Pyrrole-3-carboxamide bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9493411-B2
Application number	US-201414206061-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 12, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 , R 2 , R 3 , and R 10 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 one or more compounds of formula (I).

First claim

What is claimed is:

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

wherein
R 1 is C 1 -C 3 alkyl;
R 2 is hydrogen or C 1 -C 3 alkyl;
R 3 is —C(O)NR 8 R 9 ;
R 8 and R 9 are chosen from one of the following groups:
(i) R 8 and R 9 are both H;
(ii) R 8 is H and R 9 is C 1 -C 3 alkylene-C(O)O—C 1 -C 3 alkyl or OH; or
(iii) R 8 is C 1 -C 3 alkylene-aryl and R 9 is C 1 -C 3 alkylene-C(O)—C 1 -C 3 alkyl;

R 10 is aryl or heteroaryl, wherein R 10 is optionally substituted with 1 to 3 substituents designated as R 40 , R 41 , and R 42 and independently selected from the group consisting of
NO 2 , NR 20 R 22 , halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—C 1 -C 6 alkyl, —O—C 1 -C 6 haloalkyl, C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-C(O)OH, C 1 -C 3 alkylene-C(O)O—C 1 -C 4 alkyl, C 2 -C 3 alkenylene-O—C 1 -C 3 alkyl, —NHC(O)—C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 haloalkyl, —SO 2 —NH 2 , —C(O)—NR 20 R 22 , and -L-R 12 ,

wherein L is absent or is —C 1 -C 3 alkylene-, —C 2 -C 3 alkenylene-, —NH—, —NH—C 1 -C 3 alkylene-, —NHS(O) 2 —, NHS(O) 2 —C 1 -C 3 alkylene-, —NH—C(O)—C 1 -C 3 alkylene-, —C(O)—, —C(O)—NH—C 1 -C 3 alkylene-, or —O—;
R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 8 membered heterocycloalkyl, 5 to 12 membered heteroaryl, and aryl, which is optionally substituted with one, two, or three substituents designated R 15 , R 16 , and R 17 ,
R 15 , R 16 , and R 17 are independently selected from the group consisting of
OH, CN, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 alkyl, —O—C 1 -C 3 haloalkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-C(O)O—C 1 -C 3 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)OC 1 -C 4 alkyl, —C(O)NH—C 1 -C 3 alkylene-NR 30 R 32 , —C(O)NR 30 R 32 , —O—C 1 -C 4 alkyl-NR 30 R 32 , —NR 30 R 32 , —NHC(O)O—C 1 -C 4 alkyl, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, —S(O) 2 —C 1 -C 3 alkyl, aryl, —O-aryl, —C 1 -C 3 alkylene-aryl, C 3 -C 6 cycloalkyl, heterocycloalkyl, —C 1 -C 3 alkylene-heterocycloalkyl, —C(O)-heterocycloalkyl, 5 to 12 membered heteroaryl, and —C(O)NH—C 1 -C 3 alkylene-heteroaryl,
wherein said heterocycloalkyl, heteroaryl or aryl groups on R 15 , R 16 , and R 17 are optionally independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, —O—C 1 -C 3 -alkyl, —O—C 1 -C 3 -haloalkyl, halo, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, and —S(O) 2 —C 1 -C 3 alkyl;

