Trk inhibition

Patent metadata

Field	Value
Publication number	US-2018346451-A1
Application number	US-201815992989-A
Country	US
Kind code	A1
Filing date	May 30, 2018
Priority date	May 31, 2017
Publication date	Dec 6, 2018
Grant date	—

Abstract

The present invention relates to the use of substituted pyrimidine derivatives to modulate tropomyosin-related kinase (Trk) family protein kinase, and the use of the substituted pyrimidine derivatives for 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 the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, and C 1 -C 4 alkyl;
R 2 is selected from the group consisting of hydrogen, NH 2 and C 1 -C 4 alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, F, CN, oxo, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, CN, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, CF 3 , CF 2 H, CFH 2 , C 2 -C 6 alkynyl, and CON(R 7 )R 8 ;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and C 2 -C 6 alkanoyloxy;
n=0-3;
X is selected from the group consisting of CH 2 , NR, O or S. R represents hydrogen, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; and
Y is selected from the group consisting of N and CR 9 , wherein R 9 is selected from the group consisting of hydrogen, F, Cl, Br, I, CN, NO 2 , C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, CF 3 , CF 2 H, CFH 2 , C 2 -C 6 alkynyl, N(R 7 )R 8 , and CON(R 7 )R 8 ;
Het represents C 2 -C 8 heteroaryl, which is substituted with from 0 to 4 substituents independently chosen from:
(1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl;
(2) CON(R 7 )R 8 , N(R 7 )R 8 ; and
(3) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyloxy, mono- and di-(C 3 -C 5 cycloalkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo.

2 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, and C 1 -C 4 alkyl.
R 2 is selected from the group consisting of hydrogen, NH 2 , and C 1 -C 4 alkyl.
R 3 and R 4 are independently selected from the group consisting of hydrogen, F, CN, oxo, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, CN, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, CF 3 , CF 2 H, CFH 2 , C 2 -C 6 alkynyl, and CON(R 7 )R 8 ;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and C 2 -C 6 alkanoyloxy;
n=0-3; and
X is selected from the group consisting of CH 2 , NR, O or S. R represents hydrogen, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
Het represents C 2 -C 8 heteroaryl, which is substituted with from 0 to 4 substituents independently chosen from the group consisting of:
(1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl;
(2) CON(R 7 )R 8 , N(R 7 )R 8 ; and
(3) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyloxy, mono- and di-(C 3 -C 8 cycloalkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo.

3 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, and C 1 -C 4 alkyl;
R 2 is selected from the group consisting of hydrogen NH 2 , and C 1 -C 4 alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, F, CN, oxo, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, CN, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, CF 3 , CF 2 H, CFH 2 , C 2 -C 6 alkynyl, and CON(R 7 )R 8 ;
R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and C 2 -C 6 alkanoyloxy;
n=0-3; and
X is selected from the group consisting of CH 2 , NR, 0 or S. R represents hydrogen, C 1 -C 4 alkyl, cycloalkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
Het represents C 2 -C 8 heteroaryl, which is substituted with from 0 to 4 substituents independently chosen from the group consisting of:
(1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl;
(2) CON(R 7 )R 8 , N(R 7 )R 8 ; and
(3) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyloxy, mono- and di-(C 3 -C 8 cycloalkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, —COOH and oxo.

4 . A compound of claim 1 wherein Het is selected from the group consisting of:

5 . A compound of the formula:

or a pharmaceutically acceptable salt thereof.

6 . A compound of the formula:

or a pharmaceutically acceptable salt thereof.

7 . A compound of the formula

or a pharmaceutically acceptable salt thereof.

8 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

9 . A method for treating a disease or disorder selected from pain, cancer, i

Assignees

• Nantbio Inc

Inventors

• Tao Chunlin
• Wang Qinwei
• Asad Sharif
• Weingarten Paul
• Ci Sherry

Classifications

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61P29/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title