Inhibiting cyclic AMP-responsive element-binding protein (CREB)
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 diseases or disorders associated with the inhibition of CBP/p300 family of bromodomains (e.g., certain forms of cancer), and methods of synthesis of these compounds.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl,—OR 5 , or —NHR 5 ;
R 2 is —C 3 -C 8 cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein each cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 6 ;
R 3 is —C 1 -C 6 alkyl,—C 3 -C 8 cycloalkyl, or heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl, is optionally substituted with one or more R 7 ;
R 4 and R 4′ are each independently —H, halogen, —CN, —CH 2 CN, —COOH, or heterocycloalkyl;
each R 5 is independently —C 1 -C 6 alkyl;
R 6 and R 7 are each independently, at each occurrence, halogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, -heterocyclyl, aryl, heteroaryl, —OH, oxo, —OR 8 ,—NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 R 8′ , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
wherein any two R 6 or any two R 7 , when on non-adjacent atoms, can combine to form a cycloalkyl or heterocyclyl;
wherein any two R 6 or any two R 7 , when on adjacent atoms, can combine to form an aryl or heterocyclyl;
R 8 and R 9 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, or aryl, wherein each alkyl, or aryl is optionally substituted with one or more R 10 or R 11 ;
R 8′ and R 9′ are each independently, at each occurrence, —C 1 -C 6 alkyl or heterocyclyl, wherein each alkyl, or heterocyclyl is optionally substituted with one or more R 10 or R 11 ;
R 10 and R 11 are each independently, at each occurrence, —C 1 -C 6 alkyl, heteroaryl, aryl, —OH, halogen, —OC 1 -C 6 alkyl, or —C(O)OH, wherein each alkyl, or heteroaryl is optionally substituted with one or more —R 12 ;
wherein any two R 10 or any two R 11 , when on adjacent atoms, can combine to form a heterocyclyl or aryl; and
R 12 is independently, at each occurrence, —C 1 -C 6 alkyl, —OH, halogen, or —OC 1 -C 6 alkyl.
2. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
R 1 is —C 1 -C 6 alkyl, -C 3 cycloalkyl,—OR 5 , or —NHR 5 ;
R 2 is —C 4 -C 6 cycloalkyl; 4-6 membered heterocyclyl; 6-membered heteroaryl; or C 6 aryl;
wherein each cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 6 ;
R 3 is —C 1 -C 6 alkyl, —C 6 cycloalkyl, or 4-membered heterocyclyl, wherein each alkyl, cycloalkyl, or hetercyclyl, is optionally substituted with one or more R 7 ;
R 4 and R 4′ are each independently —H, halogen, —CN, —CH 2 CN, —COOH, or 5-membered heterocycloalkyl;
R 6 is independently, at each occurrence, halogen, —C 1 -C 6 alkyl, 4-membered heterocyclyl, —OH, oxo, —OR 8 ,—NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9′ , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl or heterocyclyl is optionally substituted with one or more R 10 ;
R 7 is independently, at each occurrence, halogen, —C 1 -C 6 alkyl, -C 6 cycloalkyl, -6-membered heterocyclyl, C 6 aryl, 5-6 membered heteroaryl, —OH, halogen, oxo, —OR 8 , —NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
wherein any two R 7 , when on adjacent atoms, can combine to form a 5-membered heterocycyl or C 6 aryl;
R 8 and R 9 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, or C 6 aryl, wherein each alkyl is optionally substituted with one or more R 10 or R 11 ;
R 8′ and R 9′ are each independently, at each occurrence, —C 1 -C 6 alkyl or 4-membered heterocyclyl, wherein each alkyl is optionally substituted with one or more R 10 or R 11 ;
R 10 and R 11 are each independently, at each occurrence, —C 1 -C 6 alkyl, 5-membered heteroaryl, C 6 aryl, —OH, halogen, —OC 1 -C 6 alkyl, or —C(O)OH, wherein each alkyl, or heteroaryl is optionally substituted with one or more —R 12 ;
wherein any two R 10 or any two R 11 , when on adjacent atoms, can combine to form a 5-membered heterocyclyl or C 6 aryl; and
R 12 is independently, at each occurrence, —C 1 -C 6 alkyl, —OH, halogen, or —OC 1 -C 6 alkyl.
3. The compound of claim 2 , or the pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl;
R 2 is —C 4 -C 6 cycloalkyl; 6 membered heterocyclyl comprising 1-2 heteroatoms selected from N and O; 6-membered heteroaryl comprising one nitrogen; or C 6 aryl; wherein each cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 6 ;
R 3 is —C 1 -C 3 alkyl optionally substituted with one or more R 7 ;
R 4 is —H or halogen;
R 4′ is —H, —CN, —CH 2 CN, —COOH, or 5-membered heterocycloalkyl;
R 6 is independently, at each occurrence, —C 1 -C 6 alkyl, —OR 8 , —S(O) 2 NR 8 R 9′ , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl or heterocyclyl is optionally substituted with one or more R 10 ;
R 7 is independently, at each occurrence, halogen, —C 1 -C 6 alkyl, -C 6 cycloalkyl, C 6 aryl, 5-6 membered heteroaryl, —OH, —OR 8 , —C(O)OR 8 , or —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl, cycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
R 8 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, or C 6 aryl, wherein each alkyl is optionally substituted with one or more R 10 or R 11 ;
R 8′ is independently, at each occurrence, —C 1 -C 6 alkyl or 4-membered heterocyclyl, wherein each alkyl is optionally substituted with one or more R 10 or R 11 ;
R 9′ is independently, at each occurrence, —C 1 -C 6 alkyl;
R 10 and R 11 are each independently, at each occurrence, —C 1 -C 6 alkyl, 5-membered heteroaryl, —OH, halogen, —OC 1 -C 6 alkyl, or —C(O)OH, wherein each alkyl is optionally substituted with one or more —R 12 ;
wherein any two R 10 or any two R 11 , when on adjacent atoms, can combine to form a 5-membered heterocyclyl or C 6 aryl; and
R 12 is independently, at each occurrence, halogen.
