PYRAZOLE DERIVATIVES AS TNIK, IKKe AND TBK1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

Patent metadata

Field	Value
Publication number	US-2016289196-A1
Application number	US-201615083503-A
Country	US
Kind code	A1
Filing date	Mar 29, 2016
Priority date	Mar 30, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

Provided is pyrazole derivatives as a TNIK (Traf2- and NCK-interacting kinase), IKKε (I-kappa-B kinase epsilon) and TBK1 (TANK-binding kinase 1) inhibitor; the pyrazole derivative 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

1 . A compound selected from the group consisting of a pyrazole derivative of formula (I) and a pharmaceutically acceptable salt, a hydrate, and a solvate thereof:

wherein:
A is benzene or thiophene ring;
X is —NH—C(═O) or —NH—S(═O) 2 —;
m is 0 or 1;
R 1 is substituted or unsubstituted C 5-14 aryl or substituted or unsubstituted 5- to 13-membered heteroaryl;
said aryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy; halogen; C 1-7 alkyl; C 1-7 alkoxy; C 1-7 alkylthio; 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more substituents selected from hydroxy, C 1-7 alkyl, C 1-7 alkoxy, t-butyloxycarbonyl or C 1-7 alkyl-carbonyl; nitro; amino; 5- to 13-membered heteroaryl; (diC 1-7 alkyl)amino; —NH—(CH 2 ) p —R 3 ; —O—(CH 2 ) p —R 3 ; and —NH—C(═O)—R 3 ; R 3 being H, hydroxy, C 1-7 alkoxy, 5- to 10-membered heterocycloalkyl which is unsubstituted or substituted with at least one alkyl, (diC 1-7 alkyl)amino, C 1-7 alkylamino, C 1-7 alkyl, saturated or unsaturated C 3-10 cycloalkyl, (trifluoromethyl) (saturated or unsaturated C 3-10 cycloalkyl), 5- to 13-membered heteroaryl or oxo-C 3-10 cycloalkyl; and p being an integer from 0 to 7;
Y is

R 4 and R 5 being each independently hydrogen, C 1-7 alkyl, C 3-10 cycloalkyl, hydroxy-C 1-7 alkyl or —CF 3 ; R 6 being hydrogen or C 1-7 alkyl; R 7 being 5- to 13-membered heteroaryl; and R 4 and R 5 being optionally bonded to each other to form C 3-10 cycloalkyl;
n is 0 or 1; and
R 2 is hydroxy, C 1-7 alkyl, cyano, hydroxy-C 1-7 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 5-14 aryl, substituted or unsubstituted 5- to 13-membered heteroaryl or substituted or unsubstituted 5- to 10-membered heterocycloalkyl; said cycloalkyl, aryl, heteroaryl or heterocycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-7 alkyl and —(CH 2 ) q -(5- to 10-membered heterocycloalkyl); and q being an integer from 0 to 2.

2 . The compound of claim 1 , wherein R 1 is substituted or unsubstituted phenyl, pyrazole or pyridine.

3 . The compound of claim 2 , wherein R 1 is phenyl which is substituted with at least one substituent selected from the group consisting of fluoro, methoxy, methylthio, methyl, tert-butyl, methylpiperazinyl, piperazinyl, morpholino, dimethylpiperazinyl, dimethylmorpholino, hydroxypiperidinyl, ethylpiperazinyl, methoxypiperidinyl, methoxyethylamino, methoxypropylamino, pyrrolidinylethylamino, morpholinoethylamino, dimethylaminopropylamino, methyl(methylaminoethylamino), tetrahydrofuranylmethylamino, dimethylamino ethylamino, isopentylamino, tetrahydropyranyl ethylamino, hexylamino, cyclohexylamino, cyclopentylamino, cycloheptylamino, cyclooctylamino, cyclohexylmethylamino, cyclohexenylethylamino, pyrrolylethylamino, tert-butyloxy carbonyl tetrahydropyridinyl, tetrahydropyridinyl, hydroxy, morpholinoethoxy, nitro, amino, cyclobutanecarboxamido, (trifluoromethyl)cyclopropanecarboxamido, oxocyclobutanecarboxamido, acetylpiperazinyl, tert-butyloxycarbonylpyrrolidinecarboxamido, acetamido, imidazolyl, methylpiperidinylamino, dimethylamino, piperidinylethylamino and hydroxyethylamino.

4 . The compound of claim 1 , wherein R 4 and R 5 are each independently hydrogen, methyl, ethyl, propyl, cyclopropyl, isobutyl, hydroxymethyl or —CF 3 .

5 . The compound of claim 1 , wherein R 4 and R 5 are bonded to each other to form cyclopropyl or cyclohexyl.

6 . The compound of claim 1 , wherein R 7 is thiophenyl.

