Bromodomain Inhibitors

Patent metadata

Field	Value
Publication number	US-2022017511-A1
Application number	US-202117183832-A
Country	US
Kind code	A1
Filing date	Feb 24, 2021
Priority date	Apr 15, 2016
Publication date	Jan 20, 2022
Grant date	—

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 6 , X 1 , and X 2 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising compounds of formula (I).

First claim

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein
R 1 is hydrogen, CD 2 CD 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3 -C 6 cycloalkyl, the phenyl, and the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups;
R 2 is G 2a , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of G 2b and —OH;
G 2a is a phenyl or a C 3 -C 6 monocyclic cycloalkyl; wherein each G 2a is optionally substituted with 1, 2, 3, or 4 independently selected R x groups;
G 2b is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R x groups;

R 3 is C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or a C 3 -C 6 monocyclic cycloalkyl wherein the C 3 -C 6 monocyclic cycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R x groups; or
R 2 and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6 monocyclic cycloalkyl, a C 4 -C 6 monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6 monocyclic cycloalkyl, the C 4 -C 6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups;
R 4 is phenyl, pyridinyl, a C 3 -C 6 monocyclic cycloalkyl, or a C 4 -C 6 monocyclic cycloalkenyl; wherein each R 4 is optionally substituted with 1, 2, 3, or 4 independently selected R y groups; or
R 4 is formula (a)

R 4a and R 4b are each independently halogen, C 4 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4c and R 4d are each independently hydrogen, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —S(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), or —(C 1 -C 6 alkylenyl)-OH;
Y is C(R 4e ) or N; wherein R 4e is hydrogen, halogen, —CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R x , at each occurrence, is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R y , at each occurrence, is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O(C 1 -C 6 alkyl), —O(C 1 -C 6 haloalkyl), or —(C 1 -C 6 alkylenyl)-OH;
X 1 and X 2 are C(R 5 ); or
one of X 1 and X 2 is N and the other is C(R 5 );
R 5 , at each occurrence, is independently hydrogen or halogen; and
R 6 is hydrogen, halogen, —CN, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl.

2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is CD 2 CD 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or a C 3 -C 6 cycloalkyl; wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R x groups.

3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2 is phenyl, cyclopropyl, cyclopentyl, C 4 -C 6 haloalkyl, or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of G 2b and —OH; and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups; and
R 3 is C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 independently selected R x groups.

4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6 monocyclic cycloalkyl, a C 4 -C 6 monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6 monocyclic cycloalkyl, the C 4 -C 6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups.

5 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 4 is phenyl, pyridinyl, a C 3 -C 6 monocyclic cycloalkyl, or a C 4 -C 6 monocyclic cycloalkenyl; wherein each R 4 is optionally substituted with 1, 2, 3, or 4 independently selected R y groups.

6 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 4 is formula (a)

7 . The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
R 4a is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4b is halogen or C 1 -C 6 alkyl;
R 4d is hydrogen or halogen; and
Y is C(R 4e ) or N; wherein R 4e is hydrogen.

8 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
X 1 is N or C(R 5 );
X 2 is C(R 5 ); and
R 5 is hydrogen.

9 . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6 monocyclic cycloalkyl, a C 4 -C 6 monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6 monocyclic cycloalkyl, the C 4 -C 6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups.

10 . The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein
R 4 is formula (a); wherein
R 4a is halogen, C 4 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4b is halogen or C 1 -C 6 alkyl;
R 4d is hydrogen or halogen; and
Y is C(R 4e ) or N; wherein R 4e is hydrogen; and

R 6 is hydrogen or halogen.

11 . The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein
R 2 is phenyl, cyclopropyl, cyclopentyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of G 2b and —OH; and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 independently selected R x groups; and
R 3 is C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 independently selected R x groups.

12 . The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein
R 4 is phenyl, pyridinyl, a C 3 -C 6 monocyclic cycloalkyl, or a C 4 -C 6 monocyclic cycloalkenyl; wherein each R 4 is optionally substituted with 1, 2, 3, or 4 independently selected R y groups; and
R 6 is hydrogen.

13 . The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein
X 1 is C(R 5 );
X 2 is C(R 5 );
R 5 is hydrogen; and
R 1 , R 2 , and R 3 are C 1 -C 6 alkyl.

14 . The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein
R 4 is formula (a); and
R 6 is hydrogen or halogen.

15 . The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein
R 4a is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4b is halogen or C 1 -C 6 alkyl;
R 4d is hydrogen or halogen; and
Y is C(R 4e ) or N; wherein R 4e is hydrogen.

16 . The compound of claim 14

Assignees

• Abbvie Inc

Inventors

• Fidanze Steven D
• Hasvold Lisa A
• Liu Dachun
• Mcdaniel Keith F
• PRATT John
• Schrimpf Michael
• SHEPPARD George
• Wang Le
• Li Bing

Classifications

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61P19/06

  Antigout agents, e.g. antihyperuricemic or uricosuric agents · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title