TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF

Patent metadata

Field	Value
Publication number	US-2016229804-A1
Application number	US-201415023634-A
Country	US
Kind code	A1
Filing date	Sep 17, 2014
Priority date	Sep 22, 2013
Publication date	Aug 11, 2016
Grant date	—

Abstract

The present invention is directed to benzyl urea compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence may be useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor Trk-A, Trk-B and/or Trk-C.

First claim

What is claimed is:

1 . A compound of formula I or Ia:

and pharmaceutically acceptable salts thereof, wherein:
R represents hydrogen, or C 1-6 alkyl;
R 1 is selected from (CRR) n C 6-10 aryl, C 5-10 heterocycle, (CHR) n C 3-10 cycloalkyl, said aryl, heterocycle, and cycloalkyl optionally substituted with 1 to 3 groups of R a ;
R a represents —CN, —O—, —(CH 2 ) n C 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, —C 1-6 alkynyl, —(CHR) n C 6-10 aryl, —(CHR) n C 5-10 heterocycle, —C 3-10 cycloalkyl, —O—(CH 2 ) n C 6-10 aryl, —O—C 5-10 heterocycle, —C(O)CF 3 , —(CH 2 ) n halo, —OR, —NRR, NHC 6-10 aryl, —SCF 3 , SO 2 CF 3 , OC(F) 2 Cl, OC 1-4 haloalkyl, C(O)NRR, SO 2 R, SO 2 NRR, OC(F) 2 C(F) 3 , S(O) 2 CH(F) 2 , OC(F) 2 CH(F) 2 , C(CH 3 ) 2 C≡N, —COC 6-10 aryl, or —CO 2 R, said cycloalkyl, alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of Rb;
R b represents, —CN, —(CH 2 ) n C 1-4 haloalkyl, —OR, —C 1-6 alkyl, (CH 2 ) n OR, —(CHR) n C 6-10 aryl, —(CHR) n C 5-10 heterocycle, —C 3-10 cycloalkyl, —(CH 2 ) n halo, said aryl and heterocycle optionally substituted with 1 to 3 groups of C 1-6 alkyl, or halo, and
n represents 0-6.

2 . The compound according to claim 1 wherein R 1 is phenyl substituted with optionally substituted phenyl, triazolyl, imidazoly, oxazolyl, tetrazolyl, oxadiazolyl, phenyl, thiadiazolyl, imidazolyl, pyrrolotriazolyl, piperazinyl, morpholinyl, or C(O)N(R) 2 .

3 . The compound according to claim 1 wherein R 1 is optionally substituted C 5-10 heterocycle.

4 . The compound according to claim 3 wherein R 1 is optionally substituted C 5-10 heterocycle selected from the group consisting of optionally substituted pyrazolyl, pyridyl, imidazolyl, imidazopyridinyl, thiazolyl, isoxazolyl, triazolyl, oxazolyl, pyrimidinyl, pyrrolopyridinyl, imidazothiazolyl, and pyrazoloquinolinyl.

5 . The compound according to claim 1 wherein R a represents —CN, —CF 3 , —OCF 3 , SCF 3 , —C 1-6 alkyl, —(CH 2 ) n halo, NRR, —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, or O(CH 2 ) n phenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl optionally substituted with 1 to 3 groups of R b .

6 . The compound according to claim 4 wherein R a selected from the group consisting of —CN, —CF 3 , —OCF 3 , SCF 3 , —C 1-6 alkyl, —(CH 2 ) n halo, NRR, —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl optionally substituted with 1 to 3 groups of R b .

7 . The compound according to claim 1 of formula I.

8 . The compound according to claim 1 of formula I represented by structural formula II:

or pharmaceutically acceptable salts there of wherein R a is selected from the group consisting of —CN, —CF 3 , —OCF 3 , SCF 3 , —C 1-6 alkyl, —(CH 2 ) n halo, NRR, —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl optionally substituted with 1 to 3 groups of R b .

