Heterocyclic amides as kinase inhibitors

Abstract

Disclosed are compounds having the formula: wherein X, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 5 , R A , m, A. L, and B are as defined herein, and methods of making and using the same.

What is claimed is: 
     
         1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         X is NH or N(CH 3 ); 
         Y is CH 2  or CH 2 CH 2 ; 
         Z 1  is N, CH or CR 1 ; 
         Z 2  is CH or CR 2 ; 
         Z 3  is N, CH or CR 3 ; 
         Z 4  is CH or CR 4 ; 
         R 1  is fluoro or methyl; 
         one of R 2  and R 3  is halogen, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 4 )alkoxy, hydroxyl, B(OH) 2 , —COOH, halo(C 1 -C 4 )alkylC(OH) 2 —, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylSO 2 —, (C 1 -C 4 )alkylSO 2 NHC(O)—, (C 1 -C 4 )alkylC(O)NH—, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)NC(O)—, (C 1 -C 4 )alkylOC(O)—, (C 1 -C 4 )alkylC(O)N(C 1 -C 4 )alkyl)-, (C 1 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylC(O)NH—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylSO 2 (C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylOC(O)NH—, hydroxy(C 1 -C 4 )alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkyl-NHC(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(O)NH, 
         wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl and —(C 1 -C 4 )alkyl-CN; 
         and the other of R 2  and R 3  is halogen, cyano or (C 1 -C 6 )alkyl; 
         R 4  is fluoro, chloro, methyl or trifluoromethyl; 
         R 5  is H or methyl; 
         A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on ring A; 
         m is 0 or m is 1 and R A  is (C 1 -C 4 )alkyl; and 
         L is O, S, NH, N(CH 3 ), CH 2 , CH 2 CH 2 , CH(CH 3 ), CHF, CF 2 , CH 2 O, CH 2 N(CH 3 ), CH 2 NH, or CH(OH); 
         B is an optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl; 
         wherein said (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or two substituents each independently selected from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, nitro, and (C 1 -C 4 )alkylC(O)—; 
         or the moiety -L-B is (C 3 -C 6 )alkyl, (C 3 -C 6 )alkoxy, halo(C 3 -C 6 )alkoxy, (C 3 -C 6 )alkenyl, or (C 3 -C 6 )alkenyloxy; 
         or a pharmaceutically acceptable salt thereof 
       
     
     
         2 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 X is O, S, SO, SO 2 , NH, CO, CH 2 , CF 2 , CH(CH 3 ), CH(OH), or N(CH 3 );   Y is CH 2  or CH 2 CH 2 ;   Z 1  is N, CH or CR 1 ;   Z 2  is CH or CR 2 ;   Z 3  is N, CH or CR 3 ;   Z 4  is CH or CR 4 ;   R 1  is fluoro or methyl;   one of R 2  and R 3  is halogen, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 4 )alkoxy, hydroxyl, B(OH) 2 , —COOH, halo(C 1 -C 4 )alkylC(OH) 2 —, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylSO 2 —, (C 1 -C 4 )alkylSO 2 NHC(O)—, (C 1 -C 4 )alkylC(O)NH—, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)NC(O)—, (C 1 -C 4 )alkylOC(O)—, (C 1 -C 4 )alkylC(O)N(C 1 -C 4 )alkyl)-, (C 1 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylC(O)NH—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylSO 2 (C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylOC(O)NH—, hydroxy(C 1 -C 4 )alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkyl-NHC(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(O)NH,   wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl and —(C 1 -C 4 )alkyl-CN;   and the other of R 2  and R 3  is halogen or (C 1 -C 6 )alkyl;   R 4  is fluoro, chloro, or methyl;   R 5  is H or methyl;   A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on ring A;   m is 0 or m is 1 and R A  is (C 1 -C 4 )alkyl; and   L is O, S, NH, N(CH 3 ), CH 2 , CH 2 CH 2 , CH(CH 3 ), CHF, CF 2 , CH 2 O, CH 2 N(CH 3 ), CH 2 NH, or CH(OH);   B is an optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl;   wherein said (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or two substituents each independently selected from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, nitro, and (C 1 -C 4 )alkylC(O)—;   or the moiety -L-B is (C 3 -C 6 )alkyl, (C 3 -C 6 )alkoxy, halo(C 3 -C 6 )alkoxy, (C 3 -C 6 )alkenyl, or (C 3 -C 6 )alkenyloxy.   
     
