g, 1.8 mmol) in CH 2 Cl 2 (45 mL) was added over 2 h to a soln of T3P (50% in EtOAc; 2.7 mL, 4.6 mmol) and i-Pr 2 NEt (1.3 mL, 7.4 mmol) in CH 2 Cl 2 (1810 mL). The soln was partially concentrated, washed with sat. aq. NaHCO 3 soln, dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 8:2 to 1:1) gave Ex. 115 (0.63 g, 75%).
Data of Ex 115: C 25 H 30 N 2 O 4 S (454.6). LC-MS (method 1d): R t =2.35 (95), 455.0 [M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.57-7.52 (m, 2H); 7.38-7.21 (m, 5H); 7.01-6.95 (m, 2H); 6.90 (d, J=7.9, 1H), 5.90 (m, 1H); 5.29 (d, J=17.2, 1H); 5.17 (d, J=10.0, 1H); 4.47-4.45 (m, 2H); 4.13-3.97 (m, 3H); 3.82 (q, J=6.5, 1H); 2.60-2.57 (m, 2H); 1.57-1.09 (m, 6H); 1.19 (d, J=6.5, 3 H).
Synthesis of Ex. 116
A soln of Ex. 115 (120 mg, 0.26 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (2.1 mL) was treated at rt for 16 h with Pd(PPh 3 ) 4 (1.2 mg) and 1,3-dimethylbarbituric acid (49 mg, 0.32 mmol). The volatiles were evaporated and the residue purified by FC (hexane/EtOAc 50:50 to 0:100, then CH 2 Cl 2 /MeOH 100:0 to 90:10) to afford Ex. 116 (82 mg, 83%).
Data of Ex. 116: C 21 H 26 N 2 O 2 S (370.5). LC-MS (method 1a): R t =1.74 (95), 371.1 ([M+H] + ).
1 H-NMR (DMSO-d 6 ): 7.76 (d, J=7.1, 1H); 7.55 (m, 1H); 7.37-7.26 (m, 4H); 7.07 (t-like m, 1H); 6.98 (dd-like m, 1H); 6.87 (d-like m, J ca 7.9, 1H), 4.14-4.01 (m, 3H); 3.32 (t, J=5.0, 1H); 2.67-2.55 (m, 2H); ca 2.6 (very br. s, 2H); 1.56 (m, 1H); 1.38-1.03 (m, 5H); 1.21 (d, J=6.3, 3H).
Synthesis of Ex. 129
At 0° C., mCPBA (70%, 876 mg, 3.55 mmol) was added in portions to a soln of Ex. 115 (808 mg, 1.78 mmol) in CH 2 Cl 2 (17 mL). The mixture was stirred at 0° C. to rt for 2 h and concentrated, followed by an aq. workup (EtOAc, sat. aq. NaHCO 3 soln, 1 M aq. Na 2 S 2 O 3 soln; Na 2 SO 4 ). FC (hexane/EtOAc 50:50 to 0:100) gave Ex. 129 (788 mg, 91%).
Data of Ex. 129:C 25 H 30 N 2 O 6 S (486.6). LC-MS (method 1a): R t =1.91 (93), 487.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.06 (dd, J=1.3, 7.9, 1H); 7.77 (dt, J=1.4, 7.5, 1H); 7.68 (dt, J=1.4, 7.7, 1H); 7.49-7.44 (m, 2H); 7.39 (t, J=8.0, 1H); 7.09-7.03 (m, 3H); 6.73 (s, 1H); 5.88 (m, 1H); 5.27 (d, J=17.3, 1H); 5.17 (d, J=10.3, 1H); 4.45 (d, J=4.9, 2 H); 4.08-3.96 (m, 3H); 3.75 (q-like m, J=7.6, 1H); 2.45 (br. m, 2H); 1.45-1.01 (m, 5H); 1.23 (d, J=6.8, 3 H); 1.01 (m, 1H).
Synthesis of Ex. 130
A soln of Ex. 129 (100 mg, 0.21 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (1.7 mL) was treated at rt for 3 h with Pd(PPh 3 ) 4 (1.0 mg) and 1.3-dimethylbarbituric acid (39 mg, 0.25 mmol). The volatiles were evaporated and the residue purified by FC (hexane/EtOAc 50:50 to 0:100, then CH 2 Cl 2 /MeOH 100:0 to 90:10) to afford Ex. 130 (82 mg, 98%).
Data of Ex. 130: C 21 H 26 N 2 O 4 S (402.5). LC-MS (method 1a): R t =1.48 (94), 403.0 ([M+H] + ).
Core 06: Synthesis of Selected Advanced Intermediates and Final Products
(Scheme 13)
Synthesis of Ex. 119
At 0° C., i-Pr 2 NEt (0.055 mL, 0.324 mmol) was slowly added to a solution of Ex. 116 (40 mg, 0.108 mmol), 1-pyrrolidineacetic acid (17 mg, 0.13 mmol), HATU (62 mg, 0.162 mmol) and HOAt (22 mg, 0.162 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 0° C., followed by an aqueous workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and purification by prep HPLC (method 3) to give Ex. 119 (30 mg, 57%).
Data of Ex. 119: cf. Table 18b.
Core 08/09: Synthesis of Ex. 143, Ex. 144 and Ex. 168, Ex. 169 (Scheme 14)
Synthesis of Thioether 72
5-Bromopyridine-3-thiol (13; 1.0 g, 5.3 mmol) was added to a soln of alcohol 30 (1.06 g, 4.0 mmol) and CMBP (1.17 g, 4.85 mmol) in toluene (15 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/EtOAc 4:1) of the residue gave 72 (1.35 g, 77%).
Data of 72: C 17 H 25 BrN 2 O 4 S (433.6). LC-MS (method 1c): R t =2.37 (93), 433.0/435.0 ([M+H] + ).
Synthesis of Phenol 73
At rt, sat. aq. NaHCO 3 soln (17.1 mL) was added to a soln of 72 (2.65 g, 6.1 mmol), 2-hydroxyphenylboronic acid (14; 2.53 g, 18.3 mmol) and Pd(PPh 3 ) 4 (707 mg, 0.61 mmol) in DME (78 mL). The mixture was heated to reflux for 1 h followed by an aq. workup (EtOAc, sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:1) to afford 73 (2.42 g, 88%).
Data of 73: C 23 H 30 N 2 O 5 S (446.6). LC-MS (method 1a): R t =1.82 (96), 447.1 ([M+H] + ).
Synthesis of Phenol 75
At 0° C., a soln of 73 (500 mg, 1.12 mmol) in CH 2 Cl 2 (4.0 mL) was treated with TFA (3.0 mL) for 2 h and concentrated. Aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded crude 74 which was dissolved in CH 2 Cl 2 (4.0 mL). The soln was cooled to 0° C. A soln of AllocOSu (245 mg, 1.23 mmol) in CH 2 Cl 2 (1.0 mL) was added dropwise. Stirring was continued for 2 h followed by an aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 1:1) to yield 75 (310 mg, 64%).
Data of 75: C 22 H 26 N 2 O 5 S (430.5). LC-MS (method 1a): R t =1.68 (94), 431.1 ([M+H] + ).
Synthesis of the Ether 76
At 0° C., ADDP (967 mg, 3.83 mmol) was added in portions to a soln of alcohol 20 (672 mg, 3.83 mmol), phenol 75 (1.1 g, 2.55 mmol) and PPh 3 (1.0 g, 3.83 mmol) in CHCl 3 (15 mL). The mixture was stirred for 4 h at rt and concentrated. FC (hexane/EtOAc 4:1 to 2:1) afforded 76 (450 mg, 30%).
Data of 76: C 30 H 41 N 3 O 7 S (587.7). LC-MS (method 1a): R t =2.33 (87), 588.2 ([M+H] + ).
Synthesis of the Amino Acid 78
At 0° C., 1 M aq. LiOH (0.67 mL, 0.67 mmol) was added to a soln of 76 (430 mg, 0.73 mmol) in THF/MeOH 2:1 (1.5 mL). The mixture was stirred at 0° C. to rt for 5 h and distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was separated, dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 80:20) gave acid 77 (288 mg) which was dissolved in dioxane (1 mL) and treated with 4 M HCl-dioxane (1.15 mL) for 6 h at rt. The volatiles were evaporated. The residue was suspended in EtOAc, filtered and dried i.v. to afford 78.2HCl (256 mg, 64%).
Data of 78.2HCl: C 24 H 31 N 3 O 5 S.2HCl (473.6, free base). LC-MS (method 1c): R t =1.39 (92), 474.1 ([M+H] + ).
Synthesis of Ex. 143
A soln of 78.2HCl (200 mg, 0.37 mmol) and i-Pr 2 NEt (0.125 mL, 0.73 mmol) in CH 2 Cl 2 (5 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc; 0.65 mL, 1.1 mmol) and i-Pr 2 NEt (0.188 mL, 1.1 mmol) in CH 2 Cl 2 (177 mL). Aq. Workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) afforded Ex. 143 (105 mg, 63%).
Data of Ex. 143: C 24 H 29 N 3 O 4 S (455.5). LC-MS (method 1d): R t =1.66 (98), 456.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.52 (d, J=2.2, 1H); 8.40 (d, J=1.9, 1H); 8.36 (s, 1H); 8.11 (d, J=5.5, 1H); 7.45-7.39 (m, 2H); 7.20 (d, J=7.6, 1H); 7.14 (d, J=8.2, 1H); 7.08 (t, J=7.5, 1H); 5.88 (m, 1H); 5.28 (d, J=16.5, 1H); 5.16 (d, J=10.4, 1 H); 4.44 (d, J=5.2, 2 H); 4.17-3.97 (m, 4H); 3.06 (m, 1H); 2.89 (m, 1H); 1.85 (m, 1H); ca 1.6-1.3 (m, 5H); 1.09 (d, J=6.3, 3 H).
Synthesis of Ex. 144
A degassed solution of Ex. 143 (200 mg, 0.44 mmol) in degassed CH 2 Cl 2 /EtOAc 1:1 (11 mL) was treated at rt for 2 h with Pd(PPh 3 ) 4 (2.0 mg) and 1,3-dimethylbarbituric acid (82 mg, 0.53 mmol). The volatiles were evaporated. FC (hexane/EtOAc 50:50 to 0:100 and then CH 2 Cl 2 /MeOH 99:1 to 95:5) gave Ex. 144 (128 mg, 78%).
Data of Ex. 144: C 20 H 25 N 3 O 2 S (371.5). LC-MS (method 1a): R t =1.30 (97), 371.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.52 (d, J=2.2, 1H); 8.40 (d, J=2.0, 1H); 8.16 (t, J=2.1, 1H); 7.77 (d, J=6.4, 1H); 7.45-7.39 (m, 2H); 7.16 (d, J=7.9, 1H); 7.07 (dt; J=0.8, 7.1, 1H); 4.13-4.04 (m, 2H); 3.97 (br. not resolved m, 1H); 3.21 (t-like m, 1H); 3.08-2.89 (m, 2H); 2.01 (br. s, 2H); 1.74-1.18 (several m, 6H); 1.12 (d, J=6.5, 3 H).
Synthesis of Ex. 168
H 2 O 2 (35% in H 2 O; 0.043 mL; 0.49 mmol) was added to a soln of Ex. 143 (32 mg, 0.07 mmol) in AcOH (1.0 mL). The mixture was stirred at rt for 20 h; after 2 h and after 3 h, 16 h and 17 h more H 2 O 2 (35% in H 2 O; 0.043 mL; 0.49 mmol) had been added. The mixture was diluted with H 2 O and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to yield Ex. 168 (28 mg, 82%).
Data of Ex. 168: C 24 H 29 N 3 O 6 S (487.5). LC-MS (method 1a): R t =1.78 (92), 488.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.99 (d, J=2.2, 1H); 8.91 (d, J=1.9, 1H); 8.52 (s, 1H); 7.86 (d, J=4.9, 1H); 7.49-7.44 (m, 2H); 7.17-7.08 (m, 3H); 5.86 (m, 1H); 5.26 (d, J=18.6, 1H); 5.15 (d, J=9.9, 1H); 4.42 (m, 2H); 4.11-3.95 (m, 3H); 3.87 (q-like m, 1H); 3.56 (m, 1H); 3.35 (m, 1H); ca 1.70 (m, 1H); ca 1.65 (m, 1H); 1.40-1.10 (m, 4H); 1.06 (d, J=6.1, 3 H).
Synthesis of Ex. 169
A soln of Ex. 168 (2.19 g, 4.5 mmol) and 1,3-dimethylbarbituric acid (2.1 g, 13.5 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (65 mL) was treated at rt for 2 h with Pd(PPh 3 ) 4 (260 mg). The volatiles were evaporated and the residue purified by FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) to afford Ex. 169 (1.81 g, quant. yield).
Data of Ex. 169: C 20 H 25 N 3 O 4 S (403.5). LC-MS (method 1a): R t =1.34 (96), 403.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.97 (d, J=2.2, 1H); 8.92 (d, J=2.0, 1H); 8.39 (t, J=2.1, 1H); 7.64 (d, J=6.5, 1H); 7.49-7.42 (m, 2H); 7.17 (d, J=8.0, 1H); 7.11 (t, J=7.4, 1H); 4.11-3.97 (m, 3H); 3.63 (m, 1H); 3.40 (m, 1H); 3.07 (m, 1H); 1.98 (br. s, 2H); 1.58 (quint, J=7.1, 2 H); 1.27-1.16 (m, 2H); 1.09 (d, J=6.0, 3 H); 1.09 (m, 1H), 0.97 (m, 1H).
Core 10/11: Synthesis of the B-A B -A C Fragment 84 (Scheme 15)
Synthesis of the Allylester 79
Oxalyl chloride (1.8 mL, 20.4 mmol) and DMF (26 μL) were added to a suspension of 10.HCl (2.0 g, 6.8 mmol) in CHCl 3 (50 mL). The mixture was stirred at rt for 1 h and concentrated (at 35° C.). The residue was suspended in THF (50 mL) and cooled to 0° C. Allyl alcohol (1.4 mL, 20.4 mmol) and Et 3 N (2.9 mL, 20.4 mmol) were added.
The mixture was stirred at rt for 1 h followed by an aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ). FC (hexane/EtOAc 3:1) yielded 79 (1.78 g, 88%).
Data of 79: C 17 H 15 NO 4 (297.3). LC-MS (method 1b): R t =1.96 (99), 298.0 ([M+H] + ).
Synthesis of the Phenol 80
3-Dimethylaminopropylamine (2.3 mL, 17.9 mmol) was added at rt to a soln of 79 (1.77 g, 5.9 mmol) in THF (65 mL). The soln was stirred at rt for 3 h followed by an aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford 80 (1.27 g, 83%).
Data of 80: C 15 H 13 NO 3 (255.3). LC-MS (method 1a): R t =1.65 (91), 255.9 ([M+H] + ).
Synthesis of the Arylether 81
A soln of ADDP (1.56 g, 6.2 mmol) in degassed CHCl 3 (10 mL) was slowly added to a soln of 80 (1.26 g, 4.9 mmol), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21; 0.83 g, 4.12 mmol) and PPh 3 (1.62 g, 6.2 mmol) in degassed CHCl 3 (20 mL). The soln was stirred at rt for 15 h followed by evaporation of the volatiles. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1) to afford 81 (1.78 g, 98%).
Data of 81: C 25 H 30 N 2 O 5 (438.5). LC-MS (method 1a): R t =2.58 (98), 439.1 ([M+H] + ).
Synthesis of Acid 84
A soln of 81 (1.76 g, 4.0 mmol) in MeOH/THF 1:1 (30 mL) was treated with 2 M aq. LiOH soln (4.0 mL, 8.0 mmol) for 1 h at rt. The mixture was concentrated. The residue was distributed between EtOAc and 1 aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give crude 82.HCl (1.5 g) which was dissolved in dioxane (15 mL) and treated with 4 M HCl-dioxane (30 mL) for 2.5 h at rt. The mixture was concentrated and repeatedly treated with CHCl 3 and concentrated to obtain crude 83.2HCl (1.79 g).
To a soln of crude 83.2HCl (1.24 g) in THF (11 mL) was added 2 M aq NaOH soln (5.3 mL). The mixture was cooled to 0° C. A soln of allyl chloroformate (0.34 mL, 3.2 mmol) in THF (5 mL) was added dropwise over 30 min (syringe pump). Stirring was continued for 30 min followed by an aq. workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1d) to yield 84.CF 3 CO 2 H (0.93 g, 67%).
Data of 84.CF 3 CO 2 H: C 21 H 22 N 2 O 5 .CF 3 CO 2 H (382.4, free form). LC-MS (method 1a): R t =1.80 (99), 383.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): ca 13.5 (br. s, 1H); 9.12 (s, 1H); 9.06 (d, J=1.9, 1H); 8.48 (s, 1H); 7.46-7.34 (m, 3H); 7.06 (d, J=7.4, 1H); 5.92 (m, 1H); 5.31-5.15 (m, 2H); 4.61-4.48 (m, 2H); 4.23-4.02 (m, 3H); 3.37-3.35 (m, 2H); ca 2.1-1.8 (m, 4H).
Core 10: Synthesis of Ex. 193a,c-h and Ex. 194b (Scheme 15)
Procedure C.1:
General Procedure for the Synthesis of Ex. 193a-h and Ex. 194b (Scheme 15)
1. Synthesis of resins 85a-h: Immobilisation of Fmoc-AA1-OH
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100-200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH 2 Cl 2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH 2 Cl 2 (80 mL). A soln of Fmoc-AA1-OH (10.3 mmol) and i-Pr 2 NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N 2 bubbling through. The resin was filtered and washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 ). Capping: The resin was shaken in CH 2 Cl 2 /MeOH/i-Pr 2 NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 , MeOH) and dried i.v. to afford resin 85.
Chlorotrityl- Yield/Loading Resin chlorid resin Fmoc-AA1-OH (mass increase) 85a, h 5 g Fmoc-β 3 - 6.79 g/0.72 mmol/g homoPhe-OH 85b, e, f, g 10 g Fmoc-NMe-β 3 - 13.0 g/0.78 mmol/g homoDAla-OH 85c, d 10 g Fmoc-β-Ala-OH 12.5 g/0.73 mmol/g
2. Synthesis of Ex. 193a,c-h and Ex. 194b
Fmoc Cleavage: The resin 85 (90-110 mg, ca 70 μmol) was swollen, in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2% v/v DBU in DMF (1 mL), shaken for 10 min, filtered off and washed (DMF). The deprotection step was repeated once. The resin was filtered and washed (DMF).
Coupling of Fmoc-AA2-OH: The resin 86 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA2-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 87 was filtered and washed (DMF).
Fmoc Cleavage: The resin was treated with 2% v/v DBU in DMF (1 mL) as described above to yield resin 88.
Coupling of Alloc-protected amino acid 84: The resin 88 was suspended in DMF (1 mL) 1) . i-Pr 2 NEt (560 μmol), 84 (35 mg, 70 μmol) and PyBOP (140 μmol) were added. The mixture was shaken for 1 h and filtered. The resin was washed (DMF). The coupling step was repeated once. The resin 89 was filtered and washed (DMF, CH 2 Cl 2 ). 1) Ex. 193c,d: Coupling of 84 was performed in DMF/NMP 6:1
Alloc Cleavage: The resin 89 was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (0.18 mL; 1.45 mmol) 2) and Pd(PPh 3 ) 4 (8 mg, 7 μmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 90 was filtered and washed (CH 2 Cl 2 , DMF, MeOH, CH 2 Cl 2 ). 2) Ex. 193c,d: 0.09 mL/0.7 mmol Phenylsilane was used
Release of the cyclization precursor: The resin 90 was treated with HFIP/CH 2 Cl 2 2:3 (1 mL) for 30 min, filtered and washed (CH 2 Cl 2 ). The cleavage step was repeated once. The combined filtrates and washings were concentrated and dried i.v. to afford crude 91a-h.
Ring closure and cleavage of side chain protective groups: Crude 91 was dissolved in dry DMF (4 mL) 3) and i-Pr 2 NEt (96 μL; 560 μmol) was added. This soln was then added dropwise to a soln of FDPP (40 mg, 105 μmol) in DMF (20 mL) 3) . The soln was stirred at rt for 15 h and the volatiles were evaporated. The residue was treated with sat. aq. Na 2 CO 3 soln (4 mL) and extracted with CHCl 3 (9 mL). The organic layer was filtered through a pad of MgSO 4 . The filtrate was concentrated and purified by prep. HPLC to afford Ex. 193a,c-h. 3) Ex. 193c,d: Ring closure was performed in a total volume of 12 mL of DMF
Crude Ex. 193b was dissolved in CH 2 Cl 2 (0.7 mL) and treated with TFA (0.3 mL) at rt for 3 h. The volatiles were evaporated and the residue was purified by prep. HPLC to give Ex. 194b.
Purification methods applied, yields, LC-MS data and systematic names of Ex. 193a,c-h and Ex. 194b are indicated in Table 22.
Ex. 193a: 1 H-NMR (DMSO-d 6 ): 9.21 (d, J=2.1, 1H); 8.80 (t, J=2.0, 1H); 8.64 (d, J=1.8, 1H); 8.50 (d, J=9.0, 1H); 8.30 (s, 1H); 7.65 (d, J=7.7, 1H); 7.40 (t, J=7.9, 1 H); 7.30-7.10 (m, 5H); 6.94 (dd, J=1.8, 8.2, 1H); 5.23 (q, J=7.2, 1H); 4.50 (d, J=11.6, 1H); 4.36-4.26 (m, 2H); 3.82 (t, J=11.2, 1H); 3.20-3.17 (m, 2H); 2.99-2.70 (m, 2H); 2.81 (s, 3H); ca 2.50 (m, 2H; superimposed by DMSO-d signal); 2.09-1.77 (m, 4H); 1.34 (d, J=7.2, 3 H).
Ex. 194b: 1 H-NMR (DMSO-d 6 , addition of D 2 O): Two sets of signals were observed; ratio 9:1; signals of major isomer: 9.17 (d, J=2.0, 1H); 8.64 (s, 1H); 8.59 (d, J=1.7, 1H); 8.09 (s, 1H); 7.57 (d, J=7.8, 1H); 7.40 (t, J=7.9, 1H); 6.93 (dd, J=1.6, 8.2, 1H); 5.54 (t-like m, 1H); 4.56-4.53 (m, 2H); 4.31 (m, 1H); 3.68 (t, J=11.3, 1H); 3.55 (br. t-like m, 1H); 3.36 (br. q-like m, 1H); 2.81 (s, 3H); 2.80 (s, 3H); 2.62-2.60 (m, 2H); 2.31-2.27 (m, 2H); ca 2.1-1.75 (m, 6H); 1.12 (d, J=6.8; 3 H).
Core 11: Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d (Scheme 16)
Procedure C.2:
General Procedure for the Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d (Scheme 16)
1. Synthesis of Resins 135a-k: Immobilisation of Fmoc-AA1-OH
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100-200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH 2 Cl 2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH 2 Cl 2 (80 mL). A soln of Fmoc-AA1-OH (10.3 mmol) and i-Pr 2 NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N 2 bubbling through. The resin was filtered and washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 ). Capping: The resin was shaken in CH 2 Cl 2 /MeOH/i-Pr 2 NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 , MeOH) and dried i.v. to afford resin 135.
Chlorotrityl- Yield/Loading Resin chlorid resin Fmoc-AA1-OH (mass increase) 135a-d 10 g Fmoc-NMe-β 3 - 13.0 g/0.78 mmol/g homoDAla-OH 135e, f, h, j 1 g Fmoc-Sar-OH 1.34 g/0.80 mmol/g 135g 1 g Fmoc-Gly-OH 1.22 g/0.70 mmol/g 135i 1 g Fmoc-Ala-OH 1.28 g/0.67 mmol/g 135k 2 g Fmoc-DAla-OH 2.35 g/0.71 mmol/g
2. Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d
Fmoc Cleavage: The resin 135 (90-107 mg, ca 70 μmol) was swollen in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2% v/v DBU in DMF (1 mL), shaken for 10 min filtered and washed (DMF). The deprotection step was repeated once. The resin 136 was filtered and washed (DMF).
Coupling of Fmoc-AA2-OH: The resin 136 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA2-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 137 was filtered and washed (DMF).
Fmoc Cleavage: The resin 137 was treated with 2% v/v DBU in DMF (1 mL) as described above to afford resin 138.
Coupling of Fmoc-AA3-OH: The resin 138 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA3-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 139 was filtered and washed (DMF).
Fmoc Cleavage: The resin 139 was treated with 2% v/v DBU in DMF (1 mL) as described above to afford resin 140.
Coupling of Alloc-protected amino acid 84: The resin 140 was suspended in DMF (1 mL). i-Pr 2 NEt (560 μmol), 84 (36 mg, 84 μmol) and PyBOP (140 μmol) were added. The mixture was shaken for 1 h and filtered. The resin 141 was washed (DMF). The coupling step was repeated once. The resin was filtered and washed (DMF, CH 2 Cl 2 ).
Alloc Cleavage: The resin 141 was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (0.18 mL; 1.4 mmol) and Pd(PPh 3 ) 4 (8 mg, 7 μmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 142 was filtered and washed (CH 2 Cl 2 , DMF, MeOH, CH 2 Cl 2 ).
Release of the cyclization precursor: The resin 142 was treated with HFIP/CH 2 Cl 2 2:3 (1 mL) for 30 min, filtered and washed (CH 2 Cl 2 ). The cleavage step was repeated once. The combined filtrates and washings were concentrated, taken up in CH 3 CN (3 mL), concentrated and dried i.v. to afford crude 143a-k.
Ring closure and cleavage of side chain protective groups: Crude 143 was dissolved in a soln of i-Pr 2 NEt (98 μL; 570 μmol) in dry DMF (4 mL). This soln was then added dropwise to a soln of FDPP (41 mg, 106 μmol) in DMF (20 mL). The soln was stirred at rt for 5 h and the volatiles were evaporated. The residue was treated with sat. aq. Na 2 CO 3 soln (4 mL) and extracted with CHCl 3 (9 mL). The organic layer was filtered through a pad of MgSO 4 . The filtrate was concentrated to afford crude Ex. 195a-k. Crude products Ex. 195a,b,e-h,j were purified by prep. HPLC to afford Ex. 195a,b,e-h,j.
A soln of crude product Ex. 195c,d,i or k in TFA/CH 2 Cl 2 3:7 (1 mL) was stirred at rt for 3 h. The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 , concentrated, dried i.v. and purified by prep. HPLC to afford Ex. 196c,i,k or Ex. 197d, respectively.
Purification methods applied, yields, LC-MS data and systematic names of Ex. 195a, b,e-h,j; Ex. 196c,i,k and Ex. 197d are indicated in Table 23a.
Ex. 195b: 1 H-NMR (CD 3 OD): 9.16 (d, J=2.1, 1H); 8.97 (t, J=2.1, 1H); 8.94 (d, J=2.0, 1H); 7.57-7.39 (m, 3H); 7.00 (m, 1H); 5.23 (m, 1H); ca 4.8 (1H, superimposed by HDO signal); 4.40 (d, J=16.8, 1H); ca. 4.4 (br. m, 1H), 4.28 (dd; J=3.8, 8.1, 1H); 3.73 (d, J=16.8, 1H); 3.77-3.60 (m, 3H); 2.98 (s, 3H); 2.65 (dd, J=2.4, 13.6, 1H); 2.37 (t, J=12.8, 1H); 2.20-2.02 (m, 4H); 1.46 (d, J=7.0, 3 H); 1.15 (d, J=7.0, 3 H).
Ex. 195h: 1 H-NMR (CD 3 OD): Two sets of signals were observed; ratio 1:1; 9.06 (d, J=2.0, 0.5H); 9.00 (d, J=2.0, 0.5H); 8.97 (d, J=1.9, 0.5H); 8.84 (d, J=1.9, 0.5H); 8.72 (t, J=2.1, 0.5H); 8.50 (t, J=2.1, 0.5H); 7.88 (s, 0.5H); 7.65 (s, 0.5H); 7.50-7.35 (m, 2H); 7.32-7.19 (m, 3.5H); 7.09-6.93 (m, 2.5H); 5.89 (d, J=16.7, 0.5H); 5.26-5.20 (q-like m, 1H), 4.79 (q, J=7.2, 0.5H); 4.65 (dd, J ca 4.7, 11.8, 1H); 4.51 (dt-like m, 1H); 4.50 (br. m, 0.5H); 4.05 (d, J=7.2, 1H); 3.90 (t, J=9.6, 0.5H); 3.75-3.44 (m, 3.5H); 3.23 (dd, J=4.5, 13.9, 0.5H); 3.12-3.05 (m, 1H); 2.98 (s, 3H); 2.24-2.04 (m, 4H); 1.43 (d, J=7.0, 1.5H); 1.36 (d, J=7.2, 1.5H).
Core 12: Synthesis of Ex. 198, Ex. 199 and Ex. 200 (Scheme 17)
Synthesis of the Mitsunobu Product 144
CMBP (9.9 mL, 38 mmol) was added to a soln of the hydroxypyridine 93 (4.32 g, 19 mmol) and the alcohol 16 (6.5 g, 22 mmol) in toluene (200 mL). The mixture was heated to 80° C. for 1 h. The volatiles were evaporated. FC (hexane/EtOAc/MeOH gradient) afforded 144 (8.60 g, 90%).
Data of 144: C 27 H 33 N 3 O 7 (511.6). LC-MS (method 1a): R t =1.91 (98), 512.3 ([M+H] + ).
Synthesis of the Carboxylic Acid 145
A soln of the ester 144 (6.56 g, 13 mmol) in MeOH (23 mL), THF (92 mL) and H 2 O (23 mL) was treated with LiOH.H 2 O (1.6 g, 38 mmol) at rt for 16 h. H 2 O (50 mL) was added followed by 1 M aq. HCl soln (100 mL). The mixture was repeatedly extracted with EtOAc. The combined organic phases were washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 145 (6.19 g, 96%).
Data of 145: C 26 H 31 N 3 O 7 (497.5). LC-MS (method 1a): R t =1.62 (97), 498.0 ([M+H] + ).
Synthesis of Amide 146
A mixture of acid 145 (6.19 g, 12 mmol), amine 28.HCl (3.6 g, 11 mmol), and HATU (5.7 g, 15 mmol) was dissolved in DMF (197 mL), followed by the addition of i-Pr 2 NEt (6.6 mL, 39 mmol). The mixture was stirred for 2 h. The mixture was diluted with sat. aq. Na 2 CO 3 soln and extracted with CH 2 Cl 2 . The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The residue was dissolved in EtOAc, washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:3) afforded 146 (7.1 g, 74%).
Data of 146: C 40 H 49 N 5 O 10 (759.8). LC-MS (method 1a): R t =2.04 (92), 760.1 ([M+H] + ).
Synthesis of the Carboxylic Acid 147
A soln of the ester 146 (7.07 g, 9.3 mmol) in MeOH (57 mL), THF (171 mL) and H 2 O (57 mL) was treated with LiOH.H 2 O (1.2 g, 28 mmol) at rt for 16 h. The mixture was poured onto ice/1 M aq. HCl soln (50 mL) and repeatedly extracted with EtOAc. The combined organic phases were washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 147 (6.8 g, quant. yield).
Data of 147: C 38 H 45 N 5 O 10 (731.8). LC-MS (method 1c): R t =1.81 (94), 731.9 ([M+H] + ).
Synthesis of Amino Acid 148
A degassed solution of ester 147 (6.8 g, 9.3 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28 mmol) in CH 2 Cl 2 (67 mL) and EtOAc (68 mL) was treated with Pd(PPh 3 ) 4 (0.54 g, 0.46 mmol) at rt for 2 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 99:1 to 80:20) afforded 148 (5.6 g, 93%).
Data of 148: C 34 H 41 N 5 O 8 (647.7). LC-MS (method 1a): R t =1.45 (91), 648.0 ([M+H] + ).
Synthesis of Ex. 198
A solution of 148 (1.08 g, 1.7 mmol) and i-Pr 2 NEt (0.86 mL, 5.0 mmol) in dry DMF (40 mL) was added over 3 h (syringe pump) to a soln of HATU (1.27 g, 3.33 mmol) in DMF (1620 mL). The volatiles were evaporated. Aq. Workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (EtOAc/MeOH 95:5) afforded Ex. 198 (0.65 g, 62%).
Data of Ex. 198: C 34 H 39 N 5 O 7 (629.7). LC-MS (method 1d): R t =1.61 (99), 630.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Three sets of broad signals were observed; 8.44 (br. d, J ca 3.7, 0.5H); 8.32, 8.28 (2 d, J=3.8, 3.9, 0.5H); 7.86-7.18 (m, 13H); 5.12-4.83 (m, 2H); 4.59-3.46 (several m, 7H); 3.32-2.72 (several m, 5H); 2.40-2.25 (m, 1H), 2.15-1.90 (m, 1H); 1.40, 1.39 (2 s, 9H).
Synthesis of Ex. 199
A soln of Ex. 198 (0.85 g, 1.34 mmol) in dioxane (17 mL) was treated with 4 M HCl dioxane soln (17 mL) for 1 h at rt. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered, washed with Et 2 O and dried to afford Ex. 199.2HCl (836 mg; quant. yield).
Data of Ex. 199.2HCl: C 29 H 31 N 5 O 5 .2HCl (529.6, free base). LC-MS (method 2c): R t =1.40 (94), 530.2 ([M+H] + ).
Synthesis of Ex. 200
A soln of Ex. 198 (1.2 g, 1.91 mmol) in MeOH (40 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 250 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 200 (0.87 g, 92%).
Data of Ex. 200: C 26 H 33 N 5 O 5 (495.6). LC-MS (method 1a): R t =1.15 (97), 496.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): two sets of signals were observed; 8.38 (br. s, 0.3H); 8.33 (d, J=4.2, 0.7H), 7.75-7.41 (m, 7H), 7.18 (br. s, 1H); 4.20-4.13 (m, 2H); 3.93-3.87 (t-like m, 2H); 3.76-3.73 (d-like m, 1H); 3.14-2.70 (several m, 4H); 2.45-2.30 (m, 2H), 2.01 (d, J=15.9, 1H), 1.85 (br. not resolved m, 1H); 1.70 (d-like m, 1H); 1.41, 1.37 (2 s, 9H).
Core 13-15: Synthesis of the Common Precursor 151 (Scheme 18)
Synthesis of the Amide 149
A soln of 98 (7.96 g, 33.4 mmol), 129.HCl (7.19 g, 36.8 mmol) and BOP (16.3 g, 36.8 mmol) in DMF (120 mL) was cooled to 0° C. i-Pr 2 NEt (22.7 mL, 134 mmol) was slowly added and stirring was continued for 30 min. Aqueous workup (EtOAc, aq. 1 M HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) followed by FC (hexane/EtOAc 2:1) afforded 149 (10.8 g, 85%).
Data of 149: C 18 H 18 FNO 5 S (379.4). LC-MS (method 1a): R t =1.98 (90), 380.2 ([M+H] + )
Synthesis of the Amine 151
A suspension of phenol 149 (8.79 g, 23.2 mmol), alcohol 16 (8.35 g, 27.8 mmol) and PPh 3 (9.11 g, 34.8 mmol) in benzene (278 mL) was degassed and cooled to 0° C. DEAD (40% in toluene; 15.9 mL, 34.8 mmol) was added dropwise. The mixture was stirred at rt for 16 h and concentrated. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc, Et 3 N 66:33:1) to give 150 (15.4 g).
A degassed soln of 150 (15.4 g) and 1,3-dimethylbarbituric acid (5.45 g, 34.9 mmol) in CH 2 Cl 2 (150 mL) and EtOAc (450 mL) was treated with Pd(PPh 3 ) 4 (0.67 g, 0.58 mmol) at rt for 1 h. Aqueous workup (EtOAc, sat.aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (EtOAc, then CH 2 Cl 2 /MeOH 95:5) afforded 151 (8.18 g, 61%).
Data of 151: C 28 H 36 FN 3 O 7 S (577.6). LC-MS (method 1a): R t =1.87 (96), 578.4 ([M+H] + )
Core 13: Synthesis of Ex. 220, Ex. 221 and Ex. 222 (Scheme 18)
Synthesis of Amide 152
At 0° C., acryloyl chloride (0.37 mL, 4.57 mmol) was slowly added to a soln of 151 (2.2 g, 3.81 mmol) and i-Pr 2 NEt (0.78 mL, 4.57 mmol) in CH 2 Cl 2 (33 mL). The mixture was stirred for 0.5 h followed by an aqueous workup (CH 2 Cl 2 , 0.1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 1:1 to 3:7) to afford 152 (2.21 g, 91%).
Data of 152: C 31 H 38 FN 3 O 8 S (631.7). LC-MS (method 4a): R t =1.60 (94), 632.1 ([M+H] + )
Synthesis of Ex. 220
The catalyst Umicore M72 SIMes (RD) (64 mg, 0.075 mmol) was added in one portion to a degassed solution of 152 (240 mg, 0.38 mmol) in toluene (380 mL) and heated to 100° C. for 0.5 h. The mixture was cooled to rt. More Umicore M72 SIMes (RD) catalyst (64 mg) was added and the mixture was heated to 100° C. for 30 min; this operation was repeated once again. 2-Mercaptonicotinic acid (59 mg, 0.38 mmol) was added and the heating to 100° C. was continued for 1 h. The mixture was concentrated. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) followed by prep. HPLC (method 3) afforded Ex. 220 (42 mg, 18%).
Data of Ex. 220: C 29 H 34 FN 3 O 8 S (603.6). LC-MS (method 1f): R t =2.18 (89), 604.0 ([M+H] + )
Synthesis of Ex. 221
A soln of Ex. 220 (0.49 g, 0.8 mmol)) in MeOH (80 mL) was hydrogenated for 2 h at rt and normal pressure in the presence palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 304 mg). The mixture was filtered through a pad of Na 2 SO 4 and celite. The solid was washed with CH 2 Cl 2 /MeOH 1:1 (300 mL). The combined filtrate and washings were concentrated to give Ex. 221 (0.25 g, 51%).
Data of Ex. 221: C 29 H 36 FN 3 O 8 S (605.7). LC-MS (method 2f): R t =2.43 (90), 606.2 ([M+H] + ). 1 H-NMR (CDCl 3 ): 8.67 (d, J=1.2, 1H); 8.01 (s, 1H); 7.69 (d, J=1.2, 1H); 7.52 (d, J=8.5, 1H); 6.98 (d, J=8.7, 1H); 6.55 (td, J=2.2, 10.2, 1H); 4.97 (td, J=2.9, 8.7, 1H); 4.82 (br. m, not resolved, 1H); 4.69 (d-like m, 1H); 4.61 (br. not resolved m, 1H); 4.31-4.22 (m, 2H); 4.04-3.90 (m, 3H); 3.80 (s, 3H); 3.74 (dd, J=2.8, 10.8, 1H); 3.65 (m, 1H); 3.46 (m, 1H); 2.53-2.41 (m, 3H); 2.02-1.88 (m, 3H); 1.48 (s, 9H).
Synthesis of Ex. 222
A soln of Ex. 221 (233 mg. 0.39 mmol) in dioxane (1 mL) was treated with 4 M HCl in dioxane (5 mL) for 2 h at rt. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered and dried i.v. to afford Ex. 222.HCl (180 mg, 86%).
Data of Ex. 222.HCl: C 24 H 28 FN 3 O 6 S (505.6, free base). LC-MS (method 1d): R t =1.55 (92), 506.2 ([M+H] + ).
Core 14: Synthesis of Ex. 227, Ex. 228 and Ex. 229 (Scheme 18)
Synthesis of Amide 153
At 0° C., i-Pr 2 NEt (2.2 mL, 13.0 mmol) was added dropwise to a soln of 151 (2.5 g, 4.3 mmol), but-3-enoic acid (0.48 g, 5.6 mmol), HATU (2.47 g, 6.5 mmol) and HOAt (0.88 g, 6.5 mmol) in DMF (60 mL). The mixture was stirred for 1.5 h at 0° C. followed by an aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:2) to give 153 (2.36 g, 84%).
Data of 153: C 32 H 40 FN 3 O 8 S (645.7). LC-MS (method 4b): R t =1.67 (96), 646.2 ([M+H] + ).
Synthesis of Ex. 227
A solution of 153 (110 mg, 0.17 mmol) and the catalyst Umicore M72 SIMes (RD) (58 mg, 0.068 mmol) in CH 2 Cl 2 (70 mL) was degassed and heated to reflux for 2 h. The mixture was allowed to cool to rt. 2-Mercaptonicotinic acid (106 mg, 0.68 mmol) was added. The mixture was heated to reflux for 1 h. The mixture was washed with sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by prep. HPLC (method 3) to afford Ex. 227 (56 mg, 53%).
Data of Ex. 227: C 30 H 36 FN 3 O 8 S (617.7). LC-MS (method 1d): R t =2.32 (87), 618.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.38 (s, 1H), 8.27-8.24 (m, 2H); 7.90 (s, 1H); 7.28-7.18 (m, 2H); 6.70 (td, J=2.1, 10.6, 1H); 5.97 (td, J=5.9, 15.8, 1H); 5.66 (td, J=4.6, 15.7, 1H); 4.75-4.63 (m, 2H); 4.31 (br. not resolved m, 1H); 4.06-3.67 (m, 7H); 3.67 (s, 3H); 3.24 (dd, J=6.4, 10.5, 1H); 3.11 (br. m, 2H); 2.30 (m, 1H); 1.92 (m, 1H); 1.39 (s, 9H).
Synthesis of Ex. 228
Trimethyltin hydroxide (263 mg; 1.46 mmol) was added to a solution of Ex. 227 (300 mg, 0.49 mmol) in DCE (15 mL). The mixture was heated to 80° C. for 16 h, followed by aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford Ex. 228 (350 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) to give Ex. 228 (13 mg).
Data of Ex. 228: C 29 H 34 FN 3 O 8 S (603.6). LC-MS (method 1a): R t =2.17 (92), 604.0 ([M+H] + ).
Synthesis of Ex. 229
A soln of Ex. 227 (287 mg, 0.46 mmol) in dioxane (5 mL) was treated with 4 M HCl in dioxane (5 mL) for 5 h at rt and concentrated. The residue was suspended in Et 2 O and filtered to afford Ex. 229.HCl (240 mg, 93%).
Data of Ex. 229.HCl: C 25 H 28 FN 3 O 6 S.HCl (517.6, free base). LC-MS (method 1a): R t =1.49 (92), 518.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.38 (br. s, 4H), 8.28 (s, 1H); 8.22 (d, J=8.0, 1H); 7.82 (s, 1H); 7.29 (d, J=9.4, 1H); 6.73 (d, J=10.6, 1H); 5.98 (td, J=6.0, 15.6, 1H); 5.69 (td, J=4.8, 15.8, 1H); 4.74-4.65 (m, 2H); 4.39 (m, 1H); 4.04-3.85 (m, 5H); 3.85-3.65 (m, 2H); 3.67 (s, 3H); 3.44 (dd, J=7.1, 10.5, 1H); 3.14 (d, J=5.6, 2 H), 2.50 (m, 1H); 2.04 (m, 1H).
Core 15: Synthesis of Ex. 242, Ex. 243 and Ex. 244 (Scheme 18)
Synthesis of Ex. 242
A soln of Ex. 227 (1.5 g, 2.4 mmol)) in MeOH (75 mL) was hydrogenated for 2.5 h at rt and normal pressure in the presence of 5% palladium on activated charcoal (moistened with 50% H 2 O; 300 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. FC (hexane/EtOAc 1:2) gave Ex. 242 (1.37 g, 91%).
Data of Ex. 242: C 30 H 38 FN 3 O 8 S (619.7). LC-MS (method 1a): R t =2.47 (92), 620.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.51 (d, J=1.1, 1H); 8.29 (d, J=1.1, 1H); 8.07 (d, J=7.9, 1H); 7.95 (s, 1H); 7.30-7.26 (m, 2H), 6.70 (td, J=2.1, 10.5, 1H); 4.70 (m, 1H); 4.60 (br. dd, 1H); 4.29 (br. not resolved m, 1H); 4.04-3.67 (m, 5H); 3.67 (s, 3H); 3.48 (br. not resolved m, 2H); 3.28 (m, 1H); 2.38-2.23 (m, 3H); 1.91 (m, 1H), 1.77 (m, 1H); 1.68-1.51 (m, 3H); 1.39 (s, 9H).
Synthesis of Ex. 243
Trimethyltin hydroxide (175 mg; 0.97 mmol) was added to a solution of Ex. 242 (200 mg, 0.32 mmol) in DCE (10 mL). The mixture was heated to 80° C. for 16 h, followed by aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford Ex. 243 (236 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) to give Ex. 243 (14 mg).
Data of Ex. 243: C 29 H 36 FN 3 O 8 S (605.7). LC-MS (method 1a): R t =2.27 (97), 606.2 ([M+H] + ).
Synthesis of Ex. 244
A soln of Ex. 242 (265 mg, 0.43 mmol) in dioxane (5 mL) was treated with 4 M HCl in dioxane (5 mL) for 6 h at rt and concentrated. The residue was taken up in CHCl 3 and concentrated to afford Ex. 244.HCl (205 mg, 86%).
Data of Ex. 244.HCl: C 25 H 30 FN 3 O 6 S.HCl (519.6, free base). LC-MS (method 1d): R t =1.55 (92), 520.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.48 (s, 1H); 8.40-8.25 (br. s, 4H); 8.05 (d, J=7.9, 1H); 7.86 (s, 1H); 7.31 (d, J=8.8, 1H); 6.73 (d, J=10.6, 1H); 4.72-4.61 (m, 2H); ca 4.4-4.3 (br. m, 2H); 4.00-3.68 (m, 5H); 3.68 (s, 3H); 3.49-3.43 (m, not resolved, 2H), ca 2.5 (m, superimposed by DMSO-d signal, 1H); 2.40-2.25 (m, 2H), 2.02 (m, 1H); 1.79-1.52 (m, 4H).
Core 15: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 18)
Synthesis of Ex. 246
At 0° C., i-Pr 2 NEt (0.054 mL, 0.32 mmol) was added to a soln of Ex. 243 (ca. 70% w/w; 55 mg, 0.064 mmol), HATU (36 mg, 0.095 mmol), HOAt (13 mg, 0.095 mmol) and aniline (0.029 mL, 0.32 mmol) in CH 2 Cl 2 (1.5 mL) and DMF (0.5 mL). The mixture was stirred for 30 min followed by an aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1.1) to afford Ex. 246 (27 mg, 62%).
Data of Ex. 246: cf. Table 27b
Synthesis of Ex. 247
At 0° C., 4 M HCl in dioxane (0.20 mL) was added to a soln of Ex. 246 (25 mg, 0.037 mmol) in dioxane (0.6 mL). The mixture was stirred for 5 h at 0° C. to rt. More 4 M HCl in dioxane (0.15 mL) was added and the mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was treated with TFA (0.15 mL) in CH 2 Cl 2 (0.75 mL) for 1 h at 0° C., followed by evaporation of the solvents, aqueous workup (EtOAc, sat.aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 90:10). The purified product (13 mg) was dissolved in dioxane (0.3 mL) and treated with 4 M HCl in dioxane (0.05 mL). The volatiles were evaporated to give Ex. 247.HCl (14 mg, 60%).
Data of Ex. 247.HCl: cf. Table 27b
1 H-NMR (DMSO-d 6 ): 10.18 (s, 1H); 8.48 (s, 1H); 8.30 (s, 1H); 8.15 (d, J=7.1, 1H); 8.15 (br. s, 3H); 7.85 (s, 1H); 7.59 (d, J=7.7, 2 H); 7.36-7.27 (m, 3H); 7.06 (t, J=7.4, 1H); 6.74 (dt-like m, 1H); 4.73-4.63 (m, 2H); 4.40 (br. not resolved m, 1H); 4.01-3.59 (m, 5H); 3.50-3.41 (m, 3H); 2.36 (br. t-like m, 2H); 2.04 (m, 1H); 1.90-1.45 (several not resolved m, 5H).
Synthesis of Ex. 256
Ex. 256 (8 mg, 14%) was obtained from Ex. 243 (ca. 70% w/w; 65 mg, 0.075 mmol) and 4-chloroaniline (48 mg, 0.38 mmol) by applying the method described for the synthesis of Ex. 246.
Data of Ex. 256: cf. Table 27b
Synthesis of Ex. 257
Ex. 257.HCl (4 mg, 66%) was obtained from Ex. 256 (7 mg, 0.01 mmol) by applying the method described for the synthesis of Ex. 247.HCl.
Data of Ex. 257.HCl: cf. Table 27b
Synthesis of Ex. 258
Ex. 258 (19 mg, 43%) was obtained from Ex. 243 (ca. 70% w/w; 55 mg, 0.064 mmol) and m-toluidine (0.034 mL, 0.32 mmol) by applying the method described for the synthesis of Ex. 246.
Data of Ex. 258: cf. Table 27b
Synthesis of Ex. 259
Ex. 259.HCl (10 mg, 66%) was obtained from Ex. 258 (17 mg, 0.024 mmol) by applying the method described for the synthesis of Ex. 247.HCl.
Data of Ex. 259.HCl: cf. Table 27b
1 H-NMR (DMSO-d 6 ): 10.07 (s, 1H); 8.47 (s, 1H); 8.30 (s, 1H); 8.12 (d, J=7.6, 1H); 8.12 (br. s, 3H); 7.85 (s, 1H); 7.42-7.30 (m, 3H), 7.18 (t, J=7.4, 1H); 6.88 (d, J ca 7.6, 1H); 6.74 (d, J=10.3, 1H); 4.78-4.60 (m, 2H); 4.40 (br. not resolved m, 1H); 4.05-3.65 (m, 5H); 3.51-3.40 (m, 3H); 2.37 (br. t-like m, 2H); 2.27 (s, 3H); 2.01 (m, 1H); 1.90-1.45 (several not resolved m, 5H).
Core 16: Synthesis of Ex. 262, Ex. 263 and Ex. 264 (Scheme 19)
Synthesis of the Mitsunobu Product 154
CMBP (8.5 mL, 32 mmol) was added to a soln of hydroxythiophene 106 (5.69 g, 20 mmol) and alcohol 118 (9.8 g, 26 mmol) in toluene (77 mL). The mixture was heated to reflux for 2 h and concentrated. FC (hexane/EtOAc 90:10 to 20:80) gave 154 (12.68 g, 98%).
Data of 154: C 29 H 34 BrN 3 O 6 S (632.6). LC-MS (method 4a): R t =2.29 (93), 634.3/632.3 ([M+H] + ).
Synthesis of the Amino Acid 157
A soln of 154 (12.6 g, 20 mmol) in CH 2 Cl 2 (128 mL) was treated with TFA (148 mL) and heated to reflux for 3 h. The volatiles were evaporated. The residue was suspended in toluene, concentrated and dried i.v. to give crude 155 (16.15 g, containing residual solvent), which was used without further purification.
At 0° C., i-Pr 2 NEt (6.85 mL, 40.3 mmol) was added to a soln of crude carboxylic acid 155 (9.27 g, ca 11.5 mmol), amine 130.HCl (5.52 g, 16.1 mmol), HATU (7.66 g, 20.1 mmol) and HOAt (2.74 g, 20.1 mmol) in DMF (170 mL). The mixture was stirred at rt for 2 h, followed by an aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 95:5) to afford 156 (11.7 g; containing residual DMF), used without further purification.
A degassed solution of 156 (11.6 g) and 1,3-dimethylbarbituric acid (6.3 g, 40 mmol) in CH 2 Cl 2 (39 mL) and EtOAc (78 mL) was treated with Pd(PPh 3 ) 4 (1.6 g, 1.3 mmol) at rt for 4 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded 157 (7.6 g, 89% over the three steps).
Data of 157: C 34 H 38 BrN 5 O 7 S (740.6). LC-MS (method 1a): R t =1.91 (87), 740.1/742.1 ([M+H] + ).
Synthesis of Ex. 262
A soln of 157 (1.9 g, 2.57 mmol) in CH 2 Cl 2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc, 7.56 mL, 12.8 mmol) and i-Pr 2 NEt (1.96 mL, 11.5 mmol) in CH 2 Cl 2 (1190 mL). Stirring at rt was continued for 4 h. The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln.; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) afforded Ex. 262 (1.63 g, 88%).
Data of Ex. 262: C 34 H 36 BrN 5 O 6 S (722.6). LC-MS (method 1d): R t =2.52 (99), 722.0/724.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.65 (d, J=6.8, 1H); 7.49 (d, J=8.0, 2 H); 7.41-7.26 (m, 8H); 7.08 (d, J=5.4, 1H); 6.64 (s, 1H); 5.06 (s, 2H); ca 4.5-4.4 (br. m, 2H); 4.48 (s, 2H); 4.32 (br. d, J ca 8.8, 1H); 4.16 (br. m, 2H); 4.01 (m, 1H); 3.86 (s, 3H); 3.69 (br. m, 1H); 3.46-3.32 (m, 2H); 2.96 (s, 3H); 2.40-2.25 (br. m, 2H), 2.10-1.90 (br. m, 2H).
Synthesis of Ex. 263
At 0° C., BCl 3 (16 mL, 16 mmol) was added dropwise to a soln of Ex. 262 (2.34 g, 3.2 mmol) in CH 2 Cl 2 (83 mL). The mixture was allowed to stir at 0° C. to rt for 16 h. The mixture was cooled to 0° C. and poured slowly into MeOH. The mixture was concentrated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded Ex. 263 (1.21 g, 89%).
Data of Ex. 263: C 19 H 25 N 5 O 4 S (419.5). LC-MS (method 1d): R t =1.11 (98), 420.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.08 (d, J=5.5, 1H); 6.63 (s, 1H); 5.17 (d, J=5.1, 1H); 4.35-4.29 (m, 2H); 4.24 (dd, J=6.6, 11.9, 1H); 4.12-3.97 (m, 3H); 3.85 (s, 3H); 3.68 (d, J=7.4, 1H); 3.61 (m, 1H); 3.17 (dd, J=6.6, 10.2, 1H); 2.97 (s, 3H); 2.28-2.19 (m, 2H); 1.95 (m, 1H), 1.90-1.75 (br. not resolved m, 3H).
Synthesis of Ex. 264
At rt, TBAF (1 M in THF; 0.119 mL, 0.119 mmol) was slowly added to a soln of Ex. 262 (160 mg, 0.221 mmol) in THF (2.5 mL). The mixture was heated to reflux for 2 h, filtered through a pad of celite and concentrated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 85:15) afforded a white solid (100 mg) was dissolved in DMF (4.0 mL) and hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 23 mg). The volatiles were evaporated. The crude product was purified by FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) to give Ex. 264 (45 mg, 40%).
Data of Ex. 264: C 26 H 31 N 5 O 4 S (509.6). LC-MS (method 1a): R t =1.62 (99), 510.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.33-7.27 (m, 5H); 7.08 (d, J=5.5, 1H); 6.65 (s, 1H); 4.53 (s, 2H); 4.41-4.17 (m, 5H); 3.98 (dd, J=5.1, 9.4, 1H); 3.85 (s, 3H); 3.72 (d, J=7.0, 1H); 3.61 (m, 1H); ca 3.3 (m, superimposed by H 2 O signal, 1H); 2.97 (s, 3H); 2.40-1.80 (several br. m, 6H).
Core 16: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 19)
Synthesis of Ex. 265
At 0° C., oxalyl chloride (0.104 mL, 1.19 mmol) and one drop of DMF were added to a soln of 2-naphthaleneacetic acid (53 mg, 0.29 mmol) in CH 2 Cl 2 (6 mL). The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in CH 2 Cl 2 (2.5 mL) and added dropwise to a soln of Ex. 263 (100 mg, 0.24 mmol) and i-Pr 2 NEt (0.204 mL, 1.19 mmol) in CH 2 Cl 2 (3.5 mL). The mixture was stirred at 0° C. for 1 h followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /i-PrOH 100:0 to 95:5) to yield Ex. 265 (110 mg, 78%).
Data of Ex. 265: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 8.54 (d, J=7.5, 1H); 7.89-7.85 (m, 3H); 7.78 (s, 1H); 7.52-7.44 (m, 3H); 7.40 (d, J=5.5, 1H); 7.09 (d, J=5.5, 1H); 6.44 (s, 1H); 5.14 (d, J=4.9, 1H); 4.65 (br. t, J=8.0, 1H); 4.40-4.31 (m, 2H); 4.11 (q, J ca 5.8, 1H); 4.03 (m, 1H), 3.84 (m, 1H); 3.84 (s, 3H); 3.68 (s, 2H); 3.64 (m, 1H); ca 3.30 (m, 1H, partially superimposed by H 2 O signal); 3.17 (dd, J=6.3, 10.5, 1H); 2.91 (s, 3H); 2.35 (m, 1H); 2.18 (m, 1H); 1.91-1.82 (m, 2H).
Synthesis of Ex. 275
Trimethyloxonium tetrafluoroborate (15 mg, 0.10 mmol) was added at 0° C. to a solution of Ex. 265 (40 mg, 0.068 mmol) and N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (22 mg, 0.102 mmol) in CH 2 Cl 2 (1.0 mL). The mixture was stirred at 0° C. to rt for 4.5 h. More N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (32 mg, 0.15 mmol) and trimethyloxonium tetrafluoroborate (22 mg, 0.15 mmol) were added at 0° C. and stirring was continued at rt for 16 h. Aqueous workup (CH 2 Cl 2 , 2 M aq. HCl soln; Na 2 SO 4 ). The residue was suspended in CH 2 Cl 2 and filtered. The filtrate was purified by FC (EtOAc/MeOH 100:0 to 97:3) and by prep. RP-HPLC (method 1a) to afford Ex. 275 (5 mg, 12%).
Data of Ex. 275: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 8.57 (d, J=7.5, 1H); 7.90-7.85 (m, 3H); 7.80 (s, 1H); 7.54-7.45 (m, 3H); 7.39 (d, J=5.5, 1H); 7.07 (d, J=5.5, 1H); 6.62 (s, 1H); 4.65 (br. t, J=7.8, 1H); 4.40 (br. not resolved m, 1H); 4.29 (dd; J=2.7, 9.5, 1H); 3.96-3.83 (m, 2H); 3.83 (s, 3H); 3.75-3.60 (m, 2H); 3.67 (s, 2H); ca 3.3-3.2 (m, 2H, partially superimposed by H 2 O signal); 3.05 (s, 3H); 2.92 (s, 3H); 2.36 (m, 1H); 2.16 (m, 1H); 1.96-1.83 (m, 2H).
Synthesis of Ex. 276
At 0° C., i-Pr 2 NEt (0.061 mL, 0.36 mmol) and 2-naphthylisocyanate (22 mg, 0.131 mmol) were added to a soln of Ex. 263 (50 mg, 0.12 mmol) in CH 2 Cl 2 (1.0 mL). The mixture was stirred at 0° C. to rt for 60 min. Aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 3) afforded Ex. 276 (50 mg, 71%).
Data of Ex. 276: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 9.00 (s, 1H) 8.05 (d, J=1.8, 1H); 7.81-7.74 (m, 3H); 7.45-7.40 (m, 3H); 7.32 (dt, J=1.2, 7.5, 1H); 7.11 (d, J=5.5, 1H); 6.74 (d, J=7.3, 1H); 6.68 (s, 1H); 5.24 (d, J=5.0, 1H); 4.77 (br. t, J=7.1, 1H); 4.38-4.32 (m, 2H); 4.29 (q-like m, 1H); 4.07-4.00 (m, 2H), 3.88 (s, 3H); 3.85 (m, 1H); ca 3.30-3.20 (m, 2H, partially superimposed by H 2 O signal); 2.98 (s, 3H); ca 2.5 (m, 1H, superimposed by DMSO-d signal); 2.27 (m, 1H); 2.00-1.92 (m, 2H).
Core 17: Synthesis of Ex. 284a, Ex. 285 and Ex. 286 (Scheme 20)
Synthesis of Amide 158
A suspension of 110.HCl (6.2 g, 19.9 mmol) in CH 2 Cl 2 (310 mL) was cooled to 0° C. Oxalyl chloride (5.1 mL, 59.7 mmol) was added followed by DMF (0.37 mL). The mixture was stirred for 1.5 h at rt and concentrated. The residue was suspended in CH 2 Cl 2 and concentrated; this operation was repeated once and the residue was then dried i.v. The residue was suspended in CH 2 Cl 2 (180 mL). A soln of 131HCl (8.86 g, 23.9 mmol) in CH 2 Cl 2 (120 mL) was added. The mixture was cooled to 0° C. followed by the slow addn of i-Pr 2 NEt (17.0 mL, 99.5 mmol). The mixture was stirred for 1 h at 0° C. Aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc gradient) gave 158 (8.1 g, 69%).
Data of 158: C 30 H 33 N 5 O 8 (591.6). LC-MS (method 1a): R t =2.43 (94), 592.1 ([M+H] + ).
Synthesis of the Mitsunobu Product 159
A soln of CMBP (6.58 g, 27.3 mmol) in toluene (30 mL) was added to a soln of phenol 158 (8.07 g, 13.6 mmol) and alcohol 120 (3.28 g, 17.7 mmol) in toluene (131 mL). The mixture was heated to reflux for 1 h and concentrated. FC (hexane/EtOAc 50:50 to 0:100) yielded 159 (7.9 g, 76%).
Data of 159: C 39 H 46 N 6 O 10 (758.8). LC-MS (method 4a): R t =1.91 (90), 759.2 ([M+H] + ).
Synthesis of the Amino Acid 160
A degassed solution of 159 (8.9 g, 11.8 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28.3 mmol) in CH 2 Cl 2 (180 mL) and EtOAc (45 mL) was treated with Pd(PPh 3 ) 4 (1.36 g, 1.18 mmol) at rt for 2 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 100:0 to 40:60) afforded 160 (7.33 g, 98%; containing some impurities; used without further purification).
Data of 160: C 32 H 38 N 6 O 8 (634.7). LC-MS (method 1a): R t =1.65 (88), 635.2 ([M+H] + ).
Synthesis of Ex. 284a and Ex. 284b
A soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump) to a soln of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) in pyridine (1500 mL). An additional portion of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) was added to the solution. Again a soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump).
The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln, H 2 O, Na 2 SO 4 ). Purification by preparative HPLC (method 1d) afforded Ex. 284a.CF 3 CO 2 H (480 mg) and Ex. 284b.CF 3 CO 2 H (186 mg, 16%).
Ex. 284a.CF 3 CO 2 H (480 mg) was dissolved in CH 2 Cl 2 and washed with sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to afford Ex. 284a (442 mg, 45%).
Data of Ex. 284a: C 32 H 36 N 6 O 7 (616.6). LC-MS (method 1d): R t =2.24 (99), 617.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.66 (d, J=2.1, 1H); 8.40 (dd, J=2.1, 8.9, 1H); 7.53-7.49 (m, 2H); 7.36-7.26 (m, 6H); 5.06 (br. d, J=12.6, 1H); 4.92 (s, 2H); 4.37 (br. dd, J ca 2.6, 13.0, 1H); 4.15 (t-like m, 1H); 3.65 (br. t, J ca 8.7, 1H); 3.55 (q-like m, 1H); 3.27 (m, 1H); 3.01 (s, 3H); 2.95-2.82 (m, 2H), 2.61 (s, 3H); 1.97-1.68 (several m, 6H), 1.23-0.90 (br. m, 4H).
Data of Ex. 284b.CF 3 CO 2 H: C 32 H 36 N 6 O 7 CF 3 CO 2 H (free base 616.6). LC-MS (method 1d): R t =2.14 (99), 617.2 ([M+H] + ).
Synthesis of Ex. 285
A soln of Ex. 284a (380 mg, 0.62 mmol) in THF (19 mL) was treated with TBAF (1 M in THF; 0.6 mL, 0.6 mmol) at 75° C. for 7 h. The mixture was cooled to rt and TBAF (1 M in THF; 0.3 mL, 0.3 mmol) was added. Stirring at 75° C. was continued for 8 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 285 (182 mg, ca 60%; containing ca 5% of tetrabutylammonium salts). An analytical sample (15 mg) was further purified by preparative HPLC (method 2a) to afford Ex. 285 (9 mg).
Data of Ex. 285: C 24 H 30 N 6 O 5 (482.5). LC-MS (method 1d): R t =1.47 (95), 483.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.66 (d, J=2.2, 1H); 8.41 (dd, J=2.2, 9.0, 1H); 7.51 (s, 1H); 7.47 (d, J=9.1, 1H); 5.17 (d, J=12.5, 1H); 4.30 (dd, J=2.3, 12.7, 1H); 4.14 (t, J=7.0, 1H); 3.51 (m, 1H); ca. 3.2 (m, 1H), 3.02 (s, 3H); 2.97 (m, 1H); 2.81-2.68 (m, 2H); 2.61 (s, 3H); 2.0-1.7 (several m, 8H); 1.4-0.6 (several m, 4H).
Synthesis of Ex. 286
A soln. of Ex. 284a (1.2 g, 1.95 mmol) in MeOH (120 mL) was hydrogenated in the presence of platinum (IV) oxide hydrate (120 mg) for 8 h at rt and normal pressure. More platinum (IV) oxide hydrate (60 mg) was added and the hydrogenation was continued for 6 h. The mixture was filtered through a pad of celite. The solid was washed (MeOH). The combined filtrate and washings were concentrated. FC (hexane/EtOAc 50:50:0 to 0:100 then CH 2 Cl 2 /MeOH 90:10) yielded Ex. 286 (0.75 g, 66%).
Data of Ex. 286: C 32 H 38 N 6 O 5 (586.7). LC-MS (method 1d): R t =1.68 (90), 587.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.67 (d, J=2.0, 1H); 7.48-7.43 (m, 2H); 7.39-7.27 (m, 6H); 6.87 (d, J=8.6, 1H); 5.06-4.93 (m, 5H); 4.11 (br. m, not resolved, 1H); 4.00 (br. d, J ca 11.7, 1H); 3.60 (br. t, J ca. 8.4, 1H); 3.49 (q-like m, 1H); 3.15 (m, 1H), 2.99 (s, 3H); 2.96 (m, 1H); 2.78 (m, 1H); 2.54 (s, 3H); 2.21 (m, 1H); 2.15-1.15 (several br. m, 8H); 0.66 (br. m, 1H).
Core 18: Synthesis of Ex. 305 and Ex. 306 (Scheme 21)
Synthesis of the Mitsunobu Product 161
DEAD (40% in toluene; 11.1 mL, 24.3 mmol) was slowly added to a soln of alcohol 122 (5.66 g, 16.2 mmol), 2-iodophenol (111; 5.33 g, 24.3 mmol) and PPh 3 (6.36 g, 24.3 mmol) in toluene (345 mL). The mixture was stirred at rt for 4 h. The volatiles were evaporated. FC (hexane/EtOAc gradient) afforded 161 (6.85 g, 77%).
Data of 161: C 24 H 29 IN 2 O 5 (552.4). LC-MS (method 1a): R t =2.71 (99), 553.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.76 (d, J=7.7, 1H); 7.60 (d, J=6.5, 1H); 7.40-7.28 (m, 6H); 7.02 (d, J=8.2, 1H); 6.76 (t, J=7.5, 1H); 5.03 (s, 2H); 4.33 (br. m, 1H); 4.17-4.07 (br. m, 3H); 3.59 (br. m, 1H); 3.29 (br. m, 1H); 2.26 (br. m, 1H); 2.02 (br. m, 1H); 1.38 (s, 9H).
Synthesis of the Biphenyl 162
Pd(dppf)Cl 2 .CH 2 Cl 2 (1.0 g, 1.2 mmol) was added to a mixture of 161 (6.8 g, 12.3 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (113; 3.0 g, 10.8 mmol), 2-(ethoxycarbonyl)phenylboronic acid (112; 2.3 g, 11.8 mmol) in DME (325 mL), EtOH (32 mL) and 1 M aq. Na 2 CO 3 soln (37 mL). The mixture was heated to 80° C. for 3 h. The mixture was diluted with sat. aq. NaHCO 3 soln and repeatedly extracted with CH 2 Cl 2 . The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc gradient) gave 162 (6.6 g, 94%).
Data of 162: C 33 H 38 N 2 O 7 (574.6). LC-MS (method 4c): R t =2.48 (96), 575.4 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.80 (d, J=7.5, 1H); 7.58 (t, J=7.3, 1H); 7.46-7.25 (m, 9H); 7.12 (m, 1H); 7.03-7.00 (m, 2H); 4.99 (s, 2H); 3.99-3.83 (br. m, 6H); 3.78 (br. not resolved m, 1H); 3.01 (br. not resolved m, 1H); 1.81 (br. not resolved m, 1H); 1.72 (br. not resolved m, 1H); 1.33 (s, 9H); 0.88 (br. t, 3H).
Synthesis of the Carboxylic Acid 164
A soln of 162 (5.2 g, 9.1 mmol) in EtOH (50 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 0.5 g). The mixture was filtered through a pad of celite. The residue was washed with EtOH. The combined filtrate and washings were concentrated to give crude 163 (4.0 g) which was dissolved in EtOH (84 mL). KOH (10.2 g, 182 mmol) dissolved in H 2 O (28 mL) was added and the mixture was stirred at 45° C. for 18 h. The solution was cooled to rt. NaHCO 3 (15.2 g, 182 mmol) and CH 2 Cl 2 (100 mL) followed by CbzOSu (2.7 g, 10.8 mmol) were successively added and the mixture was allowed to stir for 3 h. The mixture was acidified by addn of 3 M aq. HCl soln and extracted with CH 2 Cl 2 . The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (EtOAc) afforded 164 (4.87 g, 98%)
Data of 164: C 31 H 34 N 2 O 7 (546.6). LC-MS (method 1c): R t =2.44 (88), 547.1 ([M+H] + ).
Synthesis of the Amide 165
EDC.HCl (3.4 g, 17.8 mmol) was added to a soln of 164 (4.8 g, 8.9 mmol) and sarcosine tert.-butylester hydrochloride (132; 3.2 g, 17.8 mmol) in pyridine (150 mL). The mixture was stirred at rt for 3 h. Aqueous workup (CH 2 Cl 2 , aq. 2 M HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc gradient) afforded 165 (4.9 g, 82%).
Data of 165: C 38 H 47 N 3 O 8 (673.8). LC-MS (method 1a): R t =2.71 (97), 674.2 ([M+H] + ).
Synthesis of Ex. 305
A soln of 165 (4.9 g, 7.3 mmol) in CH 2 Cl 2 (50 mL) was treated with TFA (25 mL) for 4 h at rt. Evaporation of the volatiles afforded the crude amino acid 166-CF 3 CO 2 H (5.3 g, containing residual solvent) which was used without further purification.
The ring closing reaction was performed in four batches:
A soln of crude 166.CF 3 CO 2 H (1.3 g) and i-Pr 2 NEt (1.5 mL, 8.7 mmol) in CH 2 Cl 2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc, 2.2 mL, 3.7 mmol) in CH 2 Cl 2 (1200 mL). The mixture was stirred for 1 h at rt and concentrated.
The four batches were combined and purified by FC (hexane/EtOAc/MeOH gradient) to give Ex. 305 (3.7 g, quant. yield).
Data of Ex. 305: C 29 H 29 N 3 O 5 (499.5). LC-MS (method 1a): R t =2.00 (98), 500.1 ([M+H] + ). 1 H-NMR (CD 3 OD): Two sets of signals were observed; ratio 7:3; 7.48-7.21 (m, 11H), 7.12-6.96 (m, 1.3H); 6.91 (t, J=7.5, 0.7H); 5.10-5.04 (m, 2H); 4.72 (dd, J=4.2, 9.7, 0.7H); 4.40-4.28 (m, 1.3H); 4.16-4.06 (m, 1.6H); 4.03 (dt, J=4.0, 7.8, 0.7H); 3.93 (br. not resolved m, 0.7H); 3.78 (d, J=14.6, 0.3H); 3.69 (br. d, 0.7H); 3.59-3.50 (m, 1.3H); 3.10, 3.07 (2 s, 3H); 2.99 (br. d, J ca 10.0, 0.7H); 2.10-1.93 (m, 2H).
Synthesis of Ex. 306
A soln of Ex. 305 (3.68 g, 7.3 mmol) in MeOH (50 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 0.38 g). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrate and washings were concentrated. FC (hexane/EtOAc/MeOH gradient) afforded Ex. 306 (2.4 g, 89%).
Data of Ex. 306: C 21 H 23 N 3 O 3 (365.4). LC-MS (method 1a): R t =1.17 (96), 366.0 ([M+H] + ).
Core 19: Synthesis of Ex. 327, Ex. 328 and Ex. 329 (Scheme 22)
Synthesis of the Amide 167
At 0° C., i-Pr 2 NEt (4.5 mL, 26.3 mmol) was added dropwise to a soln of 117 (1.2 g, 4.4 mmol), 125.HCl (1.73 g, 5.2 mmol), HATU (1.67 g, 4.4 mmol) and HOAt (0.60 g, 4.4 mmol) in DMF (30 mL) and THF (45 mL). The mixture was stirred at rt for 1.5 h. Aqueous workup (EtOAc, 0.1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:1) afforded 167 (1.24 g, 51%).
Data of 167: C 26 H 24 F 3 N 3 O 7 (547.5). LC-MS (method 1c): R t =2.37 (89), 548.2 ([M+H] + ).
Synthesis of the Mitsunobu Product 168
A soln of phenol 167 (1.23 g, 2.2 mmol), alcohol 16 (0.81 g, 2.7 mmol) and CMBP (1.36 g, 5.6 mmol) in toluene (30 mL) was heated to reflux for 1.5 h. Evaporation of the volatiles and FC(CH 2 Cl 2 /EtOAc 3:1 to 1:1) afforded 168 (1.84 g, 99%).
Data of 168: C 40 H 46 F 3 N 5 O 11 (829.8). LC-MS (method 4a): R t =2.00 (92), 830.4 ([M+H] + ).
Synthesis of the Amino Acid 169
A degassed solution of 168 (1.8 g, 2.2 mmol) and 1,3-dimethylbarbituric acid (0.8 g, 5.3 mmol) in CH 2 Cl 2 (15 mL) and EtOAc (15 mL) was treated with Pd(PPh 3 ) 4 (0.13 g, 0.1 mmol) at rt for 1 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 99:1 to 80:20) afforded 169 (1.32 g, 85%).
Data of 169: C 33 H 38 F 3 N 5 O 9 (705.7). LC-MS (method 1a): R t =1.95 (94), 706.3 ([M+H] + ).
Synthesis of Ex. 327
A mixture of 169 (1.33 g, 1.9 mmol), i-Pr 2 NEt (1.6 mL, 9.4 mmol) and CH 2 Cl 2 (40 mL) was slowly added over 2 h (syringe pump) to a soln of T3P (50% in EtOAc; 3.3 mL, 5.6 mmol) and i-Pr 2 NEt (1.6 mL, 9.4 mmol) in CH 2 Cl 2 (1880 mL). The volatiles were partially evaporated. The soln was washed (sat. aq. NaHCO 3 soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 25:75 to 0:100) afforded Ex. 327 (0.96 g, 74%).
Data of Ex. 327: C 33 H 36 F 3 N 5 O 8 (687.6). LC-MS (method 1f): R t =2.43 (89), 688.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Three sets of signals were observed; ratio 2:1:1; 9.16 (br. s, 0.5H); 8.65 (br. s, 0.25H); 8.50 (br. s, 0.25H); 7.56-7.08 (m, 10H); 5.13-4.92 (several d, 2H); 4.40-2.98 (several br. not resolved m, 12H); 2.43-2.04 (br. not resolved m, 1H); 1.95-1.70 (br. not resolved m, 1H); 1.41, 1.39 (2 s, 9H).
Synthesis of Ex. 328
A soln of Ex. 327 (60 mg, 0.087 mmol) in EtOAc (5 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 30 mg). The mixture was filtered through a pad of celite. The residue was washed (EtOAc). The combined filtrate and washings were concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 328 (37 mg, 77%).
Data of Ex. 328: C 25 H 30 F 3 N 5 O 6 (553.5). LC-MS (method 1d): R t =1.84 (96), 554.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Two sets of signals were observed; ratio 4:6; 9.19 (t-like m, 0.4H), 8.72 (t-like m, 0.6H); 7.57 (not resolved m, 1H); 7.48-7.30 (m, 2H); 7.23 (d, J=5.1, 1H); 7.04 (not resolved m, 1H); 4.50-4.34 (2 m, 1H); 4.20-4.13 (m, 2H); 4.07-3.94 (m, 2H); 3.84-3.30 (several m, 3H); 3.19-2.66 (several m, 5H); 2.42, 2.26 (2 m, 1H); 1.95, 1.70 (2 m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 329
Ex. 327 (50 mg, 0.073 mmol) was dissolved in CH 2 Cl 2 (2 mL). At 0° C., TFA (0.03 mL, 0.36 mmol) was added and the soln was stirred for 1.5 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln, sat aq. NaCl soln; Na 2 SO 4 ) and treatment of the product with HCl in dioxane afforded Ex. 329.HCl (33 mg, 73%).
Data of Ex. 329.HCl: C 28 H 28 F 3 N 5 O 6 .HCl (free base; 587.5). LC-MS (method 1d): R t =1.69 (97), 588.2 ([M+H] + ).
General Procedures
Attachment of Substituents to the Macrocyclic Core Structures:
Synthesis of the Final Products
Acylation, Carbamoylation, Sulfonylation, and Alkylation Reactions
Procedure A
A.1.: Amide Coupling of a Macrocyclic Amine with
A.1.1: Carboxylic Acid and HATU
A soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol), a carboxylic acid (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mL) was treated at rt with i-Pr 2 NEt (3.0 equiv.). The mixture was stirred at rt for 2-15 h. The mixture was distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2: Acyl Chloride or Carboxylic Acid Anhydride
At 0° C., a soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol) in CH 2 Cl 2 (0.5 mL) was successively treated with pyridine (5 equiv.) and carboxylic acid chloride (1.05-2 equiv.) or carboxylic acid anhydride (1.05-2 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. After the addn of MeOH (0.01 mL) the soln was stirred for 10 min and concentrated. Toluene was added to the crude product and evaporated. Purification of the residue by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2.1: Acyl Chloride
Like A.1.2 and after 15 h at rt more carboxylic acid chloride (2 equiv.) and i-Pr 2 NEt (3 equiv.) were added. Stirring was continued for 24 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ).
A.1.2.2: Acyl Chloride
At 0° C., a soln of an amino macrocycle (free amine or hydrochloride; 1 mmol) in CH 2 Cl 2 (7 mL) was successively treated with i-Pr 2 NEt (5 equiv.) and carboxylic acid chloride (1.05-2 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. Aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ). Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.3: Carboxylic Acid and T3P
A soln of a carboxylic acid (2.4 equiv.), T3P (50% in DMF; 3 equiv.) and i-Pr 2 NEt (4.0 equiv.) in DMF (0.3 mL) was slowly added to a mixture of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) and DMF (0.2 mL). The mixture was stirred at rt for 2-15 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ).
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.2: Amide Coupling of a Macrocyclic Carboxylic Acid with an Amine and HATU
A soln of a macrocyxclic carboxylic acid (0.12 mmol), an amine (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mL) was treated at 4° C. with i-Pr 2 NEt (3.0 equiv.). The mixture was stirred at 4° C. for 2 h. The mixture was distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated.
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic amide.
Procedure A.3: Urea Formation with Isocyantes or Equivalents of Isocyanates
A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH 2 Cl 2 (0.5 mL) was treated at rt for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr 2 NEt (3 equiv.) followed by aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea.
Procedure A.4: Carbamate Formation with Chloroformates
At 0° C. the chloroformate (1.1 equiv.) was added to a stirred mixture of CH 2 Cl 2 (0.9 mL) and sat. aq. Na 2 CO 3 soln (0.35 mL). The amino macrocycle (free amine or hydrochloride; 0.085 mmol) and H 2 O (0.75 mL) were added. The mixture was stirred at rt for 2-15 h followed by aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic carbamate.
Procedure A.5: Sulfonamide Formation with Sulfonyl Chlorides
At 0° C. a soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH 2 Cl 2 (0.5 mL) was successively treated with triethylamine (3.0 equiv.) and the sulfonyl chloride (1.0 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. (In case of incomplete transformation, more sulfonyl chloride (1.0 equiv.) and auxiliary base (3.0 equiv.) were added and stirring continued.) Aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded the targeted macrocyclic sulfonamide.
Procedure A.6: N-Alkylation by Reductive Amination
A.6.1. N,N-Dimethylamino Macrocycles by Reductive Amination
To a soln. of the amino macrocycle (free amine or hydrochloride; 0.085 mmol) in DCE (1.2 mL) was added formaldehyde soln (36.5% in H 2 O; 5 equiv.) followed by NaBH(OAc) 3 (4 equiv.). The mixture was stirred at rt for 4 h.
Aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a dimethylamino macrocycle.
A.6.2: Synthesis of Tertiary Amines by N-Methylation of Secondary Amines
At 0° C. formaldehyde soln (36.5% in H 2 O; 5 equiv.), acetic acid (1.2 equiv.) and NaBH(OAc) 3 (4.0 equiv.) were added to a soln of the macrocyclic amine (0.25 mmol) in DCE (4 mL). The mixture was stirred at rt for 4 h followed by aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ). Purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the desired N-methyl-N,N-dialkylamino macrocycle.
A.6.3: Synthesis of Tertiary Amines by Reductive Amination of Secondary Amines
The aldehyde (1.5 equiv.) was added to a mixture of the macrocyclic amine (0.25 mmol) and THF (1.5 mL). The mixture was stirred at rt for 1 h. Acetic acid (1.2 equiv.) and NaBH(OAc) 3 (3 equiv.) were added and stirring was continued for 15 h. (In case of incomplete transformation, more aldehyde (0.5 equiv.) was added and stirring continued.) After aqueous workup (CH 2 Cl 2 , 1 M aq. Na 2 CO 3 soln; Na 2 SO 4 ) the crude product was purified by chromatography (FC, normal phase or reverse phase prep. HPLC) to afford the macrocyclic tertiary amine.
A.6.4: Synthesis of Secondary Amines by Reductive Amination
Activated molecular sieve powder (3 Å; 2 mg per mg of starting material) was added at rt to a soln of an amino macrocycle (0.1 mmol) and an aldehyde (1.1 equiv.) in THF (0.5 mL). The suspension was stirred for 2-4 h at rt, followed by the addition of acetic acid (1.1 equiv.) and NaBH(OAc) 3 (3.0 equiv.). The mixture was stirred for 18 h and filtered. Aqueous workup of the filtrate (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the alkylamino macrocycle.
Deprotection Reactions
Procedure B
Procedure B.1: Boc Cleavage
A soln of a macrocyclic Boc-amine in dioxane (1 mL per 100 mg) was treated with 4 M HCl in dioxane (1 mL per 100 mg) and stirred at rt for 2-16 h. The volatiles were evaporated. The residue was taken up in CHCl 3 , concentrated and dried i.v. Solid residues were then washed with Et 2 O/CH 2 Cl 2 .
Procedure B.2: Tert.-Butyl Ester Cleavage or Boc Cleavage
Tert.-Butyl Ester Cleavage:
TFA (1 mL per 100 mg) was slowly added to a soln of a macrocyclic tert.-butyl ester in CH 2 Cl 2 (5 mL per 100 mg). The mixture was stirred for 2 h at rt and concentrated. The residue was twice taken up in toluene and concentrated. The residue was then twice taken up in CHCl 3 and concentrated followed by washing with Et 2 O/CH 2 Cl 2 .
Boc Cleavage:
TFA (1 mL per 100 mg of starting material) was slowly added to a soln of the macrocyclic Boc-amine in CH 2 Cl 2 (3 mL per 100 mg). The mixture was stirred at rt for 3 h and concentrated. The residue was dried i.v.
Procedure B.3: Cbz Cleavage
A soln of the macrocyclic benzyl carbamate (500 mg) in MeOH (10 mL) or 2,2,2-trifluoroethanol (10 mL) was hydrogenated for 4 h at rt and at normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 15-20% Pd; 0.1 g). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrates and washings were concentrated to obtain the macrocyclic amine.
Procedure B.4: Nitro Reduction
A soln of the macrocyclic arylnitro compound (50 mg) in MeOH (5 mL) was hydrogenated for 15 h at rt and at normal pressure in the presence of platinum (IV) oxide hydrate (5 mg). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrates and washings were concentrated to obtain the macrocyclic aniline.
B.5: Methyl Ester Cleavage
A soln of the macrocyclic methyl ester (0.07 mmol) in DCE (2 mL) was treated with trimethyltin hydroxide (3 equiv.) at 80° C. for 16 h. Aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and purification by reverse phase prep. HPLC afforded the corresponding macrocyclic carboxylic acids.
Procedures for the Synthesis on Solid Support
Procedure C: Description of Examples of Core 10 and Core 11
Procedure D: Description of Examples of Core 01
Synthesis of Final Products
Advanced macrocyclic intermediates and final products depicted in Tables 13-31 (related cores cf. Scheme 23) were prepared starting from the suitable precursor macrocyclic acid, macrocyclic amine, or macrocyclic alcohol applying the general procedures (A.1-A.6; B.1-B.5) or specific procedures described above (as indicated in the corresponding Tables). Deviations from general procedures are indicated in Tables 13a-31a.
Final products of Core 01 prepared on solid support were obtained following the general procedure D (vide supra; Core 01: Synthesis of final products on solid support).
Final products of Cores 10 and 11 were prepared following the general procedure described in the text (vide supra; Procedure C.1: Core 10: Synthesis of Ex. 193a,c-h and Ex. 194b and Procedure C.2: Core 11: Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d)
Analytical data of these intermediates and final products are depicted in Tables 13b-31b.
IUPAC names of all examples are listed in Tables 13c-31c.
The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers
Reagents used in the derivatizations are commercially available with the exception of few N-succinimidyl carbamates which were synthesized from amines, anilines or heteroaryl amines according to the procedure of K. Takeda et al. Tetrahedron Lett. 1983, 24, 4569-4572.
The synthesis of selected advanced intermediates and final products is described in detail in the text above; cf. corresponding core description.
The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers.
TABLE 13a
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
Start-
Yield
ing
(iso-
Mate-
General
Purification
lated
No
R A
R B
rial
Proced.
Reagent
Method
salt)
Ex. 1-
cf. experimental description
Ex. 3
and
Ex. 330-
Ex. 331:
Ex. 4
Ex. 2
A.1.1; 1)
1-Naphthalene- acetic acid
FC (hexane/ EtOAc)
77%
Ex. 5
NH 2
Ex. 4
B.1; 1)
HCl-dioxane
crude product
quant. (HCl salt)
Ex. 6
Ex. 5
A.4
Methyl chloroformate
FC (CH 2 Cl 2 / MeOH)
82%
Ex. 7
Ex. 5
A.1.1; 1)
1-Pyrrolidineacetic acid
FC (CH 2 Cl 2 / MeOH)
71%
Ex. 7
133
D; 1)
1.1-Pyrrolidine- acetic acid 2.1-Naphthalene- acetic acid
prep. HPLC method 1a
15% (TFA salt)
Ex. 8
N(CH 3 ) 2
Ex. 5
A.6.1
Formaldehyde (36.5% in H2O)
FC (CH 2 Cl 2 / MeOH)
79%
Ex.
