Benzimidazole derivatives as bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-10017501-B2
Application number	US-201615239422-A
Country	US
Kind code	B2
Filing date	Aug 17, 2016
Priority date	May 9, 2013
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I)

wherein R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , and R 5 are described herein.

First claim

We claim:

1. A compound of Formula (Ib)

wherein
R 1a and R 1b are each independently C 1-6 alkyl optionally substituted with from 1 to 5 R 20 groups;
R 2a and R 2b are each independently H or halo;
R 3 is
—C(O)OR a , —NHC(O)OR a , —NHS(O) 2 R a , or —S(O) 2 NR a R b ; or
selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, amino, C 5-10 aryl, C 6-20 arylalkyl, C 1-10 heteroalkyl, C 5-10 heteroaryl, and C 6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups;

R 5 is
—C(O)OR a , —NHC(O)OR a , —NHS(O) 2 R a , or —S(O) 2 NR a R b ; or
selected from the group consisting of H, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy, amino, C 5-10 aryl, C 6-20 arylalkyl, C 1-10 heteroalkyl, C 5-10 heteroaryl, and C 6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups;

each R a and R b is independently selected from the group consisting of H, C 1-10 alkyl, C 5-10 aryl, C 6-20 arylalkyl, C 1-10 heteroalkyl, C 5-10 heteroaryl, and C 6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; and
each R 20 is independently selected from the group consisting of acyl, C 1-10 alkyl, C 1-10 alkoxy, amino, amido, amidino, C 5-10 aryl, C 6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C 1-10 haloalkyl, C 1-10 heteroalkyl, C 5-10 heteroaryl, C 6-20 heteroarylalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the C 1-10 alkyl, C 5-10 aryl, C 6-20 arylalkyl, C 1-10 heteroalkyl, C 5-10 heteroaryl, and C 6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, C 5-10 aryl, halo, C 1-6 haloalkyl, cyano, hydroxyl, and C 1-6 alkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein R 1a and R 1b are each independently C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , wherein R 3 is C 1-10 alkyl, C 1-10 alkoxy, or C 1-10 heteroalkyl, each of which may be optionally substituted with from 1 to 5 R 20 groups, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , wherein R 3 is an, C 5-10 aryl, C 6-20 arylalkyl, C 5-10 heteroaryl, or C 6-20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 R 20 groups, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 , wherein R 5 is C 1-10 alkyl, or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , wherein R 5 is C 1-10 haloalkyl, or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein R 5 is C 1-10 cycloalkyl, or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 of Formula (Ic)

or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 of Formula (Id)

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 , wherein R 3 is C 1-10 alkyl, C 1-10 alkoxy, or C 1-10 heteroalkyl, each of which may be optionally substituted with from 1 to 5 R 20 groups, or a pharmaceutically acceptable salt thereof.

11. A compound of claim 9 , wherein R 3 is an, C 5-10 aryl, C 6-20 arylalkyl, C 5-10 heteroaryl, or C 6-20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 R 20 groups, or a pharmaceutically acceptable salt thereof.

12. A compound of claim 9 , wherein R 5 is C 1-10 alkyl, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 9 , wherein R 5 is C 1-10 haloalkyl, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 9 , wherein R 5 is C 1-10 cycloalkyl, or a pharmaceutically acceptable salt thereof.

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

Assignees

• Gilead Sciences Inc

Inventors

• Aktoudianakis Evangelos
• Chin Gregory
• Corkey Britton Kenneth
• Du Jinfa
• Elbel Kristyna
• Jiang Robert H
• Kobayashi Tetsuya
• Lee Rick
• Martinez Ruben
• Metobo Samuel E
• Mish Michael
• Munoz Manuel
• Shevick Sophie
• Sperandio David
• Yang Hai
• Zablocki Jeff

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D453/02

  containing not further condensed quinuclidine ring systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title