Inhibiting CREB binding protein (CBP)

Patent metadata

Field	Value
Publication number	US-11254674-B2
Application number	US-202016946159-A
Country	US
Kind code	B2
Filing date	Jun 8, 2020
Priority date	Jun 29, 2018
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

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 —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or a 5-6 membered heteroaryl, wherein each alkyl, cycloalkyl, heteroaryl is optionally substituted with one or more R 10 ;
R 10 is each independently, at each occurrence, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —OC 3 -C 6 cycloalkyl, —Oaryl, —Oheteroaryl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl 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; and
R 12 is independently, at each occurrence, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl),—S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl).

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

3. The compound of claim 2 , wherein R 6 is —C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more R 10 .

4. The compound of claim 3 , wherein R 6 is methyl.

5. The compound of claim 3 , wherein R 10 is selected from —C 3 -C 8 cycloalkyl, aryl, and heteroaryl, wherein each cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more —R 12 .

6. The compound of claim 5 , wherein R 10 is selected from cyclopentyl, cyclohexyl, phenyl, and pyrazolyl, wherein each cycpentyl, cyclohexyl, phenyl, or pyrazolyl is optionally substituted with one or more —R 12 .

7. The compound of claim 5 , wherein each R 12 is independently selected from halogen.

8. The compound of claim 7 , wherein each R 12 is independently selected from F and Cl.

9. The compound of claim 7 , selected from the group consisting of:

10. The compound of claim 2 , wherein R 6 is —C 3 -C 8 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 10 .

11. The compound of claim 10 , wherein R 6 is selected from cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one or more R 10 .

12. The compound of claim 10 , wherein each R 10 is independently selected from halogen.

13. The compound of claim 12 , wherein each R 10 is F.

14. The compound of claim 12 , wherein the compound is selected from the group consisting of:

15. The compound of claim 2 , wherein R 6 is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R 10 .

16. The compound of claim 15 , wherein R 6 is pyridinyl optionally substituted with one or more R 10 .

17. The compound of claim 15 , wherein each R 10 is independently selected from halogen, or wherein any two R 10 when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl.

18. The compound of claim 17 , wherein each R 10 is Cl, or wherein any two R 10 when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl.

19. The compound of claim 17 , selected from the group consisting of:

20. A compound, selected from the group consisting of:

21. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

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

• C07D471/04 Primary

  Ortho-condensed systems · 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

• 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