NH 2
NH 2
Ex. 2
B.1
HCl-dioxane
crude product
97%
9
rt, 16 h
(HCl
salt)
Ex. 10
Ex. 3
A.1.1
2-Naphthalene- acetic acid 4° C., 1 h
FC (hexane/ EtOAc/MeOH 80:20:0 to 0:90:10)
31%
Ex. 11
NH 2
Ex. 10
B.3
H, Pd(OH) 2 —C 2,2,2- trifluoroethanol
crude product
90%
Ex. 12
Ex. 11
A.1.1
2- (Dimethylamino) acetic acid 0° C., 2 h
prep. HPLC method 1b
48% (TFA salt)
Ex. 13
Ex. 11
A.1.1
3-Methylbutanic acid 0° C., 2 h
prep. HPLC method 1b
55%
Ex. 14
Ex. 3
A.4 1)
Phenyl chloroformate 0° C., 2 h
FC (EtOAc)
96%
Ex. 332
133
D; 1)
1. Imidazol-1-yl- acetic acid 2. 1-Naphthalen- acetic acid
prep. HPLC method 1a
48% (TFA salt)
Ex. 333
133
D; 1)
1. 2,5-Dioxo- pyrrolidin- 1-yl pyridin-3- ylcarbamate 2. 1-Naphthalene- acetic acid
prep. HPLC method 1a
65% (TFA salt)
Ex. 334
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. 3-Chloro- phenylacetic acid
prep. HPLC method 1a
38% (TFA salt)
Ex. 335
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. Cyclohexylacetic acid
prep. HPLC method 1a
26% (TFA salt)
Ex. 336
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. 1-Naphthyl isocyanate
prep. HPLC method 1a
13% (TFA salt)
Ex. 337
133
D
1. 1-Pyrrolidine- acetic acid 2. Benzylsulfonyl chloride
prep. HPLC method 1a
21% (TFA salt)
Ex. 338
Ex. 3
A.1.3
1-Pyrrolidineacetic acid i-Pr 2 NEt (5 equiv.) Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 / MeOH)
80%
Ex. 339
NH 2
Ex. 338
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
98%
Ex. 340
Ex. 339
A.6.4
1-Naphthalene- acetaldehyde, 3 h; NaBH(OAc) 3 (3 eq.) Workup: CHCl 3 , sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 / MeOH) and prep. HPLC method 1a
20% (TFA salt)
1) Cf. experimental description for detailed procedure
TABLE 13b
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
Rt
Mono-
(purity
isotopic
at
[M + H] +
LC-MS-
No
R A
R B
Formula
Mass
220 nm)
found
Method
Ex. 1-
cf. experimental description
Ex. 3
and
Ex. 330-
Ex. 331:
Ex. 4
C39H42N4O6
662.3
2.27 (86)
663.2
method 1a
Ex. 5
NH 2
C34H34N4O4
562.3
1.61 (91)
563.2
method 1a
Ex. 6
C36H36N4O6
620.3
2.01 (90)
621.0
method 1a
Ex. 7
C40H43N5O5
673.3
2.13 (99)
674.3
method 2c
Ex. 8
N(CH 3 ) 2
C36H38N4O4
590.3
1.65 (97)
591.1
method 1a
Ex. 9
NH 2
NH 2
C22H26N4O3
394.2
1.01 (96)
395.2
method 1a
Ex. 10
C42H40N4O6
696.3
2.25 (91)
697.1
method 1a
Ex. 11
NH 2
C34H34N4O4
562.3
1.73 (91)
563.1
method 1a
Ex. 12
C38H41N5O5
647.3
1.71 (96)
648.1
method 1a
Ex. 13
C39H42N4O5
646.3
2.09 (89)
647.2
method 1a
Ex. 14
C37H36N4O7
648.3
2.22 (97)
649.1
method 1a
Ex. 332
C39H38N6O5
670.3
1.84 (99)
671.3
method 2c
Ex. 333
C40H38N6O5
682.3
1.94 (99)
683.2
method 2c
Ex. 334
C36H40ClN5O5
657.3
2.08 (99)
658.2
method 2c
Ex. 335
C36H47N5O5
629.4
2.10 (99)
630.3
method 2c
Ex. 336
C39H42N6O5
674.3
2.09 (98)
675.3
method 2c
Ex. 337
C35H41N5O6S
659.3
1.59 (99)
660.3
method 1a
Ex. 338
C36H41N5O6
639.3
1.63 (99)
640.2
method 1a
Ex. 339
NH 2
C28H35N5O4
505.3
1.15 (97)
506.2
method 1c
Ex. 340
C40H45N5O4
659.3
1.60 (87)
660.3
method 1a
TABLE 13c
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
No
R A
R B
IUPAC name
Ex. 1
benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14.18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 2
NH 2
tert-butyl N-[(12R,16S,18S)-12- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 3
NH 2
benzyl N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 4
tert-butyl N-[(12R,16S,18S)-12{[2-(1-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25)2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 5
NH 2
N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 6
methyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 7
N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 8
N(CH 3 ) 2
N-[(12R,16S,18S)-16-(dimethylamino)- 8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 9
NH 2
NH 2
(12R,16S,18S)-12,16-diamino-20-oxa-9,14-
diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-
1(25),2,4,6,21,23-hexaene-8,13-dione
Ex. 10
benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl] amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 11
NH 2
N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(2- naphthyl)acetamide
Ex. 12
2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2- naphthyl)acetyl]amino}-8,13-dioxo-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide
Ex. 13
3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]butanamide
Ex. 14
benzyl N-[(12R,16S,18S)-8,13-dioxo-16- [(phenoxycarbonyl)amino]-20-oxa-9,14- (diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 330
allyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 331
NH 2
allyl N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 332
2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12- {[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ] pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]acetamide
Ex. 333
N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino) carbonyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 334
2-(3-chlorophenyl)-N-[(12R,16S,18S)-8,13- dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ] pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide
Ex. 335
2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo- 16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide
Ex. 336
N-[(12R,16S,18S)-12-{[(1-naphthylamino) carbonyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 337
N-[(12R,16S,18S)-12-[(benzylsulfonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 338
benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2- (1-pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 339
NH 2
N-[(12R,16S,18S)-12-amino- 8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 340
N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyl] amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
TABLE 14a
Examples of Core 02 (Ex. 15-Ex. 40;)
Start-
Yield
ing
(iso-
Mate-
General
Purification
lated
No
R A
R B
rial
Proced.
Reagent
Method
salt)
Ex. 15-
cf. experimental description
Ex. 17:
Ex. 18
Ex. 17
A.1.1; 4)
2-Naphthaleneacetic acid
FC (EtOAc)
79%
Ex. 19
NH 2
Ex. 18
B.3; 4)
H 2 , Pd(OH) 2 —C MeOH
crude product
97%
Ex. 20
Ex. 19
A.1.1; 4)
2-(Dimethylamino) acetic acid
FC (CH 2 Cl 2 /MeOH)
30%
Ex. 21
Ex. 19
A.5
Cyclo- propanesulfonyl chloride (1.5 equiv.) Et 3 N (3 equiv.)
FC (EtOAc; then CH 2 Cl 2 /MeOH)
86%
DMAP (0.1 equiv)
CHCl 3 (0.25 mL),
50° C., 15 h
Workup: CH 2 Cl 2 ,
half-sat. aq.
NaHCO 3 soln.;
Na 2 SO 4
Ex. 22
Ex. 19
A.3
N-Succinimidyl N- methylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3
FC (CH 2 Cl 2 /MeOH)
63%
1:1 (1.0 mL)
rt, 3 h
Ex. 23
Ex. 19
A.1.2
2-Methoxyacetyl chloride (1.5 equiv.) rt, 3 h
FC (CH 2 Cl 2 /MeOH)
51%
Ex. 24
Ex. 19
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h (Mixture was
prep. HPLC method 1a
73%
concentrated
without addn
of MeOH.)
Ex. 25
Ex. 19
A.1.2; 4)
Phenylacetyl chloride
prep. HPLC method 1a
60%
Ex. 26
Ex. 19
A.1.2; 4)
Benzoyl chloride
prep. HPLC method 1a
67%
Ex. 27
Ex. 19
A.1.2
Butyryl chloride (1.2 equiv.) 0° C., 2 h (Mixture was concentrated
prep. HPLC method 1a
67%
without addn
of MeOH.)
Ex. 28
Ex. 19
A.1.2
Pentanoyl chloride (1.2 equiv.) 0° C., 2 h (Mixture was concentrated
prep. HPLC method 1a
66%
without addn
of MeOH.)
Ex. 29
Ex. 40
1)
LiOH 1)
prep. HPLC method 1a
47%
Ex. 30
Ex. 39
2)
Methyl isothiocyanate 2)
prep. HPLC method 1a
48%
Ex. 31
Ex. 32
3)
3)
FC (CH 2 Cl 2 /MeOH 100:0 to 80:20)
57%
Ex. 32
Ex. 39
A.1.1
2-(Tritylthio)acetic acid i-Pr 2 NEt (5 equiv.) 0° C., 2 h
FC (CH 2 Cl 2 /MeOH 90:10)
85%
Workup: CH 2 Cl 2 ,
sat. aq.
NaHCO 3 soln
Ex. 33
Ex. 39
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.)
prep. HPLC method 1a
77% (TFA salt)
Ex. 34
Ex. 39
A.3
2,5-Dioxo- pyrrolidin- 1-yl-3- (dimethylamino) phenyl- carbamate
prep. HPLC method 1a
77% (TFA salt)
(1.4 equiv.)
i-Pr 2 NEt (5.0 equiv.)
Ex. 35
Ex. 39
A.3
2-Naphthyl isocyanate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.)
prep. HPLC method 1a
77% (TFA salt)
Ex. 36
Ex. 39
A.5
Methanesulfonyl chloride (1.3 equiv.) Et 3 N (5 equiv.)
prep. HPLC method 1a
64% (TFA salt)
Ex. 37
Ex. 39
A.5
Phenylmethane- sulfonyl chloride (1.3 equiv.) Et 3 N (5 equiv.)
prep. HPLC method 1a
43% (TFA salt)
Ex. 38
Ex. 16
A.1.3
2-(Dimethylamino) acetic acid Workup: CH 2 Cl 2 , 1M aq. HCl
FC (CH 2 Cl 2 /MeOH/ conc. aq. NH3 soln
86%
soln; sat. aq.
95:5:2)
NaHCO 3 soln,
sat. aq. NaCl
soln; Na 2 SO 4
Ex. 39
NH 2
Ex. 38
B.1
HCl-dioxane rt, 2 h
crude product
quant. (HCl salt)
Ex. 40
Ex. 39
A.6.4
Ethyl glyoxylate (1.2 equiv.)
FC (CH 2 Cl 2 /MeOH 9:1)
37%
1) A soln of the macrocyclic ethylester Ex. 40 (63 mg, 0.11 mmol) in THF/MeOH 1:1 (1 mL) was treated at 0° C. for 2 h with 2M aq. LiOH soln (0.16 mL, 0.32 mmol). The mixture was concentrated. The residue was treated with 1M aq. HCl soln and concentrated Purification by reverse phase prep. HPLC afforded Ex. 29 (40 mg, 47%).
2) Methyl isothiocyantae (6 mg, 0.11 mmol) was added to a soln of Ex. 39 (50 mg, 0.078 mmol) and i-Pr 2 NEt (0.07 mL, 0.39 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stired for 16 h at rt. More methyl isothiocyantae (2 mg) was added and stirring continued for 1 h. Aq. Workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) afforded Ex. 30 (26 mg, 48%).
3) Triisopropylsilane (0.12 mL, 0.58 mmol) was added to a soln of Ex. 32 (50 mg, 0.115 mmol) in CH 2 Cl 2 (0.4 mL). The mixture was cooled to 0° C. followed by the addition of TFA (0.4 mL). The mixture was stirred for 30 min at 0° C. and concentrated. FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded Ex. 31 (46 mg, 57%).
4) Cf. experimental description for detailed procedure
TABLE 14b
Examples of Core 02 (Ex. 15-Ex. 40;)
Rt
Monoisotopic
(purity at
[M + H] +
LC-MS-
No
R A
R B
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 15-
Ex. 17:
Ex. 18
C44H44N4O6
724.3
2.36 (98)
725.2
method 1a
Ex. 19
NH 2
C36H38N4O4
590.3
1.76 (97)
591.2
method 1a
Ex. 20
C40H45N5O5
675.3
1.82 (95)
676.3
method 1a
Ex. 21
C39H42N4O6S
694.3
2.10 (97)
695.2
method 1a
Ex. 22
C38H41N5O5
647.3
1.96 (98)
648.2
method 1a
Ex. 23
C39H42N4O6
662.3
2.04 (99)
663.2
method 1a
Ex. 24
C41H46N4O5
674.3
2.20 (98)
675.2
method 1a
Ex. 25
C44H44N4O5
708.3
2.27 (99)
709.2
method 1a
Ex. 26
C43H42N4O5
694.3
2.26 (99)
695.2
method 1a
Ex. 27
C40H44N4O5
660.3
2.15 (99)
661.2
method 1a
Ex. 28
C41H46N4O5
674.3
2.24 (99)
675.3
method 1a
Ex. 29
C30H39N5O6
565.3
1.25 (99)
566.2
method 1a
Ex. 30
C30H40N6O4S
580.3
1.38 (95)
581.2
method 3a
Ex. 31
C30H39N5O5S
581.3
1.49 (90)
582.0
method 1a
Ex. 32
C49H53N5O5S
823.4
2.18 (90)
824.3
method 1a
Ex. 33
C30H40N6O5
564.3
1.40 (99)
565.1
method 1a
Ex. 34
C37H47N7O5
669.4
1.37 (97)
670.2
method 1a
Ex. 35
C39H44N6O5
676.3
1.84 (98)
677.3
method 1a
Ex. 36
C29H39N5O6S
585.3
1.44 (99)
586.0
method 1a
Ex. 37
C35H43N5O6S
661.3
1.68 (97)
661.8
method 1e
Ex. 38
C33H45N5O6
607.3
1.73 (93)
608.1
method 1a
Ex. 39
NH 2
C28H37N5O4
507.3
1.23 (93)
508.2
method 1a
Ex. 40
C32H43N5O6
593.3
1.38 (96)
594.1
method 1a
TABLE 14c
Examples of Core 02 (Ex. 15-Ex. 40;)
No
R A
R B
IUPAC name
Ex. 15
benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 16-yl]carbamate
Ex. 16
NH 2
tert-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate
Ex. 17
NH 2
benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]carbamate
Ex. 18
benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]carbamate
Ex. 19
NH 2
N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo [20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2- naphthyl)acetamide
Ex. 20
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 21
N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]- 2-(2-naphthyl)acetamide
Ex. 22
N-[(10S,12S,16S)-20-methyl-16-{[(methylamino)carbonyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 12-yl]-2-(2-naphthyl)acetamide
Ex. 23
2-methoxy-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide
Ex. 24
3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]butanamide
Ex. 25
N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)amino]-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 12-yl]-2-(2-naphthyl)acetamide
Ex. 26
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]benzamide
Ex. 27
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino)-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]butanamide
Ex. 28
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]pentanamide
Ex. 29
2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]amino}acetic acid
Ex. 30
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbothioyl] amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 31
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-[(2- sulfanylacetyl)amino]-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 32
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-{[2- (tritylsulfanyl)acetyl]amino}-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ] hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 33
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbonyl] amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 34
2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3-(dimethylamino)anilino]carbonyl} amino)-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ] hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 35
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(2- naphthylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide
Ex. 36
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-[(methylsulfonyl)amino]- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 37
N-[(10S,12S,16S)-12-[(benzylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 16-yl]-2-(dimethylamino)acetamide
Ex. 38
tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]carbamate
Ex. 39
NH 2
N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]-2- (dimethylamino)acetamide
Ex. 40
ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]amino}acetate
TABLE 15a
Examples of Core 03 (Ex. 41-Ex. 67;)
Starting
General
Purification
Yield
No
R E
Material
Proced.
Reagent
Method
(isolated salt)
cf. experimental description
Ex. 41-Ex. 42,
Ex. 62-Ex. 67:
Ex. 43
CONH 2
Ex. 42
A.2
NH 4 Cl (4 equiv.)
prep. HPLC method 3
64%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq.
Na 2 CO 3 , CH 2 Cl 2
Ex. 44
CONHCH 3
Ex. 42
A.2
CH 3 NH 3 Cl (4 equiv.)
prep. HPLC method 3
71%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
4° C., 1 h
Workup: Sat. aq.
Na 2 CO 3 , CH 2 Cl 2
Ex. 45
CONHPh
Ex. 42
A.2
Aniline
prep. HPLC method 3
80%
Ex. 46
Ex. 42
A.2
Pyrrolidine
prep. HPLC method 3
53%
Ex. 47
Ex. 42
A.2
N,N-Dimethyl- ethylenediamine (1.0 equiv.) Workup: Sat. aq. Na 2 CO 3 , CH 2 Cl 2
prep. HPLC method 1a
61% (TFA salt)
Ex. 48
Ex. 42
A.2
tert.-Butyl-3- aminopropylcarbamate
prep. HPLC method 3
65%
Ex. 49
Ex. 48
B.1
HCl-dioxane rt, 2 h
crude product
74% (HCl salt)
Ex. 50
Ex. 42
A.2 1)
3-Picolylamine
prep. HPLC method 1c
37% (TFA salt)
Ex. 51
Ex. 42
A.2
2-Methoxyethylamine
prep. HPLC method 3
63%
Ex. 52
Ex. 42
A.2
Cyclopropylamine
prep. HPLC method 3
84%
Ex. 53
Ex. 42
A.2
2,2,2- Trifluoroethylamine
prep. HPLC method 3
66%
Ex. 54
Ex. 42
A.2
Isobutylamine
prep. HPLC method 3
66%
Ex. 55
Ex. 42
A.2
2-Aminoethanol 4° C. 2 h and rt 3 h
prep. HPLC method 1c
82%
Ex. 56
Ex. 42
A.2
Glycine-tert.- butyl ester hydrochloride (1.5 equiv.) HATU 2.0 equiv.) HOAt (2.0 equiv.) i-Pr 2 NEt (3.0 equiv.) 4° C., 2 h
prep. HPLC method 3
76%
Ex. 57
Ex. 56
B.2
TFA, CH 2 Cl 2
crude product
80%
Ex. 58
Ex. 42
A.2
(L)-α- Methylbenzylamine 4° C. 2 h and rt 2 h
prep. HPLC method 3
55%
Ex. 59
Ex. 42
A.2
N,N,N′- Trimethylethylene- diamine
FC (CH 2 Cl 2 /MeOH/ aq. NH 3 soln)
83%
Ex. 60
Ex. 42
A.2
Naphthalen-1- ylmethanamine
prep. HPLC method 3
57%
Ex. 61
Ex. 42
A.2
Naphthalen-2- ylmethanamine
prep. HPLC method 3 and prep. HPLC method 2a
29%
1) Cf. experimental description for detailed procedure
TABLE 15b
Examples of Core 03 (Ex. 41-Ex. 67;)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R E
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 41-Ex. 42,
Ex. 62-Ex. 67:
Ex. 43
CONH 2
C23H27N3O5
425.2
1.47 (95)
426.1
method 1a
Ex. 44
CONHCH 3
C24H29N3O5
439.2
1.49 (99)
440.1
method 1a
Ex. 45
CONHPh
C29H31N3O5
501.2
1.97 (97)
502.1
method 1a
Ex. 46
C27H33N3O5
479.2
1.74 (98)
480.1
method 1a
Ex. 47
C27H36N4O5
496.3
1.32 (99)
497.2
method 1a
Ex. 48
C31H42N4O7
582.3
1.91 (99)
583.1
method 1a
Ex. 49
C26H34N4O5
482.2
1.32 (95)
483.1
method 1a
Ex. 50
C29H32N4O5
516.2
1.32 (99)
517.1
method 1a
Ex. 51
C26H33N3O6
483.2
1.57 (95)
484.1
method 1a
Ex. 52
C26H31N3O5
465.2
1.67 (99)
466.1
method 1a
Ex. 53
C25H28F3N3O5
507.2
1.80 (94)
508.0
method 1a
Ex. 54
C27H35N3O5
481.2
1.85 (95)
482.1
method 1a
Ex. 55
C25H31N3O6
469.2
1.40 (94)
470.1
method 1a
Ex. 56
C29H37N3O7
539.3
1.91 (93)
540.0
method 1a
Ex. 57
C25H29N3O7
483.2
1.47 (85)
484.1
method 1a
Ex. 58
C31H35N3O5
529.2
2.00 (93)
530.1
method 1a
Ex. 59
C28H38N4O5
510.3
1.37 (97)
511.2
method 1a
Ex. 60
C34H35N3O5
565.2
2.09 (97)
566.1
method 1a
Ex. 61
C34H35N3O5
565.2
2.12 (100)
566.1
method 1a
TABLE 15c
Examples of Core 03 (Ex. 41-Ex. 67;)
No
R E
IUPAC name
Ex. 41
CO 2 CH 2 Ph
benzyl (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate
Ex. 42
CO 2 H
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid
Ex. 43
CONH 2
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 44
CONHCH 3
(10R,15S)-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 45
CONHPh
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-phenyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 46
(10R,15S)-4-methoxy-10,16-dimethyl-15-(1-pyrrolidinylcarbonyl)-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 12,17-dione
Ex. 47
(10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-10,16-dimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide
Ex. 48
tert-butyl N-[3-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)propyl]carbamate
Ex. 49
(10R,15S)-N-(3-aminopropyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 50
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 51
(10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 52
(10R,15S)-N-cyclopropyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 53
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(2,2,2- trifluoroethyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa- 1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 54
(10R,15S)-N-isobutyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 55
(10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 56
tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetate
Ex. 57
2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetic acid
Ex. 58
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-[(1S)-1-phenylethyl]- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 59
(10R15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-N,10,16-trimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide
Ex. 60
(10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 61
(10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 62
CH 2 OH
(10R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 63
(10R,15S)-4-methoxy-10,16-dimethyl-15-[(3-pyridinyloxy)methyl]-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 12,17-dione
Ex. 64
CH 2 N 3
(10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 65
CH 2 NH 2
(10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 66
CH 2 NHCOCH 2 Ph
N-{[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl}-2-
phenylacetamide
Ex. 67
CH 2 OCONHPh
[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N-
phenylcarbamate
TABLE 16a
Examples of Core 04 (Ex. 68-Ex. 89;)
Starting
General
Purification
Yield
No
R c
Material
Proced.
Reagent
Method
(isolated salt)
cf. experimental description
Ex. 68-Ex. 69:
Ex. 70
NHCH 3
Ex. 69
A.2
CH 3 NH 3 Cl (4 equiv.)
FC (CH 2 Cl 2 /MeOH)
50%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq. Na 2 CO 3 ,
CH 2 Cl 2
Ex. 71
NH 2
Ex. 69
A.2
NH 4 Cl (4 equiv.)
prep. HPLC method 3
95
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq. Na 2 CO 3 ,
CH 2 Cl 2
Ex. 72
NHPh
Ex. 69
A.2
Aniline
prep. HPLC method 3
68
Ex. 73
Ex. 69
A.2
2-Phenylethylamine
prep. HPLC method 3
71
Ex. 74
Ex. 69
A.2
Naphthalen-1- ylmethanamine 0° C., 1 h
prep. HPLC method 3 and FC (EtOAc)
70%
Ex. 75
Ex. 69
A.2
3-Picolylamine 4°C, 1 h Workup: Sat. aq. Na 2 CO 3 , CHCl 3
prep. HPLC method 3
55%
Ex. 76
Ex. 69
A.2
(L)-α-Methylbenzylamine
prep. HPLC method 3
60%
Ex. 77
Ex. 69
A.2
2-Methoxyethylamine
prep. HPLC method 3
66%
Ex. 78
Ex. 69
A.2
2,2,2-Trifluoroethylamine
prep. HPLC method 3
72%
Ex. 79
Ex. 69
A.2
Cyclopropylamine
prep. HPLC method 3 then prep. HPLC method 1a
32%
Ex. 80
Ex. 69
A.2
Isobutylamine 4° C., 1 h
prep. HPLC method 3
77%
Ex. 81
Ex. 69
A.2
2-Aminoethanol 4° C. 2 h and rt 1 h
prep. HPLC method 1a
56%
Ex. 82
Ex. 69
A.2
Glycine-tert.-butyl ester hydrochloride (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6.0 equiv.) 4° C., 3 h
FC (EtOAc)
78%
Ex. 83
Ex. 82
B.2
TFA, CH 2 Cl 2 , rt, 4 h
prep. HPLC method 1a
78%
Ex. 84
Ex. 69
A.2
N,N-Dimethyl- ethylenediamine 4° C., 1 h Workup: Sat. aq. Na 2 CO 3 , EtOAc
prep. HPLC method 3
47%
Ex. 85
Ex. 69
A.2
1-(3-Aminopropyl) pyrrolidine
prep. HPLC method 1a
57% (TFA salt)
Ex. 86
Ex. 69
A.2
Azetidine
prep. HPLC method 3
80%
Ex. 87
Ex. 69
A.2
Morpholine
prep. HPLC method 3
74%
Ex. 88
Ex. 69
A.2
(1-Methyl-1H-imidazol- 4-yl)methanamine 4° C., 2 h and rt, 1 h
prep. HPLC method 1a
27% (TFA salt)
Ex. 89
Ex. 69
A.2
Naphthalen-2- ylmethanamine 0° C., 3 h
prep. HPLC method 3 and FC (EtOAc)
73%
TABLE 16b
Examples of Core 04 (Ex. 68-Ex. 89;)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R c
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 68-Ex. 69:
Ex.70
NHCH 3
C23H27N3O4
409.2
1.57 (96)
410.1
method 1a
Ex.71
NH 2
C22H25N3O4
395.2
1.53 (95)
396.1
method 1a
Ex.72
NHPh
C28H29N3O4
471.2
1.96 (92)
472.1
method 1a
Ex.73
C30H33N3O4
499.2
1.97 (99)
500.1
method 1a
Ex.74
C33H33N3O4
535.2
2.11 (96)
536.2
method 1a
Ex.75
C28H30N4O4
486.2
1.40 (93)
487.1
method 1a
Ex.76
C30H33N3O4
499.2
1.99 (96)
500.1
method 1a
Ex.77
C25H31N3O5
453.2
1.60 (99)
454.1
method 1a
Ex.78
C24H26F3N3O4
477.2
1.82 (96)
478.0
method 1a
Ex.79
C25H29N3O4
435.2
1.71 (98)
436.1
method 1a
Ex.80
C26H33N3O4
451.2
1.90 (98)
452.1
method 1a
Ex.81
C24H29N3O5
439.2
1.50 (91)
440.1
method 1a
Ex.82
C28H35N3O6
509.2
1.97 (95)
510.1
method 1a
Ex.83
C24H27N3O6
453.2
1.50 (98)
454.1
method 1a
Ex.84
C26H34N4O4
466.2
1.40 (99)
467.1
method 1a
Ex.85
C29H38N4O4
506.3
1.46 (99)
507.2
method 1a
Ex.86
C25H29N3O4
435.2
1.63 (92)
436.1
method 1a
Ex.87
C26H31N3O5
465.2
1.64 (92)
466.1
method 1a
Ex.88
C27H31N5O4
489.2
1.43 (99)
490.1
method 1a
Ex.89
C33H33N3O4
535.2
2.14 (93)
536.1
method 1a
TABLE 16c
Examples of Core 04 (Ex. 68-Ex. 89;)
No
R c
IUPAC name
Ex.68
OCH 2 Ph
benzyl (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]
docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxylate
Ex.69
OH
(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxylic acid
Ex.70
NHCH 3
(9S,14S)-N,9,15-trimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.71
NH 2
(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.72
NHPh
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenyl-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]
docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.73
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenethyl-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.74
(9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.75
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.76
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[(1S)-1-phenylethyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.77
(9S,14S)-N-(2-methoxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.78
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.79
(9S,14S)-N-cyclopropyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.80
(9S,14S)-N-isobutyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.81
(9S,14S)-N-(2-hydroxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.82
tert-butyl 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetate
Ex.83
2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ] docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetic acid
Ex.84
(9S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.85
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[3-(1-pyrrolidinyl)propyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.86
(9S,14S)-14-(1-azetanylcarbonyl)-9,15-dimethyl-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione
Ex.87
(9S,14S)-9,15-dimethyl-14-(morpholinocarbonyl)-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione
Ex.88
(9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16-dioxo-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.89
(9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
TABLE 17a
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
Starting
General
No
R B
R D
Material
Procedure
Reagent
Purification Method
Yield (isolated salt)
Ex. 90-Ex. 92
cf. experimental description
Ex. 93
NH 2
H
Ex. 90
B.1 1)
HCl-dioxane
prep. HPLC
17% (TFA salt)
rt, 16 h
method 1c
Ex. 94
CH 3
Ex. 91
A.6.2; 5)
Formaldehyde (36.5% in H 2 O)
FC (CH 2 Cl 2 /MeOH)
84%
Ex. 95
NH 2
CH 3
Ex. 94
B.1; 5)
HCl-dioxane
crude product
quant. (HCl salt)
rt, 2 h
Ex. 96
CH 3
Ex. 95
A.1.1; 5)
2-Naphthaleneacetic acid
FC (CH 2 Cl 2 /MeOH) and prep. HPLC method 1b
41% (TFA salt)
Ex. 97
Ex. 91
A.6.3; 5)
3-Fluorobenzaldehyde
FC (CH 2 Cl 2 /MeOH)
80%
Ex. 98
NH 2
Ex. 97
B.1; 5)
HCl-dioxane rt, 2 h
crude product
95% (HCl salt)
Ex. 99
NHCOCH 3
CH 3
Ex. 95
A.1.2.1
Acetyl chloride
prep. HPLC
61% (TFA salt)
(4.0 equiv. in total)
method 1a
Ex. 100
NHCOCH 3
Ex. 98
A.1.2.1; 5)
Acetyl chloride (4.0 equiv. in total)
prep. HPLC method 1a
64% (TFA salt)
Ex. 101
CH 3
Ex. 95
A.1.3; 5)
1-Naphthaleneacetic acid
prep. HPLC method 1a
49% (TFA salt)
Ex. 102
CH 3
Ex. 95
A.3
Phenyl isocyanate rt, 15 h
prep. HPLC method 1a
57% (TFA salt)
Ex. 103
CH 3
Ex. 95
A.5; 5)
Benzenesulfonyl chloride (2.0 equiv.) Et 3 N (3.0 equiv.) i-Pr 2 NEt (3.0 equiv.)
prep. HPLC method 1a
44% (TFA salt)
Ex. 104
Ex. 91
A.1.3
2-(Dimethylamino)- acetic acid rt, 2 h
FC (CH 2 Cl 2 /MeOH)
83%
Ex. 105
NH 2
Ex. 104
B.1
HCl-dioxane rt, 2 h
crude product
90%
Ex. 106
Ex. 105
A.1.3
2-Phenylacetic acid (4.8 equiv.) rt, 40 h
prep. HPLC method 1a
41% (TFA salt)
Ex. 107
Ex. 105
A.5
Cyclopropanesulfonyl chloride (3.0 equiv.) Et 3 N (8.0 equiv.) rt, 16 h
prep. HPLC method 1a
32% (TFA salt)
Ex. 108
Ex. 105
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
prep. HPLC method 1a
55% (TFA salt)
Ex. 109
Ex. 91
A.5
Cyclopropanesulfonyl chloride (5.2 equiv.) Et 3 N (5.0 equiv.), DMAP (0.1 equiv.) 45° C.,48 h
FC (CH 2 Cl 2 /MeOH)
64%
Ex. 110
NH 2
Ex. 109
B.1
HCl-dioxane rt, 3 h
crude product
quant. (HCl salt)
Ex. 111
Ex. 110
A.1.2.1
Benzoyl chloride (2.0 equiv) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
prep. HPLC method 1a
19% (TFA salt)
Ex. 112
Ex. 91
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
FC (CH 2 Cl 2 /MeOH)
82%
Ex. 113
NH 2
Ex. 112
B.1
HCl-dioxane rt, 4 h
crude product
quant. (HCl salt)
Ex. 114
Ex. 113
A.1.2.1
3-Fluorobenzoyl chloride (4.0 equiv. in total)
prep. HPLC method 1a
5% (TFA salt)
Ex. 341
Ex. 98
A.1.3
1-Naphthaleneacetic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
47%
Ex. 342
Ex. 98
A.1.3
2-Naphthaleneacetic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
34%
Ex. 343
Ex. 98
A.3
2-Naphthylisocyanate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
63%
Ex. 344
Ex. 98
A.5
Naphthalene-2-sulfonyl chloride i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a
41% (TFA salt)
Ex. 345
Ex. 98
A.1.3
2-Naphthalene- propanoic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
40% (TFA salt)
Ex. 346
Ex. 98
A.1.3
3-Phenylpropionic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
37% (TFA salt)
Ex. 347
Ex. 98
A.1.3
N,N-Dimethylglycine i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
9% (TFA salt)
Ex. 348
Ex. 92
A.1.3
2-Naphthaleneacetic acid i-Pr 2 NEt (6 equiv.)
FC (CH 2 Cl 2 /MeOH)
80%
Ex. 349
H
Ex. 348
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
97%
Ex. 350
Ex. 349
A.1.3
3-Fluorobenzoic acid
prep. HPLC method 1a
55% (TFA salt)
Ex. 351
Ex. 349
A.6.3
Benzaldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
51% (TFA salt)
Ex. 352
Ex. 349
A.6.3
Phenylacetaldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
37% (TFA salt)
Ex. 353
Ex. 349
A.6.3
3-Phenylpropion- aldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
30% (TFA salt)
Ex. 354
Ex. 349
A.6.3
Isovaleraldehyde (1.7 equiv.) Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
32% (TFA salt)
Ex. 355
Ex. 349
A.6.3
Isobutyraldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
68% (TFA salt)
Ex. 356
Ex. 349
2)
2-Dimethylaminoethyl- chlorid hydrochloride
FC (CH 2 Cl 2 /MeOH)
21%
Ex. 357
Ex. 349
3)
2-Dimethylaminoethyl- chlorid hydrochloride
prep. HPLC method 2a and FC (CH 2 Cl 2 /MeOH)
17%
Ex. 358
CH 3
Ex. 95
4)
3,3-Dimethylbutyryl chloride
FC (CH 2 Cl 2 /MeOH)
83%
1) Ex. 93 was obtained as a side product upon treatment of Ex. 90 with HCl-dioxane; see description of synthesis of Ex. 92
2) 2-Dimethylaminoethylchloride hydrochloride (13 mg, 0.089 mmol) was added to a mixture of Ex. 349 (50 mg, 0.089 mmol) and dry K 2 CO 3 (61 mg, 0.44 mmol) in DCE (0.5 mL). The mixture was stirred at 50° C. for 16 h. More 2-dimethylaminoethylchloride hydrochloride (6.4 mg, 0.044 mmol) was added and stirring at 50° C. continued for 2 h. Aqueous workup (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded Ex. 356 (13 mg, 21%).
3) 2-Dimethylaminoethylchloride hydrochloride (64 mg, 0.44 mmol) was added to a mixture of Ex. 349 (60 mg, 0.106 mmol) and i-Pr 2 NEt (0.121 mL; 0.71 mmol) in DMF (1 mL). The mixture was stirred at 50° C. for 3 d. More 2-dimethylamino-
ethylchloride hydrochloride (64 mg, 0.44 mmol) and i-Pr 2 NEt (0.121 mL; 0.71 mmol) were added and stirring at 50° C. was continued for 1 d. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH(conc. aq. NH 3 soln 100:0:0.1 to 90:10:0.1) afforded Ex. 357 (12 mg, 17%).
4) Synthesis of Ex. 358 3,3-Dimethylbutyryl chloride (0.019 mL, 0.14 mmol) was added at 0° C. to a suspension of Ex. 95 (60 mg, 0.116 mmol) and pyridine (0.047 mL, 0.58 mmol) in CH 2 Cl 2 (1.2 mL). The mixture was stirred at rt for 1 h and cooled to 0° C. Then i-Pr 2 NEt (0.059 mL; 0.35 mmol) and 3,3-dimethylbutyryl chloride (0.019 mL, 0.14 mmol) were added. The resulting clear soln was stirred for 30 min. MeOH (0.01 mL) was added and stirring continued for 10 min. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 358 (49 mg, 83%). Data of Ex. 358: cf. Table 17b 1 H-NMR (DMSO-d 6 ): 9.62 (br. s, 1 H); 9.22 (t, J ca. 1.9, 1 H); 9.18 (d, J = 2.0, 1 H); 8.93 (d, J = 1.9, 1 H); 8.40 (br.s, 1 H); 8.08 (d, J = 6.5, 1 H); 7.59 (d, J = 7.6, 1 H); 7.40 (t, J = 7.9, 1 H); 6.82 (dd; J = 2.0, 8.3, 1 H); 4.53-4.41 (br. not resolved m, 3 H); 3.91 (t, J = 11.2, 1 H); 3.72 (dd; J = 7.0, 9.7, 1 H); 3.46 (d, J = 17.6, 1 H); 3.38-3.24 (m, 3 H, partially superimposed by H 2 O signal); 3.13 (dd-like m, 1 H); 2.62 (m, 2 H); 2.37 (s, 3 H); 2.14 (m, 1 H); 1.96 (s, 2 H); 1.93 (m, 1 H); 0.96 (s, 9 H).
5) Cf. experimental description for detailed procedure
TABLE 17b
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
Mono-
Rt
iso-
(purity
[M +
topic
at
H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 90-
cf experimental description
Ex. 92:
Ex. 93
NH 2
H
C21H25N5O3
395.2
0.89 (97)
396.1
method 1a
Ex. 94
CH 3
C27H35N5O5
509.3
1.49 (97)
510.1
method 1a
Ex. 95
NH 2
CH 3
C22H27N5O3
409.2
1.43 (98)
410.1
method 2c
Ex. 96
CH 3
C34H35N5O4
577.3
1.59 (99)
578.1
method 1a
Ex. 97
C33H38FN5O5
603.3
2.44 (95)
604.0
method 2d
Ex. 98
NH 2
C28H30FN5O3
503.2
1.31 (90)
504.2
method 1a
Ex. 99
NHCOCH 3
CH 3
C24H29N5O4
451.2
1.10 (96)
452.2
method 1a
Ex. 100
NHCOCH 3
C30H32FN5O4
545.2
1.47 (97)
546.2
method 1a
Ex. 101
CH 3
C34H35N5O4
577.3
1.59 (98)
578.2
method 1a
Ex. 102
CH 3
C29H32N6O4
528.2
1.44 (98)
529.2
method 1a
Ex. 103
CH 3
C28H31N5O5S
549.2
1.43 (99)
550.1
method 1a
Ex. 104
C30H40N6O6
580.3
2.02 (96)
581.2
method 2d
Ex. 105
NH 2
C25H32N6O4
480.2
0.97 (95)
481.1
method 1a
Ex. 106
C33H38N6O5
598.3
1.45 (98)
599.2
method 1a
Ex. 107
C28H36N6O6S
584.2
1.30 (95)
585.1
method 1a
Ex. 108
C27H35N7O5
537.3
1.17 (97)
538.2
method 1a
Ex. 109
C29H37N5O7S
599.2
1.87 (93)
600.1
method 1a
Ex. 110
NH 2
C24H29N5O5S
499.2
1.20 (91)
500.1
method 1a
Ex. 111
C31H33N5O6S
603.2
1.73
604.0
method 1a
Ex. 112
C28H36N6O6
552.3
1.67 (94)
553.1
method 1a
Ex. 113
NH 2
C23H28N6O4
452.2
1.04 (89)
453.1
method 1a
Ex. 114
C30H31FN6O5
574.2
1.63 (95)
575.2
method 1a
Ex. 341
C40H38FN5O4
671.3
2.37 (97)
672.0
method 2c
Ex. 342
C40H38FN5O4
671.3
2.38 (94)
672.0
method 2c
Ex. 343
C39H37FN6O4
672.3
2.41 (96)
673.0
method 2c
Ex. 344
C38H36FN5O5S
693.2
2.42 (96)
694.0
method 2c
Ex. 345
C41H4OFN5O4
685.3
2.41 (97)
686.0
method 2c
Ex. 346
C37H38FN5O4
635.3
2.26 (97)
635.8
method 2c
Ex. 347
C32H37FN6O4
588.3
2.01 (89)
588.5
method 2c
Ex. 348
C41H39N5O6
697.3
2.06 (97)
698.0
method 1a
Ex. 349
H
C33H33N5O4
563.2
1.94 (88)
563.9
method 2c
Ex. 350
C40H36FN5O5
685.3
1.97 (99)
686.0
method 1a
Ex. 351
C40H39N5O4
653.3
2.38 (98)
654.0
method 2c
Ex. 352
C41H41N5O4
667.3
2.40 (94)
667.9
method 2c
Ex. 353
C42H43N5O4
681.3
2.51 (97)
682.1
method 2c
Ex. 354
C38H43N5O4
633.3
2.47 (98)
634.0
method 2c
Ex. 355
C37H41N5O4
619.3
2.41 (96)
619.9
method 2c
Ex. 356
C38H42N6O6
678.3
2.05 (96)
679.3
method 2e
Ex. 357
C37H42N6O4
634.3
2.20 (96)
635.3
method 2e
Ex. 358
CH 3
C28H37N5O4
507.3
1.43 (99)
508.2
method 1c
TABLE 17c
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
No
R B
R D
IUPAC name
Ex. 90
benzyl (9S,11R)-11-[(tert-butoxycarbonyl)amino]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxylate
Ex. 91
H
tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 92
NH 2
benzyl (9S,11R)-11-amino-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxylate
Ex. 93
NH 2
H
(9S,11R)-11-amino-7-oxa-13,16,19,23-tetraazatetracyclo
[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 94
CH 3
tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 95
NH 2
CH 3
(9S,11R)-11-amino-16-methyl-7-oxa-13,16,19,23-
tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 96
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl) acetamide
Ex. 97
tert-butyl N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 98
NH 2
(9S,11R)-11-amino-16-(3-fluorobenzyl)-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 99
NHCOCH 3
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-
tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide
Ex. 100
NHCOCH 3
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide
Ex. 101
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1-naphthyl) acetamide
Ex. 102
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-N′-phenylurea
Ex. 103
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]benzenesulfonamide
Ex. 104
tert-butyl N-[(9S,11R)-16-[2-(dimethylamino)acetyl]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate
Ex. 105
NH 2
(9S,11R)-11-amino-16-[2-(dimethylamino)acetyl]-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 106
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-11-yl]-2- phenylacetamide
Ex. 107
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl] cyclopropanesulfonamide
Ex. 108
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N′- methylurea
Ex. 109
tert-butyl N-[(9S,11R)-16-(cyclopropylsulfonyl)- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate
Ex. 110
NH 2
(9S,11R)-11-amino-16-(cyclopropylsulfonyl)-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 111
N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]benzamide
Ex. 112
tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23-hexaen- 11-yl]carbamate
Ex. 113
NH 2
(9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxamide
Ex. 114
(9S,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23-hexaene- 16-carboxamide
Ex. 341
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1- naphthyl)acetamide
Ex. 342
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 343
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N′-(2- naphthyl)urea
Ex. 344
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2- naphthalenesulfonamide
Ex. 345
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3-(2- naphthyl)propanamide
Ex. 346
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3- phenylpropanamide
Ex. 347
2-(dimethylamino)-N-[(9S,11R)-16-(3-fluorobenzyl)- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide
Ex. 348
benzyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3 ,5,21,23- hexaene-16-carboxylate
Ex. 349
H
N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl) acetamide
Ex. 350
N-[(9S,11R)-16-(3-fluorobenzoyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 351
N-[(9S,11R)-16-benzyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 352
N-[(9S,11R)-14,20-dioxo-16-phenethyl-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 353
N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropyl)-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 354
N-[(9S,11R)-16-isopentyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 355
N-[(9S,11R)-16-isobutyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 356
2-(dimethylamino)ethyl (9S,11R)-11-{[2-(2- naphthyl)acetyl]amino}-14 ,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxylate
Ex. 357
N-[(9S,11R)-16-[2-(dimethylamino)ethyl]-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide
Ex. 358
CH 3
3,3-dimethyl-N-[(9S,11R)-16-methyl-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]butanamide
TABLE 18a
Examples of Core 06 (Ex. 115-Ex. 128;)
Starting
General
Purification
No
R A
Material
Procedure
Reagent
Method
Yield (isolated salt)
Ex. 115-
cf. experimental description
Ex. 116:
Ex. 117
Ex. 116
A.1.1
1-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3, then washed with Et 2 O, then FC (hexane/EtOAc)
66%
Ex. 118
Ex. 116
A.1.1
2-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3, then washed with Et 2 O, then FC (hexane/EtOAc)
60%
Ex. 119
Ex. 116
A.1.1
1-Pyrrolidineacetic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
57%
Ex. 120
Ex. 116
A.1.1
Nicotinic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
72%
Ex. 121
Ex. 116
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h
prep. HPLC method 3
38%
Ex. 122
Ex. 116
A.4
Methyl chloroformate 0° C. to rt, 2 h
prep. HPLC method 3
83%
Ex. 123
Ex. 116
A.5
Cyclopropanesulfonyl chloride (2.0 equiv.) Et 3 N (3 equiv.) DMAP (0.1 equiv) rt, 15 h Workup: CHCl 3 , half-sat. aq. NaHCO 3 soln.; Na 2 SO 4
prep. HPLC method 3
64%
Ex. 124
Ex. 116
A.5
Benzenesulfonyl chloride (1.5 equiv.) rt, 1 h
prep. HPLC method 3
54%
Ex. 125
Ex. 116
A.3
N-Succinimidyl N- methylcarbamate (1.8 equiv.) i-Pr 2 NEt (4.5 equiv) THF/CHCl 3 1:1 (0.9 mL) rt, 16 h
chromatography; washing of crude product with EtOH and Et 2 O
73%
Ex. 126
Ex. 116
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3 1:1 (0.5 mL) rt, 15 h
chromatography; washing of crude product with EtOH and Et 2 O
70%
Ex. 127
Ex. 116
A.6.4
Isobutyraldehyde (1.05 equiv.)
prep. HPLC method 3
52%
Ex. 128
Ex. 116
A.6.4
3-Methylbutanal (1.05 equiv.)
prep. HPLC method 3 and prep. HPLC method 1a
8% (TFA salt)
TABLE 18b
Examples of Core 06 (Ex. 115-Ex. 128;)
Monoisotopic
Rt (purity at
[M + H] +
No
R A
Formula
Mass
220 nm)
found
LC-MS-Method
Ex. 115-Ex. 116:
cf. experimental description
Ex. 117
C33H34N2O3S
538.2
2.55 (95)
539.2
method 1a
Ex. 118
C33H34N2O3S
538.2
2.54 (95)
539.2
method 1a
Ex. 119
C27H35N3O3S
481.2
1.82 (97)
482.2
method 1a
Ex. 120
C27H29N3O3S
475.2
1.90 (92)
476.1
method 1a
Ex. 121
C26H34N2O3S
454.2
2.32 (90)
455.2
method 1a
Ex. 122
C23H28N2O4S
428.2
2.15 (97)
429.2
method 1a
Ex. 123
C24H30N2O4S2
474.2
2.23 (93)
475.1
method 1a
Ex. 124
C27H30N2O4S2
510.2
2.33 (82)
511.1
method 1a
Ex. 125
C23H29N3O3S
427.2
1.97 (88)
428.2
method 1a
Ex. 126
C27H30N4O3S
490.2
1.80 (95)
491.2
method 1a
Ex. 127
C25H34N2O2S
426.2
1.97 (97)
427.2
method 1a
Ex. 128
C26H36N2O2S
440.2
2.05 (98)
441.2
method 1a
TABLE 18C
Examples of Core 06 (Ex. 115-Ex. 128;)
No
R A
IUPAC name
Ex. 115
NHAlloc
allyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 116
NH 2
(13S,16R)-13-amino-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-14-one
Ex. 117
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide
Ex. 118
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide
Ex. 119
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide
Ex. 120
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 121
3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 122
methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 123
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide
Ex. 124
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 125
N-methyl-N′-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yarea
Ex. 126
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 127
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-14-one
Ex. 128
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-14-one
TABLE 19a
Examples of Core 07 (Ex. 129-Ex. 142);
Starting
General
Yield
No
R A
Material
Procedure
Reagent
Purification Method
(isolated salt)
Ex. 129-Ex. 130:
cf. experimental description
Ex. 131
Ex. 130
A.1.1
1-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3
71%
Ex. 132
Ex. 130
A.1.1
2-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3
73%
Ex. 133
Ex. 130
A.1.1
1-Pyrrolidineacetic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
46%
Ex. 134
Ex. 130
A.1.1
Nicotinic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
59%
Ex. 135
Ex. 130
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h
prep. HPLC method 3
77%
Ex. 136
Ex. 130
A.4
Methyl chloroformate 0° C., to rt, 2 h
prep. HPLC method 3
20%
Ex. 137
Ex. 130
A.5
Cyclopropanesulfonyl chloride (1.5 equiv.) Et 3 N (3 equiv.) DMAP (0.1 equiv) CHCl 3 (0.5 mL) rt, 15 h Workup: CHCl 3 , half-sat. aq. NaHCO 3 soln.; Na 2 SO 4
prep. HPLC method 3
71%
Ex. 138
Ex. 130
A.5
Benzenesulfonyl chloride (1.5 equiv.)
prep. HPLC method 3
52%
Ex. 139
Ex. 130
A.3
N-Succinimidyl-N- methylcarbamate (1.8 equiv.) i-Pr 2 NEt (4.5 equiv) THF/CHCl 3 1:1 (0.9 mL) rt, 20 h
prep. HPLC method 3
49%
Ex. 140
Ex. 130
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3 1:1 (0.5 mL) rt, 15 h
prep. HPLC method 3
64%
Ex. 141
Ex. 130
A.6.4
Isobutyraldedhyde (1.05 equiv.)
prep. HPLC method 3
57%
Ex. 142
Ex. 130
A.6.4
3-Methylbutanal (1.05 equiv.)
prep. HPLC method 3 and prep. HPLC method 1a
11% (TFA salt)
TABLE 19b
Examples of Core 07 (Ex. 129-Ex. 142);
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R A
Formula
Mass
220 nm)
found
Method
Ex. 129-Ex. 130:
cf. experimental description
Ex. 131
C33H34N2O5S
570.2
2.28 (91)
571.2
method 1a
Ex. 132
C33H34N2O5S
570.2
2.20 (97)
571.2
method 1a
Ex. 133
C27H35N3O5S
513.2
1.55 (93)
514.2
method 1a
Ex. 134
C27H29N3O5S
507.2
1.59 (99)
509.0
method 1a
Ex. 135
C26H34N2O5S
486.2
1.92 (99)
487.2
method 1a
Ex. 136
C23H28N2O6S
460.2
1.74 (99)
461.0
method 1a
Ex. 137
C24H30N2O6S2
506.2
1.84 (99)
507.1
method 1a
Ex. 138
C27H30N2O6S2
542.2
2.02 (97)
543.1
method 1a
Ex. 139
C23H29N3O5S
459.2
1.61 (99)
460.1
method 1a
Ex. 140
C27H30N4O5S
522.2
1.53 (98)
523.2
method 1a
Ex. 141
C25H34N2O4S
458.2
1.70 (99)
459.2
method 1a
Ex. 142
C26H36N2O4S
472.3
1.78 (85)
473.2
method 1a
TABLE 19c
Examples of Core 07 (Ex. 129-Ex. 142);
No
R A
IUPAC name
Ex. 129
NHAlloc
allyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-
8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,
21-hexaen-13-yl]carbamate
Ex. 130
NH 2
(13S,16R)-13-amino-16-methyl-18-oxa-8λ 6 -thia-15-
azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-
8,8,14-trione
Ex. 131
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]-2-(1-naphthyl)acetamide
Ex. 132
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]-2-(2-naphthyl)acetamide
Ex. 133
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide
Ex. 134
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]nicotinamide
Ex. 135
3-methyl-N-[(13S,16R)-16-methyl-8,8,14- trioxo-18-oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 136
methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18- oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 137
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]cyclopropanesulfonamide
Ex. 138
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23), 2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 139
N-methyl-N′-[(13S,16R)-16-methyl-8,8,14-trioxo- 18-oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]urea
Ex. 140
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 141
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-8,8,14-trione
Ex. 142
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-8,8,14-trione
TABLE 20a
Examples of Core 08 (Ex. 143-Ex. 167);
Starting
General
Purification
Yield
No
R A
Material
Procedure
Reagent
Method
(isolated salt)
Ex. 143-Ex. 144:
cf. experimental description
Ex. 145
N(CH 3 ) 2
Ex. 144
A.6.1
Formaldehyde
prep. HPLC
92%
(36% in H 2 O)
method 3
Ex. 146
Ex. 144
A.6.4
Isobutyraldehyde
prep. HPLC method 3
16%
Ex. 147
Ex. 144
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
46%
Ex. 148
Ex. 144
A.1.2
Acetic anhydrid (2.2 equiv.) Pyridine (7 equiv.); rt
prep. HPLC method 1a
94% (TFA salt)
Ex. 149
Ex. 144
A.1.1 1)
Methoxyacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
62%
Ex. 150
Ex. 144
A.1.3
2-(Dimethylamino)acetic acid i-Pr 2 NEt (6 equiv.) Workup: CHCl 3 , 10M aq NaOH soln
prep. HPLC method 3
49%
Ex. 151
Ex. 144
A.1.1
Nicotinic acid i-Pr 2 NEt (5 equiv.) Workup: CHCl 3 , 10M aq NaOH soln
prep. HPLC method 3
68%
Ex. 152
Ex. 144
A.1.1 1)
Isovaleric acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
15%
Ex. 153
Ex. 144
A.1.1 1)
N-Boc-β-alanine i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
88%
Ex. 154
Ex. 153
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
73% (TFA salt)
Ex. 155
Ex. 144
A.1.1 1)
1-Naphthaleneacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3 and FC (hexane/EtOAc)
69%
Ex. 156
Ex. 144
A.1.1 1)
2-Naphthaleneacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
66%
Ex. 157
Ex. 144
A.1.1 1)
3,3,3-Trifluoropropionic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
45%
Ex. 158
Ex. 144
A.1.1 1)
3-Fluorobenzoic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3 and FC (hexane/EtOAc)
44%
Ex. 159
Ex. 144
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
78%
Ex. 160
Ex. 144
A.3
N-Succinimidyl-N- methylcarbamamte (1.3 equiv.) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
78%
Ex. 161
Ex. 144
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino) propanoate (1.3 equiv.) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
84%
Ex. 162
Ex. 161
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
75% (TFA salt)
Ex. 163
Ex. 144
A.5
Methanesulfonyl chloride (3 equiv.) DMAP (0.1 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
71%
Ex. 164
Ex. 144
A.5
Cyclopropanesulfonyl chloride (3 equiv.) DMAP (0.1 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt to 50° C., 3 d
prep. HPLC method 1a
55% (TFA salt)
Ex. 165
Ex. 144
A.5
Benzenesulfonyl chloride (3 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
57%
Ex. 166
Ex. 144
A.4
Methyl chloroformate (0.89 equiv.); rt 2 h
prep. HPLC method 3
66%
Ex. 167
Ex. 144
A.4
2-Methoxyethyl chloro- formate (0.96 equiv.); rt, 2 h
prep. HPLC method 3
52%
1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH 2 Cl 2 and 1M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ), filtered
and concentrated.
TABLE 20b
Examples of Core 08 (Ex. 143-Ex. 167);
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R A
Formula
Mass
220 nm)
found
Method
Ex. 143-Ex. 144:
cf. experimental description
Ex. 145
N(CH 3 ) 2
C22H29N3O2S
399.2
1.35 (98)
400.1
method 1a
Ex. 146
C24H33N3O2S
427.2
1.46 (95)
428.2
method 1a
Ex. 147
C27H30FN3O2S
479.2
1.53 (95)
480.2
method 1a
Ex. 148
C22H27N3O3S
413.2
1.40 (99)
414.1
method 1a
Ex. 149
C23H29N3O4S
443.2
1.49 (94)
444.2
method 1a
Ex. 150
C24H32N4O3S
456.2
1.94 (96)
457.2
method 2c
Ex. 151
C26H28N4O3S
476.2
1.86 (92)
477.0
method 2c
Ex. 152
C25H33N3O3S
455.2
1.66 (90)
456.2
method 1a
Ex. 153
C28H38N4O5S
542.3
1.70 (90)
543.2
method 1a
Ex. 154
C23H30N4O3S
442.2
1.30 (87)
443.2
method 1c
Ex. 155
C32H33N3O3S
539.2
1.91 (93)
540.1
method 1a
Ex. 156
C32H33N3O3S
539.2
1.90 (97)
540.1
method 1a
Ex. 157
C23H26F3N3O3S
481.2
1.61 (96)
482.2
method 1a
Ex. 158
C27H28FN3O3S
493.2
1.76 (99)
494.2
method 1a
Ex. 159
C26H29N5O3S
491.2
1.86 (90)
492.1
method 2c
Ex. 160
C22H28N4O3S
428.2
1.39 (99)
429.1
method 1a
Ex. 161
C28H38N4O5S
542.3
2.13 (99)
543.1
method 2c
Ex. 162
C24H30N4O5S
486.2
1.38 (98)
487.2
method 1a
Ex. 163
C21H27N3O4S2
449.1
1.46 (99)
450.1
method 1a
Ex. 164
C23H29N3O4S2
475.2
1.55 (99)
476.0
method 1a
Ex. 165
C26H29N3O4S2
511.2
1.72 (99)
512.1
method 1a
Ex. 166
C22H27N3O4S
429.2
1.49 (99)
430.1
method 1a
Ex. 167
C24H31N3O5S
473.2
1.52 (99)
474.2
method 1a
TABLE 20c
Examples of Core 08 (Ex. 143-Ex. 167);
No
R A
IUPAC name
Ex. 143
NHAlloc
allyl N-[(10R,13S)-10-methyl-12-oxa-8-oxa-18-thia-
11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,
21-hexaen-13-yl]carbamate
Ex. 144
NH 2
(10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21-
diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-
hexaen-12-one
Ex. 145
N(CH 3 ) 2
(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-
18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-12-one
Ex. 146
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-12-one
Ex. 147
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-12-one
Ex. 148
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 149
2-methoxy-N-[(10R,13S)-10-methyl-12-oxo-8-oxa- 18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 150
2-(dimethylamino)-N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 151
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 152
3-methyl-N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 153
tert-butyl N-(3-{[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl] amino}-3-oxopropyl)carbamate
Ex. 154
3-amino-N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]propanamide
Ex. 155
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide
Ex. 156
N-[(10R,13S)-10-methyl-12-oxo-8-oxa- 18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide
Ex. 157
3,3,3-trifluoro-N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]propanamide
Ex. 158
3-fluoro-N-[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,12-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]benzamide
Ex. 159
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 160
N-methyl-N′-[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea
Ex. 161
tert-butyl 3-[({[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate
Ex. 162
3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]amino} carbonyl)amino]propanoic acid
Ex. 163
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide
Ex. 164
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl] cyclopropanesulfonamide
Ex. 165
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23), 2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 166
methyl N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 167
2-methoxyethyl N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21-diazatricyclo [17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen- 13-yl]carbamate
TABLE 21a
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
Starting
General
Purification
No
R A
Material
Procedure
Reagent
Method
Yield (isolated salt)
Ex. 168-Ex. 169 cf. experimental description
Ex. 170
N(CH 3 ) 2
Ex. 169
A.6.1
Formaldehyde (36% in H 2 O)
prep. HPLC
67%
method 3
Ex. 171
Ex. 169
A.6.4
Isobutyraldehyde
prep. HPLC method 3
44%
Ex. 172
Ex. 169
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
57%
Ex. 173
Ex. 169
A.1.2
Acetic anhydride (1.2 equiv.)
prep. HPLC method 3
79%
Ex. 174
Ex. 169
A.1.1 1)
Methoxyacetic acid
prep. HPLC method 3
27%
Ex. 175
Ex. 169
A.1.3
2-(Dimethylamino)acetic acid Workup: CH 2 Cl 2
prep. HPLC method 3
9%
Ex. 176
Ex. 169
A.1.1
Nicotinic acid Workup: CH 2 Cl 2 , sat .aq. Na 2 CO 3
prep. HPLC method 3
26%
Ex. 177
Ex. 169
A.1.1 1)
Isovaleric acid
prep. HPLC method 3
18%
Ex. 178
Ex. 169
A.1.1 1)
N-Boc-β-alanine
prep. HPLC method 3
57%
Ex. 179
Ex. 178
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
41% (TFA salt)
Ex. 180
Ex. 169
A.1.1 1)
1-Naphthaleneacetic acid
prep. HPLC method 3
42%
Ex. 181
Ex. 169
A.1.1 1)
2-Naphthaleneacetic acid
prep. HPLC method 3
40%
Ex. 182
Ex. 169
A.1.1 1)
3,3,3-Trifluoropropionic acid
prep. HPLC method 3
22%
Ex. 183
Ex. 169
A.1.1 1)
3-Fluorobenzoic acid
prep. HPLC method 3
58%
Ex. 184
Ex. 169
A.3
2,5-Dioxopyrrolidin-1-yl pyridin- 3-ylcarbamate (1.3 equiv.)
prep. HPLC method 3
73%
Ex. 185
Ex. 169
A.3
N-Succinimidyl N- methylcarbamate (1.3 equiv.)
prep. HPLC method 3
76%
Ex. 186
Ex. 169
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino)propanoate (1.3 equiv.)
prep. HPLC method 3
77%
Ex. 187
Ex. 186
B.2
TFA, CH 2 Cl 2
crude product
75%
Ex. 188
Ex. 169
A.5
Methanesulfonyl chloride (2 equiv.) DMAP (0.1 equiv.) Et 3 N (3 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
70%
Ex. 189
Ex. 169
A.5
Cyclopropanesulfonyl chloride DMAP (0.1 equiv.) Et 3 N (3 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
53%
Ex. 190
Ex. 169
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
51%
Ex. 191
Ex. 169
A.4
Methyl chloroformate (0.86 equiv); rt, 2 h
prep. HPLC method 3
52%
Ex. 192
Ex. 169
A.4
2-Methoxyethyl chloroformate (0.97equiv); rt, 2 h
prep. HPLC method 3
55%
1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH 2 Cl 2 and 1M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated.
TABLE 21b
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
Monoisotopic
Rt (purity at
No
R A
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 168-Ex. 169 cf. experimental description
Ex. 170
N(CH 3 ) 2
C22H29N3O4S
431.2
1.39 (97)
432.1
method 1a
Ex. 171
C24H33N3O4S
459.2
1.53 (95)
460.1
method 1a
Ex. 172
C27H30FN3O4S
511.2
1.61 (96)
512.1
method 1a
Ex. 173
C22H27N3O5S
445.2
1.50 (100)
446.1
method 1a
Ex. 174
C23H29N3O6S
475.2
1.57 (96)
476.0
method 1a
Ex. 175
C24H32N4O5S
488.2
1.38 (92)
489.1
method 1a
Ex. 176
C26H28N4O5S
508.2
1.43 (98)
508.9
method 1a
Ex. 177
C25H33N3O5S
487.2
1.77 (97)
488.2
method 1a
Ex. 178
C28H38N4O7S
574.2
1.83 (98)
575.1
method 2c
Ex. 179
C23H30N4O5S
474.2
1.35 (99)
475.2
method 1a
Ex. 180
C32H33N3O5S
571.2
2.03 (97)
572.0
method 1a
Ex. 181
C32H33N3O5S
571.2
2.05 (100)
572.1
method 1a
Ex. 182
C23H26F3N3O5S
513.2
1.74 (99)
514.1
method 1a
Ex. 183
C27H28FN3O5S
525.2
1.90 (92)
526.1
method 1a
Ex. 184
C26H29N5O5S
523.2
1.42 (99)
524.0
method 1a
Ex. 185
C22H28N4O5S
460.2
1.48 (99)
461.0
method 1a
Ex. 186
C28H38N4O7S
574.2
1.88 (98)
575.1
method 2c
Ex. 187
C24H30N4O7S
518.2
1.45 (97)
519.1
method 1a
Ex. 188
C21H27N3O6S2
481.1
1.58 (99)
482.1
method 1a
Ex. 189
C23H29N3O6S2
507.1
1.68 (95)
508.0
method 1a
Ex. 190
C26H29N3O6S2
543.1
1.85 (96)
544.1
method 1a
Ex. 191
C22H27N3O6S
461.2
1.60 (98)
462.1
method 1a
Ex. 192
C24H31N3O7S
505.2
1.63 (99)
506.2
method 1a
TABLE 21c
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
No
R A
IUPAC name
Ex. 168
NHAlloc
allyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-
oxa-18λ 6 -thia-11,21-
diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-
hexaen-13-yl]carbamate
Ex. 169
NH 2
(10R,13S)-13-amino-10-methyl-8-oxa-18λ 6 -thia-
11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 170
N(CH 3 ) 2
(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-
18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 171
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 172
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaene-12,18,18-trione
Ex. 173
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 174
2-methoxy-N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 175
2-(dimethylamino)-N-[(10R,13S)-10-methyl- 12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 176
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 177
3-methyl-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]butanamide
Ex. 178
tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]amino}-3-oxopropyl)carbamate
Ex. 179
3-amino-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]propanamide
Ex. 180
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide
Ex. 181
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide
Ex. 182
3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]propanamide
Ex. 183
3-fluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]benzamide
Ex. 184
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea
Ex. 185
N-methyl-N′-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]urea
Ex. 186
tert-butyl 3[({[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]amino}carbonyl)amino]propanoate
Ex. 187
3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid
Ex. 188
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide
Ex. 189
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide
Ex. 190
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide
Ex. 191
methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8- oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]carbamate
Ex. 192
2-methoxyethyl N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]carbamate
TABLE 22a
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b; continued on the following page)
General
Purification
No
Procedure
Fmoc-AA1-OH
Fmoc-AA2-OH
Method
Yield (isolated salt)
Ex. 193a
C.1
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-DAla-OH
prep. HPLC
20 mg/53%
method 2b
Ex. 193c
C.1
Fmoc-β-Ala-OH
Fmoc-NMePhe-OH
prep. HPLC
7 mg/19%
method 2b
Ex. 193d
C.1
Fmoc-β-Ala-OH
Fmoc-Phe-OH
prep. HPLC
2 mg/6%
method 2b
Ex. 193e
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMePhe-OH
prep. HPLC
7 mg/18%
method 2b
Ex. 193f
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
prep. HPLC
9 mg/27%
method 2b
Ex. 193g
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Phe-OH
prep. HPLC
8 mg/22%
method 2b
Ex. 193h
C.1
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-β-Ala-OH
prep. HPLC
13 mg/33%
method 2b
Ex. 194b
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMe-Glu(OtBu)-OH
prep. HPLC
14 mg/31%
method 1a
TABLE 22b
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b; continued on the following page)
Monoisotopic
Rt (purity at
No
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 193a
C31H34N4O4
526.2
2.03 (99)
527.2
method 1d
Ex. 193c
C30H32N4O4
512.2
1.94 (94)
513.0
method 1d
Ex. 193d
C29H30N4O4
498.2
1.80 (93)
499.2
method 1d
Ex. 193e
C32H36N4O4
540.2
2.07 (86)
541.2
method 1d
Ex. 193f
C25H30N4O4
450.2
1.50 (99)
451.2
method 1d
Ex. 193g
C31H34N4O4
526.2
1.94 (98)
527.2
method 1d
Ex. 193h
C31H34N4O4
526.2
1.78 (98)
527.2
method 1d
Ex. 194b
C28H34N4O6
522.2
1.68 (97)
523.2
method 1d
TABLE 22c
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b) (continued on the following page)
No
IUPAC name
Ex. 193a
(9S,16S,19R)-16-benzyl-19,20-dimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193c
(9S,19S)-19-benzyl-20-methyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193d
(9S,19S)-19-benzyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193e
(9S,16R,19S)-19-benzyl-16,17,20-trimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193f
(9S,16R)-16,17,20-trimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193g
(9S,16R,19S)-19-benzyl-16,17-dimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193h
(9S,16S)-16-benzyl-21-methyl-7-oxa-13,17,21,25-tetraazatetracyclo[21.3.1.1 2,6 .0 9,13 ]octacosa-
1(27),2(28),3,5,23,25-hexaene-14,18,22-trione
Ex. 194b
3-[(9S,16R,19S)-16,17,20-trimethyl-14,18,21-trioxo-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaen-19-yl]propanoic acid
TABLE 23a
Examples of Core 11 (Ex. 195a, b, e-h, j; Ex. 196c, i, k and Ex. 197d; continued on the following page)
General
Purification
Yield
No
Procedure
Fmoc-AA1-OH
Fmoc-AA2-OH
Fmoc-AA3-OH
Method
(isolated salt)
Ex. 195a
C.2
Fmoc-NMe-β 3 -
Fmoc-Sar-OH
Fmoc-NMeAla-OH
prep. HPLC
31%
homoDAla-OH
method 2a
Ex. 195b
C.2
Fmoc-NMe-β 3 -
Fmoc-Gly-OH
Fmoc-Ala-OH
prep. HPLC
18%
homoDAla-OH
method 2a
Ex. 196c
C.2
Fmoc-NMe-β 3 -
Fmoc-Ala-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
33%
homoDAla-OH
OH
method 1a
(TFA salt)
Ex. 197d
C.2
Fmoc-NMe-β 3 -
Fmoc-Lys(Boc)-
Fmoc-DAla-OH
prep. HPLC
24%
homoDAla-OH
OH
method 2a
Ex. 195e
C.2
Fmoc-Sar-OH
Fmoc-NMe-β 3 -
Fmoc-NMeAla-OH
prep. HPLC
33%
homoDAla-OH
method 2a
Ex. 195f
C.2
Fmoc-Sar-OH
Fmoc-NMeAla-OH
Fmoc-NMe-β 3 -
prep. HPLC
22%
homoDAla-OH
method 2a
Ex. 195g
C.2
Fmoc-Gly-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
prep. HPLC
17%
method 2a
Ex. 195h
C.2
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-DAla-OH
prep. HPLC
13%
method 2a
Ex. 196i
C.2
Fmoc-Ala-OH
Fmoc-DPhe-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
12%
OH
method 1a
(TFA salt)
Ex. 195j
C.2
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
prep. HPLC
13%
method 2a
Ex. 196k
C.2
Fmoc-DAla-OH
Fmoc-Phe-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
10%
OH
method 1a
(TFA salt)
TABLE 23b
Examples of Core 11 (Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d)
Monoisotopic
Rt (purity at
No
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 195a
C29H37N5O5
535.3
1.50 (98)
536.2
method 1d
Ex. 195b
C27H33N5O5
507.3
1.44 (98)
508.2
method 1d
Ex. 196c
C31H39N5O7
593.3
1.47 (98)
594.2
method 1d
Ex. 197d
C31H42N6O5
578.3
2.10 (92)
579.2
method 2f
Ex. 195e
C29H37N5O5
535.3
1.53 (98)
536.3
method 1d
Ex. 195f
C29H37N5O5
535.2
1.40 (98)
536.2
method 1d
Ex. 195g
C32H35N5O5
569.3
1.71 (97)
569.9
method 1d
Ex. 195h
C32H35N5O5
569.3
1.67 (97)
570.2
method 1d
Ex. 196i
C35H39N5O7
641.3
1.41 (90)
642.3
method 2f
Ex. 195j
C33H37N5O5
583.3
1.72 (93)
584.0
method 1d
Ex. 196k
C35H39N5O7
641.3
1.71 (99)
642.2
method 1d
TABLE 23c
Examples of Core 11 (Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d) (continued on the following page)
No
IUPAC name
Ex. 195a
(9S,16R,22S)-16,17,20,22,23-pentamethyl-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 195b
(9S,16R,22S)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-
1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 196c
3-[(9S,16R,19S,22S)-16,17,19,23-tetramethyl-14,18,21,24-tetraoxo-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid
Ex. 197d
(9S,16R,19S,22R)-19-(4-aminobutyl)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 195e
(9S,19R,22S)-16,19,20,22,23-pentamethyl-7-oxa-13,16,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,21,24-tetrone
Ex. 195f
(9S,18S,22R)-16,18,19,22,23-pentamethyl-7-oxa-13,16,19,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,20,24-tetrone
Ex. 195g
(9S,18S,21R)-18-benzyl-21,22-dimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 195h
(9S,18S,21R)-18-benzyl-16,21-dimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 196i
3-[(9S,15S,18R,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid
Ex. 195j
(9S,18S,21R)-18-benzyl-16,21,22-trimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 196k
3-[(9S,15R,18S,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid
TABLE 24a
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following pages)
Yield
Starting
General
Purification
(isolated
No
RB
R D
Material
Proced.
Reagent
Method
salt)
Ex. 198-Ex. 200: cf. experimental description
Ex. 201
CH 3
Ex. 200
(A.6.2) 1)
Formaldehyde (36.5% in H 2 O); details cf. 1)
FC (CH 2 Cl 2 /MeOH)
89%
Ex. 202
NH 2
CH 3
Ex. 201
B.1
HCl-dioxane
crude product
93%
(HCl
salt)
Ex. 203
CH 3
Ex. 202
A.1.3
2- Naphthaleneacetic acid T3P 50% in EtOAc i-Pr 2 NEt (7 equiv.)
prep. HPLC method 2a
6%
Ex. 204
CH 3
Ex. 202
A.1.3
3-Methylbutanoic acid T3P 50% in EtOAc i-Pr 2 NEt (7 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
7%
Ex. 205
CH 3
Ex. 202
A.3
3-Pyridinyl isocyanate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
24%
Ex. 206
CH 3
Ex. 202
A.5
Benzenesulfonyl chloride (1.1 equiv.) NEt 3 (5 equiv.)
prep. HPLC method 2a
68%
Ex. 207
Ex. 200
A.1.3
2- (Dimethylamino) acetic acid Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln
prep. HPLC method 2a
49%
Ex. 208
NH 2
Ex. 207
B.1
HCl-dioxane
crude product
85% (HCl salt)
Ex. 209
Ex. 208
A.1.3
2-Phenylacetic acid (3.4 equiv.) i-Pr 2 NEt (8 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
22%
Ex. 210
Ex. 208
A.3
N-Succinimidyl N- methylcarbamate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
38%
Ex. 211
Ex. 208
A.5
Cyclopropane- sulfonyl chloride NEt 3 (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
30%
Ex. 212
Ex. 199
A.1.2.2
Acetyl chloride (2 equiv.); 0° C., 2 h
FC (CH 2 Cl 2 /MeOH)
68%
Ex. 213
H
Ex. 212
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
86%
Ex. 214
Ex. 213
A.6.3
3- Fluorobenz- aldehyde (1.8 equiv.) Acetic acid (1.5 equiv.) NaBH(OAc) 3 (4 equiv.) Workup: CHCl 3 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a and prep. HPLC method 2a
8%
Ex. 215
Ex. 213
A.1.3
1- Pyrrolidineacetic acid
prep. HPLC method 1a and prep. HPLC method 2a
14%
Ex. 216
Ex. 213
A.3
Phenyl isocyanate (1.4 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
28%
Ex. 217
Ex. 213
A.5
Benzenesulfonyl chlorid
prep. HPLC method 1a and prep. HPLC method 2a
18%
Ex. 218
Ex. 219
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
87% (TFA salt)
Ex. 219
Ex. 213
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy) carbonylamino) propanoate
prep. HPLC method 1a and prep. HPLC method 2a
49%
1) At 0° C., formadehyde (36.5% in H 2 O; 0.48 mL, 6.4 mmol), acetic acid (0.088 mL, 1.5 mmol) and NaBH(OAc) 3 (1.09 g, 5.1 mmol) were added to a soln of Ex. 200 (0.635 g, 1.3 mmol) in DCE (20 mL). The mixture was stirred for 2 h at 0° C., followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ). The crude product was dissolved in MeCN (3 mL) and treated with 25% aq. NH 3 soln (1 mL) for 3 h at rt. More 25% aq. NH 3 soln (1 mL) was added and stirrig was continued for 2 h. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH 9:1) afforded Ex. 201 (0.587g, 89%).
TABLE 24b
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following page)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 198-Ex. 200: cf. experimental description
Ex. 201
CH 3
C27H35N5O5
509.3
1.58 (97)
510.3
method 2f
Ex. 202
NH 2
CH 3
C22H27N5O3
409.2
1.05 (95)
410.0
method 2f
Ex. 203
CH 3
C34H35N5O4
577.3
1.58 (97)
578.1
method 2c
Ex. 204
CH 3
C27H35N5O4
493.3
1.38 (99)
494.2
method 2c
Ex. 205
CH 3
C28H31N7O4
529.2
1.20 (99)
530.2
method 2c
Ex. 206
CH 3
C28H31N5O5S
549.2
1.48 (99)
550.1
method 2c
Ex. 207
C30H40N6O6
580.3
1.18 (98)
581.2
method 1d
Ex. 208
NH 2
C25H32N6O4
480.2
1.09 (95)
481.3
method 2f
Ex. 209
C33H38N6O5
598.3
1.44 (98)
599.1
method 2c
Ex. 210
C27H35N7O5
537.3
1.12 (99)
538.2
method 2c
Ex. 211
C28H36N6O6S
584.2
1.28 (99)
585.1
method 2c
Ex. 212
C31H33N5O6
571.2
1.18 (97)
572.0
method 1a
Ex. 213
H
C23H27N5O4
437.2
1.32 (96)
438.1
method 5a
Ex. 214
C30H32FN5O4
545.2
1.51 (99)
546.1
method 2c
Ex. 215
C29H36N6O5
548.3
1.20 (99)
549.2
method 2c
Ex. 216
C30H32N6O5
556.2
1.32 (97)
556.9
method 2c
Ex. 217
C29H31N5O6S
577.2
1.37 (100)
578.1
method 2c
Ex. 218
C27H32N6O7
552.2
1.50 (92)
553.1
method 5a
Ex. 219
C31H40N6O7
608.3
1.42 (98)
609.2
method 2c
TABLE 24c
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following pages)
No
R B
R D
IUPAC name
Ex. 198
benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21- dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 199
NH 2
benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 200
H
tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 201
CH 3
tert-butyl N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 202
NH 2
CH 3
(10S,12S)-12-amino-17-methyl-8-oxa-3,14,17,20-
tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-
1(24),2,4,6,22,25-hexaene-15,21-dione
Ex. 203
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-2-(1-naphthyl)acetamide
Ex. 204
CH 3
3-methyl-N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]butanamide
Ex. 205
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22 ,25-hexaen-12-yl]-N-(3-pyridinyl)urea
Ex. 206
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]benzenesulfonamide
Ex. 207
tert-butyl N-[(10S,12S)-17-[2-(dimethylamino)acetyl]- 15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 208
NH 2
(10S,12S)-12-amino-17-[2-(dimethylamino)acetyl]-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-15,21-dione
Ex. 209
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-2-phenylacetamide
Ex. 210
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-N′-methylurea
Ex. 211
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]cyclopropanesulfonamide
Ex. 212
benzyl (10S,12S)-12-(acetylamine)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 213
H
N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 214
N-[(10S,12S)-17-(3-fluorobenzyl)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 215
N-[(10S,12S)-15,21-dioxo-17-[2-(1-pyrrolidinyl)acetyl]-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 216
(10S,12S)-12-(acetylamino)-15,21-dioxo-N-phenyl-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxamide
Ex. 217
N-[(10S,12S)-15,21-dioxo-17-(phenylsulfonyl)-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 218
3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-17-yl]carbonyl}amino)propanoic acid
Ex. 219
tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8- oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-17-yl]carbonyl}amino)propanoate
TABLE 25a
Examples of Core 13 (Ex. 220-Ex. 226; continued on the following pages)
Starting
General
Yield
No
R B
R E
Material
Proced.
Reagent
Purification Method
(isolated salt)
Ex. 220-Ex. 222 cf. experimental description
Ex. 223
CO 2 CH 3
Ex. 222
A.1.1
2-Phenylacetic acid i-Pr 2 NEt added at 0° C. 0° C. to rt, 2 h Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 /MeOH)
93%
Ex. 224
CO 2 H
Ex. 223
B.5
Trimethyltin hydroxide
FC (CH 2 Cl 2 /MeOH) and prep. HPLC method 1a
80%
Ex. 225
CONH 2
Ex. 224
A.2
Ammoniun chloride (5.2 equiv.) HATU (3.2 equiv.) HOAt (3.2 equiv.) i-Pr 2 NEt (8.4 equiv.) Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
64%
Ex. 226
Ex. 224
A.2
Isobutylamine Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
80%
TABLE 25b
Examples of Core 13 (Ex. 220-Ex. 226)
Monoisotopic
Rt (purity at
[M + H] +
No
R B
R E
Formula
Mass
220 nm)
found
LC-MS-Method
Ex. 220-Ex. 222.: cf. experimental description
Ex. 223
CO 2 CH 3
C32H34FN3O7S
623.2
2.31 (99)
624.3
method 1d
Ex. 224
CO 2 H
C31H32FN3O7S
609.2
2.05 (99)
610.2
method 1d
Ex. 225
CONH 2
C31H33FN4O6S
608.2
1.93 (99)
609.2
method 1d
Ex. 226
C35H41FN4O6S
664.3
2.22 (89)
665.3
method 1d
TABLE 25c
Examples of Core 13 (Ex. 220-Ex. 226)
No
R B
R E
IUPAC name
Ex. 220
CO 2 CH 3
methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),12,22,24-hexaene-8-carboxylate
Ex. 221
CO 2 CH 3
methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate
Ex. 222
NH 2
CO 2 CH 3
methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-
7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa-1(26),2,5(27),22,24-
pentaene-8-carboxylate
Ex. 223
CO 2 CH 3
methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetypamino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate
Ex. 224
CO 2 H
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylic acid
Ex. 225
CONH 2
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide
Ex. 226
(8S,17S,19S)-24-fluoro-N-isobutyl-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide
TABLE 26a
Examples of Core 14 (Ex. 227-Ex. 241; continued on the following page)
Yield
Starting
General
(isolated
No
R B
R E
Material
Proced.
Reagent
Purification Method
salt)
Ex. 227-Ex. 229: cf. experimental description
Ex. 230
CO 2 CH 3
Ex. 229
A.1.2
2-Naphthalene- acetyl chloride (1.1 equiv.)
prep. HPLC method 3
57%
Ex. 231
Ex. 228
A.2
Isobutylamine
FC (hexane/EtOAc/MeOH)
40%
Ex. 232
NH 2
Ex. 231
B.1
HCl-dioxane
crude product
93% (HCl salt)
Ex. 233
Ex. 232
A.1.1
Nicotinic acid (1.3 equiv.), 0° C., 2 h Workup: EtOAc, 1M aq. HCl soln, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
14%
Ex. 234
Ex. 228
A.2
Aniline
FC (hexane/EtOAc)
4%
Ex. 235
NH 2
Ex. 234
B.1
HCl-dioxane
prep. HPLC method 1a
44% (TFA salt)
Ex. 236
CO 2 CH 3
Ex. 229
A.1.2
Phenylacetyl chloride (1.1 equiv.)
prep. HPLC method 3
75%
Ex. 237
CO 2 H
Ex. 236
B.5
Trimethylthin hydroxide
prep. HPLC method 1a
78%
Ex. 238
CO 2 CH 3
Ex. 229
A.1.2
3-Chlorobenzoyl chloride (1.1 equiv.)
prep. HPLC method 3
62%
Ex. 239
CO 2 H
Ex. 238
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
70%
Ex. 240
Ex. 241
A.2
Isobutylamine
FC (hexane/EtOAc/MeOH)
78%
Ex. 241
CO 2 H
Ex. 230
B.5
Trimethyltin hydroxide
FC (CH 2 Cl 2 /MeOH)
84%
TABLE 26b
Examples of Core 14 (Ex. 227-Ex. 241;)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R E
Formula
Mass
220 nm)
found
Method
Ex. 227-
cf. experimental description
Ex. 229:
Ex. 230
CO 2 CH 3
C37H36FN3O7S
685.2
2.28 (96)
686.2
method 1a
Ex. 231
C33H43FN4O7S
658.3
2.37 (95)
659.3
method 1a
Ex. 232
NH 2
C28H35FN4O5S
558.2
1.59 (93)
559.2
method 1a
Ex. 233
C34H38FN5O6S
663.3
1.95 (87)
664.3
method 2c
Ex. 234
C35H39FN4O7S
678.3
2.43 (77)
679.2
method 1a
Ex. 235
NH 2
C30H31FN4O5S
578.2
1.66 (95)
579.2
method 1a
Ex. 236
CO 2 CH 3
C33H34FN3O7S
635.2
2.15 (91)
636.0
method 1a
Ex. 237
CO 2 H
C32H32FN3O7S
621.2
1.98 (96)
622.1
method 1c
Ex. 238
CO 2 CH 3
C32H31ClFN3O7S
655.2
2.31 (97)
656.1
method 1a
Ex. 239
CO 2 H
C31H29ClFN3O7S
641.1
2.14 (97)
642.1
method 1a
Ex. 240
C40H43FN4O6S
726.3
2.32 (79)
727.3
method 1a
Ex. 241
CO 2 H
C36H34FN3O7S
671.2
2.15 (88)
672.1
method 1a
TABLE 26c
Examples of Core 14 (Ex. 227-Ex. 241;)
No
R B
R E
IUPAC name
Ex. 227
CO 2 CH 3
methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 228
CO 2 H
(8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid
Ex. 229
NH 2
CO 2 CH 3
methyl (8S,12E, 18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-
dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-
1(27),2,5(28),12,23,25-hexaene-8-carboxylate
Ex. 230
CO 2 CH 3
methyl (8S,12E, 18S,20S)-25-fluoro-1842-(2-naphthyl)acetyl] amino-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 231
tert-butyl N-[(8S,12E, 18S,20S)-25-fluoro-8-[8 (isobutylamino) carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen- 18-yl]carbamate
Ex. 232
NH 2
(8S,12E,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide
Ex. 233
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide
Ex. 234
tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbonyl)-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen-18- yl]carbamate
Ex. 235
NH 2
(8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide
Ex. 236
CO 2 CH 3
methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2- phenylacetyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 237
CO 2 H
(8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl) amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23 ,25-hexaene-8-carboxylic acid
Ex. 238
CO 2 CH 3
methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 239
CO 2 H
(8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylic acid
Ex. 240
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-18-{[2-(2-naphthyl) acetyl]amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide
Ex. 241
CO 2 H
(8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl] amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylic acid
TABLE 27a
Examples of Core 15 (Ex. 242-Ex. 261;)
Yield
Starting
General
Purification
(isolated
No
R B
R E
Material
Proced.
Reagent
Method
salt)
Ex. 242-
cf. experimental description
Ex. 244:
Ex. 245
CO 2 CH 3
Ex. 244
1)
2-Naphthaleneacetyl chloride
FC (EtOAc) and FC (CH 2 Cl 2 / MeOH)
52%
Ex. 246
Ex. 243
2)
Aniline (5 equiv.)
FC (hexane/ EtOAc)
62%
Ex. 247
NH 2
Ex. 246
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
60% (HCl salt)
Ex. 248
CO 2 CH 3
Ex. 244
A.1.2
Phenylacetyl chloride (1.6 equiv.)
FC (hexane/ EtOAc/ MeOH)
90%
Ex. 249
CO 2 H
Ex. 250
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
65%
Ex. 250
CO 2 CH 3
Ex. 244
A.1.2
3-Chlorobenzoyl chloride (1.6 equiv.)
FC (hexane/ EtOAc)
87%
Ex. 251
CO 2 H
Ex. 248
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
70%
Ex. 252
CO 2 H
Ex. 245
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
45%
Ex. 253
Ex. 243
A.2
Isobutylamine (1.5 equiv.) Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln
FC (hexane, EtOAc)
73%
Ex. 254
NH 2
Ex. 253
B.1
HCl-dioxane
crude product
quant. (HCl salt)
Ex. 255
Ex. 254
A.1.1
Nicotinic acid (1.3 equiv.) 0° C., 2 h Workup: EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln,
FC (CH 2 Cl 2 / MeOH)
50%
Ex. 256
Ex. 243
2)
4-Chloroaniline (5 equiv.)
