Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors

Patent metadata

Field	Value
Publication number	US-11787803-B2
Application number	US-202217669135-A
Country	US
Kind code	B2
Filing date	Feb 10, 2022
Priority date	Sep 15, 2017
Publication date	Oct 17, 2023
Grant date	Oct 17, 2023

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

The invention claimed is:

1. A compound of formula (I-h):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —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, —OR 5 , —N(R 5 ) 2 , or —NHR 5 ;
R 4 and R 4′ are each independently —H, halogen, —OH, —CN, or —NH 2 ;
each R 5 is independently —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 6 and R 7 are each independently, at each occurrence, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, —OH, halogen, oxo, —CN, —SR 8 , —OR 8 , —(CH 2 ) n —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 , —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′ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
R 8 and R 9 are each independently, at each occurrence, —H, —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, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8 and R 9 may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, 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, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8′ and R 9′ may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl 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, —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 ;
wherein any two R 10 or any two R 11 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl;
wherein any two R 10 or any two R 11 , 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, —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); and
n is an integer from 1 to 4.

2. The compound of claim 1 , wherein the compound is a compound of formula (I-h′):

3. The compound of claim 1 , wherein the compound is a compound of formula (I-h″):

4. The compound of claim 1 , wherein R 1 —OR 5 .

5. The compound of claim 4 , wherein R 5 is —C 1 -C 6 alkyl.

6. The compound of claim 4 , wherein R 5 is methyl.

7. The compound of claim 1 , wherein R 4 is —H.

8. The compound of claim 1 , wherein R 4′ is —H.

9. The compound of claim 1 , wherein R 6 is aryl and the aryl is optionally substituted with one or more R 10 .

10. The compound of claim 1 , wherein R 6 is phenyl and the phenyl is optionally substituted with one or more R 10 .

11. The compound of claim 9 , wherein each R 6 is independently selected from —C 1 -C 6 alkyl, halogen, and —OC 1 -C 6 alkyl.

12. The compound of claim 1 , wherein R 7 is selected from —OH, —CN, —OR 8 , —(CH 2 ) n —OR 8 ,
and —S(O) 2 R 8′ .

13. The compound of claim 12 , wherein R 7 is —OR 8 , and R 8 is —C 1 -C 6 alkyl.

14. The compound of claim 12 , wherein R 7 is —(CH 2 ) n —OR 8 , n is 1, and R 8 is —H.

15. The compound of claim 12 , wherein R 7 is —S(O) 2 R 8′ and R 8′ is —C 1 -C 6 alkyl.

16. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure

20. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

• Forma Therapeutics Inc

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · 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