US2011281837A1PendingUtilityA1
3-substituted-6-aryl pyridines

Assignee: HUTCHINSON ALAN JPriority: Nov 8, 2002Filed: Jan 3, 2011Published: Nov 17, 2011
Est. expiryNov 8, 2022(expired)· nominal 20-yr term from priority
Inventors:Alan Hutchinson Jun Yuan Kyungae Lee George D. Maynard Bertrand L. Chenard Nian Liu Qin Guo Zihong Guo Peter Hrnciar
A61P 9/00A61P 29/00A61P 19/02C07D 405/12C07D 401/06C07D 405/14C07D 413/06C07D 213/74A61P 17/06C07D 413/04C07D 401/04C07D 417/14C07D 213/64C07D 213/65C07D 213/42C07D 213/84C07D 213/30C07D 213/68C07D 471/04A61P 11/06C07D 213/71C07D 213/38C07D 213/89C07D 401/12C07D 413/14C07D 213/81C07D 413/12C07B 2200/05C40B 40/00
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Claims
Abstract

3-substituted-6-aryl pyridines of Formula I are provided: wherein R 1 , R 2 , R 3 , R 8 , R 9 , A and Ar are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula I bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. The present invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. In addition, the present invention provides labeled 3-substituted-6-aryl pyridines, which are useful as probes for the localization of C5a receptors.
Claims

exact text as granted — not AI-modified
1 - 88 . (canceled) 
     
     
         89 . A method for inhibiting signal-transducing activity of a cellular C5a receptor, comprising contacting a cell expressing C5a receptor with at least one compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable form thereof, wherein: 
         Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, indanyl, indenyl, benzisoxazolyl, indazolyl or indolyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
         A is OR 4 , NR 4 R 5 , CR 6 R 7  or CHR 6 R 7 ;
 R 1  is chosen from:
 (i) hydrogen, halogen, amino, and cyano; and 
 (ii) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and —S(O n )C 1 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
 
 R 2  is halogen, cyano or XR y ; 
 R 3  is hydrogen, halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono- or di-(C 1 -C 4 alkyl)amino or —S(O n )C 1 -C 4 alkyl; 
 with the proviso that at least one of R 1 , R 2  and R 3  is not hydrogen; 
 
         R 4  is:
 (i) C 1 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkylamino)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, phenylC 0 -C 4 alkyl, pyridylC 0 -C 4 alkyl, pyrimidinylC 0 -C 4 alkyl, thienylC 0 -C 4 alkyl, imidazolylC 0 -C 4 alkyl, pyrrolylC 0 -C 4 alkyl, pyrazolylC 0 -C 4 alkyl, benzoisothiazolyl or tetrahydronaphthyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , C 2 -C 4 alkanoyl, mono- and di-(C 1 -C 4 alkyl)amino(C 1 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and XR y ; or 
 (ii) joined to R 5  to form, with the nitrogen to which R 4  and R 5  are bound, a heterocycle substituted with from 0 to 4 substituents independently chosen from R x , oxo and YZ; 
 
         R 5  is:
 (i) hydrogen; 
 (ii) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 -carbocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy; or 
 (iii) joined to R 4  to form an optionally substituted heterocycle; 
 with the proviso that R 5  is not hydrogen if R 4  is C 1 -C 6 alkyl; 
 
         R 6  is:
 (i) halogen, hydroxy, cyano, amino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- or di-(C 1 -C 6 alkylamino)C 0 -C 6 alkyl, (C 3 -C 10 carbocycle)C 0 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl, C 2 -C 4 alkanoyloxy and YZ; or 
 (ii) joined to R 7  to form, with the carbon atom to which R 6  and R 7  are bound, a 3- to 10-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-(C 1 -C 4 alkylamino)C 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl and C 2 -C 4 alkanoyloxy; 
 
         R 7  is hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl or joined to R 6  to form an optionally substituted carbocycle or heterocycle; 
         R 8  is:
 (i) hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 9  to form a C 5 -C 7  cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, C 1 -C 2 alkyl and C 1 -C 2 alkoxy; 
 
