Inhibiting CREB binding protein (CBP)

Patent metadata

Field	Value
Publication number	US-10870648-B2
Application number	US-201916457596-A
Country	US
Kind code	B2
Filing date	Jun 28, 2019
Priority date	Jun 29, 2018
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

Abstract

The present disclosure is directed to inhibitors of the CBP/p300 family of bromodomains. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of the CBP/p300 family of bromodomains. For instance, the disclosure is concerned with compounds and compositions for inhibition of the CBP/p300 family of bromodomains, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of CBP/p300 family of bromodomains, and methods of synthesis of these compounds.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —OR 5 ;
R 5 is —C 1 C 6 alkyl;
R 6 is phenyl optionally substituted with one or more R 10 ;
R 10 is each independently, at each occurrence, —C 1 -C 6 alkyl, halogen, —OC 1 -C 6 alkyl, —OC 3 -C 6 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more —R 12 ; or wherein any two R 10 when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl; or wherein any two R 10 when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 12 is independently, at each occurrence, —C 1 -C 6 alkyl, —OH, or halogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 5 is —C 1 -C 3 alkyl;
R 10 is each independently, at each occurrence halogen or —OC 1 -C 6 alkyl, —OC 3 -C 6 cycloalkyl, wherein each alkyl, or cycloalkyl, is optionally substituted with one or more —R 12 ; and
R 12 is halogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein any two R 10 when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein any two R 10 when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl.

5. The compound of claim 1 , wherein R 5 is methyl.

6. The compound of claim 5 , wherein at least one R 10 is —OC 1 -C 6 alkyl optionally substituted with one or more —R 12 .

7. The compound of claim 6 , wherein R 12 is halogen.

8. The compound of claim 5 , wherein at least one R 10 is —C 1 -C 6 alkyl optionally substituted with one or more —R 12 .

9. The compound of claim 8 , wherein R 12 is halogen.

10. The compound of claim 5 , wherein at least one R 10 is —OC 3 -C 6 cycloalkyl optionally substituted with one or more —R 12 .

11. The compound of claim 10 , wherein R 12 is halogen.

12. A compound of Formula (IV-a):

or a pharmaceutically acceptable salt thereof, wherein
n is an integer of 0, 1, 2, 3, 4 or 5; and
each R 10 is independently, at each occurrence, selected from the group consisting of: —C 1 -C 6 alkyl, halogen, —OC 1 -C 6 alkyl, and —OC 3 -C 6 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or C 1 -C 6 alkyl; or
any two R 10 when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl; or
any two R 10 when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl.

13. The compound of claim 1 , wherein n is 0, 1 or 2.

14. The compound of claim 13 , wherein each R 10 is independently, at each occurrence, selected from the group consisting of:
—C 1 -C 6 alkyl, halogen, —OC 1 -C 6 salkyl, and —OC 3 -C 6 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or methyl.

15. The compound of claim 14 , wherein each halogen is independently selected from the group consisting of fluorine and chlorine.

16. The compound of claim 15 , wherein each —OC 3 -C 6 cycloalkyl is —O-cyclopropyl and each —C 1 -C 6 alkyl is methyl and each —OC 1 -C 6 alkyl is methoxy.

17. The compound of claim 1 , wherein each R 10 is independently, at each occurrence, selected from the group consisting of:
—C 1 -C 6 alkyl, halogen, —OC 1 -C 6 alkyl, and —OC 3 -C 6 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or methyl.

18. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

22. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

23. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

24. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

Assignees

• Forma Therapeutics Inc

Inventors

• Schiller Shawn E R
• Herbertz Torsten
• Li Hongbin
• Graves Bradford
• Mischke Steven
• WEST Angela
• Downing Jennifer R
• Ericsson Anna

Classifications

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title