FC (hexane/ EtOAc)
14%
Ex. 257
NH 2
Ex. 256
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
66% (HCl salt)
Ex. 258
Ex. 243
2)
m-Toluidine (5 equiv.)
FC (hexane/ EtOAc)
43%
Ex. 259
NH 2
Ex. 258
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
66% (HCl salt)
Ex. 260
Ex. 243
3)
Benzylamine (5 equiv.)
FC (hexane/ EtOAc)
57%
Ex. 261
NH 2
Ex. 260
3)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
74% (HCl salt)
1) 2-Naphthaleneacetic acid (41 mg, 0.22 mmol) in CH 2 Cl 2 (3 mL) was treated at 0° C. for 1 h with oxalyl chloride (0.08 mL, 0.93 mmol) and DMF (0.007 mL). The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 (3 mL) and added dropwise to a mixture of Ex. 244·HCl (103 mg, 0.19 mmol) and i-Pr 2 NEt (0.2 mL; 0.93 mmol) in CH 2 Cl 2 (3 mL). The solution was stirred at 0° C. for 1 h, followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ), FC (EtOAc) and FC (CH 2 Cl 2 /MeOH 99:1 to 97:3) to afford Ex. 245 (67 mg, 52%).
2) Cf. experimental description for detailed procedure
3) Ex. 260 was obtained by applying the method described for the saynthesis of Ex. 246; Ex. 261 was obtained by applying the method described for the saynthesis of Ex. 247.
TABLE 27b
Examples of Core 15 (Ex. 242-Ex. 261;)
Mono-
iso-
Rt
[M +
topic
(purity at
H] +
LC-MS-
No
R B
R E
Formula
Mass
220 nm)
found
Method
Ex. 242-
cf. experimental description
Ex. 244.:
Ex. 245
CO 2 CH 3
C37H38FN3O7S
687.2
1.62 (91)
688.2
method 4a
Ex. 246
C35H41FN4O7S
680.3
2.48 (86)
681.3
method 1a
Ex. 247
NH 2
C30H33FN4O5S
580.2
1.66 (96)
581.2
method 1a
Ex. 248
CO 2 CH 3
C33H36FN3O7S
637.2
2.21 (91)
638.2
method 1a
Ex. 249
CO 2 H
C31H31ClFN3O7S
643.2
2.22 (97)
644.1
method 1a
Ex. 250
CO 2 CH 3
C32H33ClFN3O7S
657.2
2.40 (94)
658.1
method 1c
Ex. 251
CO 2 H
C32H34FN3O7S
623.2
2.06 (97)
624.1
method 1a
Ex. 252
CO 2 H
C36H36FN3O7S
673.2
2.23 (89)
674.2
method 1g
Ex. 253
C33H45FN4O7S
660.3
2.45 (93)
661.2
method 1a
Ex. 254
NH 2
C28H37FN4O5S
560.2
1.60 (97)
561.2
method 1a
Ex. 255
C34H40FN5O6S
665.3
2.00 (95)
666.2
method 2c
Ex. 256
C35H4OClFN4O7S
714.2
2.59 (89)
715.4
method 1a
Ex. 257
NH 2
C30H32ClFN4O5S
614.2
1.80 (87)
615.2
method 1a
Ex. 258
C36H43FN4O7S
694.3
2.55 (91)
695.4
method 1a
Ex. 259
NH 2
C31H35FN4O5S
594.2
1.74 (90)
595.3
method 1a
Ex. 260
C36H43FN4O7S
694.3
2.44 (92)
695.3
method 1a
Ex. 261
NH 2
C31H35FN4O5S
594.2
1.63 (92)
595.2
method 1a
TABLE 27c
Examples of Core 15 (Ex. 242-Ex. 261;)
No
R B
R E
IUPAC name
Ex. 242
CO 2 CH 3
methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 243
CO 2 H
(8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 244
NH 2
CO 2 CH 3
methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-
dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-
1(27),2,5(28),23,25-pentaene-8-carboxylate
Ex. 245
CO 2 CH 3
methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl] amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 246
tert-butyl N-[(8S,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate
Ex. 247
NH 2
(8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 248
CO 2 CH 3
methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl) amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate
Ex. 249
CO 2 H
(8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylic acid
Ex. 250
CO 2 CH 3
methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 251
CO 2 H
(8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 252
CO 2 H
(8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 253
tert-butyl N-[(8S,18S,20S)-25-fluoro-8-[(isobutylamino) carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 254
NH 2
(8S,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 255
(8S,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3-pyridinyl- carbonyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide
Ex. 256
tert-butyl N-[(8S,18S,20S)-8-[(4-chloroanilino)carbonyl]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen- 18-yl]carbamate
Ex. 257
NH 2
(8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 258
tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidino- carbonyl)-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 259
NH 2
(8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 260
tert-butyl N-[(8S,18S,20S)-8-[(benzylamino)carbonyl]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 261
NH 2
(8S,18S,20S)-18-amino-N-benzyl-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
TABLE 28a
Examples of Core 16 (Ex. 262-Ex. 283;)
Yield
Starting
General
(isolated
No
R A
R F
Material
Proced.
Reagent
Purification Method
salt)
Ex. 262-
cf. experimental description
Ex. 264:
Ex. 265
H
Ex. 263
1)
2-Naphthaleneacetyl chloride
FC (CH 2 Cl 2 /i-PrOH)
78%
Ex. 266
Ex. 264
A.1.2
Acetic anhydride (1.3 equiv.)
prep. HPLC method 1a
58% (TFA salt)
Ex. 267
H
Ex. 263
2)
1-Naphthaleneacetyl chloride
prep. HPLC method 3
58%
Ex. 268
H
Ex. 263
A.1.2
Isovaleryl chloride (1.6 equiv.) 0° C. to rt, 16 h
prep. HPLC method 3
69%
Ex. 269
H
Ex. 263
A.1.2
3-Fluorobenzoyl chloride (1.1 equiv.)
prep. HPLC method 3
52%
Ex. 270
H
Ex. 263
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
49%
Ex. 271
H
Ex. 263
A.5
Methanesulfonyl chloride
prep. HPLC method 3
39%
Ex. 272
H
Ex. 263
A.4
Methyl chloroformate
prep. HPLC method 3
69%
Ex. 273
H
Ex. 263
A.3
N-Succinimidyl N- methylcarbamate
prep. HPLC method 3
65%
Ex. 274
H
Ex. 263
A.3
2,5-Dioxopyrrolidin- 1-ylpyridin-3- ylcarbamate 0° C. to rt, 1 h
prep. HPLC method 3
64%
Ex. 275
CH 3
Ex. 265
1)
Trimethyloxonium tetrafluoroborate
prep. HPLC method 1a
12%
Ex. 276
H
Ex. 263
1)
2-Naphthylisocyanate
prep. HPLC method 3
71%
Ex. 277
H
Ex. 263
A.1.1
Phenylacetic acid
prep. HPLC method 3
58%
Ex. 278
H
Ex. 263
A.1.2
m-Anisoyl chloride (1.1 equiv.)
prep. HPLC method 3
75%
Ex. 279
H
Ex. 263
A.5
2-Naphthalenesulfonyl chloride
prep. HPLC method 3
76%
Ex. 280
H
Ex. 263
A.1.1
3-(4- Fluorophenyl) propionic acid
prep. HPLC method 3
42%
Ex. 281
H
Ex. 263
A.1.1
1H-indole-3-acetic acid
prep. HPLC method 3 and prep. HPLC method 2a
38%
Ex. 282
H
Ex. 263
A.6.4
2- Naphthylacetaldehyde (1.3 equiv.)
prep. HPLC method 2a
26%
Ex. 283
H
Ex. 263
A.6.4
4-Fluorobenzaldehyde
prep. HPLC method 3
52%
1) Cf. experimental description for detailed procedure
2) Ex. 267 was prepared applying the protocol described for the synthesis of Ex. 265.
TABLE 28b
Examples of Core 16 (Ex. 262-Ex. 283;)
Mono-
Rt
[M +
isotopic
(purity at
H] +
LC-MS-
No
R A
R F
Formula
Mass
220 nm)
found
Method
Ex. 262-Ex. 264:
cf. experimental description
Ex. 265
H
C31H33N5O5S
587.2
1.86 (93)
587.9
method 1a
Ex. 266
C28H33N5O5S
551.2
1.86 (96)
552.2
method 1d
Ex. 267
H
C31H33N5O5S
587.2
1.85 (87)
588.0
method 1a
Ex. 268
H
C24H33N5O5S
503.2
1.54 (98)
504.2
method 1a
Ex. 269
H
C26H28FN5O5S
541.2
1.66 (98)
542.1
method 1a
Ex. 270
H
C25H29N5O6S2
559.2
1.58 (97)
560.0
method 1a
Ex. 271
H
C2OH27N5O6S2
497.1
1.30 (98)
498.0
method 1a
Ex. 272
H
C21H27N5O6S
477.2
1.34 (99)
478.1
method 1a
Ex. 273
H
C21H28N6O5S
476.2
1.23 (97)
476.9
method 1a
Ex. 274
H
C25H29N7O5S
539.2
1.19 (99)
540.0
method 1a
Ex. 275
CH 3
C32H35N5O5S
601.2
2.05 (97)
602.2
method 1d
Ex. 276
H
C30H32N6O5S
588.2
1.86 (99)
589.0
method 1a
Ex. 277
H
C27H31N5O5S
537.2
1.62 (96)
538.2
method 1a
Ex. 278
H
C27H31N5O6S
553.2
1.65 (96)
554.1
method 1a
Ex. 279
H
C29H31N5O6S2
609.2
1.82 (96)
610.1
method 1a
Ex. 280
H
C28H32FN5O5S
569.2
1.72 (92)
570.2
method 1a
Ex. 281
H
C29H32N6O5S
576.2
1.61 (78)
577.1
method 1a
Ex. 282
H
C31H35N5O4S
573.2
1.63 (89)
574.2
method 1d
Ex. 283
H
C26H30FN5O4S
527.2
1.37 (97)
528.2
method 1a
TABLE 28c
Examples of Core 16 (Ex. 262-Ex. 283;)
No
R A
R F
IUPAC name
Ex. 262
benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethyl- 14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraen-15- yl]carbamate
Ex. 263
NH 2
H
(9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethyl-7-oxa-3-thia-
13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-
1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 264
NH 2
(9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethyl-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 265
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide
Ex. 266
N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethyl-14,19-dioxo-7- oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]acetamide
Ex. 267
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1-naphthyl)acetamide
Ex. 268
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-3-methylbutanamide
Ex. 269
H
3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzamide
Ex. 270
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzenesulfonamide
Ex. 271
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]methanesulfonamide
Ex. 272
H
methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate
Ex. 273
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-N-methylurea
Ex. 274
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4 ,20(23)-tetraen-15-yl]-N-(3-pyridinyl)urea
Ex. 275
CH 3
N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide
Ex. 276
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-N-(2-naphthyl)urea
Ex. 277
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-phenylacetamide
Ex. 278
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-3-methoxybenzamide
Ex. 279
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-naphthalenesulfonamide
Ex. 280
H
3-(4-fluorophenyl)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl- 14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraen-15- yl]propanamide
Ex. 281
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1H-indol-3-yl)acetamide
Ex. 282
H
(9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl] amino}-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ] tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 283
H
(9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21- dimethyl-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione
TABLE 29a
Examples of Core 17 (Ex.284a-Ex.304; continued on the following pages)
Starting
General
Purification
Yield
No
R A
R G
Material
Proced.
Reagent
Method
(iso1ated salt)
Ex. 284a-Ex. 286: cf. experimental description
Ex. 287
Ex. 286
1)
Acetyl chloride
FC (hexane, EtOAc, MeOH)
77%
Ex. 288
NH 2
Ex 287
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
78%
Ex. 289
NO 2
Ex. 285
A.3
1-Chloro-2- isocyanatobenzene
FC (hexane, EtOAc, MeOH)
90%
Ex. 290
NH 2
Ex. 289
B.4
H 2 , PtO 2
crude product
96%
Ex. 291
Ex. 290
A.5
Methanesulfonyl chloride (1.2 equiv.)
prep. HPLC method 1a
49% (TFA salt)
Ex. 292
NO 2
Ex. 285
A.1.1
Cyclopropanecarboxylic acid, 0° C., 2 h Workup: EtOAc, 1M aq. HCl soln, sat. aq. NaHCO 3 soln,
FC (hexane, EtOAc, MeOH)
70%
sat. aq. NaCl soln
Ex. 293
NH 2
Ex. 292
B.4
H2, PtO2
crude product
95%
Ex. 294
Ex. 293
A.5
Methanesulfonyl chloride (1.2 equiv.)
prep. HPLC method 1a
45%
Ex. 295
NH 2
Ex. 296
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
86%
Ex. 296
Ex. 286
A.5
Methanesulfonyl chloride (1.2 equiv.)
FC (hexane/ EtOAc) and prep. HPLC method 3
54%
Ex. 297
Ex. 286
2)
2-Chloropyrimidine
FC (EtOAc)
38%
Ex. 298
NH 2
Ex. 297
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
100%
Ex. 299
Ex. 288
A.6.1
Formaldehyde (36.5% in H 2 O)
prep. HPLC method 1a
50% (TFA salt)
Ex. 300
Ex. 288
A.1.1
2-Phenylacetic acid (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6 equiv.)
prep. HPLC method 1a
17% (TFA salt)
Workup: EtOAc, 1M aq.
HCl soln, sat. aq.
Na 2 CO 3 soln
Ex. 301
Ex. 288
A.5
3-Chlorobenzene- sulfonyl chloride
prep. HPLC method 1a
60% (TFA salt)
Ex. 302
Ex. 288
A.3
2.5-dioxopyrrolidin-1-yl isobutylcarbamate
prep. HPLC method 1a
70% (TFA salt)
Ex. 303
Ex. 295
A.1.1
4-Fluorobenzoic acid (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6 equiv.) Workup: EtOAc, 1M aq. HCl soln, sat. aq.
prep. HPLC method 1a
11% (TFA salt)
Na 2 CO 3 soln, H 2 O
Ex. 304
Ex. 295
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 1a
55% (TFA salt)
1) Acetyl chloride (0.109 mL, 1.5 mmol) was added at 0° C. to a soln of Ex. 286 (450 mg, 0.77 mmol) and i-Pr 2 NEt (0.394 mL, 2.3 mmol) in CH 2 Cl 2 (16 mL). The soln was stirred at 0° C. to rt for 2.5 h. MeOH (0.1 mL) was added and stirring continued for 10 min, followed by evaporation of the volatiles and FC (hexane/EtOAc/MeOH gradient) to afford Ex. 287 (371 mg, 77%).
2) A soln of Ex. 286 (115 mg, 0.196 mmol), 2-chloropyrimidine (27 mg, 0.235 mmol) and pTsOH·H 2 O (45 mg, 0.235 mmol) in dioxane (3 mL) was heated to reflux for 8 h. More 2-chloropyrimidine (13 mg, 0.118 mmol) and pTsOH·H 2 O (22 mg, 0.118 mmol) were added and refluxing was continued for 6 h. The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (EtOAc) afforded Ex. 297 (50 mg, 38%).
TABLE 29b
Examples of Core 17 (Ex. 284a-Ex. 304; continued on the following page)
Monoiso-
Rt (purity at
[M + H] +
LC-MS-
No
R A
R G
Formula
topic Mass
220 nm)
found
Method
Ex. 284a-Ex. 286: cf. experimental description
Ex. 287
C34H40N6O6
628.3
1.89 (97)
629.3
method 1a
Ex. 288
NH 2
C26H34N6O4
494.3
1.20 (92)
495.3
method 1a
Ex. 289
NO 2
C31H34ClN7O6
635.2
2.26 (98)
636.2
method 1d
Ex. 290
NH 2
C31H36ClN7O4
605.3
1.66 (95)
606.2
method 1a
Ex. 291
C32H38ClN7O6S
683.2
1.98 (99)
684.3
method 1d
Ex. 292
NO 2
C28H34N6O6
550.3
1.87 (96)
551.2
method 1a
Ex. 293
NH 2
C28H36N6O4
520.3
1.32 (99)
521.3
method 1a
Ex. 294
C29H38N6O6S
598.3
1.60 (99)
599.3
method 1d
Ex. 295
NH 2
C25H34N6O5S
530.2
1.24 (90)
531.2
method 1a
Ex. 296
C33H40N6O7S
664.3
1.97 (91)
665.3
method 1a
Ex. 297
C36H40N8O5
664.3
1.96 (86)
665.4
method 1d
Ex. 298
NH 2
C28H34N8O3
530.3
1.31 (87)
531.3
method 1d
Ex. 299
C28H38N6O4
522.3
1.33 (100)
523.3
method 1d
Ex. 300
C34H40N6O5
612.3
1.82 (97)
613.3
method 1d
Ex. 301
C32H37ClN6O6S
668.2
2.03 (96)
669.3
method 1d
Ex. 302
C31H43N7O5
593.3
1.24 (94)
594.0
method 3b
Ex. 303
C32H37FN6O6S
652.2
1.95 (97)
653.3
method 1d
Ex. 304
C32H39FN6O5S
638.3
1.51 (97)
639.3
method 1d
TABLE 29c
Examples of Core 17 (Ex. 284a-Ex. 304; continued on the following pages)
No
R A
R G
IUPAC name
Ex. 284a
NO 2
benzyl N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex.284b
NO 2
benzyl N-[(13R,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 285
NH 2
NO 2
(13S,19S)-13-amino-4,8-dimethyl-23-nitro-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione
Ex. 286
NH 2
benzyl N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 287
benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 288
NH 2
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]acetamide
Ex. 289
NO 2
N-(2-chlorophenyl)-N′-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]urea
Ex. 290
NH 2
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-N′- (2-chlorophenyl)urea
Ex. 291
N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino}-4,8-dimethyl-7,14-dioxo-21- oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]methanesulfonamide
Ex. 292
NO 2
N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 293
NH 2
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 294
N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 295
NH 2
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]methanesulfonamide
Ex. 296
benzyl N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 13-yl]carbamate
Ex. 297
benzyl N-[(13S,19S)-4,8-dimethyl-7,14-dioxo-23-(2-pyrimidinylamino)-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 13-yl]carbamate
Ex. 298
NH 2
(13S,19S)-13-amino-4,8-dimethyl-23-(2-pyrimidinylamino)-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14- dione
Ex. 299
N-[(13S,19S)-13-(dimethylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]acetamide
Ex. 300
N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-2- phenylacetamide
Ex. 301
N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino}-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 23-yl]acetamide
Ex. 302
N-[(13S,19S)-13-{[(isobutylamino)carbonyl]amino}-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 23-yl]acetamide
Ex. 303
N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-4- fluorobenzamide
Ex. 304
N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4-8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]methanesulfonamide
TABLE 30a
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
Starting
General
Purification
Yield
No
R B
Material
Proced.
Reagent
Method
(isolated salt)
Ex. 305-Ex. 306: cf. experimental description
Ex. 307
N(CH 3 ) 2
Ex. 306
A.6.1
Formaldehyde (36.5% in H 2 O)
prep. HPLC method 2a
72%
Ex. 308
Ex. 306
A.1.2
Acetyl chloride (2.0 equiv.)
prep. HPLC method 3
71%
Ex. 309
Ex. 306
A.1.1
3-Methylbutanoic acid
prep. HPLC method 3
65%
Ex. 310
Ex. 306
A.1.1
2-Naphthaleneacetic acid
prep. HPLC method 3
56%
Ex. 311
Ex. 306
A.1.1
1-Naphthaleneacetic acid
prep. HPLC method 3
70%
Ex. 312
Ex. 306
A.1.3
2-(Dimethylamino) acetic
prep. HPLC method 2a
56%
Ex. 313
Ex. 306
A.1.1
N-Boc-β-alanine
FC (hexane/ EtOAc/MeOH)
80%
Ex. 314
Ex. 313
B.1
HCl-dioxane
prep. HPLC method 2a
43%
Ex. 315
Ex. 306
A.1.1
3-Fluorobenzoic acid
prep. HPLC method 3
43%
Ex. 316
Ex. 306
A.1.2
Isonicotinoyl chloride hydrochloride (2.5 equiv.) Pyridine (6.5 equiv.)
prep. HPLC method 2a
58%
Ex. 317
Ex. 306
A.3
N-Succinimidyl N- methylcarbamate
prep. HPLC method 3
67%
Ex. 318
Ex. 306
A.4
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate
prep. HPLC method 3
62%
Ex. 319
Ex. 306
A.4
2-Methoxyethyl chloro- formate
prep. HPLC method 3
70%
Ex. 320
Ex. 306
A.3
tert-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino) propanoate
FC (hexane/ EtOAc/MeOH)
82%
Ex. 321
Ex. 320
1)
HCl-dioxane
crude product
83%
Ex. 322
Ex. 306
A.5
Methanesulfonyl chloride
prep. HPLC method 3
75%
Ex. 323
Ex. 306
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
61%
Ex. 324
Ex. 306
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
69%
Ex. 325
Ex. 306
A.6.4
Isobutyraldehyde
FC (hexane/EtOAc/ MeOH)
60%
Ex. 326
Ex. 306
A.1.1
Side product from HATU coupling
prep. HPLC method 1a
—
1) A soln of Ex. 320 (82 mg, 0.15 mmol) in dioxane (0.8 mL) was treated with 4M HCl-dioxane (0.8 mL) for 2 h at rt. Evaporation of the solvents and washing of the solid crude product with CH 2 Cl 2 /Et 2 O yielded Ex. 321 (61 mg, 83%).
TABLE 30b
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R B
Formula
Mass
220 nm)
found
Method
Ex. 305-Ex. 306: cf. experimental description
Ex. 307
N(CH 3 ) 2
C23H27N3O3
393.2
1.57 (98)
394.2
method 2c
Ex. 308
C23H25N3O4
407.2
1.38 (97)
408.1
method 1a
Ex. 309
C26H31N3O4
449.2
1.68 (98)
450.2
method 1a
Ex. 310
C33H31N3O4
533.2
1.99 (93)
534.2
method 1a
Ex. 311
C33H31N3O4
533.2
1.97 (95)
534.2
method 1a
Ex.312
C25H30N4O4
450.2
1.48 (98)
451.2
method 2c
Ex. 313
C29H36N4O6
536.3
1.74 (91)
537.2
method 1a
Ex. 314
C24H28N4O4
436.2
1.23 (99)
437.2
method 1a
Ex. 315
C28H26FN3O4
487.2
1.83 (96)
488.2
method 1a
Ex. 316
C27H26N4O4
470.2
1.51 (99)
471.2
method 2c
Ex. 317
C23H26N4O4
422.2
1.37 (96)
423.2
method 1a
Ex. 318
C27H27N5O4
485.2
1.33 (98)
486.2
method 1a
Ex. 319
C25H29N3O6
467.2
1.58 (96)
468.2
method 1a
Ex. 320
C29H36N4O6
536.3
1.79 (98)
537.2
method 1a
Ex. 321
C25H28N4O6
480.2
0.99 (87)
481.2
method 2c
Ex. 322
C22H25N3O5S
443.2
1.46 (97)
444.1
method 1a
Ex. 323
C27H27N3O5S
505.2
1.82 (97)
506.1
method 1a
Ex. 324
C28H28FN3O3
473.2
1.46 (98)
474.2
method 1a
Ex. 325
C25H31N3O3
421.2
1.35 (98)
422.1
method 1a
Ex. 326
C26H33N5O3
463.3
1.35 (95)
464.2
method 1a
TABLE 30c
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
No
R B
IUPAC name
Ex. 305
benzyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate
Ex. 306
NH 2
(15R,16aS)-15-amino-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-
c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 307
N(CH 3 ) 2
(15R,16aS)-15-(dimethylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H-
dibenzo[i, k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 308
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]acetamide
Ex. 309
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-methylbutanamide
Ex. 310
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(2-naphthyl)acetamide
Ex. 311
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(1-naphthyl)acetamide
Ex. 312
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(dimethylamino)acetamide
Ex. 313
tert-butyl N-(3-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino-3-oxopropyl)carbamate
Ex. 314
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-aminopropanamide
Ex. 315
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-fluorobenzamide
Ex. 316
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]isonicotinamide
Ex. 317
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′-methylurea
Ex. 318
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N-(3-pyridinyl)urea
Ex. 319
2-methoxyethyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate
Ex. 320
tert-butyl 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoate
Ex. 321
3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoic acid
Ex. 322
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]methanesulfonamide
Ex. 323
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]benzenesulfonamide
Ex. 324
(15R,16aS)-15-[(3-fluorobenzyl)amino]-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 325
(15R,16aS)-15-(isobutylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][81,4,7]oxadiazacyclododecine-9,12-dione
Ex. 326
N″-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N,N,N′,N′-tetramethylguanidine
TABLE 31a
Examples of Core 19 (Ex. 327-Ex. 329)
Yield
Starting
General
Purification
(isolated
No
R B
R D
material
Proced.
Reagent
Method
salt)
Ex. 327-
cf. experimental description
Ex. 329:
TABLE 31b
Examples of Core 19 (Ex. 327-Ex. 329)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 327-
cf. experimental description
Ex. 329:
TABLE 31c
Examples of Core 19 (Ex. 327-Ex. 329)
No
R B
R D
IUPAC name
Ex. 327
benzyl (16S,18S)-16-[(tert-butoxycarbonyl)amino]-7,13-dioxo-4-(trifluoromethyl)- 5,20-dioxa-3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21, 23-pentaene-11-carboxylate
Ex. 328
H
tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23-pentaen-16-yl] carbamate
Ex. 329
NH 2
benzyl (16S,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23-pentaene-11- carboxylate
Cpd No
n
R XI
R XII
R XIII
R XIV
Fmoc-AA1-OH
Fmoc-AA2-OH
85a-Ex. 193a
0
CH 2 Ph
H
CH 3
CH 3
Fmoc-β 3 -homoPhe-OH
Fmoc-NMeDAla-OH
85b-Ex. 193b
0
CH 3
CH 3
(CH 2 ) 2 CO 2 tBu
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMeDGlu(OtBu)-OH
85c-Ex. 193c
0
H
H
CH 2 Ph
CH 3
Fmoc-β-Ala-OH
Fmoc-NMePhe-OH
85d-Ex. 193d
0
H
H
CH 2 Ph
H
Fmoc-β-Ala-OH
Fmoc-Phe-OH
85e-Ex. 193e
0
CH 3
CH 3
CH 2 Ph
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMePhe-OH
85f-Ex. 193f
0
CH 3
CH 3
H
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
85g-Ex. 193g
0
CH 3
CH 3
CH 2 Ph
H
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Phe-OH
85h-Ex. 193h
1
CH 2 Ph
H
H
CH 3
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-β-Ala-OH
Cpd No
l
m
n
R XI
R XII
R XIII
R XIV
R XV
R XVI
135a-Ex. 195a
1
0
0
CH 3
CH 3
H
CH 3
CH 3
CH 3
135b-Ex. 195b
1
0
0
CH 3
CH 3
H
H
CH 3
H
135c-Ex. 195c
1
0
0
CH 3
CH 3
CH 3
H
(CH 2 ) 2 CO 2 tBu
CH 3
135d-Ex. 195d
1
0
0
CH 3
CH 3
(CH 2 ) 4 NHBoc
H
CH 3
H
135e-Ex. 195e
0
1
0
H
CH 3
CH 3
CH 3
CH 3
CH 3
135f-Ex. 195f
0
0
1
H
CH 3
CH 3
CH 3
CH 3
CH 3
135g-Ex. 195g
0
0
0
H
H
CH 2 Ph
H
CH 3
CH 3
135h-Ex. 195h
0
0
0
H
CH 3
CH 2 Ph
H
CH 3
H
135i-Ex. 195i
0
0
0
CH 3
H
CH 2 Ph
H
(CH 2 ) 2 CO 2 tBu
CH 3
135j-Ex. 195j
0
0
0
H
CH 3
CH 2 Ph
H
CH 3
CH 3
135k-Ex. 195k
0
0
0
CH 3
H
CH 2 Ph
H
(CH 2 ) 2 CO 2 tBu
CH 3
Cpd No
Fmoc-AA1-OH
Fmoc-AA2-OH
Fmoc-AA3-OH
135a-Ex. 195a
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
Fmoc-NMeAla-OH
135b-Ex. 195b
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Gly-OH
Fmoc-Ala-OH
135c-Ex. 195c
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Ala-OH
Fmoc-NMeGlu(OtBu)-OH
135d-Ex. 195d
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Lys(Boc)-OH
Fmoc-DAla-OH
135e-Ex. 195e
Fmoc-Sar-OH
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMeAla-OH
135f-Ex. 195f
Fmoc-Sar-OH
Fmoc-NMeAla-OH
Fmoc-NMe-β 3 -homoDAla-OH
135g-Ex. 195g
Fmoc-Gly-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
135h-Ex. 195h
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-DAla-OH
135i-Ex. 195i
Fmoc-Ala-OH
Fmoc-DPhe-OH
Fmoc-NMeGlu(OtBu)-OH
135j-Ex. 195j
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
135k-Ex. 195k
Fmoc-DAla-OH
Fmoc-Phe-OH
Fmoc-NMeGlu(OtBu)-OH
Biological and Pharmacological Methods
1. Ca 2+ Flux Assays for the GPCRs Oxytocin Receptor (OT Receptor), Thyrotropin-Releasing Hormone Receptor (TRH Receptor) and Bombesin Receptor Subtype 3 (BB3 Receptor)
Assays were performed on a FLIPR TETRA fluorometric imaging plate reader (Molecular Devices) with ScreenWorks Version 2 (Molecular Devices) as device operating and data analysis software.
Dose dependent agonist and antagonist activities were determined. Percentage activation and percentage inhibition values were determined.
Percentage activation was determined upon initial addition of the sample compounds followed by 10 minutes' incubation at 25° C. Following compound incubation, reference agonists were added at EC 80 to determine percentage inhibition.
Reference agonists were purchased from reputable commercial vendors and prepared according to each ligand's specifications. All handling of ligands were done to ensure proper control throughout the experiments.
Example compounds were weighed on a Microbalance (Mettler MX5) and dissolved in 100% DMSO to a final concentration of 2.5 mM and subsequently diluted into the assay buffer.
The assay buffer was a supplemented HBSS (Hank's Balanced Salt Solution). HBSS was supplemented with 20 mM HEPES (4-(2-hydroxyethyl)-piperazin-1-ethansulfonic acid) and 2.5 mM Probenecid (Sigma P8761).
Assay Plate Seeding:
GPCR assays were performed using Ca 2+ optimized hematopoietic cell lines (rat) with cultures never exceeding 90% confluency. Cells were harvested and seeded (from cultures at less than 90% confluency) at 50000 cells/well for a 96-well plate (12500 cells/well for 384). After seeding, the assay plates were incubated for 45 minutes at room temperature. After room temperature incubation, the assay plates were incubated at 37° C. 5% CO 2 for 24 hours prior to assaying.
Calcium Dye Loading:
All GPCR assays were performed using Fluo-8 Ca 2+ dye.
Ca 2+ dye was prepared at 1× dye concentration in GPCR assay buffer. After 24 hours of incubation, cells were washed with GPCR assay buffer, and then Ca 2+ -dye (100 μL/well) was added.
The plates were incubated for 90 minutes at 30° C. 5% CO 2 prior to FLIPR assay.
Agonist Assay:
Compound plates were prepared to add 50 μL/well during the agonist assay mode. During the FLIPR assay, 50 μL/well from the compound plate was diluted 3-fold into the existing 100 μL/well from the dye loading step. Therefore all compounds were prepared as 3× the final concentration desired in the assay.
Antagonist Assay:
After completion of the first single addition assay run, assay plate was removed from the FLIPR Tetra and placed at 25° C. for 7 minutes before antagonist assay.
Using the EC 80 values determined during the agonist assay, all pre-incubated sample compound and reference antagonist (if applicable) wells were stimulated at the EC 80 of the reference agonist. As reference ligands for these assays their obvious natural ligands oxytocin (OT), thyrotropin-releasing hormone (TRH) and bombesin (6-14) [BN(6-14)] were used.
After the addition of the reference agonist fluorescence was monitored for 180 sec using FLIPR Tetra.
Data Analysis and Results:
From the FLIPR data, with negative control correction enabled, the maximum statistic for each well was exported and percentage activation relative to E max control was calculated.
The results of the GPCR assays are summarized in Table 32.3 to Table 32.5.
2. Enzyme Assays for the Peptidase Endothelin Converting Enzyme-1 (ECE-1) and for the Cysteine Protease Cathepsin S (CatS)
The assays were performed according to provider's (Ricerca Biosciences, LLC) protocols which in turn are based on literature procedures (for ECE-1 cf.: O. Valdenaire et al., Eur. J. Biochem. 1999, 264, 341-349; F. D. Russell, A. P. Davenport, Circ. Res. 1999, 84, 891-896; and for CatS: G P Shi et al., J. Biol. Chem. 1992, 267, 7258-62; D Brömme et al., J. Biol. Chem. 1993 268, 4832-4838.).
Procedures:
i) ECE-1 Assay:
Human recombinant ECE-1 expressed in murine myeloma cells NS0 is used. Test compound and/or vehicle is preincubated with 20 ng/ml enzyme in modified MES buffer pH 6.0 for 15 minutes at 25° C. The reaction is initiated by addition of 10 mM Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp) for another 60 minutes' incubation period. Determination of the amount of Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala formed is read spectrophotometrically at 320 nm/405 nm. Compounds are screened at 10 mM.
Reference Compound: Phosphoramidon (IC 50 0.0049 μM)
ii) CatS Assay:
Human recombinant cathepsin S expressed in a murine myeloma NS0 cells is used. Test compound and/or vehicle is preincubated with 0.1 μg/ml enzyme in modified acetate buffer pH 4.5 for 15 minutes at 25° C. The reaction is initiated by addition of 10 mM Z-Leu-Arg-AMC for another 30 minutes' incubation period. Determination of the amount of AMC formed is read spectrofluorimetrically at 360 nm/465 nm. Compounds are screened at 10 mM.
Reference Compound: E-64 (IC 50 0.0014 μM)
Data Analysis:
IC 50 values were determined by a non-linear, least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK). Inhibition constants K were calculated according to the equation of Cheng and Prusoff (Y. Cheng, W. H. Prusoff, Biochem. Pharmacol. 1973, 22, 3099-3108) using the observed IC 50 of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the K D of the ligand. The Hill coefficient (nH), defining the slope of the competitive binding curve, was calculated using MathIQ™.
The results of the assays are summarized in Table 32.1 and Table 32.2.
3. Human LTB4 Receptor Cell-Based Assay
CHO mito-i-Photina® cells (Axxam SpA) stably expressing the human leukotriene B4 receptor (LTB4R) were used for monitoring activation of the target LTB4R, a GPCR (Gαq), by measuring the flash luminescence of Ca 2+ sensitive photoprotein as reporter system with FLIPR TETRA screening instrumentation (Molecular Devices) upgraded with an ICCD Camera (MDC). For data quality check and data analysis a Genedata Screener 10.0.3 was used, and for curve fitting of reference agonist and antagonist GraphPad Prism Software.
The reference agonist LTB4 and antagonist U-75302 were purchased from reputable commercial vendors and prepared according to each ligand's specifications. All handling of ligands were done to ensure proper control throughout the experiments.
The steps of the implemented workflow and data analysis are mainly as follows:
Assay Plate Seeding:
mito-1-Photina cells are seeded (10000 c/w in 384 MTP; in complete medium 25 μL/well) for 24 hours, removed from the incubator, equilibrated at room temperature for 1 h, freed from the growth medium, loaded with 30 μL/well of Tyrode's buffer containing 10 μM coelenterazine, and incubated for 3 hours at rt.
Agonist/Antagonist Assay:
All compounds were tested at 10 μM with triplicate data points.
After incubation, the volume in all the wells is flattened to 20 μL by aspiration with CyBi®-Vario pipettor. The First Injection (10 μL of test compounds or reference antagonist U-75302 in Tyrode's buffer+DMSO 0.5%) is performed by the FLIPR TETRA and the kinetic response is monitored over a period of 120 seconds. Incubation at rt for 10 min. is followed by the Second Injection (15 μL of LTB4 at EC 80 in Tyrode's buffer) and monitoring of the kinetic response over a period of 120 seconds.
Data Analysis and Results:
The possible kinetic response is divided into two distinct phases: Monitoring the kinetic response after the First Injection is indicated as Compound Addition (CA) and measures the agonistic activity of compounds; monitoring the kinetic response after the Second Injection is indicated as Target Activation (TA) and measures the antagonistic activity of a compound.
The activity determination (IC 50 determination) experiment is performed using LTB4 as agonist (100 nM corresponding to EC 80 ). Selected compound are tested in 8 doses intraplate dose response with quadruplicate data points.
The results of the LTB4R assays are summarized in Table 32.6.
4. Antimicrobial Assays
The antimicrobial activities of the compounds were determined in 96-well plates (Greiner, polystyrene) by the standard NCCLS broth microdilution method (National Committee for Clinical Laboratory Standards 1993. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 3rd ed. Approved standard M7-A6. National Committee for Clinical laboratory standards, Wayne, Pa.) with slight modifications. Inocula of the microorganisms were diluted into Mueller-Hinton II (MH, cation adjusted) broth+0.002% P-80 and compared with a 0.5 McFarland standard to give appr. 10 6 colony forming units (CFU)/mL. Aliquots (50 μl) of inoculate were added to 50 μl of MH broth+0.002% P-80 containing the compounds in serial two-fold dilutions. The following microorganisms were used to determine antibiotic selectivity of the compounds: S. pneumoniae DSM 20566 11A11, 3313A6, 704CG4B21, 82BERG72; S. aureus ATCC 29213, ATCC 25923, DSM 11729, DSM 46320, S. aureus 39. Antimicrobial activities of the compounds were expressed as the minimal inhibitory concentration (MIC) in μg/mL at which no visible growth was observed after 18-20 hours of incubation at 36° C.
The results of the antimicrobial assays are summarized in Table 32.7 and Table 32.8.
5. Plasma and Metabolic Stability Assays
Example compounds were dissolved in DMSO/H 2 O 90:10 to a final concentration of 10 mM for plasma stability determination and metabolic stability determination.
The assays were conducted according to literature precedents (F. P. Guengerich, Analysis and Characterization of Enzymes ; in: Principles and Methods of Toxicology , A. W. Hayes (Ed.) Raven Press: New York, 1989, 777-813; R. Singh et al., In vitro metabolism of a potent HIV - protease inhibitor (141 W 94) using rat, monkey and human liver S 9 , Rapid Commun. Mass Spectrom. 1996, 10, 1019-1026).
Results of the stability assays are listed in Table 33 below.
Plasma Stability Assay
Human plasma (Blutspendedienst SRK, Basel) and CD-1 mouse plasma (mixed gender pool >50 animals, Innovative Research, Calif., USA) are both sodium citrate stabilized. The assay is performed in triplicates at 10 μM compound concentration and 37° C. Samples are taken at 0, 15, 30, 60, 120 and 240 minutes and stopped by precipitation with 3 volumes of acetonitrile/formic acid 98:2 and shaking (2 minutes, 600 rpm) followed by filtration (−20 mm Hg). The filtrate is collected. The filtrate (100 μL) is evaporated and reconstituted in the suitable solvent (cf. Table 33) to be analyzed by HPLC/MS/MS. The resulting peak area counts are expressed in percent of the 0 value and used to determine the endpoint stability in % and the half life T in minutes. In order to monitor assay integrity the degradation of propantheline is assayed with every experimental set.
Metabolic Stability Assay
Microsomes from a human 50 donor mixed gender pool and 1:1 mixtures of microsomes from CD-1 mouse single-gender pools are purchased from Celsis (Belgium). The enzymatic reaction is performed in a buffer containing an NADPH regeneration system and microsomes with the following end concentrations: 100 mM potassium phosphate buffer (all from Sigma), 1 mg/mL glucose-6-phosphate, 1 mg/mL β-nicotinamide adenine dinucleotide phosphate (NADP), 0.65 mg/mL magnesium chloride, 0.8 units/mL of glucose-6-phosphate dehydrogenase (prediluted with 5 mM citrate buffer), 10 μM compound and 1 mg/ml microsomal protein. Compounds are incubated at 37° C. in duplicates and samples are taken after 0, 5, 10, 20 and 60 minutes. After acetonitrile precipitation (3 volumes), shaking (2 minutes, 600 rpm) followed by centrifugation (10 minutes, 3200 g), the supernatant is dried reconstituted in the suitable solvent (cf. Table 33) and analyzed by HPLC/MS/MS. Metabolic turnover is expressed in % of the initial 0 minutes value and half life T½ (min) is calculated. Verapamil for human and propranolol for mouse are used as reference and are assayed with every experimental set.
TABLE 32.1
Endothelin Converting Enzyme-1 Assay
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 18
98
3.01
Ex. 25
97
4.28
Ex. 26
98
4.07
TABLE 32.2
Cathepsin S Assay
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 18
82
3.65
Ex. 20
45
14.7
Ex. 21
75
n.d.
Ex. 24
55
n.d.
Ex. 25
87
3.18
Ex. 26
81
3.83
Ex. 27
50
n.d.
Ex. 28
57
n.d.
TABLE 32.3
TRH (Thyrotropin-releasing hormone) receptor Assay
Antagonist activity
Antagonist activity
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 7
91
1.4
Ex. 332
29
n.d.
Ex. 333
35
n.d.
Ex. 334
40
n.d.
Ex. 335
34
n.d.
Ex. 336
48
8.2
TABLE 32.4
OT (Oxytocin) receptor Assay
Antagonist activity
Antagonist activity
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 94
58
3.0
Ex. 96
60
1.2
Ex. 100
57
4.6
Ex. 101
69
2.6
Ex. 103
77
6.9
TABLE 32.5
BB3 (Bombesin) receptor Assay
Agonist activity
Agonist activity
No
[% activation at 12.5 μM]
EC50 [nM]
Ex. 265
84
630
Ex. 267
61
>50′000
Ex. 275
60
780
Ex. 276
75
480 *)
Ex. 282
39
>50′000
*) Ca 75% of Bombesin efficacy
TABLE 32.6
LTB4 (Leukotriene B4) receptor Assay
Antagonist activity
Antagonist activity
No
[% inhibition at 10 μM]
IC50 [μM]
Ex. 14
46
39.4
Ex. 50
100
1.97
Ex. 116
49
15.4
Ex. 119
47
14.2
Ex. 144
41
40.9
TABLE 32.7
Antimicrobial activity
S . aureus
S . aureus
S . aureus
S . aureus
S . aureus
S . pneumoniae
ATCC 29213
39
ATCC 25923
DSM 11729
DSM 46320
DSM 20566
No
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
Ex. 2
8-16
4
16
8-16
16->16
8
Ex. 91
2-4
8
4
2
4
>16
Ex. 94
4
8
8
4
8
>16
S . aureus : Staphylococcus aureus ;
S . pneumoniae : Streptococcus pneumoniae
TABLE 32.8
Antimicrobial activity
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
DSM 20566
11A11
3313A6
704CG4B21
82BERG72
No
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
Ex. 247
16
16
16
16
8
Ex. 257
8
8
8
8
2
Ex. 259
8
16
8
8
4
S. pneumoniae : Streptococcus pneumonia
TABLE 33
Plasma Stability and Metabolic Stability Assays of Selected Examples (continued on the following pages)
Plasma Stability
Metabolic Stability
T ½
240 min
T ½
60 min
Solvent
240 min
[min]
mouse/
60 min
[min]
mouse/
for
T ½ [min]
hum
mouse/
(rat)
T ½ [min]
hum
mouse/
(rat)
No
reconstitution
hum
[% remain.]
(rat)
[% remain.]
hum
[% remain.]
(rat)
[% remain.]
Ex. 42
B
>240
91
>240
100
>60
100
>60
100
Ex. 43
B
>240
97
>240
63
>60
100
>60
83
Ex. 44
B
>240
100
>240
83
>60
68
>60
77
Ex. 45
C
>240
76
190
46
>60
66
>60
73
Ex. 46
B
>240
100
>240
78
32
26
>60
71
Ex. 47
B
>240
99
>240
86
>60
83
>60
100
Ex. 49
B
>240
95
>240
76
>60
100
>60
92
Ex. 50
B
>240
100
n.d.
n.d.
>60
53
40
34
Ex. 51
B
>240
100
>240
80
>60
71
>60
69
Ex. 52
B
>240
99
>240
95
>60
100
>60
78
Ex. 53
1)
n.d.
n.d.
>240
86
>60
100
>60
92
Ex. 54
B
>240
100
>240
100
>60
60
>60
82
Ex. 55
B
n.d.
n.d.
>240
80
>60
97
>60
98
Ex. 57
B
>240
100
>240
74
>60
100
>60
100
Ex. 58
D
>240
95
n.d.
n.d.
>60
87
>60
70
Ex. 59
B
>240
74
>240
67
>60
94
>60
81
Ex. 60
C
>240
97
n.d.
n.d.
8
0
25
19
Ex. 69
1)
>240
91
200
45
>60
100
>60
100
Ex. 70
1)
>240
99
>240
61
>60
100
>60
77
Ex. 71
B
>240
100
>240
92
>60
100
>60
89
Ex. 72
B
>240
100
>240
65
22
14
35
30
Ex. 73
B
>240
89
n.d.
n.d.
2
0
1
0
Ex. 74
C
>240
100
>240
67
7
1
3
0
Ex. 75
B
>240
93
>240
55
21
12
53
48
Ex. 76
D
>240
88
n.d.
n.d.
16
4
15
9
Ex. 77
B
>240
96
>240
85
44
41
>60
75
Ex. 78
B
>240
100
>240
86
>60
99
>60
92
Ex. 79
B
>240
100
>240
60
>60
95
>60
73
Ex. 80
1)
>240
90
>240
84
19
6
24
19
Ex. 81
2)
>240
88
>240
100
>60
100
>60
97
Ex. 83
3)
>240
85
>240
93
>60
85
>60
96
Ex. 84
B
>240
99
>240
56
>60
97
>60
71
Ex. 85
D
>240
100
>240
88
>60
100
>60
80
Ex. 86
B
n.d.
n.d.
>240
60
n.d.
n.d.
>60
71
Ex. 87
B
>240
100
>240
90
27
17
60
63
Ex. 88
1)
n.d.
n.d.
>240
81
56
49
>60
62
Ex. 89
C
>240
100
>240
76
13
8
10
2
1) Reconstitution solvent for plasma stabilty determination B; reconstitution solvent for metabolic stability determination: C
2) Reconstitution solvent for plasma stabilty determination; human: D; mouse B; reconstitution solvent for metabolic stability determination: D
3) Reconstitution solvent for plasma stability determination: B; reconstitution solvent for metabolic stability determination; human D; mouse B.
Reconstitution solvents:
Solvent A: DPBS (100 mg CaCl 2 , 100 mg MgCl 2 •6H 2 O, 200 mg KCl, 200 mg KH 2 PO 4 , 8000 mg NaCl and 2160 mg Na 2 HPO 4 •7H 2 O to be made up to 1000 mL by addition of H 2 O);
Solvent B: H 2 O/CH 3 CN 95:5 (v/v) + 0.2% formic acid;
Solvent C: DMSO/(H 2 O/CH 3 CN 95:5)/DPBS 50:45:5 + 2% formic acid;
Solvent D: H 2 O/CH 3 CN 1:1 (v/v) + 5% DPBS + 0.2% formic acid
1.PublishNumber: US-10017481-B2
2.Date Publish: 20180710
3.Inventor: OBRECHT, DANIEL
ERMERT, PHILIPP
OUMOUCH, SAID
PIETTRE, ARNAUD
GOSALBES, Jean-François
THOMMEN, MARC
4.Inventor Harmonized: OBRECHT DANIEL(CH)
ERMERT PHILIPP(CH)
OUMOUCH SAID(FR)
PIETTRE ARNAUD(FR)
GOSALBES JEAN-FRANÇOIS(FR)
THOMMEN MARC(CH)
5.Country: US
6.Claims:
(en)The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases.
7.Description:
(en)Macrocyclic natural and synthetic products have played a crucial role in the development of new drugs, especially as anti-infectives (F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich, Angew. Chem. Int. Ed. Engl. 2006, 45, 5072-5129; D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. O. Gombert, Curr. Med. Chem. 2009, 16, 42-65), as anti-cancer drugs and in other therapeutic areas (C. E. Ballard, H. Yu, B. Wang, Curr. Med. Chem. 2002, 9, 471-498; F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309-1332). They often display remarkable biological activities, and many macrocycles or their derivatives have been successfully developed into drugs (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186; D. J. Newman, G. M. Gragg, K. M. Snader, J. Nat. Prod. 2003, 66, 1022-1037). The chemical diversity of macrocyclic natural products is immense and provides a tremendous source of inspiration for drug design.
Macrocyclic natural and synthetic products generally exhibit semi-rigid backbone conformations placing appended substituents into well-defined spatial orientation. Certain ring sizes are preferred (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186), e.g. 16-membered rings are frequently found in oxygen-containing macrocycles, such as polyketides (M. Q. Zhang, B. Wilkinson, Curr. Opin. Biotechnol. 2007, 18, 478-488). It is hypothesized that semi-rigid scaffolds possess some of the favorable binding properties of rigid molecules (entropy), yet still retaining enough flexibility to adapt suitable conformations in the binding event (induced fit).
Macrocyclic natural and synthetic products are generally classified according to the chemical nature of the backbone, e.g. cyclic peptides (Y. Hamady, T. Shioiri, Chem. Rev. 2005, 105, 4441-4482; N.-H. Tan, J. Zhou, Chem. Rev. 2006, 106, 840-895); cyclic depsipeptides (F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Herrera, Curr. Med. Chem. 2004, 11, 1309-1332); macrocyclic lactones (macrolactones) and macrolides; macrocyclic lactams (macrolactams), macrocyclic amines, macrocyclic ethers, macrocyclic ureas and urethanes, and others. The conformational, physico-chemical, pharmacological and pharmacodynamic properties of macrocyclic natural and synthetic compounds depend largely on the ring size, the chemical nature of the backbone, and of appended groups (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186). By modifying these three parameters nature has created a virtually unlimited repertoire of molecular diversity. Despite their undisputed interesting biological properties, many natural products show limitations for drug development, such as low metabolic stability, i.e. short half lives, lack of or insufficient oral bioavailability as well as low tissue penetration and membrane permeability which renders them not amenable for intracellular targets. In addition, their high structural complexity imposes severe limitations to synthetic accessibility, often leaving fermentation or recombinant methods as sole options; thus making complex quality control and development processes necessary and leading to high production costs.
The present invention describes novel, fully synthetic, macrocyclic natural product-like molecules of type I (Scheme 1), accessible through a modular approach by connecting suitably protected building blocks A, B and C to a linear precursor followed by subsequent intramolecular cyclization.
Building blocks A serve as conformation-inducing templates (“Template”) and are based on appropriately substituted and protected divalent biaryl-derivatives. Biaryl as used in this context shall comprise all possible pairwise combinations of aromatic carbocyclic and/or aromatic heterocyclic ring systems connected by a C sp 2 -C sp 2 single bond, i.e. aryl-aryl, heteroaryl-heteroaryl, aryl-heteroaryl and heteroaryl-aryl.
Building blocks B are corresponding to appropriately substituted and protected primary, secondary or tertiary aminoalcohols and are functioning as conformational modulators (“Modulator”) by influencing the conformation of the macrocycle, e.g. through cis/trans-isomerization of amides.
Within the macrocycles backbone of I the building blocks A and B are connected via the “Bridge” C composed of one to three appropriately and independently substituted subunits c1, c2 and c3, which in turn are derived from suitably substituted and protected precursors, like, but not limited to, appropriately substituted and protected amino acids or amine derivatives.
The connectivity —X— between Template A and Modulator B is defined by an ether (X═O) or thioether (X═S) bond; while that between A and Bridge C is defined by the structural element —Y—Z— as detailed below. As sulfur atoms of such a thioether linkage can easily and selectively be oxidized to the corresponding sulfoxides (S═O) or sulfones (S(═O) 2 ), these higher oxidation states are also part of the invention.
The generic connection —Y—Z— between A and C corresponds in most exemplified cases to a secondary or tertiary amide bond (—C(═O)—NR 7 —). Alternative connectivities —Y—Z— are thioethers (—S—CHR 8 —) and its oxidation products, i.e. sulfoxides (—S(═O)—CHR 8 —) or sulfones (—S(═O) 2 —CHR 8 —), as well as olefinic moieties (—(CHR 9 ) t —CR 11 ═CR 10 —) and their reduced aliphatic analogs (—(CHR 9 ) t —CHR 11 —CHR 10 —). Furthermore, in case of Templates A carrying a thiophenolic Y-group (Y═S) an additional two carbon spacer can be easily introduced by reacting with β-halo carboxyl or β-halo carbonyl compounds prior to processing with the C building blocks; thus providing access to —Y—Z— groups of type —S—CHR 8 —C(═O)—NR 7 —, —S—CHR 8 —CHR 12 —NR 7 —, —S—CHR 8 —CHR 12 —NR 7 — and their corresponding S-oxidized congeners.
The functional moiety U connects Bridge C with the nitrogen atom of Modulator B. In most cases this is realized by an amide bond, in which case the moiety U corresponds to a carbonyl group (—C(═O)—). Alternatively, U can be defined as a carbamoyl moiety (—NR 7 —C(═O)—) leading to a urea (including the N-atom of B) as functional connection between B and C. Similarly, a carboxyl group (—O—C(═O)—) as U describes a carbamate linkage between B and C. In addition, U can represent an oxalyl group (—C(═O)—C(═O)—) or the corresponding acetal (—C(—OR 13 ) 2 —C(═O)—).
As mentioned before, the Bridge C itself comprises one to three (1-3) appropriately and independently substituted subunits c1, c2 and c3, which in turn are independently connected to each other by the generic groups V or W which can correspond to an amide bond (—C(═O)NR 7 —) and the corresponding inverse amide (—NR 7 C(═O)—), the methylene-heteroatom linkages —CHR 8 -Q- and -Q-CHR 8 —, an alkene[1,2]diyl moiety (—CHR 10 ═CHR 11 —) or its reduced form as alkane[1,2]diyl (—CHR 10 —CHR 11 —), an oxalyl group (—C(═O)—C(═O)—) or a disulfide bridge (—S—S—).
The spatial orientation of the substituents in macrocycles I is modulated by the ring size and the stereochemical connectivity within building blocks A, B and C. Therefore the macrocyclic backbone as well as the substituents contribute to the biological activity of compounds of type I.
Compounds of this invention are characterized by macrocyclic backbones containing an aromatic ether/thioether linkage and one or more tertiary amide bonds. In other cases secondary amide bonds, aliphatic ether linkages, ethylidene or ethylene moieties are exemplified as part of the backbone.
Ether linkages in macrocyclic molecules favorably influence physico-chemical and pharmacological properties, such as solubility in aqueous solutions, metabolic stability against proteolytic degradation, cell permeability and oral absorption (K. X. Chen et al., J. Med. Chem. 2006, 49, 995-1005). In addition, tertiary amide bonds containing macrocycles are well-known for increased proteolytic stability, cell permeability and oral bioavailability compared to the parent molecules with secondary amide bonds (E. Biron, J. Chatterjee, O. Ovadia, D. Langenegger, J. Brueggen, D. Hoyer, H. A. Schmid, R. Jelinek, C. Gilon, A. Hoffmann, H. Kessler, Angew. Chem. Int. Ed. 2008, 47, 1-6; J. Chatterjee, O. Ovadia, G. Zahn, L. Marinelli, A. Hoffmann, C. Gilon, H. Kessler, J. Med. Chem. 2007, 50, 5878-5881). For instance, the cyclic undecapeptide cyclosporin A (INN: Ciclosporin), which is used as immunosuppressant in organ transplants, contains seven N-methylated amino acids and possesses good oral bioavailability when formulated appropriately (P. R. Beauchesne, N. S. C. Chung, K. M. Wasan, Drug Develop. Ind. Pharm. 2007, 33, 211-220).
A well documented process in protein folding events is the peptidyl cis/trans isomerization of proline or pipecolic acid containing polypeptides and proteins. In vivo this process is mediated by peptidyl prolyl cis/trans isomerases such as the cyclophilins, the FK506-binding proteins and the parvulins (A. Bell, P. Monaghan, A. P. Page, Int. J. Parasitol. 2006, 36, 261-276). Besides their role in protein folding and in the immune system, peptidyl prolyl cis/trans isomerases have been implicated in cell cycle control (P. E. Shaw, EMBO Reports 2002, 3, 521-526) and therefore constitute interesting pharmaceutical targets. In the context of this invention it is worth mentioning that both FK506 and cyclosporin A are macrocyclic natural products interacting with the FK506-binding protein and cyclophilins, respectively.
An interesting structural motif found in several natural products consist of a macrocylic ring system with a biaryl moiety as backbone element. Such biaryls, which are composed of two aromatic or heteroaromatic rings connected via a single bond, are the outstanding characteristic of a number of antibacterial macrocyclic peptide classes, like the biphenomycins, arylomycins and aciculitins; not to mention the glycopeptide antibiotics with the vancomycins as most prominent representatives (L. Feliu, M. Planas, Int. J. Pept. Res. Ther. 2005, 11, 53-97).
For many extra- and intracellular biological targets the quest for small molecule hits has been disappointing; this is especially true if protein-protein interactions are involved (J. A. Robinson, S. DeMarco, F. Gombert, K. Moehle, D. Obrecht, Drug Disc. Today 2008, 13, 944-951). These so-called “difficult targets” include e.g. receptor tyrosine kinases, growth factor receptors, transcription modulators, and chaperones. Interestingly, several natural and synthetic macrocyclic compounds have been described as promising starting points for drug discovery programs around such difficult targets (D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J. DeMarco, K. Moehle, F. O. Gombert, Curr. Med. Chem. 2009, 16, 42-65).
The novel macrocycles of type I described in the embodiments of this invention are designed to combine unique features of natural macrocyclic compounds with beneficial physico-chemical and pharmacological properties of small molecules, e.g.:
Natural product-like structural complexity Good aqueous solubility High metabolic stability Improved oral bioavailability Enhanced membrane permeability Extra- and intracellular targets amenable Improved tissue penetration Small molecule-like pharmacokinetics Modular chemical synthesis Synthesis process well suited for parallelization Reasonable production costs Small molecule-like QC and development processes
The Main Embodiment of the current invention of novel and fully synthetic macrocyclic compounds I according Scheme 1 (detailed in Scheme 2 and Scheme 3) is defined by groups of selected building blocks A, B and C as shown in Table 1 to Table 3 and by the appending substituents R 1 -R 57 as detailed below.
As shortly indicated before, Template A exerts an important conformational constraint on products of type I. These structural effects of A depend on (i) the dihedral angle between the two C sp 2 -C sp 2 connected aromatic rings A B and A C that are defining the Template A entity; (ii) the relative orientation of the attachment vectors of —X— and —Y— and (iii) the spatial distance between the groups —X— and —Y—.
One possible general preparative access to the corresponding building blocks of type A consists of an C sp 2 -C sp 2 -coupling between appropriately functionalized arene and/or heteroarenes (R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A. de Meijere, F. Diederich (eds), Metal - Catalyzed Cross - Coupling Reactions, 2nd ed., Wiley-VCH 2004; especially for macrocyclic biaryls cf. Q. Wang, J. Zhu, Chimia 2011, 65, 168-174, and literature cited therein). Therefore the template A can be described by its two aryl/heteroaryl constituents A B and A C , wherein A B is defined as that structural half of A that is directly connected with building block B and A C as that half that is directly bound to building block C. In case of a biphenyl derivative as Template A such disconnection can be illustrated e.g. as:
In general, Template A of this invention is a divalent radical that is defined by the combinatorial connection of its two constituent aryl/heterorayl moieties A B and A C selected from Table 1 and Table 2.
TABLE 1
Constituents A B 1-A B 65 of Template A
A B 1
A B 2
A B 3
A B 4
A B 5
A B 6
A B 7
A B 8
A B 9
A B 10
A B 11
A B 12
A B 13
A B 14
A B 15
A B 16
A B 17
A B 18
A B 19
A B 20
A B 21
A B 22
A B 23
A B 24
A B 25
A B 26
A B 27
A B 28
A B 29
A B 30
A B 31
A B 32
A B 33
A B 34
A B 35
A B 36
A B 37
A B 38
A B 39
A B 40
A B 41
A B 42
A B 43
A B 44
A B 45
A B 46
A B 47
A B 48
A B 49
A B 50
A B 51
A B 52
A B 53
A B 54
A B 55
A B 56
A B 57
A B 58
A B 59
A B 60
A B 61
A B 62
A B 63
A B 64
A B 65
TABLE 2
Constituents A C 1-A C 66 of Template A
A C 1
A C 2
A C 3
A C 4
A C 5
A C 6
A C 7
A C 8
A C 9
A C 10
A C 11
A C 12
A C 13
A C 14
A C 15
A C 16
A C 17
A C 18
A C 19
A C 20
A C 21
A C 22
A C 23
A C 24
A C 25
A C 26
A C 27
A C 28
A C 29
A C 30
A C 31
A C 32
A C 33
A C 34
A C 35
A C 36
A C 37
A C 38
A C 39
A C 40
A C 41
A C 42
A C 43
A C 44
A C 45
A C 46
A C 47
A C 48
A C 49
A C 50
A C 51
A C 52
A C 53
A C 54
A C 55
A C 56
A C 57
A C 58
A C 59
A C 60
A C 61
A C 62
A C 63
A C 64
A C 65
A C 66
The Modulator B is a divalent radical selected from the groups of Table 3. B1-B10 are optionally substituted primary or secondary amines carrying a moiety of type —CHR 5 -LG, wherein LG is a suitable leaving group that can be replaced by the nucleophilic groups on Template A forming an ether (—O—) or a thioether (—S—) linkage (as well as its oxidized variations —S(═O)— and —S(═O) 2 —) between building blocks of type A and B. Examples of appropriate LGs include —OH, which is in situ transformed into the active LG during Mitsunobu reactions, or halogens, like —Br or —I, which are amenable to S N reactions.
For most examples of this invention, the amine nitrogen of Modulator B forms a secondary or tertiary amide bond with the carboxyl group of the Bridge C. By virtue of inducing peptidyl cis-trans isomerizations or stabilizing cis amide bonds, building blocks of type B can function as conformational modulators in macrocycles of type I.
TABLE 3
Radicals B1-B10
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
The Bridge C is a divalent radical selected from the groups of Table 4. This divalent moiety C may consist of one to three (1-3) subunits c1 to c3, i.e. (i) —Z-c1-U—, (ii) —Z-c1-V-c2-U— and (iii) —X-c1-V-c2-W-c3-U—. As a consequence Bridge C directly influences the ring size of the macrocycle and can therefore be regarded as spacer or linker. This Bridge C is joined to Template A via its terminal group Z (i.e. N-terminus in case of an amino acid) and to Modulator B via its terminal group U (i.e. C-terminus in case of an amino acid) to form the macrocyclic ring of type I. Thus C contributes to the backbone of macrocycle I with its carbon chains as well as with its functional groups Z, W, V and U (cf. Scheme 2 and 3).
TABLE 4
Generic Representations of Bridge C
C1
C2
C3
According to the preceding definitions, macrocycles I contain at least one amide bond or isosteric surrogate thereof. As emphasized in the introduction, tertiary amides generally show various ratios of cis and trans conformations in solution. In striking contrast secondary amides strongly prefer trans conformations. Such occurrence of cis and/or trans conformations in macrocyclic natural products containing tertiary amide groups is well documented. In some cases a rapid equilibration by peptidyl cis-trans isomerization is observed, whereas in other cases discrete cis and trans tertiary amide bonds are detected as two stable conformers in solution at room temperature. Consequently all possible stereoisomers, explicitly including atropisomers, conformers or rotamers of macrocycles of type I are part of this invention.
The substituents attached to the Main Embodiment of macrocycle I or its constituents A, B or C, are defined as follows:
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; C 1-12 -alkoxy or aryloxy; R 5 is H; CF 3 ; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 6 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; or —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or an N-protecting group; R 8 and R 9 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 10 , R 11 and R 12 are independently defined as H; C 1-24 -alkyl; or cycloalkyl; R 13 is C 1-24 -alkyl or cycloalkyl; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 17 , R 19 , R 21 , R 23 , R 25 , R 27 , R 29 and R 31 are independently defined as H; C 1-24 -alkyl; cycloalkyl; or heterocycloalkyl; R 16 , R 22 and R 28 are independently defined as H; CF 3 ; C 1-24 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 45 ; —(CR 51 R 53 ) q SR 45 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q OCONR 7 R 45 ; —(CR 51 R 53 ) q NR 74 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 37 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 37 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) q R 44 ; R 33 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 34 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) r OR 45 ; —(CR 51 R 53 ) r NR 7 R 45 ; —(CR 51 R 53 ) r OCONR 7 R 35 ; —(CR 51 R 53 ) r NR 7 COOR 36 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) q R 44 ; R 35 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 50 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) r NR 7 SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) q CONR 7 R 50 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or an O/S-protecting group; R 37 is C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 45 ; —(CR 51 R 53 ) q SR 45 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q OCONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) t COR 44 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) t R 39 ; —(CR 51 R 53 ) u R 40 ; —(CR 51 R 53 ) t R 41 ; or —(CR 51 R 53 ) t R 44 ; R 38 is C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl; R 39 is aryl; heteroaryl; —C 6 H 2 R 3 R 4 R 46 ; or a group of one of the formulae H1-H34 listed in Table 5.
TABLE 5
Groups of Formulae H1-H34
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
H16
H17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
H30
H31
H32
H33
H34
R 40 is a group of one of formulae H35-H41 as shown in Table 6 below.
TABLE 6
Groups of Formulae H35-H41
H35
H36
H37
H38
H39
H40
H41
R 41 is a group of one of formulae H42-H50 as shown in Table 7 below.
TABLE 7
Groups of Formulae H42-H50
H42
H43
H44
H45
H46
H47
H48
H49
H50
R 42 and R 43 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; or heteroaryl-C 1-12 -alkyl;
R 44 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 below.
TABLE 8
Groups of Formulae H51-H55
H51
H52
H53
H54
H55
R 45 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 51 R 53 ) r OR 36 ; —(CR 51 R 53 ) r NR 7 R 57 ; —(CR 51 R 53 ) r OCONR 7 R 57 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 57 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 SO 2 NR 7 R 57 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; —(CR 51 R 53 ) q R 39 ; —(CR 51 R 53 ) s R 40 ; —(CR 51 R 53 ) q R 41 ; or —(CR 51 R 53 ) s R 44 ;
R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 36 ; —(CR 51 R 53 ) q SR 36 ; —(CR 51 R 53 ) q NR 7 R 57 ; —(CR 51 R 53 ) q OCONR 7 R 57 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; or —(CR 51 R 53 ) q R 44 ;
R 47 is H; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; or —NR 7 R 45 ;
R 48 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; an N-protecting group; —(CR 51 R 53 ) r OR 45 ; —(CR 51 R 53 ) r SR 45 ; —(CR 51 R 53 ) r NR 7 R 45 ; —(CR 51 R 53 ) r OCONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 COOR 36 ; —(CR 51 R 53 ) r NR 7 COR 38 ; —(CR 51 R 53 ) r NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) r NR 7 SO 2 R 38 ; —(CR 51 R 53 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) r SO 2 NR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; —(CR 51 R 53 ) q SO 2 R 38 ; or —(CR 51 R 53 ) s R 44 ;
R 49 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 51 R 53 ) q OR 36 ; —(CR 51 R 53 ) q SR 36 ; —(CR 51 R 53 ) q NR 7 R 45 ; —(CR 51 R 53 ) q NR 7 COOR 36 ; —(CR 51 R 53 ) q NR 7 COR 38 ; —(CR 51 R 53 ) q NR 7 SO 2 R 38 ; —(CR 51 R 53 ) q NR 7 CONR 7 R 45 ; —(CR 51 R 53 ) q COOR 36 ; —(CR 51 R 53 ) q CONR 7 R 45 ; —(CR 51 R 53 ) q COR 38 ; or —(CR 51 R 53 ) q R 44 ;
R 50 is H; C 1-24 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group;
R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ;
R 52 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 COOR 36 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COOR 36 ; —CONR 7 R 57 ; —C(═NR 7 )NR 7 R 57 ; —NR 7 C(═NR 7 )NR 7 R 57 ; or a group of one of the formulae H56-H110 as shown in Table 9 below.
TABLE 9
Groups of Formulae H56-H110
H56
H57
H58
H59
H60
H61
H62
H63
H64
H65
H66
H67
H68
H69
H70
H71
H72
H73
H74
H75
H76
H77
H78
H79
H80
H81
H82
H83
H84
H85
H86
H87
H88
H89
H90
H91
H92
H93
H94
H95
H96
H97
H98
H99
H100
H101
H102
H103
H104
H105
H106
H107
H108
H109
H110
R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ;
R 55 is H; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; C 2-10 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —COOR 36 ; or —CONR 7 R 45 ;
R 56 is H; F; CF 3 ; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-12 -alkyl; heteroaryl-C 1-12 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ;
R 57 is H; C 1-24 -alkyl; C 2-24 -alkenyl; cycloalkyl; aryl; aryl-C 1-12 -alkyl; or an N-protecting group.
Taken together, the following pairs of substituents can form optionally substituted cycloalkyl or heterocycloalkyl moieties: (R 5 and R 6 ); (R 7 and R 14 ); (R 7 and R 16 ); (R 7 and R 18 ); (R 7 and R 20 ); (R 7 and R 22 ); (R 7 and R 24 ); (R 7 and R 26 ); (R 7 and R 28 ); (R 7 and R 30 ); (R 7 and R 35 ); (R 7 and R 45 ); (R 7 and R 57 ); (R 13 and R 13 ); (R 14 and R 16 ); (R 14 and R 18 ); (R 15 and R 51 ); (R 19 and R 51 ); (R 20 and R 22 ); (R 20 and R 24 ); (R 26 and R 28 ); (R 26 and R 30 ); (R 32 and R 33 ); (R 42 and R 43 ); or (R 51 and R 53 ).
In addition, the structural elements —NR 7 R 35 ; or —NR 44 R 45 can form one of the groups of formulae H111-H118 as shown in Table 10 below.
TABLE 10
Heterocyclic Groups Defined by Linking the Residues
of the Disubstituted Amino Groups —NR 7 R 35 or —NR 44 R 45 .
H111
H112
H113
H114
H115
H116
H117
H118
Generic atoms and connector groups in the aforementioned structures are:
Z, Y, X, W, V, U as defined by Scheme 3; T is CR 54 or N; Q is O; S; or NR 35 ; M is O; S; or NR 7 .
The indices in the aforementioned structures are defined as:
m is an integer of 0-8; n is an integer of 0-1; p is an integer of 0-4; q is an integer of 0-4; r is an integer of 2-4; s is an integer of 1-4; t is an integer of 0-2; u is an integer of 1-2.
For the avoidance of doubt, some of the aforementioned substituents, for example, but not limited to, R 7 , R 16 , R 17 , R 18 , R 19 , R 22 , R 23 , R 24 , R 25 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 42 , R 43 , R 45 , R 46 , and R 49 ; the indices as well as the generic atoms/connector groups (Z, Y, X, W, V, U, T, Q, M) can occur several times within the same molecular entity. In such a case each of them shall be selected independently from others specified by the same symbol.
“Salts” as understood herein are especially, but not limited to, the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, for example, as acid addition salts with organic or inorganic acids, from compounds of type I with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids; like acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzene-sulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
As used in this description, the term “alkyl”, taken alone or in combinations (i.e. as part of another group, such as “aryl-C 1-6 -alkyl”), designates saturated, straight-chain or branched hydrocarbon radicals and may be optionally substituted. The term “C x-y -alkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms. For example a C 1-6 -alkyl group contains one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
The term “alkenyl”, taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties are optionally substituted and can independently exist as E or Z configurations per double bond, which are all part of the invention. The term “C x-y -alkenyl” (x and y each being an integer) refers to an alkenyl group as defined before, containing x to y carbon atoms.
The term “alkynyl” designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four triple bonds. The term “C x-y -alkynyl” (x and y each being an integer) refers to an alkynyl group as defined before, containing x to y carbon atoms.
The term “cycloalkyl” refers to a saturated or partially unsaturated alicyclic moiety having from three to ten carbon atoms and may be optionally substituted. Examples of this moiety include, but are not limited to, cyclohexyl, norbornyl, decalinyl and the like.
The term “heterocycloalkyl” describes a saturated or partially unsaturated mono- or bicyclic moiety having from two to nine ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulphur. This term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1,7-diazaspiro[4.4]nonane and the like. Said heterocycloalkyl ring(s) might be optionally substituted.
The term “aryl”, taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted by up to three substituents such as F, Cl, Br, CF 3 , OH, OCF 3 , OCHF 2 , NH 2 , N(CH 3 ) 2 , NO 2 , CN, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, phenyl or phenoxy.
The term “heteroaryl”, taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for “aryl”.
The term “aryl-C x-y -alkyl”, as used herein, refers to an C x-y -alkyl group as defined above, substituted by an aryl group, as defined above. Representative examples of aryl-C x-y -alkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
The term “heteroaryl-C x-y -alkyl”, as used herein, refers to an C x-y -alkyl group as defined above, substituted by a heteroaryl group, as defined above. Examples of heteroaryl-C x-y -alkyl groups include pyridin-3-ylmethyl, (1H-pyrrol-2-yl)ethyl and the like.
The terms “alkoxy” and “aryloxy”, taken alone or in combinations, refer to the groups of —O-alkyl and —O-aryl respectively, wherein an alkyl group or an aryl group is as defined above. The term “C x-y -alkoxy” (x and y each being an integer) refers to an —O-alkyl group as defined before containing x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy and the like. Examples of aryloxy include e.g. phenoxy.
“Amino” designates primary, secondary or tertiary amines. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, arylalkyl-amines and diarylamines wherein the alkyl or aryl is as herein defined and optionally substituted.
The term “N-protecting group”, as use herein, refers to the following commonly known groups, suitable to protect a nitrogen atom: allyloxycarbonyl (Alloc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), 2- or 4-nitrobenzenesulfonyl (Ns), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-Trichloro-ethoxycarbonyl (Troc), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), triphenylmethyl (trityl, Tr), or 2-chlorotrityl (CTC).
The term “O/S-protecting group”, as use herein, refers to the following commonly known groups, suitable to protect either an oxygen and/or a sulfur atom: tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), tert-butyl, 2-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM), triphenylmethyl (trityl, Tr), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), or 2-(Trimethylsilyl)ethyl (TMSE).
A person skilled in the art might find easily corresponding equivalents for the above mentioned protecting groups which are considered to be as well comprised by the gist of the current invention. Examples of suitable protecting groups are as detailed in P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006.
The term “optionally substituted” is in general intended to mean that a group, such as, but not limited to C x-y -alkyl, C x-y -alkenyl, C x-y -alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C x-y -alkoxy and aryloxy may be substituted with one or more substituents independently selected from amino (—NH 2 ), dimethylamino, nitro (—NO 2 ), halogen (F, Cl, Br, I), CF 3 , cyano (—CN), hydroxy, methoxy, ethoxy, phenyloxy, benzyloxy, acetoxy, oxo (═O), carboxy, carboxamide, methyl, ethyl, n-propyl, iso-propyl, cyclo-propyl, phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate, or
—SR a , —S(O)R a , —S(O) 2 R a , —R a , —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(═NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R b , —NR a S(O) 2 R b , wherein R a , R b , R c , and R d are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl as described herein; or R b and R c may be taken together with the N-atom to which they are attached forming heterocycloalkyl or heteroaryl. These groups in turn can be substituted with one or more moieties selected from the group consisting of halogen (F, Cl, Br, or I), hydroxyl, amino, mono-, di- or tri-C 1-6 -alkylamino, mono-, di- or tri-arylamino, hydroxy, carboxy, C 1-6 -alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
As used herein, all groups that can be substituted in one embodiment are indicated to be “optionally substituted”, unless otherwise specified.
The embodiments of the present invention shall include so-called “prodrugs” of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds, which in vivo are readily convertible into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Hans Bundgaard, Design of Prodrugs , Elsevier, 1985; and in Valentino J. Stella et al., Prodrugs: Challenges and Rewards , Springer, 1st ed., 2007.
The term “isomer” comprises species of identical chemical formula, constitution and thus molecular mass, such as but not limited to C═C-double bond or amide cis/trans isomers, rotamers, conformers and diastereomers.
All possible stereoisomers—explicitly including atropisomers—conformers and rotamers as well as salts, solvates, clathrates, N-oxides, or isotopically enriched or enantiomerically enriched versions of the macrocycles of type I are part of this invention.
In a Preferred Embodiment of this invention, macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 . The connectivities between the building blocks of the preferred embodiment are defined as shown in Scheme 5.
The biaryl Template A of the Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 2; A B 1-A C 3; A B 1-A C 4; A B 1-A C 5; A B 1-A C 6; A B 1-A C 8; A B 1-A C 9; A B 1-A C 11; A B 1-A C 12; A B 1-A C 13; A B 1-A C 19; A B 1-A C 22; A B 1-A C 24; A B 1-A C 49; A B 1-A C 51; A B 2-A C 1; A B 2-A C 2; A B 2-A C 3; A B 2-A C 4; A B 2-A C 5; A B 2-A C 11; A B 2-A C 12; A B 2-A C 51; A B 3-A C 1; A B 3-A C 2; A B 3-A C 3; A B 3-A C 4; A B 3-A C 5; A B 3-A C 11; A B 3-A C 12; A B 4-A C 1; A B 4-A C 2; A B 4-A C 3; A B 4-A C 4; A B 4-A C 5; A B 4-A C 6; A B 4-A C 11; A B 4-A C 12; A B 4-A C 19; A B 4-A C 22; A B 4-A C 24; A B 4-A C 49; A B 4-A C 51; A B 4-A C 59; A B 5-A C 1; A B 5-A C 2; A B 5-A C 3; A B 5-A C 4; A B 5-A C 5; A B 5-A C 11; A B 5-A C 12; A B 5-A C 51; A B 5-A C 59; A B 6-A C 1; A B 6-A C 4; A B 6-A C 8; A B 6-A C 9; A B 6-A C 11; A B 6-A C 13; A B 6-A C 16; A B 6-A C 18; A B 6-A C 19; A B 6-A C 20; A B 6-A C 30; A B 6-A C 31; A B 6-A C 49; A B 6-A C 51; A B 9-A C 6; A B 9-A C 49; A B 10-A C 6; A B 11-A C 6; A B 12-A C 2; A B 12-A C 5; A B 12-A C 11; A B 12-A C 12; A B 13-A C 2; A B 13-A C 5; A B 13-A C 11; A B 13-A C 12; A B 13-A C 5; A B 13-A C 11; A B 13-A C 12; A B 14-A C 49; A B 20-A C 2; A B 20-A C 6; A B 20-A C 49; A B 23-A C 4; A B 23-A C 49; A B 26-A C 2; A B 26-A C 5; A B 26-A C 11; A B 26-A C 12; A B 40-A C 2; A B 40-A C 5; A B 40-A C 11; A B 40-A C 12; A B 45-A C 49; A B 45-A C 52; A B 45-A C 57; A B 45-A C 58; A B 45-A C 65; A B 45-A C 66; A B 46-A C 57; A B 46-A C 58; A B 47-A C 58; A B 49-A C 49; A B 50-A C 57; A B 50-A C 58; A B 50-A C 61; A B 51-A C 49; A B 51-A C 61; A B 53-A C 2; A B 53-A C 5; A B 53-A C 11; A B 53-A C 12; A B 58-A C 2; A B 58-A C 5; A B 58-A C 11; A B 58-A C 12; A B 59-A C 2; A B 59-A C 5; A B 59-A C 11; A B 59-A C 12; or A B 59-A C 61.
The preferred Modulator B is selected from
B1; B4; B5; B6; B7; B8; B9 or B10;
and the preferred Bridge C from
C1; C2; or C3.
The substituents R 1 -R 57 attached to the Preferred Embodiment of macrocycle I are as defined as shown below.
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; cycloalkyl; C 1-6 -alkoxy or aryloxy; R 5 is H; CF 3 ; C 1-6 -alkyl; or cycloalkyl; R 6 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 8 and R 9 are independently defined as H; CF 3 ; C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; R 10 , R 11 and R 12 are independently defined as H; C 1-6 -alkyl; or cycloalkyl; R 13 is C 1-6 -alkyl; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 17 , R 19 , R 21 , R 23 , R 25 , R 27 , R 29 and R 31 are independently defined as H; or C 1-6 -alkyl; R 16 , R 22 and R 28 are independently defined as H; CF 3 ; or C 1-6 -alkyl; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q NR 7 SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 45 ; —(CR 42 R 51 ) q SR 45 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) q OCONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) q R 44 ; R 33 is H; or C 1-6 -alkyl; R 34 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) r OR 45 ; —(CR 42 R 51 ) r NR 7 R 45 ; —(CR 42 R 51 ) r OCONR 7 R 35 ; —(CR 42 R 51 ) r NR 7 COOR 36 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) q R 44 ; R 35 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 45 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q SO 2 R 38 ; —(CR 32 R 33 ) q SO 2 NR 7 R 50 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-6 -alkyl; cycloalkyl; aryl; aryl-C 1 -alkyl; or an O/S-protecting group; R 37 is C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 45 ; —(CR 42 R 51 ) q SR 45 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) s OCONR 7 R 45 ; —(CR 42 R 51 ) s NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 44 ; —(CR 42 R 51 ) s NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) s NR 7 SO 2 R 38 ; —(CR 42 R 51 ) s R 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) t COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; —(CR 42 R 51 ) t R 39 ; —(CR 42 R 51 ) u R 40 ; —(CR 42 R 51 ) t R 41 ; or —(CR 42 R 51 ) t R 44 ; R 38 is C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; or heteroaryl-C 1-6 -alkyl; R 42 and R 43 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; or heteroaryl-C 1-6 -alkyl; R 44 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 above. R 45 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 51 ) r OR 36 ; —(CR 42 R 51 ) r NR 7 R 57 ; —(CR 42 R 51 ) r OCONR 7 R 57 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 57 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) r NR 7 SO 2 NR 7 R 57 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 33 ; —(CR 42 R 51 ) q R 39 ; —(CR 42 R 51 ) s R 40 ; —(CR 42 R 51 ) q R 41 ; or —(CR 42 R 51 ) s R 44 ; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 36 ; —(CR 42 R 51 ) q SR 36 ; —(CR 42 R 51 ) q NR 7 R 57 ; —(CR 42 R 51 ) q OCONR 7 R 57 ; —(CR 42 R 51 ) q NR 44 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; or —(CR 42 R 51 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 ; R 48 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 51 ) r OR 45 ; —(CR 42 R 51 ) r SR 45 ; —(CR 42 R 51 ) r NR 7 R 45 ; —(CR 42 R 51 ) r OCONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 COOR 36 ; —(CR 42 R 51 ) r NR 7 COR 38 ; —(CR 42 R 51 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) r NR 7 SO 2 R 38 ; —(CR 42 R 51 ) r NR 7 SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) r SO 2 NR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; —(CR 42 R 51 ) q SO 2 R 38 ; or —(CR 42 R 51 ) s R 44 ; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 51 ) q OR 36 ; —(CR 42 R 51 ) q SR 36 ; —(CR 42 R 51 ) q NR 7 R 45 ; —(CR 42 R 51 ) q NR 7 COOR 36 ; —(CR 42 R 51 ) q NR 7 COR 38 ; —(CR 42 R 51 ) q NR 7 SO 2 R 38 ; —(CR 42 R 51 ) q NR 7 CONR 7 R 45 ; —(CR 42 R 51 ) q COOR 36 ; —(CR 42 R 51 ) q CONR 7 R 45 ; —(CR 42 R 51 ) q COR 38 ; or —(CR 42 R 51 ) q R 44 ; R 50 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 COOR 36 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COOR 36 ; —CONR 7 R 57 ; —C(═NR 7 )NR 7 R 57 ; —NR 7 C(═NR 7 )NR 7 R 57 ; or a group of one of the formulae H56-H110 as shown in Table 9 above. R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl-C 1-6 -alkyl; or an N-protecting group.
Defined as for the Main Embodiment (vide supra) are i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) pairs of substituents that can be define additional cyclic structural elements.
In a Further Preferred Embodiment of this invention, the macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Further Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 4; A B 1-A C 6; A B 1-A C 8; A B 1-A C 9; A B 1-A C 11; A B 1-A C 13; A B 1-A C 19; A B 1-A C 22; A B 1-A C 24; A B 1-A C 49; A B 1-A C 51; A B 2-A C 4; A B 2-A C 51; A B 4-A C 1; A B 4-A C 4; A B 4-A C 6; A B 4-A C 19; A B 4-A C 22; A B 4-A C 24; A B 4-A C 49; A B 4-A C 51; A B 4-A C 59; A B 5-A C 51; A B 5-A C 59; A B 6-A C 1; A B 6-A C 4; A B 6-A C 8; A B 6-A C 9; A B 6-A C 11; A B 6-A C 13; A B 6-A C 16; A B 6-A C 18; A B 6-A C 19; A B 6-A C 20; A B 6-A C 30; A B 6-A C 31; A B 6-A C 49; A B 6-A C 51; A B 9-A C 6; A B 9-A C 49; A B 14-A C 49; A B 20-A C 6; A B 20-A C 49; A B 23-A C 4; A B 23-A C 49; A B 45-A C 49; A B 45-A C 52; A B 45-A C 57; A B 45-A C 58; A B 45-A C 65; A B 45-A C 66; A B 46-A C 57; A B 46-A C 58; A B 49-A C 49; A B 50-A C 57; A B 50-A C 58; A B 50-A C 61; A B 51-A C 49; A B 51-A C 61; or A B 59-A C 61.
The further preferred Modulator B is selected from
B1; B4; B5; B6; or B7;
and the further preferred Bridge of type C from
C1; C2; or C3.
The substituents R 1 -R 57 attached to the Further Preferred Embodiment of macrocycle I are as defined as described below.
