TRKA kinase inhibitors, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-9862716-B2
Application number	US-201515129206-A
Country	US
Kind code	B2
Filing date	Mar 23, 2015
Priority date	Mar 26, 2014
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The present invention is directed to a bicyclic heteroaryl benzamide compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are 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 TrkA.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of unsubstituted or substituted imidazopyridinyl, imidazothiazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazothiadiazolyl, quinoxalinyl;
R is selected from the group consisting of hydrogen, OH, or —C 1-6 alkyl;
R 1 and R 5 are independently selected from the group consisting of hydrogen, CN, OH, C 1-6 alkyl, and halogen;
R 2 and R 4 is hydrogen and the other is (CHR) n C 5-10 heterocycle, said heterocycle optionally substituted with 1 to 3 groups of R a ;
R 3 is selected from the group consisting of C 2-6 alkyl, C 1-4 haloalkyl, —OC 1-4 haloalkyl, and halogen;
R a is selected from the group consisting of —CN, NO 2 , —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, —C 1-6 alkynyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 aryl, heterocycle, —(CHR) n C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 heterocycle-0-, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, SO 2 R d , —SO 2 N(R d ) 2 , —C(O)CF 3 , COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 , -0-C 1-6 alkyl, and —OH, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein when two R d groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocycle that is optionally substituted with 1 to 3 groups of R f ;
R b is selected from the group consisting of —C 1-6 alkyl, —C 1-6 alkylOR, —C 1-4 haloalkyl, —(CH 2 ) n C 3-6 cycloalkyl, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n OR c , -0-, halogen, —CN, S(O)(NH)R g , —SO 2 R, —SO 2 N(R d ) 2 , —O—(CH 2 ) n C 4-10 heterocycle, —(CH 2 ) n C(O)N(R d ) 2 , —(CH 2 ) n NHC(O)R d , —C 1-6 alkylN(R d ) 2 , and halo, said cycloalkyl optionally substituted with 1 to 3 groups of R f , and wherein when two R d groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocycle that is optionally substituted with 1 to 3 groups of R f ;
R c is selected from the group consisting of hydrogen, —C 1-6 alkylOR g , and —C 1-6 alkyl;
R d is independently selected from the group consisting of hydrogen, —C 1-4 haloalkyl-C 1-6 alkyl, —(CH 2 ) n NR f C 4-10 heterocycle, —(CH 2 ) n C 3-6 cycloalkyl, and —(CH 2 ) n C 4-10 heterocycle said alkyl, cycloalkyl and heterocycle optionally substituted with 1 to 3 groups of R f ;
R f is selected from the group consisting of hydrogen, OR c , CN, —N(R c ) 2 , C(O)N(R g ) 2 , C(O)C 1-6 alkyl, —SO 2 R g ,-0-, —C 1-6 alkylSO 2 R g , —C 1-6 alkyl n (R g ) 2 ,
R g is selected from the group consisting of hydrogen, and —C 1-6 alkyl; and
n represents 0-6.

2. The compound according to claim 1 wherein B is unsubstituted or substituted imidazopyridinyl or imidazopyrimidinyl.

3. The compound according to claim 1 wherein the optionally substituted heterocycle of R 2 and R 4 is a five or six membered ring containing one or more heteroatoms at least one of which is nitrogen.

4. The compound according to claim 1 wherein one of R 2 and R 4 is hydrogen and the other is selected from the group consisting of optionally substituted pyrazolyl, pyridyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiadiazolyl, oxadiazolyl and triazolyl.

5. The compound according to claim 4 wherein the heterocycle is optionally substituted pyrazolyl.

6. The compound according to claim 1 wherein R 3 is selected from the group consisting of hydrogen, CF 3 , OCF 3 , chlorine, and fluorine.

7. The compound according to claim 1 of formula I wherein B is represented by structural formulas (a), (b), (c), (d), (e), (f), (g), (h), or (i):

wherein:
R 6 represents (CH 2 ) n C 6-10 aryl, or (CH 2 ) n C 5-10 heterocycle, said aryl, and heterocycle optionally substituted with 1 to 3 groups of R a ; and
R 7 , R 8 , R 9 and R 10 independently represent hydrogen, halogen, CN, C 1-6 alkyl, C(O)N(R) 2 , C(O)(CH 2 ) n C 5-10 heterocycle, (CH 2 ) n C 6-10 °aryl, or (CH 2 ) n C 5-10 heterocycle, said alkyl, aryl, and heterocycle optionally substituted with 1 to 3 groups of R a .