4. The compound of claim 3 , or the pharmaceutically acceptable salt thereof, wherein:
R 2 is —C 5 -C 6 cycloalkyl; 6 membered heterocyclyl comprising 1-2 heteroatoms selected from N and O; or C 6 aryl; wherein each cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 6 ;
R 4′ is —H, —CN, —COOH, or 5-membered heterocycloalkyl;
R 7 is independently, at each occurrence, halogen, —C 1 -C 6 alkyl, -C 6 cycloalkyl, C 6 aryl, 5-membered heteroaryl, —OH, —C(O)OR 8 , or —C(O)NR 8 S(O) 2 R 9′ , wherein each alkyl, cycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
R 10 and R 11 are each independently, at each occurrence, —C 1 -C 6 alkyl, 5-membered heteroaryl, —OH, halogen, —OC 1 -C 6 alkyl, or —C(O)OH, wherein each alkyl is optionally substituted with one or more R 12 , wherein R 12 is fluorine.
5. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 1 is —OR 5 , and optionally wherein R 5 is methyl.
6. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is C 4 -C 6 cycloalkyl, phenyl, six-membered heterocyclyl, or six-membered heteroaryl,
optionally wherein:
the six-membered heterocyclyl is selected from the group consisting of piperidinyl, tetrahydropyranyl, and piperazinyl; or
the six-membered heteroaryl is pyridinyl.
7. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 3 is:
C 1 -C 6 alkyl substituted with phenyl and with methyl; or
C 2 alkyl substituted with phenyl and at least one of halogen, —CH 3 , —COOH, —CH 2 COOH, or —C(O)NHSO 2 CH 3 , wherein the phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —CH 3 , —OCH 3 , and —COOH.
8. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is:
9. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is:
10. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is:
11. The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein R 7 is phenyl optionally substituted with one or more R 10 , wherein each R 10 is independently selected from —C 1 -C 3 alkyl, —O(C 1 -C 3 alkyl), and halogen.
12. The compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —C 5 -C 6 cycloalkyl; and
R 7 is phenyl optionally substituted with one or more R 10 , wherein each R 10 is independently selected from —C 1 -C 3 alkyl —O(C 1 -C 3 alkyl), and halogen.
13. The compound of claim 1 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
each R a is independently selected from —H, halogen, —CH 3 , —OCH 3 , and —COOH;
X is CH or N;
R 13 is —H, —COOH, —OCH 3 , or —(CO)NHSO 2 CH 3 ;
R 15 is —H or —CH 3 ;
R 16 is —H, halogen, —CH 3 , —COOH, —CH 2 COOH, or —(CO)NHSO 2 CH 3 ; and
R 17 is —H or halogen.
14. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C 1 -C 6 alkyl;
R 2 is —C 3 -C 8 cycloalkyl, or 3-8 member heterocyclyl comprising one or more O, S or N heteroatoms, wherein each cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 6 ;
R 3 is —C 1 -C 6 alkyl substituted with one or more one R 7 , and optionally additionally substituted with a COOH;
R 4 and R 4′ are each independently —H;
R 6 is each independently, at each occurrence, —C 1 -C 6 alkyl optionally substituted with one or more R 10 , —OH, halogen, oxo, —CN, —SR 8 , —OR 8 , —(CH 2 )˜-OR 8 , —NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 R 9 , —C(O)NR 8 S(O) 2 R 9′ , —NR 8 C(O)R 9′ , —NR 8 S(O) 2 R 9′ , —S(O)R 8′ , —S(O)NR 8 R 9 , or —NR 8 S(O)R 9 ;
R 7 that is a mono or bicyclic (C 5 -C 10 )aryl, (5-10 member)heteroaryl, (C 3 -C 10 )cycloalkyl, or a (3-10 member) heterocycloalkyl optionally substituted with one or more R 10 ;
R 8 and R 9 is each independently, at each occurrence, H, or (C 1 -C 4 ) alkyl optionally substituted with one or more R 10 ;
R 10 is each independently, at each occurrence, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , methyl or methoxy.
15. The compound of claim 14 , wherein R 2 is —C 5 -C 6 cycloalkyl or 5-6 member heterocyclyl comprising one or more O, S or N heteroatoms, wherein each cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 6 ;
optionally wherein R 2 is —C 6 cycloalkyl optionally substituted with one or more R 6 .
16. The compound of claim 14 , wherein R 3 is:
—C 1 -C 4 alkyl substituted with one R 7 , and R 7 is a C 5 -C 6 monocyclic aryl, a 5-6 member monocyclic heteroaryl, a C 5 -C 6 monocyclic cycloalkyl, or a 5-6 member monocyclic heterocycloalkyl; or
—C 1 -C 6 alkyl substituted with —COOH.
17. The compound of claim 14 , wherein R 3 is —C 1 -C 6 alkyl not substituted with COOH, and either R 7 or R 2 is substituted with one —COOH.
18. The compound of claim 14 , wherein R 1 is methyl.
19. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
(Currently amended) A compound or a pharmaceutically
acceptable salt thereof, wherein the compound is selected from
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