Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

• US 10,988,441 B2
• Filed: 11/20/2019
• Issued: 04/27/2021
• Est. Priority Date: 03/13/2015
• Status: Active Grant

• Current Assignee: VALO Health Incorporated
• Original Assignee: Valo Early Discovery, Inc.
• Inventors: Bair, Kenneth W., Barczak, Nicholas, Han, Bingsong, Lancia, Jr., David R., Liu, Cuixian, Martin, Matthew W., Ng, Pui Yee, Rudnitskaya, Aleksandra, Thomason, Jennifer R., Zablocki, Mary-Margaret, Zheng, Xiaozhang
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US16/689,252
• Publication Number:
  US 20200331847A1
• Time in Patent Office: 524 Days
• Field of Search: None
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Abstract

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

Claims

1. A compound of Formula (I-a):

2. The compound of claim 1, wherein

each R_d is independently C₁-C₆ alkyl or aryl, wherein each alkyl or aryl is optionally substituted with one or more R_f;

and

each R_f is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen.

3. The compound of claim 1, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, halogen, or —

(CH₂)_nO(CH₂)_mCH₃.

4. The compound of claim 3, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl, C₁-C₆ alkoxy or —

(CH₂)_nO(CH₂)_mCH₃.

5. The compound of claim 2, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl or methoxy.

6. The compound of claim 3, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl.

7. The compound of claim 3, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently halogen.

8. The compound of claim 3, wherein

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl.

9. The compound of claim 1, wherein

het is a imidazolidine-2-one, substituted with one or more R_d;

and

each R_d is independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl.

10. The compound of claim 1, wherein

each R_d is independently C₁-C₆ alkyl or 3-to-12 membered heterocycloalkyl, wherein each alkyl or heterocycloalkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl.

11. The compound of claim 1, wherein

het is a imidazolidine-2-one, substituted with one or more R_d;

and

each R_d is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —

(CH₂)_nR_e; and

R_e is C₁-C₆ alkoxy.

12. The compound of claim 1, wherein

each R_d is independently C₁-C₆ alkyl or heteroaryl, wherein each alkyl or heteroaryl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ haloalkyl.

13. The compound of claim 1, wherein

each R_d is independently C₁-C₆ alkyl, wherein each alkyl is optionally substituted with one or more R_f;

and

each R_f is independently C₁-C₆ alkyl, cycloalkyl, or 3-to-12 membered heterocycloalkyl.

14. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.

15. A pharmaceutical composition comprising a compound of claim 9 and one or more pharmaceutically acceptable carriers.

16. A compound of Formula (I-a):

17. The compound of claim 16, wherein

each R^d is independently unsubstituted C₁-C₆ alkyl or unsubstituted C₃-C₈ cycloalkyl;

or two R_d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle.

18. The compound of claim 17, wherein two R_d when attached to the same carbon atom form a 3- to 12-membered spiroheterocycle.

19. A pharmaceutical composition comprising a compound of claim 16 and one or more pharmaceutically acceptable carriers.

20. A pharmaceutical composition comprising a compound of claim 18 and one or more pharmaceutically acceptable carriers.