P300/CBP HAT inhibitors

Patent metadata

Field	Value
Publication number	US-11274090-B2
Application number	US-201916970169-A
Country	US
Kind code	B2
Filing date	Feb 15, 2019
Priority date	Feb 16, 2018
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with histone acetyltransferase (HAT).

First claim

The invention claimed is:

1. A compound having the Formula I:

or a pharmaceutically acceptable salt thereof, wherein
Ring B is aryl, heterocyclyl, or heteroaryl each of which may be optionally substituted with 1 to 4 groups selected from R b ;
R 6 is a hydrogen or C 1-6 alkyl;
R 7 is phenyl or monocyclic heteroaryl, each of which is substituted with one group selected from R f , and wherein said phenyl and monocyclic heteroaryl for R 7 may also be optionally substituted with 1 to 4 groups selected from R a ; or R 6 and R 7 taken together with the nitrogen ring to which they are attached form a fused bicyclic heterocyclyl optionally substituted with 1 to 4 groups selected from R a ;

R 1 is phenyl optionally substituted with 1 to 3 groups selected from R c ;
each of R 2 , R 3 , R 4 , and R 5 are independently hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 groups selected from halo, —C(O)OR d , —OC 1-6 alkylN(R d ) 2 , —C 1-6 alkylN(R d ) 2 , —N(R d ) 2 , —NR d C 1-6 alkylOR d , —SOR d , —S(O) 2 R d , —SON(R d ) 2 , —SO 2 N(R d ) 2 , C 3-10 cycloalkyl, C 5-10 heterocyclyl, C 5-10 heteroaryl, and C 6-10 aryl;
each of R a , R b , and R c are each independently halo, CN, oxo, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —C 1-6 alkylOR d , —C(O)R d , —C(O)OR d , —C 1-6 alkylC(O)OR d , —C(O)N(R d ) 2 , —C(O)NR d C 1-6 alkylOR d , —OC 1-6 alkylN(R d ) 2 , —C 1-6 alkylC(O)N(R d ) 2 , —C 1-6 alkylN(R d ) 2 , —N(R d ) 2 , —C(O)NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylOR d , —SOR d , —S(O) 2 R d , —SON(R d ) 2 , —SO 2 N(R d ) 2 , SF 5 , -Ocycloalkyl, —O—C 1-4 alkylaryl, —C 1-6 alkylcycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl alone and in connection with -Ocycloalkyl, —C 1-6 alkylcycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl are optionally substituted with 1 to 3 groups selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R d ) 2 , —C(O)R d , and —C 1-6 alkyl OR d ;
each R d is independently hydrogen, C 1-6 haloalkyl, or C 1-6 alkyl; and
each R f is independently cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 groups selected from halo, CN, oxo, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —C 1-6 alkylOR d , —C(O)R d , —C(O)OR d , —C 1-6 alkylC(O)OR d , —C(O)N(R d ) 2 , —C(O)NR d C 1-6 alkylOR d , —OC 1-6 alkylN(R d ) 2 , —C 1-6 alkylC(O)N(R d ) 2 , —C 1-6 alkylN(R d ) 2 , —N(R d ) 2 , —C(O)NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylOR d , —SOR d , —S(O) 2 R d , —SON(R d ) 2 , —SO 2 N(R d ) 2 , SF 5 , -Ocycloalkyl;
provided the compound is not N—[1,1′-biphenyl]-2-yl-2[[2-(3,4-dimethoxyphenyl)ethyl]amino]-propanamide, or 2-[(2-phenylpropyl)amino]-N-[4-(1H-1,2,4-triazol-1-yl)phenyl]-propanamide, or a salt thereof.

2. The compound of claim 1 , wherein Ring B is phenyl optionally substituted with 1 to 3 groups selected from R b .

3. The compound of claim 1 , wherein R 3 is hydrogen.

4. The compound of claim 1 , wherein R 5 is hydrogen.

5. The compound of claim 1 , wherein R 2 is hydrogen or C 1-4 alkyl.

6. The compound of claim 1 , wherein R 4 is hydrogen or C 1-4 alkyl.

7. The compound of claim 1 , wherein the compound is of the Formula IV or V:

or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

8. The compound of claim 1 , wherein the compound is of the Formula VI or VII:

or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

9. The compound of claim 1 , wherein the compound is of the Formula VIII or IX:

or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

10. The compound of claim 1 , wherein R c , if present, is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl.

11. The compound of claim 1 , wherein R a is C 1-4 alkoxy or halo.

12. The compound of claim 1 , wherein R f is heteroaryl or heterocyclyl, each of which may be optionally substituted with 1 to 3 groups selected from selected from halo, CN, oxo, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —C 1-6 alkylOR d , —C(O)R d , —C(O)OR d , —C 1-6 alkylC(O)OR d , —C(O)N(R d ) 2 , —C(O)NR d C 1-6 alkylOR d , —OC 1-6 alkylN(R d ) 2 , —C 1-6 alkylC(O)N(R d ) 2 , —C 1-6 alkylN(R d ) 2 , —N(R d ) 2 , —C(O)NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylOR d , —SOR d , —S(O) 2 R d , —SON(R d ) 2 , —SO 2 N(R d ) 2 , SF 5 , -Ocycloalkyl.

13. The compound of claim 1 , wherein the compound is of the Formula XII or XIII:

or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

14. The compound of claim 1 , wherein the compound is of the Formula XVI or XVII:

or a pharmaceutically acceptable salt thereof, wherein w, q, and t are each independently 0, 1, or 2.

15. The compound of claim 13 , wherein R c , if present, is independently C 1-6 alkyl, halo, or CN.

16. The compound of claim 13 , wherein w is 0 or 1.

17. The compound of claim 13 , wherein R b is halo, cyano, or —SO 2 NH 2 .

18. The compound of claim 13 , wherein t is 1.

19. The compound of claim 13 , wherein q is 1.

20. The compound of claim 13 , wherein R f is cycloalkyl, phenyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted with 1 to 3 groups selected from halo, CN, oxo, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —C 1 6 alkylOR d , —C(O)R d , —C(O)OR d , —C 1-6 alkylC(O)OR d , —C(O)N(R d ) 2 , —C(O)NR d C 1-6 alkylOR d , —OC 1-6 alkylN(R d ) 2 , —C 1-6 alkylC(O)N(R d ) 2 , —C 1-6 alkylN(R d ) 2 , —N(R d ) 2 , —C(O)NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylN(R d ) 2 , —NR d C 1-6 alkylOR d , —SOR d , —S(O) 2 R d , —SON(R d ) 2 , —SO 2 N(R d ) 2 , SF 5 , -Ocycloalkyl.

21. A compound selected from

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Wilson Jonathan E
• Brucelle Francois
• Levell Julian R

Classifications

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D211/32

  by oxygen atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D233/64

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title