9 . The compound according to claim 1 of formula I represented by structural formula III:

or pharmaceutically acceptable salts there of wherein B is pyrazolyl or imidazolyl and R a is selected from the group consisting of —CN, —CF 3 , —OCF 3 , SCF 3 , —C 1-6 alkyl, —(CH 2 ) n halo, NRR, —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl optionally substituted with 1 to 3 groups of R b .

10 . The compound according to claim 9 wherein B is pyrazolyl.

11 . The compound according to claim 9 wherein B is imidazolyl.

12 . The compound according to claim 1 of formula IV represented by structural formula IV:

or pharmaceutically acceptable salts there of wherein A is pyridyl or pyrimidinyl and R a is selected from the group consisting of —CN, —CF 3 , —OCF 3 , SCF 3 , —C 1-6 alkyl, —(CH 2 ) n halo, NRR, —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, and O(CH 2 ) n phenyl, optionally substituted with 1 to 3 groups of R b .

13 . The compound according to claim 12 wherein A is pyridyl.

14 . The compound according to claim 12 wherein A is pyrimidinyl.

15 . The compound according to claim 1 of formula Ia.

16 . A compound which is:
1-(9H-fluoren-9-yl)-3-(6-methyl-2-phenylpyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)urea; 1-(2-methyl-4-phenylpyrimidin-5-yl)-3-(9H-xanthen-9-yl)urea; 1-(9H-fluoren-9-yl)-3-(2-methyl-4-phenylpyrimidin-5-yl)urea; 1-(9H-fluoren-9-yl)-3-[2-(4-fluorophenyl)-6-methylpyridin-3-yl]urea; 1-(9H-fluoren-9-yl)-3-(6-phenylimidazo[2, 1-b][1,3]thiazol-5-yl)urea; 1-(9H-fluoren-9-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea; 1-(9H-fluoren-9-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)urea; 1-(9H-fluoren-9-yl)-3-(1-methyl-4-phenyl-1H-pyrazol-5-yl)urea; 1-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)-3-(9H-fluoren-9-yl)urea; 1-(9H-fluoren-9-yl)-3-(2-phenylpyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-(4-phenylpyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-(6-methylpyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-(1-phenyl-1H-pyrazol-5-yl)urea; 1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(9H-fluoren-9-yl)urea; 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(9H-fluoren-9-yl)urea; 1-(9H-fluoren-9-yl)-3-[3-(2-methylpropyl)-1-phenyl-1H-pyrazol-5-yl]urea; 1-[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]-3-(9H-fluoren-9-yl)urea; 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(9H-fluoren-9-yl)urea; 1-[3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl]-3-(9H-fluoren-9-yl)urea; 1-(9H-fluoren-9-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-(1-methyl-4-phenyl-1H-imidazol-5-yl)urea; 1-[4-cyano-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]-3-(9H-fluoren-9-yl)urea; 1-(9H-fluoren-9-yl)-3-[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl]urea; 1-(9H-fluoren-9-yl)-3-(2-phenyl-2H-pyrazolo[4,3-c]quinolin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-[2-(methylamino)pyridin-3-yl]urea; 1-(9H-fluoren-9-yl)-3-(2-fluoro-6-methylpyridin-3-yl)urea; 1-(9H-fluoren-9-yl)-3-[4-(4-fluorophenyl)-2-methylpyrimidin-5-yl]urea; 1-(9H-fluoren-9-yl)-3-[4-(4-fluorophenyl)-6-methylpyri

Assignees

• Cooke Andrew J
• Stump Craig A
• Zhang Xu-Fang
• Li Chun Sing
• Mao Qinghua
• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Cooke Andrew J
• Stump Craig A
• Zhang Xu-Fang
• Li Chun Sing
• Mao Qinghua

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D277/44

  Acylated amino or imino radicals · CPC title