     
         3 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 X is NH or N(CH 3 );   Y is CH 2  or CH 2 CH 2 ;   Z 1  is N, CH or CR 1 ;   Z 2  is CH or CR 2 ;   Z 3  is N, CH or CR 3 ;   Z 4  is CH or CR 4 ;   R 1  is fluoro or methyl;   one of R 2  and R 3  is halogen, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 6 )alkoxy, hydroxyl, B(OH) 2 , —COOH, halo(C 1 -C 4 )alkylC(OH) 2 —, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylSO 2 —, (C 1 -C 4 )alkylSO 2 NHC(O)—, (C 1 -C 4 )alkylC(O)NH—, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)NC(O)—, (C 1 -C 4 )alkylOC(O)—, (C 1 -C 4 )alkylC(O)N(C 1 -C 4 )alkyl)-, (C 1 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylC(O)NH—, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylSO 2 (C 2 -C 4 )alkylNHC(O)—, (C 1 -C 4 )alkylNHC(O)NH—, (C 1 -C 4 )alkylOC(O)NH—, hydroxy(C 1 -C 4 )alkylOC(O)NH—, 5-6 membered heterocycloalkyl-C(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkyl-NHC(O)—, 5-6 membered heterocycloalkyl-(C 1 -C 4 )alkoxy-, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(O)NH,   wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl and —(C 1 -C 4 )alkyl-CN;   and the other of R 2  and R 3  is halogen or (C 1 -C 6 )alkyl;   R 4  is fluoro, chloro, or methyl;   R 5  is H or methyl;   A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on ring A;   m is 0 or m is 1 and R A  is (C 1 -C 4 )alkyl; and   L is O, S, NH, N(CH 3 ), CH 2 , CH 2 CH 2 , CH(CH 3 ), CHF, CF 2 , CH 2 O, CH 2 N(CH 3 ), CH 2 NH, or CH(OH);   B is an optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl;   wherein said (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or two substituents each independently selected from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, nitro, and (C 1 -C 4 )alkylC(O)—;   or the moiety -L-B is (C 3 -C 6 )alkyl, (C 3 -C 6 )alkoxy, halo(C 3 -C 6 )alkoxy, (C 3 -C 6 )alkenyl, or (C 3 -C 6 )alkenyloxy.   
     
     
         4 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein:
 X is NH or N(CH 3 );   Y is CH 2  or CH 2 CH 2 ;   Z 1 , Z 2 , Z 3 , and Z 4  are each CH; or   Z 1  is CR 1  and Z 2 , Z 3  and Z 4  are each CH; or   Z 1 , Z 2 , and Z 4  are each CH and Z 3  is CR 3 ; or   Z 1 , Z 3 , and Z 4  are each CH and Z 2  is CR 2 ; or   Z 1 , Z 2 , and Z 3  are each CH and Z 4  is CR 4 ; or   Z 1  and Z 3  are CH, Z 2  is CR 2 , and Z 4  is CR 4 ;   or Z 1  and Z 3  are both N, Z 2  is CH and Z 4  is CH or CR 4 ; or   Z 1  is N, Z 2  is CR 2  and Z 3  and Z 4  are CH; or   Z 3  is N, and Z 2 , Z 3  and Z 4  are CH;   R 1  is methyl,   R 2  is chloro, bromo, —CN, —CH 3 , —OH, B(OH) 2 , CF 3 C(OH) 2 —, CH 3 OCH 2 CH 2 O—, 5H-tetrazol-5-yl, pyrazol-3-yl, or 5-methyl-1,3,4-oxadiazol-2-yl;   R 3  is fluoro, chloro, bromo, —OCH 3 , B(OH) 2 , —COOH, CH 3 SO 2 —, CH 3 SO 2 NHC(O)—, CH 3 C(O)NH—, (CH 3 ) 2 NC(O)—, CH 3 OC(O)—, (CH 3 )C(O)N(CH 3 )—, HOCH 2 CH 2 C(O)NH—, CH 3 OCH 2 CH 2 NHC(O)NH—, CH 3 SO 2 CH 2 CH 2 NHC(O)—, CH 3 CH 2 NHC(O)NH—, CH 3 OC(O)NH—, morpholin-4-yl-CO—, pyrrolidin-1-yl-CH 2 CH 2 NHC(O)—, tetrahydrofuran-2-yl-CH 2 O—, pyrrolidin-1-yl-CH 2 CH 2 O—, tetrazol-5-yl, 1-(2-cyanoethyl)-tetrazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrrol-4-yl-C(O)NH—, or 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl;   R 4  is fluoro or methyl;   A is furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, piperidinyl, pyrrolidinyl, phenyl or pyridyl;   m is 0 or m is 1 and R A  is methyl;   L is O, S, N(CH 3 ), CH 2 , CH 2 CH 2 , CH(CH 3 ), CF 2 , CH 2 O, CH 2 N(CH 3 ), or CH(OH); and   B is thien-2-yl, pyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 4-methylpyrazol-1-yl, 3,5-dimethylisoxazol-4-yl, tetrahydrofuran-2-yl, morpholin-4-yl, pyridin-2-yl, 2-oxo-pyridin-1-yl, 6-methylpyridin-3-yl, 2-methylpyrimidin-5-yl, cyclopentyl, cyclohexyl, phenyl, 2-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-iodophenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, or 4-methoxyphenyl;   or -L-B is —OCH 2 CH═CH 2 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —OCH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 3 , or —CH 2 CH(CH 3 ) 2 .   
     