         R 9  is:
 (i) absent, hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 8  to form an optionally substituted C 5 -C 7  cycloalkyl ring or 5- to 7-membered heterocycloalkyl ring; 
 
         R 17  is absent or oxygen; with the proviso that R 17  is absent if R 6  is C 1 -C 6 alkenyl; 
         X is a single bond, —CR A R B —, —O—, —C(═O)—, —C(═O)O—, —S(O) n — or —NR B —; and 
         R y  is:
 (i) hydrogen; or 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 carbocycleC 0 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R x , oxo, —NH(C 1 -C 6 alkanoyl), —N(C 1 -C 6 alkyl)C 1 -C 6 alkanoyl, —NHS(O n )C 1 -C 6 alkyl, —N(S(O n )C 1 -C 6 alkyl) 2 , —S(O n )N(C 1 -C 6 alkyl and —S(O n )N(C 1 -C 6 alkyl) 2 ; 
 
         Y is a single bond, —CR A R B —, —NR B — or —O—; 
         Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —COOH, hydroxy, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino and —S(O n ) C 1 -C 6 alkyl; and 
         R A  and R B  are independently selected at each occurrence from:
 (i) hydrogen; and 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, saturated or partially saturated (C 3 -C 10 carbocycle)C 0 -C 4 alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, —COOH, —C(═O)NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), —NHS(O n )C 1 -C 6 alkyl, —S(O n )C 1 -C 6 alkyl, —S(O n )NHC 1 -C 6 alkyl, —S(O n )N(C 1 -C 6 alkyl)C 1 -C 6 alkyl and Z;
 R x  is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH 2 , C 1 -C 6 alkoxycarbonyl, —C(═O)NHC 1 -C 6 alkyl, —C(═O)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkoxy, C 1 -C 2 hydroxyalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and —S(O n )C 1 -C 6 alkyl; 
 and thereby reducing signal transduction by the C5a receptor. 
 
 
       
     
     
         90 . A method according to  claim 89 , wherein the cell is contacted in vivo in an animal. 
     
     
         91 . A method according to  claim 90 , wherein the animal is a human. 
     
     
         92 . (canceled) 
     
     
         93 . (canceled) 
     
     
         94 . A method for treating a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, er-bronchial asthma, stroke, myocardial infarction, atherosclerosis, ischemic heart disease, ischemia-reperfusion injury, or cystic fibrosis, comprising administering to the patient a C5a receptor modulatory amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable form thereof, wherein: 
         Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, indanyl, indenyl, benzisoxazolyl, indazolyl or indolyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
         A is OR 4 , NR 4 R 5 , CR 6 R 7  or CHR 6 R 7 ;
 R 1  is chosen from:
 (i) hydrogen, halogen, amino, and cyano; and 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and —S(O n )C 1 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
 
 R 2  is halogen, cyano or XR y ; 
 R 3  is hydrogen, halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono- or di-(C 1 -C 4 alkyl)amino or —S(O n )C 1 -C 4 alkyl; 
 with the proviso that at least one of R 1 , R 2  and R 3  is not hydrogen; 
 
         R 4  is:
 (i) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 4 alkylamino)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, phenylC 0 -C 4 alkyl, pyridylC 0 -C 4 alkyl, pyrimidinylC 0 -C 4 alkyl, thienylC 0 -C 4 alkyl, imidazolylC 0 -C 4 alkyl, pyrrolylC 0 -C 4 alkyl, pyrazolylC 0 -C 4 alkyl, benzoisothiazolyl or tetrahydronaphthyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , C 2 -C 4 alkanoyl, mono- and di-(C 1 -C 4 alkyl)amino(C 1 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and XR y ; or 
 (ii) joined to R 5  to form, with the nitrogen to which R 4  and R 5  are bound, a heterocycle substituted with from 0 to 4 substituents independently chosen from R x , oxo and YZ; 
 
