Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
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.
1. A compound of Formula (I-a):
or a pharmaceutically acceptable salt thereof,
wherein
A is hydrogen;
het is an imidazolidine-2-one, substituted with one or more R d ;
each R d is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, or —(CH 2 ) n R e , wherein each alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
each R e is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 —C cycloalkyl, heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, or heterocycloalkyl 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, cycloalkyl, 3-to-12 membered heterocycloalkyl, halogen, —(CH 2 ) n O(CH 2 ) m CH 3 ;
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 or aryl, wherein each alkyl or aryl is optionally substituted with one or more R f ; and
each R f is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen.
3. The compound of claim 1 , wherein
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R f ; and
each R f is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, halogen, or —(CH 2 ) n O(CH 2 ) m CH 3 .
4. The compound of claim 3 , wherein
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy or —(CH 2 ) n O(CH 2 ) m CH 3 .
5. The compound of claim 2 , wherein
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 alkyl or methoxy.
6. The compound of claim 3 , wherein
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
7. The compound of claim 3 , wherein
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 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 C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 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 C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
10. The compound of claim 1 , wherein
each R d is independently C 1 -C 6 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 C 1 -C 6 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —(CH 2 ) n R e ; and
R e is C 1 -C 6 alkoxy.
12. The compound of claim 1 , wherein
each R d is independently C 1 -C 6 alkyl or heteroaryl, wherein each alkyl or heteroaryl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 haloalkyl.
13. The compound of claim 1 , wherein
each R d is independently C 1 -C 6 alkyl, wherein each alkyl is optionally substituted with one or more R f ; and
each R f is independently C 1 -C 6 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):
or a pharmaceutically acceptable salt thereof,
wherein
A is hydrogen;
het is an imidazolidine-2-one, substituted with one or more R d ;
each R d is independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more R e ;
or two R d when attached to the same carbon atom can form a 3- to 12-membered spiroheterocycle; and
each R e is independently hydrogen, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
17. The compound of claim 16 , wherein
each R d is independently unsubstituted C 1 -C 6 alkyl or unsubstituted C 3 -C 8 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.