Compounds as TNIK, IKKε and TBK1 inhibitors and pharmaceutical composition comprising same

Patent metadata

Field	Value
Publication number	US-9856216-B2
Application number	US-201615134987-A
Country	US
Kind code	B2
Filing date	Apr 21, 2016
Priority date	Apr 27, 2015
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

Provided is a compound of formula (I) as a TNIK (Traf2- and NCK-interacting kinase), IKKε (I-kappa-B kinase epsilon) and TBK1 (TANK-binding kinase 1) inhibitor; the compound according to the present invention effectively inhibits TNIK, IKKε and TBK1, and thus is useful not only as an anticancer agent for the treatment of various cancers including colorectal cancer, breast cancer, CNS cancer, colon cancer, non-small cell lung cancer, kidney cancer, prostate cancer, ovarian cancer, uterus cancer, stomach cancer, liver cancer, skin cancer, lung cancer, brain cancer, bladder cancer, esophageal cancer, pancreatic cancer, thyroid cancer, head and neck cancer, squamous cell carcinoma, osteosarcoma, B-cell or T-cell lymphoma, acute or chronic leukemia and multiple myeloma, but as a therapeutic agent for chronic inflammation.

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,
X is CH;
Y is CH 2 ;
n is 1;
R 1 is —NH—C(═O)—R 4 ;
R 2 is C 6-14 aryl, 5- to 10-membered heteroaryl, or —NH—R 17 ; and
R 3 is H or C 1-7 alkyl;
R 4 is C 1-7 alkyl, C 6-14 aryl, or 5- to 10-membered heteroaryl; and
R 17 is C 6-14 aryl or 5- to 10-membered heteroaryl;
wherein said C 6-14 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C 1-7 alkyl; —OCF 3 ; C 1-7 alkoxy; (C 1-7 alkoxy)carbonyl; (C 1-7 alkyl)carbonyl; C 6-14 aryl; (C 1-7 alkyl)thio; halogen; (C 1-7 alkyl)sulfonyl; —NH—R 20 —R 21 ; —N(CH 3 )—R 20 —R 21 ; 5- to 10-membered heteroaryl; heterocycloalkyl unsubstituted or substituted with C 1-7 alkyl or amino; (C 1-7 alkylcarbonylamino)(C 6-14 aryl); (heterocycloalkyl)-(C 1-7 alkyl)-(5- to 10-membered heteroaryl); —CF 3 ; cyano; (C 1-7 alkyl)amino; nitro; oxo; (heterocycloalkyl)-(C 1-7 alkoxy); (diC 1-7 alkyl)amino; (C 1-7 alkyl)carbonylamino; hydroxy; (heterocycloalkyl)-(C 1-7 alkyl); (tertbutoxycarbonyl)-(heterocycloalkyl)-(C 1-7 alkyl); benzyl; and amino, wherein R 20 is C 6-14 aryl, 5- to 10-membered heteroaryl or C 1-7 alkyl which is unsubstituted or substituted with hydroxy; and R 21 is 5- to 10-membered heteroaryl or heterocycloalkyl which is unsubstituted or substituted with H, hydroxy, halogen, amino, C 1-7 alkyl, (diC 1-7 alkyl)amino, C 1-7 alkylcarbonylamino, C 1-7 alkoxy, methyl or oxo;
wherein said 5- to 10-membered heteroaryl is a mono or bicyclic heteroaryl comprising one to three heteroatoms selected from the group consisting of O, N, and S and
wherein said heterocycloalkyl is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, azepanyl and piperazinyl.

2. The compound of claim 1 , wherein R 4 is C 1-4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted furanyl, or substituted or unsubstituted pyridinyl.

3. The compound of claim 2 , wherein said phenyl, thiophenyl, furanyl, or pyridinyl is substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, amino, tertbutyloxycarbonyl, methyl, methylthio, methylsulfonyl, methoxy, acetamido, methylpiperazinyl, aminopiperidinyl, morpholino, morpholinoethoxy, methylamino, dimethylamino, dimethylaminoethylamino, dimethylaminopropylamino, aminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, methoxyethylamino, methoxypropylamino, methyl(2-(methylamino)ethyl)amino, acetamidoethylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, piperidinylethylamino, piperidinylpropylamino, azepanylethylamino, morpholinoethylamino, morpholinopropylamino, methylpiperazinylethylamino, methylpiperazinylpropylamino, thiophenylmethylamino, oxopyrrolidinylpropylamino, and (2-hydroxy-3-(piperidinyl)propyl)amino.

4. The compound of claim 1 , wherein R 2 is substituted or unsubstituted phenyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrimidinyl, thiophenyl, furanyl, benzo[d]oxazol-7-yl, quinolinyl, indolyl, benzo[d]imidazolyl or benzofuranyl.

