BENZIMIDAZOLE DERIVATIVES AS BROMODOMAIN INHIBITORS

• US 20140336190A1
• Filed: 05/08/2014
• Published: 11/13/2014
• Est. Priority Date: 05/09/2013
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: 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, Shevick, Sophie, Sperandio, David, Yang, Hai, Zablocki, Jeff, Munoz, Manuel
• Granted Patent: US 9,458,145 B2
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

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, R², R^2b, R³, R^4a, R^4b, and R⁵ are described herein.

Claims

1. A compound of Formula (I)

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 R³ 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 R²⁰ groups, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1, wherein R³ 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 R²⁰ groups, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1, wherein R⁵ is C_1-10 alkyl.

6. A compound of claim 1 of Formula (Ia)

7. A compound of claim 1 of Formula (Ib)

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

10. A compound of claim 1 of Formula (Ie)

11. A compound of claim 10, wherein R³ 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 R²⁰ groups, or a pharmaceutically acceptable salt thereof.

12. A compound of claim 10, wherein R³ 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 R²⁰ groups, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 selected from the group consisting of

14. A compound of claim 1 selected from the group consisting of

15. A compound of claim 1 selected from the group consisting of

16. A compound of claim 1 selected from the group consisting of

17. A compound of claim 1 selected from the group consisting of

18. A compound of claim 1 selected from the group consisting of

19. A compound of claim 1 selected from the group consisting of

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

21. A method of treating a disease or condition responsive to the inhibition of a bromodomain-containing protein, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the bromodomain-containing protein is BRD4.

23. The method of claim 21, wherein the disease or condition is a neoplasm, cancer or tumor of the colon, rectum, prostate, lung, pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast, skin, or the nervous system

24. The method of claim 21, wherein the disease or condition is diffuse large B-cell lymphoma or multiple myeloma.

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