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 —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.