5. The compound of claim 1 , wherein R 2 is selected from the group consisting of thiazolyl; pyrazolyl; methylpyrazolyl; imidazolyl; methylimidazolyl; triazolyl; methyltriazolyl; pyridinyl; chloropyridinyl; fluoropyridinyl; methoxyphenylaminopyridinyl; methoxypyridinyl; phenyl-1H-pyrrolo[2,3-b]pyridinyl; 1H-pyrrolo[2,3-b]pyridinyl; acetamidophenyl-1H-pyrrolo[2,3-b]pyridinyl; morpholinomethylthiophenyl-1H-pyrrolo[2,3-b]pyridinyl; pyrimidinyl; dichloropyrimidinyl; methoxyphenylaminopyrimidinyl; methylpyrazolylaminopyrimidinyl; phenylaminopyrimidinyl; fluorophenylaminopyrimidinyl; acetamidophenylaminopyrimidinyl; methylpiperazinylpyrimidinyl; morpholinopyrimidinyl; tolylaminopyrimidinyl; chloropyrimidinyl; thiophenyl; pyrrolidinylmethylthiophenyl; piperidinylmethylthiophenyl; morpholinomethylthiophenyl; tertbutyloxycarbonylpiperazinylmethylthiophenyl; furanyl; benzo[d]oxazol-7-yl; methyl-benzo[d]oxazol-7-yl; quinolinyl; indolyl; benzo[d]imidazolyl; and benzofuranyl.

6. The compound of claim 1 , wherein R 3 is methyl.

7. The compound of claim 1 , which is selected from the group consisting of:
(1) N-(7-(2-ethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(2) N-(7-(3-isopropylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(3) N-(7-(4-(tert-butyl)phenyl)-3-oxoisoindolin-4-yl)benzamide;
(4) N-(3-oxo-7-(2-(trifluoromethoxy)phenyl)isoindolin-4-yl)benzamide;
(5) N-(3-oxo-7-(3-(trifluoromethoxy)phenyl)isoindolin-4-yl)benzamide;
(6) N-(7-(2-isopropoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(7) N-(7-(3-isopropoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(8) methyl 2-(7-benzamido-1-oxoisoindolin-4-yl)benzoate;
(9) methyl 3-(7-benzamido-1-oxoisoindolin-4-yl)benzoate;
(10) methyl 4-(7-benzamido-1-oxoisoindolin-4-yl)benzoate;
(11) N-(7-(2-acetylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(12) N-(7-(3-acetylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(13) N-(7-(4-acetylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(14) N-(7-(2-(methylthio)phenyl)-3-oxoisoindolin-4-yl)benzamide;
(15) N-(7-(2,4-difluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(16) N-(7-(2,3-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(17) N-(7-(2,3-dichlorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(18) N-(7-(2,4-dichlorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(19) N-(7-(2,5-dichlorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(20) N-(7-(3,4-dichlorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(21) N-(7-(3,5-dichlorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(22) N-(7-(4-fluoro-2-methoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(23) N-(7-(2-chloro-3-fluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(24) N-(7-(2-fluoro-3-methoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(25) N-(3-oxo-7-(2,3,4-trimethoxyphenyl)isoindolin-4-yl)benzamide;
(26) N-(7-(3,4-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(27) N-(7-(3,5-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(28) N-(7-(2,6-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(30) N-(7-(3,5-difluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(31) N-(7-(2,5-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(32) N-(7-(2,5-difluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(33) N-(7-(3,4-difluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(34) N-(7-(2,3-difluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(38) N-(7-(2,4-dimethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(39) N-(7-(4-ethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(40) N-(7-(4-isopropoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(41) N-(7-(4-(methylthio)phenyl)-3-oxoisoindolin-4-yl)benzamide;
(42) N-(7-(3-ethylphenyl)-3-oxoisoindolin-4-yl)benzamide;
(43) N-(3-oxo-7-(2-propoxyphenyl)isoindolin-4-yl)benzamide;
(44) N-(3-oxo-7-(3-propoxyphenyl)isoindolin-4-yl)benzamide;
(45) N-(7-(2-butoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(46) N-(7-(3-butoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(47) N-(7-(2-(methylsulfonyl)phenyl)-3-oxoisoindolin-4-yl)benzamide;
(48) N-(7-(3-fluoro-2-methoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(49) N-(7-(4-chloro-2-methoxyphenyl)-3-oxoisoindolin-4-yl)benzamide;
(50) N-(7-(3-chloro-2-fluorophenyl)-3-oxoisoindolin-4-yl)benzamide;
(51) N-(3-oxo-7-(thiazol-5-yl)isoindolin-4-yl)benzamide;
(52) N-(3-oxo-7-(thiazol-4-yl)isoindolin-4-yl)benzamide;
(53) N-(3-oxo-7-(thiazol-2-yl)isoindolin-4-yl)benzamide;
(54) N-(7-(1H-imidazol-4-yl)-3-oxoisoindolin-4-yl)benzamide;
(55) N-(3-oxo-7-(1H-pyrazol

Assignees

• Green Cross Corp

Inventors

• Choi Soongyu
• Park Eun-Jung
• Seo Hee Jeong
• Kong Younggyu
• Son Ickhwan
• Ma Sang-Ho
• Cha Man-Young
• Kim Mi-Soon
• Park Kisoo

Classifications

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title