         R 5  is:
 (i) hydrogen; 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 -carbocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy; or 
 (iii) joined to R 4  to form an optionally substituted heterocycle; 
 
         with the proviso that R 5  is not hydrogen if R 4  is C 1 -C 6 alkyl; 
         R 6  is:
 (i) halogen, hydroxy, cyano, amino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- or di-(C 1 -C 6 alkylamino)C 0 -C 6 alkyl, (C 3 -C 10 carbocycle)C 0 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl, C 2 -C 4 alkanoyloxy and YZ; or 
 (ii) joined to R 7  to form, with the carbon atom to which R 6  and R 7  are bound, a 3- to 10-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-(C 1 -C 4 alkylamino)C 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl and C 2 -C 4 alkanoyloxy; 
 
         R 7  is hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl or joined to R 6  to form an optionally substituted carbocycle or heterocycle; 
         R 8  is:
 (i) hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 9  to form a C 5 -C 7  cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, C 1 -C 2 alkyl and C 1 -C 2 alkoxy; 
 
         R 9  is:
 (i) absent, hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 8  to form an optionally substituted C 5 -C 7  cycloalkyl ring or 5- to 7-membered heterocycloalkyl ring; 
 
         R 17  is absent or oxygen; with the proviso that R 17  is absent if R 6  is C 1 -C 6 alkenyl; 
         X is a single bond, —CR A R B —, —O—, —C(═O)—, —C(═O)O—, —S(O) n — or —NR B —; and 
         R y  is:
 (i) hydrogen; or 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 carbocycleC 0 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R x , oxo, —NH(C 1 -C 6 alkanoyl), —N(C 1 -C 6 alkyl)C 1 -C 6 alkanoyl, —NHS(O n )C 1 -C 8 alkyl, —N(S(O n )C 1 -C 8 alkyl) 2 , —S(O n )NHC 1 -C 6 alkyl and —S(O n )N(C 1 -C 6 alkyl) 2 ; 
 
         Y is a single bond, —CR A R B —, —NR B — or —O—; 
         Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —COOH, hydroxy, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino and —S(O n ) C 1 -C 6 alkyl; and 
         R A  and R B  are independently selected at each occurrence from:
 (i) hydrogen; and 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, saturated or partially saturated (C 3 -C 10 carbocycle)C 0 -C 4 alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, —COOH, —C(═O)NH 2 , —NHC(═O)(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)C(═O)(C 1 -C 8 alkyl), —NHS(O n )C 1 -C 8 alkyl, —S(O n )C 1 -C 8 alkyl, —S(O n )NHC 1 -C 8 alkyl, —S(O n )N(C 1 -C 8 alkyl)C 1 -C 6 alkyl and Z;
 R x  is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH 2 , C 1 -C 6 alkoxycarbonyl, —C(═O)NHC 1 -C 6 alkyl, —C(═O)N(C 1 -C 8 alkyl) 2 , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkoxy, C 1 -C 2 hydroxyalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and —S(O n )C 1 -C 6 alkyl. 
 
 
       
     
     
         95 . (canceled) 
     
     
         96 . (canceled) 
     
     
         97 . A method for inhibiting C5a receptor-mediated cellular chemotaxis, comprising contacting mammalian white blood cells with a C5a receptor modulatory amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable form thereof, wherein: 
         Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, indanyl, indenyl, benzisoxazolyl, indazolyl or indolyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
         A is OR 4 , NR 4 R 5 , CR 6 R 7  or CHR 6 R 7 ;
 R 1  is chosen from:
 (i) hydrogen, halogen, amino, and cyano; and 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and —S(O n )C 1 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x ; 
 
 R 2  is halogen, cyano or XR y ; 
 R 3  is hydrogen, halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono- or di-(C 1 -C 4 alkyl)amino or —S(O n )C 1 -C 4 alkyl; 
 with the proviso that at least one of R 1 , R 2  and R 3  is not hydrogen; 
 