R 26 is C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl;
R 20 and R 22 are independently selected from the group consisting of H and C 1 -C 6 alkyl; and
R 30 and R 32 are independently selected from the group consisting of H and C 1 -C 4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are both H.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 10 is heteroaryl, which is optionally substituted with 1 to 3 substituents designated as R 40 , R 41 , and R 42 and independently selected from the group consisting of
NO 2 , NR 20 R 22 , halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—C 1 -C 6 alkyl, —O—C 1 -C 6 haloalkyl, C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-C(O)OH, C 1 -C 3 alkylene-C(O)O—C 1 -C 4 alkyl, C 2 -C 3 alkenylene-O—C 1 -C 3 alkyl, —NHC(O)—C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 haloalkyl, —SO 2 —NH 2 , —C(O)—NR 20 R 22 , and -L-R 12 ,
wherein L is absent or is —C 1 -C 3 alkylene-, —C 2 -C 3 alkenylene-, —NH—, —NH—C 1 -C 3 alkylene-, —NR 26 —, —NHS(O) 2 —, NHS(O) 2 —C 1 -C 3 alkylene-, —NH—C(O)—C 1 -C 3 alkylene-, —C(O)—, —C(O)—NH—C 1 -C 3 alkylene-, or —O—;
R 12 is selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 8 membered heterocycloalkyl, 5 to 12 membered heteroaryl, and aryl, which is optionally substituted with one, two, or three substituents designated R 15 , R 16 , and R 17 ,
R 15 , R 16 , and R 17 are independently selected from the group consisting of
OH, CN, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 alkyl, —O—C 1 -C 3 haloalkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-C(O)O—C 1 -C 3 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)OC 1 -C 4 alkyl, —C(O)NH—C 1 -C 3 alkylene-NR 30 R 32 , —C(O)NR 30 R 32 , —O—C 1 -C 4 alkyl-NR 30 N 32 , —NR 30 R 32 , —NHC(O)O—C 1 -C 4 alkyl, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, —S(O) 2 —C 1 -C 3 alkyl, aryl, —O-aryl, —C 1 -C 3 alkylene-aryl, C 3 -C 6 cycloalkyl, heterocycloalkyl, —C 1 -C 3 alkylene-heterocycloalkyl, —C(O)-heterocycloalkyl, 5 to 12 membered heteroaryl, and —C(O)NH—C 1 -C 3 alkylene-heteroaryl,
wherein said heterocycloalkyl, heteroaryl or aryl groups on R 15 , R 16 , and R 17 are optionally independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, —O—C 1 -C 3 -alkyl, —O—C 1 -C 3 -haloalkyl, halo, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, and —S(O) 2 —C 1 -C 3 alkyl.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 10 is phenyl which is optionally substituted with 1 to 3 substituents designated as R 40 , R 41 , and R 42 and independently selected from the group consisting of
NO 2 , NR 20 R 22 , halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—C 1 -C 6 alkyl, —O—C 1 -C 6 haloalkyl, C 1 -C 3 alkylene-OH, C 1 -C 3 alkylene-C(O)OH, C 1 -C 3 alkylene-C(O)O—C 1 -C 4 alkyl, C 2 -C 3 alkenylene-O—C 1 -C 3 alkyl, —NHC(O)—C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 alkyl, —NH—SO 2 —C 1 -C 3 haloalkyl, —SO 2 —NH 2 , —C(O)—NR 20 R 22 , and -L-R 12 ,
wherein L is absent or is —C 1 -C 3 alkylene-, —C 2 -C 3 alkenylene-, —NH—, —NH—C 1 -C 3 alkylene-, —NR 26 —, —NHS(O) 2 —, NHS(O) 2 —C 1 -C 3 alkylene-, —NH—C(O)—C 1 -C 3 alkylene-, —C(O)—, —C(O)—NH—C 1 -C 3 alkylene-, and or —O—;
R 12 is selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 8 membered heterocycloalkyl, 5 to 12 membered heteroaryl, and aryl, which is optionally substituted with one, two, or three substituents designated R 15 , R 16 , and R 17 ,
R 15 , R 16 , and R 17 are independently selected from the group consisting of
OH, CN, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 alkyl, —O—C 1 -C 3 haloalkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-C(O)O—C 1 -C 3 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)OC 1 -C 4 alkyl, —C(O)NH—C 1 -C 3 alkylene-NR 30 R 32 , —C(O)NR 30 R 32 , —O—C 1 -C 4 alkyl-NR 30 N 32 , —NR 30 R 32 , —NHC(O)O—C 1 -C 4 alkyl, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, —S(O) 2 —C 1 -C 3 alkyl, aryl, —O-aryl, —C 1 -C 3 alkylene-aryl, C 3 -C 6 cycloalkyl, heterocycloalkyl, —C 1 -C 3 alkylene-heterocycloalkyl, —C(O)-heterocycloalkyl, 5 to 12 membered heteroaryl, and —C(O)NH—C 1 -C 3 alkylene-heteroaryl,

wherein said heterocycloalkyl, heteroaryl or aryl groups on R 15 , R 16 , and R 17 are optionally independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, —O—C 1 -C 3 -alkyl, —O—C 1 -C 3 -haloalkyl, halo, —NH—S(O) 2 —C 1 -C 3 alkyl, —NH—S(O) 2 —C 1 -C 3 haloalkyl, and —S(O) 2 —C 1 -C 3 alkyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof,

Assignees

• Abbvie Inc

Inventors

• Hasvold Lisa A
• PRATT John
• Mcdaniel Keith F
• Sheppard George S
• Liu Dachun
• Elmore Steven W
• Hubbard Robert D

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title