8. The compound according to claim 7 wherein B is imidazopyridinyl or indazolyl represented by structural formula (a) or (b), respectively.

9. The compound according to claim 8 wherein B is imidazopyridinyl or indazolyl represented by structural formula (a) or (b), respectively, R 6 is unsubstituted or substituted phenyl, thiazolyl, pyrazolyl, pyridyl, isoxazolyl, oxazoly, or pyrimidinyl, R 8 and R 9 are independently selected from hydrogen, halogen, CN, CH 2 OH, C(O)N(R) 2 , and optionally substituted C 1-6 alkyl, phenyl, pyrazolyl, isoxazolyl, oxazolyl, (CH 2 ) n azetidinyl, and C(O)NHazetidinyl and R 7 and R 10 are independently selected from hydrogen, C 1-6 alkyl, and halogen, said alkyl optionally substituted with 1 to 3 groups of R b .

10. The compound of formula II according to claim 1 :

wherein:
R 6 is unsubstituted or substituted phenyl, thiazolyl, pyrazolyl, pyridyl, isoxazolyl, oxazolyl or pyrimidinyl, R 8 and R 9 are independently selected from hydrogen, halogen, CN, CH 2 OH, C(O)N(R) 2 , and optionally substituted C 1-6 alkyl, phenyl, pyrazolyl, isoxazolyl, oxazolyl, (CH 2 ) n azetidinyl, and C(O)NHazetidinyl, R 7 and R 10 are independently selected from hydrogen, C 1-6 alkyl, and halogen, said alkyl optionally substituted with 1 to 3 groups of R b , R 3 is selected from the group consisting of hydrogen, CF 3 , OCF 3 , CH 3 , chlorine and fluorine, and one of R 2 and R 4 is hydrogen and the other is (CHR) n C 5-10 heterocycle, said heterocycle optionally substituted with 1 to 3 groups of R a .

11. The compound according to claim 10 wherein R 1 and R 5 are both hydrogen or one is hydrogen and the other halogen, R 3 is OCF 3 , or CF 3 , one of R 2 and R 4 is hydrogen and the other is an optionally substituted (CHR) n C 5-10 heterocycle that is a five or six membered ring containing one or more heteroatoms at least one of which is nitrogen.

12. The compound according to claim 11 wherein the optionally substituted heterocycle of R 2 and R 4 is selected from the group consisting of pyrazolyl, pyridyl, thiazolyl, oxazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiadiazolyl, oxadiazolyl and triazolyl.

13. The compound according to claim 10 wherein one of R 2 and R 4 is hydrogen and the other is is pyrazolyl, R 6 is optionally substituted phenyl and R 3 is CF 3 .

14. A compound which is selected from the group consisting of
N-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4-(trifluoromethoxy)benzamide;
2-fluoro-N-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-4-(trifluoromethyl)benzamide;
3-(1-methyl-1H-pyrazol-3-yl)-N-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)-4-(trifluoromethyl)benzamide;
3-(1-methyl-1H-pyrazol-3-yl)-N-(2-pyridin-2-ylimidazo[1,2-a]pyridin-3-yl)-4-(trifluoromethyl)benzamide;
3-(1-methyl-1H-pyrazol-3-yl)-N-(2-phenylimidazo[1,2-b]pyridazin-3-yl)-4-(trifluoromethyl)benzamide;
2-fluoro-N-[5-(1-methylethyl)-2-phenylimidazo[1,2-a]pyridin-3-yl]-4-(trifluoromethyl)benzamide;
3-(1-methy

Assignees

• Merck Sharp & Dohme

Inventors

• Mitchell Helen
• Fraley Mark E
• Cooke Andrew J
• Stump Craig A
• Chen Yi-Heng
• Zhang Xu-Fang
• Mccomas Casey C
• Schirripa Kathy
• Mcwherter Melody
• Mercer Swati P
• Moore Keith P
• Liu Ping
• Wood Harold B
• Li Chun Sing
• Mao Qinghua
• Beshore Douglas C

Classifications

• 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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · 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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title