Inhibiting cyclic AMP-responsive element-binding protein (CREB)

Patent metadata

Field	Value
Publication number	US-12351577-B2
Application number	US-202017439646-A
Country	US
Kind code	B2
Filing date	Mar 13, 2020
Priority date	Mar 15, 2019
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

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 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.

First claim

The invention claimed is:

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 a

Assignees

• Forma Therapeutics Inc

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4745 Primary

  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