         R 4  is:
 (i) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 4 alkylamino)C 0 -C 4 alkyl, (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, phenylC 0 -C 4 alkyl, pyridylC 0 -C 4 alkyl, pyrimidinylC 0 -C 4 alkyl, thienylC 0 -C 4 alkyl, imidazolylC 0 -C 4 alkyl, pyrrolylC 0 -C 4 alkyl, pyrazolylC 0 -C 4 alkyl, benzoisothiazolyl or tetrahydronaphthyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , C 2 -C 4 alkanoyl, mono- and di-(C 1 -C 4 alkyl)amino(C 0 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), (3- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and XR y ; or 
 (ii) joined to R 5  to form, with the nitrogen to which R 4  and R 5  are bound, a heterocycle substituted with from 0 to 4 substituents independently chosen from R x , oxo and YZ; 
 
         R 5  is:
 (i) hydrogen; 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 -carbocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy; or 
 (iii) joined to R 4  to form an optionally substituted heterocycle; 
 with the proviso that R 5  is not hydrogen if R 4  is C 1 -C 6 alkyl; 
 
         R 6  is:
 (i) halogen, hydroxy, cyano, amino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- or di-(C 1 -C 6 alkylamino)C 0 -C 6 alkyl, (C 3 -C 10 carbocycle)C 8 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkyl), mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl, C 2 -C 4 alkanoyloxy and YZ; or 
 (ii) joined to R 7  to form, with the carbon atom to which R 6  and R 7  are bound, a 3- to 10-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from R x , oxo, mono- and di-(C 1 -C 4 alkylamino)C 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino(C 1 -C 4 alkoxy), C 2 -C 4 alkanoyl and C 2 -C 4 alkanoyloxy; 
 
         R 7  is hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl or joined to R 6  to form an optionally substituted carbocycle or heterocycle; 
         R 8  is:
 (i) hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 9  to form a C 5 -C 7  cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, C 1 -C 2 alkyl and C 1 -C 2 alkoxy; 
 
         R 9  is:
 (i) absent, hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 7 cycloalkyl C 0 -C 4 alkyl; or 
 (ii) joined to R 8  to form an optionally substituted C 5 -C 7  cycloalkyl ring or 5- to 7-membered heterocycloalkyl ring; 
 
         R 17  is absent or oxygen; with the proviso that R 17  is absent if R 6  is C 1 -C 6 alkenyl; 
         X is a single bond, —CR A R B —, —O—, —C(═O)—, —C(═O)O—, —S(O) n — or —NR B —; and 
         R y  is:
 (i) hydrogen; or 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 carbocycleC 0 -C 4 alkyl or (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R x , oxo, —NH(C 1 -C 6 alkanoyl), —N(C 1 -C 6 alkyl)C 1 -C 6 alkanoyl, —NHS(O n )C 1 -C 6 alkyl, —N(S(O n )C 1 -C 6 alkyl) 2 , —S(O n )N(C 1 -C 6 alkyl and —S(O n )N(C 1 -C 6 alkyl) 2 ; 
 
         Y is a single bond, —CR A R B —, —NR B — or —O—; 
         Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —COOH, hydroxy, amino, cyano, C 1 -C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono- and di-(C 1 -C 6 alkyl)amino and —S(O n ) C 1 -C 6 alkyl; and 
         R A  and R B  are independently selected at each occurrence from:
 (i) hydrogen; and 
 (ii) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, saturated or partially saturated (C 3 -C 10 carbocycle)C 0 -C 4 alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, —COOH, —C(═O)NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), —NHS(O n )C 1 -C 6 alkyl, —S(O n )C 1 -C 6 alkyl, —S(O n )NHC 1 -C 6 alkyl, —S(O n )N(C 1 -C 6 alkyl)C 1 -C 6 alkyl and Z;
 R x  is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH 2 , C 1 -C 6 alkoxycarbonyl, —C(═O)NHC 1 -C 6 alkyl, —C(═O)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- and di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkoxy, C 1 -C 2 hydroxyalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and —S(O n )C 1 -C 6 alkyl. 
 
 
       
     
     
         98 . (canceled) 
     
     
         99 . (canceled) 
     
     
         100 . (canceled) 
     
     
         101 . (canceled)
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