R 1 and R 2 are independently defined as H; F; Cl; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) q R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 . R 3 and R 4 are independently defined as H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; or C 1-6 -alkoxy; R 5 is H; CF 3 ; or C 1-6 -alkyl; R 6 is H; C 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(R 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(R 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are defined as in the Preferred Embodiment; R 14 , R 20 and R 26 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q SR 34 ; —(CR 32 R 33 ) q NR 7 R 35 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q SO 2 NR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 15 , R 16 , R 17 , R 19 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 and R 31 are defined as in the Preferred Embodiment; R 18 , R 24 and R 30 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 32 R 33 ) q OR 34 ; —(CR 32 R 33 ) q NR 7 R 37 ; —(CR 32 R 33 ) q OCONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 COOR 36 ; —(CR 32 R 33 ) q NR 7 COR 37 ; —(CR 32 R 33 ) q NR 7 CONR 7 R 35 ; —(CR 32 R 33 ) q NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 35 ; —(CR 32 R 33 ) q COR 37 ; or —(CR 32 R 33 ) q R 44 ; R 32 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 45 ; —(CR 42 R 43 ) q SR 45 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 ) q NR 7 COOR 36 ; —(CR 42 R 43 ) q NR 7 COR 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 )COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) q R 44 ; R 33 is H; or C 1-6 -alkyl; R 34 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; —(CR 42 R 43 ) r OR 45 ; —(CR 42 R 43 ) r NR 7 R 45 ; —(CR 42 R 43 ) r OCONR 7 R 35 ; —(CR 42 R 43 ) r NR 7 COOR 36 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) q R 44 ; R 35 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 32 R 33 ) r OR 45 ; —(CR 32 R 33 ) r NR 7 R 45 ; —(CR 32 R 33 ) r OCONR 7 R 45 ; —(CR 32 R 33 ) r NR 7 COOR 36 ; —(CR 32 R 33 ) r NR 7 COR 37 ; —(CR 32 R 33 ) r NR 7 CONR 7 R 50 ; —(CR 32 R 33 ) r NR 7 SO 2 R 38 ; —(CR 32 R 33 ) q COOR 36 ; —(CR 32 R 33 ) q CONR 7 R 45 ; —(CR 32 R 33 ) q COR 38 ; —(CR 32 R 33 ) q R 39 ; —(CR 32 R 33 ) s R 40 ; —(CR 32 R 33 ) q R 41 ; or —(CR 32 R 33 ) q R 44 ; R 36 is H; C 1-6 -alkyl; cycloalkyl; aryl; aryl-C 1-6 -alkyl; or an O/S-protecting group; R 37 is C 1-6 -alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 45 ; —(CR 42 R 43 ) q SR 45 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 ) s OCONR 7 R 45 ; —(CR 42 R 43 ) s NR 7 COOR 36 ; —(CR 42 R 43 ) s NR 7 COR 44 ; —(CR 42 R 43 ) s NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) s NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 )CONR 7 R 45 ; —(CR 42 R 43 ) t COR 38 ; —(CR 42 R 43 ) t R 39 ; —(CR 42 R 43 ) u R 40 ; —(CR 42 R 43 ) t R 41 ; or —(CR 42 R 43 ) t R 44 ; R 38 , R 42 , R 43 and R 44 are defined as in the Preferred Embodiment; R 39 , R 40 , and R 41 are as defined in the Main Embodiment; R 45 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 43 ) r OR 36 ; —(CR 42 R 43 ) r NR 7 R 57 ; —(CR 42 R 43 ) r OCONR 7 R 57 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 57 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q COR 38 ; —(CR 42 R 43 ) q R 39 ; —(CR 42 R 43 ) s R 40 ; —(CR 42 R 43 ) q R 41 ; or —(CR 42 R 43 ) s R 44 ; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 36 ; —(CR 42 R 43 ) q NR 7 R 57 ; —(CR 42 R 43 ) q NR 7 COR 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q SO 2 NR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 . R 48 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; an N-protecting group; —(CR 42 R 43 ) r OR 45 ; —(CR 42 R 43 ) r SR 45 ; —(CR 42 R 43 ) r NR 7 R 45 ; —(CR 42 R 43 ) r OCONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 COOR 36 ; —(CR 42 R 43 ) r NR 7 COR 38 ; —(CR 42 R 43 ) r NR 7 CONR 7 R 45 ; —(CR 42 R 43 ) r NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) s R 44 ; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) q OR 36 ; —(CR 42 R 43 ) q NR 7 R 45 ; —(CR 42 R 43 )NR 7 COR 38 ; —(CR 42 R 43 ) q NR 7 SO 2 R 38 ; —(CR 42 R 43 ) q COOR 36 ; —(CR 42 R 43 ) q CONR 7 R 45 ; —(CR 42 R 43 ) q COR 38 ; or —(CR 42 R 43 ) q R 44 ; R 50 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or an N-protecting group; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is defined as in the Preferred Embodiment; R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is defined as in the Preferred Embodiment;
as are (vide supra) i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In a Particularly Preferred Embodiment of this invention, the macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R 1 -R 57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Particularly Preferred Embodiment is selected from
A B 1-A C 1; A B 1-A C 4; A B 1-A C 19; A B 2-A C 4; A B 4-A C 1; A B 4-A C 4; A B 4-A C 19; A B 4-A C 59; A B 5-A C 51; A B 5-A C 59; A B 6-A C 31; A B 9-A C 6; or A B 46-A C 58.
The particularly preferred Modulator building block of type B and the Bridge of type C are selected as described in the Further Preferred Embodiment.
The substituents R 1 -R 57 attached to the Particularly Preferred Embodiment of macrocycle I are as defined as described below.
R 1 and R 2 are defined as in the Further Preferred Embodiment; R 3 and R 4 are independently defined as H; F; CF 3 ; OCF 3 ; OCHF 2 ; CN; or C 1-6 -alkoxy; R 5 is H; CF 3 ; or C 1-6 -alkyl; R 6 is defined as in the Further Preferred Embodiment; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are defined as in the Preferred Embodiment; R 14 , R 20 and R 26 are defined as in the Further Preferred Embodiment; R 15 , R 16 , R 17 , R 19 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 and R 31 are defined as in the Preferred Embodiment, R 18 , R 24 , R 30 and R 32 are defined as in the Further Preferred Embodiment; R 33 is H; or C 1-6 -alkyl; R 34 , R 35 , R 36 and R 37 are defined as in the Further Preferred Embodiment; R 38 , R 42 , R 43 and R 44 are defined as in the Preferred Embodiment; R 39 , R 40 , and R 41 are as defined in the Main Embodiment; R 45 is defined as in the Further Preferred Embodiment; R 46 is H; F; Cl; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —(CR 42 R 43 ) q R 44 ; R 47 is H; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —NR 7 R 45 ; R 48 is defined as in the Further Preferred Embodiment; R 49 is H; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; or —(CR 42 R 43 ) q R 44 ; R 50 is defined as in the Further Preferred Embodiment; R 51 and R 53 are independently defined as H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) t OR 36 ; —(CR 42 R 43 ) t NR 7 R 57 ; —(CR 42 R 43 ) t COOR 36 ; or —(CR 42 R 43 ) t CONR 7 R 57 ; R 52 is defined as in the Preferred Embodiment; R 54 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; NO 2 ; CN; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —OR 36 ; —NR 7 R 57 ; —NR 7 COR 38 ; —NR 7 SO 2 R 38 ; —NR 7 CONR 7 R 57 ; —COR 38 ; or —SO 2 R 38 ; R 55 is H; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —COOR 36 ; or —CONR 7 R 45 ; R 56 is H; F; CF 3 ; C 1-6 -alkyl; C 2-6 -alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CR 42 R 43 ) s OR 36 ; —(CR 42 R 43 ) s NR 7 R 45 ; —(CR 42 R 43 ) q COOR 36 ; or —(CR 42 R 43 ) q CONR 7 R 45 ; R 57 is defined as in the Preferred Embodiment; as are (vide supra) i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In an Specific Representation of the Particularly Preferred Embodiment
the Bridge C is represented by
wherein
C AA is an amino acid selected from the readily accessible amino acids listed in Table 11. Even though only one stereoisomer, usually the L-enantiomer, is cited within Table 11, it is understood that the complementary enantiomer is also part to the embodiment. Also not listed explicitly, but part of the embodiment are the simple N-methyl derivatives of the listed amino acids.
TABLE 11
Structures representing subunits C AA of Bridge C (continued on the following pages)
Code
Chemical Name
Ala
L-Alanine
Arg
L-Arginine
Asn
L-Asparagine
Asp
L-Aspartic acid
Cys
L-Cysteine
Glu
L-Glutamic acid
Gln
L-Glutamine
Gly
Glycine
His
L-Histidine
Ile
L-Isoleucine
Leu
L-Leucine
Lys
L-Lysine
Met
L-Methionine
Phe
L-Phenylalanine
Pro
L-Proline
Ser
L-Serine
Thr
L-Threonine
Trp
L-Tryptophan
Tyr
L-Tyrosine
Val
L-Valine
Apa
3-Amino-propanoic acid
H-β 3 -HAla-OH
(3S)-3-Amino-butyric acid
H-β 3 -HVal-OH
(3R)-3-Amino-4-methyl-valeric acid
H-β 3 -HIle-OH
(3R,4S)-3-Amino-4-methyl-hexanoic acid
H-β 3 -HLeu-OH
(3S)-3-Amino-5-methyl-hexanoic acid
H-β 3 -HMet-OH
(3S)-3-Amino-5-methylthio pentanoic acid
H-β 3 -HTyr-OH
(3S)-3-Amino-4-(4′-hydroxyphenyl)-butyric acid
H-β 3 -HHis-OH
(3S)-3-Amino-4-(imidazole-4′-yl)-butyric acid
H-β 3 -HPhe-OH
(3S)-3-Amino-4-phenyl butyric acid
H-β 3 -HTrp-OH
(3S)-3-Amino-4-(indol-3′-yl)-butyric acid
H-β 3 -HSer-OH
(3R)-3-Amino-4-hydroxy-butyric acid
H-β 3 -HAsp-OH
3-Amino-pentanedioic acid
H-β 3 -HGlu-OH
(3S)-3-Amino-hexanedioic acid
H-β 3 -HLys-OH
(3S)-3,7-Diamino-heptanoic acid
H-β 3 -HArg-OH
(3S)-3-Amino-6-guanidino-hexanoic-acid
H-β 3 -HCys-OH
(3R)-3-Amino-4-mercapto-butyric acid
H-β 3 -HAsn-OH
(3S)-3-Amino-4-carbamoyl-butyric acid
H-β 3 -HGln-OH
(3S)-3-Amino-5-carbamoyl-pentanoic acid
H-β 3 -HThr-OH
(3R,4R)-3-Amino-4-hydroxy-pentanoic acid
Gaba
4-Amino-butyric acid
H-γ 4 -DiHAla-OH
(4S)-4-Amino-pentanoic acid
H-γ 4 -DiHVal-OH
(4R)-4-Amino-5-methyl-hexanoic acid
H-γ 4 -DiHIle-OH
(4R,5S)-4-Amino-5-methyl-heptanoic acid
H-γ 4 -DiHLeu-OH
(4R)-4-Amino-6-methyl-heptanoic acid
H-γ 4 -DiHMet-OH
(4R)-4-Amino-6-methylthio-hexanoic acid
H-γ 4 -DiHTyr-OH
(4R)-4-Amino-5-(4′-hydroxyphenyl)-pentanoic acid
H-γ 4 -DiHHis-OH
(4R)-4-Amino-5-(imidazole-4′-yl)-pentanoic acid
H-γ 4 -DiHPhe-OH
(4R)-4-Amino-5-phenyl-pentanoic acid
H-γ 4 -DiHTrp-OH
(4R)-4-Amino-5-(indol-3′-yl)-pentanoic acid
H-γ 4 -DiHSer-OH
(4R)-4-Amino-5-hydroxy-pentanoic acid
H-γ 4 -DiHAsp-OH
(4R)-4-Amino-hexanedioic acid
H-γ 4 -DiHGlu-OH
4-Amino-heptanedioic acid
H-γ 4 -DiHLys-OH
(4S)-4,8-Diamino-octanoic acid
H-γ 4 -DiHArg-OH
(4S)-4-Amino-7-guanidino-heptanoic-acid
H-γ 4 -DiHCys-OH
(4R)-4-Amino-5-mercapto-pentanoic acid
H-γ 4 -DiHAsn-OH
(4R)-4-Amino-5-carbamoyl-pentanoic acid
H-γ 4 -DiHGln-OH
(3S)-3-Amino-5-carbamoyl-hexanoic acid
H-γ 4 -DiHThr-OH
(4R,5R)-4-Amino-5-hydroxy-hexanoic acid
Cit
L-Citrulline
Orn
L-Ornithine
tBuA
L-t-Butylalanine
Sar
Sarcosine
Pen
L-Penicillamine
tBuG
L-tert-Butylglycine
4AmPhe
L-para-Aminophenylalanine
3AmPhe
L-meta-Aminophenylalanine
2AmPhe
L-ortho-Aminophenylalanine
Phe(mC(NH 2 )═NH)
L-meta-Amidinophenylalanine
Phe(pC(NH 2 )═NH)
L-para-Amidinophenylalanine
Phe(mNHC(NH 2 )═NH)
L-meta-Guanidinophenylalanine
Phe(pNHC(NH 2 )═NH)
L-para-Guanidinophenylalanine
2Pal
(2S)-2-Amino-3-(pyridine-2′-yl)-propionic acid
4Pal
(2S)-2-Amino-3-(pyridine-4′-yl)-propionic acid
Phg
L-Phenylglycine
Cha
L-Cyclohexylalanine
C 4 al
L-3-Cyclobutylalanine
C 5 al
L-3-Cyclopentylalanine
Nle
L-Norleucine
2-Nal
L-2-Naphthylalanine
1-Nal
L-1-Naphthylalanine
4ClPhe
L-4-Chlorophenylalanine
3ClPhe
L-3-Chlorophenylalanine
2ClPhe
L-2-Chlorophenylalanine
3,4Cl 2 Phe
L-3,4-Dichlorophenylalanine
4FPhe
L-4-Fluorophenylalanine
3FPhe
L-3-Fluorophenylalanine
2FPhe
L-2-Fluorophenylalanine
Thi
L-β-2-Thienylalanine
Tza
L-2-Thiazolylalanine
Mso
L-Methionine sulfoxide
AcLys
N-Acetyllysine
Dap
2,3-Diaminopropionic acid
Dab
2,4-Diaminobutyric acid
Dbu
(2S)-2,3-Diamino-butyric acid
Abu
γ-Aminobutyric acid (GABA)
Aha
ε-Aminohexanoic acid
Aib
α-Aminoisobutyric acid
ACC
1-Amino cyclopropane carboxylic acid
ACBC
1-Amino cyclobutane carboxylic acid
ACPC
1-Amino cyclopentane carboxylic acid
1-ACHC
1-Amino cyclohexane carboxylic acid
2-ACHC
2-Amino cyclohexane carboxylic acid
3-ACHC
3-Amino cyclohexane carboxylic acid
4-ACHC
4-Amino cyclohexane carboxylic acid
Y(Bzl)
L-O-Benzyltyrosine
H(Bzl)
(3S)-2-Amino-3-(1′-benzylimidazole-4′-yl)-propionic acid
Bip
L-(4-phenyl)phenylalanine
S(Bzl)
L-O-Benzylserine
T(Bzl)
L-O-Benzylthreonine
alloT
(2S,3S)-2-Amino-3-hydroxy-butyric acid
Leu3OH
(2S,3R)-2-Amino-3-hydroxy-4-methyl-pentanoic acid
hAla
L-Homo-alanine
hArg
L-Homo-arginine
hCys
L-Homo-cysteine
hGlu
L-Homo-glutamic acid
hGln
L-Homo-glutamine
hHis
L-Homo-histidine
hIle
L-Homo-isoleucine
hLeu
L-Homo-leucine
hNle
L-Homo-norleucine
hLys
L-Homo-lysine
hMet
L-Homo-Methionine
hPhe
L-Homo-phenylalanine
hSer
L-Homo-serine
hThr
L-Homo-threonine
hTrp
L-Homo-tryptophan
hTyr
L-Homo-tyrosine
hVal
L-Homo-valine
hCha
L-Homo-cyclohexylalanine
Bpa
L-4-Benzoylphenylalanine
OctG
L-Octylglycine
Tic
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid
Tiq
(1S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid
Oic
(2S,3aS,7aS)-1-Octahydro-1H-indole-2-carboxylic acid
4AmPyrr1
(2S,4S)-4-Amino-pyrrolidine-2-carboxylic acid
4AmPyrr2
(2S,4R)-4-Amino-pyrrolidine-2-carboxylic acid
4PhePyrr1
(2S,4R)-4-Phenyl-pyrrolidine-2-carboxylic acid
4PhePyrr2
(2S,4S)-4-Phenyl-pyrrolidine-2-carboxylic acid
5PhePyrr1
(2S,5R)-5-Phenyl-pyrrolidine-2-carboxylic acid
5PhePyrr2
(2S,5S)-5-Phenyl-pyrrolidine-2-carboxylic acid
4Hyp1
(4S)-L-Hydroxyproline
4Hyp2
(4R)-L-Hydroxyproline
4Mp1
(4S)-L-Mercaptoproline
4Mp2
(4R)-L-Mercaptoproline
Pip
L-Pipecolic acid
H-β 3 -HCit-OH
(3S)-3-Amino-6-carbamidyl-hexanoic acid
H-β 3 -HOrn-OH
(3S)-3,6-Diamino-hexanoic acid
H-β 3 -HtBuA-OH
(3S)-3-Amino-5,5-dimethyl-hexanoic acid
H-β 3 -HSar-OH
N-Methyl-3-amino-propionic acid
H-β 3 -HPen-OH
(3R)-3-Amino-4-methyl-4-mercapto-pentanoic acid
H-β 3 -HtBuG-OH
(3R)-3-Amino-4,4-dimethyl-pentanoic acid
H-β 3 -H4AmPhe-OH
(3S)-3-Amino-4-(4′-aminophenyl)-butyric acid
H-β 3 -H3AmPhe-OH
(3S)-3-Amino-4-(3′-aminophenyl)-butyric acid
H-β 3 -H2AmPhe-OH
(3S)-3-Amino-4-(2′-aminophenyl)-butyric acid
H-β 3 -HPhe(mC(NH 2 )═NH)—
(3S)-3-Amino-4-(3′-amidinophenyl)-butyric acid
OH
H-β 3 -HPhe(pC(NH 2 )═NH)—
(3S)-3-Amino-4-(4′-amidinophenyl)-butyric acid
OH
H-β 3 -HPhe(mNHC(NH 2 )═
(3S)-3-Amino-4-(3′-guanidinophenyl)-butyric acid
NH)—OH
H-β 3 -HPhe(pNHC(NH 2 )═
(3S)-3-Amino-4-(4′-guanidino-phenyl)-butyric acid
NH)—OH
H-β 3 -H2Pal-OH
(3S)-3-Amino-4-(pyridine-2′-yl)-butyric acid
H-β 3 -H4Pal-OH
(3S)-3-Amino-4-(pyridine-4′-yl)-butyric acid
H-β 3 -HPhg-OH
(3R)-3-Amino-3-phenyl-propionic acid
H-β 3 -HCha-OH
(3S)-3-Amino-4-cyclohexyl-butyric acid
H-β 3 -HC 4 al-OH
(3S)-3-Amino-4-cyclobutyl-butyric acid
H-β 3 -HC 5 al-OH
(3S)-3-Amino-4-cyclopentyl-butyric acid
H-β 3 -HNle-OH
(3S)-3-Amino-heptanoic acid
H-β 3 -H2Nal-OH
(3S)-3-Amino-4-(2′-naphthyl)-butyric acid
H-β 3 -H1Nal-OH
(3S)-3-Amino-4-(1′-naphthyl)-butyric acid
H-β 3 -H4ClPhe-OH
(3S)-3-Amino-4-(4′-chlorophenyl)-butyric acid
H-β 3 -H3ClPhe-OH
(3S)-3-Amino-4-(3′-chlorophenyl)-butyric acid
H-β 3 -H2ClPhe-OH
(3S)-3-Amino-4-(2′-chlorophenyl)-butyric acid
H-β 3 -H3,4Cl 2 Phe-OH
(3S)-3-Amino-4-(3′,4′-dichlorophenyl)-butyric acid
H-β 3 -H4FPhe-OH
(3S)-3-Amino-4-(4′-fluorophenyl)-butyric acid
H-β 3 -H3FPhe-OH
(3S)-3-Amino-4-(3′-fluorophenyl)-butyric acid
H-β 3 -H2FPhe-OH
(3S)-3-Amino-4-(2′-fluorophenyl)-butyric acid
H-β 3 -HThi-OH
(3R)-3-Amino-4-(2′-thienyl)-butyric acid
H-β 3 -HTza-OH
(3R)-3-Amino-4-(2′-thiazolyl)-butyric acid
H-β 3 -HMso-OH
(3R)-3-Amino-4-methylsulfoxyl-butyric acid
H-β 3 -HAcLys-OH
(3S)-7-Acetylamino-3-amino-heptanoic acid
H-β 3 -HDpr-OH
(3R)-3,4-diamino-butyric acid
H-β 3 -HA 2 Bu—OH
(3S)-3,5-Diamino-pentanoic acid
H-β 3 -HDbu-OH
(3R)-3,4-Diamino-pentanoic acid
H-β 3 -HAib-OH
Amino-dimethyl acetic acid
H-β 3 -HCyp-OH
1-Amino-cyclopentane-1-yl-acetic acid
H-β 3 -HY(Bzl)-OH
(3S)-3-Amino-4-(4′-benzyloxyphenyl)-butyric acid
H-β 3 -HH(Bzl)-OH
(3S)-3-Amino-4-(1′-benzylimidazole-4′-yl)-butyric acid
H-β 3 -HBip-OH
(3S)-3-Amino-4-biphenylyl-butyric acid
H-β 3 -HS(Bzl)-OH
(3S)-3-Amino-4-(benzyloxy)-butyric acid
H-β 3 -HT(Bzl)-OH
(3R,4R)-3-Amino-4-benzyloxy-pentanoic acid
H-β 3 -HalloT-OH
(3R,4S)-3-Amino-4-hydroxy-pentanoic acid
H-β 3 -HLeu3OH—OH
(3R,4R)-3-Amino-4-hydroxy-5-methyl-hexanoic acid
H-β 3 -HhAla-OH
(3S)-3-Amino-pentanoic acid
H-β 3 -HhArg-OH
(3S)-3-Amino-7-guanidino-heptanoic acid
H-β 3 -HhCys-OH
(3R)-Amino-5-mercapto-pentanoic acid
H-β 3 -HhGlu-OH
(3S)-3-Amino-heptanedioic acid
H-β 3 -HhGln-OH
(3S)-3-Amino-6-carbamoyl hexanoic acid
H-β 3 -HhHis-OH
(3S)-3-Amino-5-(imidazole-4′-yl)-pentanoic acid
H-β 3 -HhIle-OH
(3S,5S)-3-Amino-5-methyl-heptanoic acid
H-β 3 -HhLeu-OH
(3S)-3-Amino-6-methyl-heptanoic acid
H-β 3 -HhNle-OH
(3S)-3-Amino-octanoic acid
H-β 3 -DiAoc-OH
(3S)-3,8-Diamino-octanoic acid
H-β 3 -HhMet-OH
(3S)-3-Amino-6-methylthio-hexanoic acid
H-β 3 -HhPe-OH
(3S)-3-Amino-5-phenyl-pentanoic acid
H-β 3 -HhSer-OH
(3S)-3-Amino-5-hydroxy-pentanoic acid
H-β 3 -HhThr-OH
(3S,5R)-3-Amino-5-hydroxy-hexanoic acid
H-β 3 -HhTrp-OH
(3S)-3-Amino-5-(indol-3′-yl)-pentanoic acid
H-β 3 -HhThr-OH
(3S)-3-Amino-5-(4′-hydroxyphenyl)-pentanoic acid
H-β 3 -HhCha-OH
(3S)-3-Amino-5-cyclohexyl-pentanoic acid
H-β 3 -HBpa-OH
(3S)-3-Amino-4-(4′-benzoylphenyl)-butyric acid
H-β 3 -HOctG-OH
(3S)-3-Amino-undecanoic acid
H-β 3 -HNle-OH
(3S)-3-Amino-heptanoic acid
H-β 3 -HTic-OH
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-yl-acetic acid
H-β 3 -HTiq-OH
(1S)-1,2,3,4-Tetrahydroisoquinoline-1-acetic acid
H-β 3 -HOic-OH
(2S,3aS,7aS)-1-Octahydro-1H-indole-2-yl-acetic acid
H-β 3 -H4AmPyrr1-OH
(2S,4S)-4-Amino-pyrrolidine-2-acetic acid
H-β 3 -H4AmPyrr2-OH
(2S,4R)-4-Amino-pyrrolidine-2-acetic acid
H-β 3 -H4PhePyrr1-OH
(2S,4R)-4-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H4PhePyrr2-OH
(2S,4S)-4-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H5PhePyrr1-OH
(2S,5R)-5-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H5PhePyrr2-OH
(2S,5S)-5-Phenyl-pyrrolidine-2-acetic acid
H-β 3 -H4Hyp1-OH
(2S,4S)-4-Hydroxy-pyrrolidine-2-acetic acid
H-β 3 -H4Hyp2-OH
(2S,4R)-4-Hydroxy-pyrrolidine-2-acetic acid
H-β 3 -H4Mp1-OH
(2R,4S)-4-Mercapto-pyrrolidine-2-acetic acid
H-β 3 -H4Mp2-OH
(2R,4R)-4-Mercapto-pyrrolidine-2-acetic acid
H-β 3 -HPip-OH
(2S)-Piperidine-2-acetic acid
H-β 3 -HPro-OH
(2S)-Pyrrolidine-2-acetic acid
Ahb
4-Amino-2-hydroxy butyric acid
H-γ 4 -DiHCit-OH
(4S)-4-Amino-7-carbamidyl-heptanoic acid
H-γ 4 -DiHOrn-OH
(4S)-4,7-Diamino-heptanoic acid
H-γ 4 -DiHtBuA-OH
(4R)-4-Amino-6,6-dimethyl-heptanoic acid
H-γ 4 -DiHSar-OH
N-Methyl-4-amino-butyric acid
H-γ 4 -DiHPen-OH
(4R)-4-Amino-5-methyl-5-mercapto-hexanoic acid
H-γ 4 -DiHtBuG-OH
(4R)-4-Amino-5,5-dimethyl-hexanoic acid
H-γ 4 -DiH4AmPhe-OH
(4R)-4-Amino-5-(4′-aminophenyl)-pentanoic acid
H-γ 4 -DiH3AmPhe-OH
(4R)-4-Amino-5-(3′-aminophenyl)-pentanoic acid
H-γ 4 -DiH2AmPhe-OH
(4R)-4-Amino-5-(2′-aminophenyl)-pentanoic acid
H-γ 4 -DiHPhe(mC(NH 2 )═
(4R)-4-Amino-5-(3′-amidinophenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(pC(NH 2 )═
(4R)-4-Amino-5-(4′-amidinophenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(mNHC(NH 2 )═
(4R)-4-Amino-5-(3′-guanidino-phenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiHPhe(pNHC(NH 2 )═
(4R)-4-Amino-5-(4′-guanidino-phenyl)-pentanoic acid
NH)—OH
H-γ 4 -DiH2Pal-OH
(4R)-4-Amino-5-(pyridine-4′-yl)-pentanoic acid
H-γ 4 -DiH4Pal-OH
(4R)-4-Amino-5-(pyridine-4′-yl)-pentanoic acid
H-γ 4 -DiHPhg-OH
(4R)-4-Amino-4-phenyl-butyric acid
H-γ 4 -DiHCha-OH
(4R)-4-Amino-5-cyclohexyl-pentanoic acid
H-γ 4 -DiHC 4 al-OH
(4R)-4-Amino-5-cyclobutyl-pentanoic acid
H-γ 4 -DiHC 5 al-OH
(4R)-4-Amino-5-cyclopentyl-pentanoic acid
H-γ 4 -DiHNle-OH
(4S)-4-Amino-octanoic acid
H-γ 4 -DiH2Nal-OH
(4S)-4-Amino-5-(2′-naphthyl)-pentanoic acid
H-γ 4 -DiH1Nal-OH
(4S)-4-Amino-5-(1′-naphthyl)-pentanoic acid
H-γ 4 -DiH4ClPhe-OH
(4R)-4-Amino-5-(4′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH3ClPhe-OH
(4R)-4-Amino-5-(3′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH2ClPhe-OH
(4R)-4-Amino-5-(2′-chlorophenyl)-pentanoic acid
H-γ 4 -DiH3,4Cl 2 Phe-OH
(4R)-4-Amino-5-(3′,4′-dichloro-phenyl)-pentanoic acid
H-γ 4 -DiH4FPhe-OH
(4R)-4-Amino-5-(4′-fluorophenyl)-pentanoic acid
H-γ 4 -DiH3FPhe-OH
(4R)-4-Amino-5-(3′-fluorophenyl)-pentanoic acid
H-γ 4 -DiH2FPhe-OH
(4R)-4-Amino-5-(2′-fluorophenyl)-pentanoic acid
H-γ 4 -DiHThi-OH
(4R)-4-Amino-5-(2′-thienyl)-pentanoic acid
H-γ 4 -DiHTza-OH
(4R)-4-Amino-5-(2′-thiazolyl)-pentanoic acid
H-γ 4 -DiHMso-OH
(4R)-4-Amino-5-methylsulfoxyl-pentanoic acid
H-γ 4 -DiHAcLys-OH
(4S)-8-Acetylamino-4-amino-ocatanoic acid
H-γ 4 -DiHDpr-OH
(4R)-4,5-diamino-pentanoic acid
H-γ 4 -DiHA 2 Bu—OH
(4R)-4,5-Diamino-hexanoic acid
H-γ 4 -DiHDbu-OH
(4R)-4,5-Diamion-hexanoic acid
H-γ 4 -DiHAib-OH
3-Amino-3,3-dimethyl propionic acid
H-γ 4 -DiHCyp-OH
(1′-Amino-cyclopentane-1′-yl)-3-propionic acid
H-γ 4 -DiHY(Bzl)-OH
(4R)-4-Amino-5-(4′-benzyloxyphenyl)-pentanoic acid
H-γ 4 -DiHH(Bzl)-OH
(4R)-4-Amino-5-(1′-benzylimidazole-4′-yl)-pentanoic
acid
H-γ 4 -DiHBip-OH
(4R)-4-Amino-5-biphenylyl-pentanoic acid
H-γ 4 -DiHS(Bzl)-OH
(4S)-4-Amino-5-(benzyloxy)-pentanoic acid
H-γ 4 -DiHT(Bzl)-OH
(4R,5R)-4-Amino-5-benzyloxy-hexanoic acid
H-γ 4 -DiHalloT-OH
(4R,5S)-4-Amino-5-hydroxy-hexanoic acid
H-γ 4 -DiHLeu3OH—OH
(4R,5R)-4-Amino-5-hydroxy-6-methyl-heptanoic acid
H-γ 4 -DiHhAla-OH
(4S)-4-Amino-hexanoic acid
H-γ 4 -DiHhArg-OH
(4S)-4-Amino-8-guanidino-octanoic acid
H-γ 4 -DiHhCys-OH
(4R)-Amino-6-mercapto-hexanoic acid
H-γ 4 -DiHhGlu-OH
(4S)-4-Amino-ocatanedioic acid
H-γ 4 -DiHhGln-OH
(4S)-4-Amino-7-carbamoyl-heptanoic acid
H-γ 4 -DiHhHis-OH
(4S)-4-Amino-6-(imidazole-4′-yl)-hexanoic acid
H-γ 4 -DiHhIle-OH
(4S,6S)-4-Amino-6-methyl-octanoic acid
H-γ 4 -DiHhLeu-OH
(4S)-4-Amino-7-methyl-ocatanoic acid
H-γ 4 -DiHhNle-OH
(4S)-4-Amino-nonanoic acid
H-γ 4 -DiHhLys-OH
(4S)-4,9-Diamino-nonanoic acid
H-γ 4 -DiHhMet-OH
(4R)-4-Amino-7-methylthioheptanoic acid
H-γ 4 -DiHhPhe-OH
(4S)-4-Amino-6-phenyl-hexanoic acid
H-γ 4 -DiHhSer-OH
(4R)-4-Amino-6-hydroxy-hexanoic acid
H-γ 4 -DiHhThr-OH
(4R,6R)-4-Amino-6-hydroxy-heptanoic acid
H-γ 4 -DiHhTrp-OH
(4S)-4-Amino-6-(indol-3′-yl)-hexanoi cacid
H-γ 4 -DiHhTyr-OH
(4S)-4-Amino-6-(4′-hydroxyphenyl)-hexanoic acid
H-γ 4 -DiHhCha-OH
(4R)-4-Amino-5-cyclohexyl-pentanoic acid
H-γ 4 -DihBpa-OH
(4R)-4-Amino-5-(4′-benzoylphenyl)-pentanoic acid
H-γ 4 -DiHOctG-OH
(4S)-4-Amino-dodecanoic acid
H-γ 4 -DiHNle-OH
(4S)-4-Amino-octanoic acid
H-γ 4 -DiHTic-OH
(3R)-1′,2′,3′,4′-Tetrahydroisoquinoline-3′-yl-3-propionic
acid
H-γ 4 -DiHTiq-OH
(1′R)-1′,2′,3′,4′-Tetrahydroisoquinoline-1′-yl-3-propionic
acid
H-γ 4 -DiHOic-OH
(2′S,3′aS,7′aS)-1′-Octahydro-1H-indole-2′-yl-3-
propionic acid
H-γ 4 -DiH4AmPyrr1-OH
(2′R,4′S)-4′-Amino-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4AmPyrr2-OH
(2′R,4′R)-4′-Amino-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4PhePyrr1-OH
(2′R,4′R)-4′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4PhePyrr2-OH
(2′R,4′S)-4′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH5PhePyrr1-OH
(2′S,5′R)-5′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH5PhePyrr2-OH
(2′S,5′S)-5′-Phenyl-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Hyp1-OH
(2′R,4′S)-4′-Hydroxy-pyrrolidine-2′-yl-2-propionic acid
H-γ 4 -DiH4Hyp2-OH
(2′R,4′R)-4′-Hydroxy-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Mp1-OH
(2′R,4′S)-4′-Mercapto-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiH4Mp2-OH
(2′R,4′R)-4′-Mercapto-pyrrolidine-2′-yl-3-propionic acid
H-γ 4 -DiHPip-OH
(2′S)-Piperidine-2′-yl-3-propionic acid
H-γ 4 -DiHPro-OH
(2′S)-Pyrrolidine-2′-yl-3-propionic acid
(AEt)G
N-(2-Aminoethyl)glycine
(APr)G
N-(3-Amino-n-propyl)glycine
(ABu)G
N-(4-Amino-n-butyl)glycine
(APe)G
N-(5-Amino-n-pentyl)glycine
(GuEt)G
N-(2-Guanidinoethyl)glycine
(GuPr)G
N-(3-Guanidino-n-propyl)glycine
(GuBu)G
N-(4-Guanidino-n-butyl)glycine
(GuPe)G
N-(5-Guanidino-n-pentyl)glycine
(PEG 3 -NH 2 )G
N—[H 2 N—(CH 2 ) 3 —(OCH 2 —CH 2 ) 2 —O(CH 2 ) 3 ]glycine
(Me)G
N-Methylglycine
(Et)G
N-Ethylglycine
(Bu)G
N-Butylglycine
(Pe)G
N-Pentylglycine
(Ip)G
N-Isopropylglycine
(2MePr)G
N-(2-Methylpropyl)glycine
(3MeBu)G
N-(3-Methylbutyl)glycine
(1MePr)G
(1S)-N-(1-Methylpropyl)glycine
(2MeBu)G
(2S)-N-(2-Methylbutyl)glycine
(MthEt)G
N-(Methylthioethyl)glycine
(MthPr)G
N-(Methylthiopropyl)glycine
(Ben)G
N-(Benzyl)glycine
(PhEt)G
N-(2-Phenylethyl)glycine
(HphMe)G
N-([4′-hydroxyphenyl]methyl)glycine
(HphEt)G
N-(2-[4′-hydroxyphenyl]ethyl)glycine
(ImMe)G
N-(Imidazol-5-yl-methyl)glycine
(ImEt)G
N-(2-(Imidazol-5′-yl)ethyl)glycine
(InMe)G
N-(Indol-2-yl-methyl)glycine
(InEt)G
N-(2-(Indol-2′-yl)ethyl)glycine
(CboMe)G
N-(Carboxymethyl)glycine
(CboEt)G
N-(2-Carboxyethyl)glycine
(CboPr)G
N-(3-Carboxypropyl)glycine
(CbaMe)G
N-(Carbamoylmethyl)glycine
(CbaEt)G
N-(2-Carbamoylethyl)glycine
(CbaPr)G
N-(3-Carbamoylpropyl)glycine
(HyEt)G
N-(2-Hydroxyethyl)glycine
(HyPr)G
(2R)-N-(2-Hydroxypropyl)glycine
(Mcet)G
N-(2-Mercaptoethyl)glycine
Nip
(S)-Nipecotic acid/(S)-3-Piperidinecarboxylic acid
INip
Isonipecotic acid/4-Piperidinecarboxylic acid
PCA
(S)-2-Piperazinecarboxylic acid
(S)betaPro
(S)-β-Proline/(S)-Pyrrolidine-3-carboxylic acid
In a Specific Embodiment of this invention, the macrocycles of formula I are selected from the following list (Table 12).
TABLE 12 IUPAC Names of the Examples (continued on the following pages) Example IUPAC Name Ex. 1 benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 2 tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]carbamate Ex. 3 benzyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]carbamate Ex. 4 tert-butyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]carbamate Ex. 5 N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]-2-(1-naphthyl)acetamide Ex. 6 methyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]carbamate Ex. 7 N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]-2-(1-naphthyl)acetamide Ex. 8 N-[(12R,16S,18S)-16-(dimethylamino)-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]-2-(1-naphthyl)acetamide Ex. 9 (12R,16S,18S)-12,16-diamino-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaene- 8,13-dione Ex. 10 benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 11 N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(2-naphthyl)acetamide Ex. 12 2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}- 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide Ex. 13 3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]butanamide Ex. 14 benzyl N-[(12R,16S,18S)-8,13-dioxo-16-[(phenoxycarbonyl)amino]-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 15 benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]carbamate Ex. 16 tert-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate Ex. 17 benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]carbamate Ex. 18 benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]carbamate Ex. 19 N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]-2-(2-naphthyl)acetamide Ex. 20 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2- naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 21 N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 22 N-[(10S,12S,16S)-20-methyl-16-{[(methylamino)carbonyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 23 2-methoxy-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide Ex. 24 3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]butanamide Ex. 25 N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)amino]-8- oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]-2-(2-naphthyl)acetamide Ex. 26 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]benzamide Ex. 27 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]butanamide Ex. 28 N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]pentanamide Ex. 29 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]amino}acetic acid Ex. 30 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- {[(methylamino)carbothioyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 31 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-[(2- sulfanylacetyl)amino]-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 32 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-{[2- (tritylsulfanyl)acetyl]amino}-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 33 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- {[(methylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 34 2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3- (dimethylamino)anilino]carbonyl}amino)-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide Ex. 35 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(2- naphthylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 36 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12- [(methylsulfonyl)amino]-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]acetamide Ex. 37 N-[(10S,12S,16S)-12-[(benzylsulfonyl)amino]-20-methyl-15,21-dioxo-8- oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]-2-(dimethylamino)acetamide Ex. 38 tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20- methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate Ex. 39 N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]-2-(dimethylamino)acetamide Ex. 40 ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]amino}acetate Ex. 41 benzyl (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate Ex. 42 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid Ex. 43 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 44 (10R,15S)-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 45 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-phenyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 46 (10R,15S)-4-methoxy-10,16-dimethyl-15-(1-pyrrolidinylcarbonyl)-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17- dione Ex. 47 (10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-10,16-dimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide Ex. 48 tert-butyl N-[3-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)propyl]carbamate Ex. 49 (10R,15S)-N-(3-aminopropyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 50 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 51 (10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 52 (10R,15S)-N-cyclopropyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 53 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(2,2,2-trifluoroethyl)- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 54 (10R,15S)-N-isobutyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 55 (10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15- carboxamide Ex. 56 tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetate Ex. 57 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetic acid Ex. 58 (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-[(1S)-1-phenylethyl]- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 59 (10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-N,10,16-trimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide Ex. 60 (10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 61 (10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide Ex. 62 (10R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 63 (10R,15S)-4-methoxy-10,16-dimethyl-15-[(3-pyridinyloxy)methyl]-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17- dione Ex. 64 (10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 65 (10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione Ex. 66 N-{[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl}-2- phenylacetamide Ex. 67 [(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N- phenylcarbamate Ex. 68 benzyl (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxylate Ex. 69 (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxylic acid Ex. 70 (9S,14S)-N,9,15-trimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 71 (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 72 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 73 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenethyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 74 (9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 75 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 76 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-[(1S)-1-phenylethyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 77 (9S,14S)-N-(2-methoxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 78 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 79 (9S,14S)-N-cyclopropyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 80 (9S,14S)-N-isobutyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 81 (9S,14S)-N-(2-hydroxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 82 tert-butyl 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14- yl]carbonyl}amino)acetate Ex. 83 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14- yl]carbonyl}amino)acetic acid Ex. 84 (9S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethyl-11,16-dioxo-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 85 (9S,14S)-9,15-dimethyl-11,16-dioxo-N-[3-(1-pyrrolidinyl)propyl]-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 86 (9S,14S)-14-(1-azetanylcarbonyl)-9,15-dimethyl-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16- dione Ex. 87 (9S,14S)-9,15-dimethyl-14-(morpholinocarbonyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16- dione Ex. 88 (9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16- dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19- hexaene-14-carboxamide Ex. 89 (9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14- carboxamide Ex. 90 benzyl (9S,11R)-11-[(tert-butoxycarbonyl)amino]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 91 tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 92 benzyl (9S,11R)-11-amino-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxylate Ex. 93 (9S,11R)-11-amino-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 94 tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 95 (9S,11R)-11-amino-16-methyl-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 96 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 97 tert-butyl N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate Ex. 98 (9S,11R)-11-amino-16-(3-fluorobenzyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 99 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide Ex. 100 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide Ex. 101 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(1-naphthyl)acetamide Ex. 102 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-phenylurea Ex. 103 N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]benzenesulfonamide Ex. 104 tert-butyl N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 105 (9S,11R)-11-amino-16-[2-(dimethylamino)acetyl]-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 106 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-phenylacetamide Ex. 107 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]cyclopropanesulfonamide Ex. 108 N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-methylurea Ex. 109 tert-butyl N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 110 (9S,11R)-11-amino-16-(cyclopropylsulfonyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-14,20-dione Ex. 111 N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]benzamide Ex. 112 tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate Ex. 113 (9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxamide Ex. 114 (95,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxamide Ex. 115 allyl N-[(135,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 116 (135,16R)-13-amino-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 117 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 118 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 119 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- pyrrolidinyl)acetamide Ex. 120 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide Ex. 121 3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide Ex. 122 methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 123 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 124 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 125 N-methyl-N′-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 126 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 127 (13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 128 (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-14-one Ex. 129 allyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 130 (13S,16R)-13-amino-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 131 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 132 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 133 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- pyrrolidinyl)acetamide Ex. 134 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide Ex. 135 3-methyl-N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide Ex. 136 methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 137 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 138 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 139 N-methyl-N′-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 140 N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 141 (13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 142 (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione Ex. 143 allyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 144 (10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 145 (10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 146 (10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 147 (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex. 148 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 149 2-methoxy-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 150 2-(dimethylamino)-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 151 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]nicotinamide Ex. 152 3-methyl-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]butanamide Ex. 153 tert-butyl N-(3-{[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3- oxopropyl)carbamate Ex. 154 3-amino-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 155 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 156 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 157 3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 158 3-fluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide Ex. 159 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 160 N-methyl-N′-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 161 tert-butyl 3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate Ex. 162 3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid Ex. 163 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide Ex. 164 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 165 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 166 methyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 167 2-methoxyethyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 168 allyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 169 (10R,13S)-13-amino-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 170 (10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 171 (10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 172 (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione Ex. 173 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 174 2-methoxy-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex. 175 2-(dimethylamino)-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 - thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]acetamide Ex. 176 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]nicotinamide Ex. 177 3-methyl-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]butanamide Ex. 178 tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}-3-oxopropyl)carbamate Ex. 179 3-amino-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 180 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide Ex. 181 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide Ex. 182 3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]propanamide Ex. 183 3-fluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide Ex. 184 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea Ex. 185 N-methyl-N′-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea Ex. 186 tert-butyl 3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate Ex. 187 3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid Ex. 188 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide Ex. 189 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide Ex. 190 N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide Ex. 191 methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate Ex. 192 2-methoxyethyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18λ 6 -thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]carbamate Ex. 193a (9S,16S,19R)-16-benzyl-19,20-dimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193c (9S,19S)-19-benzyl-20-methyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193d (9S,19S)-19-benzyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193e (9S,16R,19S)-19-benzyl-16,17,20-trimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193f (9S,16R)-16,17,20-trimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193g (9S,16R,19S)-19-benzyl-16,17-dimethyl-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaene-14,18,21-trione Ex. 193h (9S,16S)-16-benzyl-21-methyl-7-oxa-13,17,21,25- tetraazatetracyclo[21.3.1.1 2,6 .0 9,13 ]octacosa-1(27),2(28),3,5,23,25- hexaene-14,18,22-trione Ex. 194b 3-[(9S,16R,19S)-16,17,20-trimethyl-14,18,21-trioxo-7-oxa-13,17,20,24- tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24- hexaen-19-yl]propanoic acid Ex. 195a (9S,16R,22S)-16,17,20,22,23-pentamethyl-7-oxa-13,17,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,18,21,24-tetrone Ex. 195b (9S,16R,22S)-16,17,22-trimethyl-7-oxa-13,17,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,18,21,24-tetrone Ex. 195e (9S,19R,22S)-16,19,20,22,23-pentamethyl-7-oxa-13,16,20,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,17,21,24-tetrone Ex. 195f (9S,18S,22R)-16,18,19,22,23-pentamethyl-7-oxa-13,16,19,23,27- pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27- hexaene-14,17,20,24-tetrone Ex. 195g (9S,18S,21R)-18-benzyl-21,22-dimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 195h (9S,18S,21R)-18-benzyl-16,21-dimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 195j (9S,18S,21R)-18-benzyl-16,21,22-trimethyl-7-oxa-13,16,19,22,26- pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26- hexaene-14,17,20,23-tetrone Ex. 196c 3-[(9S,16R,19S,22S)-16,17,19,23-tetramethyl-14,18,21,24-tetraoxo-7- oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta- 1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid Ex. 196i 3-[(9S,15S,18R,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7- oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa- 1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid Ex. 196k 3-[(9S,15R,18S,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7- oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa- 1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid Ex. 197d (9S,16R,19S,22R)-19-(4-aminobutyl)-16,17,22-trimethyl-7-oxa- 13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta- 1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone Ex. 198 benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate Ex. 199 benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxylate Ex. 200 tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]carbamate Ex. 201 tert-butyl N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]carbamate Ex. 202 (10S,12S)-12-amino-17-methyl-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 15,21-dione Ex. 203 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-2-(1-naphthyl)acetamide Ex. 204 3-methyl-N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]butanamide Ex. 205 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-N′-(3-pyridinyl)urea Ex. 206 N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]benzenesulfonamide Ex. 207 tert-butyl N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate Ex. 208 (10S,12S)-12-amino-17-[2-(dimethylamino)acetyl]-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 15,21-dione Ex. 209 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-2-phenylacetamide Ex. 210 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]-N′-methylurea Ex. 211 N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]cyclopropanesulfonamide Ex. 212 benzyl (10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxylate Ex. 213 N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 214 N-[(10S,12S)-17-(3-fluorobenzyl)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 215 N-[(10S,12S)-15,21-dioxo-17-[2-(1-pyrrolidinyl)acetyl]-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 216 (10S,12S)-12-(acetylamino)-15,21-dioxo-N-phenyl-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaene- 17-carboxamide Ex. 217 N-[(10S,12S)-15,21-dioxo-17-(phenylsulfonyl)-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 12-yl]acetamide Ex. 218 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 17-yl]carbonyl}amino)propanoic acid Ex. 219 tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22,25-hexaen- 17-yl]carbonyl}amino)propanoate Ex. 220 methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),12,22,24-hexaene-8-carboxylate Ex. 221 methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate Ex. 222 methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia- 7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa-1(26),2,5(27),22,24- pentaene-8-carboxylate Ex. 223 methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate Ex. 224 (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylic acid Ex. 225 (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide Ex. 226 (8S,17S,19S)-24-fluoro-N-isobutyl-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide Ex. 227 methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 228 (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 229 methyl (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4- thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 230 methyl (8S,12E,18S,20S)-25-fluoro-18-[2-(2-naphthyl)acetyl]amino-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 231 tert-butyl N-[(8S,12E,18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]- 6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen- 18-yl]carbamate Ex. 232 (8S,12E,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa- 4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide Ex. 233 (8S,12E,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide Ex. 234 tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaen-18-yl]carbamate Ex. 235 (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa- 4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide Ex. 236 methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2- phenylacetyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxylate Ex. 237 (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 238 methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylate Ex. 239 (8S,12E 18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 240 (8S,12E,18S,20S)-25-fluoro-N-isobutyl-18-{[2-(2-naphthyl)acetyl]amino}- 6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide Ex. 241 (8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid Ex. 242 methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 243 (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 244 methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxylate Ex. 245 methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 246 tert-butyl N-[(8S,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 247 (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 248 methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 249 (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 250 methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylate Ex. 251 (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 252 (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxylic acid Ex. 253 tert-butyl N-[(8S,18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 254 (8S,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa-4- thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 255 (8S,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxamide Ex. 256 tert-butyl N-[(8S,18S,20S)-8-[(4-chloroanilino)carbonyl]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 257 (8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide Ex. 258 tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidinocarbonyl)- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 259 (8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide Ex. 260 tert-butyl N-[(8S,18S,20S)-8-[(benzylamino)carbonyl]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaen-18-yl]carbamate Ex. 261 (8S,18S,20S)-18-amino-N-benzyl-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- 7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide Ex. 262 benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethyl-14,19- dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate Ex. 263 (9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethyl-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraene-14,19-dione Ex. 264 (9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethyl-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraene-14,19-dione Ex. 265 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(2-naphthyl)acetamide Ex. 266 N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]acetamide Ex. 267 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(1-naphthyl)acetamide Ex. 268 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-3-methylbutanamide Ex. 269 3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzamide Ex. 270 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]benzenesulfonamide Ex. 271 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]methanesulfonamide Ex. 272 methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate Ex. 273 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-methylurea Ex. 274 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-(3-pyridinyl)urea Ex. 275 N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(2-naphthyl)acetamide Ex. 276 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-N′-(2-naphthyl)urea Ex. 277 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-phenylacetamide Ex. 278 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-3-methoxybenzamide Ex. 279 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-naphthalenesulfonamide Ex. 280 3-(4-fluorophenyl)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19- dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]propanamide Ex. 281 N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia- 13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)- tetraen-15-yl]-2-(1H-indol-3-yl)acetamide Ex. 282 (9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl]amino}- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione Ex. 283 (9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21-dimethyl-7- oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione Ex. 284a benzyl N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate EX. 284b benzyl N-[(13R,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate Ex. 285 (13S,19S)-13-amino-4,8-dimethyl-23-nitro-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaene-7,14-dione Ex. 286 benzyl N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]carbamate Ex. 287 benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 288 N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]acetamide Ex. 289 N-(2-chlorophenyl)-N′-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]urea Ex. 290 N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]-N′-(2-chlorophenyl)urea Ex. 291 N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino}-4,8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide Ex. 292 N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]cyclopropanecarboxamide Ex. 293 N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]cyclopropanecarboxamide Ex. 294 N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]cyclopropanecarboxamide Ex. 295 N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]methanesulfonamide Ex. 296 benzyl N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo- 21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 297 benzyl N-[(13S,19S)-4,8-dimethyl-7,14-dioxo-23-(2-pyrimidinylamino)-21- oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate Ex. 298 (13S,19S)-13-amino-4,8-dimethyl-23-(2-pyrimidinylamino)-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaene-7,14-dione Ex. 299 N-[(13S,19S)-13-(dimethylamino)-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 300 N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-13-yl]-2-phenylacetamide Ex. 301 N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino}-4.8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 302 N-[(13S,19S)-13-{[(isobutylamino)carbonyl]amino}-4,8-dimethyl-7,14- dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide Ex. 303 N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-13-yl]-4-fluorobenzamide Ex. 304 N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa- 1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide Ex. 305 benzyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]carbamate Ex. 306 (15R,16aS)-15-amino-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione Ex. 307 (15R,16aS)-15-(dimethylamino)-10-methyl-10,11,15,16,16a,17- hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine- 9,12-dione Ex. 308 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]acetamide Ex. 309 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- methylbutanamide Ex. 310 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(2- naphthyl)acetamide Ex. 311 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(1- naphthyl)acetamide Ex. 312 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2- (dimethylamino)acetamide Ex. 313 tert-butyl N-(3-[(15R,16aS)-10-methyl-9,12-dioxo- 9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1- c][1,4,7]oxadiazacyclododecin-15-yl]amino-3-oxopropyl)carbamate Ex. 314 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- aminopropanamide Ex. 315 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3- fluorobenzamide Ex. 316 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]isonicotinamide Ex. 317 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′- methylurea Ex. 318 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′-(3- pyridinyl)urea Ex. 319 2-methoxyethyl N-[(15R,16aS)-10-methyl-9,12-dioxo- 9,10,11,12,15,16,163,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1- c][1,4,7]oxadiazacyclododecin-15-yl]carbamate Ex. 320 tert-butyl 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]amino}carbonyl)amino]propanoate Ex. 321 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17- octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]amino}carbonyl)amino]propanoic acid Ex. 322 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]methanesulfonamide Ex. 323 N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15- yl]benzenesulfonamide Ex. 324 (15R,16aS)-15-[(3-fluorobenzyl)amino]-10-methyl-10,11,15,16,16a,17- hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine- 9,12-dione Ex. 325 (15R,16aS)-15-(isobutylamino)-10-methyl-10,11,15,16,16a,17-hexahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione Ex. 326 N″-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro- 14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]- N,N,N′,N′-tetramethylguanidine Ex. 327 benzyl (16S,18S)-16-[(tert-butoxycarbonyl)amino]-7,13-dioxo-4- (trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23- pentaene-11-carboxylate Ex. 328 tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa- 3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa- 1(25),2(6),3,21,23-pentaen-16-yl]carbamate Ex. 329 benzyl (165,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa- 3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa- 1(25),2(6),3,21,23-pentaene-11-carboxylate Ex. 330 allyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 331 allyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]carbamate Ex. 332 2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}- 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]acetamide Ex. 333 N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]-2-(1-naphthyl)acetamide Ex. 334 2-(3-chlorophenyl)-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide Ex. 335 2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide Ex. 336 N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide Ex. 337 N-[(12R,16S,18S)-12-[(benzylsulfonyl)amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(1-pyrrolidinyl)acetamide Ex. 338 benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}- 20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-12-yl]carbamate Ex. 339 N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]-2-(1-pyrrolidinyl)acetamide Ex. 340 N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyl]amino}-8,13-dioxo-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-1(25),2,4,6,21,23- hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide Ex. 341 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(1-naphthyl)acetamide Ex. 342 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 343 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-N′-(2-naphthyl)urea Ex. 344 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-naphthalenesulfonamide Ex. 345 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-3-(2-naphthyl)propanamide Ex. 346 N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-3-phenylpropanamide Ex. 347 2-(dimethylamino)-N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide Ex. 348 benzyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 349 N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 350 N-[(9S,11R)-16-(3-fluorobenzoyl)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 351 N-[(9S,11R)-16-benzyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 352 N-[(9S,11R)-14,20-dioxo-16-phenethyl-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 353 N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropyl)-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 354 N-[(9S,11R)-16-isopentyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 355 N-[(9S,11R)-16-isobutyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 356 2-(dimethylamino)ethyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex. 357 N-[(9S,11R)-16-[2-(dimethylamino)ethyl]-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide Ex. 358 3,3-dimethyl-N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]butanamide
Synthesis of the Building Blocks
Readily available examples of amino acids representing subunits of the Bridge C are detailed to the level of fully-defined structures in Table 11. Additional analogs can be accessed smoothly, and a plethora of literature precedents are published. Therefore this section focuses on synthetic approaches towards building blocks of the Template A and the Modulator B.
Functional groups not involved in ring connections of the macrocyclic backbone can be diversified by standard methods of organic synthesis, preferably by parallel/combinatorial chemistry introducing so-called high variation substituents. These derivatization methods are well-known to those skilled in the art and do not require further exemplification (selected references: A. R. Katritzky et al. (eds), Comprehensive Functional Group Transformations , Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups , Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; D. Obrecht, J. M. Villalgordo (eds), Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Pergamon, 1998; W. Bannwarth et al. (eds), Combinatorial Chemistry: From Theory to Application, 2 ed., Wiley-VCH 2006).
a) Synthesis of Template a Building Blocks
Over the last decades the coupling to suitably functionalized aromatic or heteroaromatic compounds has reached a highly mature status providing an easy and reliable route to biaryl derivatives of nearly any substitution pattern (cf. leading reviews covering several types of coupling reactions and the references cited therein: R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A. de Meijere, F. Diederich (eds), Metal - Catalyzed Cross - Coupling Reactions, 2nd ed., Wiley-VCH 2004; with focus on heteroaromatic substrates: G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644-4680; especially for macrocyclic biaryls: Q. Wang, J. Zhu, Chimia 2011, 65, 168-174). Most prominent among these coupling reactions is definitely the Suzuki-Miyaura cross coupling of aryl boronic acid derivatives with aryl halides under palladium catalysis (N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; S. Kotha et al., Tetrahedron 2002, 58, 9633-9695; S. L. Buchwald et al., J. Am. Chem. Soc. 2005, 127, 4685-4696). Special catalysts, especially the Nolan's catalysts make the Suzuki-Miyaura reaction also amenable to highly sterically hindered substrates (S. P. Nolan et al., J. Am. Chem. Soc. 2003, 125, 16194-16195; S. P. Nolan et al., Org. Lett. 2005, 7, 1829-1832). More recent developments broadened the scope of the Suzuki coupling from aryl halides to other substrates like aryl mesylates (F. Y. Kwong et al., Angew. Chem. Int. Ed. 2008, 47, 8059-8063) or aryl carbamates, carbonates and sulfamates (N. K. Garg et al., J. Am. Chem. Soc. 2009, 131, 17748-17749).
The biaryl compounds obtained by such coupling protocols might require further functional group transformations as described below.
General Functional Group Interconversions
The majority of the Templates A are carrying an aromatic or heteroaromatic hydroxy (—OH) or sulfanyl (thiol) group (—SH) in the A B substructure and a carboxylic acid group (—COOH) or sulfanyl moiety (—SH) or its respective oxidation products in the Ac substructure.
As more phenolic precursors are commercially available than the corresponding thiophenols, a transformation of a phenol into a thiophenol might be required. Alternatively thiophenols might be derived from the corresponding aryl halides or diazonium salts. Selected functional group transformations for introducing a sulfanyl group (—SH), i.e. Ar/Hetar-X→Ar/Hetar-SH (X═OH, F, Cl, Br, I, N 2 + ), are the compiled below (T-I to T-VII):
T-I: A sequence of broad applicability is the transformation of a phenol into a thiocarbamate with N,N-dimethylthiocarbamoyl chloride, followed by Newman-Kwart rearrangement and subsequent hydrolysis (A. Gallardo-Godoy et al., J. Med. Chem. 2005, 48, 2407-2419; P. Beaulieu et al., Bioorg. Med. Chem. Lett. 2006, 16, 4987-4993; H. Sugiyama et al., Chem. Pharm. Bull. 2007, 55, 613-624; S. Lin et al., Org. Prep. Proced. Int. 2000; 547-556).
T-II: The direct transformation of an —OH adjacent to a pyridinic nitrogen (i.e. equivalent to the pyridone tautomer) can be accomplished by heating with P 2 S 5 (K. Hirai et al., Heterocycles 1994, 38, 277-280).
T-III: As an alternative to phenols, halogen-substituted (esp. with F or Cl) aromatic ring systems might serve as precursors. In case the halogen is in a position activated by an electron withdrawing group in ortho- or para-position the —SH moiety or a protected surrogate can be introduced under mild conditions by nucleophilic aromatic substitution reactions (S N Ar) (G. J. Atwell et al., J. Med. Chem. 1994, 37, 371-380). Especially in the field of heterocyclic compounds, where the electron withdrawing effect is exerted by pyridine-like nitrogen atoms, this type of substitution is often utilized (S. McCombie et al., Heterocycles, 1993, 35, 93-97).
T-IV: Similarly, in Sandmeyer-type reactions a diazonium group (—N 2 + ) can be replaced (C. Mukherjee, E. Biehl, Heterocycles 2004, 63, 2309-2318).
T-V: In positions not activated for an S N Ar the substitution of halogen atoms (esp. Br or I) can be accomplished via the corresponding organolithium or Grignard reagents (J. L. Kice, A. G. Kutateladze, J. Org. Chem. 1993, 58, 917-923; P. C. Kearney et al., J. Am. Chem. Soc. 1993, 115, 9907-9919). Alternatively, transition metal-catalyzed transformations are feasible for this type of reaction, e.g. Cu-catalyzed substitution with benzothioic S-acid (N. Sawada et al., Tetrahedron Lett. 2006, 47, 6595-6597), or Pd-catalyzed substitution with KS—Si(i-Pr) 3 followed by desilylation of the introduced —SSi(i-Pr) 3 group (A. M. Rane et al., Tetrahedron Lett. 1994, 35, 3225-3226).
The thus introduced —SH moieties constitute a thia-bridge —S— in the later macrocyclic products and can be selectively transformed into higher oxidation states. Therefore the building blocks with sulfanyl moieties are also regarded as building blocks for the introduction of sulfinyl (—S(═O)—; i.e. sulfoxide) and sulfonyl (—S(═O) 2 —; i.e. sulfone) moieties. Suitable oxidation methods are:
T-VI: The selective oxidation of a thioether (—S—) to a sulfoxide (—S(═O)—) can be highly selectively and mildly achieved with hexamethylenetetramine-bromine HMTAB (K. Choudhary et al.; J. Phys. Org. Chem. 2000, 13, 283-292); under these conditions primary hydroxyl groups for example are not affected. In a number of related reactions chlorotrimethylsilane showed high selectivity, too (Y.-J. Chen et al., Tetrahedron Lett. 2000, 41, 5233-5236).
T-VII: Stronger oxidants directly transfer the sulfanyl (—S—) into the sulfonyl group (—S(═O) 2 —). Among the many reagents mentioned in literature the system periodic acid/chromium(VI)oxide for example can be applied in the presence of C═C-double bonds (US2007/293548 A1).
Hydroxyl groups attached to aromatic rings (Ar—OH or Heteroaryl-OH) in turn, if not already part of a synthesized or commercially available biaryl, can be introduced by various methods, e.g. H-I to H-IV:
H-I: Analogously to T-III) the hydroxy group or its surrogate can be introduced by an S N Ar reaction of halogen atoms, esp. Cl or F, ortho or para to an electron withdrawing substituent (W. Cantrell, Tetrahedron Lett. 2006, 47, 4249-4251) or to a pyridinic nitrogen atom (S. D. Taylor et al., J. Org. Chem. 2006, 71, 9420-9430).
H-II: Sandmeyer-type hydroxylations of aromatic amines via intermediate diazonium salts (P. Madsen et al., J. Med. Chem. 2002, 45, 5755-5775).
H-III: The substitution of halogen atoms (esp. Br and I), which are not activated for an S N Ar, can be achieved by transition metal-catalyzed C—O-couplings. Predominant are Pd-catalysts (K. W. Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695; B. J. Gallon et al., Angew. Chem., Int. Ed. 2007, 46, 7251-7254), but also others find application, like Cu-catalysts (J. E. Ellis, S. R. Lenger, Synth. Commun. 1998, 28, 1517-1524).
H-IV: Of broad scope is also a two-step process which first transforms halogen atoms (Cl, Br and I) into a boronate and then oxidatively cleaves the carbon-boron bond to the phenol (J. R. Vyvyan et al., J. Org. Chem. 2004, 69, 2461-2468).
The carboxylic acid group of the biaryl A building blocks, if not already present in commercially available coupling precursors, can be introduced by standard procedures like C-I to C-IV:
C-I: The oxidation of functional groups like hydroxymethyl (—CH 2 —OH) or aldehyde (—C(═O)H) can be achieved under mild conditions (G. V. M. Sharma et al., Synth. Commun. 2000, 30, 397-406; C. Wiles et al., Tetrahedron Lett. 2006, 47, 5261-5264). Also methyl groups on benzene rings can be oxidized; however, as harsh reaction conditions are usually required, its applicability is limited. In contrast, the relatively acidic methyl groups ortho or para to a pyridine nitrogen can be oxidized under milder conditions; making this the method of choice for many pyridine analogs (T. R. Kelly, F. Lang, J. Org. Chem. 1996, 61, 4623-4633).
C-II: Halogen atoms can easily be replaced by a carboxyl group or surrogate thereof, e.g. by halogen metal exchange and subsequent carboxylation of the intermediate Grignard or organolithium species (C. G. Screttas, B. R. Steele, J. Org. Chem. 1989, 54, 1013-1017), or by utilizing Mander's reagent (methyl cyanoformate) (A. Lepretre et al., Tetrahedron 2000, 56, 265-274).
C-III: In the case that acidified ring positions are to be carboxylated, a viable method is deprotonation with a strong base (usually tert-butyl lithium) followed by carboxylation of the intermediate organolithium species in analogy to C-II).
C-IV: Hydrolysis of ester, amide or nitrile groups. The CN group in turn can easily be introduced by treating organic halides with CuCN (Rosenmund-von Braun reaction: C. F. Koelsch, A. G. Whitney, J. Org. Chem., 1941, 6, 795-803).
Applied to commercially available starting materials or biarlys obtained by coupling route, these general transformations offer a tool box for accessing a huge variety of Templates A. Additional literature examples are cited below within the sections on specific derivatives.
b) Synthesis of Modulator B Building Blocks
The Modulator B moieties of macrocycle I are derived from appropriately substituted aminoalcohols, wherein the amino and alcohol group, which contribute to the ring connectivity, are separated by 2-4 C-atoms.
If not already present in a commercial building block, the substituent R 6 can be introduced by standard nucleophilic addition of organometallic reagents to carbonyl or carboxyl derivatives. Alkyl (as R 6 ) substituted analogs of B1 and derivatives of B2-B10 with no additional C-substituent on their ring system are commercially available, as are many derivatives with an amino (—NH 2 ) or alcohol (—OH) substituent as R 6 . In the such cases the diversification of the substitution pattern can be easily achieved by standard transformations of the free amine or hydroxy functionalities.
Possible pathways to more complex pyrrolidine derivatives of type B4-B6 or piperidine derivatives of type B7-B9 rely on the same strategy: Intramolecular cyclization reactions are the predominant route applicable to diversely substituted substrates. Amines carrying a residue with a leaving group in the ω-position lead directly to the desired saturated ring systems by intramolecular nucleophilic substitution (G. Ceulemans et al., Tetrahedron 1997, 53, 14957-14974; S. H. Kang, D. H. Ryu, Tetrahedron Lett. 1997, 38, 607-610; J. L. Ruano et al., Synthesis 2006, 687-691). Also N-haloamines can be directly transformed into the desired compounds by a Hofmann-Löffler-Freytag reaction (M. E. Wolff, Chem. Rev. 1963, 63, 55-64). Alternatively, amines carrying two substituents, each with an alkene or alkyne bond, can be subjected to a ring closing metathesis (RCM) reaction (Y. Coquerel, J. Rodriguez, Eur. J. Org. Chem. 2008, 1125-1132) and subsequent reduction of the partially unsaturated ring to the saturated heterocycle.
Another possible access, reduction of aromatic five- or six-membered heterocycles to their saturated analogs, is described in the literature. Due to the large number of commercially available pyridines this approach is especially useful for the synthesis of the piperidine system (J. Bolos et al., J. Heterocycl. Chem. 1994, 31, 1493-1496; A. Solladie-Cavallo et al., Tetrahedron Lett. 2003, 44, 8501-8504; R. Naef et al., J. Agric. Food Chem. 2005, 53, 9161-9164).
General Processes for the Synthesis of Macrocyclic Compounds I
General procedures for the synthesis of libraries of macrocyclic compounds of general structure I are described below. It will be immediately apparent to those skilled in the art how these procedures have to be modified for the synthesis of individual macrocyclic compounds of type I.
The macrocyclic compounds of this invention are obtained by cyclization of suitable linear precursors which are derived from optionally substituted bifunctional hydroxy- or mercapto biaryls/heteroaryls X-A B -A C -Y (Template A B -A C ), substituted amino alcohols B (Modulator), and one to three building blocks forming Bridge C.
Hydroxy- or mercapto biaryls/heteroaryls X-A B -A C -Y consist of two optionally substituted building blocks X-A B and A C -Y. Building blocks X-A B comprise hydroxyaryl, hydroxyheteroaryl-, mercaptoaryl- and mercaptoheteroaryl compounds. Building blocks A c -Y comprise carboxyaryl-, carboxyheteroaryl-, mercaptoaryl-, mercaptoheteroaryl, alkenylaryl, and alkenylheteroaryl compounds. X-A B and A C -Y are six-membered aromatic or five- or six-membered heteroaromatic rings. Templates X-A B -A C -Y can be obtained by combination of two six-membered rings, two five-membered rings or a five- and a six-membered ring. The building blocks X-A B and A C -Y are connected by a carbon-carbon bond to form the biaryls X-A B -A C -Y.
Variable substituents are introduced by pre- or postcyclative derivatization of one or more orthogonally protected functional group (e.g. amino groups, carboxyl groups, hydroxyl groups) attached to B, C or A. Variable R-groups may also be introduced as side chain motifs of the subunits of Bridge C.
The macrocyclic products of this invention can be prepared either in solution or on solid support.
The essential ring closure reaction is possible between any of the building blocks; and macrocycles I are obtained by e.g.
Macrolactamization between C and B; Macrolactamization between A B -A C and C; Macrolactamization between any two subunits of Bridge C; Arylether or arylthioether formation between A B -A C and B; Arylthioether formation between A B -A C and C; Biaryl synthesis by coupling reaction (e.g. Suzuki coupling) between A B and A C ; Ring closing metathesis (RCM) reaction between any two subunits of C or upon formation of such a subunit; Ring closing metathesis reaction between A B -A C and C.
SW-1: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
Macrocycles of structure I with orthogonally protected exocyclic functional groups (attachment points for derivatizations) are prepared in solution by the process outlined below. Throughout all steps the orthogonal protection of the side chains stays intact and is not affected by protecting group manipulations of the main chain.
a1) Condensation of an appropriately protected hydroxy- or mercapto-biaryl/heteroaryl carboxylic acid PG 1 -X-A B -A C -CO 2 H and a suitable C-terminally and side-chain protected C-subunit building block H—NR 7 -c1-CO—OPG 2 to form PG 1 -X-A B -A C -CONR 7 -c1-CO—OPG 2 ;
b1) If required, deprotection of the aryl/heteroaryl hydroxy or mercapto group;
c1) Aryl/heteroaryl ether or thioether formation with a suitably N-protected amino alcohol PG 3 -B-OH leading to the fully protected linear precursor PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 ;
d1) Cleavage of the “main chain” protective groups affording the free amino acid H—B—X-A B -A C -CONR 7 -c1-CO—OH, which is subjected to macrocyclization
e1) Intramolecular amide coupling to cyclo(B—X-A B -A C -CONR 7 -c1-CO—) as macrocyclic product.
In addition to the steps described above, chain elongation by one or two additional C-subunits (c2, c3) and subsequent macrolactamization starts with coupling of a second suitably C-protected amino acid to the free carboxylic acid functionality of the product obtained by N-reprotection of the product of step d1. Cleavage of the main chain protective groups and either macrolactamization or repetition of the chain elongation steps and macrolactamization provides either cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—) or cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CONR 7 -c3-CO—).
The free carboxylic acid functionality of the N-reprotected product derived from any of the three linear macrolactamization precursors (product of step d1, or corresponding product after coupling of one or two additional C-subunits) can be further elaborated by chain extensions/homologizations (e.g. Arndt-Eistert reaction) or functional group interconversions like Curtius rearrangement ultimately affording homologous macrocycles or those where the connection between Modulator B and Bridge C corresponds to a urea moiety.
SW-2: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
As an alternative to SW-1 the intermediate H—X-A B -A C -Y-Z-c1-CO—OPG 2 (product of step b1) can be prepared by
a2) S-alkylation of a suitable mercapto-substituted haloaryl/heteroaryl compound Hal-A C -SH (Hal represents a halogen atom) with a C-terminally and side-chain protected C-subunit building block LG-CHR 8 -c1-CO—OPG 2 (LG represents a leaving group like halide, alkyl-, arylsulfonate or activated OH like e.g. under Mitsunobu conditions);
b2) Suzuki coupling reaction between the product of step a2) and a suitable hydroxyl-substituted boronic acid or boronic ester HX-A B -B(OR) 2 leading to HX-A B -A C -S—CHR 8 -c1-CO—OPG 2 .
In analogy, amide coupling of a suitable C-terminally and side-chain protected C-subunit building block H—NR 7 -c1-CO—OPG 2 to a haloaryl/heteroaryl carboxylic acid Hal-A C -CO—OH and subsequent Suzuki biaryl coupling reaction with a suitable hydroxyl-substituted boronic acid or boronic ester would provide H—X-A B -A C -CONR 7 -c1-CO—OPG 2 .
Possible subsequent steps are as described in SW-1, providing cyclo(B—X-A B -A C -Y-Z-c1-CO—) with Y—Z═CONR 7 , S—CHR 8 .
Oxidation of cyclo(B—X-A B -A C -S—CHR 8 -c1-CO—) leads to the corresponding sulfoxides cyclo(B—X-A B -A C -SO—CHR 8 -c1-CO—) or sulfone cyclo(B—X-A B -A C -SO 2 —CHR 8 -c1-CO—).
SW-3: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Macrolactamization in Solution
As an alternative to SW-1 the protected cyclization precursor PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 can also be synthesized by an inverted order of reaction steps:
a3) Arylether or arylthioether formation between a hydroxyl or mercapto-aryl/heteroaryl ester H—X-A B -A C -CO—OPG 4 and a suitably protected amino alcohol PG 3 -B-OH to afford PG 3 -B-X-A B -A C -CO—OPG 4 .
Further more, PG 3 -B-X-A B -A C -CO—OPG 4 can also be obtained by arylether or arylthio ether formation between a suitably protected aminoalcohol PG 3 -B-OH and an optionally substituted hydroxyl- or mercaptoaryl halide or heteroaryl halide HX-A B -Hal leading to PG 3 -B-X-A B -Hal and subsequent coupling of an optionally substituted alkoxycarbonyl aryl or heteroaryl boronic acid or boronic ester (RO) 2 B-A C -CO—OPG 4 .
b3) Deprotection of the carboxylic acid group to PG 3 -B-X-A B -A C -CO—OH;
c3) Condensation with a C-terminally and side-chain protected building block H—NR 7 -c1-CO—OPG 2 to PG 3 -B-X-A B -A C -CONR 7 -c1-CO—OPG 2 .
Possible subsequent steps are as described in SW-1.
In analogy to step c3), PG 3 -B-X-A B -A C -CO 2 H can be coupled to a previously formed di- or tripeptide leading to protected cyclization precursors such as PG 3 -B-X-A B A C -CONR 7 -c1-CONR 7 -c2-CO—OPG 2 or PG 3 -B-X-A B -A C -CONR 7 -c1-CONR 7 -c2-CONR 7 -c3-CO—OPG 2 . If applying this approach for the synthesis of macrocycles I, the synthesis is best performed by preparation of the linear N-terminal deprotected cyclization precursor on solid support, followed by release from resin and cyclization as well as cleavage of side chain protective groups in solution, as detailed in SW4.
SW-4: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Combined Solid Phase and Solution Phase Chemistry
Macrocyclic compounds of general formula I with highly variable side chain motifs in Bridge C can advantageously be prepared in parallel array synthesis applying a combination of solid phase and solution phase synthesis methodologies.
The solid support (polymer, resin) is preferably a trityl resin e.g. chlorotrityl chloride resin (cross-linked with 1-5% divinylbenzene), which is useful as polymer-bound protective group for carboxylic acids (D. Obrecht, J.-M. Villalgordo, Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998; K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520; K. Barlos et al., Angew. Chem. Int. Ed. 1991, 30, 590-593).
a4) The suitably side-chain protected C-subunit PG 5 NR 7 -c2-CO—OH is attached to the solid support;
b4) The N-terminal protective group is cleaved;
c4) The suitably side-chain protected C-subunit PG 5 NR 7 -c1-CO—OH is coupled; subsequent N-terminal deprotection leads to HNR 7 -c1-CO—NR 7 -c2-CO—O-chlorotrityl resin;
d4) Coupling of a suitably side chain protected building block PG 3 -B-X-A B -A C -CO—OH (cf. SW-3, product of step b3) and cleavage of the N-terminal protective group;
e4) Release of the linear main-chain deprotected macrolactamization precursor H—B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—OH from the resin;
f4) Macrolactamization to cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—).
g4) Optional: Cleavage of protective groups of side-chain functions.
Immobilization of an amino acid PG 5 NR 7 -c3-CO—OH and two additional amino acid coupling/deprotection cycles would lead to HNR 7 -c1-CO—NR 7 -c2-CO—NR 7 -c3-CO—O-chlorotrityl resin. Possible subsequent steps are as described above, providing cyclo(B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—NR 7 -c3-CO—).
The ring closure of linear precursors like H—B—X-A B -A C -CONR 7 -c1-CONR 7 -c2-CO—OH may be achieved using soluble coupling reagents as described below or by engaging polymer-supported coupling reagents such as N-cyclohexyl-carbodiimide-N′-methylpolystyrene or N-alkyl-2-chloro pyridinium triflate resin (S. Crosignani et al, Org. Lett. 2004, 6, 4579-4582).
Further viable alternatives for the synthesis of macrocycles I by combined application of solid phase and solution phase conditions could involve macrolactamization in other positions, e.g. between two subunits in Bridge C. Alternative cyclization precursors like H—NR 7 -c2-CO—B—X-A B -A C -CONR 7 -c1-CO—OH can be obtained from the same building blocks (as described for SW4) by changing the sequence of coupling/deprotection steps.
SW-5: Synthesis Workflow for the Preparation of Side-Chain Protected Macrocycles I by Ring-Closing Metathesis in Solution
Ring-closing metathesis (RCM) of olefinic precursors was applied for the synthesis of subunits of Bridge C, wherein e.g. c2=c2′−c2″:
a5) Coupling of an optionally substituted alkenyl amine building block H—NR 7 -c1-V-c2′=CH 2 with suitably protected carboxylic acid derivatives PG 1 -X-A B -A C -CO 2 H to afford PG 1 -X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 ;
b5) if required release of the aryl/heteroaryl hydroxyl or mercapto group;
c5) Arylether or arylthioether formation between H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 and PG 3 -B-OH leading to PG 3 -B-X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2
d5) Cleavage of the N-terminal protective group leading to H—B—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2
e5) Coupling of a suitable (optionally substituted and suitably protected) enoic acid to H 2 C=c2″-CO—B—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 ;
f5) Ring-closing metathesis to cyclo(c2″-CO—B—X-A B -A C -CO—NR 7 -c1-V-c2′) [=cyclo(B—X-A B -A C -CO—NR 7 -c1-V-c2-CO—)]
g5) Optional: Hydrogenation of the newly formed C—C double bond of the metathesis product.
In addition, it is also feasible to prepare olefinic macrocycles with modified Bridges C such as cyclo(B—X-A B -A C -Y-Z-c1-V-c2-CO—NR 7 -c3-CO—), or cyclo(B—X-A B -A C -Y-Z-c1-CO—), and subsequently the respective hydrogenated analogs.
General Procedures for Synthetic Steps Utilized in SW-1 to SW-5
In all general procedures below Y—Z represents CONR n or SCHR n .
Amidation Reactions (Steps a1, c3, a5, e5)
An appropriately protected (preferably as acetyloxy or acetylmercapto) and optionally substituted biaryl/heteroaryl carboxylic acid (PG 3 -X-A B -A C -CO 2 H) or a more advanced intermediate like PG 3 -B-X-A B -A C -CO 2 H is condensed with a suitably protected amino acid ester H—NR 7 -c1-CO—OPG 2 or an amine H—NR 7 -c1-V-c2′=CH 2 in the presence of a coupling reagent (e.g. benzotriazole derivatives like HBTU, HCTU, BOP, PyBOP; their aza analogs like HATU; or carbodiimides like EDC; others like PyClu, T3P), an auxiliary base (e.g. i-Pr 2 NEt, Et 3 N, pyridine, collidine) in solvents like CH 2 Cl 2 , DMF, pyridine. Benzotriazole-based coupling reagents and carbodiimides can be used together with suitable auxiliary reagents HOBt or HOAt.
Hydroxybiaryl/heteroaryl carboxylic acids H—X-A B -A C -CO 2 H do not necessarily require protection of the phenolic OH-group and can directly be coupled with the H—NR 7 -c1-CO—OPG 2 to the free phenol derivative H—X-A B -A C -CONR 7 -c1-CO—OPG 2 .
As an alternative, the amidation can also be accomplished with the corresponding acid derivatives like acid chlorides, anhydrides, or active esters.
Deprotection of Aromatic Hydroxy or Mercapto Groups (Steps b1, b5)
Deacylation of PG 1 -X-A B -A C -CONR 7 -c1-CO—OPG 2 or PG 1 -X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 to the corresponding free hydroxyl or mercapto aryl/heteroaryl amide H—X-A B -A C -CONR 7 -c1-CO—OPG 2 or H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 is achieved by aminolysis, which is advantageously carried out with a dialkylaminoalkyl amine in solvents like degassed THF at 0-25° C. Acyl amine side products formed in the course of the reaction are easily removed by extraction with acidic aqueous solutions.
Arylether or Arylthioether Formation Between A and B (Steps c1, a3, c5)
Alkylation of the phenol or thiophenol like H—X-A B -A C -Y-Z-c1-CO—OPG 2 , H—X-A B -A C -CO—OPG 4 , or H—X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 with a suitably N-protected amino alcohol PG 3 -B-OH to the ether or thioether PG 3 -B-X-A B -A C -Y-Z-c1-CO—OPG 2 , PG 3 -B-X-A B -A C -CO—OPG 4 , or PG 3 -B-X-A B -A C -CO—NR 7 -c1-V-c2′=CH 2 is accomplished with azodicarboxylic acid derivatives such as DEAD, DIAD, TMAD or ADDP in the presence of trialkyl or triaryl phosphines in solvents like benzene, toluene, CH 2 Cl 2 , CHCl 3 or THF at 0° C. to room temperature. As a variation, the reaction is performed with CMBP in toluene at temperatures of 20-110° C.
In an alternative approach, the alcohol PG 3 -B-OH is converted into the corresponding sulfonate (e.g. mesylate, tosylate or triflate) or halide (e.g. chloride, bromide or iodide) and subsequently treated with the phenol/thiophenol H—X-A B -A C -CO—OPG 4 in the presence of an auxiliary base such as NaH or K 2 CO 3 in solvents like DMF, DMSO, NMP, HMPA, or THF, to yield PG 3 -B-X-A B -A C -CO—OPG 4 .
Cleavage of the Main Chain Protective Groups (Step d1)
Simultaneous or stepwise cleavage of the main chain protective groups provides the linear amino acids as cyclization precursors. The preferred protecting groups are Alloc as PG 3 and/or allylester as PG 2 , which can be cleaved simultaneously by palladium catalysts (e.g. Pd(PPh 3 ) 4 ) in the presence of 1,3-dimethyl barbituric acid in solvents like CH 2 Cl 2 or EtOAc or mixtures thereof.
Also applied were Boc as PG 3 and methyl, ethyl or tert-butyl ester as PG 2 . Boc and groups and t-Bu esters are cleaved either with TFA in CH 2 Cl 2 or with HCl-dioxane. Methyl or ethyl esters are best saponified with aq. LiOH in mixtures of MeOH and THF.
Macrolactamization (Steps e1, f4)
Macrolactamization occurs upon treatment of the cyclization precursor with coupling reagents like T3P or FDPP (if required in the presence of an auxiliary base such as i-Pr 2 NEt) in solvents like CH 2 Cl 2 or DMF under high dilution conditions and at temperatures ranging from 20 to 100° C.
Due to their synthetic importance, macrolactamizations are a well-investigated class of transformations. The favorable application of FDPP as cyclization mediator is described e.g. by J. Dudash et al., Synth. Commun. 1993, 23, 349-356; and R. Samy et al., J. Org. Chem. 1999, 64, 2711-2728. Many other coupling reagents were successfully utilized in related head to tail cyclizations and might be applied instead; examples include benzotriazole derivatives like HBTU, HCTU, PyBOP; or their aza analogs such as HATU, as well as DPPA, and carbodiimides like EDC or DIC (P. Li, P. P. Roller, Curr. Top. Med. Chem. 2002, 2, 325-341; D. L. Boger et al., J. Am. Chem. Soc. 1999, 121, 10004-10011). Still another route to macrolactams relies on the intramolecular reaction of an active ester with an in situ released amino group (e.g. by carbamate deprotection or azide reduction) as demonstrated in the synthesis of peptide alkaloids and vancomycin model systems (U. Schmidt et al., J. Org. Chem. 1982, 47, 3261-3264; K. C. Nicolaou et al., Chem. Commun. 1997, 1899-1900).
Ring-Closing Metathesis (RCM) (Step f5)
Ring-closing metathesis (RCM) of olefinic precursors to macrocyclic compounds is well documented (e.g. A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811-4820) and supplements the macrocyclization strategies described above.
The ring-closing metathesis is conveniently performed in solvents like CH 2 Cl 2 or toluene at temperatures of 20-100° C. in the presence of indenylidene-ruthenium complexes such as [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(II); dichloro-(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexyl-phosphine)-ruthenium(II); [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene(tri-cyclohexylphosphine)-ruthenium(II); or [1,3-bis(2,4,6-tri-methylphenyl)-2-imidazolidinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene)(pyridyl)ruthenium(II) (S. Monsaert et al., Eur. J. Inorg. Chem. 2008, 432-440 and references cited therein).
In addition to ring closing transformations described above, biaryl coupling reactions such as intramolecular Suzuki coupling and Suzuki-Miyaura conditions have been applied to prepare macrocyclic compounds with biaryl motifs (M. Kaiser et al., Org. Lett. 2003, 5, 3435-3437; R. Lépine et al., Org. Lett. 2005, 7, 2981-2984).
The coupling of arylboronato-carboxylic acids to amines is also described (cf ref. above, M. Kaiser et al., R. Lépine et al.); therefore the synthesis of linear precursors Hal-A B -X-B—CO-c1-NR 7 —CO-A C -B(OR) 2 (Hal represents a halogen atom or a triflate, B(OR) 2 a boronic acid or boronic ester functionality) an their cyclization in a Pd-catalyzed coupling reaction is a feasible alternative.
General Procedures for Synthetic Steps in SW-4
Synthesis of Linear Cyclization Precursors on Solid Support (Steps a4 to e4)
Chlorotrityl resins are frequently used in solid phase peptide synthesis. Therefore, attachment of Fmoc- or Alloc-protected amino acids to these resins as well as subsequent deprotection steps and coupling/deprotection of additional amino acids are well described (K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520; K. Barlos et al., Angew. Chem. Int. Ed. 1991, 30, 590-593). For the examples of the present invention, chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB) is treated with an N-terminally Fmoc-protected amino acid in CH 2 Cl 2 in the presence of an auxiliary base like i-Pr 2 NEt. Fmoc deprotection (DBU, DMF) and coupling/deprotection of Fmoc- or Alloc-protected amino acids provides a linear, N-terminally deprotected cyclization precursor, still attached to the resin. Fmoc- or Alloc-protected amino acids are coupled in the presence of reagents like HATU or PyBOP in DMF in the presence of i-Pr 2 NEt. Alloc protective groups were removed by treatment of the carbamate with Pd(PPh 3 ) 4 and phenylsilane in CH 2 Cl 2 . The linear cyclization precursor is then released by treatment of the resin with HFIP in CH 2 Cl 2 (R. Bollhagen et al. J. Chem. Soc. Chem. Commun. 1994, 2559-2560). It is well known, that peptides can also be cleaved from the resin using TFA in CH 2 Cl 2 or mixtures of acetic acid, 2,2,2-trifluoroethanol and CH 2 Cl 2 (K. Barlos et al., Int. J. Peptide Protein Res. 1991, 37, 513-520). The subsequent macrolactaminzation step is described above.
