P300/CBP hat inhibitors

Patent metadata

Field	Value
Publication number	US-11414384-B2
Application number	US-201916970046-A
Country	US
Kind code	B2
Filing date	Feb 15, 2019
Priority date	Feb 16, 2018
Publication date	Aug 16, 2022
Grant date	Aug 16, 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 of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
Ring A is bicyclic heteroaryl optionally substituted with 1 to 4 groups selected from R a ;
Ring B is aryl, heterocyclyl, or heteroaryl each of which may be optionally substituted with 1 to 4 groups selected from R b ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, —C 1-6 alkylOR c , —C 1-6 alkylN(R d ) 2 , —C 1-6 alkylC(O)OR d , —C 1-6 alkylOC 1-6 alkylN(R d ) 2 , —C 1-6 alkylSOR d , —C 1-6 alkylS(O) 2 R d , —C 1-6 alkylSON(R d ) 2 , —C 1-6 alkylSO 2 N(R d ) 2 , —C 1-6 alkylcycloalkyl, —C 1-6 alkylheterocyclyl, —C 1-6 alkylheteroaryl, —C 1-6 alkylaryl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl alone and in connection with —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 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 , cycloalkyl, heterocyclyl, heteroaryl, and 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, —Oheterocyclyl, —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, oxo, 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 alkylOR d ; and
each R d is independently hydrogen, heterocyclyl, C 1-6 haloalkyl, or C 1-6 alkyl, wherein said heterocyclyl is optionally substituted with 1 or 2 groups selected from C 1-4 haloalkyl and C 1-4 alkyl and said C 1-6 alkyl is optionally substituted with —SO 2 C 1-4 alkyl or heterocyclyl optionally substituted with oxo;
provided the compound is not 4-(2-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzenesulfonamide; 4-[2-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]ethyl]benzenesulfonamide; 2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone, or a salt thereof.

2. The compound of claim 1 , wherein Ring A is selected from

wherein each q is 0, 1, or 2; and R e and R f are each independently is hydrogen, C 1-6 alkyl, and —C 1-6 alkylOR d .

3. The compound of claim 2 , wherein Ring A is

4. The compound of claim 1 , wherein Ring B is phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 5-6 membered heterocyclyl, each optionally substituted with 1 to 3 groups selected from R b .

5. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, aryl, cycloalkyl, or heteroaryl, wherein each of said aryl, cycloalkyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from R c .

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

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

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

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

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

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

11. 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.

12. The compound of claim 1 , wherein R a is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, halo, —C 1-4 alkylC(O)N(R d ) 2 , —C 1-4 alkylC(O)OR d , —C(O)OR d , —C(O)NR d C 1-4 alkylN(R d ) 2 , —C(O)NR d C 1-4 alkylOR d , —C(O)N(R d ) 2 , —OC 1-4 alkylaryl, heterocyclyl, and heteroaryl, wherein said heterocyclyl is optionally substituted with C 1-4 alkyl or —C(O)R d and wherein said heteroaryl is optionally substituted with C 1-4 alkyl, —C 1-4 alkylC(O)N(R d ) 2 , —C 1-4 alkylOR d .

13. The compound of claim 1 , wherein R b is selected from —SON(R d ) 2 , halo, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkyl, —N(R d ) 2 , oxo, —NR d C 1-6 alkylOR d , CN, heteroaryl, —C(O)N(R d ) 2 , C(O)OR d , and —C 1-4 alkylC(O)N(R d ) 2 .

14. The compound of claim 13 , wherein R d is hydrogen or C 1-4 alkyl.

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

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

16. The compound of claim 1 , wherein R b is CN.

17. The compound of claim 1 , wherein R a is selected from C 1-4 alkyl, —C(O)NR d C 1-4 alkylOR d , —C(O)N(R d ) 2 , heterocyclyl, —Oheterocyclyl, and heteroaryl, wherein said heterocyclyl and —Oheterocyclyl are each optionally substituted with oxo and wherein said heteroaryl is optionally substituted with C 1-4 alkyl.

18. The compound of claim 1 , wherein each R d is independently hydrogen, heterocyclyl, C 1-6 haloalkyl, or C 1-6 alkyl, wherein said heterocyclyl is optionally substituted with 1 or 2 groups selected from C 1-4 haloalkyl, oxo, and C 1-4 alkyl and said C 1-6 alkyl is optionally substituted with —SO 2 C 1-4 alkyl or heterocyclyl optionally substituted with oxo.

19. A pharmaceutical composition comprising
1) the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and
2) a pharmaceutically acceptable carrier.

20. The compound of claim 1 , wherein the compound is selected from

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Wilson Jonathan E
• Levell Julian R

Classifications

• C07D209/14 Primary

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title