TrkA kinase inhibitors, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-9862707-B2
Application number	US-201515128793-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 indazolyl, pyrazolopyrimidinyl, pyrazolopyridinonyl, and pyrazolopyridinyl, wherein when B is indazolyl it is substituted with 1 to 3 groups of Ra and when B is pyrazolopyrimidinyl, pyrazolopyridinonyl, and pyrazolopyridinyl B is optionally substituted with 1 to 3 groups of R a ;
R is selected from the group consisting of hydrogen, OH, —C 1-6 alkylOH, 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 are independently selected from the group consisting of hydrogen, halogen, C 1-4 haloalkyl, C1-6 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 , provided that at least one of R 2 and R 4 are is (CHR) n C 5-10 heterocycle,
R 3 is selected from the group consisting of C 1-4 haloalkyl, and —OC 1-4 haloalkyl;
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, —(CH 2 ) n C 3-6 cycloalkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 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, —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 , SO 2 N(R d ) 2 , —C(O)CF 3 , COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(c))R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O))N(R d ) 2 , —O—C 1-6 alkyl, 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 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 , —O—, 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 , —C 1-4 haloalkyl 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 C4-10heterocycle said alkyl, cycloalkyl and heterocycle optionally substituted with 1 to 3 groups of Rf;
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 , —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, and —C 1-6 alkyl; and
n represents 0-6.

2. The compound according to claim 1 wherein B is unsubstituted or substituted and pyrazolopyridinyl, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein B is unsubstituted or substituted pyrazolopyrimidinyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein 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 and R 3 is selected from the group consisting of CF 3 , OCF 3 , or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 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, or a pharmaceutically acceptable salt thereof.

6. 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, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 wherein the heterocycle is optionally substituted pyrazolyl, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 3 is selected from the group consisting of CF 3 , OCF 3 , or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 of formula I wherein B is represented by structural formulas (a), (b), (c), (d), (e), and (f):

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, —O—, C 1-6 alkyl, (CH 2 ) n N(R) 2 , C(CH 3 ) 2 N(R) 2 , C(CF 3 ) 2 N(R) 2 , C 1-4 haloalkyl, (CH 2 ) n C(O)N(R) 2 , (CH 2 ) n C 3-10 cyclopropyl, (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 , or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 wherein B is pyrazolopyridinyl represented by structural formula II:

or a pharmaceutically acceptable salt thereof,
wherein one of Ya, Yb, Yc, and Yd is nitrogen and the others are —CH—.

11. The compound according to claim 10 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 , CH(CH 3 )OH, C(CH 3 ) 2 OH, 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, C(O)NH 2 , and halogen, said alkyl optionally substituted with 1 to 3 groups of R b , or a pharmaceutically acceptable salt thereof.

12. The compound of formula III according to claim 1 :

or a pharmaceutically acceptable salt thereof,
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 , CH(CH 3 )OH, C(CH 3 ) 2 OH, 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, C(O)NH 2 , and halogen, said alkyl optionally substituted with 1 to 3 groups of R b , R 3 is selected from the group consisting of CF 3 , and OCF 3 , 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 .

13. The compound according to claim 12 w

Assignees

• Merck Sharp & Dohme

Inventors

• Mitchell Helen
• Wood Harold B
• 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

• 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

• A61P25/02

  for peripheral neuropathies · CPC title