Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

Patent metadata

Field	Value
Publication number	US-10508077-B2
Application number	US-201916387937-A
Country	US
Kind code	B2
Filing date	Apr 18, 2019
Priority date	Mar 13, 2015
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

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.

First claim

The invention claimed is:

1. A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein
A is hydrogen;
het is a 3-to-12 membered heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
each R d is independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, oxo, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) n R e , —(CH 2 ) n O(CH 2 ) m R e , —(CH 2 ) n NR e R f , —C(O)(CH 2 ) n R e , —(CH 2 ) n C(O)OR e , —C(O)(CH 2 ) n SR e , —(CH 2 ) n C(O)NR e R f , —NH(CH 2 ) n R e , —NHC(O)(CH 2 ) n R e , —NHC(O)(CH 2 ) n OR e , —NHC(O)(CH 2 ) n SR e , —NHS(O) 2 R e , —OR e , or —S(O) 2 R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a C 5 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle, wherein the spirocycle or the spiroheterocycle are optionally substituted with one or more R e or R f ;
each R e is independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)(CH 2 ) n R f , or —(CH 2 ) n C(O)R f , wherein each alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R f ;
each R f is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, oxo, cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 )alkylaryl, halogen, —(CH 2 ) n O(CH 2 ) m CH 3 , —(CH 2 ) n N(CH 3 ) 2 , —(CH 2 ) n O(CH 2 ) m N(CH 3 ) 2 , —(CH 2 ) n NR e R f , —N(CH 3 )S(O) 2 CH 3 , —S(CH 2 ) m CH 3 , or —S(O) 2 (CH 2 ) m CH 3 , wherein each alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, oxo, halogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, 3, or 4.

2. The compound of claim 1 , wherein
each R d is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, or —(CH 2 ) n R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle wherein the spiroheterocycle is optionally substituted with one or more R e or R f .

3. The compound of claim 2 , wherein each R e is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R f .

4. The compound of claim 3 , wherein each R f is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cycloalkyl, 3- to 12-membered heterocycloalkyl, or halogen.

5. The compound of claim 1 , wherein het is imidazolidin-2-one substituted with one or more R d .

6. The compound of claim 5 , wherein
each R d is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, or —(CH 2 ) n R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle wherein the spiroheterocycle is optionally substituted with one or more R e or R f .

7. The compound of claim 6 , wherein each R e is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R f .

8. The compound of claim 7 , wherein each R f is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cycloalkyl, 3- to 12-membered heterocycloalkyl, or halogen.

9. The compound of claim 5 , wherein
each R d is independently C 1 -C 6 haloalkyl, oxo, C 3 -C 8 cycloalkyl, or 3-to-12 membered heterocycloalkyl, wherein each haloalkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R e or R f .

10. The compound of claim 9 , wherein each haloalkyl, alkoxy, cycloalkyl, or heterocycloalkyl of R d is optionally substituted with one or more R e , wherein each R e is independently C 1 -C 6 alkoxy.

11. The compound of claim 9 , wherein each haloalkyl, alkoxy, cycloalkyl, or heterocycloalkyl of R d is optionally substituted with one or more R f , wherein each R f is independently C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or halogen.

12. The compound of claim 1 , wherein het is 1,3-dihydro-2H-benzo[d]imidazole-2-one substituted with one or more R d .

13. The compound of claim 12 , wherein
each R d is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, or —(CH 2 ) n R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle wherein the spiroheterocycle is optionally substituted with one or more R e or R f .

14. The compound of claim 13 , wherein each R e is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R f .

15. The compound of claim 14 wherein each R f is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cycloalkyl, 3- to 12-membered heterocycloalkyl, or halogen.

16. The compound of claim 12 , wherein each R d is independently C 1 -C 6 alkyl, oxo, or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R e or R f .

17. The compound of claim 16 , wherein each R e is independently C 1 -C 6 alkyl.

18. The compound of claim 12 , wherein
each R d is independently C 1 -C 6 alkyl, oxo, or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle.

19. The compound of claim 18 , wherein each R e is independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.

20. The compound of claim 18 , wherein each R f is independently C 1 -C 6 haloalkyl or halogen.

Assignees

• Forma Therapeutics 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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title