7 . The compound of claim 1 , wherein R 2 is phenyl, furanyl, thiophenyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine, morpholinomethylthiophenyl, cyano, methylthiophenyl, chlorothiophenyl, trifluoromethylphenyl, cyclohexyl, cyclopropyl, propyl, isobutyl, oxadiazolyl, thiazolyl, pyridinyl, furanyl, methylpyridinyl, trifluoromethylpyridinyl, hydroxy, cyclopentyl, hydroxyethyl, triazolyl, cyclobutyl, oxazolyl, piperazinyl, isoxazolyl, fluorophenyl, methyloxazolyl, methylthiazolyl, methyl, morpholinomethyl, ethyloxazolyl, pyrrolidinyl or ethylthiazolyl.

8 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
(1) N-benzyl-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (2) N-(furan-2-yl-methyl)-3-(4-methoxybenzamido)-1H-indazole-5-carboxamide; (3) 3-(4-methoxybenzamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (4) 3-(4-methoxybenzamido)-N-methyl-N-(thiophen-2-ylmethyl)-1H-indazole-5-carb oxamide; (5) 4-methoxy-N-(5-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-6-carbonyl)-1H-indazol-3-yl)benzamide (6) 3-(4-(methylthio)benzamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (7) 3-(1-methyl-1H-pyrazole-4-carboxamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (8) 3-(5-methoxypicolinamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide hydrochloride; (9) 3-(2-methoxynicotinamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (10) 3-(4-tert-butylbenzamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (11) 4-methoxy-N-(5-((thiophen-2-ylmethyl)amino)-1H-indazol-3-yl)benzamide; (12) 4-methoxy-N-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-indazol-3-yl)benzamide; (13) 3-benzamido-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (14) 3-(4-fluorobenzamido)-N-(1-(thiophen-2-yl)ethyl)-1H-indazole-5-carboxamide; (15) 3-(4-fluorobenzamido)-N-(1-(thiophen-2-yl)cyclopropyl)-1H-indazole-5-carboxamide; (16) N-(1-cyanocyclopropyl)-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (17) 3-(4-fluorobenzamido)-N-(1-(thiophen-2-yl)propyl)-1H-indazole-5-carboxamide; (18) 3-(4-fluorobenzamido)-N-(1-(thiophen-2-yl)butyl)-1H-indazole-5-carboxamide; (19) 3-(4-fluorobenzamido)-N-((5-methylthiophen-2-yl)methyl)-1H-indazole-5-carboxamide; (20) 3-(4-fluorobenzamido)-N-(2-phenylpropan-2-yl)-1H-indazole-5-carboxamide; (21) 3-(4-fluorobenzamido)-N-(4-(trifluoromethyl)benzyl)-1H-indazole-5-carboxamide; (22) N-(cyclohexylmethyl)-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (23) N-(cyclopropylmethyl)-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (24) N-butyl-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (25) 3-(4-fluorobenzamido)-N-isopentyl-1H-indazole-5-carboxamide; (26) N-((1,2,4-oxadiazol-3-yl)methyl)-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (27) 3-(4-fluorobenzamido)-N-(thiazol-5-ylmethyl)-1H-indazole-5-carboxamide 2,2,2-trifluoroacetate; (28) 3-(4-fluorobenzamido)-N-(pyridin-2-ylmethyl)-1H-indazole-5-carboxamide2,2,2-trifluoroacetate; (29) 3-(4-fluorobenzamido)-N-(pyridin-4-ylmethyl)-1H-indazole-5-carboxamide; (30) N-(cyclopropyl(thiophen-2-yl)methyl)-3-(4-fluorobenzamido)-1H-indazole-5-carboxamide; (31) 4-fluoro-N-(5-(((thiophen-2-ylmethyl)amino)methyl)-1H-indazol-3-yl)benzamide hydrochloride; (32) 4-fluoro-N-(5-(((1-(thiophen-2-yl)propyl)amino)methyl)-1H-indazol-3-yl)benzamide; (33) 3-(4-fluorobenzamido)-N-(3-methyl-1-(thiophen-2-yl)butyl)-1H-indazole-5-carboxamide; (34) 3-(4-fluorobenzamido)-N-(2-(thiophen-2-yl)butan-2-yl)-1H-indazole-5-carboxamide; (35) 3-(2,4-difluorobenzamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (36) 3-(4-fluorobenzamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (37) 3-(4-fluorobenzamido)-N-(1-phenylethyl)-1H-indazole-5-carboxamide; (38) 3-(4-fluorobenzamido)-N-(1-phenylpropyl)-1H-indazole-5-carboxamide; (39) 3-(phenylsulfonamido)-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; (40) N-b

Assignees

• Green Cross Corp

Inventors

• Choi Soongyu
• Park Kisoo
• Seo Hee Jeong
• Park Eun-Jung
• Kong Younggyu
• Son Ickhwan
• Ma Sang-Ho
• Song Kwang-Seop
• Kim Min Ju
• Park So Ok
• Cha Man-Young
• Kim Mi-Soon
• Kang Sang Mi
• Jang Dong Hyuk
• Hong Jangwon

Classifications

• C07D409/04

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

• C07D231/56 Primary

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/12

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