ENHANCER OF ZESTE HOMOLOG 2 INHIBITORS

• US 20170029412A1
• Filed: 10/13/2016
• Published: 02/02/2017
• Est. Priority Date: 04/30/2013
• Status: Active Grant

• Current Assignee: Glaxosmithkline Intellectual Property Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxosmithkline Intellectual Property Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: BLACKLEDGE, Charles William Jr., BURGESS, Joelle Lorraine, JOHNSON, Neil W., KASPAREC, Jiri, KNIGHT, Steven David, LaFRANCE, Louis V. III, LUENGO, Juan I., MILLER, William Henry, NEWLANDER, Kenneth Allen, ROMERIL, Stuart Paul, SCHULZ, Mark, SU, Dai-Shi, TIAN, Xinrong
• Granted Patent: US 9,790,212 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

This invention relates to novel compounds according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.

Claims

1. A compound according to Formula (III)(a):

2. The compound according to claim 1, wherein R¹ and R² are each independently (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R¹ and R² are each methyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein R⁴ is methyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, wherein R⁴ is methyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is optionally substituted by halogen, —

OR^a, —

NR^aR^b, —

NHCO₂R^a, nitro, (C₁-C₃)alkyl, R^aR^bN(C₁-C₃)alkyl-, R^aO(C₁-C₃)alkyl-, (C₃-C₅)cycloalkyl, cyano, —

CO₂R^a, —

C(O)NR^aR^b, —

SO₂NR^aR^b, heterocycloalkyl, aryl, or heteroaryl, wherein said (C₃-C₅)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 or 2 times, independently, by halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, —

CO(C₁-C₄)alkyl, —

CO₂(C₁-C₄)alkyl, —

NR^aR^b, —

NHCO₂R^a, hydroxyl, oxo, (C₁-C₄)alkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl-, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is optionally substituted by halogen, —

OR^a, —

NR^aR^b, —

NHCO₂R^a, nitro, (C₁-C₃)alkyl, R^aR^bN(C₁-C₃)alkyl-, R^aO(C₁-C₃)alkyl-, (C₃-C₅)cycloalkyl, cyano, —

CO₂R^a, —

C(O)NR^aR^b, —

SO₂NR^aR^b, heterocycloalkyl, aryl, or heteroaryl, wherein said (C₃-C₅)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 or 2 times, independently, by halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, —

CO(C₁-C₄)alkyl, —

CO₂(C₁-C₄)alkyl, —

NR^aR^b, —

NHCO₂R^a, hydroxyl, oxo, (C₁-C₄)alkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl-, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is substituted by heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, —

CO(C₁-C₄)alkyl, —

CO₂(C₁-C₄)alkyl, —

NR^aR^b, —

NHCO₂R^a, hydroxyl, oxo, (C₁-C₄)alkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl-, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 5, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is substituted by heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, —

CO(C₁-C₄)alkyl, —

CO₂(C₁-C₄)alkyl, —

NR^aR^b, —

NHCO₂R^a, hydroxyl, oxo, (C₁-C₄)alkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl-, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is substituted by heterocycloalkyl, wherein said heterocycloalkyl is substituted by (C₁-C₄)alkoxy, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 5, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl-which is substituted by heterocycloalkyl, wherein said heterocycloalkyl is substituted by (C₁-C₄)alkoxy, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein R⁶ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 5, wherein R⁶ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 11, wherein R⁶ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein R⁶ is hydrogen, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 5, wherein R⁶ is hydrogen, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 11, wherein R⁶ is hydrogen, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

19. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 16 and a pharmaceutically acceptable excipient.

20. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 17 and a pharmaceutically acceptable excipient.