Heterocyclic amides as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10933070-B2
Application number	US-201916299254-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Feb 15, 2013
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

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):

or pharmaceutically acceptable salt thereof, wherein:
X is NH;
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 .

2. The compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein Y is CH 2 .

3. A pharmaceutical composition comprising the compound according to claim 1 , or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

4. A method of treating a RIP1 kinase mediated disease or disorder comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof, according to claim 1 to a human in need thereof, wherein the disease or disorder is selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, spondyloarthritis, systemic onset juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, multiple sclerosis, sepsis, ischemia reperfusion injury of solid organs, and systemic inflammatory response syndrome.

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

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P1/02

  Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title