SW-6: Synthesis Workflow for Derivatizations of Attachment Points in Solution
The macrocyclic compounds obtained according to SW-1 to SW-3 and SW-5 can be further modified by transformations involving functional groups like, but not limited to, amino, carboxyl or hydroxyl groups. In addition, aromatic halides or sulfonates can be subjected to transition-metal catalyzed C—C or C-heteroatom-coupling reactions. The orthogonal protection of the attachment points allows stepwise deprotections and derivatizations which are carried out in a parallel fashion to generate substance libraries:
a6) Cleavage of the first protective group;
b6) Derivatization of the unmasked functional group;
c6) Cleavage of the second protective group;
d6) Derivatization of the liberated functional group; etc.
General Procedures for Synthetic Steps Utilized in SW-6
Protecting Group Cleavage (Steps a6 and c6)
The utilized amine protecting groups (e.g. Boc, Cbz, Teoc, Alloc, Fmoc, etc.), carboxylic acid protecting groups (e.g. tert-butyl, benzyl, allyl, methyl, etc.) or alcohol protecting groups (e.g. tert-butyl, benzyl, allyl, acetyl, benzoyl, pivaloyl) are removed under standard conditions (P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006; P. J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005).
Aryl nitro groups are reduced to anilines.
Attachment Point Derivatizations (Steps b6 and d6)
Derivatizations of the liberated functional groups are based on standard synthesis procedures (A. R. Katritzky et al. (eds), Comprehensive Functional Group Transformations , Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups , Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; leading reviews for Mitsunobu reaction: O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. Reactions ; Wiley, 1992, Vol. 42; leading reviews for reductive amination/alkylation: A. F. Abdel-Magid et al., J. Org. Chem. 1996, 61, 3849; E. W. Baxter, A. B. Reitz, Org. Reactions , Wiley, 2002, Vol. 59).
Such prototypical transformations include, but are not limited to:
(i) Amino group derivatizations such as
Amidations with carbonyl chlorides, carboxylic acid anhydrides, active esters; or with carboxylic acids in the presence of coupling reagents (cf. the general procedures);
Formation of sulfonamides with sulfonyl chlorides;
Reductive alkylation with carbonyl compounds; or alkylation with alkyl halides, alkylsulfonates or Michael acceptors;
Formation of ureas by reacting with isocyanates or their equivalents like carbamoyl chlorides or hydroxysuccinimidyl esters;
Transformation into thioureas with isothiocyanates or their equivalents;
Carbamate formation by reacting with chloroformates or their surrogates such as hydroxysuccinimidyl carbonates;
N-arylation to the corresponding N-aryl or N-heteroaryl derivatives with activated aromatic or heteroaromatic halides or sulfonates in the presence of an auxiliary base and/or transition metal catalyst like Pd or Cu catalyst (e.g. Buchwald-Hartwig coupling).
(ii) Carboxyl group derivatizations like
Amidation with amines in the presence of a coupling reagent;
Esterification with alcohols.
Reduction to alcohols (also obtained by reduction of the corresponding esters)
(iii) Alcoholic hydroxyl group derivatizations such as
Alkylation to alkyl ethers with alkyl halides or alkylsulfonates, trialkyloxonium tetrafluoroborates;
Transformation into aryl or heteroaryl ethers by reaction with (a) phenols in the presence of azodicarboxylic acid derivatives and triaryl or trialkyl phosphines (Mitsunobu type reactions); or (b) suitably activated aryl or heteroaryl halides or sulfonates;
Conversion into carbamates by reaction with isocyanates;
Conversion into primary amines (obtained e.g. by hydrogenation of azides, which in turn are prepared by the reaction of an alcohol with DPPA, PPh 3 , and DEAD) and derivatization of these amines as described above;
Oxidation to carbonyl compounds, which in turn can be further elaborated by e.g. reductive amination, Wittig reaction or related olefination reactions, etc.;
Esterification with carboxylic acids or their activated surrogates.
(iv) Aryl halide or sulfonate derivatizations by e.g. Suzuki, Sonogashira, Buchwald, Negishi or Kumada coupling reactions etc.
SW-7: Synthesis Workflow for Derivatizations of Functional Groups at the Solid Phase
As a possible alternative to SW-6, macrocyclic compounds I with one or more orthogonally protected exocyclic functional groups and one free primary amino group can be converted into fully derivatized products on solid support as previously described for related macrocyclic compounds (WO2011/014973) by:
a7) Attachment of the macrocyclic amine to an appropriately functionalized solid support by reductive amination;
b7) Acylation, carbamoylation, or sulfonylation, of the secondary amine functionality generated in the previous step a7 or conversion of this secondary amine functionality into carbamates;
c7) Removal of the protecting group from the second attachment point;
d7) Derivatization of the liberated second functional group whereby e.g. amino groups can be alkylated or converted into amides, ureas, thioureas carbamates, or sulfonamides; and carboxylic acid moieties can be transformed into amides or esters;
e7) Repetitions of steps c7 and d7 if a third, fourth etc. attachment point is available;
f7) Release of the final product from the solid support.
In case of macrocyclic carboxylic acids the attachment to a polymer-supported amine is followed by derivatizations and release in analogy to c7 to f7:
a8) Attachment of an amine to an appropriately functionalized solid support by reductive amination;
b8) Coupling of the macrocyclic carboxylic acid to the polymer-supported amine of step a8;
c8-f8) Derivatizations and release in analogy to steps c7-f7.
General Procedures for Synthetic Steps Utilized in SW-7
The Functionalized Solid Support
The solid support (polymer, resin) is preferably a derivative of polystyrene cross-linked with 1-5% divinylbenzene, of polystyrene coated with polyethyleneglycol (Tentagel™), or of polyacrylamide (D. Obrecht, J.-M. Villalgordo, Solid - Supported Combinatorial and Parallel Synthesis of Small - Molecular - Weight Compound Libraries , Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998). It is functionalized by means of a linker, i.e. an α,ω-bifunctional spacer molecule with an anchoring group for the solid support on one end, and on the other end by means of a selectively cleavable functional group that is used for subsequent transformations and finally for release of the product. For the examples of the present invention linkers are used that release an N-acyl (amide, urea, carbamate) or an N-sulfonyl (sulfonamide) derivative under acidic conditions. These kinds of linkers have been applied in the backbone amide linker (BAL) strategy for solid-phase synthesis of linear and cyclic peptides (K. J. Jensen et al., J. Am. Chem. Soc. 1998, 120, 5441-5452; J. Alsina et al., Chem. Eur. J. 1999, 5, 2787-2795) and heterocyclic compounds as well (T. F. Herpin et al., J. Comb. Chem. 2000, 2, 513-521; M. del Fresno et al., Tetrahedron Lett. 1998, 39, 2639-2642; N. S. Gray et al., Tetrahedron Lett. 1997, 38, 1161-1164).
Examples of such functionalized resins include DFPE polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene), DFPEM polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene), FMPB resins (4-(4-formyl-3-methoxy-phenoxy)butyryl AM-resin), FMPE polystyrene HL (2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL), FMPB NovaGel™ (4-(4-formyl-3-methoxyphenoxy)butyryl NovaGel; a PEG PS resin).
Attachment of the Macrocyclic Amine to the Functionalized Resin (Steps a7 and b7) and Subsequent N-Acylation or N-Sulfonylation
The macrocyclic primary amine is attached to the functionalized solid support by reductive amination preferably with NaBH(OAc) 3 as reducing agent in 1,2-dichloroethane and in the presence of trimethyl orthoformate or i-Pr 2 NEt.
The use of reductive aminations for such processes as well as the subsequent N-acylation or N-sulfonylation are well-documented; for example NaBH 3 CN in DMF or in methanol, or NaBH(OAc) 3 in DMF/acetic acid or in dichloromethane/acetic acid have been used (cf. references cited for the functionalized solid support). The N-acylation is favorably conducted with carboxylic acids in the presence of coupling reagents like PyBOP, PyBroP, or HATU or with carboxylic acid fluorides/chlorides or carboxylic acid anhydrides.
Deprotection (steps c7)
The second attachment point is an Alloc or Fmoc protected amino group or a carboxyl group protected as allyl ester. Standard methods (cf. SW-6) are applied for their deprotection and derivatization.
Release from the Resin (Step f7)
The final products are detached from the solid support by acids dissolved in organic solvents and/or H 2 O. The use of TFA in dichloromethane, of TFA in dichloromethane in the presence of a scavenger such as H 2 O or dimethyl sulfide, or of TFA/H 2 O and TFA/H 2 O/dimethylsulfide has been described (cf. references cited for the functionalized solid support).
Attachment of the Macrocyclic Carboxylic Acid to the Functionalized Resin (Steps a8 and b8)
A primary amine is attached to the functionalized solid support by reductive amination preferably using NaBH(OAc) 3 in 1,2-dichloroethane in the presence of trimethyl orthoformate.
Subsequent acylation with the macrocyclic carboxylic acids is favorably conducted in the presence of coupling reagents like HATU, PyBOP, or PyBroP.
It is worth mentioning that the initially attached primary amine corresponds to an attachment point derivatization of the carboxylic acid.
Properties and Usefulness
The macrocycles of type I of the present invention interact with specific biological targets. In particular, they show i) inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1), ii) inhibitory activity on the cysteine protease cathepsin S (CatS), iii) antagonistic activity on the oxytocin (OT) receptor), iv) antagonistic activity on the thyrotropin-releasing hormone (TRH) receptor), v) agonistic activity on the bombesin 3 (BB3) receptor, vi) antagonistic activity on the leukotriene B4 (LTB4) receptor, and/or vii) antimicrobial activity against at least one bacterial strain, in particular Staphylococcus aureus or Streptococcus pneumoniae.
Accordingly, these compounds are useful for the prevention or treatment of i) diseases resulting from abnormally high plasma or tissue levels of the potent vasoconstrictive peptide endothelin-1 (ET-1), like systemic and pulmonary hypertension, cerebral vasospasm and stroke, asthma, cardiac and renal failure, atherosclerosis, preeclampsia, benign prostatic hyperplasia, and carcinogenesis (S. De Lombaert et al., J. Med. Chem. 2000, 43, 488-504); ii) a wide range of diseases related to Cathepsin S, including neuropathic hyperalgesia, obesity, and in particular diseases of the immune system, like rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis, transplant rejection, diabetes, Sjøgrens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, and chronic obstructive pulmonary disease (COPD) (O. Irie et al., J. Med. Chem. 2008, 51, 5502-5505; WO2009/1112826); iii) diseases and conditions associated to an overexpression of oxytocin (OT), like preterm delivery (P. D. Williams, D. J. Pettibone, Curr. Pharm. Des. 1996, 2, 41-58; A. D. Borthwick, J. Med. Chem. 2010, 53, 6525-6538); iv) diseases related to a dysfunction in the homoestatic system of the thyrotropin-releasing hormone (TRH), such as infantile spasms, generalized and refractory partial seizures, edematous and destructive forms of acute pancreatitis, and certain inflammatory disorders (e.g. autoimmune diseases, inflammatory bowel diseases, cancer-related fatigue or depression, and Alzheimer's disease) (P.-Y. Deng et al., J. Physiol. 2006, 497-511; J. Kamath et al., Pharmacol. Ther. 2009, 121, 20-28); v) diseases related to a dysfunction of the bombesin 3 (BB3) receptor, like obesity and impairment of glucose metabolism, disorders of lung development, pulmonary diseases, CNS disorders and carcinogenesis (R. T. Jensen, Pharmacol. Rev. 2008, 60, 1-42); vi) diseases potentially treatable by blockade of the leukotriene B4 (LTB4) receptor, especially inflammatory and allergic diseases like asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, obliterative bronchiolitis after lung transplantation, or interstitial lung diseases (R. A. Goodnow, Jr., et al., J. Med. Chem. 2010, 53, 3502-3516; E. W. Gelfand et al., H. Ohnishi et., Allergol. Int. 2008, 57, 291-298); and/or vii) a wide range of infections caused by microorganisms, in particular strains of Staphylococcus aureus or Streptococcus pneumonia , comprising infections related to: a) respiratory diseases like cystic fibrosis, emphysema, asthma or pneumonia, b) skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles, c) gastrointestinal diseases including epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis, d) eye diseases such as keratitis and endophthalmitis, e) ear diseases, e.g. otitis, f) CNS diseases including brain abscess and meningitis or encephalitis, g) bone diseases such as osteochondritis and osteomyelitis, h) cardiovascular diseases like endocartitis and pericarditis, or i) genitourinal diseases such as epididymitis, prostatitis and urethritis (R. P. Rennie, Handb. Exp. Pharmacol. 2012, 211, 45-65; W. Bereket et al., Eur. Rev. Med. Pharmacol. Sci. 2012, 16, 1039-1044; D. P. Calfee, Curr. Opin. Infect. Dis. 2012, 25, 385-394). Additional uses of antimicrobial macrocycles of type I comprise the treatment or prevention of microbial infections in plants and animals or as disinfectants or preservatives for materials such as foodstuff, cosmetics, medicaments and other nutrient-containing materials.
The macrocycles, as such or after further optimization, may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well-known in the art.
When used to treat or prevent the diseases mentioned above the macrocycles can be administered singly, as mixtures of several macrocycles, or in combination with other pharmaceutically active agents. The macrocycles can be administered per se or as pharmaceutical compositions.
Pharmaceutical compositions comprising macrocycles of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active macrocycles into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
For topical administration the macrocycles of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
For injections, the macrocycles of type I may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the macrocycles of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
For oral administration, the compounds can be readily formulated per se or by combining the active macrocycles of the invention with pharmaceutically acceptable carriers well known in the art. Such carriers enable the macrocycles of type I to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, (e.g. lactose, sucrose, mannitol or sorbitol) or such as cellulose preparations (e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose); and/or granulating agents; and/or binding agents such as polyvinylpyrrolidone (PVP). If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. Solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.
For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.
For administration by inhalation, the macrocycles of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. hydrofluoroalkanes (HFA) such as HFA 134a (1,1,1,2,-tetrafluoroethane); carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocycles of the invention and a suitable powder base such as lactose or starch.
The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases like cocoa butter or other glycerides.
In addition to the formulations described above, the macrocycles of the invention may also be formulated as depot preparations. Such slow release, long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the macrocycles of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble salts.
Furthermore, other pharmaceutical delivery systems may be employed such as liposomes and emulsions. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the macrocycles of type I may be delivered using a sustained-release system, such as semi-permeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well-known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds over a period of a few days up to several months. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for stabilization may be employed.
As the macrocycles of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base or acid forms.
The macrocycles of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is understood that the amount used will depend on a particular application.
For example, the therapeutically effective dose for systemic administration can be estimated initially from in vitro assays: A dose can be formulated in animal models to achieve a circulating macrocycle concentration range that includes the IC 50 or EC 50 as determined in the cell culture (i.e. the concentration of a test compound that shows half maximal inhibitory concentration in case of antagonists or half maximal effective concentration in case agonists). Such information can be used to more accurately determine useful doses in humans.
Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art.
Dosage amounts for applications such as gastroparesis or schizophrenia etc. may be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.
In cases of local administration or selective uptake, the effective local concentration of the macrocycles of the invention may not be related to plasma concentration.
Those having the ordinary skill in the art will be able to optimize therapeutically effective dosages without undue experimentation.
The amount of macrocycle administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the method of administration and the judgment of the prescribing physician.
Normally, a therapeutically effective dose of the macrocycles described herein will provide therapeutic benefit without causing substantial toxicity.
Toxicity of the macrocycles can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LD 100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the macrocycles of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form and the route of administration. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (cf. E. Fingl et al. in L. Goodman und A. Gilman (eds), The Pharmacological Basis of Therapeutics, 5 th ed. 1975, Ch. 1, p. 1).
Another embodiment of the present invention may also include compounds, which are identical to the compounds of formula I, except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2 H (D), 3 H, 11 C, 14 C, 125 I etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and/or diagnostics, for example, but not limited to, fine-tuning of in vivo half-life.
EXAMPLES
The following examples illustrate the invention in more detail but are not intended to limit its scope in any way. Before specific examples are described in detail the used abbreviations and applied general methods are listed.
Ac: acetyl
addn: addition
ADDP: azodicarboxylic dipiperidide
Alloc: allyloxycarbonyl
AllocCl: allyl chloroformate
AllocOSu: allyloxycarbonyl-N-hydroxysuccinimide
AM-resin: aminomethyl resin
AM-PS: aminomethyl polystyrene
aq.: aqueous
arom.: aromatic
Bn: benzyl
BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
Boc: tert-butoxycarbonyl
br.: broad
Cbz: benzyloxycarbonyl
CbzCl: benzyl chloroformate
CbzOSu: N-(benzyloxycarbonyloxy)succinimide
Cl-HOBt: 6-chloro-1-hydroxybenzotriazole
CMBP: cyanomethylenetributyl-phosphorane
m-CPBA: 3-chloroperbenzoic acid
d: day(s) or doublet (spectral)
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCE: 1,2-dichloroethane
DEAD: diethyl azodicarboxylate
DFPE polystyrene: 2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene
DIAD: diisopropyl azodicarboxylate
DIC: N,N′-diisopropylcarbodiimide
DMAP: 4-(dimethylamino)pyridine
DME: 1,2-dimethoxyethane
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
DPPA: diphenyl phosphoryl azide
DVB: divinylbenzene
EDC: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
equiv.: equivalent
Et: ethyl
Et 3 N: triethylamine
Et 2 O: diethyl ether
EtOAc: ethyl acetate
EtOH: ethanol
exp.: experimental
FC: flash chromatography
FDPP: pentafluorophenyl diphenylphosphinate
FI-MS: flow injection mass spectrometry
Fmoc: 9-fluorenylmethoxycarbonyl
Fmoc-Cl: Fmoc chloride, 9-fluorenylmethyl chloroformate
Fmoc-OSu: (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (or 9-fluorenylmethyl-succinimidyl carbonate)
h: hour(s)
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
HBTU: O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
mCPBA: 3-chloroperbenzoic acid
HCTU: O-(6-chlorobenoztriazol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate
HFIP: Hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol)
HL: high loading
HOAt: 1-hydroxy-7-azabenzotriazole
HOBt.H 2 O: 1-hydroxybenzotriazole hydrate
HMPA: hexamethylphosphoramide
i.v.: in vacuo
m: multiplet (spectral)
MeCN: acetonitrile
MeOH: methanol
Me: methyl
NMP: 1-methyl-2-pyrrolidinone
Ns: 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl
PdCl 2 (PPh 3 ) 2 : bis(triphenylphosphine)palladium (II) dichloride
Pd(dppf)Cl 2 .CH 2 Cl 2 : [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane
Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium(0)
PEG PS resin: polyethyleneglycol coated polystyrene resin
PG: protective group
Ph: phenyl
PPh 3 : triphenylphosphine
prep.: preparative
i-Pr: isopropyl
i-Pr 2 NEt: N-ethyl-N,N-diisopropylamine
i-PrOH: isopropanol
PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
PyBroP: bromotripyrrolidinophosphonium hexafluorophosphate
PyClu: N,N,N′,N′-bis-(tetramethylene)-chloroforamidinium hexafluorophosphate
q: quartet (spectral)
quant.: quantitative
quint: quintet (spectral)
rt: room temperature
s: singlet (spectral)
sat.: saturated
soln: solution
TBAF: tetrabutylammonium fluoride
t: triplet (spectral)
Teoc: 2-(trimethylsilyl)ethoxycarbonyl
tert.: tertiary
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TLC: thin layer chromatography
TMAD: tetramethylazodicarboxamide
T3P=T3P™: propanephosphonic acid cyclic anhydride
p-TsOH: p-toluenesulfonic acid
Umicore M72 SIMes (RD): [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(II)
General Methods
TLC: Merck (silica gel 60 F254, 0.25 mm).
Flash chromatography (FC): Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm).
I. Analytical HPLC-MS methods:
R t in min (purity at 220 nm in %), m/z [M+H] +
UV wave length 220 nm, 254 nm
MS: Electrospray Ionization
Volume of injection: 5 μL
Method 1
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 3×50 mm (53811U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 1a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 1b: MS scan range: 95-800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 1c: MS scan range: 95-1800 Da; centroid mode, positive mode 20V, scan time: 1 sec
Method 1d: MS scan range: 95-1800 Da; profile mode, positive mode 40V, scan time: 1 sec
Method 1e: MS scan range: 95-1800 Da; profile mode, positive mode 80V, scan time: 1 sec
Method 1f: MS scan range: 95-1800 Da; profile mode, positive mode 20V, scan time: 1 sec
Method 1g: MS scan range: 95-1800 Da; centroid mode, positive mode 80V, scan time: 1 sec
Method 2
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 3×50 mm (53811U—Supelco Inc.)
Mobile Phases: A: Ammonium Bicarbonate 1 mM in Water—pH=10 in Water; B: MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 2a: MS scan range: 95-800 Da; centroid mode, negative mode 40V scan time: 1 sec
Method 2b: MS scan range: 95-1800 Da; centroid mode, negative mode 40V scan time: 1 sec
Method 2c: MS scan range: 95-1800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 2d: MS scan range: 95-1800 Da; centroid mode, positive mode 20V scan time: 1 sec
Method 2e: MS scan range: 95-800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 2f: MS scan range: 95-1800 Da; profile mode, positive mode 40V scan time: 1 sec
Method 3
LC-MS: Dionex Ultimate 3000 RS (DAD detector)
Column: Ascentis Express™ C18 2.7 μm, 2.1×50 mm (53822-U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.4 97 3 0.05 1.4 97 3 1.95 1.4 3 97 2.15 1.4 3 97 2.18 1.4 97 3 2.3 1.4 97 3
Method 3a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V scan time: 1 sec
Method 3b: MS scan range: 95-1800 Da; profile mode, positive mode 40V scan time: 1 sec
Method 4
LC-MS: Agilent HP1100 (DAD detector)
Column: Ascentis Express™ F5 2.7 μm, 3×50 mm (53576-U—Supelco Inc.)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Method 4a and method 4b
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 70 30 0.05 1.3 70 30 2.95 1.3 30 97 3.15 1.3 30 97 3.17 1.3 70 30 3.2 1.3 70 30
Method 4a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
Method 4b: MS scan range: 95-1800 Da; profile mode, positive mode 40V, scan time: 1 sec
Method 4c
Gradient:
Time Flow [min.] [mL/min] % A % B 0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3
Method 4c: MS scan range: 95-1800 Da; centroid mode, positive mode 20V, scan time: 1 sec
Method 5
LC-MS: Agilent HP1100 (DAD detector)
Column: Atlantis™ T3 3 μm, 2.1×50 mm (186003717—Waters AG)
Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55° C.
Gradient:
Time Flow [min.] [mL/min] % A % B 0 0.8 100 0 0.1 0.8 100 0 2.9 0.8 50 50 2.95 0.8 3 97 3.2 0.8 3 97 3.22 0.8 100 100 3.3 0.8 100 100
Method 5a: MS scan range: 95-1800 Da; centroid mode, positive mode 40V, scan time: 1 sec
II. Preparative HPLC methods:
1. Reverse Phase—Acidic Conditions
Method 1a
Column: XBridge™ C18 5 μm, 30×150 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1b
Column: XBridge™ C18 5 μm, 30×100 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1c
Column: Gemini-NX™ C18 5 μm, 30×100 mm (Phenomenex Inc.)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: 0.1% TFA Acetonitrile
Method 1d
Column: XBridge™ Prep C18 10 μm, 50×250 mm (Waters AG)
Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v
B: Acetonitrile
Flow rate: 150 mL/min
2. Reverse Phase—Basic conditions
Method 2a
Column: XBridge™ C18 5 μm, 30×150 mm (Waters AG)
Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v
B: Acetonitrile
Method 2b
Column: XBridge™ C18 5 μm, 30×100 mm (Waters AG)
Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v
B: Acetonitrile
3. Normal Phase
Method 3
Column: VP 100/21 NUCLEOSIL™ 50-10, 21×100 mm (Macherey-Nagel AG)
Mobile phases:
A: Hexane B: Ethylacetate C: Methanol
FI-MS: Agilent HP1100; m/z [M+H] +
NMR Spectroscopy: Bruker Avance 300, 1 H-NMR (300 MHz) in the indicated solvent at ambient temperature. Chemical shifts δ in ppm, coupling constants J in Hz.
SPECIFIC EXAMPLES
In the examples below and if no other sources are cited, leading reference for standard conditions of protecting group manipulations (protection and deprotection) are 1) P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , John Wiley and Sons, 4th Edition, 2006; 2) P. J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005; and 3) M. Goodman (ed.), Methods of Organic Chemistry (Houben-Weyl), Vol E22a, Synthesis of Peptides and Peptidomimetics, Georg Thieme Verlag 2004.
Starting Materials
Template A Building Blocks (Scheme 5):
3′-Hydroxybiphenyl-2-carboxylic acid (1) is commercially available.
Methyl 3′-hydroxybiphenyl-2-carboxylate (2)
Thionyl chloride (7.7 mL, 105 mmol) was added at 0° C. to a soln of 1 (4.5 g, 21.0 mmol) in MeOH (55 mL). The mixture was stirred for 10 min at 0° C. and then heated to reflux for 4 h. Evaporation of the volatiles, aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 5:1) afforded the ester 2 (4.34 g, 90%).
Data of 2: C 14 H 12 O 3 (228.2). 1 H-NMR (DMSO-d 6 ): 9.52 (br. s, OH); 7.68 (dd, J=1.1, 7.6, 1H); 7.59 (dt, J=1.5, 7.6, 1H); 7.47 (dt, J=1.3, 7.5, 1H); 7.40 (dd, J=0.9, 7.6, 1H); 7.20 (t-like m, J=8.0, 1H); 6.75 (m, 1H); 6.70-6.67 (m, 2H); 3.59 (s, 3H).
2′-Hydroxybiphenyl-3-carboxylic acid (3) is commercially available.
Methyl 2′-hydroxybiphenyl-3-carboxylate (4)
Thionyl chloride (6.8 mL, 93 mmol) was added at 0° C. to a soln of 3 (4.0 g, 18.6 mmol) in MeOH (60 mL). The mixture was stirred for 10 min at 0° C. and then heated to reflux for 3 h. Evaporation of the volatiles and aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded the ester 4 (3.68 g, 86%).
Data of 4: C 14 H 12 O 3 (228.2). LC-MS (method 2a): R t =1.95 (98), 226.9 ([M−H] − ). 1 H-NMR (DMSO-d 6 ): 9.66 (s, 1H); 8.16 (t, J=1.6, 1H); 7.89 (d-like m, 1H); 7.81 (d-like m, 1H); 7.56 (t, J=7.7, 1H); 7.29 (dd, J=1.7, 7.6, 1H); 7.20 (t-like m, 1H); 6.98-6.88 (m, 2H); 3.87 (s, 3H).
2′-Hydroxy-5′-methoxybiphenyl-3-carboxylic acid (5) is commercially available.
Methyl 2′-hydroxy-5′-methoxybiphenyl-3-carboxylate (6)
Thionyl chloride (5.14 mL, 71 mmol) was added at 0° C. to a soln of 5 (5.74 g, 23.5 mmol) in MeOH (100 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 4:1) afforded the ester 6 (5.1 g, 84%).
Data of 6: C 15 H 14 O 4 (258.3). 1 H-NMR (DMSO-d 6 ): 9.18 (s, OH); 8.17 (t, J=1.7, 1H); 7.89 (td, J=1.4, 7.8, 1H); 7.82 (td, J=1.5, 8.0, 1H); 7.56 (t, J=7.8, 1H); 6.91-6.78 (m, 3H); 3.87 (s, 3H); 3.72 (s, 3H).
3′-Hydroxybiphenyl-3-carboxylic acid (7) is commercially available.
Methyl 3′-hydroxybiphenyl-3-carboxylate (8)
Thionyl chloride (4.1 mL, 56 mmol) was added at 0° C. to a soln of 7 (4.0 g, 18.6 mmol) in MeOH (160 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, filtration of the residue through a pad of silica gel (EtOAc) and FC (hexane/EtOAc 93:7 to 0:100) afforded the ester 8 (4.0 g, 94%).
Data of 8: C 14 H 12 O 3 (228.2). LC-MS (method 2a): R t =1.90 (98), 227.3 ([M−H] − ). 1 H-NMR (DMSO-d 6 ): 9.63 (br. s, OH); 8.13 (t, J=1.6, 1H); 7.96-7.88 (m, 2H), 7.61 (t, J=7.7, 1H); 7.29 (t, J=7.8, 1H); 7.10 (m, 1H); 7.06 (t, J=2.0, 1H); 6.81 (m, 1H); 3.89 (s, 3H).
5-(3-Hydroxyphenyl)nicotinic acid (9) is commercially available.
5-(3-Acetoxyphenyl)nicotinic acid (10)
At 0° C. acetic anhydride (18.8 mL, 0.2 mol) was added dropwise to a soln of 5-(3-hydroxyphenyl)nicotinic acid (9; 7.13 g, 0.033 mol) in 4 M aq. NaOH soln (41.4 mL, 0.166 mol). The mixture was stirred for 1 h. A precipitate was formed. The mixture was diluted with 4 M aq. NaOH soln (41.4 mL, 0.166 mol). More acetic anhydride (18.8 mL, 0.2 mol) was added and stirring was continued for 2 h followed by the addition of H 2 O (50 mL). The mixture was acidified to pH 1 by addition of 3 M aq. HCl soln. The solid was filtered, washed (H 2 O) and dried i.v. to afford 10.HCl (8.22 g, 84%).
Data of 10.HCl: C 14 H 11 NO 4 .HCl (257.2, free base). LC-MS (method 1b): R t =1.22 (99), 258.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.62 (very br. s, 1H); 9.12 (d, J=2.0, 1H); 9.07 (d, J=1.3, 1H); 8.46 (s, 1H); 7.71 (d, J=7.7, 1H); 7.63 (s, 1H); 7.57 (t, J=7.9, 1H); 7.23 (d, J=8.0, 1H); 2.31 (s, 3H).
2-Bromothiophenol (11) is commercially available.
3-Hydroxyphenylboronic acid (12) is commercially available.
5-Bromopyridine-3-thiol (13) was prepared as described in the literature (S. A. Thomas et al. Bioorg. Med. Chem. Lett. 2006, 16, 3740-3744).
2-Hydroxyphenylboronic acid (14) is commercially available.
4-(3-Hydroxypyridin-2-yl)benzoic acid (92) is commercially available.
Methyl 4-(3-hydroxypyridin-2-yl)benzoate (93)
Thionyl chloride (7.6 mL, 104 mmol) was added at 4° C. to a soln of 92 (4.5 g, 21.0 mmol) in MeOH (130 mL). The mixture was heated to 70° C. for 14 h and concentrated. The residue was dissolved in CHCl 3 (200 mL) and EtOH (20 mL) and treated with aq. NaHCO 3 soln (100 mL). The organic phase was separated, the aq. phase was extracted repeatedly with CHCl 3 . The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated to afford the ester 93 (4.45 g, 92%).
Data of 93: C 13 H 11 NO 3 (229.2). LC-MS (method 1a): R t =1.07 (90), 230.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 10.40 (br. s, OH), 8.32-8.18 (m, 3H); 8.02 (d, J=8.6, 2 H), 7.38 (dd, J=1.4, 8.2, 1H); 7.26 (dd, J=4.4, 8.2, 1H); 3.88 (s, 3H).
4-(3-Fluoro-5-hydroxyphenyl)thiophene-2-carboxylic acid (98)
At rt, a solution of tert-butyl 2,2,2-trichloroacetimidate (27.7 mL, 155 mmol) in CH 2 Cl 2 (50 mL) was added dropwise to a soln of 4-bromothiophene-2-carboxylic acid (94; 16.0 g, 77.3 mmol) in CH 2 Cl 2 (150 mL). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%).
Sat. aq. NaHCO 3 soln (183 mL) was added to a soln of 95 (17.2 g, 65.2 mmol), 3-fluoro-5-hydroxyphenylboronic acid (96; 15.3 g, 97.9 mmol) and Pd(PPh 3 ) 4 (3.77 g, 3.26 mmol) in dioxane (517 mL). The mixture was heated to reflux for 2 h. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 90:10) afforded 97 (12.55 g, 65%).
TFA (150 mL) was added at rt to a mixture of 97 (12.5 g, 42.6 mmol) in CH 2 Cl 2 (150 mL). The soln was stirred for 2.5 h and concentrated to give 98 (10.3 g, quant. yield).
Data of 98: C 11 H 7 FO 3 S (238.2). 1 H-NMR (DMSO-d 6 ): 13.23 (br. s, 1H); 10.03 (br. s, 1H); 8.21 (d, J=1.6, 1H); 8.05 (d, J=1.6, 1H); 7.05 (m, 1H); 6.95 (t, J=1.7, 1H), 6.53 (td, J=2.2, 10.7, 1H).
3-(Allyloxy)-N-methoxy-N-methylthiophene-2-carboxamide (102)
At 0° C., allyl bromide (18.1 mL, 209 mmol) was added dropwise to a mixture of 3-hydroxythiophene-2-carboxylic acid (99; 10.0 g, 69.8 mmol) and K 2 CO 3 (48.2 g, 349 mmol) in DMF (255 mL). The mixture was allowed to stir for 2 h at 0° C. to rt. The mixture was filtered and the residue was washed with EtOAc. The filtrate was concentrated, followed by an aqueous workup (Et 20 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, H 2 O; Na 2 SO 4 ) to give ester 100 (15.5 g).
At rt, 2 M aq. LiOH soln (346 mL, 691 mmol) was added to a soln of the crude ester 100 (15.5 g) in DME (315 mL). The mixture was heated to 50° C. for 16 h and concentrated. The residue was distributed between H 2 O and EtOAc. The aqueous phase was acidified with 1 M aq. HCl soln and repeatedly extracted with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to afford the acid 101 (11.5 g, 90%).
At 5° C., i-Pr 2 NEt (42.3 mL, 249 mmol) was added dropwise to a mixture of 101 (11.45 g, 62.2 mmol), N,O-dimethylhydroxylamine hydrochloride (7.28 g, 74.6 mmol), EDC-HCl (14.3 g, 74.6 mmol), HOBt.H 2 O (11.4 g, 74.6 mmol) and DMAP (1.52 g, 12.4 mmol) in DMF (116 mL). The mixture was allowed to warm to rt over 5 h followed by an aqueous workup (EtOAc, 1 M aq. HCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1) to afford 102 (9.69 g, 69%).
Data of 102: C 10 H 13 NO 3 S (227.3). LC-MS (method 1c): R t =1.59 (92), 228.1 ([M+H] + ).
tert-Butyl 3-(3-hydroxythiophen-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (106)
n-Butyllithium (1.6 M in hexane; 41.9 mL, 67.0 mmol) was added dropwise within 10 min at −55 to −50° C. to a soln of tert-butyl propiolate (103; 8.76 mL, 63.8 mmol) in dry THF (200 mL). The mixture was allowed to stir at −40° C. for 1.5 h. The mixture was cooled to −78° C. A soln of 102 (7.25 g, 31 9 mmol) in THF (66 mL) was added within 10 min with the temperature not exceeding −64° C. The mixture was stirred for 0.5 h at −78° C., then warmed to −40° C. and allowed to slowly warm to 0° C. over 3 h. The mixture was poured into 1 M aq. KHSO 4 soln and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and concentrated. FC (hexane/EtOAc 90:10 to 70:30) afforded the ketone 104 (8.34 g, 89%).
Methylhydrazine (1.0 mL, 18.8 mmol) was added at rt to a soln of 104 (4.6 g, 16 mmol) in EtOH (62 mL). Stirring was continued for 1 h and the volatiles were evaporated. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 90:10) gave pyrazole 105 (4.25 g, 84%).
Data of 105: C 16 H 20 N 2 O 3 S (320.4). LC-MS (method 4a): R t =1.80 (96), 321.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.08 (s, 1H); 7.07 (d, J ca 5.9, 1H); 6.06 (m, 1H); 5.43 (qd, J=1.7, 17.3, 1H); 5.29 (qd, J=1.6, 10.6, 1H); 4.69 (td, J=1.6, 5.0, 2 H); 4.05 (s, 3H); 1.55 (s, 9H).
Phenylsilane (15.0 mL, 121 mmol) was added to a soln of 105 (7.75 g, 24 mmol) and Pd(PPh 3 ) 4 (1.4 g, 1.2 mmol) in THF (78 mL). The mixture was stirred at rt for 16 h. More Pd(PPh 3 ) 4 (0.8 g, 0.7 mmol) and phenylsilane (6.0 mL, 48 mmol) were added and stirring was continued for 24 h. The volatiles were evaporated followed by an aqueous workup (EtOAc, 1 M NH 4 Cl soln) and FC (hexane/EtOAc 90:10) to yield 106 (5.75 g, 84%).
Data of 106: C 13 H 16 N 2 O 3 S (280.3). LC-MS (method 1a): R t =2.40 (94), 281.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 10.01 (br. s, 1H); 7.24 (d, J=5.3, 1H); 7.04 (s, 1H); 6.72 (d, J=5.3, 1H); 4.04 (s, 3H); 1.55 (s, 9H).
2-(4-Hydroxy-3-nitrophenyl)-6-methylpyrimidine-4-carboxylic acid (110)
Sat. aq. Na 2 CO 3 soln (52.5 mL) was added to a soln of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (107; 5.0 g, 26.8 mmol), 4-methoxy-3-nitrophenylboronic acid (108; 6.86 g, 34.8 mmol) and PdCl 2 (PPh 3 ) 2 (0.94 g, 1.3 mmol) in dioxane (175 mL). The mixture was heated to reflux for 4 h and partially concentrated, followed by an aqueous workup (EtOAc, 1 M aq. HCl soln; sat. aq. NaCl soln; Na 2 SO 4 ). The crude product was suspended in CH 2 Cl 2 /MeOH 2:1; the solid was filtered, washed (MeOH) and dried i.v to afford 109.HCl (3.7 g, 42%). The filtrate was concentrated and purified by FC(CH 2 Cl 2 /MeOH 100:0 to 70:30) to give 109.HCl (3.87 g, 44%).
A mixture of 109.HCl (7.5 g, 23.1 mmol) and LiCl (4.9 g, 11.5 mmol) in DMF (100 mL) was heated to 145° C. for 18 h. The volatiles were mostly evaporated. The residue was cooled to 0° C. and treated with 1 M aq. HCl soln (250 mL). The resulting suspension was sonicated and filtered. The solid material was washed (Et 2 O) and dried. The solid material was suspended in CH 2 Cl 2 /Et 2 O 1:4, filtered and dried to give 110.HCl (6.5 g, 80%).
Data of 110.HCl: C 12 H 9 N 3 O 5 .HCl (free base, 275.2). LC-MS (method 1a): R t =1.73 (83), 276.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.91 (d, J=1.9, 1H); 8.56 (dd, J=1.9, 8.8, 1H); 7.80 (s, 1H); 7.30 (d, J=8.8, 1H); 2.63 (s, 3H).
2-Iodophenol (111) is commercially available.
2-(Ethoxycarbonyl)phenylboronic acid (112) is commercially available.
Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (113) is commercially available.
4-(3-Hydroxyphenyl)-2-(trifluoromethyl)oxazole-5-carboxylic acid (117)
The aminoacrylic acid ester 115 was prepared according to J. H. Lee et al, J. Org. Chem. 2007, 72, 10261.
The 2-(trifluoromethyl)oxazole 116 was prepared as described by F. Zhao et al. J. Org. Chem. 2011, 76, 10338 for similar compounds:
A degassed soln of 115 (2.15 g, 9.72 mmol) in DCE (500 mL) was warmed to 45° C. [Bis(trifluoroacetoxy)iodo]benzene (5.02 g, 11.67 mmol) was added in one portion, and stirring at 45° C. was continued for 16 h. Evaporation of the volatiles and FC (hexane/EtOAc 98:2) afforded 116 (1.55 g, 50%).
Data of 116: C 14 H 12 F 3 NO 4 (315.2). 1 H-NMR (DMSO-d 6 ): 7.62-7.57 (m, 2H); 7.45 (t, J=8.0, 1H); 7.11 (m, 1H); 4.38 (q, J=7.1, 2 H); 3.81 (s, 3H); 1.31 (t, J=7.1, 3 H). At 0° C., BBr 3 (1 M in THF; 24.2 mL, 24.2 mmol) was added dropwise to a soln of 116 (1.5 g, 4.85 mmol) in CH 2 Cl 2 (3.5 mL). The mixture was stirred for 16 h at 0° C. to rt, slowly added onto ice-cold water (500 mL) and extracted with EtOAc. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 75:25 to 0:100, then CH 2 Cl 2 /MeOH 90:10) afforded 117 (1.24 g, 95%).
Data of 117: C 11 H 6 F 3 NO 4 (273.2). 1 H-NMR (DMSO-d 6 ): 9.54 (br. s, 1H), 7.71-7.65 (m, 2H); 7.23 (t, J=7.9, 1H); 6.80 (m, 1H).
Modulator B Building Blocks (Scheme 6):
tert-Butyl (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (15.HCl) is commercially available.
(2S,4S)-Allyl 4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (16) was prepared by Alloc protection of the secondary amino group of 15.HCl with allyl chloroformate in CH 2 Cl 2 in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 16: C 14 H 24 N 2 O 5 (300.4). 1 H-NMR (DMSO-d 6 ): 7.12 (br. d, J=6.1, 1H); 5.91 (m, 1H); 5.27 (m, 1H); 5.18 (m, 1H); 4.49 (m, 2H); ca 3.9 (br. m, 1H); 3.89-3.57 (several m, 4H); 3.48 (dd, J=3.1, 10.6, 1H); 2.95 (br. m, 1H); 2.21 (br. m, 1H); 1.75 (br. m, 1H); 1.38 (s, 9H).
tert-Butyl (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (17.HCl) is commercially available.
(2S,4R)-Allyl 4-(tert-butoxycarbonylamino)-2-(hydroxylmethyl)-pyrrolidin-1-carboxylate (18) was prepared by Alloc protection of the secondary amino group of 17.HCl with allyl chloroformate in CH 2 Cl 2 in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 18: C 14 H 24 N 2 O 5 (300.4). 1 H-NMR (DMSO-d 6 ): 7.08 (br. d, J=7.1, 1H); 5.91 (m, 1H); 5.26 (br. m, 1H); 5.18 (br. d, J ca 10.4, 1H); 4.52 (br. m, 2H), ca 4.1 (br. m, 2H); 3.82 (br. m, 1H); ca 3.5-3.35 (br. s-like m, 3H); 3.19 (br. m, 1H); 2.05 (br. m, 1H); 1.79 (br. m, 1H); 1.38 (s, 9H).
N-Boc-L-alaninol (19) is commercially available.
N-Boc-D-alaninol (20) is commercially available.
(S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21) is commercially available.
(2S,4S)-Allyl 4-(4-bromobenzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (118) was prepared as described in the preceding patent application (WO 2011/014973 A2).
(S)-(+)-Prolinol (119) is commercially available.
(S)-Allyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (120) was prepared by Alloc protection of the secondary amino group of (S)-(+)-prolinol (119) with allyl chloroformate in dioxane in the presence of aq. NaHCO 3 soln applying standard conditions.
Data of 120: C 9 H 15 NO 3 (185.2). FI-MS: 186.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 5.92 (m, 1H); 5.28 (br. dd-like m, 1H); 5.18 (br. dd-like m, 1H); 4.72 (br. not resolved m, 1H); 4.60-4.45 (br. not resolved m, 2H); 3.73 (br. not resolved m, 1H); 3.50 (br. not resolved m, 1H); 3.35-3.25 (br. not resolved m, 3H); 2.0-1.75 (br. not resolved m, 4H).
(2S,4R)-tert-Butyl 4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate hydrochloride (121.HCl) is commercially available.
(2S,4R)-tert-Butyl 4-(benzyloxycarbonylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (122) was prepared by Cbz protection of the primary amino group of 121.HCl with benzyl chloroformate in CH 2 Cl 2 in the presence of aq. Na 2 CO 3 soln applying standard conditions.
Data of 122: C 18 H 26 N 2 O 5 (350.4). LC-MS (method 1c): R t =1.89 (95), 351.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.49 (d, J=6.8, 1H); 7.42-7.28 (m, 5H); 5.02 (s, 2H); 4.76 (br. s, 1H); 4.13 (br. not resolved m, 1H), 3.76 (br. not resolved m, 1H); 3.40 (m, 3 H; partially superimposed by H 2 O signal); 3.11 (dd; J=6.4, 10.6, 1H); 2.07 (br. not resolved m, 1H); 1.82 (br. not resolved m, 1H); 1.38 (s, 9H).
Building Blocks for Subunits of Bridge C (Scheme 7):
(R)-Allyl 4-amino-2-(benzyloxycarbonylamino)butanoate toluene-4-sulfonate (22.pTsOH) was prepared as described for the (S)-enantiomer in the preceding patent application (WO 2011/014973 A2).
(S)-Allyl 2-(benzyloxycarbonylamino)-(5-methylamino)pentanoate hydrochloride (23.HCl), (S)-5-allyl 1-benzyl 2-(methylamino)pentanedioate hydrochloride (24.HCl) and (S)-5-allyl 1-benzyl 2-aminopentanedioate hydrochloride (25.HCl) were prepared as described in the preceding patent application (WO 2011/014973 A2).
Ethyl 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (28.HCl)
Ethyl 2-(2-(tert-butoxycarbonylamino)ethylamino)acetate hydrochloride (26.HCl; 25.0 g, 88 mmol) was added to a mixture of dioxane (250 mL) and 1 M aq. Na 2 CO 3 soln (250 mL). After 5 min, CbzCl (17.0 g, 98 mmol) was slowly added and the mixture was stirred for 2 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 ; Na 2 SO 4 ) and FC (hexane/EtOAc 8:2 to 1:1) afforded 27 (29.0 g, 85%). A solution of 27 (29.5 g, 77.5 mmol) in 4 M HCl-dioxane (300 mL) was stirred at rt for 2 h and concentrated. The residue was washed with Et 2 O to give 28.HCl (24.3 g, 99%).
Data of 28.HCl: C 14 H 20 N 2 O 4 .HCl (280.3, free base). LC-MS (method 1a): R t =1.33 (99), 281.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.05 (br. s, NH 3 + ); 7.39-7.28 (m, 5 arom. H); 5.12, 5.07 (2 s; 2H); 4.16-4.04 (m, 4H); 3.54 (m, 2H); 2.97 (br m, 2H); 1.19, 1.32 (2 t, J=7.1, 3 H).
(S)-Methyl 2-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (30)
At 0° C., iodomethane (8.18 mL, 131 mmol) was added to a suspension of Boc-L-6-hydroxynorleucine (29; 25 g, 101 mmol) and NaHCO 3 (42.5 g, 505 mmol) in DMF (790 mL). The mixture was stirred at 0° C. to rt for 16 h. The mixture was filtered. The filtrate was distributed between EtOAc and 1 M aq. HCl soln. The organic layer was subsequently washed with H 2 O, sat. aq. NaHCO 3 soln and sat. aq. NaCl soln. The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated to afford 30 (24.54 g, 92%).
Data of 30: C 12 H 23 NO 5 (261.3). FI-MS: 262.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.21 (d, J=7.8, 1H); 4.36 (t, J=5.2, 1H); 3.92 (m, 1H); 3.61 (s, 3H); 3.36 (q, J=5.8, 2 H); 1.59 (m, 2H); 1.44 (s, 9H); 1.44-1.26 (m, 4H).
(S)-3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid (31; Fmoc-β 3 -homoPhe-OH) is commercially available.
3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanoic acid (33; Fmoc-NMe-β-Ala-OH) was prepared from 3-(methylamino)propanoic acid hydrochloride (32.HCl) applying Fmoc-OSu and Na 2 CO 3 in H 2 O and dioxane.
Data of 33: C 19 H 19 NO 4 (325.3). LC-MS (method 1a): R t =1.95 (96), 326.0 ([M+H] + ).
3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)propanoic acid (34; Fmoc-β-Ala-OH) is commercially available.
Synthesis of (R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)butanoic acid (40; Fmoc-NMe-β 3 -homoDAla-OH)
At 0° C., 4 M HCl-dioxane (37.8 mL, 151 mmol) was added dropwise to a mixture of (R)-homo-β-alanine (35; 13.0 g, 126 mmol) in CH 2 Cl 2 (170 mL). PCl 5 (31.5 g, 151 mmol) was added to the suspension. The mixture was stirred at 0° C. to rt for 15 h. A clear solution resulted. The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 (150 mL). Allyl alcohol (10.3 mL, 151 mmol) was added slowly and the mixture was stirred for 2 h at rt. The volatiles were evaporated to afford crude 36.HCl (25.6 g).
Pyridine (115 mL) was added to a soln of crude 36.HCl (25.5 g) in CH 2 Cl 2 (275 mL). The mixture was cooled to 0° C., followed by the addition of 4-nitrobenzenesulfonyl chloride (63 g, 284 mmol). The mixture was stirred at 0° C. to rt for 16 h. Aq. workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 9:1 to 1:1) yielded 37 (26.7 g, 64%).
K 2 CO 3 (56 g, 404 mmol) was added to a solution of 37 (26.5 g, 81 mmol) in DMF (295 mL). Iodomethane (50 mL, 807 mmol) was added at 0° C. and the mixture was allowed to warm to rt over 3 h. Aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) gave crude 38 (27.6 g).
K 2 CO 3 (16.7 g, 121 mmol) was added to a soln of crude 38 (13.8 g, ca 40 mmol) in CH 3 CN (275 mL). The mixture was degassed, cooled to 0° C. and treated with thiophenol (6.15 mL, 60 mmol). The mixture was stirred at 0° C. to rt for 15 h. H 2 O (115 mL) and (in portions) Fmoc-Cl (10.5 g, 40.3 mmol) were added. Stirring was continued for 3 h followed by an aq. workup (EtOAc, sat. aq. Na 2 CO 3 ; Na 2 SO 4 ) and FC (hexane/EtOAc 95:5 to 70:30). The material obtained (11.5 g) was purified again by FC (hexane/CH 2 Cl 2 8:2, then CH 2 Cl 2 , then CH 2 Cl 2 /EtOAc) to give 39 (9.2 g, 60%). A degassed soln of 39 (18.3 g, 48.2 mmol) in CH 2 Cl 2 (175 mL)/EtOAc (210 mL) was treated with Pd(PPh 3 ) 4 (0.9 g, 0.77 mmol) and 1,3-dimethylbarbituric acid (9.04 g, 57.9 mmol) for 3 h at rt. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded 40 (7.55 g, 46%) and impure material which was further purified by prep. HPLC (method 1d) to give more 40 (5.61 g, 34%).
Data of 40: C 20 H 21 NO 4 (339.4). LC-MS (method 1a): R t =2.03 (96), 340.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 12.2 (br. s, 1H); 7.89 (d, J=7.4, 2 H); 7.65 (br. s, 2H); 7.41 (t, J=7.4, 2 H); 7.33 (t, J=7.3, 2 H); 4.40-4.24 (m, 4H), 2.67 (s, 3H); 2.45-2.30 (br. m, 2H); 1.37 (br. d, 3H).
Allyl 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (125.HCl)
At 4° C., LiOH.H 2 O (6.36 g, 152 mmol) was added to a soln of 27 (28.82 g, 75.8 mmol) in MeOH (86 mL), H 2 O (85 mL) and THF (270 mL). The mixture was stirred for 18 h at rt, acidified with 1 M aq. HCl soln (500 mL) and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to give 123 (26.5 g, 99%). NaHCO 3 (17.7 g, 210 mmol) was added to a soln of 123 (37.1 g, 105.4 mmol) in DMF (530 mL). The mixture was stirred for 5 min followed by the addn of allyl bromide (18.0 mL; 208 mmol). The mixture was stirred at rt for 18 h. More NaHCO 3 (2.0 g, 24 mmol) and allyl bromide (2.0 mL; 23.1 mmol) were added and stirring was continued for 4 h. Aq. Workup (EtOAc, 1 M aq. HCl soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 99.5:0.5 to 98:2) afforded 124 (38.8 g, 94%).
A soln of 124 (22.5 g, 53.3 mmol) in dioxane (23 mL) was treated at rt with 4 M HCl in dioxane (80 mL) for 3 h. Dioxane (50 mL) was added and stirring was continued for 1 h. The volatiles were evaporated and the residue was washed (Et 2 O) and dried i.v. to yield 125.HCl (17.0 g, 97%).
Data of 125.HCl: C 15 H 20 N 2 O 4 .HCl (free base, 292.3). FI-MS: 292.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.03 (br s, 3H); 7.39-7-28 (m, 5H); 5.87 (m, 1H); 5.35-5.17 (m, 2H); 5.12, 5.07 (2 s, 2H); 4.59 (m, 2H); 4.16 (d, J=7.5, 2 H); 3.54 (q-like m, 2H); 2.97 (br m, 2H).
All Fmoc-α-amino acids and Fmoc-N-methyl-α-amino acids applied in the synthesis of Core 10 and Core 11 are commercially available:
Fmoc-L-alanine (Fmoc-Ala-OH)
Fmoc-N-methyl-L-alanine (Fmoc-NMe-Ala-OH)
Fmoc-D-alanine (Fmoc-DAla-OH)
Fmoc-N-methyl-D-alanine (Fmoc-NMe-DAla-OH)
Fmoc-N-methyl-L-glutamic acid 5 tert.-butyl ester (Fmoc-NMe-Glu(OtBu)-OH)
Fmoc-glycine (Fmoc-Gly-OH)
N-α-Fmoc-N-ε-Boc-L-lysine (Fmoc-Lys(Boc)-OH)
Fmoc-L-phenylalanine (Fmoc-Phe-OH)
Fmoc-N-methyl-L-phenylalanine (Fmoc-NMe-Phe-OH)
Fmoc-D-phenylalanine (Fmoc-DPhe-OH)
Fmoc-N-methyl-D-phenylalanine (Fmoc-NMe-DPhe-OH)
Fmoc-sarcosine (Fmoc-Sar-OH)
(S)-Methyl 3-(allyloxy)-2-aminopropanoate hydrochloride (129)
A soln of Boc-serine (126; 14.0 g, 68.2 mmol) in DMF (143 mL) was cooled to 0° C. NaHCO 3 (17.2 g 205 mmol) was added and the mixture was stirred for 15 min. Iodomethane (8.5 mL, 136 mmol) was added dropwise. The mixture was stirred at 0° C. to rt for 16 h and again cooled to 0° C. More iodomethane (4.2 mL, 67 mmol) was slowly added and stirring was continued for 3 h. The mixture was diluted with H 2 O and extracted with EtOAc. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give crude 127 (14.2 g).
A soln of crude 127 (14.2 g) and Pd(PPh 3 ) 4 (0.64 g) in THF (416 mL) was degassed. Carbonic acid allyl methyl ester (9.6 g, 82.8 mmol) was added and the mixture was heated to 60° C. for 2 h. The volatiles were evaporated. FC (hexane/EtOAc 9:1) afforded 128 (11.4 g, 79%)
A soln of 128 (11.4 g, 43.9 mmol) in dioxane (110 mL) was treated with 4 M HCl in dioxane (110 mL) for 4 h at rt. Additional 4 M HCl in dioxane (30 mL) was added and stirring was continued for 30 min. The volatiles were evaporated and the residue was washed with Et 2 O to give 129.HCl (8.3 g, 96%).
Data of 129.HCl: C 7 H 13 NO 3 .HCl (159.2, free base). FI-MS: 160.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.70 (br. s, 3H); 5.85 (m, 1H); 5.29 (qd, J=1.7, 17.3, 1H), 5.19 (qd, J=1.5, 10.4, 1H); 4.33 (t, J=3.6, 1H); 4.07-3.93 (m, 2H); 3.86-3.78 (m, 2H); 3.76 (s, 3H).
(S)-Allyl 2-(benzyloxycarbonylamino)-4-(methylamino)butanoate hydrochloride (130.HCl) and
(S)-Allyl 2-(benzyloxycarbonylamino)-6-(methylamino)hexanoate hydrochloride (131.HCl) were prepared described in the preceding patent application (WO 2011/014973 A2).
Sarcosine tert-butylester hydrochloride (132.HCl) is commercially available.
Core 01: Synthesis of Ex. 1, Ex. 2 and Ex. 3 (Scheme 8)
Synthesis of the Mitsunobu Product 41
At 0° C., ADDP (7.08 g, 28.1 mmol) was added in portions to a mixture of phenol 2 (4.27 g, 18.7 mmol), alcohol 16 (6.18 g, 20.6 mmol) and PPh 3 (7.36 g, 28.1 mmol) in CHCl 3 (110 mL). The stirred mixture was allowed to warm to rt over 15 h.
The volatiles were evaporated. The residue was suspended in CH 2 Cl 2 and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1) to yield 41 (5.98 g, 62%).
Data of 41: C 28 H 34 N 2 O 7 (510.6). LC-MS (method 1a): R t =2.58 (94), 511.2 ([M+H] + ).
Synthesis of the Acid 42
Aq. LiOH soln (2 M; 11 mL, 22.0 mmol) was added to a solution of ester 41 (5.65 g, 11.1 mmol) in MeOH (11 mL) and THF (19 mL). The mixture was heated to 65° C. for 4 h, partially concentrated, acidified with 1 M aq. HCl soln to pH 1 and extracted twice with EtOAc. The combined organic layer was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 42 (4.46 g, 81%).
Data of 42: C 27 H 32 N 2 O 7 (496.6). LC-MS (method 1a): R t =2.28 (90), 497.2 ([M+H] + ).
Synthesis of the Amide 43
A solution of acid 42 (4.46 g, 9.0 mmol), amine 22.pTsOH (5.6 g, 11 mmol), HATU (5.1 g, 13 mmol), HOAt (1.8 g, 13 mmol) in DMF (70 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (6.2 mL, 36 mmol). The mixture was allowed to warm to rt over 15 h. The mixture was diluted with 0.5 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:1) of the crude product afforded 43 (5.56 g, 80%).
Data of 43: C 42 H 50 N 4 O 10 (770.9). LC-MS (method 1a): R t =2.55 (95), 771.3 ([M+H] + ).
Synthesis of Amino Acid 44
A degassed solution of amide 43 (5.55 g, 7.2 mmol) and 1,3-dimethylbarbituric acid (2.5 g, 16 mmol) in CH 2 Cl 2 (40 mL) and EtOAc (40 mL) was treated with Pd(PPh 3 ) 4 (0.41 g, 0.36 mmol) at rt. After 2 h, more CH 2 Cl 2 (40 mL) and Pd(PPh 3 ) 4 (0.41 g, 0.36 mmol) were added and stirring was continued for 1 h. The volatiles were evaporated. The solid was suspended in EtOAc, filtered, washed (EtOAc) and dried i.v. to afford 44 (3.94 g, 83%).
Data of 44: C 35 H 42 N 4 O 8 (646.7). LC-MS (method 1a): R t =1.75 (97), 647.2 ([M+H] + ).
Synthesis of Ex. 1
The amino acid 44 (2.77 g, 4.28 mmol) was added in portions over 2 h to a solution of T3P (50% in EtOAc; 13 mL, 22.1 mmol) and i-Pr 2 NEt (5.8 mL, 34.3 mmol) in dry CH 2 Cl 2 (800 mL). Stirring was continued for 30 min. The mixture was washed (sat. aq. NaHCO 3 soln.), dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /THF 9:1) of the crude product yielded Ex. 1 (2.35 g, 87%).
Data of Ex. 1: C 35 H 40 N 4 O 7 (628.7). LC-MS (method 1a): R t =2.17 (94), 629.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.18 (br. t, 1H); 7.67 (d, J=7.2, 1H); 7.52-7.23 (m, 11H); 7.11-7.06 (m, 2H); 6.98 (d, J=8.1, 1H); 4.98 (s, 2H); 4.64 (br. m, 1H); ca 4.3-4.0 (several br. m, 4H); 3.85 (br. m, 1H); 3.10 (br. m, 1H); 2.98 (m, 1H); 2.31 (br. m, 1H); ca 2.0-1.75 (br. m, 2H); 1.53 (br. m, 1H); 1.41 (s, 9H); 0.83 (br. m, 1H).
Synthesis of Ex. 2
A soln of Ex. 1 (300 mg, 0.477 mmol) in MeOH (6.0 mL) was hydrogenated for 16 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 63 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 80:20) gave Ex. 2 (206 mg, 87%).
Data of Ex. 2: C 27 H 34 N 4 O 5 (494.6). LC-MS (method 1a): R t =1.60 (99), 495.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.21 (t-like m, 1H); 7.52-7.36 (m, 5H); 7.21 (br. d, 1H), 7.15-7.00 (m, 2H); 7.00 (s, 1H), 4.43 (br. not resolved m, 1H); 4.24-4.01 (m, 3H); 3.89 (q-like m, 1H); 3.58-3.12 (several br. m, 3H); 2.98 (dd, J=6.2, 12.1, 1H); 2.33 (m, 1H); 1.89 (m, 1H); 1.65-1.55 (br. not resolved m, 2H); 1.41 (s, 9H).
Synthesis of Ex. 3
A soln of Ex. 1 (750 mg, 1.19 mmol) in CH 2 Cl 2 (5 mL) was cooled to 0° C. TFA (2.0 mL) was slowly added and the mixture was stirred at 0° C. to rt for 4 h. The volatiles were evaporated. The residue was taken up in CHCl 3 and concentrated.
The residue was taken up in CH 2 Cl 2 (6 mL), treated with 4 M HCl in dioxane (2 mL) to give a precipitate. The volatiles were evaporated. The treatment with CH 2 Cl 2 /4 M HCl in dioxane was repeated. The residue was suspended in Et 2 O, filtered, washed (Et 2 O) and dried i.v. to afford Ex. 3.HCl (613 mg, 90%).
Data of Ex. 3.HCl: C 30 H 32 N 4 O 5 .HCl (528.6, free base). LC-MS (method 1a): R t =1.55 (99), 529.1 ([M+H] + ).
Core 01: Synthesis of Ex. 330, Ex. 331 and the Resin 133 (Scheme 8)
Synthesis of Ex. 330
Sat. aq. NaHCO 3 soln (131 mL) and H 2 O (53.5 mL) were added to a soln of Ex. 2 (14.4 g, 29 mmol) in dioxane (131 mL) and THF (78 mL). The mixture was cooled to 0° C. Allyl chloroformate (3.71 mL, 34.9 mmol) was slowly added. Stirring was continued for 2 h at 0° C. to rt. The mixture was diluted with sat. aq. Na 2 CO 3 soln and extracted with CH 2 Cl 2 . The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to give Ex. 330 (16.18 g, 96%).
Data of Ex. 330: C 31 H 38 N 4 O 7 (578.6). LC-MS (method 1c): R t =2.06 (97), 578.9 ([M+H] + ).
Synthesis of Ex. 331
At 0° C., TFA (40.6 mL) was added to a soln of Ex. 330 (15.8 g, 27.3 mmol) in CH 2 Cl 2 (160 mL). The cooling bath was removed and stirring was continued for 2 h. The volatiles were evaporated. The residue was dissolved in CHCl 3 (76 mL) and 4 M HCl in dioxane (14.0 mL) was added. The volatiles were evaporated. The residue was again taken up in CHCl 3 (76 mL), treated with 4 M HCl in dioxane (14.0 mL) and concentrated. The residue was distributed between sat. aq. Na 2 CO 3 soln and EtOAc. The organic layer was separated, the aqueous layer repeatedly extracted with EtOAc. The combined organic phases were concentrated. The residue was dissolved in CH 2 Cl 2 (200 mL). Then 4 M HCl in dioxane (17.7 mL) was slowly added to give a thick precipitate. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered, washed (Et 2 O) and dried i.v. to afford Ex. 331.HCl (12.5 g, 89%).
Data of Ex. 331.HCl: C 26 H 30 N 4 O 5 .HCl (free base, 478.5). LC-MS (method 1a): R t =1.36 (96), 479.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.43 (br. s, 3H); 8.27 (br. t, J ca 5.3, 1H); 7.67 (d, J=6.9, 1H); 7.52-7.37 (m, 5H); 7.12-7.09 (m, 2H); 7.02 (d, J=8.8, 1H); 5.88 (m, 1H); 5.26 (dd, J=1.2, 17.2, 1H); 5.17 (dd, J=1.1, 10.4, 1H); 4.67 (br. m, not resolved, 1H); 4.43 (d, J=5.2, 2 H); 4.31-4.11 (m, 4H); 3.56 (br. m, not resolved, 1H); 3.31-3.16 (br. m, 2H); 3.19 (dd, J=8.1, 12.1, 1H); 2.60 (m, 1H); 2.12 (m, 1H); 1.83 (br. m, 1H); 1.47 (br. m, 1H).
Synthesis of the Resin 133
Under Ar, DFPE polystyrene (1% DVB, 100-200 mesh, loading 0.87 mmol/g; 11.1 g, 9.6 mmol) was swollen in DCE (110 mL) for 1 h. Ex. 331.HCl (5.7 g, 10.6 mmol) and i-Pr 2 NEt (4.9 mL, 28.9 mmol) were added. The mixture was shaken at rt for 1 h. NaBH(OAc) 3 (4.09 g, 19.3 mmol) was added and the mixture was shaken for 20 h. The resin was filtered and successively washed with MeOH twice, then three times each with DCE, 10% i-Pr 2 NEt in DMF, DMF, CH 2 Cl 2 and MeOH. The resin was dried i.v. to give 133 (15.73 g; loading 0.6 mmol/g).
Procedure D:
Core 01: Synthesis of Final Products on Solid Support
Synthesis of Resin 134
1) First Derivatization Step
Resin 133 (loading 0.6 mmol/g; 96 mg, 0.055 mmol) was swollen in DMF (1 mL) for 60 min and filtered. The resin was resuspended in DMF/CH 2 Cl 2 1:1 (1 mL). i-Pr 2 NEt (8 equiv.) the carboxylic acid R III CO 2 H (4 equiv.) and HATU (4 equiv.) or the succinimidyl carbamate R III NHCO 2 Su (4 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was washed with DMF. The coupling step was repeated. The resin was washed three times with DMF.
2) Cleavage of the Alloc Group
The resin was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (10 equiv.) and Pd(PPh 3 ) 4 (0.2 equiv.) were added, then the mixture was shaken for 15 min and filtered. The deprotection step was repeated. The resin was filtered, washed three times each with CH 2 Cl 2 , DMF, twice with MeOH and three times with CH 2 Cl 2 .
3) Second Derivatization Step
The resin was resuspended in DMF/CH 2 Cl 2 1:1 (1 mL). i-Pr 2 NEt (8 equiv.) and the carboxylic acid R IV CO 2 H (4 equiv.) and PyBOP (4 equiv.) or the isocyanate R IV NCO (4 equiv) or the sulfonyl chlorides R IV SO 2 Cl (4 equiv) and DMAP (1 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was filtered, washed three times with DMF to afford resin 134.
Release of the Final Products
The resin 134 was treated with 20% TFA in CH 2 Cl 2 (1 mL) for 30 min, filtered and washed with CH 2 Cl 2 . The cleavage step was repeated once. The combined filtrates and washings were concentrated. The residue was treated with CH 3 CN, evaporated and dried i.v. Purification of the crude product by normal phase or reverse phase prep. HPLC afforded Ex. 7 and Ex. 332-Ex. 337.
Core 01: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 8)
Synthesis on Solid Support:
Ex. 7.CF 3 CO 2 H (6.6 mg, 15%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 7.CF 3 CO 2 H: cf. Table 13b.
1 H-NMR (DMSO-d 6 ): 9.94 (br. s, 1H); 8.77 (d, J=5.3, 1H); 8.65 (d, J=7.7, 1H); 8.06 (t, J=5.4, 1H); 8.01 (m, 1H); 7.92 (m, 1H); 7.81 (d, J=7.9, 1H); 7.55-7.37 (m, 8H); 7.34 (t, J=8.0, 1H); 7.09-7.05 (m, 2H); 6.91 (dd, J=2.0, 8.2, 1H); 4.58 (br. not resolved m, 1H); 4.44 (br. not resolved m, 1H); 4.19 (dd, J=4.9, 11.5, 1H); 4.12-4.00 (m, 5H); 3.94 (d, J=14.9, 1H); 3.87 (d, J=14.9, 1H); ca 3.6-3.5 (br m, 2H), 3.30 (1H, superimposed by H 2 O signal); 3.07-3.02 (br. m, 4H); 2.15-1.84 (br. m, 7H); 1.67 (br. m, 1H).
Ex. 332.CF 3 CO 2 H (21 mg, 48%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with imidazol-1-yl acetic acid (in total 55 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 332.CF 3 CO 2 H: cf. Table 13b.
Ex. 333.CF 3 CO 2 H (29 mg, 65%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 2,5-dioxopyrrolidin-1-yl pyridine-3-ylcarbamate (in total 103 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 333.CF 3 CO 2 H: cf. Table 13b.
Ex. 334.CF 3 CO 2 H (16 mg, 38%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 3-chlorophenylacetic acid (37 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 334.CF 3 CO 2 H: cf. Table 13b.
Ex. 335.CF 3 CO 2 H (11 mg, 26%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with cyclohexylacetic acid (31 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 335.CF 3 CO 2 H: cf. Table 13b.
Ex. 336.CF 3 CO 2 H (6 mg, 13%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol; first coupling step) and with 1-naphthyl isocyanate (0.031 mL, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex. 336.CF 3 CO 2 H: cf. Table 13b.
1 H-NMR (DMSO-d 6 ): 9.94 (br. s, 1H); 8.81 (d, J=4.9, 1H); 8.63 (s, 1H); 8.27 (t, J=5.6, 1H); 8.06 (d, J=8.0, 1H); 7.96 (dd, J=1.0, 7.6, 1H); 7.89 (d, J ca 9.3, 1H); 7.59-7.38 (m, 9H); 7.16-7.13 (m, 2H); 7.04-6.99 (t-like m, 2H); 4.82 (br. not resolved m, 1H); 4.45 (t-like m, 1H); 4.29 (dd, J=5.9, 11.5, 1H); 4.22-4.13 (br. m, 3H); 4.01 (s, 2H); 3.65-3.45 (br. m, 3H); 3.25-3.0 (br. m, 4H); 2.45 (m, 1H); 2.10-1.70 (br. m, 7H).
Synthesis in Solution:
Synthesis of Ex. 4
At rt, i-Pr 2 NEt (0.27 mL, 1.57 mmol) was added to a soln of Ex. 2 (258 mg, 0.52 mmol), 1-naphthaleneacetic acid (117 mg, 0.63 mmol), HATU (298 mg, 0.78 mmol) and HOAt (107 mg, 0.78 mmol) in DMF (4.3 mL). The mixture was stirred at rt for 15 h and distributed between CH 2 Cl 2 and 1 M aq. Na 2 CO 3 soln. The organic phase was separated, washed (H 2 O), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 34:66 to 0:100) afforded Ex. 4 (267 mg, 77%).
Data of Ex. 4: cf. Table 13b
Synthesis of Ex. 5
A soln of Ex. 4 (220 mg, 0.33 mmol) in dioxane (4.0 mL) was treated with 4 M HCl-dioxane (1.0 mL) for 2 h. The volatiles were evaporated to afford Ex. 5.HCl (208 mg, quant.)
Data of Ex. 5.HCl: cf. Table 13b
Synthesis of Ex. 7
At rt, i-Pr 2 NEt (0.057 mL, 0.33 mmol) was added to a soln of Ex. 5.HCl (50 mg, 0.08 mmol), 1-Pyrrolidineacetic acid (22 mg, 0.17 mmol), HATU (63 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (1.2 mL). The mixture was stirred at rt for 4 h and distributed between EtOAc and sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 7 (40 mg, 71%).
Data of Ex. 7: C 40 H 43 N 5 O 5 (673.8). LC-MS (method 1a): R t =1.70 (96), 674.2 ([M+H] + ).
Synthesis of Ex. 14
At 0° C., phenyl chloroformate (87 mg, 0.55 mmol) was slowly added to a mixture of Ex. 3 (285 mg, 0.50 mmol) in CH 2 Cl 2 (5 mL) and sat. aq. Na 2 CO 3 soln (1.7 mL). Stirring was continued for 2 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln., Na 2 SO 4 ) and FC (EtOAc) afforded Ex. 14 (315 mg, 96%)
Data of Ex. 14: cf. Table 13b
Core 02: Synthesis of Ex. 15, Ex. 16 and Ex. 17 (Scheme 9)
Synthesis of the Mitsunobu Product 45
At 0° C., a solution of TMAD (7.57 g, 43.9 mmol) in benzene (80 mL) was added dropwise to a degassed solution of the phenol 4 (3.68 g, 16.1 mmol), alcohol 16 (4.40 g, 14.65 mmol) and PPh 3 (11.5 g, 43.9 mmol) in benzene (80 mL). The stirred mixture was allowed to warm to rt over 15 h.
The volatiles were evaporated. The residue was suspended in hexane and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 5:1) to yield 45 (5.45 g, 73%).
Data of 45: C 28 H 34 N 2 O 7 (510.6). LC-MS (method 1c): R t =2.67 (97), 511.2 ([M+H] + ).
Synthesis of the Acid 46
At 0° C., aq. LiOH soln (2 M; 10.6 mL, 21.1 mmol) was added to a solution of ester 45 (5.4 g, 10.6 mmol) in MeOH (10 mL) and THF (20 mL). The mixture was allowed to warm to rt over 16 h. The volatiles were evaporated. The residue was taken up in 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1 to 0:100 then EtOAc/MeOH 100:0 to 90:10 gave 46 (4.48 g, 85%).
Data of 46: C 27 H 32 N 2 O 7 (496.6). LC-MS (method 1c): R t =2.29 (99), 497.2 ([M+H] + ).
Synthesis of the Amide 47
A solution of acid 46 (4.28 g, 8.6 mmol), amine 23.HCl (4.6 g, 10.3 mmol), HATU (4.9 g, 12.9 mmol) and HOAt (1.76 g, 12.9 mmol) in DMF (80 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (5.9 mL, 34.5 mmol). The mixture was allowed to warm to rt over 15 h. The mixture was diluted with H 2 O and EtOAc. The organic layer was washed (aq. 1 M HCl soln, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:1) of the crude product afforded 47 (6.1 g, 89%).
Data of 47: C 44 H 54 N 4 O 10 (798.9). LC-MS (method 1a): R t =2.72 (97), 799.4 ([M+H] + ).
Synthesis of Amino Acid 48
A degassed solution of 47 (6.14 g, 7.7 mmol) and 1,3-dimethylbarbituric acid (2.64 g, 16.9 mmol) in CH 2 Cl 2 (70 mL) and EtOAc (42 mL) was treated with Pd(PPh 3 ) 4 (0.44 g, 0.38 mmol) at rt for 1 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 98:2 to 80:20) afforded 48 (4.64 g, 89%).
Data of 48: C 37 H 46 N 4 O 8 (674.8). LC-MS (method 1a): R t =1.86 (97), 675.3 ([M+H] + ).
Synthesis of Ex. 15
A soln of the amino acid 48 (1.12 g, 1.66 mmol) in CH 2 Cl 2 (60 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 2.45 mL, 4.15 mmol) and i-Pr 2 NEt (1.14 mL, 6.64 mmol) in dry CH 2 Cl 2 (770 mL). Evaporation of the volatiles, aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) yielded Ex. 15 (0.96 g, 88%).
Data of Ex. 15: C 37 H 44 N 4 O 7 (656.7). LC-MS (method 1d): R t =2.29 (97), 657.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.6-7.0 (br. m, 13H); 7.13 (d, J=7.9, 1H); 7.03 (t, J=7.3, 1H); 5.01 (br. s, 2H); 4.37 (br. d, J ca 9.7, 1H); ca 4.25-3.7 (several br. m, 4H); 3.25 (br. m, 1H); 2.95 (br. s, 3H); 2.64 (br. m, 1H); 2.40 (br. m, 1H); 2.18 (br. m, 1H); ca. 1.85-1.0 (several br. m, 6H); 1.37 (s, 9H).
Synthesis of Ex. 16
A soln of Ex. 15 (1.3 g, 2.0 mmol) in MeOH (60 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 240 mg). The mixture was filtered through a pad of celite and Na 2 SO 4 . The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 16 (1.03 g, 99%).
Data of Ex. 16: C 29 H 38 N 4 O 5 (522.6). LC-MS (method 1a): R t =1.68 (97), 523.1 ([M+H] + ).
Synthesis of Ex. 17
A soln of Ex. 15 (600 mg, 0.91 mmol) in dioxane (6 mL) was treated with 4 M HCl in dioxane (6 mL) at rt for 1 h followed by evaporation of the volatiles. The residue was taken up in CHCl 3 and concentrated to afford Ex. 17 (571 mg, quant. yield).
Data of Ex. 17.HCl: C 32 H 36 N 4 O 5 .HCl (556.6, free base). LC-MS (method 1a): R t =1.65 (96), 557.2 ([M+H] + ).
Core 02: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 9)
Synthesis of Ex. 18
At 0° C., i-Pr 2 NEt (0.635 mL, 3.71 mmol) was added dropwise to a soln of Ex. 17.HCl (550 mg, 0.93 mmol), 2-naphthaleneacetic acid (207 mg, 1.11 mmol), HATU (529 mg, 1.39 mmol) and HOAt (189 mg, 1.39 mmol) in DMF (10 mL). The mixture was stirred at 0° C. for 4 h and distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was separated, washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (EtOAc) afforded Ex. 18 (530 mg, 79%).
Data of Ex. 18: cf. Table 14b
Synthesis of Ex. 19
A soln of Ex. 18 (520 mg, 0.72 mmol) in MeOH (5 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 94 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 19 (412 mg, 97%).
Data of Ex. 19: cf. Table 14b
Synthesis of Ex. 20
i-Pr 2 NEt (0.043 mL, 0.25 mmol) was added to a soln of Ex. 19 (50 mg, 0.085 mmol), 2-(dimethylamino)acetic acid (17 mg, 0.17 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol). The mixture was stirred at rt for 15 h and distributed between CH 2 Cl 2 and sat. aq. Na 2 CO 3 soln. The organic phase was separated, dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 20 (17 mg, 30%).
Data of Ex. 20: cf. Table 14b
Synthesis of Ex. 25
Phenylacetyl chloride (0.013 mL, 0.098 mmol) was added at 0° C. to a soln of Ex. 19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at 0° C. for 2 h followed by the addition of more phenylacetyl chloride (0.006 mL, 0.045 mmol). Stirring was continued for 1 h. Evaporation of the volatiles and prep. HPLC (method 1a) afforded Ex. 25 (36 mg, 60%).
Data of Ex. 25: cf. Table 14b
Synthesis of Ex. 26
Benzoyl chloride (0.012 mL, 0.10 mmol) was added at 0° C. to a soln of Ex. 19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at 0° C. for 2 h followed by evaporation of the volatiles and prep. HPLC (method 1a) to afford Ex. 26 (40 mg, 67%).
Data of Ex. 26: cf. Table 14b
Core 03: Synthesis of Ex. 41, Ex. 42, Ex. 50 and Ex. 62-Ex. 67 (Scheme 10)
Synthesis of the Mitsunobu Product 49
At 0° C., ADDP (7.32 g, 29.0 mmol) was added in portions to a mixture of phenol 6 (5.0 g, 19.4 mmol), alcohol 20 (5.08 g, 29.0 mmol) and PPh 3 (7.62 g, 29.0 mmol) in CHCl 3 (82 mL). The stirred mixture was allowed to warm to rt over 15 h.
More 20 (5.08 g, 29.0 mmol), PPh 3 (7.62 g, 29.0 mmol) and finally ADDP (7.32 g, 29.0 mmol) were added at 0° C. Stirring was continued at rt for 6 h. The mixture was filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 90:10 to 80:20) to yield 49 (7.57 g, 94%).
Data of 49: C 23 H 29 NO 6 (415.5). LC-MS (method 1a): R t =2.54 (99), 416.2 ([M+H] + ).
Synthesis of the Acid 50
At 0° C., aq. LiOH soln (2 M; 27 mL, 54.0 mmol) was added dropwise to a solution of ester 49 (7.44 g, 17.9 mmol) in MeOH (27 mL) and THF (50 mL). The mixture was stirred at rt for 5 h, partially concentrated, acidified with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give 50 (7.1 g, 98%).
Data of 50: C 22 H 27 NO 6 (401.4). LC-MS (method 1a): R t =2.20 (98), 402.1 ([M+H] + ).
Synthesis of the Amide 51
A solution of acid 50 (7.0 g, 17.4 mmol), amine 24.HCl (6.86 g, 20.9 mmol), HATU (9.95 g, 26.2 mmol) and HOAt (3.56 g, 26.2 mmol) in DMF (180 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (11.9 mL, 69.7 mmol). The mixture was allowed to warm to rt over 7 h. More 24.HCl (6.86 g, 20.9 mmol) was added and stirring continued for 15 h. The mixture was diluted with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 2:1) of the crude product afforded 51 (10.05 g, 85%).
Data of 51: C 38 H 46 N 2 O 9 (674.8). LC-MS (method 1a): R t =2.69 (97), 675.2 ([M+H] + ).
Synthesis of the Amino Ester 52
A soln of 51 (10.0 g, 14.8 mmol) in dioxane (10 mL) was treated at rt with 4 M HCl in dioxane (40 mL) for 5 h. The volatiles were evaporated. The residue was taken up in CH 2 Cl 2 and concentrated to afford 52.HCl (9.2 g, quant. yield).
Data of 52.HCl: C 33 H 38 N 2 O 7 .HCl (574.6, free base). LC-MS (method 1a): R t =1.94 (94), 575.2 ([M+H] + ).
Synthesis of Amino Acid 53
A degassed solution of ester 52 (9.2 g, 15 mmol) and 1,3-dimethylbarbituric acid (2.8 g, 18 mmol) in CH 2 Cl 2 (30 mL) and EtOAc (60 mL) was treated with Pd(PPh 3 ) 4 (1.8 g, 1.5 mmol) at rt for 2 h. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 98:2 to 70:30) afforded 53 (8.2 g, quant.).
Data of 53: C 30 H 34 N 2 O 7 (534.6). LC-MS (method 1a): R t =1.70 (94), 535.2 ([M+H] + ).
Synthesis of Ex. 41
A soln of the amino acid 53 (4.0 g, 7.5 mmol) in CH 2 Cl 2 (80 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 11.0 mL, 18.7 mmol) and i-Pr 2 NEt (5.12 mL, 29.9 mmol) in dry CH 2 Cl 2 (1360 mL). Evaporation of the volatiles, aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 20:80 to 0:100) yielded Ex. 41 (3.0 g, 77%).
Data of Ex. 41: C 30 H 32 N 2 O 6 (516.5). LC-MS (method 1d): R t =2.14 (96), 517.0 ([M+H] + ). 1 H-NMR (CDCl 3 ): 7.78 (s, 1H); 7.50-7.35 (m, 7H); 7.25 (m, 1H), 6.92-6.82 (m, 3H); 5.59 (d, J=8.4, 1H); 5.32 (d, J=12.2, 1H); 5.26 (d, J=12.2, 1H); 4.78 (d, J=11.9, 1H); 4.16 (q-like m, 1H); 3.81 (s, 3H); 3.71 (d, J=9.0, 1H); 3.38 (t-like m, 1H); 2.98 (s, 3H); 2.64 (br. t, J ca. 12.7, 1H); 2.37 (dd, J=5.6, 16.2, 1H); 2.01-1.90 (m, 2H); 1.24 (d, J=6.8, 3 H).
Synthesis of Ex. 42
A soln of Ex. 41 (2.0 g, 3.87 mmol) in MeOH (30 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 220 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 42 (1.77 g, quant. yield).
Data of Ex. 42: C 23 H 26 N 2 O 6 (426.5). LC-MS (method 1d): R t =1.55 (93), 427.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.2 (br. s, 1H); 8.03 (d, J=8.2, 1H); 7.59 (s, 1H); 7.46-7.41 (m, 2H); 7.16 (m, 1H); 7.04 (d, J=8.9, 1H); 6.90 (dd, J=3.0, 8.8, 1H); 6.83 (d, J=3.0, 1H); 4.13 (dd, J=3.0, 12.2, 1H); 4.03-3.91 (m, 2H); 3.74 (s, 3H); 3.52 (t, J=9.2, 1H); 2.86 (s, 3H); 2.39 (br. t, J ca 13.2, 1H); 2.19 (br. dd, J ca 4.9, 15.9, 1H); 1.99 (d-like m, 1H); 1.86 (m, 1H); 1.03 (d, J=6.6, 3 H).
Core 03: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 10)
Synthesis of Ex. 62
A soln of Ex. 41 (50 mg, 0.1 mmol) in THF (1 mL) was cooled to 0° C. LiBH 4 (5 mg, 0.213 mmol) and MeOH (3.9 μL, 0.1 mmol) in THF (0.5 mL) were added. The mixture was stirred at rt for 20 h followed by the addition of acetone (0.1 mL). Aqueous workup (CHCl 3 , 1 M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 90:10) yielded Ex. 62 (25 mg, 61%).
Data of Ex. 62: C 23 H 28 N 2 O 5 (412.5). LC-MS (method 1a): R t =1.49 (97), 413.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.90 (d, J=8.2, 1H); 7.56-7.53 (m, 2H); 7.41-7.32 (m, 2H); 7.00 (d, J=8.9, 1H); 6.89 (dd, J=3.1, 8.9, 1H); 6.80 (d, J=3.1, 1H); 5.05 (t, J=5.3, 1H); 4.01-3.87 (m, 2H); 3.74 (s, 3H); 3.74 (m, 1H); 3.61-3.38 (m, 3H); 2.78 (s, 3H); 2.11 (dd, J=5.6, 15.9, 1H); 1.99 (br. t, 1H); 1.85 (br. t, 1H); 1.45 (dt, J=6.1, 12.7, 1H); 1.00 (d, J=6.7, 3 H).
Synthesis of Ex. 63
At 0° C., DEAD (40% in toluene; 0.05 mL, 0.109 mmol) was slowly added to a soln of Ex. 62 (30 mg, 0.073 mmol), 3-hydroxypyridine (8.3 mg, 0.087 mmol) and PPh 3 (29 mg, 0.109 mmol) in degassed benzene/THF 1:1 (2 mL). The mixture was stirred at rt for 16 h and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 90:10) afforded Ex. 63 (26 mg, 73%).
Data of Ex. 63: C 28 H 31 N 3 O 5 (489.5). LC-MS (method 1a): R t =1.44 (95), 490.1 ([M+H] + ).
Synthesis of Ex. 64
At 0° C., DEAD (40% in toluene; 0.83 mL, 1.82 mmol) was slowly added to a soln of Ex. 62 (250 mg, 0.61 mmol), PPh 3 (477 mg, 1.82 mmol) and DPPA (0.394 mL; 1.82 mmol) in degassed benzene (10 mL). The mixture was stirred for 30 min at rt and for 1 h at 50° C. The volatiles were evaporated. The residue was suspended in Et 2 O. The solid was collected to afford Ex. 64 (169 mg, 63%).
Data of Ex. 64: C 23 H 27 N 5 O 4 (437.5). LC-MS (method 1a): R t =1.86 (94), 438.2 ([M+H] + ).
Synthesis of Ex. 65
A soln of Ex. 64 (166 mg, 0.38 mmol) in MeOH/CH 2 Cl 2 2:1 (3 mL) was hydrogenated at rt for 4 h in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 71 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. The residue was dissolved in CHCl 3 and evaporated. The residue was dissolved in CH 2 Cl 2 (3 mL), treated with 4 M HCl-dioxane (0.285 mL, 1.1 mmol). A precipitate was obtained which was filtered and washed (EtOAc) to afford Ex. 65.HCl (149 mg, 87%).
