Tgf beta r antagonists

Patent metadata

Field	Value
Publication number	US-2016176871-A1
Application number	US-201514977709-A
Country	US
Kind code	A1
Filing date	Dec 22, 2015
Priority date	Dec 22, 2014
Publication date	Jun 23, 2016
Grant date	—

Abstract

The invention relates generally to compounds that modulate the activity of TGFβR-1 and TGFβR-2, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.

First claim

What is claimed is:

1 . The compound of the formula

wherein:
R is

or a heterocylic or heterobicyclic group substituted with 0-4 R 2 ;
X 1 , X 2 , X 3 and X 4 are independently —CR 4 or —N—, wherein at least one is —N—;
R 1 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
R x is hydrogen, halogen, —OH, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, or —CN;
R 2 is independently one or more hydrogen, —CD 3 , OCD 3 , halogen, —CF 3 , —CHF 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or —SO 2 (C 1 -C 6 )alkyl;
R 3 is independently one or more hydrogen, CD 3 , OCD 3 , halogen, —CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 6 )alkylamino-, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, —NR 5 R 6 , —CONR 5 R 6 , —COOR 4 , —COR 4 , —SO 2 R 4 , —CHCF 2 COOCH 2 OH or —CHCF 2 CONH 2 , any of which except the hydrogen is substituted with 0-4 R y ;
R y is hydrogen, halogen, —OH, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, —NHCOOH, or —CN;
R 4 is hydrogen or (C 1 -C 6 )alkyl;
R 5 and R 6 are independently hydrogen, —C(O)alkyl or (C 1 -C 6 )alkyl; or
R 5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered heterocyclo ring;
R 7 is independently one or more hydrogen, halogen, halo(C 1 -C 6 )alkyl or —CN;
R 8 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 ;
R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocyclylalkyl-, heterocyclyl(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl- or (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2 or 3;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2 . A compound according to claim 1 of formula (II)

wherein:
X 1 , X 2 , X 3 and X 4 are independently —CR 4 or —N—, wherein at least one is —N—;
R 1 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
R x is hydrogen, halogen, —OH, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, or —CN;
R 2 is independently one or more hydrogen, —CD 3 , OCD 3 , halogen, —CF 3 , —CHF 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or —SO 2 (C 1 -C 6 )alkyl;
R 3 is independently one or more hydrogen, CD 3 , OCD 3 , halogen, —CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 6 )alkylamino-, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, —NR 5 R 6 , —CONR 5 R 6 , —COOR 4 , —COR 4 , —SO 2 R 4 , —CHCF 2 COOCH 2 OH or —CHCF 2 CONH 2 , any of which except the hydrogen is substituted with 0-4 R y ;
R y is hydrogen, halogen, —OH, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, —NHCOOH, or —CN;
R 4 is hydrogen or (C 1 -C 6 )alkyl;
R 5 and R 6 are independently hydrogen, —C(O)alkyl or (C 1 -C 6 )alkyl; or
R 5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered heterocyclo ring;
R 7 is independently one or more hydrogen, halogen, halo(C 1 -C 6 )alkyl or —CN;
R 8 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 ;
R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocyclylalkyl-, heterocyclyl(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl- or (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2 or 3;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3 . A compound according to claim 2 of the formula

wherein:
X 1 , X 2 , X 3 and X 4 are independently —CR 4 or —N—, wherein at least one is —N—;
R 1 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
R x is hydrogen, halogen, —OH, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, or —CN;
R 2 is independently one or more hydrogen, —CD 3 , OCD 3 , halogen, —CF 3 , —CHF 2 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or —SO 2 (C 1 -C 3 )alkyl;
R 3 is independently one or more hydrogen, CD 3 , OCD 3 , halogen, —CN, (C 1 -C 3 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 3 )alkoxy, (C 3 -C 8 )cycloalkyl, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino-, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, —NR 5 R 6 , —CONR 5 R 6 , —COOR 4 , —COR 4 , —SO 2 R 4 , —CHCF 2 COOCH 2 OH or —CHCF 2 CONH 2 , any of which except the hydrogen is substituted with 0-4 R y ;
R y is hydrogen, halogen, —OH, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, —NHCOOH, or —CN;
R 4 is hydrogen or (C 1 -C 6 )alkyl;
R 5 and R 6 are independently hydrogen, —C(O)alkyl or (C 1 -C 6 )alkyl; or
R 5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered heterocyclo ring;
R 7 is independently one or more hydrogen, halogen, halo(C 1 -C 6 )alkyl or —CN;
R 8 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 ;
R 9 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocyclylalkyl-, heterocyclyl(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl- or (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2 or 3;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4 . A compound according to claim 3 of the formula

wherein:
X 1 and X 2 are independently —CH or —N—;
R 1 is hydrogen, (C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl, —CONHR 9 , —COOR 9 , —COR 9 or —SO 2 R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
R x is hydrogen, halogen, —OH, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, or —CN;
R 2 is independently one or more hydrogen, —CD 3 , OCD 3 , halogen, —CF 3 , —CHF 2 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or —SO 2 (C 1 -C 3 )alkyl;
R 3 is independently one or more hydrogen, CD 3 , OCD 3 , halogen, —CN, (C 1 -C 3 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 3 )alkoxy, (C 3 -C 8 )cycloalkyl, hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino-, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, —NR 5 R 6 , —CONR 5 R 6 , —COOR 4 , —COR 4 , —SO 2 R 4 , —CHCF 2 COOCH 2 OH or —CHCF 2 CONH 2 , any of which except the hydrogen is substituted with 0-4 R y ;
R y is hydrogen, halogen, —OH, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, -amino(C 1 -C 3 )alkyl, —NHCOOH, or —CN;
R 4 is hydrogen or (C 1 -C 3 )alkyl;
R 5 and R 6 are independently hydrogen, —C(O)alkyl or (C 1 -C 3 )alkyl; or
R 5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered heterocyclo ring;
R 7 is independently one or more hydrogen, halogen, halo(C 1 -C 3 )alkyl or —CN;
R 8 is hydrogen, (C 1 -C 3 )alkyl

Assignees

• Bristol Myers Squibb Co

Inventors

• Fink Brian E
• Zhao Yufen
• Borzilleri Robert M
• Zhang Liping
• Kim Kyoung S
• Kamau Muthoni G
• Tebben Andrew J

Classifications

• A61P35/02

  specific for leukemia · 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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title