     
         5 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein X is NH. 
     
     
         6 . The compound according to  claim 5 , or pharmaceutically acceptable salt thereof, wherein Y is CH 2 . 
     
     
         7 . The compound according to  claim 6 , or pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 , Z 3 , and Z 4  are each CH. 
     
     
         8 . The compound according to  claim 7 , or pharmaceutically acceptable salt thereof, wherein R 5  is methyl. 
     
     
         9 . The compound according to  claim 8 , or pharmaceutically acceptable salt thereof, wherein B is unsubstituted phenyl or B is phenyl, substituted by 1 or 2 substituents independently selected from fluoro, chloro, bromo, and methyl. 
     
     
         10 . The compound according to  claim 9 , or pharmaceutically acceptable salt thereof, wherein B is phenyl, substituted by 1 or 2 fluoro substituents. 
     
     
         11 . The compound according to  claim 9 , or pharmaceutically acceptable salt thereof, wherein L is CH 2 . 
     
     
         12 . The compound according to  claim 9 , or pharmaceutically acceptable salt thereof, wherein L is N(CH 3 ), CH(CH 3 ), or CH(OH). 
     
     
         13 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, having Formula (II): 
       
         
           
           
               
               
           
         
         wherein A 1  and A 4  are each C, and A 2 , A 3  and A 5  are each independently selected from N and NH to form a triazolyl ring moiety. 
       
     
     
         14 . The compound according to  claim 4 , or pharmaceutically acceptable salt thereof, having Formula (II): 
       
         
           
           
               
               
           
         
         wherein A 1  and A 4  are each C, and A 2 , A 3  and A 5  are each independently selected from N and NH to form a triazolyl ring moiety. 
       
     
     
         15 . The compound according to  claim 9 , or pharmaceutically acceptable salt thereof, having Formula (II): 
       
         
           
           
               
               
           
         
         wherein A 1  and A 4  are each C, and A 2 , A 3  and A 5  are each independently selected from N and NH to form a triazolyl ring moiety. 
       
     
     
         16 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a tautomer thereof. 
     
     
         17 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof, having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a tautomer thereof. 
     
     
         18 . A pharmaceutical composition comprising the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         19 . A pharmaceutical composition comprising the compound according to  claim 4 , or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         20 . A pharmaceutical composition comprising the compound according to  claim 9 , or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         21 . A method of treating ulcerative colitis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         22 . A method of treating Crohn's disease comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         23 . A method of treating psoriasis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         24 . A method of treating rheumatoid arthritis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         25 . A method of treating spondyloarthritis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         26 . A method of treating systemic onset juvenile idiopathic arthritis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         27 . A method of treating psoriatic arthritis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         28 . A method of treating osteoarthritis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         29 . A method of treating ischemia reperfusion injury of solid organs comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         30 . A method of treating multiple sclerosis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         31 . A method of treating sepsis comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         32 . A method of treating systemic inflammatory response syndrome comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         33 . A method of treating a hematological malignancy comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof. 
     
     
         34 . A method of treating a solid organ malignancy comprising administering a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salt thereof, to a human in need thereof.