Data of Ex. 65.HCl: C 23 H 29 N 3 O 4 (411.5). LC-MS (method 1a): R t =1.35 (86), 412.2 ([M+H] + ).
Synthesis of Ex. 66
At 0° C., i-Pr 2 NEt (0.076 mL, 0.45 mmol) was added dropwise to a soln of Ex. 65.HCl (50 mg, 0.11 mmol), phenylacetic acid (18 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.167 mmol) in DMF (0.5 mL). The mixture was stirred at 0° C. for 2 h. Aq. workup (EtOAc, 0.2 M HCl soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and prep. HPLC (method 3) afforded Ex. 66 (33 mg, 55%).
Data of Ex. 66: C 31 H 35 N 3 O 5 (529.6). LC-MS (method 1a): R t =1.89 (91), 530.2 ([M+H] + ).
Synthesis of Ex. 67
i-Pr 2 NEt (0.031 mL, 0.18 mmol) was added to a soln of Ex. 62 (50 mg, 0.12 mmol) and phenyl isocyanate (17 mg, 0.15 mmol) in THF/DMF 1:1 (1.0 mL). The mixture was stirred at rt for 16 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and prep. HPLC (method 3) to afford Ex. 67 (46 mg, 72%).
Data of Ex. 67: C 30 H 33 N 3 O 6 (531.6). LC-MS (method 1a): R t =2.06 (90), 532.2 ([M+H] + ).
Synthesis of Ex. 50
3-Picolylamine (0.014 mL, 0.141 mmol) and i-Pr 2 NEt (0.06 mL, 0.352 mmol) were slowly added to a cold solution of Ex. 42 (50 mg, 0.117 mmol), HATU (67 mg, 0.176 mmol) and HOAt (24 mg, 0.176 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 4° C., followed by an aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) and purification by prep HPLC (method 1c) to give Ex. 50.CF 3 CO 2 H (28 mg, 37%).
Data of Ex. 50.CF 3 CO 2 H: cf. Table 15b.
1 H-NMR (DMSO-d 6 and D 2 O): 8.90 (br. s, 1H); 8.50 (very br. s, 1H); 7.56 (s, 1H); 7.40 (br. s, 1H); 7.30 (very br. s, 1H); 7.01 (m, 2H); 6.88 (dd, J=2.9, 8.9, 1H); 6.78 (d, J=2.7, 1H); 4.60 (br. not resolved m, 2H); 4.08 (br. d, J=9.8, 1H); 3.98-3.89 (br. m, 2H); 3.71 (s, 3H); 3.51 (t, J=9.2, 1H); 2.84 (s, 3H); 2.43 (br. not resolved m, 1H), 2.21 (br. m, 1H); 1.96-1.76 (m, 2H); 1.00 (d, J=6.5, 3 H).
An analytical sample of Ex. 50.CF 3 CO 2 H was dissolved in CH 2 Cl 2 and washed with sat. aq. Na 2 CO 3 soln. The organic phase was separated, dried (Na 2 SO 4 ) and concentrated to give Ex. 50.
Data of Ex. 50: 1 H-NMR (DMSO-d 6 ): 8.88 (t, J=6.0, 1H); 8.59 (d, J=1.6, 1H); 8.56 (dd, J=1.5, 4.8, 1H); 8.09 (d, J=8.2, 1H); 7.82 (td, J=1.9, 7.9, 1H); 7.67 (s, 1H); 7.50-7.44 (m, 2H); 7.32 (t, J=7.6, 1H); 7.13-7.08 (m, 2H); 6.95 (dd; J=3.1, 8.9, 1H); 6.87 (d, J=3.1, 1H); 4.43-4.40 (m, 2H); 4.15-3.96 (m, 3H); 3.80 (s, 3H); 3.57 (t, J ca 9.0, 1H); 2.91 (s, 3H); ca 2.5 (1H, superimposed by DMSO-d signal); 2.26 (br. dd, 1H); 1.98 (br. dd, 1H), 1.81 (dt; J=5.3, 10.0, 1H); 1.08 (d, J=6.7, 3 H).
Core 04: Synthesis of Ex. 68 and Ex. 69 (Scheme 11)
Synthesis of the Mitsunobu Product 54
ADDP (6.61 g, 26.2 mmol) was added to a mixture of the phenol 8 (3.98 g, 17.5 mmol), the alcohol 19 (4.59 g, 26.2 mmol) and PPh 3 (6.87 g, 26.2 mmol) in CHCl 3 (160 mL). The mixture was stirred at rt for 15 h. Silica gel (20 g) was added. The volatiles were evaporated and the residue was purified by FC (hexane/EtOAc 5:1) to give 54 (3.2 g, 48%).
Data of 54: C 22 H 27 NO 5 (385.5). LC-MS (method 2b): R t =2.56 (90), 384.0 ([M−H] − ).
Synthesis of the Acid 55
LiOH.H 2 O (1.6 g, 38 mmol) was added to a solution of ester 54 (4.89 g, 12.7 mmol) in THF (72 mL), MeOH (24 mL) and H 2 O (24 mL). The mixture was stirred at rt for 4.5 h, partially concentrated, diluted with H 2 O (30 mL), acidified with 1 M aq. HCl soln (ca 40 mL) and extracted twice with EtOAc. The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give 55 (4.67 g, 99%).
Data of 55: C 21 H 25 NO 5 (371.4). LC-MS (method 2a): R t =1.32 (98), 369.9 ([M−H] − ).
Synthesis of the Amide 56
PyClu (2.2 g, 6.62 mmol) and i-Pr 2 NEt (2.95 mL, 17.3 mmol) were successively added to a solution of acid 55 (2.14 g, 5.76 mmol) and amine 24.HCl (2.52 g, 7.7 mmol), in DMF (50 mL). The mixture was stirred at rt for 1 h followed by an aq. workup (Et 2 O, 0.5 M aq. HCl soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ). FC (hexane/EtOAc 7:3 to 4:6) afforded 56 (2.29 g, 61%).
Data of 56: C 37 H 44 N 2 O 8 (644.8). LC-MS (method 1a): R t =2.69 (95), 645.3 ([M+H] + ).
Synthesis of the Amino Ester 57
A soln of 56 (5.6 g, 8.66 mmol) in dry CH 2 Cl 2 (75 mL) was treated with TFA (15 mL) at rt for 1 h. The volatiles were evaporated. Aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) of the residue gave 57 (4.93 g, quant. yield).
Data of 57: C 32 H 36 N 2 O 6 (544.6). LC-MS (method 1a): R t =1.88 (93), 545.2 ([M+H] + ).
Synthesis of Amino Acid 58
A degassed solution of ester 57 (4.7 g, 8.66 mmol) and 1,3-dimethylbarbituric acid (1.62 g, 10.4 mmol) in CH 2 Cl 2 (73 mL) and EtOAc (73 mL) was treated with Pd(PPh 3 ) 4 (0.3 g, 0.26 mmol) at rt for 1.5 h. The volatiles were evaporated. The solid was suspended in EtOAc (200 mL), filtered and washed (EtOAc). The solid was suspended in CH 2 Cl 2 . The volatiles were evaporated. The residue was dried i.v. to yield 58 (3.94 g, 90%).
Data of 58: C 29 H 32 N 2 O 6 (504.6). LC-MS (method 1a): R t =1.61 (91), 505.2 ([M+H] + ).
Synthesis of Ex. 68
A soln of the amino acid 58 (3.45 g, 6.8 mmol) in CH 2 Cl 2 (150 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 10 mL, 17.1 mmol) and i-Pr 2 NEt (4.7 mL, 27.4 mmol) in dry CH 2 Cl 2 (1250 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 98.5:1.5) yielded Ex. 68 (2.57 g, 78%).
Data of Ex. 68: C 29 H 30 N 2 O 5 (486.5). LC-MS (method 1d): R t =2.23 (95), 486.9 ([M+H] + ).
Synthesis of Ex. 69
A soln of Ex. 68 (2.5 g, 5.2 mmol) in MeOH (50 mL) and CH 2 Cl 2 (25 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium on activated charcoal (moistened with 50% H 2 O; 1.9 g). The mixture was filtered through a pad of celite. The solid was washed with MeOH/CH 2 Cl 2 2:1. The combined filtrate and washings were concentrated to give Ex. 69 (2.0 g, 98%).
Data of Ex. 69: C 22 H 24 N 2 O 5 (396.4). LC-MS (method 1a): R t =1.58 (98), 397.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 13.05 (br. s, 1H); 8.21 (br. s, 1H); 7.86-7.17 (several m, 6.33H); 7.06 (s, 0.66H); 6.96 (d, J=8.2, 0.66H); 6.90 (dd, J=1.9, 8.2, 0.33H); 4.49-4.31 (m, 1.66H); 4.15 (s, 2H); 3.57 (t, J=11.8, 0.33H); 2.91, 2.86 (2 br. s, 3H); 2.45-2.20 (m, 2.33H); 2.2-2.0 (m, 1.66H); 1.15-1.12 (2 d, 3H).
Core 05: Synthesis of Ex. 90, Ex. 91 and Ex. 92 (Scheme 12)
Synthesis of Amide 59
A mixture of acid 10.HCl (9.34 g, 31.8 mmol), amine 28.HCl (13.1 g, 41.3 mmol), HATU (19.3 g, 51 mmol) and HOAt (6.93 g, 51 mmol) in DMF (75 mL) was cooled to 0° C., followed by the addition of i-Pr 2 NEt (21.6 mL, 127 mmol). The mixture was stirred for 4 h and concentrated to ca 50% of its volume. The mixture was diluted with 1 M aq. HCl soln and extracted twice with EtOAc. The combined organic layer was washed (H 2 O, sat. aq. NaHCO 3 soln,), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 50:50 to 20:80) of the crude product afforded 59 (13.4 g, 80%).
Data of 59: C 28 H 29 N 3 O 7 (519.5). LC-MS (method 1a): R t =1.89 (98), 520.0 ([M+H] + ).
Synthesis of Phenol 60
At 0° C. 3-(dimethylamino)propylamine (12.0 mL, 95.4 mmol) was slowly added to a soln of 59 (16.53 g, 31.8 mmol) in THF (110 mL). The soln was allowed to warm to rt over 2 h. Aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) yielded 60 (14.45 g, 95%).
Data of 60: C 26 H 27 N 3 O 6 (477.5). LC-MS (method 1a): R t =1.67 (97), 478.1 ([M+H] + ).
Synthesis of the Mitsunobu Product 61
The phenol 60 (4.35 g, 9.1 mmol) and the alcohol 18 (3.56 g, 11.8 mmol) were dissolved in toluene (39 mL). CMBP (3.0 mL, 11.4 mmol) was added and the mixture was heated to reflux for 0.5 h. More CMBP (0.31 mL, 1.2 mmol) was added and the mixture was refluxed for 0.5 h followed by evaporation of the volatiles and FC (hexane/EtOAc 50:50 to 0:100) to afford 61 (5.25 g, 77%).
Data of 61: C 40 H 49 N 5 O 10 (759.8). LC-MS (method 1a): R t =2.24 (92), 760.2 ([M+H] + ).
Synthesis of the Amino Acid 63
A soln of 61 (11.8 g, 16 mmol) in THF (59 mL) and MeOH (30 mL) was treated with 2 M aq. LiOH soln (31 mL, 62 mmol) at rt for 2 h. The volatiles were partially evaporated. The remaining mixture was acidified to pH ca 1 by addition of 3 M aq. HCl soln and repeatedly extracted with EtOAc. The combined organic phase was dried (Na 2 SO 4 ) and concentrated to afford crude acid 62 (12.6 g).
1,3-Dimethylbarbituric acid (3.2 g, 20.5 mmol) and acid 62 (12.5 g) were dissolved in CH 2 Cl 2 /EtOAc 1:1 (300 mL). The mixture was degassed, treated with Pd(PPh 3 ) 4 (1.98 g, 1.71 mmol) and stirred at rt for 2 h. The volatiles were evaporated. The residue was suspended in EtOAc and filtered to give 63 (9.80 g, 97%).
Data of 63: C 34 H 41 N 5 O 8 (647.7). LC-MS (method 1c): R t =1.51 (83), 648.1 ([M+H] + ).
Synthesis of Ex. 90
A soln of the amino acid 63 (2.0 g, 3.1 mmol) in DMF (50 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in EtOAc; 9.1 mL, 15 mmol) and i-Pr 2 NEt (4.2 mL, 25 mmol) in dry CH 2 Cl 2 (600 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 97:3) yielded Ex. 90 (1.18 g, 60%).
Data of Ex. 90: C 34 H 39 N 5 O 7 (629.7). LC-MS (method 1d): R t =2.00 (99), 630.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 9.68, 9.62 (2 s, 1H); 9.18 (s, 1H); 9.11 (s, 1H); 8.97 (s, 1H); 8.41 (br. s, 1H); 7.58 (d, J=7.5, 1H); 7.40 (t, J=7.9, 1H); 7.40-7.20 (m, 5H); 7.17 (m, 1H); 6.94 (d, J=8.0, 1H); 5.15 (d, J=12.1, 0.5H); 5.12 (s, 1H); 5.01 (d, J=12.9, 0.5H); 4.55-4.15 (m, 4H); 4.15-3.5 (several m, 5H); 3.5-3.1 (several m, 3H); 2.11 (m, 1H); 1.91 (m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 91
A soln of Ex. 90 (200 mg, 0.32 mmol) in MeOH (5 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 50 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 91 (150 mg, 95%).
Data of Ex. 91: C 26 H 33 N 5 O 5 (495.6). LC-MS (method 1a): R t =1.48 (97), 496.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 9.73 (br. s, 1H); 9.26 (t, J=1.9, 1H); 9.18 (d, J=1.9, 1H); 8.94 (d, J=1.9, 1H); 8.51 (s, 1H); 7.59 (d, J=7.7, 1H); 7.40 (t, J=7.9, 1H); 7.26 (d, J=6.5, 1H); 6.94 (dd; J=1.9, 8.1, 1H); 4.5-4.4 (m, 2H); 4.26 (m, 1H); 3.89 (t, J ca. 11.5, 1H); 3.67 (dd, J=7.2, 9.7, 1H); 3.53 (d, J=17.9, 1H); 3.39 (d, J=17.8, 1H); 3.21-3.08 (m, 3H); 2.55 (m, 1H); ca 2.45 (m, 1H); 2.11 (m, 1H); 1.89 (m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 92
A soln of Ex. 90 (200 mg, 0.32 mmol) in dioxane (2 mL) was treated with 4 M HCl in dioxane (2 mL) for 15 h. The volatiles were evaporated. Purification by prep. HPLC (method 1c) afforded Ex. 92.2CF 3 CO 2 H (89 mg, 37%) and Ex. 93.3CF 3 CO 2 H (34 mg, 17%).
Data of Ex. 92.2 CF 3 CO 2 H: C 29 H 31 N 5 O 5 (529.6, free base). LC-MS (method 1a): R t =1.38 (98), 530.1 ([M+H] + ).
Data of Ex. 93.3 CF 3 CO 2 H: Cf Table 17b
Core 05: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 12)
Synthesis of Ex. 94
A soln of Ex. 91 (137 mg, 0.28 mmol) in DCE (4.0 mL) was cooled to 0° C. Aq. formaldehyde soln. (36.5%; 0.104 mL, 1.38 mmol) was added followed by acetic acid (0.019 mL, 0.332 mmol) and NaBH(OAc) 3 (234 mg, 1.106 mmol). The mixture was stirred at 0° C. for 4 h followed by an aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln). FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 94 (119 mg, 84%).
Data of Ex. 94: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.60 (br. s, 1H); 9.21 (t, J=1.9, 1H); 9.17 (d, J=1.9, 1H); 8.93 (d, J=1.9, 1H), 8.48 (s, 1H); 7.58 (d, J=7.7, 1H); 7.39 (t, J=8.0, 1H); 7.28 (d, J=6.4, 1H); 6.94 (dd, J=1.9, 8.1, 1H); 4.45-4.41 (br, m, 2H); 4.26 (m, 1H); 3.88 (br. t, J ca 11.5, 1H); 3.68 (dd, J=7.2, 9.7, 1H); 3.45 (d, J=17.6, 1H); 3.89-3.21 (m, 3H, signal partially superimposed by H 2 O signal); 3.15 (t-like m, J ca 9, 1H); 2.62 (br. not resolved m, 2H), 2.37 (s, 3H); 2.11 (m, 1H); 1.90 (m, 1H); 1.41 (s, 9H).
Synthesis of Ex. 95
A soln of Ex. 94 (100 mg, 0.196 mmol) in dioxane (1.0 mL) was treated with 4 M HCl-dioxane (1.0 mL) for 2 h. The volatiles were evaporated to afford Ex. 95.3HCl (116 mg, quant.).
Data of Ex. 95.3HCl: cf. Table 17b
Synthesis of Ex. 96
At 0° C., i-Pr 2 NEt (0.11 mL, 0.65 mmol) was slowly added to a soln of Ex. 95.3HCl (97 mg, 0.19 mmol), 2-naphthaleneacetic acid (49 mg, 0.26 mmol), HATU (124 mg, 0.326 mmol) and HOAt (44 mg, 0.323 mmol) in DMF (1.0 mL). The mixture was stirred at at 0° C. for 2 h and distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) and prep. HPLC (method 1b) afforded Ex. 96.2CF 3 CO 2 H (62 mg, 41%).
Data of Ex. 96: cf. Table 17b
1 H-NMR (DMSO-d 6 ): Ca. 9.7 (very br. s, 1H); 9.28 (very br. s, 1H); 9.14 (br. s, 1H); 8.96 (very br. s, 1H); 8.62 (d, J=5.4, 1H); 8.54 (br. s, 1H); 8.30 (br. s, 1H); 7.90-7.85 (m, 3H); 7.77 (s, 1H); 7.65 (d, J=7.6, 1H); 7.53-7.41 (m, 4H); 6.98 (d, J=8.3, 1H); 4.55-4.33 (2 br. not resolved m, 5H); 4.01 (t, J=11.2, 1H); 3.85 (br. t, J ca 8.4, 1H); 3.65 (br. not resolved m, 2H); 3.63 (s, 2H); 3.39 (br. not resolved m, 2H); 3.11 (t, J=9.0, 1H); 2.89 (s, 3H); 2.26 (m, 1H); 2.04 (m, 1H).
Synthesis of Ex. 101
A soln of 1-naphthaleneacetic acid (43 mg, 0.23 mmol) and T3P (50% in DMF; 0.17 mL; 0.29 mmol) in DMF (0.3 mL) was added dropwise to a suspension of Ex. 95.3HCl (50 mg, 0.096 mmol) in DMF (0.2 mL). The mixture was stirred at rt for 15 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 101.2 CF 3 CO 2 H (38 mg, 49%).
Data of Ex. 101.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.71 (very br. s, 1H); 9.26 (d, J=1.9, 1H); 9.13 (br. s, 1H); 8.93 (d, J=1.5, 1H); 8.68 (d, J=5.6, 1H); 8.52 (br. s, 1H); 8.30 (s, 1H); 8.10 (m, 1H), 7.93 (m, 1H); 7.84 (dd, J=1.9, 7.3, 1H); 7.66 (d, J=7.7, 1H); 7.57-7.41 (m, 5H); 6.98 (dd, J=1.8, 8.3, 1H); 4.55-4.39 (2 br. not resolved m, 5H); 4.04-3.94 (m, 3H); 3.83 (br. t, J ca 8.5, 1H); 3.68 (br. not resolved m, 2H); 3.41 (br. not resolved m, 2H); 3.12 (t, J=9.0, 1H); 2.89 (s, 3H); 2.26 (m, 1H); 2.03 (m, 1H).
Synthesis of Ex. 103
At 4° C., Et 3 N (0.04 mL, 0.29 mmol) and then benzenesulfonyl chloride (17 mg, 0.096 mmol) were added to a soln of Ex. 95.3HCl (50 mg, 0.096 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stirred at rt for 15 h; i-Pr 2 NEt (0.049 mL, 0.29 mmol) and more benzenesulfonyl chloride (17 mg, 0.096 mmol) were added. Stirring was continued for 1 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln, Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 103.2 CF 3 CO 2 H (33 mg, 44%).
Data of Ex. 103.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): 9.69 (br. s, 1H); 9.24 (d, J=1.9, 1H); 9.09 (br. s, 1H); 8.92 (d, J=1.6, 1H); 8.47 (br. s, 1H); 8.30 (br. s, 1H); 8.22 (br. s, 1H); 7.90-7.88 (m, 2H); 7.74-7.63 (m, 4H); 7.41 (t, J=7.9, 1H); 6.93 (dd; J=1.9, 8.2, 1H); ca. 4.5-4.2 (m, 4H); 4.00 (br. not resolved m, 1H); 3.89 (t, J ca. 11.4, 1H); 3.69-3.63 (m, 3H); 3.42 (br. not resolved m, 2H); 3.23 (dd, J=8.4, 9.7; 1H); 2.91 (s, 3H); 2.02 (m, 1H); 1.88 (m, 1H).
Synthesis of Ex. 97
3-Fluorobenzaldehyde (50 mg, 0.40 mmol) was added to a soln of Ex. 91 (120 mg, 0.24 mmol) in THF (1.5 mL). The soln was stirred at rt for 1 h followed by the addn of acetic acid (0.015 mL, 0.27 mmol) and NaBH(OAc) 3 (154 mg, 0.73 mmol). The mixture was stirred at rt for 16 h. More 3-fluorobenzaldehyde (15 mg, 0.12 mmol) was added and stirring continued. Aq. workup (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH) afforded Ex. 97 (117 mg, 80%).
Data of Ex. 97: cf. Table 17b
Synthesis of Ex. 98
A soln of Ex. 97 (94 mg, 0.156 mmol) in dioxane (0.8 mL) was treated with 4 M HCl-dioxane (0.8 mL) for 2 h. The volatiles were evaporated to afford Ex. 98.3HCl (91 mg, 95%).
Data of Ex. 98.3HCl: cf. Table 17b
Synthesis of Ex. 100
A soln of Ex. 98.3HCl (62 mg, 0.10 mmol) in CH 2 Cl 2 (0.6 mL) was treated with pyridine (0.041 mL, 0.51 mmol) and acetyl chloride (16 mg, 0.2 mmol) at rt for 16 h. i-Pr 2 NEt (0.052 mL, 0.3 mmol) and more acetyl chloride (16 mg, 0.2 mmol) were added and stirring was continued for 24 h followed by an aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) to afford Ex. 100.2 CF 3 CO 2 H (50 mg, 64%).
Data of Ex. 100.2 CF 3 CO 2 H: cf. Table 17b
1 H-NMR (DMSO-d 6 ): Ca. 9.5 (br. s, 1H); 9.23 (s, 2H); 8.96 (d, J=1.0, 1H); 8.45 (br. s, 1H); 8.17 (d, J=6.5, 1H); 7.62 (d, J=7.7, 1H); 7.42 (t, J=7.9, 1H); ca 7.4 (br. not resolved m, 1H); ca 7.35-7.25 (br. not resolved m, 2H); 7.15 (br. t-like m, 1H); 6.97 (dd; J=1.9, 8.2, 1H); 4.52-4.39 (m, 4H); ca 4.2-3.8 (br. not resolved m, 3H); 3.90 (t, J=11.3, 1H); 3.71 (t-like m, 2H); 3.49 (m, 1H); 3.33 (br. t-like m, 1H); 3.07 (t, J=9.0, 1H); 2.95 (br. not resolved m, 2H); 2.14 (m, 1H); 1.89 (m, 1H); 1.81 (s, 3H).
Core 06/07: Synthesis of Ex. 115, Ex. 116 and Ex. 129, Ex. 130 (Scheme 13)
Synthesis of the Arylbromide 65
2-Bromothiophenol (11; 2.71 mL, 23 mmol) was added to a soln of 30 (5.0 g, 19.1 mmol) and CMBP (6.02 mL, 23 mmol) in toluene (50 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/EtOAc 4:1) afforded 65 7.31 g, 88%)
Data of 65: C 18 H 26 BrNO 4 S (432.3). LC-MS (method 1c): R t =2.58 (97), 434.0/431.9 ([M+H] + ).
Synthesis of the Biphenyl 66
Sat. aq. NaHCO 3 soln (37.8 mL) was added dropwise to a soln of 65 (5.0 g, 11.6 mmol), 3-hydroxyphenylboronic acid (12, 4.79 g, 34.7 mmol) and Pd(PPh 3 ) 4 (1.34 g, 1.16 mmol) in DME (150 mL). The mixture was heated to reflux for 4 h. The volatiles were evaporated and the residue was distributed between EtOAc and sat. aq. Na 2 CO 3 soln. The organic phase was repeatedly washed (sat. aq. Na 2 CO 3 soln), dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /EtOAc 100:0 to 95:5) afforded 66 (3.91 g, 75%).
Data of 66: C 24 H 31 NO 5 S (445.5). LC-MS (method 1a): R t =2.46 (94), 446.1 ([M+H] + ).
Synthesis of the Phenol 68
At 0° C., TFA (11.9 mL) was slowly added to a soln of 66 (2.38 g, 5.34 mmol) in CH 2 Cl 2 (24 mL). Stirring was continued for 1 h followed by evaporation of the volatiles. The residue was dissolved in CHCl 3 and concentrated to afford 67-CF 3 CO 2 H as a brown oil which was dissolved in CH 2 Cl 2 (12 mL) and cooled to 0° C. i-Pr 2 NEt (2.73 mL, 16.0 mmol) was slowly added. Allyl chloroformate (0.63 mL, 5.88 mmol) in CH 2 Cl 2 (12 mL) was added over 30 min. The mixture was stirred for 2 h followed by evaporation of the volatiles. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 9:1 to 7:3) yielded 68 (2.02 g, 88%).
Data of 68: C 23 H 27 NO 5 S (429.5). LC-MS (method 1a): R t =2.29 (92), 430.1 ([M+H] + ).
Synthesis of the Ether 69
A soln of ADDP (1.34 g, 5.31 mmol) in degassed CHCl 3 (5.0 mL) was added at 0° C. to a soln of 68 (1.52 g, 3.54 mmol), Boc-D-alaminol (20; 0.93 g, 5.31 mmol) and PPh 3 (1.39 g, 5.31 mmol) in CHCl 3 (20 mL). The mixture was stirred at 0° C. to rt for 16 h. More Boc-D-alaminol (20; 0.93 g, 5.31 mmol) and PPh 3 (1.39 g, 5.31 mmol) were added. The mixture was cooled to 0° C. followed by the slow addition of ADDP (1.34 g, 5.31 mmol) in CHCl 3 (5.0 mL). The mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1 to 3:1) to afford 69 (1.6 g, 77%). Data of 69: C 31 H 42 N 2 O 7 S (586.7). LC-MS (method 1a): R t =2.78 (97), 587.1 ([M+H] + ).
Synthesis of the Amino Acid 71
A soln of 69 (3.2 g, 5.5 mmol) in THF (17 mL) and MeOH (17 mL) was treated at 0° C. with 1 M aq. LiOH soln (6.5 mL, 6.5 mmol). The mixture was allowed to stir at 0° C. to rt for 16 h. The volatiles were evaporated. The residue was distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ) and concentrated to afford crude acid 70 (3.02 g) which was dissolved in dioxane (12.5 mL) and treated with 4 M HCl-dioxane (7.9 mL) for 4 h. The volatiles were evaporated. The residue was taken up in CHCl 3 and concentrated to afford crude 71.HCl (2.84 g, quant. yield) which was used without further purification.
Data of 71.HCl: C 25 H 32 N 2 O 5 S.HCl (472.6, free base). LC-MS (method 1a): R t =1.76 (89), 473.1 ([M+H] + ).
Synthesis of Ex. 115
A soln of crude 71.HCl (0.94 g, 1.8 mmol) in CH 2 Cl 2 (45 mL) was added over 2 h to a soln of T3P (50% in EtOAc; 2.7 mL, 4.6 mmol) and i-Pr 2 NEt (1.3 mL, 7.4 mmol) in CH 2 Cl 2 (1810 mL). The soln was partially concentrated, washed with sat. aq. NaHCO 3 soln, dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 8:2 to 1:1) gave Ex. 115 (0.63 g, 75%).
Data of Ex 115: C 25 H 30 N 2 O 4 S (454.6). LC-MS (method 1d): R t =2.35 (95), 455.0 [M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.57-7.52 (m, 2H); 7.38-7.21 (m, 5H); 7.01-6.95 (m, 2H); 6.90 (d, J=7.9, 1H), 5.90 (m, 1H); 5.29 (d, J=17.2, 1H); 5.17 (d, J=10.0, 1H); 4.47-4.45 (m, 2H); 4.13-3.97 (m, 3H); 3.82 (q, J=6.5, 1H); 2.60-2.57 (m, 2H); 1.57-1.09 (m, 6H); 1.19 (d, J=6.5, 3 H).
Synthesis of Ex. 116
A soln of Ex. 115 (120 mg, 0.26 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (2.1 mL) was treated at rt for 16 h with Pd(PPh 3 ) 4 (1.2 mg) and 1,3-dimethylbarbituric acid (49 mg, 0.32 mmol). The volatiles were evaporated and the residue purified by FC (hexane/EtOAc 50:50 to 0:100, then CH 2 Cl 2 /MeOH 100:0 to 90:10) to afford Ex. 116 (82 mg, 83%).
Data of Ex. 116: C 21 H 26 N 2 O 2 S (370.5). LC-MS (method 1a): R t =1.74 (95), 371.1 ([M+H] + ).
1 H-NMR (DMSO-d 6 ): 7.76 (d, J=7.1, 1H); 7.55 (m, 1H); 7.37-7.26 (m, 4H); 7.07 (t-like m, 1H); 6.98 (dd-like m, 1H); 6.87 (d-like m, J ca 7.9, 1H), 4.14-4.01 (m, 3H); 3.32 (t, J=5.0, 1H); 2.67-2.55 (m, 2H); ca 2.6 (very br. s, 2H); 1.56 (m, 1H); 1.38-1.03 (m, 5H); 1.21 (d, J=6.3, 3H).
Synthesis of Ex. 129
At 0° C., mCPBA (70%, 876 mg, 3.55 mmol) was added in portions to a soln of Ex. 115 (808 mg, 1.78 mmol) in CH 2 Cl 2 (17 mL). The mixture was stirred at 0° C. to rt for 2 h and concentrated, followed by an aq. workup (EtOAc, sat. aq. NaHCO 3 soln, 1 M aq. Na 2 S 2 O 3 soln; Na 2 SO 4 ). FC (hexane/EtOAc 50:50 to 0:100) gave Ex. 129 (788 mg, 91%).
Data of Ex. 129:C 25 H 30 N 2 O 6 S (486.6). LC-MS (method 1a): R t =1.91 (93), 487.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.06 (dd, J=1.3, 7.9, 1H); 7.77 (dt, J=1.4, 7.5, 1H); 7.68 (dt, J=1.4, 7.7, 1H); 7.49-7.44 (m, 2H); 7.39 (t, J=8.0, 1H); 7.09-7.03 (m, 3H); 6.73 (s, 1H); 5.88 (m, 1H); 5.27 (d, J=17.3, 1H); 5.17 (d, J=10.3, 1H); 4.45 (d, J=4.9, 2 H); 4.08-3.96 (m, 3H); 3.75 (q-like m, J=7.6, 1H); 2.45 (br. m, 2H); 1.45-1.01 (m, 5H); 1.23 (d, J=6.8, 3 H); 1.01 (m, 1H).
Synthesis of Ex. 130
A soln of Ex. 129 (100 mg, 0.21 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (1.7 mL) was treated at rt for 3 h with Pd(PPh 3 ) 4 (1.0 mg) and 1.3-dimethylbarbituric acid (39 mg, 0.25 mmol). The volatiles were evaporated and the residue purified by FC (hexane/EtOAc 50:50 to 0:100, then CH 2 Cl 2 /MeOH 100:0 to 90:10) to afford Ex. 130 (82 mg, 98%).
Data of Ex. 130: C 21 H 26 N 2 O 4 S (402.5). LC-MS (method 1a): R t =1.48 (94), 403.0 ([M+H] + ).
Core 06: Synthesis of Selected Advanced Intermediates and Final Products
(Scheme 13)
Synthesis of Ex. 119
At 0° C., i-Pr 2 NEt (0.055 mL, 0.324 mmol) was slowly added to a solution of Ex. 116 (40 mg, 0.108 mmol), 1-pyrrolidineacetic acid (17 mg, 0.13 mmol), HATU (62 mg, 0.162 mmol) and HOAt (22 mg, 0.162 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 0° C., followed by an aqueous workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and purification by prep HPLC (method 3) to give Ex. 119 (30 mg, 57%).
Data of Ex. 119: cf. Table 18b.
Core 08/09: Synthesis of Ex. 143, Ex. 144 and Ex. 168, Ex. 169 (Scheme 14)
Synthesis of Thioether 72
5-Bromopyridine-3-thiol (13; 1.0 g, 5.3 mmol) was added to a soln of alcohol 30 (1.06 g, 4.0 mmol) and CMBP (1.17 g, 4.85 mmol) in toluene (15 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/EtOAc 4:1) of the residue gave 72 (1.35 g, 77%).
Data of 72: C 17 H 25 BrN 2 O 4 S (433.6). LC-MS (method 1c): R t =2.37 (93), 433.0/435.0 ([M+H] + ).
Synthesis of Phenol 73
At rt, sat. aq. NaHCO 3 soln (17.1 mL) was added to a soln of 72 (2.65 g, 6.1 mmol), 2-hydroxyphenylboronic acid (14; 2.53 g, 18.3 mmol) and Pd(PPh 3 ) 4 (707 mg, 0.61 mmol) in DME (78 mL). The mixture was heated to reflux for 1 h followed by an aq. workup (EtOAc, sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:1) to afford 73 (2.42 g, 88%).
Data of 73: C 23 H 30 N 2 O 5 S (446.6). LC-MS (method 1a): R t =1.82 (96), 447.1 ([M+H] + ).
Synthesis of Phenol 75
At 0° C., a soln of 73 (500 mg, 1.12 mmol) in CH 2 Cl 2 (4.0 mL) was treated with TFA (3.0 mL) for 2 h and concentrated. Aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded crude 74 which was dissolved in CH 2 Cl 2 (4.0 mL). The soln was cooled to 0° C. A soln of AllocOSu (245 mg, 1.23 mmol) in CH 2 Cl 2 (1.0 mL) was added dropwise. Stirring was continued for 2 h followed by an aq. workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 1:1) to yield 75 (310 mg, 64%).
Data of 75: C 22 H 26 N 2 O 5 S (430.5). LC-MS (method 1a): R t =1.68 (94), 431.1 ([M+H] + ).
Synthesis of the Ether 76
At 0° C., ADDP (967 mg, 3.83 mmol) was added in portions to a soln of alcohol 20 (672 mg, 3.83 mmol), phenol 75 (1.1 g, 2.55 mmol) and PPh 3 (1.0 g, 3.83 mmol) in CHCl 3 (15 mL). The mixture was stirred for 4 h at rt and concentrated. FC (hexane/EtOAc 4:1 to 2:1) afforded 76 (450 mg, 30%).
Data of 76: C 30 H 41 N 3 O 7 S (587.7). LC-MS (method 1a): R t =2.33 (87), 588.2 ([M+H] + ).
Synthesis of the Amino Acid 78
At 0° C., 1 M aq. LiOH (0.67 mL, 0.67 mmol) was added to a soln of 76 (430 mg, 0.73 mmol) in THF/MeOH 2:1 (1.5 mL). The mixture was stirred at 0° C. to rt for 5 h and distributed between EtOAc and 0.2 M aq. HCl soln. The organic phase was separated, dried (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 /MeOH 100:0 to 80:20) gave acid 77 (288 mg) which was dissolved in dioxane (1 mL) and treated with 4 M HCl-dioxane (1.15 mL) for 6 h at rt. The volatiles were evaporated. The residue was suspended in EtOAc, filtered and dried i.v. to afford 78.2HCl (256 mg, 64%).
Data of 78.2HCl: C 24 H 31 N 3 O 5 S.2HCl (473.6, free base). LC-MS (method 1c): R t =1.39 (92), 474.1 ([M+H] + ).
Synthesis of Ex. 143
A soln of 78.2HCl (200 mg, 0.37 mmol) and i-Pr 2 NEt (0.125 mL, 0.73 mmol) in CH 2 Cl 2 (5 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc; 0.65 mL, 1.1 mmol) and i-Pr 2 NEt (0.188 mL, 1.1 mmol) in CH 2 Cl 2 (177 mL). Aq. Workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) afforded Ex. 143 (105 mg, 63%).
Data of Ex. 143: C 24 H 29 N 3 O 4 S (455.5). LC-MS (method 1d): R t =1.66 (98), 456.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.52 (d, J=2.2, 1H); 8.40 (d, J=1.9, 1H); 8.36 (s, 1H); 8.11 (d, J=5.5, 1H); 7.45-7.39 (m, 2H); 7.20 (d, J=7.6, 1H); 7.14 (d, J=8.2, 1H); 7.08 (t, J=7.5, 1H); 5.88 (m, 1H); 5.28 (d, J=16.5, 1H); 5.16 (d, J=10.4, 1 H); 4.44 (d, J=5.2, 2 H); 4.17-3.97 (m, 4H); 3.06 (m, 1H); 2.89 (m, 1H); 1.85 (m, 1H); ca 1.6-1.3 (m, 5H); 1.09 (d, J=6.3, 3 H).
Synthesis of Ex. 144
A degassed solution of Ex. 143 (200 mg, 0.44 mmol) in degassed CH 2 Cl 2 /EtOAc 1:1 (11 mL) was treated at rt for 2 h with Pd(PPh 3 ) 4 (2.0 mg) and 1,3-dimethylbarbituric acid (82 mg, 0.53 mmol). The volatiles were evaporated. FC (hexane/EtOAc 50:50 to 0:100 and then CH 2 Cl 2 /MeOH 99:1 to 95:5) gave Ex. 144 (128 mg, 78%).
Data of Ex. 144: C 20 H 25 N 3 O 2 S (371.5). LC-MS (method 1a): R t =1.30 (97), 371.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.52 (d, J=2.2, 1H); 8.40 (d, J=2.0, 1H); 8.16 (t, J=2.1, 1H); 7.77 (d, J=6.4, 1H); 7.45-7.39 (m, 2H); 7.16 (d, J=7.9, 1H); 7.07 (dt; J=0.8, 7.1, 1H); 4.13-4.04 (m, 2H); 3.97 (br. not resolved m, 1H); 3.21 (t-like m, 1H); 3.08-2.89 (m, 2H); 2.01 (br. s, 2H); 1.74-1.18 (several m, 6H); 1.12 (d, J=6.5, 3 H).
Synthesis of Ex. 168
H 2 O 2 (35% in H 2 O; 0.043 mL; 0.49 mmol) was added to a soln of Ex. 143 (32 mg, 0.07 mmol) in AcOH (1.0 mL). The mixture was stirred at rt for 20 h; after 2 h and after 3 h, 16 h and 17 h more H 2 O 2 (35% in H 2 O; 0.043 mL; 0.49 mmol) had been added. The mixture was diluted with H 2 O and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to yield Ex. 168 (28 mg, 82%).
Data of Ex. 168: C 24 H 29 N 3 O 6 S (487.5). LC-MS (method 1a): R t =1.78 (92), 488.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.99 (d, J=2.2, 1H); 8.91 (d, J=1.9, 1H); 8.52 (s, 1H); 7.86 (d, J=4.9, 1H); 7.49-7.44 (m, 2H); 7.17-7.08 (m, 3H); 5.86 (m, 1H); 5.26 (d, J=18.6, 1H); 5.15 (d, J=9.9, 1H); 4.42 (m, 2H); 4.11-3.95 (m, 3H); 3.87 (q-like m, 1H); 3.56 (m, 1H); 3.35 (m, 1H); ca 1.70 (m, 1H); ca 1.65 (m, 1H); 1.40-1.10 (m, 4H); 1.06 (d, J=6.1, 3 H).
Synthesis of Ex. 169
A soln of Ex. 168 (2.19 g, 4.5 mmol) and 1,3-dimethylbarbituric acid (2.1 g, 13.5 mmol) in degassed EtOAc/CH 2 Cl 2 1:1 (65 mL) was treated at rt for 2 h with Pd(PPh 3 ) 4 (260 mg). The volatiles were evaporated and the residue purified by FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) to afford Ex. 169 (1.81 g, quant. yield).
Data of Ex. 169: C 20 H 25 N 3 O 4 S (403.5). LC-MS (method 1a): R t =1.34 (96), 403.9 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.97 (d, J=2.2, 1H); 8.92 (d, J=2.0, 1H); 8.39 (t, J=2.1, 1H); 7.64 (d, J=6.5, 1H); 7.49-7.42 (m, 2H); 7.17 (d, J=8.0, 1H); 7.11 (t, J=7.4, 1H); 4.11-3.97 (m, 3H); 3.63 (m, 1H); 3.40 (m, 1H); 3.07 (m, 1H); 1.98 (br. s, 2H); 1.58 (quint, J=7.1, 2 H); 1.27-1.16 (m, 2H); 1.09 (d, J=6.0, 3 H); 1.09 (m, 1H), 0.97 (m, 1H).
Core 10/11: Synthesis of the B-A B -A C Fragment 84 (Scheme 15)
Synthesis of the Allylester 79
Oxalyl chloride (1.8 mL, 20.4 mmol) and DMF (26 μL) were added to a suspension of 10.HCl (2.0 g, 6.8 mmol) in CHCl 3 (50 mL). The mixture was stirred at rt for 1 h and concentrated (at 35° C.). The residue was suspended in THF (50 mL) and cooled to 0° C. Allyl alcohol (1.4 mL, 20.4 mmol) and Et 3 N (2.9 mL, 20.4 mmol) were added.
The mixture was stirred at rt for 1 h followed by an aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ). FC (hexane/EtOAc 3:1) yielded 79 (1.78 g, 88%).
Data of 79: C 17 H 15 NO 4 (297.3). LC-MS (method 1b): R t =1.96 (99), 298.0 ([M+H] + ).
Synthesis of the Phenol 80
3-Dimethylaminopropylamine (2.3 mL, 17.9 mmol) was added at rt to a soln of 79 (1.77 g, 5.9 mmol) in THF (65 mL). The soln was stirred at rt for 3 h followed by an aq. workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford 80 (1.27 g, 83%).
Data of 80: C 15 H 13 NO 3 (255.3). LC-MS (method 1a): R t =1.65 (91), 255.9 ([M+H] + ).
Synthesis of the Arylether 81
A soln of ADDP (1.56 g, 6.2 mmol) in degassed CHCl 3 (10 mL) was slowly added to a soln of 80 (1.26 g, 4.9 mmol), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21; 0.83 g, 4.12 mmol) and PPh 3 (1.62 g, 6.2 mmol) in degassed CHCl 3 (20 mL). The soln was stirred at rt for 15 h followed by evaporation of the volatiles. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc 4:1) to afford 81 (1.78 g, 98%).
Data of 81: C 25 H 30 N 2 O 5 (438.5). LC-MS (method 1a): R t =2.58 (98), 439.1 ([M+H] + ).
Synthesis of Acid 84
A soln of 81 (1.76 g, 4.0 mmol) in MeOH/THF 1:1 (30 mL) was treated with 2 M aq. LiOH soln (4.0 mL, 8.0 mmol) for 1 h at rt. The mixture was concentrated. The residue was distributed between EtOAc and 1 aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give crude 82.HCl (1.5 g) which was dissolved in dioxane (15 mL) and treated with 4 M HCl-dioxane (30 mL) for 2.5 h at rt. The mixture was concentrated and repeatedly treated with CHCl 3 and concentrated to obtain crude 83.2HCl (1.79 g).
To a soln of crude 83.2HCl (1.24 g) in THF (11 mL) was added 2 M aq NaOH soln (5.3 mL). The mixture was cooled to 0° C. A soln of allyl chloroformate (0.34 mL, 3.2 mmol) in THF (5 mL) was added dropwise over 30 min (syringe pump). Stirring was continued for 30 min followed by an aq. workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1d) to yield 84.CF 3 CO 2 H (0.93 g, 67%).
Data of 84.CF 3 CO 2 H: C 21 H 22 N 2 O 5 .CF 3 CO 2 H (382.4, free form). LC-MS (method 1a): R t =1.80 (99), 383.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): ca 13.5 (br. s, 1H); 9.12 (s, 1H); 9.06 (d, J=1.9, 1H); 8.48 (s, 1H); 7.46-7.34 (m, 3H); 7.06 (d, J=7.4, 1H); 5.92 (m, 1H); 5.31-5.15 (m, 2H); 4.61-4.48 (m, 2H); 4.23-4.02 (m, 3H); 3.37-3.35 (m, 2H); ca 2.1-1.8 (m, 4H).
Core 10: Synthesis of Ex. 193a,c-h and Ex. 194b (Scheme 15)
Procedure C.1:
General Procedure for the Synthesis of Ex. 193a-h and Ex. 194b (Scheme 15)
1. Synthesis of resins 85a-h: Immobilisation of Fmoc-AA1-OH
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100-200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH 2 Cl 2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH 2 Cl 2 (80 mL). A soln of Fmoc-AA1-OH (10.3 mmol) and i-Pr 2 NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N 2 bubbling through. The resin was filtered and washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 ). Capping: The resin was shaken in CH 2 Cl 2 /MeOH/i-Pr 2 NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 , MeOH) and dried i.v. to afford resin 85.
Chlorotrityl- Yield/Loading Resin chlorid resin Fmoc-AA1-OH (mass increase) 85a, h 5 g Fmoc-β 3 - 6.79 g/0.72 mmol/g homoPhe-OH 85b, e, f, g 10 g Fmoc-NMe-β 3 - 13.0 g/0.78 mmol/g homoDAla-OH 85c, d 10 g Fmoc-β-Ala-OH 12.5 g/0.73 mmol/g
2. Synthesis of Ex. 193a,c-h and Ex. 194b
Fmoc Cleavage: The resin 85 (90-110 mg, ca 70 μmol) was swollen, in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2% v/v DBU in DMF (1 mL), shaken for 10 min, filtered off and washed (DMF). The deprotection step was repeated once. The resin was filtered and washed (DMF).
Coupling of Fmoc-AA2-OH: The resin 86 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA2-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 87 was filtered and washed (DMF).
Fmoc Cleavage: The resin was treated with 2% v/v DBU in DMF (1 mL) as described above to yield resin 88.
Coupling of Alloc-protected amino acid 84: The resin 88 was suspended in DMF (1 mL) 1) . i-Pr 2 NEt (560 μmol), 84 (35 mg, 70 μmol) and PyBOP (140 μmol) were added. The mixture was shaken for 1 h and filtered. The resin was washed (DMF). The coupling step was repeated once. The resin 89 was filtered and washed (DMF, CH 2 Cl 2 ). 1) Ex. 193c,d: Coupling of 84 was performed in DMF/NMP 6:1
Alloc Cleavage: The resin 89 was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (0.18 mL; 1.45 mmol) 2) and Pd(PPh 3 ) 4 (8 mg, 7 μmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 90 was filtered and washed (CH 2 Cl 2 , DMF, MeOH, CH 2 Cl 2 ). 2) Ex. 193c,d: 0.09 mL/0.7 mmol Phenylsilane was used
Release of the cyclization precursor: The resin 90 was treated with HFIP/CH 2 Cl 2 2:3 (1 mL) for 30 min, filtered and washed (CH 2 Cl 2 ). The cleavage step was repeated once. The combined filtrates and washings were concentrated and dried i.v. to afford crude 91a-h.
Ring closure and cleavage of side chain protective groups: Crude 91 was dissolved in dry DMF (4 mL) 3) and i-Pr 2 NEt (96 μL; 560 μmol) was added. This soln was then added dropwise to a soln of FDPP (40 mg, 105 μmol) in DMF (20 mL) 3) . The soln was stirred at rt for 15 h and the volatiles were evaporated. The residue was treated with sat. aq. Na 2 CO 3 soln (4 mL) and extracted with CHCl 3 (9 mL). The organic layer was filtered through a pad of MgSO 4 . The filtrate was concentrated and purified by prep. HPLC to afford Ex. 193a,c-h. 3) Ex. 193c,d: Ring closure was performed in a total volume of 12 mL of DMF
Crude Ex. 193b was dissolved in CH 2 Cl 2 (0.7 mL) and treated with TFA (0.3 mL) at rt for 3 h. The volatiles were evaporated and the residue was purified by prep. HPLC to give Ex. 194b.
Purification methods applied, yields, LC-MS data and systematic names of Ex. 193a,c-h and Ex. 194b are indicated in Table 22.
Ex. 193a: 1 H-NMR (DMSO-d 6 ): 9.21 (d, J=2.1, 1H); 8.80 (t, J=2.0, 1H); 8.64 (d, J=1.8, 1H); 8.50 (d, J=9.0, 1H); 8.30 (s, 1H); 7.65 (d, J=7.7, 1H); 7.40 (t, J=7.9, 1 H); 7.30-7.10 (m, 5H); 6.94 (dd, J=1.8, 8.2, 1H); 5.23 (q, J=7.2, 1H); 4.50 (d, J=11.6, 1H); 4.36-4.26 (m, 2H); 3.82 (t, J=11.2, 1H); 3.20-3.17 (m, 2H); 2.99-2.70 (m, 2H); 2.81 (s, 3H); ca 2.50 (m, 2H; superimposed by DMSO-d signal); 2.09-1.77 (m, 4H); 1.34 (d, J=7.2, 3 H).
Ex. 194b: 1 H-NMR (DMSO-d 6 , addition of D 2 O): Two sets of signals were observed; ratio 9:1; signals of major isomer: 9.17 (d, J=2.0, 1H); 8.64 (s, 1H); 8.59 (d, J=1.7, 1H); 8.09 (s, 1H); 7.57 (d, J=7.8, 1H); 7.40 (t, J=7.9, 1H); 6.93 (dd, J=1.6, 8.2, 1H); 5.54 (t-like m, 1H); 4.56-4.53 (m, 2H); 4.31 (m, 1H); 3.68 (t, J=11.3, 1H); 3.55 (br. t-like m, 1H); 3.36 (br. q-like m, 1H); 2.81 (s, 3H); 2.80 (s, 3H); 2.62-2.60 (m, 2H); 2.31-2.27 (m, 2H); ca 2.1-1.75 (m, 6H); 1.12 (d, J=6.8; 3 H).
Core 11: Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d (Scheme 16)
Procedure C.2:
General Procedure for the Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d (Scheme 16)
1. Synthesis of Resins 135a-k: Immobilisation of Fmoc-AA1-OH
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100-200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH 2 Cl 2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH 2 Cl 2 (80 mL). A soln of Fmoc-AA1-OH (10.3 mmol) and i-Pr 2 NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N 2 bubbling through. The resin was filtered and washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 ). Capping: The resin was shaken in CH 2 Cl 2 /MeOH/i-Pr 2 NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH 2 Cl 2 , DMF, CH 2 Cl 2 , MeOH) and dried i.v. to afford resin 135.
Chlorotrityl- Yield/Loading Resin chlorid resin Fmoc-AA1-OH (mass increase) 135a-d 10 g Fmoc-NMe-β 3 - 13.0 g/0.78 mmol/g homoDAla-OH 135e, f, h, j 1 g Fmoc-Sar-OH 1.34 g/0.80 mmol/g 135g 1 g Fmoc-Gly-OH 1.22 g/0.70 mmol/g 135i 1 g Fmoc-Ala-OH 1.28 g/0.67 mmol/g 135k 2 g Fmoc-DAla-OH 2.35 g/0.71 mmol/g
2. Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d
Fmoc Cleavage: The resin 135 (90-107 mg, ca 70 μmol) was swollen in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2% v/v DBU in DMF (1 mL), shaken for 10 min filtered and washed (DMF). The deprotection step was repeated once. The resin 136 was filtered and washed (DMF).
Coupling of Fmoc-AA2-OH: The resin 136 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA2-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 137 was filtered and washed (DMF).
Fmoc Cleavage: The resin 137 was treated with 2% v/v DBU in DMF (1 mL) as described above to afford resin 138.
Coupling of Fmoc-AA3-OH: The resin 138 was suspended in DMF (1 mL). i-Pr 2 NEt (280 μmol), Fmoc-AA3-OH (140 μmol) and HATU (140 μmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 139 was filtered and washed (DMF).
Fmoc Cleavage: The resin 139 was treated with 2% v/v DBU in DMF (1 mL) as described above to afford resin 140.
Coupling of Alloc-protected amino acid 84: The resin 140 was suspended in DMF (1 mL). i-Pr 2 NEt (560 μmol), 84 (36 mg, 84 μmol) and PyBOP (140 μmol) were added. The mixture was shaken for 1 h and filtered. The resin 141 was washed (DMF). The coupling step was repeated once. The resin was filtered and washed (DMF, CH 2 Cl 2 ).
Alloc Cleavage: The resin 141 was suspended in CH 2 Cl 2 (1 mL). Phenylsilane (0.18 mL; 1.4 mmol) and Pd(PPh 3 ) 4 (8 mg, 7 μmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 142 was filtered and washed (CH 2 Cl 2 , DMF, MeOH, CH 2 Cl 2 ).
Release of the cyclization precursor: The resin 142 was treated with HFIP/CH 2 Cl 2 2:3 (1 mL) for 30 min, filtered and washed (CH 2 Cl 2 ). The cleavage step was repeated once. The combined filtrates and washings were concentrated, taken up in CH 3 CN (3 mL), concentrated and dried i.v. to afford crude 143a-k.
Ring closure and cleavage of side chain protective groups: Crude 143 was dissolved in a soln of i-Pr 2 NEt (98 μL; 570 μmol) in dry DMF (4 mL). This soln was then added dropwise to a soln of FDPP (41 mg, 106 μmol) in DMF (20 mL). The soln was stirred at rt for 5 h and the volatiles were evaporated. The residue was treated with sat. aq. Na 2 CO 3 soln (4 mL) and extracted with CHCl 3 (9 mL). The organic layer was filtered through a pad of MgSO 4 . The filtrate was concentrated to afford crude Ex. 195a-k. Crude products Ex. 195a,b,e-h,j were purified by prep. HPLC to afford Ex. 195a,b,e-h,j.
A soln of crude product Ex. 195c,d,i or k in TFA/CH 2 Cl 2 3:7 (1 mL) was stirred at rt for 3 h. The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 , concentrated, dried i.v. and purified by prep. HPLC to afford Ex. 196c,i,k or Ex. 197d, respectively.
Purification methods applied, yields, LC-MS data and systematic names of Ex. 195a, b,e-h,j; Ex. 196c,i,k and Ex. 197d are indicated in Table 23a.
Ex. 195b: 1 H-NMR (CD 3 OD): 9.16 (d, J=2.1, 1H); 8.97 (t, J=2.1, 1H); 8.94 (d, J=2.0, 1H); 7.57-7.39 (m, 3H); 7.00 (m, 1H); 5.23 (m, 1H); ca 4.8 (1H, superimposed by HDO signal); 4.40 (d, J=16.8, 1H); ca. 4.4 (br. m, 1H), 4.28 (dd; J=3.8, 8.1, 1H); 3.73 (d, J=16.8, 1H); 3.77-3.60 (m, 3H); 2.98 (s, 3H); 2.65 (dd, J=2.4, 13.6, 1H); 2.37 (t, J=12.8, 1H); 2.20-2.02 (m, 4H); 1.46 (d, J=7.0, 3 H); 1.15 (d, J=7.0, 3 H).
Ex. 195h: 1 H-NMR (CD 3 OD): Two sets of signals were observed; ratio 1:1; 9.06 (d, J=2.0, 0.5H); 9.00 (d, J=2.0, 0.5H); 8.97 (d, J=1.9, 0.5H); 8.84 (d, J=1.9, 0.5H); 8.72 (t, J=2.1, 0.5H); 8.50 (t, J=2.1, 0.5H); 7.88 (s, 0.5H); 7.65 (s, 0.5H); 7.50-7.35 (m, 2H); 7.32-7.19 (m, 3.5H); 7.09-6.93 (m, 2.5H); 5.89 (d, J=16.7, 0.5H); 5.26-5.20 (q-like m, 1H), 4.79 (q, J=7.2, 0.5H); 4.65 (dd, J ca 4.7, 11.8, 1H); 4.51 (dt-like m, 1H); 4.50 (br. m, 0.5H); 4.05 (d, J=7.2, 1H); 3.90 (t, J=9.6, 0.5H); 3.75-3.44 (m, 3.5H); 3.23 (dd, J=4.5, 13.9, 0.5H); 3.12-3.05 (m, 1H); 2.98 (s, 3H); 2.24-2.04 (m, 4H); 1.43 (d, J=7.0, 1.5H); 1.36 (d, J=7.2, 1.5H).
Core 12: Synthesis of Ex. 198, Ex. 199 and Ex. 200 (Scheme 17)
Synthesis of the Mitsunobu Product 144
CMBP (9.9 mL, 38 mmol) was added to a soln of the hydroxypyridine 93 (4.32 g, 19 mmol) and the alcohol 16 (6.5 g, 22 mmol) in toluene (200 mL). The mixture was heated to 80° C. for 1 h. The volatiles were evaporated. FC (hexane/EtOAc/MeOH gradient) afforded 144 (8.60 g, 90%).
Data of 144: C 27 H 33 N 3 O 7 (511.6). LC-MS (method 1a): R t =1.91 (98), 512.3 ([M+H] + ).
Synthesis of the Carboxylic Acid 145
A soln of the ester 144 (6.56 g, 13 mmol) in MeOH (23 mL), THF (92 mL) and H 2 O (23 mL) was treated with LiOH.H 2 O (1.6 g, 38 mmol) at rt for 16 h. H 2 O (50 mL) was added followed by 1 M aq. HCl soln (100 mL). The mixture was repeatedly extracted with EtOAc. The combined organic phases were washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 145 (6.19 g, 96%).
Data of 145: C 26 H 31 N 3 O 7 (497.5). LC-MS (method 1a): R t =1.62 (97), 498.0 ([M+H] + ).
Synthesis of Amide 146
A mixture of acid 145 (6.19 g, 12 mmol), amine 28.HCl (3.6 g, 11 mmol), and HATU (5.7 g, 15 mmol) was dissolved in DMF (197 mL), followed by the addition of i-Pr 2 NEt (6.6 mL, 39 mmol). The mixture was stirred for 2 h. The mixture was diluted with sat. aq. Na 2 CO 3 soln and extracted with CH 2 Cl 2 . The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The residue was dissolved in EtOAc, washed (H 2 O, sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 1:3) afforded 146 (7.1 g, 74%).
Data of 146: C 40 H 49 N 5 O 10 (759.8). LC-MS (method 1a): R t =2.04 (92), 760.1 ([M+H] + ).
Synthesis of the Carboxylic Acid 147
A soln of the ester 146 (7.07 g, 9.3 mmol) in MeOH (57 mL), THF (171 mL) and H 2 O (57 mL) was treated with LiOH.H 2 O (1.2 g, 28 mmol) at rt for 16 h. The mixture was poured onto ice/1 M aq. HCl soln (50 mL) and repeatedly extracted with EtOAc. The combined organic phases were washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated to give 147 (6.8 g, quant. yield).
Data of 147: C 38 H 45 N 5 O 10 (731.8). LC-MS (method 1c): R t =1.81 (94), 731.9 ([M+H] + ).
Synthesis of Amino Acid 148
A degassed solution of ester 147 (6.8 g, 9.3 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28 mmol) in CH 2 Cl 2 (67 mL) and EtOAc (68 mL) was treated with Pd(PPh 3 ) 4 (0.54 g, 0.46 mmol) at rt for 2 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 99:1 to 80:20) afforded 148 (5.6 g, 93%).
Data of 148: C 34 H 41 N 5 O 8 (647.7). LC-MS (method 1a): R t =1.45 (91), 648.0 ([M+H] + ).
Synthesis of Ex. 198
A solution of 148 (1.08 g, 1.7 mmol) and i-Pr 2 NEt (0.86 mL, 5.0 mmol) in dry DMF (40 mL) was added over 3 h (syringe pump) to a soln of HATU (1.27 g, 3.33 mmol) in DMF (1620 mL). The volatiles were evaporated. Aq. Workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (EtOAc/MeOH 95:5) afforded Ex. 198 (0.65 g, 62%).
Data of Ex. 198: C 34 H 39 N 5 O 7 (629.7). LC-MS (method 1d): R t =1.61 (99), 630.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Three sets of broad signals were observed; 8.44 (br. d, J ca 3.7, 0.5H); 8.32, 8.28 (2 d, J=3.8, 3.9, 0.5H); 7.86-7.18 (m, 13H); 5.12-4.83 (m, 2H); 4.59-3.46 (several m, 7H); 3.32-2.72 (several m, 5H); 2.40-2.25 (m, 1H), 2.15-1.90 (m, 1H); 1.40, 1.39 (2 s, 9H).
Synthesis of Ex. 199
A soln of Ex. 198 (0.85 g, 1.34 mmol) in dioxane (17 mL) was treated with 4 M HCl dioxane soln (17 mL) for 1 h at rt. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered, washed with Et 2 O and dried to afford Ex. 199.2HCl (836 mg; quant. yield).
Data of Ex. 199.2HCl: C 29 H 31 N 5 O 5 .2HCl (529.6, free base). LC-MS (method 2c): R t =1.40 (94), 530.2 ([M+H] + ).
Synthesis of Ex. 200
A soln of Ex. 198 (1.2 g, 1.91 mmol) in MeOH (40 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 250 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated to give Ex. 200 (0.87 g, 92%).
Data of Ex. 200: C 26 H 33 N 5 O 5 (495.6). LC-MS (method 1a): R t =1.15 (97), 496.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): two sets of signals were observed; 8.38 (br. s, 0.3H); 8.33 (d, J=4.2, 0.7H), 7.75-7.41 (m, 7H), 7.18 (br. s, 1H); 4.20-4.13 (m, 2H); 3.93-3.87 (t-like m, 2H); 3.76-3.73 (d-like m, 1H); 3.14-2.70 (several m, 4H); 2.45-2.30 (m, 2H), 2.01 (d, J=15.9, 1H), 1.85 (br. not resolved m, 1H); 1.70 (d-like m, 1H); 1.41, 1.37 (2 s, 9H).
Core 13-15: Synthesis of the Common Precursor 151 (Scheme 18)
Synthesis of the Amide 149
A soln of 98 (7.96 g, 33.4 mmol), 129.HCl (7.19 g, 36.8 mmol) and BOP (16.3 g, 36.8 mmol) in DMF (120 mL) was cooled to 0° C. i-Pr 2 NEt (22.7 mL, 134 mmol) was slowly added and stirring was continued for 30 min. Aqueous workup (EtOAc, aq. 1 M HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) followed by FC (hexane/EtOAc 2:1) afforded 149 (10.8 g, 85%).
Data of 149: C 18 H 18 FNO 5 S (379.4). LC-MS (method 1a): R t =1.98 (90), 380.2 ([M+H] + )
Synthesis of the Amine 151
A suspension of phenol 149 (8.79 g, 23.2 mmol), alcohol 16 (8.35 g, 27.8 mmol) and PPh 3 (9.11 g, 34.8 mmol) in benzene (278 mL) was degassed and cooled to 0° C. DEAD (40% in toluene; 15.9 mL, 34.8 mmol) was added dropwise. The mixture was stirred at rt for 16 h and concentrated. The residue was suspended in Et 2 O and filtered. The filtrate was concentrated and purified by FC (hexane/EtOAc, Et 3 N 66:33:1) to give 150 (15.4 g).
A degassed soln of 150 (15.4 g) and 1,3-dimethylbarbituric acid (5.45 g, 34.9 mmol) in CH 2 Cl 2 (150 mL) and EtOAc (450 mL) was treated with Pd(PPh 3 ) 4 (0.67 g, 0.58 mmol) at rt for 1 h. Aqueous workup (EtOAc, sat.aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (EtOAc, then CH 2 Cl 2 /MeOH 95:5) afforded 151 (8.18 g, 61%).
Data of 151: C 28 H 36 FN 3 O 7 S (577.6). LC-MS (method 1a): R t =1.87 (96), 578.4 ([M+H] + )
Core 13: Synthesis of Ex. 220, Ex. 221 and Ex. 222 (Scheme 18)
Synthesis of Amide 152
At 0° C., acryloyl chloride (0.37 mL, 4.57 mmol) was slowly added to a soln of 151 (2.2 g, 3.81 mmol) and i-Pr 2 NEt (0.78 mL, 4.57 mmol) in CH 2 Cl 2 (33 mL). The mixture was stirred for 0.5 h followed by an aqueous workup (CH 2 Cl 2 , 0.1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 1:1 to 3:7) to afford 152 (2.21 g, 91%).
Data of 152: C 31 H 38 FN 3 O 8 S (631.7). LC-MS (method 4a): R t =1.60 (94), 632.1 ([M+H] + )
Synthesis of Ex. 220
The catalyst Umicore M72 SIMes (RD) (64 mg, 0.075 mmol) was added in one portion to a degassed solution of 152 (240 mg, 0.38 mmol) in toluene (380 mL) and heated to 100° C. for 0.5 h. The mixture was cooled to rt. More Umicore M72 SIMes (RD) catalyst (64 mg) was added and the mixture was heated to 100° C. for 30 min; this operation was repeated once again. 2-Mercaptonicotinic acid (59 mg, 0.38 mmol) was added and the heating to 100° C. was continued for 1 h. The mixture was concentrated. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) followed by prep. HPLC (method 3) afforded Ex. 220 (42 mg, 18%).
Data of Ex. 220: C 29 H 34 FN 3 O 8 S (603.6). LC-MS (method 1f): R t =2.18 (89), 604.0 ([M+H] + )
Synthesis of Ex. 221
A soln of Ex. 220 (0.49 g, 0.8 mmol)) in MeOH (80 mL) was hydrogenated for 2 h at rt and normal pressure in the presence palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 304 mg). The mixture was filtered through a pad of Na 2 SO 4 and celite. The solid was washed with CH 2 Cl 2 /MeOH 1:1 (300 mL). The combined filtrate and washings were concentrated to give Ex. 221 (0.25 g, 51%).
Data of Ex. 221: C 29 H 36 FN 3 O 8 S (605.7). LC-MS (method 2f): R t =2.43 (90), 606.2 ([M+H] + ). 1 H-NMR (CDCl 3 ): 8.67 (d, J=1.2, 1H); 8.01 (s, 1H); 7.69 (d, J=1.2, 1H); 7.52 (d, J=8.5, 1H); 6.98 (d, J=8.7, 1H); 6.55 (td, J=2.2, 10.2, 1H); 4.97 (td, J=2.9, 8.7, 1H); 4.82 (br. m, not resolved, 1H); 4.69 (d-like m, 1H); 4.61 (br. not resolved m, 1H); 4.31-4.22 (m, 2H); 4.04-3.90 (m, 3H); 3.80 (s, 3H); 3.74 (dd, J=2.8, 10.8, 1H); 3.65 (m, 1H); 3.46 (m, 1H); 2.53-2.41 (m, 3H); 2.02-1.88 (m, 3H); 1.48 (s, 9H).
Synthesis of Ex. 222
A soln of Ex. 221 (233 mg. 0.39 mmol) in dioxane (1 mL) was treated with 4 M HCl in dioxane (5 mL) for 2 h at rt. The volatiles were evaporated. The residue was suspended in Et 2 O, filtered and dried i.v. to afford Ex. 222.HCl (180 mg, 86%).
Data of Ex. 222.HCl: C 24 H 28 FN 3 O 6 S (505.6, free base). LC-MS (method 1d): R t =1.55 (92), 506.2 ([M+H] + ).
Core 14: Synthesis of Ex. 227, Ex. 228 and Ex. 229 (Scheme 18)
Synthesis of Amide 153
At 0° C., i-Pr 2 NEt (2.2 mL, 13.0 mmol) was added dropwise to a soln of 151 (2.5 g, 4.3 mmol), but-3-enoic acid (0.48 g, 5.6 mmol), HATU (2.47 g, 6.5 mmol) and HOAt (0.88 g, 6.5 mmol) in DMF (60 mL). The mixture was stirred for 1.5 h at 0° C. followed by an aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:2) to give 153 (2.36 g, 84%).
Data of 153: C 32 H 40 FN 3 O 8 S (645.7). LC-MS (method 4b): R t =1.67 (96), 646.2 ([M+H] + ).
Synthesis of Ex. 227
A solution of 153 (110 mg, 0.17 mmol) and the catalyst Umicore M72 SIMes (RD) (58 mg, 0.068 mmol) in CH 2 Cl 2 (70 mL) was degassed and heated to reflux for 2 h. The mixture was allowed to cool to rt. 2-Mercaptonicotinic acid (106 mg, 0.68 mmol) was added. The mixture was heated to reflux for 1 h. The mixture was washed with sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by prep. HPLC (method 3) to afford Ex. 227 (56 mg, 53%).
Data of Ex. 227: C 30 H 36 FN 3 O 8 S (617.7). LC-MS (method 1d): R t =2.32 (87), 618.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.38 (s, 1H), 8.27-8.24 (m, 2H); 7.90 (s, 1H); 7.28-7.18 (m, 2H); 6.70 (td, J=2.1, 10.6, 1H); 5.97 (td, J=5.9, 15.8, 1H); 5.66 (td, J=4.6, 15.7, 1H); 4.75-4.63 (m, 2H); 4.31 (br. not resolved m, 1H); 4.06-3.67 (m, 7H); 3.67 (s, 3H); 3.24 (dd, J=6.4, 10.5, 1H); 3.11 (br. m, 2H); 2.30 (m, 1H); 1.92 (m, 1H); 1.39 (s, 9H).
Synthesis of Ex. 228
Trimethyltin hydroxide (263 mg; 1.46 mmol) was added to a solution of Ex. 227 (300 mg, 0.49 mmol) in DCE (15 mL). The mixture was heated to 80° C. for 16 h, followed by aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford Ex. 228 (350 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) to give Ex. 228 (13 mg).
Data of Ex. 228: C 29 H 34 FN 3 O 8 S (603.6). LC-MS (method 1a): R t =2.17 (92), 604.0 ([M+H] + ).
Synthesis of Ex. 229
A soln of Ex. 227 (287 mg, 0.46 mmol) in dioxane (5 mL) was treated with 4 M HCl in dioxane (5 mL) for 5 h at rt and concentrated. The residue was suspended in Et 2 O and filtered to afford Ex. 229.HCl (240 mg, 93%).
Data of Ex. 229.HCl: C 25 H 28 FN 3 O 6 S.HCl (517.6, free base). LC-MS (method 1a): R t =1.49 (92), 518.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.38 (br. s, 4H), 8.28 (s, 1H); 8.22 (d, J=8.0, 1H); 7.82 (s, 1H); 7.29 (d, J=9.4, 1H); 6.73 (d, J=10.6, 1H); 5.98 (td, J=6.0, 15.6, 1H); 5.69 (td, J=4.8, 15.8, 1H); 4.74-4.65 (m, 2H); 4.39 (m, 1H); 4.04-3.85 (m, 5H); 3.85-3.65 (m, 2H); 3.67 (s, 3H); 3.44 (dd, J=7.1, 10.5, 1H); 3.14 (d, J=5.6, 2 H), 2.50 (m, 1H); 2.04 (m, 1H).
Core 15: Synthesis of Ex. 242, Ex. 243 and Ex. 244 (Scheme 18)
Synthesis of Ex. 242
A soln of Ex. 227 (1.5 g, 2.4 mmol)) in MeOH (75 mL) was hydrogenated for 2.5 h at rt and normal pressure in the presence of 5% palladium on activated charcoal (moistened with 50% H 2 O; 300 mg). The mixture was filtered through a pad of celite. The solid was washed with MeOH. The combined filtrate and washings were concentrated. FC (hexane/EtOAc 1:2) gave Ex. 242 (1.37 g, 91%).
Data of Ex. 242: C 30 H 38 FN 3 O 8 S (619.7). LC-MS (method 1a): R t =2.47 (92), 620.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.51 (d, J=1.1, 1H); 8.29 (d, J=1.1, 1H); 8.07 (d, J=7.9, 1H); 7.95 (s, 1H); 7.30-7.26 (m, 2H), 6.70 (td, J=2.1, 10.5, 1H); 4.70 (m, 1H); 4.60 (br. dd, 1H); 4.29 (br. not resolved m, 1H); 4.04-3.67 (m, 5H); 3.67 (s, 3H); 3.48 (br. not resolved m, 2H); 3.28 (m, 1H); 2.38-2.23 (m, 3H); 1.91 (m, 1H), 1.77 (m, 1H); 1.68-1.51 (m, 3H); 1.39 (s, 9H).
Synthesis of Ex. 243
Trimethyltin hydroxide (175 mg; 0.97 mmol) was added to a solution of Ex. 242 (200 mg, 0.32 mmol) in DCE (10 mL). The mixture was heated to 80° C. for 16 h, followed by aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) to afford Ex. 243 (236 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) to give Ex. 243 (14 mg).
Data of Ex. 243: C 29 H 36 FN 3 O 8 S (605.7). LC-MS (method 1a): R t =2.27 (97), 606.2 ([M+H] + ).
Synthesis of Ex. 244
A soln of Ex. 242 (265 mg, 0.43 mmol) in dioxane (5 mL) was treated with 4 M HCl in dioxane (5 mL) for 6 h at rt and concentrated. The residue was taken up in CHCl 3 and concentrated to afford Ex. 244.HCl (205 mg, 86%).
Data of Ex. 244.HCl: C 25 H 30 FN 3 O 6 S.HCl (519.6, free base). LC-MS (method 1d): R t =1.55 (92), 520.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.48 (s, 1H); 8.40-8.25 (br. s, 4H); 8.05 (d, J=7.9, 1H); 7.86 (s, 1H); 7.31 (d, J=8.8, 1H); 6.73 (d, J=10.6, 1H); 4.72-4.61 (m, 2H); ca 4.4-4.3 (br. m, 2H); 4.00-3.68 (m, 5H); 3.68 (s, 3H); 3.49-3.43 (m, not resolved, 2H), ca 2.5 (m, superimposed by DMSO-d signal, 1H); 2.40-2.25 (m, 2H), 2.02 (m, 1H); 1.79-1.52 (m, 4H).
Core 15: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 18)
Synthesis of Ex. 246
At 0° C., i-Pr 2 NEt (0.054 mL, 0.32 mmol) was added to a soln of Ex. 243 (ca. 70% w/w; 55 mg, 0.064 mmol), HATU (36 mg, 0.095 mmol), HOAt (13 mg, 0.095 mmol) and aniline (0.029 mL, 0.32 mmol) in CH 2 Cl 2 (1.5 mL) and DMF (0.5 mL). The mixture was stirred for 30 min followed by an aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1.1) to afford Ex. 246 (27 mg, 62%).
Data of Ex. 246: cf. Table 27b
Synthesis of Ex. 247
At 0° C., 4 M HCl in dioxane (0.20 mL) was added to a soln of Ex. 246 (25 mg, 0.037 mmol) in dioxane (0.6 mL). The mixture was stirred for 5 h at 0° C. to rt. More 4 M HCl in dioxane (0.15 mL) was added and the mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was treated with TFA (0.15 mL) in CH 2 Cl 2 (0.75 mL) for 1 h at 0° C., followed by evaporation of the solvents, aqueous workup (EtOAc, sat.aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 90:10). The purified product (13 mg) was dissolved in dioxane (0.3 mL) and treated with 4 M HCl in dioxane (0.05 mL). The volatiles were evaporated to give Ex. 247.HCl (14 mg, 60%).
Data of Ex. 247.HCl: cf. Table 27b
1 H-NMR (DMSO-d 6 ): 10.18 (s, 1H); 8.48 (s, 1H); 8.30 (s, 1H); 8.15 (d, J=7.1, 1H); 8.15 (br. s, 3H); 7.85 (s, 1H); 7.59 (d, J=7.7, 2 H); 7.36-7.27 (m, 3H); 7.06 (t, J=7.4, 1H); 6.74 (dt-like m, 1H); 4.73-4.63 (m, 2H); 4.40 (br. not resolved m, 1H); 4.01-3.59 (m, 5H); 3.50-3.41 (m, 3H); 2.36 (br. t-like m, 2H); 2.04 (m, 1H); 1.90-1.45 (several not resolved m, 5H).
Synthesis of Ex. 256
Ex. 256 (8 mg, 14%) was obtained from Ex. 243 (ca. 70% w/w; 65 mg, 0.075 mmol) and 4-chloroaniline (48 mg, 0.38 mmol) by applying the method described for the synthesis of Ex. 246.
Data of Ex. 256: cf. Table 27b
Synthesis of Ex. 257
Ex. 257.HCl (4 mg, 66%) was obtained from Ex. 256 (7 mg, 0.01 mmol) by applying the method described for the synthesis of Ex. 247.HCl.
Data of Ex. 257.HCl: cf. Table 27b
Synthesis of Ex. 258
Ex. 258 (19 mg, 43%) was obtained from Ex. 243 (ca. 70% w/w; 55 mg, 0.064 mmol) and m-toluidine (0.034 mL, 0.32 mmol) by applying the method described for the synthesis of Ex. 246.
Data of Ex. 258: cf. Table 27b
Synthesis of Ex. 259
Ex. 259.HCl (10 mg, 66%) was obtained from Ex. 258 (17 mg, 0.024 mmol) by applying the method described for the synthesis of Ex. 247.HCl.
Data of Ex. 259.HCl: cf. Table 27b
1 H-NMR (DMSO-d 6 ): 10.07 (s, 1H); 8.47 (s, 1H); 8.30 (s, 1H); 8.12 (d, J=7.6, 1H); 8.12 (br. s, 3H); 7.85 (s, 1H); 7.42-7.30 (m, 3H), 7.18 (t, J=7.4, 1H); 6.88 (d, J ca 7.6, 1H); 6.74 (d, J=10.3, 1H); 4.78-4.60 (m, 2H); 4.40 (br. not resolved m, 1H); 4.05-3.65 (m, 5H); 3.51-3.40 (m, 3H); 2.37 (br. t-like m, 2H); 2.27 (s, 3H); 2.01 (m, 1H); 1.90-1.45 (several not resolved m, 5H).
Core 16: Synthesis of Ex. 262, Ex. 263 and Ex. 264 (Scheme 19)
Synthesis of the Mitsunobu Product 154
CMBP (8.5 mL, 32 mmol) was added to a soln of hydroxythiophene 106 (5.69 g, 20 mmol) and alcohol 118 (9.8 g, 26 mmol) in toluene (77 mL). The mixture was heated to reflux for 2 h and concentrated. FC (hexane/EtOAc 90:10 to 20:80) gave 154 (12.68 g, 98%).
Data of 154: C 29 H 34 BrN 3 O 6 S (632.6). LC-MS (method 4a): R t =2.29 (93), 634.3/632.3 ([M+H] + ).
Synthesis of the Amino Acid 157
A soln of 154 (12.6 g, 20 mmol) in CH 2 Cl 2 (128 mL) was treated with TFA (148 mL) and heated to reflux for 3 h. The volatiles were evaporated. The residue was suspended in toluene, concentrated and dried i.v. to give crude 155 (16.15 g, containing residual solvent), which was used without further purification.
At 0° C., i-Pr 2 NEt (6.85 mL, 40.3 mmol) was added to a soln of crude carboxylic acid 155 (9.27 g, ca 11.5 mmol), amine 130.HCl (5.52 g, 16.1 mmol), HATU (7.66 g, 20.1 mmol) and HOAt (2.74 g, 20.1 mmol) in DMF (170 mL). The mixture was stirred at rt for 2 h, followed by an aqueous workup (EtOAc, 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 100:0 to 95:5) to afford 156 (11.7 g; containing residual DMF), used without further purification.
A degassed solution of 156 (11.6 g) and 1,3-dimethylbarbituric acid (6.3 g, 40 mmol) in CH 2 Cl 2 (39 mL) and EtOAc (78 mL) was treated with Pd(PPh 3 ) 4 (1.6 g, 1.3 mmol) at rt for 4 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded 157 (7.6 g, 89% over the three steps).
Data of 157: C 34 H 38 BrN 5 O 7 S (740.6). LC-MS (method 1a): R t =1.91 (87), 740.1/742.1 ([M+H] + ).
Synthesis of Ex. 262
A soln of 157 (1.9 g, 2.57 mmol) in CH 2 Cl 2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc, 7.56 mL, 12.8 mmol) and i-Pr 2 NEt (1.96 mL, 11.5 mmol) in CH 2 Cl 2 (1190 mL). Stirring at rt was continued for 4 h. The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln.; Na 2 SO 4 ) and FC (hexane/EtOAc 50:50 to 0:100) afforded Ex. 262 (1.63 g, 88%).
Data of Ex. 262: C 34 H 36 BrN 5 O 6 S (722.6). LC-MS (method 1d): R t =2.52 (99), 722.0/724.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.65 (d, J=6.8, 1H); 7.49 (d, J=8.0, 2 H); 7.41-7.26 (m, 8H); 7.08 (d, J=5.4, 1H); 6.64 (s, 1H); 5.06 (s, 2H); ca 4.5-4.4 (br. m, 2H); 4.48 (s, 2H); 4.32 (br. d, J ca 8.8, 1H); 4.16 (br. m, 2H); 4.01 (m, 1H); 3.86 (s, 3H); 3.69 (br. m, 1H); 3.46-3.32 (m, 2H); 2.96 (s, 3H); 2.40-2.25 (br. m, 2H), 2.10-1.90 (br. m, 2H).
Synthesis of Ex. 263
At 0° C., BCl 3 (16 mL, 16 mmol) was added dropwise to a soln of Ex. 262 (2.34 g, 3.2 mmol) in CH 2 Cl 2 (83 mL). The mixture was allowed to stir at 0° C. to rt for 16 h. The mixture was cooled to 0° C. and poured slowly into MeOH. The mixture was concentrated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) afforded Ex. 263 (1.21 g, 89%).
Data of Ex. 263: C 19 H 25 N 5 O 4 S (419.5). LC-MS (method 1d): R t =1.11 (98), 420.0 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.08 (d, J=5.5, 1H); 6.63 (s, 1H); 5.17 (d, J=5.1, 1H); 4.35-4.29 (m, 2H); 4.24 (dd, J=6.6, 11.9, 1H); 4.12-3.97 (m, 3H); 3.85 (s, 3H); 3.68 (d, J=7.4, 1H); 3.61 (m, 1H); 3.17 (dd, J=6.6, 10.2, 1H); 2.97 (s, 3H); 2.28-2.19 (m, 2H); 1.95 (m, 1H), 1.90-1.75 (br. not resolved m, 3H).
Synthesis of Ex. 264
At rt, TBAF (1 M in THF; 0.119 mL, 0.119 mmol) was slowly added to a soln of Ex. 262 (160 mg, 0.221 mmol) in THF (2.5 mL). The mixture was heated to reflux for 2 h, filtered through a pad of celite and concentrated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC(CH 2 Cl 2 /MeOH 85:15) afforded a white solid (100 mg) was dissolved in DMF (4.0 mL) and hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 23 mg). The volatiles were evaporated. The crude product was purified by FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) to give Ex. 264 (45 mg, 40%).
Data of Ex. 264: C 26 H 31 N 5 O 4 S (509.6). LC-MS (method 1a): R t =1.62 (99), 510.1 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.40 (d, J=5.5, 1H); 7.33-7.27 (m, 5H); 7.08 (d, J=5.5, 1H); 6.65 (s, 1H); 4.53 (s, 2H); 4.41-4.17 (m, 5H); 3.98 (dd, J=5.1, 9.4, 1H); 3.85 (s, 3H); 3.72 (d, J=7.0, 1H); 3.61 (m, 1H); ca 3.3 (m, superimposed by H 2 O signal, 1H); 2.97 (s, 3H); 2.40-1.80 (several br. m, 6H).
Core 16: Synthesis of Selected Advanced Intermediates and Final Products (Scheme 19)
Synthesis of Ex. 265
At 0° C., oxalyl chloride (0.104 mL, 1.19 mmol) and one drop of DMF were added to a soln of 2-naphthaleneacetic acid (53 mg, 0.29 mmol) in CH 2 Cl 2 (6 mL). The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in CH 2 Cl 2 (2.5 mL) and added dropwise to a soln of Ex. 263 (100 mg, 0.24 mmol) and i-Pr 2 NEt (0.204 mL, 1.19 mmol) in CH 2 Cl 2 (3.5 mL). The mixture was stirred at 0° C. for 1 h followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /i-PrOH 100:0 to 95:5) to yield Ex. 265 (110 mg, 78%).
Data of Ex. 265: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 8.54 (d, J=7.5, 1H); 7.89-7.85 (m, 3H); 7.78 (s, 1H); 7.52-7.44 (m, 3H); 7.40 (d, J=5.5, 1H); 7.09 (d, J=5.5, 1H); 6.44 (s, 1H); 5.14 (d, J=4.9, 1H); 4.65 (br. t, J=8.0, 1H); 4.40-4.31 (m, 2H); 4.11 (q, J ca 5.8, 1H); 4.03 (m, 1H), 3.84 (m, 1H); 3.84 (s, 3H); 3.68 (s, 2H); 3.64 (m, 1H); ca 3.30 (m, 1H, partially superimposed by H 2 O signal); 3.17 (dd, J=6.3, 10.5, 1H); 2.91 (s, 3H); 2.35 (m, 1H); 2.18 (m, 1H); 1.91-1.82 (m, 2H).
Synthesis of Ex. 275
Trimethyloxonium tetrafluoroborate (15 mg, 0.10 mmol) was added at 0° C. to a solution of Ex. 265 (40 mg, 0.068 mmol) and N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (22 mg, 0.102 mmol) in CH 2 Cl 2 (1.0 mL). The mixture was stirred at 0° C. to rt for 4.5 h. More N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (32 mg, 0.15 mmol) and trimethyloxonium tetrafluoroborate (22 mg, 0.15 mmol) were added at 0° C. and stirring was continued at rt for 16 h. Aqueous workup (CH 2 Cl 2 , 2 M aq. HCl soln; Na 2 SO 4 ). The residue was suspended in CH 2 Cl 2 and filtered. The filtrate was purified by FC (EtOAc/MeOH 100:0 to 97:3) and by prep. RP-HPLC (method 1a) to afford Ex. 275 (5 mg, 12%).
Data of Ex. 275: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 8.57 (d, J=7.5, 1H); 7.90-7.85 (m, 3H); 7.80 (s, 1H); 7.54-7.45 (m, 3H); 7.39 (d, J=5.5, 1H); 7.07 (d, J=5.5, 1H); 6.62 (s, 1H); 4.65 (br. t, J=7.8, 1H); 4.40 (br. not resolved m, 1H); 4.29 (dd; J=2.7, 9.5, 1H); 3.96-3.83 (m, 2H); 3.83 (s, 3H); 3.75-3.60 (m, 2H); 3.67 (s, 2H); ca 3.3-3.2 (m, 2H, partially superimposed by H 2 O signal); 3.05 (s, 3H); 2.92 (s, 3H); 2.36 (m, 1H); 2.16 (m, 1H); 1.96-1.83 (m, 2H).
Synthesis of Ex. 276
At 0° C., i-Pr 2 NEt (0.061 mL, 0.36 mmol) and 2-naphthylisocyanate (22 mg, 0.131 mmol) were added to a soln of Ex. 263 (50 mg, 0.12 mmol) in CH 2 Cl 2 (1.0 mL). The mixture was stirred at 0° C. to rt for 60 min. Aqueous workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 3) afforded Ex. 276 (50 mg, 71%).
