EZH2 inhibitors and uses thereof

• US 10,633,371 B2
• Filed: 04/21/2017
• Issued: 04/28/2020
• Est. Priority Date: 04/22/2016
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Bradner, James E., Paulk, Joshiawa, Qi, Jun
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US16/095,188
• Publication Number:
  US 20190135796A1
• Time in Patent Office: 1,103 Days
• Field of Search: 546255
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• 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 413/14 containing three or more hetero rings

Abstract

The present disclosure provides compounds of any one of Formulae (I), (II), and (III). The compounds described herein are inhibitors of histone methyltransferases (e.g., enhancer of zeste homolog 1 (EZH1) and enhancer of zeste homolog 2 (EZH2)) and are useful in treating and/or preventing a broad range of diseases (e.g., proliferative diseases). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein the compound is of the formula:

3. The compound of claim 1, wherein R^A1 is of the formula:

4. The compound of claim 1, wherein R^A1 is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl comprising 0, 1, or 2 double bonds in the heterocyclic ring system, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur.

5. The compound of claim 1, wherein R^A1 is substituted or unsubstituted alkyl.

6. The compound of claim 1, wherein R^A2 is substituted or unsubstituted acyl.

7. The compound of claim 1, wherein R^A2 is substituted or unsubstituted heterocyclyl.

8. The compound of claim 1, wherein R^A3 is hydrogen, substituted or unsubstituted alkyl, or is substituted or unsubstituted acyl.

9. The compound of claim 1, wherein R^A4 is hydrogen.

10. The compound of claim 1, wherein R^A5 is of the formula:

11. The compound of claim 1, wherein R^A6 is substituted or unsubstituted C_1-6 alkyl.

12. The compound of claim 1, wherein at least one of R^A2, R^A10, R^A12, and R^A17 is a warhead.

13. The compound of claim 1, wherein R^A20 is hydrogen, methyl, or of the formula:

14. The compound of claim 1, wherein the compound is of the formula:

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

16. A method of inhibiting the activity of an histone methyltransferase in a subject in need thereof, the method comprising administering to the subject an effective amount of claim 1.

17. A method of inhibiting the activity of an histone methyltransferase in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1.