IP Library › Patent Application 15835747

Patent Application

App. No. 15/835,747

HETEROCYCLIC AMIDES AS KINASE INHIBITORS

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Patent No.: US None
App. No.: 15/835,747

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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.

Claims (115)

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;

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;

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;

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.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 8, 2017

From: BANDYOPADHYAY, DEEPAK; EIDAM, PATRICK M.; GOUGH, PETER J.; HARRIS, PHILIP ANTHONY; JEONG, JAE U.; KANG, JIANXING; KING, BRYAN WAYNE; SHAH, AMI LAKDAWALA; LEISTER, LARA KATHRYN; MARQUIS, ROBERT W., JR.; RAHMAN, ATTIQ; RAMANJULU, JOSHI M.; SEHON, CLARK A.; SINGHAUS, ROBERT, JR.; ZHANG, DAOHUA

To: GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED

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