Data of Ex. 276: cf. Table 28b
1 H-NMR (DMSO-d 6 ): 9.00 (s, 1H) 8.05 (d, J=1.8, 1H); 7.81-7.74 (m, 3H); 7.45-7.40 (m, 3H); 7.32 (dt, J=1.2, 7.5, 1H); 7.11 (d, J=5.5, 1H); 6.74 (d, J=7.3, 1H); 6.68 (s, 1H); 5.24 (d, J=5.0, 1H); 4.77 (br. t, J=7.1, 1H); 4.38-4.32 (m, 2H); 4.29 (q-like m, 1H); 4.07-4.00 (m, 2H), 3.88 (s, 3H); 3.85 (m, 1H); ca 3.30-3.20 (m, 2H, partially superimposed by H 2 O signal); 2.98 (s, 3H); ca 2.5 (m, 1H, superimposed by DMSO-d signal); 2.27 (m, 1H); 2.00-1.92 (m, 2H).
Core 17: Synthesis of Ex. 284a, Ex. 285 and Ex. 286 (Scheme 20)
Synthesis of Amide 158
A suspension of 110.HCl (6.2 g, 19.9 mmol) in CH 2 Cl 2 (310 mL) was cooled to 0° C. Oxalyl chloride (5.1 mL, 59.7 mmol) was added followed by DMF (0.37 mL). The mixture was stirred for 1.5 h at rt and concentrated. The residue was suspended in CH 2 Cl 2 and concentrated; this operation was repeated once and the residue was then dried i.v. The residue was suspended in CH 2 Cl 2 (180 mL). A soln of 131HCl (8.86 g, 23.9 mmol) in CH 2 Cl 2 (120 mL) was added. The mixture was cooled to 0° C. followed by the slow addn of i-Pr 2 NEt (17.0 mL, 99.5 mmol). The mixture was stirred for 1 h at 0° C. Aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc gradient) gave 158 (8.1 g, 69%).
Data of 158: C 30 H 33 N 5 O 8 (591.6). LC-MS (method 1a): R t =2.43 (94), 592.1 ([M+H] + ).
Synthesis of the Mitsunobu Product 159
A soln of CMBP (6.58 g, 27.3 mmol) in toluene (30 mL) was added to a soln of phenol 158 (8.07 g, 13.6 mmol) and alcohol 120 (3.28 g, 17.7 mmol) in toluene (131 mL). The mixture was heated to reflux for 1 h and concentrated. FC (hexane/EtOAc 50:50 to 0:100) yielded 159 (7.9 g, 76%).
Data of 159: C 39 H 46 N 6 O 10 (758.8). LC-MS (method 4a): R t =1.91 (90), 759.2 ([M+H] + ).
Synthesis of the Amino Acid 160
A degassed solution of 159 (8.9 g, 11.8 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28.3 mmol) in CH 2 Cl 2 (180 mL) and EtOAc (45 mL) was treated with Pd(PPh 3 ) 4 (1.36 g, 1.18 mmol) at rt for 2 h. The volatiles were evaporated. FC (EtOAc, then CH 2 Cl 2 /MeOH 100:0 to 40:60) afforded 160 (7.33 g, 98%; containing some impurities; used without further purification).
Data of 160: C 32 H 38 N 6 O 8 (634.7). LC-MS (method 1a): R t =1.65 (88), 635.2 ([M+H] + ).
Synthesis of Ex. 284a and Ex. 284b
A soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump) to a soln of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) in pyridine (1500 mL). An additional portion of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) was added to the solution. Again a soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump).
The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln, H 2 O, Na 2 SO 4 ). Purification by preparative HPLC (method 1d) afforded Ex. 284a.CF 3 CO 2 H (480 mg) and Ex. 284b.CF 3 CO 2 H (186 mg, 16%).
Ex. 284a.CF 3 CO 2 H (480 mg) was dissolved in CH 2 Cl 2 and washed with sat. aq. NaHCO 3 soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated to afford Ex. 284a (442 mg, 45%).
Data of Ex. 284a: C 32 H 36 N 6 O 7 (616.6). LC-MS (method 1d): R t =2.24 (99), 617.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.66 (d, J=2.1, 1H); 8.40 (dd, J=2.1, 8.9, 1H); 7.53-7.49 (m, 2H); 7.36-7.26 (m, 6H); 5.06 (br. d, J=12.6, 1H); 4.92 (s, 2H); 4.37 (br. dd, J ca 2.6, 13.0, 1H); 4.15 (t-like m, 1H); 3.65 (br. t, J ca 8.7, 1H); 3.55 (q-like m, 1H); 3.27 (m, 1H); 3.01 (s, 3H); 2.95-2.82 (m, 2H), 2.61 (s, 3H); 1.97-1.68 (several m, 6H), 1.23-0.90 (br. m, 4H).
Data of Ex. 284b.CF 3 CO 2 H: C 32 H 36 N 6 O 7 CF 3 CO 2 H (free base 616.6). LC-MS (method 1d): R t =2.14 (99), 617.2 ([M+H] + ).
Synthesis of Ex. 285
A soln of Ex. 284a (380 mg, 0.62 mmol) in THF (19 mL) was treated with TBAF (1 M in THF; 0.6 mL, 0.6 mmol) at 75° C. for 7 h. The mixture was cooled to rt and TBAF (1 M in THF; 0.3 mL, 0.3 mmol) was added. Stirring at 75° C. was continued for 8 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 285 (182 mg, ca 60%; containing ca 5% of tetrabutylammonium salts). An analytical sample (15 mg) was further purified by preparative HPLC (method 2a) to afford Ex. 285 (9 mg).
Data of Ex. 285: C 24 H 30 N 6 O 5 (482.5). LC-MS (method 1d): R t =1.47 (95), 483.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 8.66 (d, J=2.2, 1H); 8.41 (dd, J=2.2, 9.0, 1H); 7.51 (s, 1H); 7.47 (d, J=9.1, 1H); 5.17 (d, J=12.5, 1H); 4.30 (dd, J=2.3, 12.7, 1H); 4.14 (t, J=7.0, 1H); 3.51 (m, 1H); ca. 3.2 (m, 1H), 3.02 (s, 3H); 2.97 (m, 1H); 2.81-2.68 (m, 2H); 2.61 (s, 3H); 2.0-1.7 (several m, 8H); 1.4-0.6 (several m, 4H).
Synthesis of Ex. 286
A soln. of Ex. 284a (1.2 g, 1.95 mmol) in MeOH (120 mL) was hydrogenated in the presence of platinum (IV) oxide hydrate (120 mg) for 8 h at rt and normal pressure. More platinum (IV) oxide hydrate (60 mg) was added and the hydrogenation was continued for 6 h. The mixture was filtered through a pad of celite. The solid was washed (MeOH). The combined filtrate and washings were concentrated. FC (hexane/EtOAc 50:50:0 to 0:100 then CH 2 Cl 2 /MeOH 90:10) yielded Ex. 286 (0.75 g, 66%).
Data of Ex. 286: C 32 H 38 N 6 O 5 (586.7). LC-MS (method 1d): R t =1.68 (90), 587.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.67 (d, J=2.0, 1H); 7.48-7.43 (m, 2H); 7.39-7.27 (m, 6H); 6.87 (d, J=8.6, 1H); 5.06-4.93 (m, 5H); 4.11 (br. m, not resolved, 1H); 4.00 (br. d, J ca 11.7, 1H); 3.60 (br. t, J ca. 8.4, 1H); 3.49 (q-like m, 1H); 3.15 (m, 1H), 2.99 (s, 3H); 2.96 (m, 1H); 2.78 (m, 1H); 2.54 (s, 3H); 2.21 (m, 1H); 2.15-1.15 (several br. m, 8H); 0.66 (br. m, 1H).
Core 18: Synthesis of Ex. 305 and Ex. 306 (Scheme 21)
Synthesis of the Mitsunobu Product 161
DEAD (40% in toluene; 11.1 mL, 24.3 mmol) was slowly added to a soln of alcohol 122 (5.66 g, 16.2 mmol), 2-iodophenol (111; 5.33 g, 24.3 mmol) and PPh 3 (6.36 g, 24.3 mmol) in toluene (345 mL). The mixture was stirred at rt for 4 h. The volatiles were evaporated. FC (hexane/EtOAc gradient) afforded 161 (6.85 g, 77%).
Data of 161: C 24 H 29 IN 2 O 5 (552.4). LC-MS (method 1a): R t =2.71 (99), 553.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.76 (d, J=7.7, 1H); 7.60 (d, J=6.5, 1H); 7.40-7.28 (m, 6H); 7.02 (d, J=8.2, 1H); 6.76 (t, J=7.5, 1H); 5.03 (s, 2H); 4.33 (br. m, 1H); 4.17-4.07 (br. m, 3H); 3.59 (br. m, 1H); 3.29 (br. m, 1H); 2.26 (br. m, 1H); 2.02 (br. m, 1H); 1.38 (s, 9H).
Synthesis of the Biphenyl 162
Pd(dppf)Cl 2 .CH 2 Cl 2 (1.0 g, 1.2 mmol) was added to a mixture of 161 (6.8 g, 12.3 mmol), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (113; 3.0 g, 10.8 mmol), 2-(ethoxycarbonyl)phenylboronic acid (112; 2.3 g, 11.8 mmol) in DME (325 mL), EtOH (32 mL) and 1 M aq. Na 2 CO 3 soln (37 mL). The mixture was heated to 80° C. for 3 h. The mixture was diluted with sat. aq. NaHCO 3 soln and repeatedly extracted with CH 2 Cl 2 . The combined organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc gradient) gave 162 (6.6 g, 94%).
Data of 162: C 33 H 38 N 2 O 7 (574.6). LC-MS (method 4c): R t =2.48 (96), 575.4 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): 7.80 (d, J=7.5, 1H); 7.58 (t, J=7.3, 1H); 7.46-7.25 (m, 9H); 7.12 (m, 1H); 7.03-7.00 (m, 2H); 4.99 (s, 2H); 3.99-3.83 (br. m, 6H); 3.78 (br. not resolved m, 1H); 3.01 (br. not resolved m, 1H); 1.81 (br. not resolved m, 1H); 1.72 (br. not resolved m, 1H); 1.33 (s, 9H); 0.88 (br. t, 3H).
Synthesis of the Carboxylic Acid 164
A soln of 162 (5.2 g, 9.1 mmol) in EtOH (50 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 0.5 g). The mixture was filtered through a pad of celite. The residue was washed with EtOH. The combined filtrate and washings were concentrated to give crude 163 (4.0 g) which was dissolved in EtOH (84 mL). KOH (10.2 g, 182 mmol) dissolved in H 2 O (28 mL) was added and the mixture was stirred at 45° C. for 18 h. The solution was cooled to rt. NaHCO 3 (15.2 g, 182 mmol) and CH 2 Cl 2 (100 mL) followed by CbzOSu (2.7 g, 10.8 mmol) were successively added and the mixture was allowed to stir for 3 h. The mixture was acidified by addn of 3 M aq. HCl soln and extracted with CH 2 Cl 2 . The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. FC (EtOAc) afforded 164 (4.87 g, 98%)
Data of 164: C 31 H 34 N 2 O 7 (546.6). LC-MS (method 1c): R t =2.44 (88), 547.1 ([M+H] + ).
Synthesis of the Amide 165
EDC.HCl (3.4 g, 17.8 mmol) was added to a soln of 164 (4.8 g, 8.9 mmol) and sarcosine tert.-butylester hydrochloride (132; 3.2 g, 17.8 mmol) in pyridine (150 mL). The mixture was stirred at rt for 3 h. Aqueous workup (CH 2 Cl 2 , aq. 2 M HCl soln, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (hexane/EtOAc gradient) afforded 165 (4.9 g, 82%).
Data of 165: C 38 H 47 N 3 O 8 (673.8). LC-MS (method 1a): R t =2.71 (97), 674.2 ([M+H] + ).
Synthesis of Ex. 305
A soln of 165 (4.9 g, 7.3 mmol) in CH 2 Cl 2 (50 mL) was treated with TFA (25 mL) for 4 h at rt. Evaporation of the volatiles afforded the crude amino acid 166-CF 3 CO 2 H (5.3 g, containing residual solvent) which was used without further purification.
The ring closing reaction was performed in four batches:
A soln of crude 166.CF 3 CO 2 H (1.3 g) and i-Pr 2 NEt (1.5 mL, 8.7 mmol) in CH 2 Cl 2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in EtOAc, 2.2 mL, 3.7 mmol) in CH 2 Cl 2 (1200 mL). The mixture was stirred for 1 h at rt and concentrated.
The four batches were combined and purified by FC (hexane/EtOAc/MeOH gradient) to give Ex. 305 (3.7 g, quant. yield).
Data of Ex. 305: C 29 H 29 N 3 O 5 (499.5). LC-MS (method 1a): R t =2.00 (98), 500.1 ([M+H] + ). 1 H-NMR (CD 3 OD): Two sets of signals were observed; ratio 7:3; 7.48-7.21 (m, 11H), 7.12-6.96 (m, 1.3H); 6.91 (t, J=7.5, 0.7H); 5.10-5.04 (m, 2H); 4.72 (dd, J=4.2, 9.7, 0.7H); 4.40-4.28 (m, 1.3H); 4.16-4.06 (m, 1.6H); 4.03 (dt, J=4.0, 7.8, 0.7H); 3.93 (br. not resolved m, 0.7H); 3.78 (d, J=14.6, 0.3H); 3.69 (br. d, 0.7H); 3.59-3.50 (m, 1.3H); 3.10, 3.07 (2 s, 3H); 2.99 (br. d, J ca 10.0, 0.7H); 2.10-1.93 (m, 2H).
Synthesis of Ex. 306
A soln of Ex. 305 (3.68 g, 7.3 mmol) in MeOH (50 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 0.38 g). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrate and washings were concentrated. FC (hexane/EtOAc/MeOH gradient) afforded Ex. 306 (2.4 g, 89%).
Data of Ex. 306: C 21 H 23 N 3 O 3 (365.4). LC-MS (method 1a): R t =1.17 (96), 366.0 ([M+H] + ).
Core 19: Synthesis of Ex. 327, Ex. 328 and Ex. 329 (Scheme 22)
Synthesis of the Amide 167
At 0° C., i-Pr 2 NEt (4.5 mL, 26.3 mmol) was added dropwise to a soln of 117 (1.2 g, 4.4 mmol), 125.HCl (1.73 g, 5.2 mmol), HATU (1.67 g, 4.4 mmol) and HOAt (0.60 g, 4.4 mmol) in DMF (30 mL) and THF (45 mL). The mixture was stirred at rt for 1.5 h. Aqueous workup (EtOAc, 0.1 M aq. HCl soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (hexane/EtOAc 2:1 to 1:1) afforded 167 (1.24 g, 51%).
Data of 167: C 26 H 24 F 3 N 3 O 7 (547.5). LC-MS (method 1c): R t =2.37 (89), 548.2 ([M+H] + ).
Synthesis of the Mitsunobu Product 168
A soln of phenol 167 (1.23 g, 2.2 mmol), alcohol 16 (0.81 g, 2.7 mmol) and CMBP (1.36 g, 5.6 mmol) in toluene (30 mL) was heated to reflux for 1.5 h. Evaporation of the volatiles and FC(CH 2 Cl 2 /EtOAc 3:1 to 1:1) afforded 168 (1.84 g, 99%).
Data of 168: C 40 H 46 F 3 N 5 O 11 (829.8). LC-MS (method 4a): R t =2.00 (92), 830.4 ([M+H] + ).
Synthesis of the Amino Acid 169
A degassed solution of 168 (1.8 g, 2.2 mmol) and 1,3-dimethylbarbituric acid (0.8 g, 5.3 mmol) in CH 2 Cl 2 (15 mL) and EtOAc (15 mL) was treated with Pd(PPh 3 ) 4 (0.13 g, 0.1 mmol) at rt for 1 h. The volatiles were evaporated. FC(CH 2 Cl 2 /MeOH 99:1 to 80:20) afforded 169 (1.32 g, 85%).
Data of 169: C 33 H 38 F 3 N 5 O 9 (705.7). LC-MS (method 1a): R t =1.95 (94), 706.3 ([M+H] + ).
Synthesis of Ex. 327
A mixture of 169 (1.33 g, 1.9 mmol), i-Pr 2 NEt (1.6 mL, 9.4 mmol) and CH 2 Cl 2 (40 mL) was slowly added over 2 h (syringe pump) to a soln of T3P (50% in EtOAc; 3.3 mL, 5.6 mmol) and i-Pr 2 NEt (1.6 mL, 9.4 mmol) in CH 2 Cl 2 (1880 mL). The volatiles were partially evaporated. The soln was washed (sat. aq. NaHCO 3 soln), dried (Na 2 SO 4 ), filtered and concentrated. FC (hexane/EtOAc 25:75 to 0:100) afforded Ex. 327 (0.96 g, 74%).
Data of Ex. 327: C 33 H 36 F 3 N 5 O 8 (687.6). LC-MS (method 1f): R t =2.43 (89), 688.3 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Three sets of signals were observed; ratio 2:1:1; 9.16 (br. s, 0.5H); 8.65 (br. s, 0.25H); 8.50 (br. s, 0.25H); 7.56-7.08 (m, 10H); 5.13-4.92 (several d, 2H); 4.40-2.98 (several br. not resolved m, 12H); 2.43-2.04 (br. not resolved m, 1H); 1.95-1.70 (br. not resolved m, 1H); 1.41, 1.39 (2 s, 9H).
Synthesis of Ex. 328
A soln of Ex. 327 (60 mg, 0.087 mmol) in EtOAc (5 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 30 mg). The mixture was filtered through a pad of celite. The residue was washed (EtOAc). The combined filtrate and washings were concentrated. FC(CH 2 Cl 2 /MeOH 95:5 to 90:10) afforded Ex. 328 (37 mg, 77%).
Data of Ex. 328: C 25 H 30 F 3 N 5 O 6 (553.5). LC-MS (method 1d): R t =1.84 (96), 554.2 ([M+H] + ). 1 H-NMR (DMSO-d 6 ): Two sets of signals were observed; ratio 4:6; 9.19 (t-like m, 0.4H), 8.72 (t-like m, 0.6H); 7.57 (not resolved m, 1H); 7.48-7.30 (m, 2H); 7.23 (d, J=5.1, 1H); 7.04 (not resolved m, 1H); 4.50-4.34 (2 m, 1H); 4.20-4.13 (m, 2H); 4.07-3.94 (m, 2H); 3.84-3.30 (several m, 3H); 3.19-2.66 (several m, 5H); 2.42, 2.26 (2 m, 1H); 1.95, 1.70 (2 m, 1H); 1.40 (s, 9H).
Synthesis of Ex. 329
Ex. 327 (50 mg, 0.073 mmol) was dissolved in CH 2 Cl 2 (2 mL). At 0° C., TFA (0.03 mL, 0.36 mmol) was added and the soln was stirred for 1.5 h. Aqueous workup (EtOAc, sat. aq. NaHCO 3 soln, sat aq. NaCl soln; Na 2 SO 4 ) and treatment of the product with HCl in dioxane afforded Ex. 329.HCl (33 mg, 73%).
Data of Ex. 329.HCl: C 28 H 28 F 3 N 5 O 6 .HCl (free base; 587.5). LC-MS (method 1d): R t =1.69 (97), 588.2 ([M+H] + ).
General Procedures
Attachment of Substituents to the Macrocyclic Core Structures:
Synthesis of the Final Products
Acylation, Carbamoylation, Sulfonylation, and Alkylation Reactions
Procedure A
A.1.: Amide Coupling of a Macrocyclic Amine with
A.1.1: Carboxylic Acid and HATU
A soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol), a carboxylic acid (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mL) was treated at rt with i-Pr 2 NEt (3.0 equiv.). The mixture was stirred at rt for 2-15 h. The mixture was distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2: Acyl Chloride or Carboxylic Acid Anhydride
At 0° C., a soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol) in CH 2 Cl 2 (0.5 mL) was successively treated with pyridine (5 equiv.) and carboxylic acid chloride (1.05-2 equiv.) or carboxylic acid anhydride (1.05-2 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. After the addn of MeOH (0.01 mL) the soln was stirred for 10 min and concentrated. Toluene was added to the crude product and evaporated. Purification of the residue by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2.1: Acyl Chloride
Like A.1.2 and after 15 h at rt more carboxylic acid chloride (2 equiv.) and i-Pr 2 NEt (3 equiv.) were added. Stirring was continued for 24 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ).
A.1.2.2: Acyl Chloride
At 0° C., a soln of an amino macrocycle (free amine or hydrochloride; 1 mmol) in CH 2 Cl 2 (7 mL) was successively treated with i-Pr 2 NEt (5 equiv.) and carboxylic acid chloride (1.05-2 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. Aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ). Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.3: Carboxylic Acid and T3P
A soln of a carboxylic acid (2.4 equiv.), T3P (50% in DMF; 3 equiv.) and i-Pr 2 NEt (4.0 equiv.) in DMF (0.3 mL) was slowly added to a mixture of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) and DMF (0.2 mL). The mixture was stirred at rt for 2-15 h followed by an aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ).
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.2: Amide Coupling of a Macrocyclic Carboxylic Acid with an Amine and HATU
A soln of a macrocyxclic carboxylic acid (0.12 mmol), an amine (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mL) was treated at 4° C. with i-Pr 2 NEt (3.0 equiv.). The mixture was stirred at 4° C. for 2 h. The mixture was distributed between CH 2 Cl 2 and 1 M aq. HCl soln. The organic phase was washed (sat. aq. NaCl soln), dried (Na 2 SO 4 ), filtered and concentrated.
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic amide.
Procedure A.3: Urea Formation with Isocyantes or Equivalents of Isocyanates
A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH 2 Cl 2 (0.5 mL) was treated at rt for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr 2 NEt (3 equiv.) followed by aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea.
Procedure A.4: Carbamate Formation with Chloroformates
At 0° C. the chloroformate (1.1 equiv.) was added to a stirred mixture of CH 2 Cl 2 (0.9 mL) and sat. aq. Na 2 CO 3 soln (0.35 mL). The amino macrocycle (free amine or hydrochloride; 0.085 mmol) and H 2 O (0.75 mL) were added. The mixture was stirred at rt for 2-15 h followed by aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic carbamate.
Procedure A.5: Sulfonamide Formation with Sulfonyl Chlorides
At 0° C. a soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH 2 Cl 2 (0.5 mL) was successively treated with triethylamine (3.0 equiv.) and the sulfonyl chloride (1.0 equiv.). The mixture was stirred at 0° C. to rt for 2-15 h. (In case of incomplete transformation, more sulfonyl chloride (1.0 equiv.) and auxiliary base (3.0 equiv.) were added and stirring continued.) Aq. workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded the targeted macrocyclic sulfonamide.
Procedure A.6: N-Alkylation by Reductive Amination
A.6.1. N,N-Dimethylamino Macrocycles by Reductive Amination
To a soln. of the amino macrocycle (free amine or hydrochloride; 0.085 mmol) in DCE (1.2 mL) was added formaldehyde soln (36.5% in H 2 O; 5 equiv.) followed by NaBH(OAc) 3 (4 equiv.). The mixture was stirred at rt for 4 h.
Aq. workup (EtOAc, sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a dimethylamino macrocycle.
A.6.2: Synthesis of Tertiary Amines by N-Methylation of Secondary Amines
At 0° C. formaldehyde soln (36.5% in H 2 O; 5 equiv.), acetic acid (1.2 equiv.) and NaBH(OAc) 3 (4.0 equiv.) were added to a soln of the macrocyclic amine (0.25 mmol) in DCE (4 mL). The mixture was stirred at rt for 4 h followed by aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ). Purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the desired N-methyl-N,N-dialkylamino macrocycle.
A.6.3: Synthesis of Tertiary Amines by Reductive Amination of Secondary Amines
The aldehyde (1.5 equiv.) was added to a mixture of the macrocyclic amine (0.25 mmol) and THF (1.5 mL). The mixture was stirred at rt for 1 h. Acetic acid (1.2 equiv.) and NaBH(OAc) 3 (3 equiv.) were added and stirring was continued for 15 h. (In case of incomplete transformation, more aldehyde (0.5 equiv.) was added and stirring continued.) After aqueous workup (CH 2 Cl 2 , 1 M aq. Na 2 CO 3 soln; Na 2 SO 4 ) the crude product was purified by chromatography (FC, normal phase or reverse phase prep. HPLC) to afford the macrocyclic tertiary amine.
A.6.4: Synthesis of Secondary Amines by Reductive Amination
Activated molecular sieve powder (3 Å; 2 mg per mg of starting material) was added at rt to a soln of an amino macrocycle (0.1 mmol) and an aldehyde (1.1 equiv.) in THF (0.5 mL). The suspension was stirred for 2-4 h at rt, followed by the addition of acetic acid (1.1 equiv.) and NaBH(OAc) 3 (3.0 equiv.). The mixture was stirred for 18 h and filtered. Aqueous workup of the filtrate (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the alkylamino macrocycle.
Deprotection Reactions
Procedure B
Procedure B.1: Boc Cleavage
A soln of a macrocyclic Boc-amine in dioxane (1 mL per 100 mg) was treated with 4 M HCl in dioxane (1 mL per 100 mg) and stirred at rt for 2-16 h. The volatiles were evaporated. The residue was taken up in CHCl 3 , concentrated and dried i.v. Solid residues were then washed with Et 2 O/CH 2 Cl 2 .
Procedure B.2: Tert.-Butyl Ester Cleavage or Boc Cleavage
Tert.-Butyl Ester Cleavage:
TFA (1 mL per 100 mg) was slowly added to a soln of a macrocyclic tert.-butyl ester in CH 2 Cl 2 (5 mL per 100 mg). The mixture was stirred for 2 h at rt and concentrated. The residue was twice taken up in toluene and concentrated. The residue was then twice taken up in CHCl 3 and concentrated followed by washing with Et 2 O/CH 2 Cl 2 .
Boc Cleavage:
TFA (1 mL per 100 mg of starting material) was slowly added to a soln of the macrocyclic Boc-amine in CH 2 Cl 2 (3 mL per 100 mg). The mixture was stirred at rt for 3 h and concentrated. The residue was dried i.v.
Procedure B.3: Cbz Cleavage
A soln of the macrocyclic benzyl carbamate (500 mg) in MeOH (10 mL) or 2,2,2-trifluoroethanol (10 mL) was hydrogenated for 4 h at rt and at normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H 2 O; 15-20% Pd; 0.1 g). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrates and washings were concentrated to obtain the macrocyclic amine.
Procedure B.4: Nitro Reduction
A soln of the macrocyclic arylnitro compound (50 mg) in MeOH (5 mL) was hydrogenated for 15 h at rt and at normal pressure in the presence of platinum (IV) oxide hydrate (5 mg). The mixture was filtered through a pad of celite. The residue was washed (MeOH). The combined filtrates and washings were concentrated to obtain the macrocyclic aniline.
B.5: Methyl Ester Cleavage
A soln of the macrocyclic methyl ester (0.07 mmol) in DCE (2 mL) was treated with trimethyltin hydroxide (3 equiv.) at 80° C. for 16 h. Aqueous workup (CH 2 Cl 2 , 1 M aq. HCl soln; Na 2 SO 4 ) and purification by reverse phase prep. HPLC afforded the corresponding macrocyclic carboxylic acids.
Procedures for the Synthesis on Solid Support
Procedure C: Description of Examples of Core 10 and Core 11
Procedure D: Description of Examples of Core 01
Synthesis of Final Products
Advanced macrocyclic intermediates and final products depicted in Tables 13-31 (related cores cf. Scheme 23) were prepared starting from the suitable precursor macrocyclic acid, macrocyclic amine, or macrocyclic alcohol applying the general procedures (A.1-A.6; B.1-B.5) or specific procedures described above (as indicated in the corresponding Tables). Deviations from general procedures are indicated in Tables 13a-31a.
Final products of Core 01 prepared on solid support were obtained following the general procedure D (vide supra; Core 01: Synthesis of final products on solid support).
Final products of Cores 10 and 11 were prepared following the general procedure described in the text (vide supra; Procedure C.1: Core 10: Synthesis of Ex. 193a,c-h and Ex. 194b and Procedure C.2: Core 11: Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d)
Analytical data of these intermediates and final products are depicted in Tables 13b-31b.
IUPAC names of all examples are listed in Tables 13c-31c.
The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers
Reagents used in the derivatizations are commercially available with the exception of few N-succinimidyl carbamates which were synthesized from amines, anilines or heteroaryl amines according to the procedure of K. Takeda et al. Tetrahedron Lett. 1983, 24, 4569-4572.
The synthesis of selected advanced intermediates and final products is described in detail in the text above; cf. corresponding core description.
The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers.
TABLE 13a
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
Start-
Yield
ing
(iso-
Mate-
General
Purification
lated
No
R A
R B
rial
Proced.
Reagent
Method
salt)
Ex. 1-
cf. experimental description
Ex. 3
and
Ex. 330-
Ex. 331:
Ex. 4
Ex. 2
A.1.1; 1)
1-Naphthalene- acetic acid
FC (hexane/ EtOAc)
77%
Ex. 5
NH 2
Ex. 4
B.1; 1)
HCl-dioxane
crude product
quant. (HCl salt)
Ex. 6
Ex. 5
A.4
Methyl chloroformate
FC (CH 2 Cl 2 / MeOH)
82%
Ex. 7
Ex. 5
A.1.1; 1)
1-Pyrrolidineacetic acid
FC (CH 2 Cl 2 / MeOH)
71%
Ex. 7
133
D; 1)
1.1-Pyrrolidine- acetic acid 2.1-Naphthalene- acetic acid
prep. HPLC method 1a
15% (TFA salt)
Ex. 8
N(CH 3 ) 2
Ex. 5
A.6.1
Formaldehyde (36.5% in H2O)
FC (CH 2 Cl 2 / MeOH)
79%
Ex.
NH 2
NH 2
Ex. 2
B.1
HCl-dioxane
crude product
97%
9
rt, 16 h
(HCl
salt)
Ex. 10
Ex. 3
A.1.1
2-Naphthalene- acetic acid 4° C., 1 h
FC (hexane/ EtOAc/MeOH 80:20:0 to 0:90:10)
31%
Ex. 11
NH 2
Ex. 10
B.3
H, Pd(OH) 2 —C 2,2,2- trifluoroethanol
crude product
90%
Ex. 12
Ex. 11
A.1.1
2- (Dimethylamino) acetic acid 0° C., 2 h
prep. HPLC method 1b
48% (TFA salt)
Ex. 13
Ex. 11
A.1.1
3-Methylbutanic acid 0° C., 2 h
prep. HPLC method 1b
55%
Ex. 14
Ex. 3
A.4 1)
Phenyl chloroformate 0° C., 2 h
FC (EtOAc)
96%
Ex. 332
133
D; 1)
1. Imidazol-1-yl- acetic acid 2. 1-Naphthalen- acetic acid
prep. HPLC method 1a
48% (TFA salt)
Ex. 333
133
D; 1)
1. 2,5-Dioxo- pyrrolidin- 1-yl pyridin-3- ylcarbamate 2. 1-Naphthalene- acetic acid
prep. HPLC method 1a
65% (TFA salt)
Ex. 334
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. 3-Chloro- phenylacetic acid
prep. HPLC method 1a
38% (TFA salt)
Ex. 335
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. Cyclohexylacetic acid
prep. HPLC method 1a
26% (TFA salt)
Ex. 336
133
D; 1)
1. 1-Pyrrolidine- acetic acid 2. 1-Naphthyl isocyanate
prep. HPLC method 1a
13% (TFA salt)
Ex. 337
133
D
1. 1-Pyrrolidine- acetic acid 2. Benzylsulfonyl chloride
prep. HPLC method 1a
21% (TFA salt)
Ex. 338
Ex. 3
A.1.3
1-Pyrrolidineacetic acid i-Pr 2 NEt (5 equiv.) Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 / MeOH)
80%
Ex. 339
NH 2
Ex. 338
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
98%
Ex. 340
Ex. 339
A.6.4
1-Naphthalene- acetaldehyde, 3 h; NaBH(OAc) 3 (3 eq.) Workup: CHCl 3 , sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 / MeOH) and prep. HPLC method 1a
20% (TFA salt)
1) Cf. experimental description for detailed procedure
TABLE 13b
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
Rt
Mono-
(purity
isotopic
at
[M + H] +
LC-MS-
No
R A
R B
Formula
Mass
220 nm)
found
Method
Ex. 1-
cf. experimental description
Ex. 3
and
Ex. 330-
Ex. 331:
Ex. 4
C39H42N4O6
662.3
2.27 (86)
663.2
method 1a
Ex. 5
NH 2
C34H34N4O4
562.3
1.61 (91)
563.2
method 1a
Ex. 6
C36H36N4O6
620.3
2.01 (90)
621.0
method 1a
Ex. 7
C40H43N5O5
673.3
2.13 (99)
674.3
method 2c
Ex. 8
N(CH 3 ) 2
C36H38N4O4
590.3
1.65 (97)
591.1
method 1a
Ex. 9
NH 2
NH 2
C22H26N4O3
394.2
1.01 (96)
395.2
method 1a
Ex. 10
C42H40N4O6
696.3
2.25 (91)
697.1
method 1a
Ex. 11
NH 2
C34H34N4O4
562.3
1.73 (91)
563.1
method 1a
Ex. 12
C38H41N5O5
647.3
1.71 (96)
648.1
method 1a
Ex. 13
C39H42N4O5
646.3
2.09 (89)
647.2
method 1a
Ex. 14
C37H36N4O7
648.3
2.22 (97)
649.1
method 1a
Ex. 332
C39H38N6O5
670.3
1.84 (99)
671.3
method 2c
Ex. 333
C40H38N6O5
682.3
1.94 (99)
683.2
method 2c
Ex. 334
C36H40ClN5O5
657.3
2.08 (99)
658.2
method 2c
Ex. 335
C36H47N5O5
629.4
2.10 (99)
630.3
method 2c
Ex. 336
C39H42N6O5
674.3
2.09 (98)
675.3
method 2c
Ex. 337
C35H41N5O6S
659.3
1.59 (99)
660.3
method 1a
Ex. 338
C36H41N5O6
639.3
1.63 (99)
640.2
method 1a
Ex. 339
NH 2
C28H35N5O4
505.3
1.15 (97)
506.2
method 1c
Ex. 340
C40H45N5O4
659.3
1.60 (87)
660.3
method 1a
TABLE 13c
Examples of Core 01 (Ex. 1-Ex. 14 and Ex. 330-Ex. 340;)
No
R A
R B
IUPAC name
Ex. 1
benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14.18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 2
NH 2
tert-butyl N-[(12R,16S,18S)-12- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 3
NH 2
benzyl N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 4
tert-butyl N-[(12R,16S,18S)-12{[2-(1-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25)2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 5
NH 2
N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 6
methyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]carbamate
Ex. 7
N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1- pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 8
N(CH 3 ) 2
N-[(12R,16S,18S)-16-(dimethylamino)- 8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 9
NH 2
NH 2
(12R,16S,18S)-12,16-diamino-20-oxa-9,14-
diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa-
1(25),2,4,6,21,23-hexaene-8,13-dione
Ex. 10
benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl] amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 11
NH 2
N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(2- naphthyl)acetamide
Ex. 12
2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2- naphthyl)acetyl]amino}-8,13-dioxo-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide
Ex. 13
3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl) acetyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]butanamide
Ex. 14
benzyl N-[(12R,16S,18S)-8,13-dioxo-16- [(phenoxycarbonyl)amino]-20-oxa-9,14- (diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 330
allyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 331
NH 2
allyl N-[(12R,16S,18S)-16- amino-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 332
2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12- {[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ] pentacosa-1(25),2,4,6,21,23-hexaen-16- yl]acetamide
Ex. 333
N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino) carbonyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]-2-(1- naphthyl)acetamide
Ex. 334
2-(3-chlorophenyl)-N-[(12R,16S,18S)-8,13- dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20- oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ] pentacosa-1(25),2,4,6,21,23-hexaen-12- yl]acetamide
Ex. 335
2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo- 16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa- 9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]acetamide
Ex. 336
N-[(12R,16S,18S)-12-{[(1-naphthylamino) carbonyl]amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 337
N-[(12R,16S,18S)-12-[(benzylsulfonyl) amino]-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 338
benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2- (1-pyrrolidinyl)acetyl]amino}-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-12-yl]carbamate
Ex. 339
NH 2
N-[(12R,16S,18S)-12-amino- 8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
Ex. 340
N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyl] amino}-8,13-dioxo-20-oxa-9,14- diazatetracyclo[19.3.1.0 2,7 .0 14,18 ]pentacosa- 1(25),2,4,6,21,23-hexaen-16-yl]-2-(1- pyrrolidinyl)acetamide
TABLE 14a
Examples of Core 02 (Ex. 15-Ex. 40;)
Start-
Yield
ing
(iso-
Mate-
General
Purification
lated
No
R A
R B
rial
Proced.
Reagent
Method
salt)
Ex. 15-
cf. experimental description
Ex. 17:
Ex. 18
Ex. 17
A.1.1; 4)
2-Naphthaleneacetic acid
FC (EtOAc)
79%
Ex. 19
NH 2
Ex. 18
B.3; 4)
H 2 , Pd(OH) 2 —C MeOH
crude product
97%
Ex. 20
Ex. 19
A.1.1; 4)
2-(Dimethylamino) acetic acid
FC (CH 2 Cl 2 /MeOH)
30%
Ex. 21
Ex. 19
A.5
Cyclo- propanesulfonyl chloride (1.5 equiv.) Et 3 N (3 equiv.)
FC (EtOAc; then CH 2 Cl 2 /MeOH)
86%
DMAP (0.1 equiv)
CHCl 3 (0.25 mL),
50° C., 15 h
Workup: CH 2 Cl 2 ,
half-sat. aq.
NaHCO 3 soln.;
Na 2 SO 4
Ex. 22
Ex. 19
A.3
N-Succinimidyl N- methylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3
FC (CH 2 Cl 2 /MeOH)
63%
1:1 (1.0 mL)
rt, 3 h
Ex. 23
Ex. 19
A.1.2
2-Methoxyacetyl chloride (1.5 equiv.) rt, 3 h
FC (CH 2 Cl 2 /MeOH)
51%
Ex. 24
Ex. 19
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h (Mixture was
prep. HPLC method 1a
73%
concentrated
without addn
of MeOH.)
Ex. 25
Ex. 19
A.1.2; 4)
Phenylacetyl chloride
prep. HPLC method 1a
60%
Ex. 26
Ex. 19
A.1.2; 4)
Benzoyl chloride
prep. HPLC method 1a
67%
Ex. 27
Ex. 19
A.1.2
Butyryl chloride (1.2 equiv.) 0° C., 2 h (Mixture was concentrated
prep. HPLC method 1a
67%
without addn
of MeOH.)
Ex. 28
Ex. 19
A.1.2
Pentanoyl chloride (1.2 equiv.) 0° C., 2 h (Mixture was concentrated
prep. HPLC method 1a
66%
without addn
of MeOH.)
Ex. 29
Ex. 40
1)
LiOH 1)
prep. HPLC method 1a
47%
Ex. 30
Ex. 39
2)
Methyl isothiocyanate 2)
prep. HPLC method 1a
48%
Ex. 31
Ex. 32
3)
3)
FC (CH 2 Cl 2 /MeOH 100:0 to 80:20)
57%
Ex. 32
Ex. 39
A.1.1
2-(Tritylthio)acetic acid i-Pr 2 NEt (5 equiv.) 0° C., 2 h
FC (CH 2 Cl 2 /MeOH 90:10)
85%
Workup: CH 2 Cl 2 ,
sat. aq.
NaHCO 3 soln
Ex. 33
Ex. 39
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.)
prep. HPLC method 1a
77% (TFA salt)
Ex. 34
Ex. 39
A.3
2,5-Dioxo- pyrrolidin- 1-yl-3- (dimethylamino) phenyl- carbamate
prep. HPLC method 1a
77% (TFA salt)
(1.4 equiv.)
i-Pr 2 NEt (5.0 equiv.)
Ex. 35
Ex. 39
A.3
2-Naphthyl isocyanate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.)
prep. HPLC method 1a
77% (TFA salt)
Ex. 36
Ex. 39
A.5
Methanesulfonyl chloride (1.3 equiv.) Et 3 N (5 equiv.)
prep. HPLC method 1a
64% (TFA salt)
Ex. 37
Ex. 39
A.5
Phenylmethane- sulfonyl chloride (1.3 equiv.) Et 3 N (5 equiv.)
prep. HPLC method 1a
43% (TFA salt)
Ex. 38
Ex. 16
A.1.3
2-(Dimethylamino) acetic acid Workup: CH 2 Cl 2 , 1M aq. HCl
FC (CH 2 Cl 2 /MeOH/ conc. aq. NH3 soln
86%
soln; sat. aq.
95:5:2)
NaHCO 3 soln,
sat. aq. NaCl
soln; Na 2 SO 4
Ex. 39
NH 2
Ex. 38
B.1
HCl-dioxane rt, 2 h
crude product
quant. (HCl salt)
Ex. 40
Ex. 39
A.6.4
Ethyl glyoxylate (1.2 equiv.)
FC (CH 2 Cl 2 /MeOH 9:1)
37%
1) A soln of the macrocyclic ethylester Ex. 40 (63 mg, 0.11 mmol) in THF/MeOH 1:1 (1 mL) was treated at 0° C. for 2 h with 2M aq. LiOH soln (0.16 mL, 0.32 mmol). The mixture was concentrated. The residue was treated with 1M aq. HCl soln and concentrated Purification by reverse phase prep. HPLC afforded Ex. 29 (40 mg, 47%).
2) Methyl isothiocyantae (6 mg, 0.11 mmol) was added to a soln of Ex. 39 (50 mg, 0.078 mmol) and i-Pr 2 NEt (0.07 mL, 0.39 mmol) in CH 2 Cl 2 (0.5 mL). The mixture was stired for 16 h at rt. More methyl isothiocyantae (2 mg) was added and stirring continued for 1 h. Aq. Workup (CHCl 3 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and purification by prep. HPLC (method 1a) afforded Ex. 30 (26 mg, 48%).
3) Triisopropylsilane (0.12 mL, 0.58 mmol) was added to a soln of Ex. 32 (50 mg, 0.115 mmol) in CH 2 Cl 2 (0.4 mL). The mixture was cooled to 0° C. followed by the addition of TFA (0.4 mL). The mixture was stirred for 30 min at 0° C. and concentrated. FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded Ex. 31 (46 mg, 57%).
4) Cf. experimental description for detailed procedure
TABLE 14b
Examples of Core 02 (Ex. 15-Ex. 40;)
Rt
Monoisotopic
(purity at
[M + H] +
LC-MS-
No
R A
R B
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 15-
Ex. 17:
Ex. 18
C44H44N4O6
724.3
2.36 (98)
725.2
method 1a
Ex. 19
NH 2
C36H38N4O4
590.3
1.76 (97)
591.2
method 1a
Ex. 20
C40H45N5O5
675.3
1.82 (95)
676.3
method 1a
Ex. 21
C39H42N4O6S
694.3
2.10 (97)
695.2
method 1a
Ex. 22
C38H41N5O5
647.3
1.96 (98)
648.2
method 1a
Ex. 23
C39H42N4O6
662.3
2.04 (99)
663.2
method 1a
Ex. 24
C41H46N4O5
674.3
2.20 (98)
675.2
method 1a
Ex. 25
C44H44N4O5
708.3
2.27 (99)
709.2
method 1a
Ex. 26
C43H42N4O5
694.3
2.26 (99)
695.2
method 1a
Ex. 27
C40H44N4O5
660.3
2.15 (99)
661.2
method 1a
Ex. 28
C41H46N4O5
674.3
2.24 (99)
675.3
method 1a
Ex. 29
C30H39N5O6
565.3
1.25 (99)
566.2
method 1a
Ex. 30
C30H40N6O4S
580.3
1.38 (95)
581.2
method 3a
Ex. 31
C30H39N5O5S
581.3
1.49 (90)
582.0
method 1a
Ex. 32
C49H53N5O5S
823.4
2.18 (90)
824.3
method 1a
Ex. 33
C30H40N6O5
564.3
1.40 (99)
565.1
method 1a
Ex. 34
C37H47N7O5
669.4
1.37 (97)
670.2
method 1a
Ex. 35
C39H44N6O5
676.3
1.84 (98)
677.3
method 1a
Ex. 36
C29H39N5O6S
585.3
1.44 (99)
586.0
method 1a
Ex. 37
C35H43N5O6S
661.3
1.68 (97)
661.8
method 1e
Ex. 38
C33H45N5O6
607.3
1.73 (93)
608.1
method 1a
Ex. 39
NH 2
C28H37N5O4
507.3
1.23 (93)
508.2
method 1a
Ex. 40
C32H43N5O6
593.3
1.38 (96)
594.1
method 1a
TABLE 14c
Examples of Core 02 (Ex. 15-Ex. 40;)
No
R A
R B
IUPAC name
Ex. 15
benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 16-yl]carbamate
Ex. 16
NH 2
tert-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12- yl]carbamate
Ex. 17
NH 2
benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16- yl]carbamate
Ex. 18
benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]carbamate
Ex. 19
NH 2
N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo [20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2- naphthyl)acetamide
Ex. 20
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 21
N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]- 2-(2-naphthyl)acetamide
Ex. 22
N-[(10S,12S,16S)-20-methyl-16-{[(methylamino)carbonyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 12-yl]-2-(2-naphthyl)acetamide
Ex. 23
2-methoxy-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide
Ex. 24
3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21- dioxo-8-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]butanamide
Ex. 25
N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)amino]-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 12-yl]-2-(2-naphthyl)acetamide
Ex. 26
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]benzamide
Ex. 27
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino)-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]butanamide
Ex. 28
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]pentanamide
Ex. 29
2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-dioxo- 8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]amino}acetic acid
Ex. 30
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbothioyl] amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 31
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-[(2- sulfanylacetyl)amino]-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 32
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-{[2- (tritylsulfanyl)acetyl]amino}-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ] hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 33
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbonyl] amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 34
2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3-(dimethylamino)anilino]carbonyl} amino)-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ] hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 35
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(2- naphthylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-16-yl]acetamide
Ex. 36
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-[(methylsulfonyl)amino]- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-16-yl]acetamide
Ex. 37
N-[(10S,12S,16S)-12-[(benzylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa- 14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen- 16-yl]-2-(dimethylamino)acetamide
Ex. 38
tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl- 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa- 1(26),2,4,6,22,24-hexaen-12-yl]carbamate
Ex. 39
NH 2
N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20- diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]-2- (dimethylamino)acetamide
Ex. 40
ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21- dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14 ]hexacosa-1(26),2,4,6,22,24- hexaen-12-yl]amino}acetate
TABLE 15a
Examples of Core 03 (Ex. 41-Ex. 67;)
Starting
General
Purification
Yield
No
R E
Material
Proced.
Reagent
Method
(isolated salt)
cf. experimental description
Ex. 41-Ex. 42,
Ex. 62-Ex. 67:
Ex. 43
CONH 2
Ex. 42
A.2
NH 4 Cl (4 equiv.)
prep. HPLC method 3
64%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq.
Na 2 CO 3 , CH 2 Cl 2
Ex. 44
CONHCH 3
Ex. 42
A.2
CH 3 NH 3 Cl (4 equiv.)
prep. HPLC method 3
71%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
4° C., 1 h
Workup: Sat. aq.
Na 2 CO 3 , CH 2 Cl 2
Ex. 45
CONHPh
Ex. 42
A.2
Aniline
prep. HPLC method 3
80%
Ex. 46
Ex. 42
A.2
Pyrrolidine
prep. HPLC method 3
53%
Ex. 47
Ex. 42
A.2
N,N-Dimethyl- ethylenediamine (1.0 equiv.) Workup: Sat. aq. Na 2 CO 3 , CH 2 Cl 2
prep. HPLC method 1a
61% (TFA salt)
Ex. 48
Ex. 42
A.2
tert.-Butyl-3- aminopropylcarbamate
prep. HPLC method 3
65%
Ex. 49
Ex. 48
B.1
HCl-dioxane rt, 2 h
crude product
74% (HCl salt)
Ex. 50
Ex. 42
A.2 1)
3-Picolylamine
prep. HPLC method 1c
37% (TFA salt)
Ex. 51
Ex. 42
A.2
2-Methoxyethylamine
prep. HPLC method 3
63%
Ex. 52
Ex. 42
A.2
Cyclopropylamine
prep. HPLC method 3
84%
Ex. 53
Ex. 42
A.2
2,2,2- Trifluoroethylamine
prep. HPLC method 3
66%
Ex. 54
Ex. 42
A.2
Isobutylamine
prep. HPLC method 3
66%
Ex. 55
Ex. 42
A.2
2-Aminoethanol 4° C. 2 h and rt 3 h
prep. HPLC method 1c
82%
Ex. 56
Ex. 42
A.2
Glycine-tert.- butyl ester hydrochloride (1.5 equiv.) HATU 2.0 equiv.) HOAt (2.0 equiv.) i-Pr 2 NEt (3.0 equiv.) 4° C., 2 h
prep. HPLC method 3
76%
Ex. 57
Ex. 56
B.2
TFA, CH 2 Cl 2
crude product
80%
Ex. 58
Ex. 42
A.2
(L)-α- Methylbenzylamine 4° C. 2 h and rt 2 h
prep. HPLC method 3
55%
Ex. 59
Ex. 42
A.2
N,N,N′- Trimethylethylene- diamine
FC (CH 2 Cl 2 /MeOH/ aq. NH 3 soln)
83%
Ex. 60
Ex. 42
A.2
Naphthalen-1- ylmethanamine
prep. HPLC method 3
57%
Ex. 61
Ex. 42
A.2
Naphthalen-2- ylmethanamine
prep. HPLC method 3 and prep. HPLC method 2a
29%
1) Cf. experimental description for detailed procedure
TABLE 15b
Examples of Core 03 (Ex. 41-Ex. 67;)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R E
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 41-Ex. 42,
Ex. 62-Ex. 67:
Ex. 43
CONH 2
C23H27N3O5
425.2
1.47 (95)
426.1
method 1a
Ex. 44
CONHCH 3
C24H29N3O5
439.2
1.49 (99)
440.1
method 1a
Ex. 45
CONHPh
C29H31N3O5
501.2
1.97 (97)
502.1
method 1a
Ex. 46
C27H33N3O5
479.2
1.74 (98)
480.1
method 1a
Ex. 47
C27H36N4O5
496.3
1.32 (99)
497.2
method 1a
Ex. 48
C31H42N4O7
582.3
1.91 (99)
583.1
method 1a
Ex. 49
C26H34N4O5
482.2
1.32 (95)
483.1
method 1a
Ex. 50
C29H32N4O5
516.2
1.32 (99)
517.1
method 1a
Ex. 51
C26H33N3O6
483.2
1.57 (95)
484.1
method 1a
Ex. 52
C26H31N3O5
465.2
1.67 (99)
466.1
method 1a
Ex. 53
C25H28F3N3O5
507.2
1.80 (94)
508.0
method 1a
Ex. 54
C27H35N3O5
481.2
1.85 (95)
482.1
method 1a
Ex. 55
C25H31N3O6
469.2
1.40 (94)
470.1
method 1a
Ex. 56
C29H37N3O7
539.3
1.91 (93)
540.0
method 1a
Ex. 57
C25H29N3O7
483.2
1.47 (85)
484.1
method 1a
Ex. 58
C31H35N3O5
529.2
2.00 (93)
530.1
method 1a
Ex. 59
C28H38N4O5
510.3
1.37 (97)
511.2
method 1a
Ex. 60
C34H35N3O5
565.2
2.09 (97)
566.1
method 1a
Ex. 61
C34H35N3O5
565.2
2.12 (100)
566.1
method 1a
TABLE 15c
Examples of Core 03 (Ex. 41-Ex. 67;)
No
R E
IUPAC name
Ex. 41
CO 2 CH 2 Ph
benzyl (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate
Ex. 42
CO 2 H
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid
Ex. 43
CONH 2
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 44
CONHCH 3
(10R,15S)-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 45
CONHPh
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-phenyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 46
(10R,15S)-4-methoxy-10,16-dimethyl-15-(1-pyrrolidinylcarbonyl)-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 12,17-dione
Ex. 47
(10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-10,16-dimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide
Ex. 48
tert-butyl N-[3-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)propyl]carbamate
Ex. 49
(10R,15S)-N-(3-aminopropyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 50
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 51
(10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 52
(10R,15S)-N-cyclopropyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 53
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(2,2,2- trifluoroethyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa- 1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 54
(10R,15S)-N-isobutyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide
Ex. 55
(10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 56
tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetate
Ex. 57
2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16- diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15- yl]carbonyl}amino)acetic acid
Ex. 58
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-[(1S)-1-phenylethyl]- 8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 59
(10R15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-N,10,16-trimethyl-12,17- dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20- hexaene-15-carboxamide
Ex. 60
(10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 61
(10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo-8- oxa-11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 15-carboxamide
Ex. 62
CH 2 OH
(10R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 63
(10R,15S)-4-methoxy-10,16-dimethyl-15-[(3-pyridinyloxy)methyl]-8-oxa- 11,16-diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene- 12,17-dione
Ex. 64
CH 2 N 3
(10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 65
CH 2 NH 2
(10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione
Ex. 66
CH 2 NHCOCH 2 Ph
N-{[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl}-2-
phenylacetamide
Ex. 67
CH 2 OCONHPh
[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-
diazatricyclo[16.3.1.0 2,7 ]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N-
phenylcarbamate
TABLE 16a
Examples of Core 04 (Ex. 68-Ex. 89;)
Starting
General
Purification
Yield
No
R c
Material
Proced.
Reagent
Method
(isolated salt)
cf. experimental description
Ex. 68-Ex. 69:
Ex. 70
NHCH 3
Ex. 69
A.2
CH 3 NH 3 Cl (4 equiv.)
FC (CH 2 Cl 2 /MeOH)
50%
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq. Na 2 CO 3 ,
CH 2 Cl 2
Ex. 71
NH 2
Ex. 69
A.2
NH 4 Cl (4 equiv.)
prep. HPLC method 3
95
HATU (2.0 equiv.)
HOAT (2.0 equiv.)
i-Pr 2 NEt (6 equiv.)
rt, 2 h
Workup: Sat. aq. Na 2 CO 3 ,
CH 2 Cl 2
Ex. 72
NHPh
Ex. 69
A.2
Aniline
prep. HPLC method 3
68
Ex. 73
Ex. 69
A.2
2-Phenylethylamine
prep. HPLC method 3
71
Ex. 74
Ex. 69
A.2
Naphthalen-1- ylmethanamine 0° C., 1 h
prep. HPLC method 3 and FC (EtOAc)
70%
Ex. 75
Ex. 69
A.2
3-Picolylamine 4°C, 1 h Workup: Sat. aq. Na 2 CO 3 , CHCl 3
prep. HPLC method 3
55%
Ex. 76
Ex. 69
A.2
(L)-α-Methylbenzylamine
prep. HPLC method 3
60%
Ex. 77
Ex. 69
A.2
2-Methoxyethylamine
prep. HPLC method 3
66%
Ex. 78
Ex. 69
A.2
2,2,2-Trifluoroethylamine
prep. HPLC method 3
72%
Ex. 79
Ex. 69
A.2
Cyclopropylamine
prep. HPLC method 3 then prep. HPLC method 1a
32%
Ex. 80
Ex. 69
A.2
Isobutylamine 4° C., 1 h
prep. HPLC method 3
77%
Ex. 81
Ex. 69
A.2
2-Aminoethanol 4° C. 2 h and rt 1 h
prep. HPLC method 1a
56%
Ex. 82
Ex. 69
A.2
Glycine-tert.-butyl ester hydrochloride (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6.0 equiv.) 4° C., 3 h
FC (EtOAc)
78%
Ex. 83
Ex. 82
B.2
TFA, CH 2 Cl 2 , rt, 4 h
prep. HPLC method 1a
78%
Ex. 84
Ex. 69
A.2
N,N-Dimethyl- ethylenediamine 4° C., 1 h Workup: Sat. aq. Na 2 CO 3 , EtOAc
prep. HPLC method 3
47%
Ex. 85
Ex. 69
A.2
1-(3-Aminopropyl) pyrrolidine
prep. HPLC method 1a
57% (TFA salt)
Ex. 86
Ex. 69
A.2
Azetidine
prep. HPLC method 3
80%
Ex. 87
Ex. 69
A.2
Morpholine
prep. HPLC method 3
74%
Ex. 88
Ex. 69
A.2
(1-Methyl-1H-imidazol- 4-yl)methanamine 4° C., 2 h and rt, 1 h
prep. HPLC method 1a
27% (TFA salt)
Ex. 89
Ex. 69
A.2
Naphthalen-2- ylmethanamine 0° C., 3 h
prep. HPLC method 3 and FC (EtOAc)
73%
TABLE 16b
Examples of Core 04 (Ex. 68-Ex. 89;)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R c
Formula
Mass
220 nm)
found
Method
cf. experimental description
Ex. 68-Ex. 69:
Ex.70
NHCH 3
C23H27N3O4
409.2
1.57 (96)
410.1
method 1a
Ex.71
NH 2
C22H25N3O4
395.2
1.53 (95)
396.1
method 1a
Ex.72
NHPh
C28H29N3O4
471.2
1.96 (92)
472.1
method 1a
Ex.73
C30H33N3O4
499.2
1.97 (99)
500.1
method 1a
Ex.74
C33H33N3O4
535.2
2.11 (96)
536.2
method 1a
Ex.75
C28H30N4O4
486.2
1.40 (93)
487.1
method 1a
Ex.76
C30H33N3O4
499.2
1.99 (96)
500.1
method 1a
Ex.77
C25H31N3O5
453.2
1.60 (99)
454.1
method 1a
Ex.78
C24H26F3N3O4
477.2
1.82 (96)
478.0
method 1a
Ex.79
C25H29N3O4
435.2
1.71 (98)
436.1
method 1a
Ex.80
C26H33N3O4
451.2
1.90 (98)
452.1
method 1a
Ex.81
C24H29N3O5
439.2
1.50 (91)
440.1
method 1a
Ex.82
C28H35N3O6
509.2
1.97 (95)
510.1
method 1a
Ex.83
C24H27N3O6
453.2
1.50 (98)
454.1
method 1a
Ex.84
C26H34N4O4
466.2
1.40 (99)
467.1
method 1a
Ex.85
C29H38N4O4
506.3
1.46 (99)
507.2
method 1a
Ex.86
C25H29N3O4
435.2
1.63 (92)
436.1
method 1a
Ex.87
C26H31N3O5
465.2
1.64 (92)
466.1
method 1a
Ex.88
C27H31N5O4
489.2
1.43 (99)
490.1
method 1a
Ex.89
C33H33N3O4
535.2
2.14 (93)
536.1
method 1a
TABLE 16c
Examples of Core 04 (Ex. 68-Ex. 89;)
No
R c
IUPAC name
Ex.68
OCH 2 Ph
benzyl (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]
docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxylate
Ex.69
OH
(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxylic acid
Ex.70
NHCH 3
(9S,14S)-N,9,15-trimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.71
NH 2
(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-
1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.72
NHPh
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenyl-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ]
docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.73
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenethyl-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.74
(9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.75
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.76
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[(1S)-1-phenylethyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.77
(9S,14S)-N-(2-methoxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.78
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.79
(9S,14S)-N-cyclopropyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.80
(9S,14S)-N-isobutyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.81
(9S,14S)-N-(2-hydroxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.82
tert-butyl 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetate
Ex.83
2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6 ] docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetic acid
Ex.84
(9S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethyl-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.85
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[3-(1-pyrrolidinyl)propyl]-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.86
(9S,14S)-14-(1-azetanylcarbonyl)-9,15-dimethyl-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione
Ex.87
(9S,14S)-9,15-dimethyl-14-(morpholinocarbonyl)-7-oxa-10,15-diazatricyclo [15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione
Ex.88
(9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16-dioxo-7-oxa- 10,15-diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
Ex.89
(9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15- diazatricyclo[15.3.1.1 2,6 ]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide
TABLE 17a
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
Starting
General
No
R B
R D
Material
Procedure
Reagent
Purification Method
Yield (isolated salt)
Ex. 90-Ex. 92
cf. experimental description
Ex. 93
NH 2
H
Ex. 90
B.1 1)
HCl-dioxane
prep. HPLC
17% (TFA salt)
rt, 16 h
method 1c
Ex. 94
CH 3
Ex. 91
A.6.2; 5)
Formaldehyde (36.5% in H 2 O)
FC (CH 2 Cl 2 /MeOH)
84%
Ex. 95
NH 2
CH 3
Ex. 94
B.1; 5)
HCl-dioxane
crude product
quant. (HCl salt)
rt, 2 h
Ex. 96
CH 3
Ex. 95
A.1.1; 5)
2-Naphthaleneacetic acid
FC (CH 2 Cl 2 /MeOH) and prep. HPLC method 1b
41% (TFA salt)
Ex. 97
Ex. 91
A.6.3; 5)
3-Fluorobenzaldehyde
FC (CH 2 Cl 2 /MeOH)
80%
Ex. 98
NH 2
Ex. 97
B.1; 5)
HCl-dioxane rt, 2 h
crude product
95% (HCl salt)
Ex. 99
NHCOCH 3
CH 3
Ex. 95
A.1.2.1
Acetyl chloride
prep. HPLC
61% (TFA salt)
(4.0 equiv. in total)
method 1a
Ex. 100
NHCOCH 3
Ex. 98
A.1.2.1; 5)
Acetyl chloride (4.0 equiv. in total)
prep. HPLC method 1a
64% (TFA salt)
Ex. 101
CH 3
Ex. 95
A.1.3; 5)
1-Naphthaleneacetic acid
prep. HPLC method 1a
49% (TFA salt)
Ex. 102
CH 3
Ex. 95
A.3
Phenyl isocyanate rt, 15 h
prep. HPLC method 1a
57% (TFA salt)
Ex. 103
CH 3
Ex. 95
A.5; 5)
Benzenesulfonyl chloride (2.0 equiv.) Et 3 N (3.0 equiv.) i-Pr 2 NEt (3.0 equiv.)
prep. HPLC method 1a
44% (TFA salt)
Ex. 104
Ex. 91
A.1.3
2-(Dimethylamino)- acetic acid rt, 2 h
FC (CH 2 Cl 2 /MeOH)
83%
Ex. 105
NH 2
Ex. 104
B.1
HCl-dioxane rt, 2 h
crude product
90%
Ex. 106
Ex. 105
A.1.3
2-Phenylacetic acid (4.8 equiv.) rt, 40 h
prep. HPLC method 1a
41% (TFA salt)
Ex. 107
Ex. 105
A.5
Cyclopropanesulfonyl chloride (3.0 equiv.) Et 3 N (8.0 equiv.) rt, 16 h
prep. HPLC method 1a
32% (TFA salt)
Ex. 108
Ex. 105
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
prep. HPLC method 1a
55% (TFA salt)
Ex. 109
Ex. 91
A.5
Cyclopropanesulfonyl chloride (5.2 equiv.) Et 3 N (5.0 equiv.), DMAP (0.1 equiv.) 45° C.,48 h
FC (CH 2 Cl 2 /MeOH)
64%
Ex. 110
NH 2
Ex. 109
B.1
HCl-dioxane rt, 3 h
crude product
quant. (HCl salt)
Ex. 111
Ex. 110
A.1.2.1
Benzoyl chloride (2.0 equiv) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
prep. HPLC method 1a
19% (TFA salt)
Ex. 112
Ex. 91
A.3
N-Succinimidyl N- methylcarbamate (1.4 equiv.) i-Pr 2 NEt (5.0 equiv.) rt, 16 h
FC (CH 2 Cl 2 /MeOH)
82%
Ex. 113
NH 2
Ex. 112
B.1
HCl-dioxane rt, 4 h
crude product
quant. (HCl salt)
Ex. 114
Ex. 113
A.1.2.1
3-Fluorobenzoyl chloride (4.0 equiv. in total)
prep. HPLC method 1a
5% (TFA salt)
Ex. 341
Ex. 98
A.1.3
1-Naphthaleneacetic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
47%
Ex. 342
Ex. 98
A.1.3
2-Naphthaleneacetic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
34%
Ex. 343
Ex. 98
A.3
2-Naphthylisocyanate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and FC (CH 2 Cl 2 /MeOH)
63%
Ex. 344
Ex. 98
A.5
Naphthalene-2-sulfonyl chloride i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a
41% (TFA salt)
Ex. 345
Ex. 98
A.1.3
2-Naphthalene- propanoic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
40% (TFA salt)
Ex. 346
Ex. 98
A.1.3
3-Phenylpropionic acid i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
37% (TFA salt)
Ex. 347
Ex. 98
A.1.3
N,N-Dimethylglycine i-Pr 2 NEt (9 equiv.)
prep. HPLC method 1a
9% (TFA salt)
Ex. 348
Ex. 92
A.1.3
2-Naphthaleneacetic acid i-Pr 2 NEt (6 equiv.)
FC (CH 2 Cl 2 /MeOH)
80%
Ex. 349
H
Ex. 348
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
97%
Ex. 350
Ex. 349
A.1.3
3-Fluorobenzoic acid
prep. HPLC method 1a
55% (TFA salt)
Ex. 351
Ex. 349
A.6.3
Benzaldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
51% (TFA salt)
Ex. 352
Ex. 349
A.6.3
Phenylacetaldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
37% (TFA salt)
Ex. 353
Ex. 349
A.6.3
3-Phenylpropion- aldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
30% (TFA salt)
Ex. 354
Ex. 349
A.6.3
Isovaleraldehyde (1.7 equiv.) Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
32% (TFA salt)
Ex. 355
Ex. 349
A.6.3
Isobutyraldehyde Workup: CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a
68% (TFA salt)
Ex. 356
Ex. 349
2)
2-Dimethylaminoethyl- chlorid hydrochloride
FC (CH 2 Cl 2 /MeOH)
21%
Ex. 357
Ex. 349
3)
2-Dimethylaminoethyl- chlorid hydrochloride
prep. HPLC method 2a and FC (CH 2 Cl 2 /MeOH)
17%
Ex. 358
CH 3
Ex. 95
4)
3,3-Dimethylbutyryl chloride
FC (CH 2 Cl 2 /MeOH)
83%
1) Ex. 93 was obtained as a side product upon treatment of Ex. 90 with HCl-dioxane; see description of synthesis of Ex. 92
2) 2-Dimethylaminoethylchloride hydrochloride (13 mg, 0.089 mmol) was added to a mixture of Ex. 349 (50 mg, 0.089 mmol) and dry K 2 CO 3 (61 mg, 0.44 mmol) in DCE (0.5 mL). The mixture was stirred at 50° C. for 16 h. More 2-dimethylaminoethylchloride hydrochloride (6.4 mg, 0.044 mmol) was added and stirring at 50° C. continued for 2 h. Aqueous workup (CH 2 Cl 2 , sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH 100:0 to 80:20) afforded Ex. 356 (13 mg, 21%).
3) 2-Dimethylaminoethylchloride hydrochloride (64 mg, 0.44 mmol) was added to a mixture of Ex. 349 (60 mg, 0.106 mmol) and i-Pr 2 NEt (0.121 mL; 0.71 mmol) in DMF (1 mL). The mixture was stirred at 50° C. for 3 d. More 2-dimethylamino-
ethylchloride hydrochloride (64 mg, 0.44 mmol) and i-Pr 2 NEt (0.121 mL; 0.71 mmol) were added and stirring at 50° C. was continued for 1 d. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH(conc. aq. NH 3 soln 100:0:0.1 to 90:10:0.1) afforded Ex. 357 (12 mg, 17%).
4) Synthesis of Ex. 358 3,3-Dimethylbutyryl chloride (0.019 mL, 0.14 mmol) was added at 0° C. to a suspension of Ex. 95 (60 mg, 0.116 mmol) and pyridine (0.047 mL, 0.58 mmol) in CH 2 Cl 2 (1.2 mL). The mixture was stirred at rt for 1 h and cooled to 0° C. Then i-Pr 2 NEt (0.059 mL; 0.35 mmol) and 3,3-dimethylbutyryl chloride (0.019 mL, 0.14 mmol) were added. The resulting clear soln was stirred for 30 min. MeOH (0.01 mL) was added and stirring continued for 10 min. The volatiles were evaporated. FC (CH 2 Cl 2 /MeOH 100:0 to 95:5) afforded Ex. 358 (49 mg, 83%). Data of Ex. 358: cf. Table 17b 1 H-NMR (DMSO-d 6 ): 9.62 (br. s, 1 H); 9.22 (t, J ca. 1.9, 1 H); 9.18 (d, J = 2.0, 1 H); 8.93 (d, J = 1.9, 1 H); 8.40 (br.s, 1 H); 8.08 (d, J = 6.5, 1 H); 7.59 (d, J = 7.6, 1 H); 7.40 (t, J = 7.9, 1 H); 6.82 (dd; J = 2.0, 8.3, 1 H); 4.53-4.41 (br. not resolved m, 3 H); 3.91 (t, J = 11.2, 1 H); 3.72 (dd; J = 7.0, 9.7, 1 H); 3.46 (d, J = 17.6, 1 H); 3.38-3.24 (m, 3 H, partially superimposed by H 2 O signal); 3.13 (dd-like m, 1 H); 2.62 (m, 2 H); 2.37 (s, 3 H); 2.14 (m, 1 H); 1.96 (s, 2 H); 1.93 (m, 1 H); 0.96 (s, 9 H).
5) Cf. experimental description for detailed procedure
TABLE 17b
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
Mono-
Rt
iso-
(purity
[M +
topic
at
H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 90-
cf experimental description
Ex. 92:
Ex. 93
NH 2
H
C21H25N5O3
395.2
0.89 (97)
396.1
method 1a
Ex. 94
CH 3
C27H35N5O5
509.3
1.49 (97)
510.1
method 1a
Ex. 95
NH 2
CH 3
C22H27N5O3
409.2
1.43 (98)
410.1
method 2c
Ex. 96
CH 3
C34H35N5O4
577.3
1.59 (99)
578.1
method 1a
Ex. 97
C33H38FN5O5
603.3
2.44 (95)
604.0
method 2d
Ex. 98
NH 2
C28H30FN5O3
503.2
1.31 (90)
504.2
method 1a
Ex. 99
NHCOCH 3
CH 3
C24H29N5O4
451.2
1.10 (96)
452.2
method 1a
Ex. 100
NHCOCH 3
C30H32FN5O4
545.2
1.47 (97)
546.2
method 1a
Ex. 101
CH 3
C34H35N5O4
577.3
1.59 (98)
578.2
method 1a
Ex. 102
CH 3
C29H32N6O4
528.2
1.44 (98)
529.2
method 1a
Ex. 103
CH 3
C28H31N5O5S
549.2
1.43 (99)
550.1
method 1a
Ex. 104
C30H40N6O6
580.3
2.02 (96)
581.2
method 2d
Ex. 105
NH 2
C25H32N6O4
480.2
0.97 (95)
481.1
method 1a
Ex. 106
C33H38N6O5
598.3
1.45 (98)
599.2
method 1a
Ex. 107
C28H36N6O6S
584.2
1.30 (95)
585.1
method 1a
Ex. 108
C27H35N7O5
537.3
1.17 (97)
538.2
method 1a
Ex. 109
C29H37N5O7S
599.2
1.87 (93)
600.1
method 1a
Ex. 110
NH 2
C24H29N5O5S
499.2
1.20 (91)
500.1
method 1a
Ex. 111
C31H33N5O6S
603.2
1.73
604.0
method 1a
Ex. 112
C28H36N6O6
552.3
1.67 (94)
553.1
method 1a
Ex. 113
NH 2
C23H28N6O4
452.2
1.04 (89)
453.1
method 1a
Ex. 114
C30H31FN6O5
574.2
1.63 (95)
575.2
method 1a
Ex. 341
C40H38FN5O4
671.3
2.37 (97)
672.0
method 2c
Ex. 342
C40H38FN5O4
671.3
2.38 (94)
672.0
method 2c
Ex. 343
C39H37FN6O4
672.3
2.41 (96)
673.0
method 2c
Ex. 344
C38H36FN5O5S
693.2
2.42 (96)
694.0
method 2c
Ex. 345
C41H4OFN5O4
685.3
2.41 (97)
686.0
method 2c
Ex. 346
C37H38FN5O4
635.3
2.26 (97)
635.8
method 2c
Ex. 347
C32H37FN6O4
588.3
2.01 (89)
588.5
method 2c
Ex. 348
C41H39N5O6
697.3
2.06 (97)
698.0
method 1a
Ex. 349
H
C33H33N5O4
563.2
1.94 (88)
563.9
method 2c
Ex. 350
C40H36FN5O5
685.3
1.97 (99)
686.0
method 1a
Ex. 351
C40H39N5O4
653.3
2.38 (98)
654.0
method 2c
Ex. 352
C41H41N5O4
667.3
2.40 (94)
667.9
method 2c
Ex. 353
C42H43N5O4
681.3
2.51 (97)
682.1
method 2c
Ex. 354
C38H43N5O4
633.3
2.47 (98)
634.0
method 2c
Ex. 355
C37H41N5O4
619.3
2.41 (96)
619.9
method 2c
Ex. 356
C38H42N6O6
678.3
2.05 (96)
679.3
method 2e
Ex. 357
C37H42N6O4
634.3
2.20 (96)
635.3
method 2e
Ex. 358
CH 3
C28H37N5O4
507.3
1.43 (99)
508.2
method 1c
TABLE 17c
Examples of Core 05 (Ex. 90-Ex. 114 and Ex. 341-Ex. 358;)
No
R B
R D
IUPAC name
Ex. 90
benzyl (9S,11R)-11-[(tert-butoxycarbonyl)amino]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaene-16-carboxylate
Ex. 91
H
tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 92
NH 2
benzyl (9S,11R)-11-amino-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxylate
Ex. 93
NH 2
H
(9S,11R)-11-amino-7-oxa-13,16,19,23-tetraazatetracyclo
[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 94
CH 3
tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 95
NH 2
CH 3
(9S,11R)-11-amino-16-methyl-7-oxa-13,16,19,23-
tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 96
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl) acetamide
Ex. 97
tert-butyl N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate
Ex. 98
NH 2
(9S,11R)-11-amino-16-(3-fluorobenzyl)-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 99
NHCOCH 3
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-
tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa-
1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide
Ex. 100
NHCOCH 3
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide
Ex. 101
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1-naphthyl) acetamide
Ex. 102
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-N′-phenylurea
Ex. 103
CH 3
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]benzenesulfonamide
Ex. 104
tert-butyl N-[(9S,11R)-16-[2-(dimethylamino)acetyl]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate
Ex. 105
NH 2
(9S,11R)-11-amino-16-[2-(dimethylamino)acetyl]-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 106
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-11-yl]-2- phenylacetamide
Ex. 107
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl] cyclopropanesulfonamide
Ex. 108
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo- 7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N′- methylurea
Ex. 109
tert-butyl N-[(9S,11R)-16-(cyclopropylsulfonyl)- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]carbamate
Ex. 110
NH 2
(9S,11R)-11-amino-16-(cyclopropylsulfonyl)-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaene-14,20-dione
Ex. 111
N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]benzamide
Ex. 112
tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23-hexaen- 11-yl]carbamate
Ex. 113
NH 2
(9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxamide
Ex. 114
(9S,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23-hexaene- 16-carboxamide
Ex. 341
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1- naphthyl)acetamide
Ex. 342
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 343
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N′-(2- naphthyl)urea
Ex. 344
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2- naphthalenesulfonamide
Ex. 345
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3-(2- naphthyl)propanamide
Ex. 346
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3- phenylpropanamide
Ex. 347
2-(dimethylamino)-N-[(9S,11R)-16-(3-fluorobenzyl)- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]acetamide
Ex. 348
benzyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}- 14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3 ,5,21,23- hexaene-16-carboxylate
Ex. 349
H
N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl) acetamide
Ex. 350
N-[(9S,11R)-16-(3-fluorobenzoyl)-14,20-dioxo-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 351
N-[(9S,11R)-16-benzyl-14,20-dioxo-7-oxa-13,16,19,23- tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ]hexacosa- 1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 352
N-[(9S,11R)-14,20-dioxo-16-phenethyl-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 353
N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropyl)-7- oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 354
N-[(9S,11R)-16-isopentyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 355
N-[(9S,11R)-16-isobutyl-14,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2- naphthyl)acetamide
Ex. 356
2-(dimethylamino)ethyl (9S,11R)-11-{[2-(2- naphthyl)acetyl]amino}-14 ,20-dioxo-7-oxa- 13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13 ] hexacosa-1(25),2(26),3,5,21,23-hexaene-16- carboxylate
Ex. 357
N-[(9S,11R)-16-[2-(dimethylamino)ethyl]-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]-2-(2-naphthyl)acetamide
Ex. 358
CH 3
3,3-dimethyl-N-[(9S,11R)-16-methyl-14,20- dioxo-7-oxa-13,16,19,23-tetraazatetracyclo [19.3.1.1 2,6 .0 9,13 ]hexacosa-1(25),2(26),3,5,21,23- hexaen-11-yl]butanamide
TABLE 18a
Examples of Core 06 (Ex. 115-Ex. 128;)
Starting
General
Purification
No
R A
Material
Procedure
Reagent
Method
Yield (isolated salt)
Ex. 115-
cf. experimental description
Ex. 116:
Ex. 117
Ex. 116
A.1.1
1-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3, then washed with Et 2 O, then FC (hexane/EtOAc)
66%
Ex. 118
Ex. 116
A.1.1
2-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3, then washed with Et 2 O, then FC (hexane/EtOAc)
60%
Ex. 119
Ex. 116
A.1.1
1-Pyrrolidineacetic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
57%
Ex. 120
Ex. 116
A.1.1
Nicotinic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
72%
Ex. 121
Ex. 116
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h
prep. HPLC method 3
38%
Ex. 122
Ex. 116
A.4
Methyl chloroformate 0° C. to rt, 2 h
prep. HPLC method 3
83%
Ex. 123
Ex. 116
A.5
Cyclopropanesulfonyl chloride (2.0 equiv.) Et 3 N (3 equiv.) DMAP (0.1 equiv) rt, 15 h Workup: CHCl 3 , half-sat. aq. NaHCO 3 soln.; Na 2 SO 4
prep. HPLC method 3
64%
Ex. 124
Ex. 116
A.5
Benzenesulfonyl chloride (1.5 equiv.) rt, 1 h
prep. HPLC method 3
54%
Ex. 125
Ex. 116
A.3
N-Succinimidyl N- methylcarbamate (1.8 equiv.) i-Pr 2 NEt (4.5 equiv) THF/CHCl 3 1:1 (0.9 mL) rt, 16 h
chromatography; washing of crude product with EtOH and Et 2 O
73%
Ex. 126
Ex. 116
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3 1:1 (0.5 mL) rt, 15 h
chromatography; washing of crude product with EtOH and Et 2 O
70%
Ex. 127
Ex. 116
A.6.4
Isobutyraldehyde (1.05 equiv.)
prep. HPLC method 3
52%
Ex. 128
Ex. 116
A.6.4
3-Methylbutanal (1.05 equiv.)
prep. HPLC method 3 and prep. HPLC method 1a
8% (TFA salt)
TABLE 18b
Examples of Core 06 (Ex. 115-Ex. 128;)
Monoisotopic
Rt (purity at
[M + H] +
No
R A
Formula
Mass
220 nm)
found
LC-MS-Method
Ex. 115-Ex. 116:
cf. experimental description
Ex. 117
C33H34N2O3S
538.2
2.55 (95)
539.2
method 1a
Ex. 118
C33H34N2O3S
538.2
2.54 (95)
539.2
method 1a
Ex. 119
C27H35N3O3S
481.2
1.82 (97)
482.2
method 1a
Ex. 120
C27H29N3O3S
475.2
1.90 (92)
476.1
method 1a
Ex. 121
C26H34N2O3S
454.2
2.32 (90)
455.2
method 1a
Ex. 122
C23H28N2O4S
428.2
2.15 (97)
429.2
method 1a
Ex. 123
C24H30N2O4S2
474.2
2.23 (93)
475.1
method 1a
Ex. 124
C27H30N2O4S2
510.2
2.33 (82)
511.1
method 1a
Ex. 125
C23H29N3O3S
427.2
1.97 (88)
428.2
method 1a
Ex. 126
C27H30N4O3S
490.2
1.80 (95)
491.2
method 1a
Ex. 127
C25H34N2O2S
426.2
1.97 (97)
427.2
method 1a
Ex. 128
C26H36N2O2S
440.2
2.05 (98)
441.2
method 1a
TABLE 18C
Examples of Core 06 (Ex. 115-Ex. 128;)
No
R A
IUPAC name
Ex. 115
NHAlloc
allyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 116
NH 2
(13S,16R)-13-amino-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-14-one
Ex. 117
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide
Ex. 118
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide
Ex. 119
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide
Ex. 120
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 121
3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 122
methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 123
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide
Ex. 124
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 125
N-methyl-N′-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yarea
Ex. 126
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 127
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-14-one
Ex. 128
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-14-one
TABLE 19a
Examples of Core 07 (Ex. 129-Ex. 142);
Starting
General
Yield
No
R A
Material
Procedure
Reagent
Purification Method
(isolated salt)
Ex. 129-Ex. 130:
cf. experimental description
Ex. 131
Ex. 130
A.1.1
1-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3
71%
Ex. 132
Ex. 130
A.1.1
2-Naphthaleneacetic acid 0° C., 2 h
prep. HPLC method 3
73%
Ex. 133
Ex. 130
A.1.1
1-Pyrrolidineacetic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
46%
Ex. 134
Ex. 130
A.1.1
Nicotinic acid 0° C., 2 h aq. workup (EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln; Na 2 SO 4 )
prep. HPLC method 3
59%
Ex. 135
Ex. 130
A.1.2
3-Methylbutanoyl chloride (1.2 equiv.) 0° C., 2 h
prep. HPLC method 3
77%
Ex. 136
Ex. 130
A.4
Methyl chloroformate 0° C., to rt, 2 h
prep. HPLC method 3
20%
Ex. 137
Ex. 130
A.5
Cyclopropanesulfonyl chloride (1.5 equiv.) Et 3 N (3 equiv.) DMAP (0.1 equiv) CHCl 3 (0.5 mL) rt, 15 h Workup: CHCl 3 , half-sat. aq. NaHCO 3 soln.; Na 2 SO 4
prep. HPLC method 3
71%
Ex. 138
Ex. 130
A.5
Benzenesulfonyl chloride (1.5 equiv.)
prep. HPLC method 3
52%
Ex. 139
Ex. 130
A.3
N-Succinimidyl-N- methylcarbamate (1.8 equiv.) i-Pr 2 NEt (4.5 equiv) THF/CHCl 3 1:1 (0.9 mL) rt, 20 h
prep. HPLC method 3
49%
Ex. 140
Ex. 130
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv.) i-Pr 2 NEt (3 equiv) THF/CHCl 3 1:1 (0.5 mL) rt, 15 h
prep. HPLC method 3
64%
Ex. 141
Ex. 130
A.6.4
Isobutyraldedhyde (1.05 equiv.)
prep. HPLC method 3
57%
Ex. 142
Ex. 130
A.6.4
3-Methylbutanal (1.05 equiv.)
prep. HPLC method 3 and prep. HPLC method 1a
11% (TFA salt)
TABLE 19b
Examples of Core 07 (Ex. 129-Ex. 142);
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R A
Formula
Mass
220 nm)
found
Method
Ex. 129-Ex. 130:
cf. experimental description
Ex. 131
C33H34N2O5S
570.2
2.28 (91)
571.2
method 1a
Ex. 132
C33H34N2O5S
570.2
2.20 (97)
571.2
method 1a
Ex. 133
C27H35N3O5S
513.2
1.55 (93)
514.2
method 1a
Ex. 134
C27H29N3O5S
507.2
1.59 (99)
509.0
method 1a
Ex. 135
C26H34N2O5S
486.2
1.92 (99)
487.2
method 1a
Ex. 136
C23H28N2O6S
460.2
1.74 (99)
461.0
method 1a
Ex. 137
C24H30N2O6S2
506.2
1.84 (99)
507.1
method 1a
Ex. 138
C27H30N2O6S2
542.2
2.02 (97)
543.1
method 1a
Ex. 139
C23H29N3O5S
459.2
1.61 (99)
460.1
method 1a
Ex. 140
C27H30N4O5S
522.2
1.53 (98)
523.2
method 1a
Ex. 141
C25H34N2O4S
458.2
1.70 (99)
459.2
method 1a
Ex. 142
C26H36N2O4S
472.3
1.78 (85)
473.2
method 1a
TABLE 19c
Examples of Core 07 (Ex. 129-Ex. 142);
No
R A
IUPAC name
Ex. 129
NHAlloc
allyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-
8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,
21-hexaen-13-yl]carbamate
Ex. 130
NH 2
(13S,16R)-13-amino-16-methyl-18-oxa-8λ 6 -thia-15-
azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaene-
8,8,14-trione
Ex. 131
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]-2-(1-naphthyl)acetamide
Ex. 132
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 -thia-15- azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen-13- yl]-2-(2-naphthyl)acetamide
Ex. 133
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide
Ex. 134
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]nicotinamide
Ex. 135
3-methyl-N-[(13S,16R)-16-methyl-8,8,14- trioxo-18-oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 136
methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18- oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 137
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8λ 6 - thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6, 19,21-hexaen-13-yl]cyclopropanesulfonamide
Ex. 138
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa-1(23), 2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 139
N-methyl-N′-[(13S,16R)-16-methyl-8,8,14-trioxo- 18-oxa-8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]urea
Ex. 140
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 141
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-8,8,14-trione
Ex. 142
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa- 8λ 6 -thia-15-azatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-8,8,14-trione
TABLE 20a
Examples of Core 08 (Ex. 143-Ex. 167);
Starting
General
Purification
Yield
No
R A
Material
Procedure
Reagent
Method
(isolated salt)
Ex. 143-Ex. 144:
cf. experimental description
Ex. 145
N(CH 3 ) 2
Ex. 144
A.6.1
Formaldehyde
prep. HPLC
92%
(36% in H 2 O)
method 3
Ex. 146
Ex. 144
A.6.4
Isobutyraldehyde
prep. HPLC method 3
16%
Ex. 147
Ex. 144
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
46%
Ex. 148
Ex. 144
A.1.2
Acetic anhydrid (2.2 equiv.) Pyridine (7 equiv.); rt
prep. HPLC method 1a
94% (TFA salt)
Ex. 149
Ex. 144
A.1.1 1)
Methoxyacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
62%
Ex. 150
Ex. 144
A.1.3
2-(Dimethylamino)acetic acid i-Pr 2 NEt (6 equiv.) Workup: CHCl 3 , 10M aq NaOH soln
prep. HPLC method 3
49%
Ex. 151
Ex. 144
A.1.1
Nicotinic acid i-Pr 2 NEt (5 equiv.) Workup: CHCl 3 , 10M aq NaOH soln
prep. HPLC method 3
68%
Ex. 152
Ex. 144
A.1.1 1)
Isovaleric acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
15%
Ex. 153
Ex. 144
A.1.1 1)
N-Boc-β-alanine i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
88%
Ex. 154
Ex. 153
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
73% (TFA salt)
Ex. 155
Ex. 144
A.1.1 1)
1-Naphthaleneacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3 and FC (hexane/EtOAc)
69%
Ex. 156
Ex. 144
A.1.1 1)
2-Naphthaleneacetic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
66%
Ex. 157
Ex. 144
A.1.1 1)
3,3,3-Trifluoropropionic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
45%
Ex. 158
Ex. 144
A.1.1 1)
3-Fluorobenzoic acid i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3 and FC (hexane/EtOAc)
44%
Ex. 159
Ex. 144
A.3
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate (1.3 equiv) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
78%
Ex. 160
Ex. 144
A.3
N-Succinimidyl-N- methylcarbamamte (1.3 equiv.) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
78%
Ex. 161
Ex. 144
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino) propanoate (1.3 equiv.) i-Pr 2 NEt (5 equiv.)
prep. HPLC method 3
84%
Ex. 162
Ex. 161
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
75% (TFA salt)
Ex. 163
Ex. 144
A.5
Methanesulfonyl chloride (3 equiv.) DMAP (0.1 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
71%
Ex. 164
Ex. 144
A.5
Cyclopropanesulfonyl chloride (3 equiv.) DMAP (0.1 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt to 50° C., 3 d
prep. HPLC method 1a
55% (TFA salt)
Ex. 165
Ex. 144
A.5
Benzenesulfonyl chloride (3 equiv.) NEt 3 (5 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
57%
Ex. 166
Ex. 144
A.4
Methyl chloroformate (0.89 equiv.); rt 2 h
prep. HPLC method 3
66%
Ex. 167
Ex. 144
A.4
2-Methoxyethyl chloro- formate (0.96 equiv.); rt, 2 h
prep. HPLC method 3
52%
1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH 2 Cl 2 and 1M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ), filtered
and concentrated.
