Carbazole compounds useful as bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9492460-B2
Application number	US-201414190477-A
Country	US
Kind code	B2
Filing date	Feb 26, 2014
Priority date	Feb 27, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention is directed to carbazole compounds, pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

First claim

What is claimed is:

1. A compound of formula (I)

wherein:
A is an isoxazole, oxazole or triazole group substituted with 0-4 R 14 ;
R is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted heteroaryl(C 1 -C 6 )alkyl, optionally substituted heterocyclo(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-CO—, optionally substituted aryl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted heteroaryl, optionally substituted heterocyclo-CO—, optionally substituted aryl-SO 2 —, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted heteroaryl-SO 2 —, optionally substituted (C 1 -C 6 )alkyl-OCO— or optionally substituted (C 3 -C 8 )cycloalkyl-OCO—; or
R is

wherein
X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;
R 1 is halogen, —CN, OH, —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NHOCOR 7 , —NHCONR 7 R 8 , —NHSO 2 NR 7 R 8 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NHSO 2 -optionally substituted (C 1 -C 6 )alkyl, —NHSO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NHSO 2 — or optionally substituted heterocyclo-NHSO 2 —;
R 2 is H, halogen, —CN, —COOH, —CONR 7 R 8 , —NHCOR 3 R 4 , —OCONR 3 R 4 , —NHCOOR 3 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted heteroaryl or optionally substituted heterocyclo;
R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,
R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;
or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;
R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;
R 7 and R 8 are independently hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl;
or R 7 and R 8 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;
R 12 and R 13 are independently hydrogen, halogen, —CN, OH, —CONR 3 R 4 , —NHCOOR 4 , —NHCONR 3 R 4 , —NHCOR 4 , —NHSO 2 R 7 , —SO 2 NR 3 R 4 , —NHSO 2 NR 3 R 4 , —SO 2 R 7 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
R 14 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, —CN, —NR 3 R 4 , OH, —NHOCOR 7 , —OCONR 7 R 8 , —NHCONR 7 R 8 or —CF 3 ;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

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

wherein:
A is an isoxazole, oxazole or triazole group substituted with 0-4 R 14 ;
R is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted heteroaryl(C 1 -C 6 )alkyl, optionally substituted heterocyclo(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-CO—, optionally substituted aryl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted heteroaryl, optionally substituted heterocyclo-CO—, optionally substituted aryl-SO 2 —, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted heteroaryl-SO 2 —, optionally substituted (C 1 -C 6 )alkyl-OCO— or optionally substituted (C 3 -C 8 )cycloalkyl-OCO—; or
R is

wherein
X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;
R 1 is halogen, —CN, OH, —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NHOCOR 7 , —NHCONR 7 R 8 , —NHSO 2 NR 7 R 8 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NHSO 2 -optionally substituted (C 1 -C 6 )alkyl, —NHSO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NHSO 2 — or optionally substituted heterocyclo-NHSO 2 —;
R 2 is H, halogen, —CN, —COOH, —CONR 7 R 8 , —NHCOR 3 R 4 , —OCONR 3 R 4 , —NHCOOR 3 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted heteroaryl or optionally substituted heterocyclo;
R 3 is hydrogen, optional

Assignees

• Bristol Myers Squibb Co

Inventors

• Poss Michael A
• Tortolani David R
• Dodd Dharmpal S
• Mussari Christopher P
• Tokarski John S
• Gavai Ashvinikumar V
• Zhao Yufen
• Delucca George V
• O'Malley Daniel
• Norris Derek J
• Gill Patrice
• Quesnelle Claude A
• Han Wen-Ching

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P13/08

  of the prostate · CPC title