Enhancer of Zeste Homolog 2 inhibitors

• US 9,382,234 B2
• Filed: 12/12/2013
• Issued: 07/05/2016
• Est. Priority Date: 12/13/2012
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Donatelli, Carla A., Knight, Steven David, Miller, William Henry, Newlander, Kenneth Allen
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): Chen, Po-Chih
• Application Number:
  US14/651,711
• Publication Number:
  US 20150307480A1
• Time in Patent Office: 936 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 213/68 attached in position 4
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 309/38 one oxygen atom in position 2 or 4, e.g. pyrones
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : 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 409/12 : linked by a chain containing hetero atoms as chain links

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, wherein Y is NH, or a pharmaceutically acceptable salt thereof.

3. 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, (C₃-C₈)cycloalkyl, hydroxy(C₁-C₄)alkyl, (C₃-C₈)cycloalkyl(C₁-C₄)alkyl-, (C ₁ -C₄)alkylO(O)CNH(C₁-C₄)alkyl-, heterocycloalkyl, heterocycloalkyl(C₁-C₄)alkyl-, aryl, aryl(C₁-C₄)alkyl-, heteroaryl, and heteroaryl(C₁-C₄)alkyl-, wherein each (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 or 2 times, independently, by hydroxyl, halogen, nitro, (C₁-C₄)alkyl, cyano, (C₁-C₄)alkoxy, —

NH(C₁-C₄)alkyl, —

N((C₁-C₄)alkyl)₂, or —

CO₂(C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, 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 R^l and R² are each independently (C₁-C₄)alkyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R³ is hydrogen.

7. 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.

8. 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.

9. 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.

10. The compound according to claim 9, 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.

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

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

12. The compound according to claim 11, 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.

13. The compound according to claim 11, 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.

14. 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.

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

16. The compound according to claim 1 which is:

benzyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-l-carboxylate;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzamide;

3-(((trans)-4-(benzylcarbamoyl)cyclohexyl)oxy)-5-chloro-N-((2,6-dimethyl-4-oxo -1,4-dihydropyridin-3-yl)methyl)-2-methylbenzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-4H-pyran-3-yl)methyl)-2-methyl-3-((1-(pyrimidin -4-yl)piperidin-4-yl)oxy)benzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-4H-pyran-3-yl)methyl)-3-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzamide;

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

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide;

tert-butyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-1-carboxylate;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-(piperidin-4-yloxy)benzamide;

tert-butyl ((1r,4r)-4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)cyclohexyl)carbamate;

3-(((1r,4r)-4-aminocyclohexyl)oxy)-5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methylbenzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-(((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)oxy)benzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzamide;

5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-3-(((trans)-4-(dimethylamino)cyclohexyl)oxy)-2-methylbenzamide;

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

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

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

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

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

or

N-((5-amino-2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-5-bromo-3-(ethyl((1r,4r)-4-morpholinocyclohexyl)amino)-2-methylbenzamide;

or a pharmaceutically acceptable salt thereof.

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

18. A method of therapeutically treating cancer mediated by EZH2 comprising administering to a patient with cancer a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 17.

19. The method of claim 18, wherein said cancer is selected from the group consisting of:

brain cancer, glioblastomas, leukemias, lymphomas, breast cancer, Wilm'"'"'s tumor, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, renal cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, giant cell tumor of bone, and thyroid cancer.