TrkA kinase inhibitors, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-9718782-B2
Application number	US-201415023634-A
Country	US
Kind code	B2
Filing date	Sep 17, 2014
Priority date	Sep 22, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

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:

and pharmaceutically acceptable salts thereof, wherein:
R represents hydrogen, or C 1-6 alkyl;
R 1 is selected from C 5-10 heterocycle, selected from the group consisting of pyrazolyl, pyridyl, imidazolyl, imidazopyridinyl, thiazolyl, isoxazolyl, triazolyl, oxazolyl, pyrimidinyl, pyrrolopyridinyl, and imidazothiazolyl, said heterocycle, optionally substituted with 1 to 3 groups of R a ;
R a represents —CN, —(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 R b , wherein the C 5-10 heterocycle is selected from the group consisting of pyrazolyl, pyridyl, imidazolyl, imidazopyridinyl, thiazolyl, isoxazolyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, furanyl, pyrimidinyl, pyrrolopyridinyl, and imidazothiazolyl;
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, wherein the C 5-10 heterocycle is selected from the group consisting of pyrazolyl, pyridyl, imidazolyl, imidazopyridinyl, thiazolyl, isoxazolyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, furanyl, pyrimidinyl, pyrrolopyridinyl, and imidazothiazolyl, and
n represents 0-6.

2. 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 .

3. 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 .

4. The compound according to claim 3 wherein B is pyrazolyl.

5. The compound according to claim 3 wherein B is imidazolyl.

6. 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 .

7. The compound according to claim 6 wherein A is pyridyl.

8. The compound according to claim 6 wherein A is pyrimidinyl.

9. 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-(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-(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-methylpyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-(4-phenylpyrimidin-5-yl)urea;
1-(9H-fluoren-9-yl)-3-(3-methyl-1-pyridin-2-yl-1H-pyrazol-5-yl)urea;
1-(2-cyclohexylpyridin-3-yl)-3-(9H-fluoren-9-yl)urea;
1-(9H-fluoren-9-yl)-3-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]urea;
1-(2,4′-bipyridin-3-yl)-3-(9H-fluoren-9-yl)urea;
1-(2,3′-bipyridin-3-yl)-3-(9H-fluoren-9-yl)urea;
1-(9H-fluoren-9-yl)-3-[2-(4-fluorophenyl)pyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-(2′-fluoro-2,4′-bipyridin-3-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-furan-2-ylpyridin-3-yl)urea;
1-(9H-fluoren-9-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;
1-(1,2-dimethyl-4-phenyl-1H-imidazol-5-yl)-3-(9H-fluoren-9-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-methyl-4-phenyl-1H-imidazol-5-yl)urea;
1-(9H-fluoren-9-yl)-3-pyridin-3-ylurea;
1-(9H-fluoren-9-yl)-3-(1-phenyl-1H-1,2,4-triazol-5-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-furan-2-ylimidazo[1,2-a]pyridin-3-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-pyridin-4-ylimidazo[1,2-a]pyridin-3-yl)urea;
1-(9H-fluoren-9-yl)-3-(3-phenylisoxazol-4-yl)urea;
1-(9H-fluoren-9-yl)-3-(5-methyl-2-phenylpyridin-3-yl)urea;
1-(3,3′-bipyridin-5-yl)-3-(9H-fluoren-9-yl)urea;
1-(9H-fluoren-9-yl)-3-[5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-[5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-3- yl]urea;
1-(9H-fluoren-9-yl)-3-[2-(3-fluorophenyl)pyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-[2-(2-fluorophenyl)pyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-[2-(2-methylphenyl)pyridin-3-yl]urea;
1-(9H-fluoren-9-yl)-3-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-phenylpyridin-4-yl)urea;
1-(9H-fluoren-9-yl)-3-(2-methyl-4-phenyl-1,3-oxazol-5-yl)urea,
1-(9H-fluoren-9-yl)-3-[5-(1-meth

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

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

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• C07D405/12

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