TrkA kinase inhibitors, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-9896447-B2
Application number	US-201415023145-A
Country	US
Kind code	B2
Filing date	Sep 17, 2014
Priority date	Sep 22, 2013
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

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;
One of R 1 and R 2 is imidazopyridinyl and the other is selected from the group consisting of imidazopyridinyl, imidazopyridazinyl, imidazothiazolyl, or pyrazopyrimidinyl, said groups 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 R b ,
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,
n represents 0-6; and
m represents 0.

2. The compound according to claim 1 wherein structural formula I is represented by structural formula II when R 1 is imidazopyridyl:

wherein R a and R 2 are as originally defined, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein one of R 1 and R 2 is optionally substituted imidazopyridinyl and the other is optionally substituted imidazopyridinyl, or imidazopyridazinyl, imidazothiazolyl.

4. The compound according to claim 1 wherein one of R 1 and R 2 is optionally substituted imidazopyridinyl and the other is optionally substituted imidazopyridinyl.

5. The compound according to claim 1 wherein one of R 1 and R 2 is optionally substituted imidazopyridinyl and the other is optionally substituted imidazopyridinyl.

6. A compound which is:
1,3-bis(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
1-naphthalen-1-yl-3-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)urea;
1-(2-methyl-4-phenylpyrimidin-5-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
1-[2-chloro-4-(trifluoromethyl)phenyl]-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]urea;
1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-(2-phenylpyridin-3-yl)urea;
1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
1-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
1-[3-(1-methyl-1H-imidazol-2-yl)phenyl]-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
ethyl 3-{[(2-phenylimidazo[1,2-a]pyridin-3-yl)carbamoyl]amino}imidazo[1,2-a]pyridine-2-carboxylate;
1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-[2-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl]urea;
1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)urea;
1-(6-chloro-2-phenylimidazo[1,2-b]pyridazin-3-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;
N-methyl-3-{[(2-phenylimidazo[1,2-a]pyridin-3-yl)carbamoyl]amino}imidazo[1,2-a]pyridine-2-carboxamide;
and pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A compound according to claim 1 for use as a medicament.

9. A method of treating a disease or disorder mediated by Trk receptors, wherein said disease or disorder is selected from the group consisting 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- in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

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

Inventors

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

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title