Imidazopiperazine inhibitors of transcription activating proteins

Patent metadata

Field	Value
Publication number	US-11058688-B2
Application number	US-201916370404-A
Country	US
Kind code	B2
Filing date	Mar 29, 2019
Priority date	Mar 29, 2018
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of transcription activating proteins such as CBP and P300 for the treatment or prevention of diseases such as proliferative diseases, inflammatory disorders, autoimmune diseases, and fibrotic diseases.

First claim

What is claimed is:

1. A compound of structural Formula III:

or a salt thereof, wherein:
R 1 is monocyclic heterocycloalkyl with 3 to 8 ring members of which 1 to 2 ring members are heteroatom chosen from N, O and S, optionally substituted with 1 or 2 R 5 groups;
R 2 is —CH 3 or —NHCH 3 ;
R 4a and R 4b are independently chosen from H and methyl;
W is chosen from C(R 7a ) and N;
X 1 is C(R 7b );
X 2 is C(H);
X 3 is C(H);
Y is chosen from CH and N;
Z is CH;
each R 5 is independently chosen from halo;
R 7a is chosen from H, alkyl, alkoxy, cyano, halo, and haloalkyl;
R 7b is chosen from H and fluoro;
R 8 is a monocyclic heteroaryl having up to 4 hetero atoms selected from N, O and S, and is optionally substituted with 1 or 2 R 10 groups; and
each R 10 is independently chosen from alkyl and CONHCH 3.

2. The compound as recited in claim 1 , or a salt thereof, wherein R 2 is —CH 3 .

3. The compound as recited in claim 1 , or a salt thereof, wherein R 2 is —NHCH 3 .

4. The compound as recited in claim 1 , or a salt thereof, wherein R 4a and R 4b are H.

5. The compound as recited in claim 1 , or a salt thereof, wherein R 1 is

and is optionally substituted with 1 R 5 group.

6. The compound as recited in claim 1 , or a salt thereof, wherein R 1 is

7. The compound as recited in claim 1 , or a salt thereof, wherein R 8 is thiazolyl, optionally substituted with 1 or 2 R 10 groups.

8. The compound as recited in claim 1 , or a salt thereof, wherein:
R 2 is —CH 3 ;
R 4a and R 4b are H;
R 1 is

and
R 8 is thiazolyl, optionally substituted with 1 or 2 R 10 groups.

9. The compound as recited in claim 1 , or a salt thereof, wherein:
R 2 is —NHCH 3 ;
R 4a and R 4b are H;
R 1 is

and
R 8 is thiazolyl, optionally substituted with 1 or 2 R 10 groups.

10. A pharmaceutical composition comprising a compound as recited in claim 8 , or a salt thereof, together with a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound as recited in claim 9 , or a salt thereof, together with a pharmaceutically acceptable carrier.

12. A compound of structural Formula III:

or a salt thereof, wherein:
R 1 is C 3 -C 6 cycloalkyl, optionally substituted with 1 or 2 R 5 groups; or R 1 is monocyclic heterocycloalkyl with 3 to 8 ring members of which 1 to 2 ring members are heteroatoms chosen from N, O, and S, optionally substituted with 1 or 2 R 5 groups;
R 2 is —CH 3 or —NHCH 3 ;
R 4a and R 4b are independently chosen from H and methyl;
W is chosen from C(R 7a ) and N;
X 1 is C(R 7b );
X 2 and X 3 are independently chosen from C(H) and N;
at most one of X 2 and X 3 is N;
Y is chosen from CH and N;
Z is CH;
each R 5 is independently chosen from halo;
R 7a is chosen from H, alkyl, alkoxy, cyano, halo, and haloalkyl;
R 7b is chosen from H and fluoro;
R 8 is a monocyclic heteroaryl having up to 4 hetero atoms selected from N, O and S, and is optionally substituted with 1 or 2 R 10 groups; and
each R 10 is independently chosen from alkyl and CONHCH 3 .

13. The compound as recited in claim 12 , or a salt thereof, wherein R 1 is chosen from —CH 3 , —CH(CH 3 ) 2 ,

and is optionally substituted with 1 or 2 R 5 groups.

14. The compound as recited in claim 12 , or a salt thereof, wherein R 1 is

and is optionally substituted with 1 R 5 group.

15. The compound as recited in claim 12 , or a salt thereof, wherein R 1 is

and is optionally substituted with 1 or 2 R 5 groups.

16. The compound as recited in claim 12 , or a salt thereof, wherein R 1 is

and is optionally substituted with 1 R 5 group.

17. The compound as recited in claim 12 , or a salt thereof, wherein R 2 is —CH 3 .

18. The compound as recited in claim 12 , or a salt thereof, wherein R 2 is —NHCH 3 .

19. The compound as recited in claim 12 , or a salt thereof, wherein X 1 is chosen from CH and CF.

20. The compound as recited in claim 12 , or a salt thereof, wherein
X 1 is C(R 7b ),
X 2 is C(H), and
X 3 is N.

21. The compound as recited in claim 12 , or a salt thereof, wherein W is C(R 7a ).

22. The compound as recited in claim 12 , or a salt thereof, wherein exactly one of W and Y is N.

23. The compound as recited in claim 22 , or a salt thereof, wherein W is N.

24. The compound as recited in claim 23 , or a salt thereof, wherein Y is CH.

25. The compound as recited in claim 12 , or a salt thereof, wherein R 7a is chosen from H, alkyl, alkoxy, cyano, and haloalkyl.

26. The compound as recited in claim 25 , or a salt thereof, wherein R 7a is cyano.

27. The compound as recited in claim 25 , or a salt thereof, wherein R 7a is haloalkyl.

28. The compound as recited in claim 27 , or a salt thereof, wherein R 7a is difluoromethyl.

29. The compound as recited in claim 27 , or a salt thereof, wherein R 7a is trifluoromethyl.

30. The compound as recited in claim 25 , or a salt thereof, wherein Y is N.

31. The compound as recited in claim 12 , or a salt thereof, wherein R 7b is H.

32. The compound as recited in claim 12 , or a salt thereof, wherein R 7b is fluoro.

33. The compound as recited in claim 12 , or a salt thereof, wherein R 8 is 5-membered monocyclic heteroaryl, optionally substituted with 1 or 2 R 10 groups.

34. The compound as recited in claim 33 , or a salt thereof, wherein R 8 is chosen from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, thienyl, and thiazolyl, optionally substituted with 1 or 2 R 10 groups.

35. The compound as recited in claim 12 , or a salt thereof, wherein R 8 is 6-membered monocyclic heteroaryl, optionally substituted with 1 or 2 R 10 groups.

36. The compound as recited in claim 35 , or a salt thereof, wherein R 8 is chosen from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, optionally substituted with 1 or 2 R 10 groups.

37. The compound as recited in claim 12 , or a salt thereof, wherein each R 10 is alkyl.

38. The compound as recited in claim 12 , or a salt thereof, wherein each R 10 is CONHCH 3 .

39. A compound ch

Assignees

• Univ Texas

Inventors

• Le Kang
• Soth Michael J
• Jones Philip
• Cross Jason Bryant
• Carroll Christopher L
• Mcafoos Timothy Joseph
• Mandal Pijus Kumar

Classifications

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · 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

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title