TrkA kinase inhibitors, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-9815846-B2
Application number	US-201515128689-A
Country	US
Kind code	B2
Filing date	Mar 23, 2015
Priority date	Mar 26, 2014
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present invention is directed to six membered 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 pharmaceutically acceptable salts thereof, wherein:
B represents a six membered heteroaryl having at least one heteroatom that is nitrogen, said heteroaryl optionally substituted with 1 to 3 groups of R a ;
R represents hydrogen, OH, or —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R f ;
R 1 is selected from the group consisting of hydrogen, CN, OH, —C 1-6 alkyl and halogen;
R 2 is hydrogen or (CHR) n C 5-10 heterocycle, said heterocycle optionally substituted with 1 to 3 groups of R a , wherein when R 2 is hydrogen then R 4 is (CHR) n C 5-10 heterocycle;
R 4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, (CHR) n C 6-10 aryl and (CHR) n C 5-10 heterocycle, said alkyl, aryl, and heterocycle optionally substituted with 1 to 3 groups of R a ,
R 3 represents C 1-4 haloalkyl,
R 5 is hydrogen or halogen;
R a is selected from the group consisting of hydrogen, —CN, NO 2 , —(CH 2 ) n C(O)OR f , —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, —C 1-6 alkynyl, —(CH 2 ) n C 3-6 cycloalkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —(CH 2 ) 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, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, SO 2 R d , (CH 2 ) n NHSO 2 R d , —(CH 2 ) n SO 2 N(R d ) 2 , S(O)(NH)R g , —C(O)CF 3 , COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NRC(O)NHR d , —(CH 2 ) n NHC(O)OR d , CHR) n C(O)N(R d ) 2 —OC 1-6 alkyl, —O—, and —OH, said alkyl, cycloalkyl, 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 heterocyle that is optionally substituted with 1 to 3 groups of R f ;
R b is selected from the group consisting of halogen, —C 1-6 alkyl, —C 1-6 alkylOR, —C 1-4 haloalkyl, —(CH 2 ) n N(R d ) 2 , —OR c , —O—, —CN, S(O)(NH)R g , —SO 2 R, —SO 2 N(R d ) 2 , —(CH 2 ) n C(O)N(R d ) 2 , —(CH 2 ) n NHC(O)R d , COR, C(O)OR, C 3-6 cycloalkyl, —O—(CH 2 ) n C 4-10 heterocycle, and —C 1-6 alkylN(R d ) 2 , said alkyl and heterocycle optionally substituted with 1 to 3 groups of R f ;
R c is selected from the group consisting of hydrogen, —C 1-6 alkylORg, —C 1-4 haloalkyl and —C 1-6 alkyl;
R d is independently selected from the group consisting of hydrogen, halogen, —C 1-4 haloalkyl —C 1-6 alkyl, COR, —(CH 2 ) n SO 2 R, —(CH 2 ) n NR f C 4-10 heterocycle, —(CH 2 ) n C 3-6 cycloalkyl, —(CH 2 ) n C 4-10 heterocycle said alkyl, cycloalkyl and heterocycle optionally substituted with 1 to 3 groups of R f ; wherein when two R d groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocyle that is optionally substituted with 1 to 3 groups of R f ;
R f is selected from the group consisting of hydrogen, C 1-6 alkyl, OR c , CN, —N(R c ) 2 , C(O)N(R g ) 2 , C(O)C 1-6 alkyl, —SO 2 R g , —O—, —C 1-6 alkylSO 2 R g , —C 1-6 alkylOR g , —C 1-6 alkylN(R g ) 2 ,
R g is selected from the group consisting of hydrogen, —C 1-6 alkyl; and
n represents 0-6.

2. The compound according to claim 1 wherein B is an unsubstituted or substituted six membered heterocycle selected from the group consisting of pyridyl, pyrimidinyl, pyradizinyl, and pyrazinyl.

3. The compound according to claim 2 wherein B is unsubstituted or substituted pyridyl.

4. The compound according to claim 2 wherein B is unsubstituted or substituted pyrimidinyl.

5. The compound according to claim 1 wherein one of R 2 and R 4 is hydrogen and the other is optionally substituted (CHR) n C 5-10 heterocycle and R 1 and R 5 are independently selected from hydrogen and halogen.

6. The compound according to claim 5 wherein the heterocycle of R 2 and R 4 is selected from the group consisting of optionally substituted pyrazolyl, pyridyl, thiazolyl, triazolyl, oxazolyl, oxadiazolyl, and pyrimidinyl.

7. The compound according to claim 1 wherein R 3 is CF 3 .

8. The compound according to claim 1 wherein B is a pyrimidinyl substituted with 1 to 3 groups of R a selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6- 10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, 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 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2.

9. The compound according to claim 1 wherein B is a pyridyl substituted with 1 to 3 groups of R a selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, 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 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2.

10. The compound according to claim 1 represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as originally described and R a1 , R a2 , R a3 , and R a4 all equal R a and R a is as originally described.

11. The compound according to claim 10 wherein R a1 , R a2 , R a3 , and R a4 are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4- 10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, 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 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein at least two of R a1 , R a2 , R a3 , and R a4 on the pryidyl are hydrogen, and one of R a1 , R a2 , R a3 , and R a4 is phenyl, R 1 and R 5 are independently selected from hydrogen and halogen, R 3 is CF 3 , or halogen, and one of R 2 and R 4 is hydrogen and the other is (CHR) n C 5-10 heterocycle.

12. The compound according to claim 10 wherein R a4 is phenyl, R 1 is hydrogen, R 3 is CF 3 , R 5 is fluorine, R 2 is optionally substituted pyrazolyl, and R 4 is hydrogen.

13. The compound according to claim 1 represented by structural formula II:

and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as originally described, and R w , R v and R y =R a .

14. The compound according to claim 13 wherein R w , R v , and R y are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 hetero

Assignees

• Merck Sharp & Dohme
• Msd R & D (China) Co Ltd

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
• Babaoglu Kerim
• Meng Dongfang
• Wu Jane
• Liu Ping
• Wood Harold B
• Bao Jianming
• Li Chun Sing
• Mao Qinghua
• Qi Zhiqi

Classifications

• A61P43/00

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · 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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title