Enhancer of zeste homolog 2 inhibitors

• US 9,556,157 B2
• Filed: 07/09/2014
• Issued: 01/31/2017
• Est. Priority Date: 07/10/2013
• Status: Expired due to Fees

• Current Assignee: Glaxosmithkline Intellectual Property Limited (GSK plc)
• Original Assignee: Glaxosmithkline Intellectual Property Limited (GSK plc)
• Inventors: Burgess, Joelle Lorraine, Knight, Steven David
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US14/898,178
• Publication Number:
  US 20160130261A1
• Time in Patent Office: 937 Days
• Field of Search: None
• 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 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 (I):

2. The compound according to claim 1 represented by Formula (III)(a):

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

4. The compound according to claim 2, wherein:

R¹ and R² are each independently (C₁-C₄)alkyl;

R³ is hydrogen;

R⁴ is selected from the group consisting of (C₁-C₃)alkyl and halogen;

R⁵ is —

NR^aR^b;

R⁶ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy;

R^a is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl, each of which is optionally substituted 1 or 2 times, independently, by (C₁-C₄)alkyl;

or

R^a is cyclopentyl or cyclohexyl, each of which is optionally substituted by amino, —

NH(C₁-C₄)alkyl, or —

N((C₁-C₄)alkyl)₂; and

R^b is hydrogen or (C₁-C₄)alkyl;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R³ is hydrogen, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R⁴ is selected from the group consisting of (C₁-C₃)alkyl and halogen, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R⁵ is selected from the group consisting of (C₃-C₆)alkoxy, (C₃-C₆)cycloalkyloxy-, heterocycloalkyloxy-, heterocycloalkyl, —

NH((C₃-C₆)cycloalkyl), —

N((C₁-C₃)alkyl)((C₃-C₆)cycloalkyl), —

NH(heterocycloalkyl), and —

N((C₁-C₃)alkyl)(heterocycloalkyl), wherein any said (C₃-C₆)alkoxy, (C₃-C₆)cycloalkyloxy-, heterocycloalkyloxy-, heterocycloalkyl, or (C₃-C₆)cycloalkyl is optionally substituted 1 or 2 times, independently, by halogen, hydroxyl, (C₁-C₃)alkoxy, amino, —

NH(C₁-C₃)alkyl, —

N((C₁-C₃)alkyl)₂, (C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl-, amino(C₁-C₃)alkyl-, ((C₁-C₃)alkyl)NH(C₁-C₃)alkyl-, ((C₁-C₃)alkyl)₂N(C₁-C₃)alkyl-, (C₃-C₈)cycloalkyl, cyano, —

CO₂R^a, —

C(O)NR^aR^b, —

SO₂NR^aR^b, phenyl, or heteroaryl, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein R⁵ is selected from the group consisting of (C₃-C₆)alkoxy, (C₃-C₈)cycloalkyloxy-, and heterocycloalkyloxy-, each of which is optionally substituted by hydroxyl, (C₁-C₃)alkoxy, amino, —

NH(C₁-C₃)alkyl, —

N((C₁-C₃)alkyl)₂, (C₁-C₃)alkyl, —

CO₂R^a, —

C(O)NR^aR^b, —

SO₂NR^aR^b, phenyl, or heteroaryl, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 7, wherein R⁵ is selected from the group consisting of cyclopentyloxy, cyclohexyloxy, pyrrolidinyloxy, piperidinyloxy, and tetrahydropyranyloxy, each of which is optionally substituted by hydroxyl, (C₁-C₃)alkoxy, amino, —

NH(C₁-C₃)alkyl, —

N((C₁-C₃)alkyl)₂, (C₁-C₃)alkyl, —

CO₂R^a, —

C(O)NR^aR^b, —

SO₂NR^aR^b, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, wherein R^a is (C₁-C₄)alkyl or phenyl(C₁-C₂)alkyl and R^b is hydrogen or (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein R⁵ is —

NR^aR^b, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein R^a is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or tetrahydropyranyl, each of which is optionally substituted 1 or 2 times, independently, by (C₁-C₄)alkyl, and R^b is hydrogen or (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 10, wherein R^a is cyclopentyl or cyclohexyl, each of which is optionally substituted by amino, —

NH(C₁-C₄)alkyl, or —

N((C₁-C₄)alkyl)₂, and R^b is hydrogen or (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein R⁶ is selected from the group consisting of hydrogen, —

SO₂(C₁-C₄)alkyl, halogen, (C₁-C₆)alkyl, (C₁-C₄)alkoxy, phenyl, heteroaryl, and cyano, wherein said phenyl or heteroaryl group is optionally substituted 1 or 2 times, independently, by (C₁-C₄)alkoxy, —

NR^aR^b, R^aR^bN(C₁-C₄)alkyl-, (C₁-C₄)alkylheterocycloalkyl-, halogen, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

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

15. The compound according to claim 13, wherein R⁶ is hydrogen, fluorine, chlorine, or bromine, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein R⁷ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl, and heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted 1 or 2 times, independently, by (C₁-C₄)alkoxy, —

NR^aR^b, R^aR^bN(C₁-C₄)alkyl-, (C₁-C₄)alkylheterocycloalkyl-, halogen, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein R⁷ is hydrogen or (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, wherein R⁸ is selected from the group consisting of (C₄-C₆)alkyl, (C₄-C₆)cycloalkyl, heterocycloalkyl, and phenyl, wherein said (C₄-C₆)alkyl, (C₄-C₆)cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted 1 or 2 times, independently, by —

OR^a, —

NR^aR^b, —

NHCO₂R^a, (C₁-C₃)alkyl, R^aR^bN(C₁-C₃)alkyl-, R^aO(C₁-C₃)alkyl-, —

CO₂R^a, —

C(O)NR^aR^b, or —

SO₂NR^aR^b, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 which is:

N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylthiophene-3-carboxamide;

N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-5-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-4-methylthiophene-3-carboxamide;

N-((5-amino-2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-5-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-4-methylthiophene-3-carboxamide;

or

2-bromo-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-5-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-4-methylthiophene-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

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