Enhancer of zeste homolog 2 inhibitors

• US 9,505,745 B2
• Filed: 04/25/2014
• Issued: 11/29/2016
• 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: LaFrance, Louis V. III, Schulz, Mark, Su, Dai-Shi, Blackledge, Charles William Jr., Burgess, Joelle Lorraine, Johnson, Neil W., Kasparec, Jiri, Knight, Steven David, Luengo, Juan I., Miller, William Henry, Newlander, Kenneth Allen, Romeril, Stuart Paul, Tian, Xinrong
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US14/787,866
• Publication Number:
  US 20160102083A1
• Time in Patent Office: 949 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 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 (I):

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

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

4. The compound according to claim 1, wherein R¹, R², and R³ are each independently selected from the group consisting of hydrogen, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl-, halo(C₁-C₄)alkyl, and hydroxy(C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

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

6. The compound according to claim 5, wherein R¹ and R² are each methyl, or a pharmaceutically acceptable salt thereof.

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

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

9. The compound according to claim 7, wherein R⁴ is selected from the group consisting of (C₁-C₃)alkyl and halogen, or a pharmaceutically acceptable salt thereof.

10. 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.

11. The compound according to claim 1, wherein R⁵ is (C₃-C₈)cycloalkyl(C₁-C₂)alkyl- or heterocycloalkyl(C₁-C₂)alkyl-, each of which is optionally substituted 1 or 2 times, independently, by —

NR^aR^b, —

NHCO₂R^a, (C₁-C₃)alkyl, or R^aR^bN(C₁-C₃)alkyl- or a pharmaceutically acceptable salt thereof.

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

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

13. The compound according to claim 12, 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.

14. The compound according to claim 12, 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.

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

16. The compound according to claim 9, wherein R⁶ is hydrogen, fluorine, chlorine, or bromine, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 which is:

18. The compound according to claim 9 which is:

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-isopropoxy-3-methylthiophene-2-carboxamide;

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

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

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

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

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

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

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

tert-butyl 4-((4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)(ethyl)amino)piperidine-1-carboxylate;

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

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)thiophene-3-carboxamide;

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

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

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

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

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

tert-butyl 4-((4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)(hydroxy)methyl)piperidine-1-carboxylate;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(hydroxy(piperidin-4-yl)methyl)-4-methylthiophene-3-carboxamide;

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

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thiophene-3-carboxamide;

tert-butyl 3-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)pyrrolidine-1-carboxylate;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(2-methylpyrrolidin-1-yl)thiophene-3-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-morpholinoethyl)thiophene-3-carboxamide;

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

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylamino)piperidin-1-yl)propyl)-4-methylthiophene-3-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-morpholinopropyl)thiophene-3-carboxamide;

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

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

(E)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-(piperidin-4-yl)prop-1-en-1-yl)thiophene-3-carboxamide;

tert-butyl ((trans)-4-((E)-1-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)prop-1-en-1-yl)cyclohexyl)carbamate;

5-((E)-1-((trans)-4-aminocyclohexyl)prop-1-en-1-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methylthiophene-3-carboxamide;

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

5-(((trans)-4-aminocyclohexyl)(hydroxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methylthiophene-3-carboxamide;

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

tert-butyl 4-(1-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)propyl)piperidine-1-carboxylate;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-(piperidin-4-yl)propyl)thiophene-3-carboxamide;

(S)-(−

)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylamino)piperidin-1-yl)propyl)-4-methylthiophene-3-carboxamide;

(R)-(+)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylamino)piperidin-1-yl)propyl)-4-methylthiophene-3-carboxamide;

5-(1-((trans)-4-aminocyclohexyl)propyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methylthiophene-3-carboxamide;

(−

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

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

(+)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((cis)-4-(dimethylamino)cyclohexyl)propyl)-4-methylthiophene-3-carboxamide;

(−

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

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-(piperidin-4-ylidene)propyl)thiophene-3-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1-(piperidin-4-yl)vinyl)thiophene-3-carboxamide;

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

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

2-bromo-5-(diethylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methylthiophene-3-carboxamide;

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

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

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

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

tert-butyl 3-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylthiophen-2-yl)pyrrolidine-1-carboxylate;

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

tert-butyl 4-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylthiophen-2-yl)piperidine-1-carboxylate;

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

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

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

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

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

ethyl (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methylthiophen-2-yl)(ethyl)carbamate;

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

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

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(2-(piperidin-4-yl)pyrrolidin-1-yl)thiophene-3-carboxamide;

5-([2,4′

-bipiperidin]-1-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methylthiophene-3-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)thiophene-3-carboxamide;

(Z)—

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(5-morpholinopent-2-en-3-yl)thiophene-3-carboxamide;

(Z)—

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(6-(4-methylpiperazin-1-yl)hex-2-en-3-yl)thiophene-3-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-5-(6-(4-methylpiperazin-1-yl)hexan-3-yl)thiophene-3-carboxamide;

(Z)—

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-(4-(dimethylamino)piperidin-1-yl)hex-2-en-3-yl)-4-methylthiophene-3-carboxamide;

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

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

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

or

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

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 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.