Heterocyclic amides as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10292987-B2
Application number	US-201715459141-A
Country	US
Kind code	B2
Filing date	Mar 15, 2017
Priority date	Feb 15, 2013
Publication date	May 21, 2019
Grant date	May 21, 2019

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.

First claim

What is claimed is:

1. A compound according to Formula (I):

wherein:
X is O;
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 )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 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 1 -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;
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 )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 1 -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 O;
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 )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 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 1 -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 2 , or pharmaceutically acceptable salt thereof, wherein:
X is O
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

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Jeong Jae U
• Bandyopadhyay Deepak
• Eidam Patrick M
• Harris Philip Anthony
• Kang Jianxing
• King Bryan Wayne
• Lakdawala Shah Ami
• Leister Lara Kathryn
• Rahman Attiq
• Ramanjulu Joshi M
• Sehon Clark A
• Singhaus Jr Robert
• Zhang Daohua

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title