TABLE 20b
Examples of Core 08 (Ex. 143-Ex. 167);
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R A
Formula
Mass
220 nm)
found
Method
Ex. 143-Ex. 144:
cf. experimental description
Ex. 145
N(CH 3 ) 2
C22H29N3O2S
399.2
1.35 (98)
400.1
method 1a
Ex. 146
C24H33N3O2S
427.2
1.46 (95)
428.2
method 1a
Ex. 147
C27H30FN3O2S
479.2
1.53 (95)
480.2
method 1a
Ex. 148
C22H27N3O3S
413.2
1.40 (99)
414.1
method 1a
Ex. 149
C23H29N3O4S
443.2
1.49 (94)
444.2
method 1a
Ex. 150
C24H32N4O3S
456.2
1.94 (96)
457.2
method 2c
Ex. 151
C26H28N4O3S
476.2
1.86 (92)
477.0
method 2c
Ex. 152
C25H33N3O3S
455.2
1.66 (90)
456.2
method 1a
Ex. 153
C28H38N4O5S
542.3
1.70 (90)
543.2
method 1a
Ex. 154
C23H30N4O3S
442.2
1.30 (87)
443.2
method 1c
Ex. 155
C32H33N3O3S
539.2
1.91 (93)
540.1
method 1a
Ex. 156
C32H33N3O3S
539.2
1.90 (97)
540.1
method 1a
Ex. 157
C23H26F3N3O3S
481.2
1.61 (96)
482.2
method 1a
Ex. 158
C27H28FN3O3S
493.2
1.76 (99)
494.2
method 1a
Ex. 159
C26H29N5O3S
491.2
1.86 (90)
492.1
method 2c
Ex. 160
C22H28N4O3S
428.2
1.39 (99)
429.1
method 1a
Ex. 161
C28H38N4O5S
542.3
2.13 (99)
543.1
method 2c
Ex. 162
C24H30N4O5S
486.2
1.38 (98)
487.2
method 1a
Ex. 163
C21H27N3O4S2
449.1
1.46 (99)
450.1
method 1a
Ex. 164
C23H29N3O4S2
475.2
1.55 (99)
476.0
method 1a
Ex. 165
C26H29N3O4S2
511.2
1.72 (99)
512.1
method 1a
Ex. 166
C22H27N3O4S
429.2
1.49 (99)
430.1
method 1a
Ex. 167
C24H31N3O5S
473.2
1.52 (99)
474.2
method 1a
TABLE 20c
Examples of Core 08 (Ex. 143-Ex. 167);
No
R A
IUPAC name
Ex. 143
NHAlloc
allyl N-[(10R,13S)-10-methyl-12-oxa-8-oxa-18-thia-
11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,
21-hexaen-13-yl]carbamate
Ex. 144
NH 2
(10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21-
diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-
hexaen-12-one
Ex. 145
N(CH 3 ) 2
(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-
18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaen-12-one
Ex. 146
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-12-one
Ex. 147
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-12-one
Ex. 148
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 149
2-methoxy-N-[(10R,13S)-10-methyl-12-oxo-8-oxa- 18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 150
2-(dimethylamino)-N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 151
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 152
3-methyl-N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]butanamide
Ex. 153
tert-butyl N-(3-{[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl] amino}-3-oxopropyl)carbamate
Ex. 154
3-amino-N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]propanamide
Ex. 155
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide
Ex. 156
N-[(10R,13S)-10-methyl-12-oxo-8-oxa- 18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide
Ex. 157
3,3,3-trifluoro-N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]propanamide
Ex. 158
3-fluoro-N-[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,12-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]benzamide
Ex. 159
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3-pyridinyl)urea
Ex. 160
N-methyl-N′-[(10R,13S)-10-methyl-12-oxo- 8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ] tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea
Ex. 161
tert-butyl 3-[({[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoate
Ex. 162
3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]amino} carbonyl)amino]propanoic acid
Ex. 163
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide
Ex. 164
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18- thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl] cyclopropanesulfonamide
Ex. 165
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-thia- 11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23), 2,4,6,19,21-hexaen-13-yl]benzenesulfonamide
Ex. 166
methyl N-[(10R,13S)-10-methyl-12-oxo-8- oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]carbamate
Ex. 167
2-methoxyethyl N-[(10R,13S)-10-methyl- 12-oxo-8-oxa-18-thia-11,21-diazatricyclo [17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-hexaen- 13-yl]carbamate
TABLE 21a
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
Starting
General
Purification
No
R A
Material
Procedure
Reagent
Method
Yield (isolated salt)
Ex. 168-Ex. 169 cf. experimental description
Ex. 170
N(CH 3 ) 2
Ex. 169
A.6.1
Formaldehyde (36% in H 2 O)
prep. HPLC
67%
method 3
Ex. 171
Ex. 169
A.6.4
Isobutyraldehyde
prep. HPLC method 3
44%
Ex. 172
Ex. 169
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
57%
Ex. 173
Ex. 169
A.1.2
Acetic anhydride (1.2 equiv.)
prep. HPLC method 3
79%
Ex. 174
Ex. 169
A.1.1 1)
Methoxyacetic acid
prep. HPLC method 3
27%
Ex. 175
Ex. 169
A.1.3
2-(Dimethylamino)acetic acid Workup: CH 2 Cl 2
prep. HPLC method 3
9%
Ex. 176
Ex. 169
A.1.1
Nicotinic acid Workup: CH 2 Cl 2 , sat .aq. Na 2 CO 3
prep. HPLC method 3
26%
Ex. 177
Ex. 169
A.1.1 1)
Isovaleric acid
prep. HPLC method 3
18%
Ex. 178
Ex. 169
A.1.1 1)
N-Boc-β-alanine
prep. HPLC method 3
57%
Ex. 179
Ex. 178
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
41% (TFA salt)
Ex. 180
Ex. 169
A.1.1 1)
1-Naphthaleneacetic acid
prep. HPLC method 3
42%
Ex. 181
Ex. 169
A.1.1 1)
2-Naphthaleneacetic acid
prep. HPLC method 3
40%
Ex. 182
Ex. 169
A.1.1 1)
3,3,3-Trifluoropropionic acid
prep. HPLC method 3
22%
Ex. 183
Ex. 169
A.1.1 1)
3-Fluorobenzoic acid
prep. HPLC method 3
58%
Ex. 184
Ex. 169
A.3
2,5-Dioxopyrrolidin-1-yl pyridin- 3-ylcarbamate (1.3 equiv.)
prep. HPLC method 3
73%
Ex. 185
Ex. 169
A.3
N-Succinimidyl N- methylcarbamate (1.3 equiv.)
prep. HPLC method 3
76%
Ex. 186
Ex. 169
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino)propanoate (1.3 equiv.)
prep. HPLC method 3
77%
Ex. 187
Ex. 186
B.2
TFA, CH 2 Cl 2
crude product
75%
Ex. 188
Ex. 169
A.5
Methanesulfonyl chloride (2 equiv.) DMAP (0.1 equiv.) Et 3 N (3 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
70%
Ex. 189
Ex. 169
A.5
Cyclopropanesulfonyl chloride DMAP (0.1 equiv.) Et 3 N (3 equiv.) CHCl 3 , rt, 2 d
prep. HPLC method 3
53%
Ex. 190
Ex. 169
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
51%
Ex. 191
Ex. 169
A.4
Methyl chloroformate (0.86 equiv); rt, 2 h
prep. HPLC method 3
52%
Ex. 192
Ex. 169
A.4
2-Methoxyethyl chloroformate (0.97equiv); rt, 2 h
prep. HPLC method 3
55%
1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH 2 Cl 2 and 1M aq. HCl soln. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated.
TABLE 21b
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
Monoisotopic
Rt (purity at
No
R A
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 168-Ex. 169 cf. experimental description
Ex. 170
N(CH 3 ) 2
C22H29N3O4S
431.2
1.39 (97)
432.1
method 1a
Ex. 171
C24H33N3O4S
459.2
1.53 (95)
460.1
method 1a
Ex. 172
C27H30FN3O4S
511.2
1.61 (96)
512.1
method 1a
Ex. 173
C22H27N3O5S
445.2
1.50 (100)
446.1
method 1a
Ex. 174
C23H29N3O6S
475.2
1.57 (96)
476.0
method 1a
Ex. 175
C24H32N4O5S
488.2
1.38 (92)
489.1
method 1a
Ex. 176
C26H28N4O5S
508.2
1.43 (98)
508.9
method 1a
Ex. 177
C25H33N3O5S
487.2
1.77 (97)
488.2
method 1a
Ex. 178
C28H38N4O7S
574.2
1.83 (98)
575.1
method 2c
Ex. 179
C23H30N4O5S
474.2
1.35 (99)
475.2
method 1a
Ex. 180
C32H33N3O5S
571.2
2.03 (97)
572.0
method 1a
Ex. 181
C32H33N3O5S
571.2
2.05 (100)
572.1
method 1a
Ex. 182
C23H26F3N3O5S
513.2
1.74 (99)
514.1
method 1a
Ex. 183
C27H28FN3O5S
525.2
1.90 (92)
526.1
method 1a
Ex. 184
C26H29N5O5S
523.2
1.42 (99)
524.0
method 1a
Ex. 185
C22H28N4O5S
460.2
1.48 (99)
461.0
method 1a
Ex. 186
C28H38N4O7S
574.2
1.88 (98)
575.1
method 2c
Ex. 187
C24H30N4O7S
518.2
1.45 (97)
519.1
method 1a
Ex. 188
C21H27N3O6S2
481.1
1.58 (99)
482.1
method 1a
Ex. 189
C23H29N3O6S2
507.1
1.68 (95)
508.0
method 1a
Ex. 190
C26H29N3O6S2
543.1
1.85 (96)
544.1
method 1a
Ex. 191
C22H27N3O6S
461.2
1.60 (98)
462.1
method 1a
Ex. 192
C24H31N3O7S
505.2
1.63 (99)
506.2
method 1a
TABLE 21c
Examples of Core 09 (Ex. 168-Ex. 192; continued on the following pages)
No
R A
IUPAC name
Ex. 168
NHAlloc
allyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-
oxa-18λ 6 -thia-11,21-
diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21-
hexaen-13-yl]carbamate
Ex. 169
NH 2
(10R,13S)-13-amino-10-methyl-8-oxa-18λ 6 -thia-
11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 170
N(CH 3 ) 2
(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-
18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa-
1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 171
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaene-12,18,18-trione
Ex. 172
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaene-12,18,18-trione
Ex. 173
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]acetamide
Ex. 174
2-methoxy-N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 175
2-(dimethylamino)-N-[(10R,13S)-10-methyl- 12,18,18-trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]acetamide
Ex. 176
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide
Ex. 177
3-methyl-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]butanamide
Ex. 178
tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]amino}-3-oxopropyl)carbamate
Ex. 179
3-amino-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]propanamide
Ex. 180
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(1- naphthyl)acetamide
Ex. 181
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-2-(2- naphthyl)acetamide
Ex. 182
3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]propanamide
Ex. 183
3-fluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo- 8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]benzamide
Ex. 184
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl]-N′-(3- pyridinyl)urea
Ex. 185
N-methyl-N′-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]urea
Ex. 186
tert-butyl 3[({[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]amino}carbonyl)amino]propanoate
Ex. 187
3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]amino}carbonyl)amino]propanoic acid
Ex. 188
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]methanesulfonamide
Ex. 189
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]cyclopropanesulfonamide
Ex. 190
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa- 18λ 6 -thia-11,21-diazatricyclo[17.3.1.0 2,7 ]tricosa- 1(23),2,4,6,19,21-hexaen-13- yl]benzenesulfonamide
Ex. 191
methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8- oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]carbamate
Ex. 192
2-methoxyethyl N-[(10R,13S)-10-methyl-12,18,18- trioxo-8-oxa-18λ 6 -thia-11,21- diazatricyclo[17.3.1.0 2,7 ]tricosa-1(23),2,4,6,19,21- hexaen-13-yl]carbamate
TABLE 22a
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b; continued on the following page)
General
Purification
No
Procedure
Fmoc-AA1-OH
Fmoc-AA2-OH
Method
Yield (isolated salt)
Ex. 193a
C.1
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-DAla-OH
prep. HPLC
20 mg/53%
method 2b
Ex. 193c
C.1
Fmoc-β-Ala-OH
Fmoc-NMePhe-OH
prep. HPLC
7 mg/19%
method 2b
Ex. 193d
C.1
Fmoc-β-Ala-OH
Fmoc-Phe-OH
prep. HPLC
2 mg/6%
method 2b
Ex. 193e
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMePhe-OH
prep. HPLC
7 mg/18%
method 2b
Ex. 193f
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
prep. HPLC
9 mg/27%
method 2b
Ex. 193g
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Phe-OH
prep. HPLC
8 mg/22%
method 2b
Ex. 193h
C.1
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-β-Ala-OH
prep. HPLC
13 mg/33%
method 2b
Ex. 194b
C.1
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMe-Glu(OtBu)-OH
prep. HPLC
14 mg/31%
method 1a
TABLE 22b
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b; continued on the following page)
Monoisotopic
Rt (purity at
No
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 193a
C31H34N4O4
526.2
2.03 (99)
527.2
method 1d
Ex. 193c
C30H32N4O4
512.2
1.94 (94)
513.0
method 1d
Ex. 193d
C29H30N4O4
498.2
1.80 (93)
499.2
method 1d
Ex. 193e
C32H36N4O4
540.2
2.07 (86)
541.2
method 1d
Ex. 193f
C25H30N4O4
450.2
1.50 (99)
451.2
method 1d
Ex. 193g
C31H34N4O4
526.2
1.94 (98)
527.2
method 1d
Ex. 193h
C31H34N4O4
526.2
1.78 (98)
527.2
method 1d
Ex. 194b
C28H34N4O6
522.2
1.68 (97)
523.2
method 1d
TABLE 22c
Examples of Core 10 (Ex. 193a, c-h and Ex. 194b) (continued on the following page)
No
IUPAC name
Ex. 193a
(9S,16S,19R)-16-benzyl-19,20-dimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193c
(9S,19S)-19-benzyl-20-methyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193d
(9S,19S)-19-benzyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193e
(9S,16R,19S)-19-benzyl-16,17,20-trimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193f
(9S,16R)-16,17,20-trimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-
1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193g
(9S,16R,19S)-19-benzyl-16,17-dimethyl-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione
Ex. 193h
(9S,16S)-16-benzyl-21-methyl-7-oxa-13,17,21,25-tetraazatetracyclo[21.3.1.1 2,6 .0 9,13 ]octacosa-
1(27),2(28),3,5,23,25-hexaene-14,18,22-trione
Ex. 194b
3-[(9S,16R,19S)-16,17,20-trimethyl-14,18,21-trioxo-7-oxa-13,17,20,24-
tetraazatetracyclo[20.3.1.1 2,6 .0 9,13 ]heptacosa-1(26),2(27),3,5,22,24-hexaen-19-yl]propanoic acid
TABLE 23a
Examples of Core 11 (Ex. 195a, b, e-h, j; Ex. 196c, i, k and Ex. 197d; continued on the following page)
General
Purification
Yield
No
Procedure
Fmoc-AA1-OH
Fmoc-AA2-OH
Fmoc-AA3-OH
Method
(isolated salt)
Ex. 195a
C.2
Fmoc-NMe-β 3 -
Fmoc-Sar-OH
Fmoc-NMeAla-OH
prep. HPLC
31%
homoDAla-OH
method 2a
Ex. 195b
C.2
Fmoc-NMe-β 3 -
Fmoc-Gly-OH
Fmoc-Ala-OH
prep. HPLC
18%
homoDAla-OH
method 2a
Ex. 196c
C.2
Fmoc-NMe-β 3 -
Fmoc-Ala-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
33%
homoDAla-OH
OH
method 1a
(TFA salt)
Ex. 197d
C.2
Fmoc-NMe-β 3 -
Fmoc-Lys(Boc)-
Fmoc-DAla-OH
prep. HPLC
24%
homoDAla-OH
OH
method 2a
Ex. 195e
C.2
Fmoc-Sar-OH
Fmoc-NMe-β 3 -
Fmoc-NMeAla-OH
prep. HPLC
33%
homoDAla-OH
method 2a
Ex. 195f
C.2
Fmoc-Sar-OH
Fmoc-NMeAla-OH
Fmoc-NMe-β 3 -
prep. HPLC
22%
homoDAla-OH
method 2a
Ex. 195g
C.2
Fmoc-Gly-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
prep. HPLC
17%
method 2a
Ex. 195h
C.2
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-DAla-OH
prep. HPLC
13%
method 2a
Ex. 196i
C.2
Fmoc-Ala-OH
Fmoc-DPhe-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
12%
OH
method 1a
(TFA salt)
Ex. 195j
C.2
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
prep. HPLC
13%
method 2a
Ex. 196k
C.2
Fmoc-DAla-OH
Fmoc-Phe-OH
Fmoc-NMeGlu(OtBu)-
prep. HPLC
10%
OH
method 1a
(TFA salt)
TABLE 23b
Examples of Core 11 (Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d)
Monoisotopic
Rt (purity at
No
Formula
Mass
220 nm)
[M + H] + found
LC-MS-Method
Ex. 195a
C29H37N5O5
535.3
1.50 (98)
536.2
method 1d
Ex. 195b
C27H33N5O5
507.3
1.44 (98)
508.2
method 1d
Ex. 196c
C31H39N5O7
593.3
1.47 (98)
594.2
method 1d
Ex. 197d
C31H42N6O5
578.3
2.10 (92)
579.2
method 2f
Ex. 195e
C29H37N5O5
535.3
1.53 (98)
536.3
method 1d
Ex. 195f
C29H37N5O5
535.2
1.40 (98)
536.2
method 1d
Ex. 195g
C32H35N5O5
569.3
1.71 (97)
569.9
method 1d
Ex. 195h
C32H35N5O5
569.3
1.67 (97)
570.2
method 1d
Ex. 196i
C35H39N5O7
641.3
1.41 (90)
642.3
method 2f
Ex. 195j
C33H37N5O5
583.3
1.72 (93)
584.0
method 1d
Ex. 196k
C35H39N5O7
641.3
1.71 (99)
642.2
method 1d
TABLE 23c
Examples of Core 11 (Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d) (continued on the following page)
No
IUPAC name
Ex. 195a
(9S,16R,22S)-16,17,20,22,23-pentamethyl-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 195b
(9S,16R,22S)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-
1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 196c
3-[(9S,16R,19S,22S)-16,17,19,23-tetramethyl-14,18,21,24-tetraoxo-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid
Ex. 197d
(9S,16R,19S,22R)-19-(4-aminobutyl)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone
Ex. 195e
(9S,19R,22S)-16,19,20,22,23-pentamethyl-7-oxa-13,16,20,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,21,24-tetrone
Ex. 195f
(9S,18S,22R)-16,18,19,22,23-pentamethyl-7-oxa-13,16,19,23,27-
pentaazatetracyclo[23.3.1.1 2,6 .0 9,13 ]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,20,24-tetrone
Ex. 195g
(9S,18S,21R)-18-benzyl-21,22-dimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 195h
(9S,18S,21R)-18-benzyl-16,21-dimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 196i
3-[(9S,15S,18R,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid
Ex. 195j
(9S,18S,21R)-18-benzyl-16,21,22-trimethyl-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone
Ex. 196k
3-[(9S,15R,18S,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-
pentaazatetracyclo[22.3.1.1 2,6 .0 9,13 ]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid
TABLE 24a
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following pages)
Yield
Starting
General
Purification
(isolated
No
RB
R D
Material
Proced.
Reagent
Method
salt)
Ex. 198-Ex. 200: cf. experimental description
Ex. 201
CH 3
Ex. 200
(A.6.2) 1)
Formaldehyde (36.5% in H 2 O); details cf. 1)
FC (CH 2 Cl 2 /MeOH)
89%
Ex. 202
NH 2
CH 3
Ex. 201
B.1
HCl-dioxane
crude product
93%
(HCl
salt)
Ex. 203
CH 3
Ex. 202
A.1.3
2- Naphthaleneacetic acid T3P 50% in EtOAc i-Pr 2 NEt (7 equiv.)
prep. HPLC method 2a
6%
Ex. 204
CH 3
Ex. 202
A.1.3
3-Methylbutanoic acid T3P 50% in EtOAc i-Pr 2 NEt (7 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
7%
Ex. 205
CH 3
Ex. 202
A.3
3-Pyridinyl isocyanate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
24%
Ex. 206
CH 3
Ex. 202
A.5
Benzenesulfonyl chloride (1.1 equiv.) NEt 3 (5 equiv.)
prep. HPLC method 2a
68%
Ex. 207
Ex. 200
A.1.3
2- (Dimethylamino) acetic acid Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln
prep. HPLC method 2a
49%
Ex. 208
NH 2
Ex. 207
B.1
HCl-dioxane
crude product
85% (HCl salt)
Ex. 209
Ex. 208
A.1.3
2-Phenylacetic acid (3.4 equiv.) i-Pr 2 NEt (8 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
22%
Ex. 210
Ex. 208
A.3
N-Succinimidyl N- methylcarbamate i-Pr 2 NEt (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
38%
Ex. 211
Ex. 208
A.5
Cyclopropane- sulfonyl chloride NEt 3 (5 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
30%
Ex. 212
Ex. 199
A.1.2.2
Acetyl chloride (2 equiv.); 0° C., 2 h
FC (CH 2 Cl 2 /MeOH)
68%
Ex. 213
H
Ex. 212
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
86%
Ex. 214
Ex. 213
A.6.3
3- Fluorobenz- aldehyde (1.8 equiv.) Acetic acid (1.5 equiv.) NaBH(OAc) 3 (4 equiv.) Workup: CHCl 3 , sat. aq. Na 2 CO 3 soln
prep. HPLC method 1a and prep. HPLC method 2a
8%
Ex. 215
Ex. 213
A.1.3
1- Pyrrolidineacetic acid
prep. HPLC method 1a and prep. HPLC method 2a
14%
Ex. 216
Ex. 213
A.3
Phenyl isocyanate (1.4 equiv.)
prep. HPLC method 1a and prep. HPLC method 2a
28%
Ex. 217
Ex. 213
A.5
Benzenesulfonyl chlorid
prep. HPLC method 1a and prep. HPLC method 2a
18%
Ex. 218
Ex. 219
B.2
TFA, CH 2 Cl 2 rt, 2 h
crude product
87% (TFA salt)
Ex. 219
Ex. 213
A.3
tert.-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy) carbonylamino) propanoate
prep. HPLC method 1a and prep. HPLC method 2a
49%
1) At 0° C., formadehyde (36.5% in H 2 O; 0.48 mL, 6.4 mmol), acetic acid (0.088 mL, 1.5 mmol) and NaBH(OAc) 3 (1.09 g, 5.1 mmol) were added to a soln of Ex. 200 (0.635 g, 1.3 mmol) in DCE (20 mL). The mixture was stirred for 2 h at 0° C., followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ). The crude product was dissolved in MeCN (3 mL) and treated with 25% aq. NH 3 soln (1 mL) for 3 h at rt. More 25% aq. NH 3 soln (1 mL) was added and stirrig was continued for 2 h. Aqueous workup (EtOAc, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln; Na 2 SO 4 ) and FC (CH 2 Cl 2 /MeOH 9:1) afforded Ex. 201 (0.587g, 89%).
TABLE 24b
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following page)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 198-Ex. 200: cf. experimental description
Ex. 201
CH 3
C27H35N5O5
509.3
1.58 (97)
510.3
method 2f
Ex. 202
NH 2
CH 3
C22H27N5O3
409.2
1.05 (95)
410.0
method 2f
Ex. 203
CH 3
C34H35N5O4
577.3
1.58 (97)
578.1
method 2c
Ex. 204
CH 3
C27H35N5O4
493.3
1.38 (99)
494.2
method 2c
Ex. 205
CH 3
C28H31N7O4
529.2
1.20 (99)
530.2
method 2c
Ex. 206
CH 3
C28H31N5O5S
549.2
1.48 (99)
550.1
method 2c
Ex. 207
C30H40N6O6
580.3
1.18 (98)
581.2
method 1d
Ex. 208
NH 2
C25H32N6O4
480.2
1.09 (95)
481.3
method 2f
Ex. 209
C33H38N6O5
598.3
1.44 (98)
599.1
method 2c
Ex. 210
C27H35N7O5
537.3
1.12 (99)
538.2
method 2c
Ex. 211
C28H36N6O6S
584.2
1.28 (99)
585.1
method 2c
Ex. 212
C31H33N5O6
571.2
1.18 (97)
572.0
method 1a
Ex. 213
H
C23H27N5O4
437.2
1.32 (96)
438.1
method 5a
Ex. 214
C30H32FN5O4
545.2
1.51 (99)
546.1
method 2c
Ex. 215
C29H36N6O5
548.3
1.20 (99)
549.2
method 2c
Ex. 216
C30H32N6O5
556.2
1.32 (97)
556.9
method 2c
Ex. 217
C29H31N5O6S
577.2
1.37 (100)
578.1
method 2c
Ex. 218
C27H32N6O7
552.2
1.50 (92)
553.1
method 5a
Ex. 219
C31H40N6O7
608.3
1.42 (98)
609.2
method 2c
TABLE 24c
Examples of Core 12 (Ex. 198-Ex. 219; continued on the following pages)
No
R B
R D
IUPAC name
Ex. 198
benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21- dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 199
NH 2
benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 200
H
tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 201
CH 3
tert-butyl N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 202
NH 2
CH 3
(10S,12S)-12-amino-17-methyl-8-oxa-3,14,17,20-
tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-
1(24),2,4,6,22,25-hexaene-15,21-dione
Ex. 203
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-2-(1-naphthyl)acetamide
Ex. 204
CH 3
3-methyl-N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]butanamide
Ex. 205
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa-1(24),2,4,6,22 ,25-hexaen-12-yl]-N-(3-pyridinyl)urea
Ex. 206
CH 3
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]benzenesulfonamide
Ex. 207
tert-butyl N-[(10S,12S)-17-[2-(dimethylamino)acetyl]- 15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]carbamate
Ex. 208
NH 2
(10S,12S)-12-amino-17-[2-(dimethylamino)acetyl]-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-15,21-dione
Ex. 209
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-2-phenylacetamide
Ex. 210
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]-N′-methylurea
Ex. 211
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]cyclopropanesulfonamide
Ex. 212
benzyl (10S,12S)-12-(acetylamine)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxylate
Ex. 213
H
N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 214
N-[(10S,12S)-17-(3-fluorobenzyl)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 215
N-[(10S,12S)-15,21-dioxo-17-[2-(1-pyrrolidinyl)acetyl]-8- oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 216
(10S,12S)-12-(acetylamino)-15,21-dioxo-N-phenyl-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaene-17-carboxamide
Ex. 217
N-[(10S,12S)-15,21-dioxo-17-(phenylsulfonyl)-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-12-yl]acetamide
Ex. 218
3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa- 3,14,17,20-tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-17-yl]carbonyl}amino)propanoic acid
Ex. 219
tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8- oxa-3,14,17,20- tetraazatetracyclo[20.2.2.0 2,7 .0 10,14 ]hexacosa- 1(24),2,4,6,22,25-hexaen-17-yl]carbonyl}amino)propanoate
TABLE 25a
Examples of Core 13 (Ex. 220-Ex. 226; continued on the following pages)
Starting
General
Yield
No
R B
R E
Material
Proced.
Reagent
Purification Method
(isolated salt)
Ex. 220-Ex. 222 cf. experimental description
Ex. 223
CO 2 CH 3
Ex. 222
A.1.1
2-Phenylacetic acid i-Pr 2 NEt added at 0° C. 0° C. to rt, 2 h Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln
FC (CH 2 Cl 2 /MeOH)
93%
Ex. 224
CO 2 H
Ex. 223
B.5
Trimethyltin hydroxide
FC (CH 2 Cl 2 /MeOH) and prep. HPLC method 1a
80%
Ex. 225
CONH 2
Ex. 224
A.2
Ammoniun chloride (5.2 equiv.) HATU (3.2 equiv.) HOAt (3.2 equiv.) i-Pr 2 NEt (8.4 equiv.) Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
64%
Ex. 226
Ex. 224
A.2
Isobutylamine Workup: EtOAc, 1M aq. HCl soln, H 2 O, sat. aq. NaHCO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
80%
TABLE 25b
Examples of Core 13 (Ex. 220-Ex. 226)
Monoisotopic
Rt (purity at
[M + H] +
No
R B
R E
Formula
Mass
220 nm)
found
LC-MS-Method
Ex. 220-Ex. 222.: cf. experimental description
Ex. 223
CO 2 CH 3
C32H34FN3O7S
623.2
2.31 (99)
624.3
method 1d
Ex. 224
CO 2 H
C31H32FN3O7S
609.2
2.05 (99)
610.2
method 1d
Ex. 225
CONH 2
C31H33FN4O6S
608.2
1.93 (99)
609.2
method 1d
Ex. 226
C35H41FN4O6S
664.3
2.22 (89)
665.3
method 1d
TABLE 25c
Examples of Core 13 (Ex. 220-Ex. 226)
No
R B
R E
IUPAC name
Ex. 220
CO 2 CH 3
methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),12,22,24-hexaene-8-carboxylate
Ex. 221
CO 2 CH 3
methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14- dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate
Ex. 222
NH 2
CO 2 CH 3
methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-
7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa-1(26),2,5(27),22,24-
pentaene-8-carboxylate
Ex. 223
CO 2 CH 3
methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetypamino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylate
Ex. 224
CO 2 H
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxylic acid
Ex. 225
CONH 2
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21- dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide
Ex. 226
(8S,17S,19S)-24-fluoro-N-isobutyl-6,14-dioxo-17-[(2-phenylacetyl)amino]- 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.1 2,5 .0 15,19 ]heptacosa- 1(26),2,5(27),22,24-pentaene-8-carboxamide
TABLE 26a
Examples of Core 14 (Ex. 227-Ex. 241; continued on the following page)
Yield
Starting
General
(isolated
No
R B
R E
Material
Proced.
Reagent
Purification Method
salt)
Ex. 227-Ex. 229: cf. experimental description
Ex. 230
CO 2 CH 3
Ex. 229
A.1.2
2-Naphthalene- acetyl chloride (1.1 equiv.)
prep. HPLC method 3
57%
Ex. 231
Ex. 228
A.2
Isobutylamine
FC (hexane/EtOAc/MeOH)
40%
Ex. 232
NH 2
Ex. 231
B.1
HCl-dioxane
crude product
93% (HCl salt)
Ex. 233
Ex. 232
A.1.1
Nicotinic acid (1.3 equiv.), 0° C., 2 h Workup: EtOAc, 1M aq. HCl soln, sat. aq. Na 2 CO 3 soln, sat. aq. NaCl soln
FC (CH 2 Cl 2 /MeOH)
14%
Ex. 234
Ex. 228
A.2
Aniline
FC (hexane/EtOAc)
4%
Ex. 235
NH 2
Ex. 234
B.1
HCl-dioxane
prep. HPLC method 1a
44% (TFA salt)
Ex. 236
CO 2 CH 3
Ex. 229
A.1.2
Phenylacetyl chloride (1.1 equiv.)
prep. HPLC method 3
75%
Ex. 237
CO 2 H
Ex. 236
B.5
Trimethylthin hydroxide
prep. HPLC method 1a
78%
Ex. 238
CO 2 CH 3
Ex. 229
A.1.2
3-Chlorobenzoyl chloride (1.1 equiv.)
prep. HPLC method 3
62%
Ex. 239
CO 2 H
Ex. 238
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
70%
Ex. 240
Ex. 241
A.2
Isobutylamine
FC (hexane/EtOAc/MeOH)
78%
Ex. 241
CO 2 H
Ex. 230
B.5
Trimethyltin hydroxide
FC (CH 2 Cl 2 /MeOH)
84%
TABLE 26b
Examples of Core 14 (Ex. 227-Ex. 241;)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R E
Formula
Mass
220 nm)
found
Method
Ex. 227-
cf. experimental description
Ex. 229:
Ex. 230
CO 2 CH 3
C37H36FN3O7S
685.2
2.28 (96)
686.2
method 1a
Ex. 231
C33H43FN4O7S
658.3
2.37 (95)
659.3
method 1a
Ex. 232
NH 2
C28H35FN4O5S
558.2
1.59 (93)
559.2
method 1a
Ex. 233
C34H38FN5O6S
663.3
1.95 (87)
664.3
method 2c
Ex. 234
C35H39FN4O7S
678.3
2.43 (77)
679.2
method 1a
Ex. 235
NH 2
C30H31FN4O5S
578.2
1.66 (95)
579.2
method 1a
Ex. 236
CO 2 CH 3
C33H34FN3O7S
635.2
2.15 (91)
636.0
method 1a
Ex. 237
CO 2 H
C32H32FN3O7S
621.2
1.98 (96)
622.1
method 1c
Ex. 238
CO 2 CH 3
C32H31ClFN3O7S
655.2
2.31 (97)
656.1
method 1a
Ex. 239
CO 2 H
C31H29ClFN3O7S
641.1
2.14 (97)
642.1
method 1a
Ex. 240
C40H43FN4O6S
726.3
2.32 (79)
727.3
method 1a
Ex. 241
CO 2 H
C36H34FN3O7S
671.2
2.15 (88)
672.1
method 1a
TABLE 26c
Examples of Core 14 (Ex. 227-Ex. 241;)
No
R B
R E
IUPAC name
Ex. 227
CO 2 CH 3
methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 228
CO 2 H
(8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid
Ex. 229
NH 2
CO 2 CH 3
methyl (8S,12E, 18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-
dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-
1(27),2,5(28),12,23,25-hexaene-8-carboxylate
Ex. 230
CO 2 CH 3
methyl (8S,12E, 18S,20S)-25-fluoro-1842-(2-naphthyl)acetyl] amino-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 231
tert-butyl N-[(8S,12E, 18S,20S)-25-fluoro-8-[8 (isobutylamino) carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen- 18-yl]carbamate
Ex. 232
NH 2
(8S,12E,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),12,23,25-hexaene-8-carboxamide
Ex. 233
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3- pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide
Ex. 234
tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbonyl)-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaen-18- yl]carbamate
Ex. 235
NH 2
(8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide
Ex. 236
CO 2 CH 3
methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2- phenylacetyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 237
CO 2 H
(8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl) amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),12,23 ,25-hexaene-8-carboxylic acid
Ex. 238
CO 2 CH 3
methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylate
Ex. 239
CO 2 H
(8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylic acid
Ex. 240
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-18-{[2-(2-naphthyl) acetyl]amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16- diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25- hexaene-8-carboxamide
Ex. 241
CO 2 H
(8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl] amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),12,23,25-hexaene-8- carboxylic acid
TABLE 27a
Examples of Core 15 (Ex. 242-Ex. 261;)
Yield
Starting
General
Purification
(isolated
No
R B
R E
Material
Proced.
Reagent
Method
salt)
Ex. 242-
cf. experimental description
Ex. 244:
Ex. 245
CO 2 CH 3
Ex. 244
1)
2-Naphthaleneacetyl chloride
FC (EtOAc) and FC (CH 2 Cl 2 / MeOH)
52%
Ex. 246
Ex. 243
2)
Aniline (5 equiv.)
FC (hexane/ EtOAc)
62%
Ex. 247
NH 2
Ex. 246
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
60% (HCl salt)
Ex. 248
CO 2 CH 3
Ex. 244
A.1.2
Phenylacetyl chloride (1.6 equiv.)
FC (hexane/ EtOAc/ MeOH)
90%
Ex. 249
CO 2 H
Ex. 250
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
65%
Ex. 250
CO 2 CH 3
Ex. 244
A.1.2
3-Chlorobenzoyl chloride (1.6 equiv.)
FC (hexane/ EtOAc)
87%
Ex. 251
CO 2 H
Ex. 248
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
70%
Ex. 252
CO 2 H
Ex. 245
B.5
Trimethyltin hydroxide
prep. HPLC method 1a
45%
Ex. 253
Ex. 243
A.2
Isobutylamine (1.5 equiv.) Workup: CH 2 Cl 2 , sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln
FC (hexane, EtOAc)
73%
Ex. 254
NH 2
Ex. 253
B.1
HCl-dioxane
crude product
quant. (HCl salt)
Ex. 255
Ex. 254
A.1.1
Nicotinic acid (1.3 equiv.) 0° C., 2 h Workup: EtOAc, sat. aq. NaHCO 3 soln, H 2 O, sat. aq. NaCl soln,
FC (CH 2 Cl 2 / MeOH)
50%
Ex. 256
Ex. 243
2)
4-Chloroaniline (5 equiv.)
FC (hexane/ EtOAc)
14%
Ex. 257
NH 2
Ex. 256
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
66% (HCl salt)
Ex. 258
Ex. 243
2)
m-Toluidine (5 equiv.)
FC (hexane/ EtOAc)
43%
Ex. 259
NH 2
Ex. 258
2)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
66% (HCl salt)
Ex. 260
Ex. 243
3)
Benzylamine (5 equiv.)
FC (hexane/ EtOAc)
57%
Ex. 261
NH 2
Ex. 260
3)
HCl-dioxane then TFA, CH 2 Cl 2
FC (CH 2 Cl 2 / MeOH)
74% (HCl salt)
1) 2-Naphthaleneacetic acid (41 mg, 0.22 mmol) in CH 2 Cl 2 (3 mL) was treated at 0° C. for 1 h with oxalyl chloride (0.08 mL, 0.93 mmol) and DMF (0.007 mL). The volatiles were evaporated. The residue was dissolved in CH 2 Cl 2 (3 mL) and added dropwise to a mixture of Ex. 244·HCl (103 mg, 0.19 mmol) and i-Pr 2 NEt (0.2 mL; 0.93 mmol) in CH 2 Cl 2 (3 mL). The solution was stirred at 0° C. for 1 h, followed by an aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ), FC (EtOAc) and FC (CH 2 Cl 2 /MeOH 99:1 to 97:3) to afford Ex. 245 (67 mg, 52%).
2) Cf. experimental description for detailed procedure
3) Ex. 260 was obtained by applying the method described for the saynthesis of Ex. 246; Ex. 261 was obtained by applying the method described for the saynthesis of Ex. 247.
TABLE 27b
Examples of Core 15 (Ex. 242-Ex. 261;)
Mono-
iso-
Rt
[M +
topic
(purity at
H] +
LC-MS-
No
R B
R E
Formula
Mass
220 nm)
found
Method
Ex. 242-
cf. experimental description
Ex. 244.:
Ex. 245
CO 2 CH 3
C37H38FN3O7S
687.2
1.62 (91)
688.2
method 4a
Ex. 246
C35H41FN4O7S
680.3
2.48 (86)
681.3
method 1a
Ex. 247
NH 2
C30H33FN4O5S
580.2
1.66 (96)
581.2
method 1a
Ex. 248
CO 2 CH 3
C33H36FN3O7S
637.2
2.21 (91)
638.2
method 1a
Ex. 249
CO 2 H
C31H31ClFN3O7S
643.2
2.22 (97)
644.1
method 1a
Ex. 250
CO 2 CH 3
C32H33ClFN3O7S
657.2
2.40 (94)
658.1
method 1c
Ex. 251
CO 2 H
C32H34FN3O7S
623.2
2.06 (97)
624.1
method 1a
Ex. 252
CO 2 H
C36H36FN3O7S
673.2
2.23 (89)
674.2
method 1g
Ex. 253
C33H45FN4O7S
660.3
2.45 (93)
661.2
method 1a
Ex. 254
NH 2
C28H37FN4O5S
560.2
1.60 (97)
561.2
method 1a
Ex. 255
C34H40FN5O6S
665.3
2.00 (95)
666.2
method 2c
Ex. 256
C35H4OClFN4O7S
714.2
2.59 (89)
715.4
method 1a
Ex. 257
NH 2
C30H32ClFN4O5S
614.2
1.80 (87)
615.2
method 1a
Ex. 258
C36H43FN4O7S
694.3
2.55 (91)
695.4
method 1a
Ex. 259
NH 2
C31H35FN4O5S
594.2
1.74 (90)
595.3
method 1a
Ex. 260
C36H43FN4O7S
694.3
2.44 (92)
695.3
method 1a
Ex. 261
NH 2
C31H35FN4O5S
594.2
1.63 (92)
595.2
method 1a
TABLE 27c
Examples of Core 15 (Ex. 242-Ex. 261;)
No
R B
R E
IUPAC name
Ex. 242
CO 2 CH 3
methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 243
CO 2 H
(8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 244
NH 2
CO 2 CH 3
methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-
dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa-
1(27),2,5(28),23,25-pentaene-8-carboxylate
Ex. 245
CO 2 CH 3
methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl] amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 246
tert-butyl N-[(8S,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate
Ex. 247
NH 2
(8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 248
CO 2 CH 3
methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl) amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate
Ex. 249
CO 2 H
(8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylic acid
Ex. 250
CO 2 CH 3
methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaene-8- carboxylate
Ex. 251
CO 2 H
(8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]- 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 252
CO 2 H
(8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid
Ex. 253
tert-butyl N-[(8S,18S,20S)-25-fluoro-8-[(isobutylamino) carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 254
NH 2
(8S,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 255
(8S,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3-pyridinyl- carbonyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25- pentaene-8-carboxamide
Ex. 256
tert-butyl N-[(8S,18S,20S)-8-[(4-chloroanilino)carbonyl]-25- fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen- 18-yl]carbamate
Ex. 257
NH 2
(8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 258
tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidino- carbonyl)-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 259
NH 2
(8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15- dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ] octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide
Ex. 260
tert-butyl N-[(8S,18S,20S)-8-[(benzylamino)carbonyl]-25-fluoro- 6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo [21.3.1.1 2,5 .0 16,20 ]octacosa-1(27),2,5(28),23,25-pentaen-18- yl]carbamate
Ex. 261
NH 2
(8S,18S,20S)-18-amino-N-benzyl-25-fluoro-6,15-dioxo-10,22- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5 .0 16,20 ]octacosa- 1(27),2,5(28),23,25-pentaene-8-carboxamide
TABLE 28a
Examples of Core 16 (Ex. 262-Ex. 283;)
Yield
Starting
General
(isolated
No
R A
R F
Material
Proced.
Reagent
Purification Method
salt)
Ex. 262-
cf. experimental description
Ex. 264:
Ex. 265
H
Ex. 263
1)
2-Naphthaleneacetyl chloride
FC (CH 2 Cl 2 /i-PrOH)
78%
Ex. 266
Ex. 264
A.1.2
Acetic anhydride (1.3 equiv.)
prep. HPLC method 1a
58% (TFA salt)
Ex. 267
H
Ex. 263
2)
1-Naphthaleneacetyl chloride
prep. HPLC method 3
58%
Ex. 268
H
Ex. 263
A.1.2
Isovaleryl chloride (1.6 equiv.) 0° C. to rt, 16 h
prep. HPLC method 3
69%
Ex. 269
H
Ex. 263
A.1.2
3-Fluorobenzoyl chloride (1.1 equiv.)
prep. HPLC method 3
52%
Ex. 270
H
Ex. 263
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
49%
Ex. 271
H
Ex. 263
A.5
Methanesulfonyl chloride
prep. HPLC method 3
39%
Ex. 272
H
Ex. 263
A.4
Methyl chloroformate
prep. HPLC method 3
69%
Ex. 273
H
Ex. 263
A.3
N-Succinimidyl N- methylcarbamate
prep. HPLC method 3
65%
Ex. 274
H
Ex. 263
A.3
2,5-Dioxopyrrolidin- 1-ylpyridin-3- ylcarbamate 0° C. to rt, 1 h
prep. HPLC method 3
64%
Ex. 275
CH 3
Ex. 265
1)
Trimethyloxonium tetrafluoroborate
prep. HPLC method 1a
12%
Ex. 276
H
Ex. 263
1)
2-Naphthylisocyanate
prep. HPLC method 3
71%
Ex. 277
H
Ex. 263
A.1.1
Phenylacetic acid
prep. HPLC method 3
58%
Ex. 278
H
Ex. 263
A.1.2
m-Anisoyl chloride (1.1 equiv.)
prep. HPLC method 3
75%
Ex. 279
H
Ex. 263
A.5
2-Naphthalenesulfonyl chloride
prep. HPLC method 3
76%
Ex. 280
H
Ex. 263
A.1.1
3-(4- Fluorophenyl) propionic acid
prep. HPLC method 3
42%
Ex. 281
H
Ex. 263
A.1.1
1H-indole-3-acetic acid
prep. HPLC method 3 and prep. HPLC method 2a
38%
Ex. 282
H
Ex. 263
A.6.4
2- Naphthylacetaldehyde (1.3 equiv.)
prep. HPLC method 2a
26%
Ex. 283
H
Ex. 263
A.6.4
4-Fluorobenzaldehyde
prep. HPLC method 3
52%
1) Cf. experimental description for detailed procedure
2) Ex. 267 was prepared applying the protocol described for the synthesis of Ex. 265.
TABLE 28b
Examples of Core 16 (Ex. 262-Ex. 283;)
Mono-
Rt
[M +
isotopic
(purity at
H] +
LC-MS-
No
R A
R F
Formula
Mass
220 nm)
found
Method
Ex. 262-Ex. 264:
cf. experimental description
Ex. 265
H
C31H33N5O5S
587.2
1.86 (93)
587.9
method 1a
Ex. 266
C28H33N5O5S
551.2
1.86 (96)
552.2
method 1d
Ex. 267
H
C31H33N5O5S
587.2
1.85 (87)
588.0
method 1a
Ex. 268
H
C24H33N5O5S
503.2
1.54 (98)
504.2
method 1a
Ex. 269
H
C26H28FN5O5S
541.2
1.66 (98)
542.1
method 1a
Ex. 270
H
C25H29N5O6S2
559.2
1.58 (97)
560.0
method 1a
Ex. 271
H
C2OH27N5O6S2
497.1
1.30 (98)
498.0
method 1a
Ex. 272
H
C21H27N5O6S
477.2
1.34 (99)
478.1
method 1a
Ex. 273
H
C21H28N6O5S
476.2
1.23 (97)
476.9
method 1a
Ex. 274
H
C25H29N7O5S
539.2
1.19 (99)
540.0
method 1a
Ex. 275
CH 3
C32H35N5O5S
601.2
2.05 (97)
602.2
method 1d
Ex. 276
H
C30H32N6O5S
588.2
1.86 (99)
589.0
method 1a
Ex. 277
H
C27H31N5O5S
537.2
1.62 (96)
538.2
method 1a
Ex. 278
H
C27H31N5O6S
553.2
1.65 (96)
554.1
method 1a
Ex. 279
H
C29H31N5O6S2
609.2
1.82 (96)
610.1
method 1a
Ex. 280
H
C28H32FN5O5S
569.2
1.72 (92)
570.2
method 1a
Ex. 281
H
C29H32N6O5S
576.2
1.61 (78)
577.1
method 1a
Ex. 282
H
C31H35N5O4S
573.2
1.63 (89)
574.2
method 1d
Ex. 283
H
C26H30FN5O4S
527.2
1.37 (97)
528.2
method 1a
TABLE 28c
Examples of Core 16 (Ex. 262-Ex. 283;)
No
R A
R F
IUPAC name
Ex. 262
benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethyl- 14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraen-15- yl]carbamate
Ex. 263
NH 2
H
(9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethyl-7-oxa-3-thia-
13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa-
1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 264
NH 2
(9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethyl-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 265
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide
Ex. 266
N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethyl-14,19-dioxo-7- oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]acetamide
Ex. 267
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1-naphthyl)acetamide
Ex. 268
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-3-methylbutanamide
Ex. 269
H
3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzamide
Ex. 270
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]benzenesulfonamide
Ex. 271
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]methanesulfonamide
Ex. 272
H
methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo- 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]carbamate
Ex. 273
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-N-methylurea
Ex. 274
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4 ,20(23)-tetraen-15-yl]-N-(3-pyridinyl)urea
Ex. 275
CH 3
N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide
Ex. 276
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-N-(2-naphthyl)urea
Ex. 277
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-phenylacetamide
Ex. 278
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-3-methoxybenzamide
Ex. 279
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-naphthalenesulfonamide
Ex. 280
H
3-(4-fluorophenyl)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl- 14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraen-15- yl]propanamide
Ex. 281
H
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3- thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ]tricosa- 1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1H-indol-3-yl)acetamide
Ex. 282
H
(9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl] amino}-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6 .0 9,13 ] tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione
Ex. 283
H
(9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21- dimethyl-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo [18.2.1.0 2,6 .0 9,13 ]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione
TABLE 29a
Examples of Core 17 (Ex.284a-Ex.304; continued on the following pages)
Starting
General
Purification
Yield
No
R A
R G
Material
Proced.
Reagent
Method
(iso1ated salt)
Ex. 284a-Ex. 286: cf. experimental description
Ex. 287
Ex. 286
1)
Acetyl chloride
FC (hexane, EtOAc, MeOH)
77%
Ex. 288
NH 2
Ex 287
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
78%
Ex. 289
NO 2
Ex. 285
A.3
1-Chloro-2- isocyanatobenzene
FC (hexane, EtOAc, MeOH)
90%
Ex. 290
NH 2
Ex. 289
B.4
H 2 , PtO 2
crude product
96%
Ex. 291
Ex. 290
A.5
Methanesulfonyl chloride (1.2 equiv.)
prep. HPLC method 1a
49% (TFA salt)
Ex. 292
NO 2
Ex. 285
A.1.1
Cyclopropanecarboxylic acid, 0° C., 2 h Workup: EtOAc, 1M aq. HCl soln, sat. aq. NaHCO 3 soln,
FC (hexane, EtOAc, MeOH)
70%
sat. aq. NaCl soln
Ex. 293
NH 2
Ex. 292
B.4
H2, PtO2
crude product
95%
Ex. 294
Ex. 293
A.5
Methanesulfonyl chloride (1.2 equiv.)
prep. HPLC method 1a
45%
Ex. 295
NH 2
Ex. 296
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
86%
Ex. 296
Ex. 286
A.5
Methanesulfonyl chloride (1.2 equiv.)
FC (hexane/ EtOAc) and prep. HPLC method 3
54%
Ex. 297
Ex. 286
2)
2-Chloropyrimidine
FC (EtOAc)
38%
Ex. 298
NH 2
Ex. 297
B.3
H 2 , Pd(OH) 2 —C, MeOH
crude product
100%
Ex. 299
Ex. 288
A.6.1
Formaldehyde (36.5% in H 2 O)
prep. HPLC method 1a
50% (TFA salt)
Ex. 300
Ex. 288
A.1.1
2-Phenylacetic acid (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6 equiv.)
prep. HPLC method 1a
17% (TFA salt)
Workup: EtOAc, 1M aq.
HCl soln, sat. aq.
Na 2 CO 3 soln
Ex. 301
Ex. 288
A.5
3-Chlorobenzene- sulfonyl chloride
prep. HPLC method 1a
60% (TFA salt)
Ex. 302
Ex. 288
A.3
2.5-dioxopyrrolidin-1-yl isobutylcarbamate
prep. HPLC method 1a
70% (TFA salt)
Ex. 303
Ex. 295
A.1.1
4-Fluorobenzoic acid (2.2 equiv.) HATU (2.5 equiv.) HOAt (2.5 equiv.) i-Pr 2 NEt (6 equiv.) Workup: EtOAc, 1M aq. HCl soln, sat. aq.
prep. HPLC method 1a
11% (TFA salt)
Na 2 CO 3 soln, H 2 O
Ex. 304
Ex. 295
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 1a
55% (TFA salt)
1) Acetyl chloride (0.109 mL, 1.5 mmol) was added at 0° C. to a soln of Ex. 286 (450 mg, 0.77 mmol) and i-Pr 2 NEt (0.394 mL, 2.3 mmol) in CH 2 Cl 2 (16 mL). The soln was stirred at 0° C. to rt for 2.5 h. MeOH (0.1 mL) was added and stirring continued for 10 min, followed by evaporation of the volatiles and FC (hexane/EtOAc/MeOH gradient) to afford Ex. 287 (371 mg, 77%).
2) A soln of Ex. 286 (115 mg, 0.196 mmol), 2-chloropyrimidine (27 mg, 0.235 mmol) and pTsOH·H 2 O (45 mg, 0.235 mmol) in dioxane (3 mL) was heated to reflux for 8 h. More 2-chloropyrimidine (13 mg, 0.118 mmol) and pTsOH·H 2 O (22 mg, 0.118 mmol) were added and refluxing was continued for 6 h. The volatiles were evaporated. Aqueous workup (CH 2 Cl 2 , sat. aq. NaHCO 3 soln; Na 2 SO 4 ) and FC (EtOAc) afforded Ex. 297 (50 mg, 38%).
TABLE 29b
Examples of Core 17 (Ex. 284a-Ex. 304; continued on the following page)
Monoiso-
Rt (purity at
[M + H] +
LC-MS-
No
R A
R G
Formula
topic Mass
220 nm)
found
Method
Ex. 284a-Ex. 286: cf. experimental description
Ex. 287
C34H40N6O6
628.3
1.89 (97)
629.3
method 1a
Ex. 288
NH 2
C26H34N6O4
494.3
1.20 (92)
495.3
method 1a
Ex. 289
NO 2
C31H34ClN7O6
635.2
2.26 (98)
636.2
method 1d
Ex. 290
NH 2
C31H36ClN7O4
605.3
1.66 (95)
606.2
method 1a
Ex. 291
C32H38ClN7O6S
683.2
1.98 (99)
684.3
method 1d
Ex. 292
NO 2
C28H34N6O6
550.3
1.87 (96)
551.2
method 1a
Ex. 293
NH 2
C28H36N6O4
520.3
1.32 (99)
521.3
method 1a
Ex. 294
C29H38N6O6S
598.3
1.60 (99)
599.3
method 1d
Ex. 295
NH 2
C25H34N6O5S
530.2
1.24 (90)
531.2
method 1a
Ex. 296
C33H40N6O7S
664.3
1.97 (91)
665.3
method 1a
Ex. 297
C36H40N8O5
664.3
1.96 (86)
665.4
method 1d
Ex. 298
NH 2
C28H34N8O3
530.3
1.31 (87)
531.3
method 1d
Ex. 299
C28H38N6O4
522.3
1.33 (100)
523.3
method 1d
Ex. 300
C34H40N6O5
612.3
1.82 (97)
613.3
method 1d
Ex. 301
C32H37ClN6O6S
668.2
2.03 (96)
669.3
method 1d
Ex. 302
C31H43N7O5
593.3
1.24 (94)
594.0
method 3b
Ex. 303
C32H37FN6O6S
652.2
1.95 (97)
653.3
method 1d
Ex. 304
C32H39FN6O5S
638.3
1.51 (97)
639.3
method 1d
TABLE 29c
Examples of Core 17 (Ex. 284a-Ex. 304; continued on the following pages)
No
R A
R G
IUPAC name
Ex. 284a
NO 2
benzyl N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex.284b
NO 2
benzyl N-[(13R,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 285
NH 2
NO 2
(13S,19S)-13-amino-4,8-dimethyl-23-nitro-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione
Ex. 286
NH 2
benzyl N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 287
benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]carbamate
Ex. 288
NH 2
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]acetamide
Ex. 289
NO 2
N-(2-chlorophenyl)-N′-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]urea
Ex. 290
NH 2
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-N′- (2-chlorophenyl)urea
Ex. 291
N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino}-4,8-dimethyl-7,14-dioxo-21- oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25- hexaen-23-yl]methanesulfonamide
Ex. 292
NO 2
N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 293
NH 2
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 294
N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13- yl]cyclopropanecarboxamide
Ex. 295
NH 2
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]methanesulfonamide
Ex. 296
benzyl N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 13-yl]carbamate
Ex. 297
benzyl N-[(13S,19S)-4,8-dimethyl-7,14-dioxo-23-(2-pyrimidinylamino)-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 13-yl]carbamate
Ex. 298
NH 2
(13S,19S)-13-amino-4,8-dimethyl-23-(2-pyrimidinylamino)-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14- dione
Ex. 299
N-[(13S,19S)-13-(dimethylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]acetamide
Ex. 300
N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-2- phenylacetamide
Ex. 301
N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino}-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 23-yl]acetamide
Ex. 302
N-[(13S,19S)-13-{[(isobutylamino)carbonyl]amino}-4,8-dimethyl-7,14-dioxo-21-oxa- 3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6 0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen- 23-yl]acetamide
Ex. 303
N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-4- fluorobenzamide
Ex. 304
N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4-8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27- tetraazatetracyclo[20.2.2.1 2,6 .0 15,19 ]heptacosa-1(24),2(27),3,5,22,25-hexaen-23- yl]methanesulfonamide
TABLE 30a
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
Starting
General
Purification
Yield
No
R B
Material
Proced.
Reagent
Method
(isolated salt)
Ex. 305-Ex. 306: cf. experimental description
Ex. 307
N(CH 3 ) 2
Ex. 306
A.6.1
Formaldehyde (36.5% in H 2 O)
prep. HPLC method 2a
72%
Ex. 308
Ex. 306
A.1.2
Acetyl chloride (2.0 equiv.)
prep. HPLC method 3
71%
Ex. 309
Ex. 306
A.1.1
3-Methylbutanoic acid
prep. HPLC method 3
65%
Ex. 310
Ex. 306
A.1.1
2-Naphthaleneacetic acid
prep. HPLC method 3
56%
Ex. 311
Ex. 306
A.1.1
1-Naphthaleneacetic acid
prep. HPLC method 3
70%
Ex. 312
Ex. 306
A.1.3
2-(Dimethylamino) acetic
prep. HPLC method 2a
56%
Ex. 313
Ex. 306
A.1.1
N-Boc-β-alanine
FC (hexane/ EtOAc/MeOH)
80%
Ex. 314
Ex. 313
B.1
HCl-dioxane
prep. HPLC method 2a
43%
Ex. 315
Ex. 306
A.1.1
3-Fluorobenzoic acid
prep. HPLC method 3
43%
Ex. 316
Ex. 306
A.1.2
Isonicotinoyl chloride hydrochloride (2.5 equiv.) Pyridine (6.5 equiv.)
prep. HPLC method 2a
58%
Ex. 317
Ex. 306
A.3
N-Succinimidyl N- methylcarbamate
prep. HPLC method 3
67%
Ex. 318
Ex. 306
A.4
2,5-Dioxopyrrolidin-1-yl pyridin-3-ylcarbamate
prep. HPLC method 3
62%
Ex. 319
Ex. 306
A.4
2-Methoxyethyl chloro- formate
prep. HPLC method 3
70%
Ex. 320
Ex. 306
A.3
tert-Butyl 3-((2,5- dioxopyrrolidin-1- yloxy)carbonylamino) propanoate
FC (hexane/ EtOAc/MeOH)
82%
Ex. 321
Ex. 320
1)
HCl-dioxane
crude product
83%
Ex. 322
Ex. 306
A.5
Methanesulfonyl chloride
prep. HPLC method 3
75%
Ex. 323
Ex. 306
A.5
Benzenesulfonyl chloride
prep. HPLC method 3
61%
Ex. 324
Ex. 306
A.6.4
3-Fluorobenzaldehyde
prep. HPLC method 3
69%
Ex. 325
Ex. 306
A.6.4
Isobutyraldehyde
FC (hexane/EtOAc/ MeOH)
60%
Ex. 326
Ex. 306
A.1.1
Side product from HATU coupling
prep. HPLC method 1a
—
1) A soln of Ex. 320 (82 mg, 0.15 mmol) in dioxane (0.8 mL) was treated with 4M HCl-dioxane (0.8 mL) for 2 h at rt. Evaporation of the solvents and washing of the solid crude product with CH 2 Cl 2 /Et 2 O yielded Ex. 321 (61 mg, 83%).
TABLE 30b
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
Monoisotopic
Rt (purity at
[M + H] +
LC-MS-
No
R B
Formula
Mass
220 nm)
found
Method
Ex. 305-Ex. 306: cf. experimental description
Ex. 307
N(CH 3 ) 2
C23H27N3O3
393.2
1.57 (98)
394.2
method 2c
Ex. 308
C23H25N3O4
407.2
1.38 (97)
408.1
method 1a
Ex. 309
C26H31N3O4
449.2
1.68 (98)
450.2
method 1a
Ex. 310
C33H31N3O4
533.2
1.99 (93)
534.2
method 1a
Ex. 311
C33H31N3O4
533.2
1.97 (95)
534.2
method 1a
Ex.312
C25H30N4O4
450.2
1.48 (98)
451.2
method 2c
Ex. 313
C29H36N4O6
536.3
1.74 (91)
537.2
method 1a
Ex. 314
C24H28N4O4
436.2
1.23 (99)
437.2
method 1a
Ex. 315
C28H26FN3O4
487.2
1.83 (96)
488.2
method 1a
Ex. 316
C27H26N4O4
470.2
1.51 (99)
471.2
method 2c
Ex. 317
C23H26N4O4
422.2
1.37 (96)
423.2
method 1a
Ex. 318
C27H27N5O4
485.2
1.33 (98)
486.2
method 1a
Ex. 319
C25H29N3O6
467.2
1.58 (96)
468.2
method 1a
Ex. 320
C29H36N4O6
536.3
1.79 (98)
537.2
method 1a
Ex. 321
C25H28N4O6
480.2
0.99 (87)
481.2
method 2c
Ex. 322
C22H25N3O5S
443.2
1.46 (97)
444.1
method 1a
Ex. 323
C27H27N3O5S
505.2
1.82 (97)
506.1
method 1a
Ex. 324
C28H28FN3O3
473.2
1.46 (98)
474.2
method 1a
Ex. 325
C25H31N3O3
421.2
1.35 (98)
422.1
method 1a
Ex. 326
C26H33N5O3
463.3
1.35 (95)
464.2
method 1a
TABLE 30c
Examples of Core 18 (Ex. 305-Ex. 326; continued on the following pages)
No
R B
IUPAC name
Ex. 305
benzyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate
Ex. 306
NH 2
(15R,16aS)-15-amino-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-
c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 307
N(CH 3 ) 2
(15R,16aS)-15-(dimethylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H-
dibenzo[i, k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 308
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]acetamide
Ex. 309
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-methylbutanamide
Ex. 310
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(2-naphthyl)acetamide
Ex. 311
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(1-naphthyl)acetamide
Ex. 312
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(dimethylamino)acetamide
Ex. 313
tert-butyl N-(3-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino-3-oxopropyl)carbamate
Ex. 314
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-aminopropanamide
Ex. 315
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-fluorobenzamide
Ex. 316
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]isonicotinamide
Ex. 317
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N′-methylurea
Ex. 318
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N-(3-pyridinyl)urea
Ex. 319
2-methoxyethyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate
Ex. 320
tert-butyl 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoate
Ex. 321
3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoic acid
Ex. 322
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]methanesulfonamide
Ex. 323
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]benzenesulfonamide
Ex. 324
(15R,16aS)-15-[(3-fluorobenzyl)amino]-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione
Ex. 325
(15R,16aS)-15-(isobutylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][81,4,7]oxadiazacyclododecine-9,12-dione
Ex. 326
N″-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H- dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N,N,N′,N′-tetramethylguanidine
TABLE 31a
Examples of Core 19 (Ex. 327-Ex. 329)
Yield
Starting
General
Purification
(isolated
No
R B
R D
material
Proced.
Reagent
Method
salt)
Ex. 327-
cf. experimental description
Ex. 329:
TABLE 31b
Examples of Core 19 (Ex. 327-Ex. 329)
Mono-
Rt
isotopic
(purity at
[M + H] +
LC-MS-
No
R B
R D
Formula
Mass
220 nm)
found
Method
Ex. 327-
cf. experimental description
Ex. 329:
TABLE 31c
Examples of Core 19 (Ex. 327-Ex. 329)
No
R B
R D
IUPAC name
Ex. 327
benzyl (16S,18S)-16-[(tert-butoxycarbonyl)amino]-7,13-dioxo-4-(trifluoromethyl)- 5,20-dioxa-3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21, 23-pentaene-11-carboxylate
Ex. 328
H
tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23-pentaen-16-yl] carbamate
Ex. 329
NH 2
benzyl (16S,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14- tetraazatetracyclo[19.3.1.0 2,6 .0 14,18 ]pentacosa-1(25),2(6),3,21,23-pentaene-11- carboxylate
Cpd No
n
R XI
R XII
R XIII
R XIV
Fmoc-AA1-OH
Fmoc-AA2-OH
85a-Ex. 193a
0
CH 2 Ph
H
CH 3
CH 3
Fmoc-β 3 -homoPhe-OH
Fmoc-NMeDAla-OH
85b-Ex. 193b
0
CH 3
CH 3
(CH 2 ) 2 CO 2 tBu
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMeDGlu(OtBu)-OH
85c-Ex. 193c
0
H
H
CH 2 Ph
CH 3
Fmoc-β-Ala-OH
Fmoc-NMePhe-OH
85d-Ex. 193d
0
H
H
CH 2 Ph
H
Fmoc-β-Ala-OH
Fmoc-Phe-OH
85e-Ex. 193e
0
CH 3
CH 3
CH 2 Ph
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMePhe-OH
85f-Ex. 193f
0
CH 3
CH 3
H
CH 3
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
85g-Ex. 193g
0
CH 3
CH 3
CH 2 Ph
H
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Phe-OH
85h-Ex. 193h
1
CH 2 Ph
H
H
CH 3
Fmoc-β 3 -homoPhe-OH
Fmoc-NMe-β-Ala-OH
Cpd No
l
m
n
R XI
R XII
R XIII
R XIV
R XV
R XVI
135a-Ex. 195a
1
0
0
CH 3
CH 3
H
CH 3
CH 3
CH 3
135b-Ex. 195b
1
0
0
CH 3
CH 3
H
H
CH 3
H
135c-Ex. 195c
1
0
0
CH 3
CH 3
CH 3
H
(CH 2 ) 2 CO 2 tBu
CH 3
135d-Ex. 195d
1
0
0
CH 3
CH 3
(CH 2 ) 4 NHBoc
H
CH 3
H
135e-Ex. 195e
0
1
0
H
CH 3
CH 3
CH 3
CH 3
CH 3
135f-Ex. 195f
0
0
1
H
CH 3
CH 3
CH 3
CH 3
CH 3
135g-Ex. 195g
0
0
0
H
H
CH 2 Ph
H
CH 3
CH 3
135h-Ex. 195h
0
0
0
H
CH 3
CH 2 Ph
H
CH 3
H
135i-Ex. 195i
0
0
0
CH 3
H
CH 2 Ph
H
(CH 2 ) 2 CO 2 tBu
CH 3
135j-Ex. 195j
0
0
0
H
CH 3
CH 2 Ph
H
CH 3
CH 3
135k-Ex. 195k
0
0
0
CH 3
H
CH 2 Ph
H
(CH 2 ) 2 CO 2 tBu
CH 3
Cpd No
Fmoc-AA1-OH
Fmoc-AA2-OH
Fmoc-AA3-OH
135a-Ex. 195a
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Sar-OH
Fmoc-NMeAla-OH
135b-Ex. 195b
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Gly-OH
Fmoc-Ala-OH
135c-Ex. 195c
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Ala-OH
Fmoc-NMeGlu(OtBu)-OH
135d-Ex. 195d
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-Lys(Boc)-OH
Fmoc-DAla-OH
135e-Ex. 195e
Fmoc-Sar-OH
Fmoc-NMe-β 3 -homoDAla-OH
Fmoc-NMeAla-OH
135f-Ex. 195f
Fmoc-Sar-OH
Fmoc-NMeAla-OH
Fmoc-NMe-β 3 -homoDAla-OH
135g-Ex. 195g
Fmoc-Gly-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
135h-Ex. 195h
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-DAla-OH
135i-Ex. 195i
Fmoc-Ala-OH
Fmoc-DPhe-OH
Fmoc-NMeGlu(OtBu)-OH
135j-Ex. 195j
Fmoc-Sar-OH
Fmoc-Phe-OH
Fmoc-NMeDAla-OH
135k-Ex. 195k
Fmoc-DAla-OH
Fmoc-Phe-OH
Fmoc-NMeGlu(OtBu)-OH
Biological and Pharmacological Methods
1. Ca 2+ Flux Assays for the GPCRs Oxytocin Receptor (OT Receptor), Thyrotropin-Releasing Hormone Receptor (TRH Receptor) and Bombesin Receptor Subtype 3 (BB3 Receptor)
Assays were performed on a FLIPR TETRA fluorometric imaging plate reader (Molecular Devices) with ScreenWorks Version 2 (Molecular Devices) as device operating and data analysis software.
Dose dependent agonist and antagonist activities were determined. Percentage activation and percentage inhibition values were determined.
Percentage activation was determined upon initial addition of the sample compounds followed by 10 minutes' incubation at 25° C. Following compound incubation, reference agonists were added at EC 80 to determine percentage inhibition.
Reference agonists were purchased from reputable commercial vendors and prepared according to each ligand's specifications. All handling of ligands were done to ensure proper control throughout the experiments.
Example compounds were weighed on a Microbalance (Mettler MX5) and dissolved in 100% DMSO to a final concentration of 2.5 mM and subsequently diluted into the assay buffer.
The assay buffer was a supplemented HBSS (Hank's Balanced Salt Solution). HBSS was supplemented with 20 mM HEPES (4-(2-hydroxyethyl)-piperazin-1-ethansulfonic acid) and 2.5 mM Probenecid (Sigma P8761).
Assay Plate Seeding:
GPCR assays were performed using Ca 2+ optimized hematopoietic cell lines (rat) with cultures never exceeding 90% confluency. Cells were harvested and seeded (from cultures at less than 90% confluency) at 50000 cells/well for a 96-well plate (12500 cells/well for 384). After seeding, the assay plates were incubated for 45 minutes at room temperature. After room temperature incubation, the assay plates were incubated at 37° C. 5% CO 2 for 24 hours prior to assaying.
Calcium Dye Loading:
All GPCR assays were performed using Fluo-8 Ca 2+ dye.
Ca 2+ dye was prepared at 1× dye concentration in GPCR assay buffer. After 24 hours of incubation, cells were washed with GPCR assay buffer, and then Ca 2+ -dye (100 μL/well) was added.
The plates were incubated for 90 minutes at 30° C. 5% CO 2 prior to FLIPR assay.
Agonist Assay:
Compound plates were prepared to add 50 μL/well during the agonist assay mode. During the FLIPR assay, 50 μL/well from the compound plate was diluted 3-fold into the existing 100 μL/well from the dye loading step. Therefore all compounds were prepared as 3× the final concentration desired in the assay.
Antagonist Assay:
After completion of the first single addition assay run, assay plate was removed from the FLIPR Tetra and placed at 25° C. for 7 minutes before antagonist assay.
Using the EC 80 values determined during the agonist assay, all pre-incubated sample compound and reference antagonist (if applicable) wells were stimulated at the EC 80 of the reference agonist. As reference ligands for these assays their obvious natural ligands oxytocin (OT), thyrotropin-releasing hormone (TRH) and bombesin (6-14) [BN(6-14)] were used.
After the addition of the reference agonist fluorescence was monitored for 180 sec using FLIPR Tetra.
Data Analysis and Results:
From the FLIPR data, with negative control correction enabled, the maximum statistic for each well was exported and percentage activation relative to E max control was calculated.
The results of the GPCR assays are summarized in Table 32.3 to Table 32.5.
2. Enzyme Assays for the Peptidase Endothelin Converting Enzyme-1 (ECE-1) and for the Cysteine Protease Cathepsin S (CatS)
The assays were performed according to provider's (Ricerca Biosciences, LLC) protocols which in turn are based on literature procedures (for ECE-1 cf.: O. Valdenaire et al., Eur. J. Biochem. 1999, 264, 341-349; F. D. Russell, A. P. Davenport, Circ. Res. 1999, 84, 891-896; and for CatS: G P Shi et al., J. Biol. Chem. 1992, 267, 7258-62; D Brömme et al., J. Biol. Chem. 1993 268, 4832-4838.).
Procedures:
i) ECE-1 Assay:
Human recombinant ECE-1 expressed in murine myeloma cells NS0 is used. Test compound and/or vehicle is preincubated with 20 ng/ml enzyme in modified MES buffer pH 6.0 for 15 minutes at 25° C. The reaction is initiated by addition of 10 mM Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp) for another 60 minutes' incubation period. Determination of the amount of Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala formed is read spectrophotometrically at 320 nm/405 nm. Compounds are screened at 10 mM.
Reference Compound: Phosphoramidon (IC 50 0.0049 μM)
ii) CatS Assay:
Human recombinant cathepsin S expressed in a murine myeloma NS0 cells is used. Test compound and/or vehicle is preincubated with 0.1 μg/ml enzyme in modified acetate buffer pH 4.5 for 15 minutes at 25° C. The reaction is initiated by addition of 10 mM Z-Leu-Arg-AMC for another 30 minutes' incubation period. Determination of the amount of AMC formed is read spectrofluorimetrically at 360 nm/465 nm. Compounds are screened at 10 mM.
Reference Compound: E-64 (IC 50 0.0014 μM)
Data Analysis:
IC 50 values were determined by a non-linear, least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK). Inhibition constants K were calculated according to the equation of Cheng and Prusoff (Y. Cheng, W. H. Prusoff, Biochem. Pharmacol. 1973, 22, 3099-3108) using the observed IC 50 of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the K D of the ligand. The Hill coefficient (nH), defining the slope of the competitive binding curve, was calculated using MathIQ™.
The results of the assays are summarized in Table 32.1 and Table 32.2.
3. Human LTB4 Receptor Cell-Based Assay
CHO mito-i-Photina® cells (Axxam SpA) stably expressing the human leukotriene B4 receptor (LTB4R) were used for monitoring activation of the target LTB4R, a GPCR (Gαq), by measuring the flash luminescence of Ca 2+ sensitive photoprotein as reporter system with FLIPR TETRA screening instrumentation (Molecular Devices) upgraded with an ICCD Camera (MDC). For data quality check and data analysis a Genedata Screener 10.0.3 was used, and for curve fitting of reference agonist and antagonist GraphPad Prism Software.
The reference agonist LTB4 and antagonist U-75302 were purchased from reputable commercial vendors and prepared according to each ligand's specifications. All handling of ligands were done to ensure proper control throughout the experiments.
The steps of the implemented workflow and data analysis are mainly as follows:
Assay Plate Seeding:
mito-1-Photina cells are seeded (10000 c/w in 384 MTP; in complete medium 25 μL/well) for 24 hours, removed from the incubator, equilibrated at room temperature for 1 h, freed from the growth medium, loaded with 30 μL/well of Tyrode's buffer containing 10 μM coelenterazine, and incubated for 3 hours at rt.
Agonist/Antagonist Assay:
All compounds were tested at 10 μM with triplicate data points.
After incubation, the volume in all the wells is flattened to 20 μL by aspiration with CyBi®-Vario pipettor. The First Injection (10 μL of test compounds or reference antagonist U-75302 in Tyrode's buffer+DMSO 0.5%) is performed by the FLIPR TETRA and the kinetic response is monitored over a period of 120 seconds. Incubation at rt for 10 min. is followed by the Second Injection (15 μL of LTB4 at EC 80 in Tyrode's buffer) and monitoring of the kinetic response over a period of 120 seconds.
Data Analysis and Results:
The possible kinetic response is divided into two distinct phases: Monitoring the kinetic response after the First Injection is indicated as Compound Addition (CA) and measures the agonistic activity of compounds; monitoring the kinetic response after the Second Injection is indicated as Target Activation (TA) and measures the antagonistic activity of a compound.
The activity determination (IC 50 determination) experiment is performed using LTB4 as agonist (100 nM corresponding to EC 80 ). Selected compound are tested in 8 doses intraplate dose response with quadruplicate data points.
The results of the LTB4R assays are summarized in Table 32.6.
4. Antimicrobial Assays
The antimicrobial activities of the compounds were determined in 96-well plates (Greiner, polystyrene) by the standard NCCLS broth microdilution method (National Committee for Clinical Laboratory Standards 1993. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 3rd ed. Approved standard M7-A6. National Committee for Clinical laboratory standards, Wayne, Pa.) with slight modifications. Inocula of the microorganisms were diluted into Mueller-Hinton II (MH, cation adjusted) broth+0.002% P-80 and compared with a 0.5 McFarland standard to give appr. 10 6 colony forming units (CFU)/mL. Aliquots (50 μl) of inoculate were added to 50 μl of MH broth+0.002% P-80 containing the compounds in serial two-fold dilutions. The following microorganisms were used to determine antibiotic selectivity of the compounds: S. pneumoniae DSM 20566 11A11, 3313A6, 704CG4B21, 82BERG72; S. aureus ATCC 29213, ATCC 25923, DSM 11729, DSM 46320, S. aureus 39. Antimicrobial activities of the compounds were expressed as the minimal inhibitory concentration (MIC) in μg/mL at which no visible growth was observed after 18-20 hours of incubation at 36° C.
The results of the antimicrobial assays are summarized in Table 32.7 and Table 32.8.
5. Plasma and Metabolic Stability Assays
Example compounds were dissolved in DMSO/H 2 O 90:10 to a final concentration of 10 mM for plasma stability determination and metabolic stability determination.
The assays were conducted according to literature precedents (F. P. Guengerich, Analysis and Characterization of Enzymes ; in: Principles and Methods of Toxicology , A. W. Hayes (Ed.) Raven Press: New York, 1989, 777-813; R. Singh et al., In vitro metabolism of a potent HIV - protease inhibitor (141 W 94) using rat, monkey and human liver S 9 , Rapid Commun. Mass Spectrom. 1996, 10, 1019-1026).
Results of the stability assays are listed in Table 33 below.
Plasma Stability Assay
Human plasma (Blutspendedienst SRK, Basel) and CD-1 mouse plasma (mixed gender pool >50 animals, Innovative Research, Calif., USA) are both sodium citrate stabilized. The assay is performed in triplicates at 10 μM compound concentration and 37° C. Samples are taken at 0, 15, 30, 60, 120 and 240 minutes and stopped by precipitation with 3 volumes of acetonitrile/formic acid 98:2 and shaking (2 minutes, 600 rpm) followed by filtration (−20 mm Hg). The filtrate is collected. The filtrate (100 μL) is evaporated and reconstituted in the suitable solvent (cf. Table 33) to be analyzed by HPLC/MS/MS. The resulting peak area counts are expressed in percent of the 0 value and used to determine the endpoint stability in % and the half life T in minutes. In order to monitor assay integrity the degradation of propantheline is assayed with every experimental set.
Metabolic Stability Assay
Microsomes from a human 50 donor mixed gender pool and 1:1 mixtures of microsomes from CD-1 mouse single-gender pools are purchased from Celsis (Belgium). The enzymatic reaction is performed in a buffer containing an NADPH regeneration system and microsomes with the following end concentrations: 100 mM potassium phosphate buffer (all from Sigma), 1 mg/mL glucose-6-phosphate, 1 mg/mL β-nicotinamide adenine dinucleotide phosphate (NADP), 0.65 mg/mL magnesium chloride, 0.8 units/mL of glucose-6-phosphate dehydrogenase (prediluted with 5 mM citrate buffer), 10 μM compound and 1 mg/ml microsomal protein. Compounds are incubated at 37° C. in duplicates and samples are taken after 0, 5, 10, 20 and 60 minutes. After acetonitrile precipitation (3 volumes), shaking (2 minutes, 600 rpm) followed by centrifugation (10 minutes, 3200 g), the supernatant is dried reconstituted in the suitable solvent (cf. Table 33) and analyzed by HPLC/MS/MS. Metabolic turnover is expressed in % of the initial 0 minutes value and half life T½ (min) is calculated. Verapamil for human and propranolol for mouse are used as reference and are assayed with every experimental set.
TABLE 32.1
Endothelin Converting Enzyme-1 Assay
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 18
98
3.01
Ex. 25
97
4.28
Ex. 26
98
4.07
TABLE 32.2
Cathepsin S Assay
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 18
82
3.65
Ex. 20
45
14.7
Ex. 21
75
n.d.
Ex. 24
55
n.d.
Ex. 25
87
3.18
Ex. 26
81
3.83
Ex. 27
50
n.d.
Ex. 28
57
n.d.
TABLE 32.3
TRH (Thyrotropin-releasing hormone) receptor Assay
Antagonist activity
Antagonist activity
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 7
91
1.4
Ex. 332
29
n.d.
Ex. 333
35
n.d.
Ex. 334
40
n.d.
Ex. 335
34
n.d.
Ex. 336
48
8.2
TABLE 32.4
OT (Oxytocin) receptor Assay
Antagonist activity
Antagonist activity
No
[% Inhibition at 10 μM]
IC50 [μM]
Ex. 94
58
3.0
Ex. 96
60
1.2
Ex. 100
57
4.6
Ex. 101
69
2.6
Ex. 103
77
6.9
TABLE 32.5
BB3 (Bombesin) receptor Assay
Agonist activity
Agonist activity
No
[% activation at 12.5 μM]
EC50 [nM]
Ex. 265
84
630
Ex. 267
61
>50′000
Ex. 275
60
780
Ex. 276
75
480 *)
Ex. 282
39
>50′000
*) Ca 75% of Bombesin efficacy
TABLE 32.6
LTB4 (Leukotriene B4) receptor Assay
Antagonist activity
Antagonist activity
No
[% inhibition at 10 μM]
IC50 [μM]
Ex. 14
46
39.4
Ex. 50
100
1.97
Ex. 116
49
15.4
Ex. 119
47
14.2
Ex. 144
41
40.9
TABLE 32.7
Antimicrobial activity
S . aureus
S . aureus
S . aureus
S . aureus
S . aureus
S . pneumoniae
ATCC 29213
39
ATCC 25923
DSM 11729
DSM 46320
DSM 20566
No
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
Ex. 2
8-16
4
16
8-16
16->16
8
Ex. 91
2-4
8
4
2
4
>16
Ex. 94
4
8
8
4
8
>16
S . aureus : Staphylococcus aureus ;
S . pneumoniae : Streptococcus pneumoniae
TABLE 32.8
Antimicrobial activity
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
DSM 20566
11A11
3313A6
704CG4B21
82BERG72
No
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
MIC [μg/mL]
Ex. 247
16
16
16
16
8
Ex. 257
8
8
8
8
2
Ex. 259
8
16
8
8
4
S. pneumoniae : Streptococcus pneumonia
TABLE 33
Plasma Stability and Metabolic Stability Assays of Selected Examples (continued on the following pages)
Plasma Stability
Metabolic Stability
T ½
240 min
T ½
60 min
Solvent
240 min
[min]
mouse/
60 min
[min]
mouse/
for
T ½ [min]
hum
mouse/
(rat)
T ½ [min]
hum
mouse/
(rat)
No
reconstitution
hum
[% remain.]
(rat)
[% remain.]
hum
[% remain.]
(rat)
[% remain.]
Ex. 42
B
>240
91
>240
100
>60
100
>60
100
Ex. 43
B
>240
97
>240
63
>60
100
>60
83
Ex. 44
B
>240
100
>240
83
>60
68
>60
77
Ex. 45
C
>240
76
190
46
>60
66
>60
73
Ex. 46
B
>240
100
>240
78
32
26
>60
71
Ex. 47
B
>240
99
>240
86
>60
83
>60
100
Ex. 49
B
>240
95
>240
76
>60
100
>60
92
Ex. 50
B
>240
100
n.d.
n.d.
>60
53
40
34
Ex. 51
B
>240
100
>240
80
>60
71
>60
69
Ex. 52
B
>240
99
>240
95
>60
100
>60
78
Ex. 53
1)
n.d.
n.d.
>240
86
>60
100
>60
92
Ex. 54
B
>240
100
>240
100
>60
60
>60
82
Ex. 55
B
n.d.
n.d.
>240
80
>60
97
>60
98
Ex. 57
B
>240
100
>240
74
>60
100
>60
100
Ex. 58
D
>240
95
n.d.
n.d.
>60
87
>60
70
Ex. 59
B
>240
74
>240
67
>60
94
>60
81
Ex. 60
C
>240
97
n.d.
n.d.
8
0
25
19
Ex. 69
1)
>240
91
200
45
>60
100
>60
100
Ex. 70
1)
>240
99
>240
61
>60
100
>60
77
Ex. 71
B
>240
100
>240
92
>60
100
>60
89
Ex. 72
B
>240
100
>240
65
22
14
35
30
Ex. 73
B
>240
89
n.d.
n.d.
2
0
1
0
Ex. 74
C
>240
100
>240
67
7
1
3
0
Ex. 75
B
>240
93
>240
55
21
12
53
48
Ex. 76
D
>240
88
n.d.
n.d.
16
4
15
9
Ex. 77
B
>240
96
>240
85
44
41
>60
75
Ex. 78
B
>240
100
>240
86
>60
99
>60
92
Ex. 79
B
>240
100
>240
60
>60
95
>60
73
Ex. 80
1)
>240
90
>240
84
19
6
24
19
Ex. 81
2)
>240
88
>240
100
>60
100
>60
97
Ex. 83
3)
>240
85
>240
93
>60
85
>60
96
Ex. 84
B
>240
99
>240
56
>60
97
>60
71
Ex. 85
D
>240
100
>240
88
>60
100
>60
80
Ex. 86
B
n.d.
n.d.
>240
60
n.d.
n.d.
>60
71
Ex. 87
B
>240
100
>240
90
27
17
60
63
Ex. 88
1)
n.d.
n.d.
>240
81
56
49
>60
62
Ex. 89
C
>240
100
>240
76
13
8
10
2
1) Reconstitution solvent for plasma stabilty determination B; reconstitution solvent for metabolic stability determination: C
2) Reconstitution solvent for plasma stabilty determination; human: D; mouse B; reconstitution solvent for metabolic stability determination: D
3) Reconstitution solvent for plasma stability determination: B; reconstitution solvent for metabolic stability determination; human D; mouse B.
Reconstitution solvents:
Solvent A: DPBS (100 mg CaCl 2 , 100 mg MgCl 2 •6H 2 O, 200 mg KCl, 200 mg KH 2 PO 4 , 8000 mg NaCl and 2160 mg Na 2 HPO 4 •7H 2 O to be made up to 1000 mL by addition of H 2 O);
Solvent B: H 2 O/CH 3 CN 95:5 (v/v) + 0.2% formic acid;
Solvent C: DMSO/(H 2 O/CH 3 CN 95:5)/DPBS 50:45:5 + 2% formic acid;
Solvent D: H 2 O/CH 3 CN 1:1 (v/v) + 5% DPBS + 0.2% formic acid
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