Enhancer of zeste homolog 2 inhibitors

• US 10,604,531 B2
• Filed: 05/01/2017
• Issued: 03/31/2020
• Est. Priority Date: 05/05/2016
• Status: Active Grant

• Current Assignee: Glaxosmithkline Intellectual Property Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxosmithkline Intellectual Property Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Knight, Steven David, Lafrance, III, Louis Vincent, Tian, Xinrong
• Primary Examiner(s): Jarrell, Noble E
• Application Number:
  US16/097,322
• Publication Number:
  US 20190092785A1
• Time in Patent Office: 1,065 Days
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

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) or a pharmaceutically acceptable salt thereof:

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is (C₁-C₄)alkyl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is methyl, ethyl, n-propyl, or methoxy.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is methyl.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R² is methyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R³ is (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₅)cycloalkyl, or (C₆-C₁₀)bicycloalkyl, wherein said (C₃-C₅)cycloalkyl or (C₆-C₁₀)bicycloalkyl are each optionally substituted by one or two groups independently selected from halogen and (C₁-C₄)alkyl.

7. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein R³ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl.

8. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein R³ is (C₃-C₅)cycloalkyl or (C₆-C₁₀)bicycloalkyl, each of which is optionally substituted by one or two groups independently selected from halogen and (C₁-C₄)alkyl.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein R³ is (C₃-C₅)cycloalkyl which is optionally substituted by fluoro or methyl.

10. The compound according to claim 1 which is:

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-2-(1-(1-neopentylpiperidin-4-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-2-(1-(1-(cyclobutylmethyl)piperidin-4-yl)ethyl)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-isobutylpiperidin-4-yl)ethyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-2-(1-(1-(cyclopentylmethyl)piperidin-4-yl)ethyl)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(2,2-dimethylbutyl)piperidin-4-yl)ethyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)ethyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-2-(1-(1-(cyclopropylmethyl)piperidin-4-yl)ethyl)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-2-(1-(1-((1-methylcyclopentyl)methyl)piperidin-4-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-2-(1-(1-(bicyclo[2.2.2]octan-1-ylmethyl)piperidin-4-yl)ethyl)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-2-(1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

or

(R)-5-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-2-(1-(1-((1-methylcyclopropyl)methyl)piperidin-4-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 which is:

12. The compound or pharmaceutically acceptable salt thereof according to claim 11 which is a hydrochloric acid salt.

13. The hydrochloric acid salt according to claim 12 in a crystalline form which is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu K_α

radiation, of about 8.9, 10.7, 14.3, 14.8, 16.9, and 24.0 degrees 2θ

.

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

15. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 11 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising the hydrochloric acid salt according to claim 13 and a pharmaceutically acceptable excipient.