Inhibiting CREB binding protein (CBP)
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.
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