BRM/BRG1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12509453-B2
Application number	US-202017425041-A
Country	US
Kind code	B2
Filing date	Jan 29, 2020
Priority date	Jan 29, 2019
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

The compounds disclosed herein may be inhibitors of BRG1 (Brahma-related gene-1) and/or BRM (Brahma). The compounds or pharmaceutically acceptable salts thereof are useful for the treatment of disorders associated with an alteration in a BAF complex, e.g., a disorder associated with an alteration in one or both of the BRG1 and BRM proteins. Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.

First claim

The invention claimed is:

1 . A compound having the structure:

wherein Y is N or CH;
R 1 is hydrogen, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 9 heterocyclyl, or —SO 2 R 8 ;
R 2 is halo, or optionally substituted C 1 -C 6 alkyl;
R 3 is halo, hydrogen or optionally substituted C 1 -C 6 alkyl, or R 2 and R 3 combine with the carbons to which they are attached to form a 5- or 6-membered ring;
R 4 , R 5 , and R 7 are, independently, hydrogen or optionally substituted C 1 -C 6 alkyl;
R 6 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkyl C 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkyl C 2 -C 9 heteroaryl;
R 8 is optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 8 cycloalkyl, or —NR 9 R 10 ;
R 9 and R 10 are, independently, optionally substituted C 1 -C 6 alkyl;
Het is a 5- or 6-membered heteroaryl;
A is optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heterocyclyl, or optionally substituted C 2 -C 9 heteroaryl;
L is absent, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, or optionally substituted C 1 -C 6 heteroalkyl; and
B is cyano, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 cycloalkyl, optionally substituted C 2 -C 9 heterocyclyl, or optionally substituted C 2 -C 9 heteroaryl;
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein R 5 is hydrogen.

3 . The compound of claim 1 , wherein Het is

4 . The compound of claim 1 , wherein A is optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl.

5 . The compound of claim 1 , wherein the compound has the structure:

6 . The compound of claim 1 , wherein B is optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl.

7 . The compound of claim 1 , wherein R 4 is hydrogen.

8 . The compound of claim 1 , wherein R 7 is hydrogen.

9 . The compound of claim 1 , wherein R 1 is —SO 2 R 8 .

10 . The compound of claim 9 , wherein R 8 is optionally substituted C 1 -C 6 alkyl.

11 . The compound of claim 1 , wherein R 2 is optionally substituted C 1 -C 6 alkyl or halo.

12 . The compound of claim 1 , wherein R 3 is hydrogen.

13 . The compound of claim 1 , wherein R 3 is optionally substituted C 1 -C 6 alkyl or halo.

14 . The compound of claim 1 , wherein R 2 and R 3 combine with the carbons to which they are attached to form a 5- or 6-membered ring.

15 . The compound of claim 14 , wherein the compound has the structure:

wherein X 1 and X 2 are N or CH.

16 . The compound of claim 1 , wherein the compound has the structure:

17 . The compound of claim 1 , wherein the compound is any one of compounds:

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

19 . A method of treating melanoma, hematologic cancer, prostate cancer, breast cancer, or bone cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .

Assignees

• Foghorn Therapeutics Inc

Inventors

• Anthony Neville John
• Vaswani Rishi G
• Millan David Simon
• Schiller Shawn E R

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title