Substituted heterocycles as aldehyde dehydrogenase inhibitors

Patent metadata

Field	Value
Publication number	US-12054475-B2
Application number	US-202318488924-A
Country	US
Kind code	B2
Filing date	Oct 17, 2023
Priority date	Apr 22, 2021
Publication date	Aug 6, 2024
Grant date	Aug 6, 2024

Abstract

Provided herein are novel heterocyclic compounds, for example, compounds of Formula (IV-C). Also provided herein are pharmaceutical compositions comprising the compounds and methods of using the same, for example, in inhibiting aldehyde dehydrogenases, retinoid pathway activation, and/or for treating various cancers, cancer metastasis, type 2 diabetes, pulmonary arterial hypertension (PAH) or neointimal hyperplasia (NIH) or as a male contraceptive.

First claim

What is claimed is:

1. A compound of Formula (IV-C):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R 20 is H, halo, or C 1-4 alkyl;
R 20′ is H, halo, or C 1-4 alkyl;
R 21 is H, halo, or C 1-4 alkyl;
R 21′ is H, halo, or C 1-4 alkyl; or
R 20 and R 20′ , taken together with the carbon atoms to which they are attached, form a C 3-8 carbocyclyl or 3- to 8-membered heterocyclyl;
R 22 is halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or carbocyclyl;
R 22′ is H, halo, C 1-6 alkyl, or C 1-6 haloalkyl; or
R 22 and R 22′ , taken together with the carbon atoms to which they are attached, form a carbocyclyl, heterocyclyl, or heteroaryl, wherein the carbocyclyl, heterocyclyl, or heteroaryl is optionally substituted with one or more independently selected halo substituents;
each R 100 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-carbocyclyl, or C 1-6 alkylene-heterocyclyl; or
two vicinal R 100 , taken together with the carbon atoms to which they are attached, form a carbocyclyl or heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more independently selected halo substituents; and
p is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
(i) R 20 is H, halo, or C 1-4 alkyl;
R 20′ is H;
R 21 is H, halo, or C 1-4 alkyl; and
R 21 is H; or

(ii) R 20 and R 20′ , taken together with the carbon atoms to which they are attached, form a cyclopropyl or 5- or 6-membered heterocyclyl;
R 21 is H; and
R 21′ is H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 20 is H, F, or CH 3 ;
R 20′ is H;
R 21 is H, F, or CH 3 ; and
R 21′ is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 20 is H;
R 20′ is H;
R 21 is H;
R 21′ is H;
R 22 is C 1-6 alkyl; and
R 22′ is C 1-6 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 20 is H;
R 20′ is H;
R 21 is H;
R 21′ is H;
R 100 is CH 2 CF 3 ; and
p is 1.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 22 is C 1-6 alkyl;
R 100 is CH 2 CF 3 ; and
p is 1.

7. The compound of claim 1 , wherein the compound is of Formula (IV-D):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R 22 is halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or carbocyclyl;
R 22′ is H, halo, C 1-6 alkyl, or C 1-6 haloalkyl; and
each R 100 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-carbocyclyl, or C 1-6 alkylene-heterocyclyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is halo or C 1-4 alkyl.

9. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is F.

10. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is C 1-4 alkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22′ is H.

12. The compound of claim 10 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 100 is an independently selected C 1-6 haloalkyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 100 is an independently selected C 1-6 haloalkyl.

14. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is CH 3 .

15. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is H, halo or C 1-6 alkyl.

16. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is H.

17. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is F.

18. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 22 is CH 3 .

19. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 100 is independently halo, C 1-6 alkyl, or C 1-6 haloalkyl.

20. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 100 is independently Cl, CH 2 CH 3 , or CH 2 CF 3 .

21. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein p is 1.

22. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein p is 2.

23. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 100 is CH 2 CH 3 ; and
p is 1.

24. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R 100 is CH 2 CF 3 ; and
p is 1.

25. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
each R 10′ is independently C1 or CH 2 CF 3 ; and
p is 2.

26. The compound of claim 7 , wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.

27. The compound of claim 7 , wherein the compound is:

or a pharmaceutically acceptable salt or tautomer thereof.

28. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

29. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

30. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

Assignees

• Kayothera Inc
• Univ Princeton

Inventors

• Esposito Mark
• Proudfoot John
• Kang Yibin
• Piwinski John

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title