Selective histone deactylase 6 inhibitors
Disclosed are selective histone deactylase inhibitors (HDACi) that having Formula (I). Methods of making and using these inhibitors for the treatment of cancer, in particular melanoma are also disclosed.
1. A compound having Formula I:
wherein
A is C 1 -C 8 alkyl, phenyl, pyridyl, oxazolidyl, or pyrimidyl optionally substituted with one or more groups chosen from C 1 -C 5 alkyl, C 1 -C 4 alkoxy, or halo; and
R 1 and R 2 are independently chosen from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, C 1 -C 3 alkylaryl, aryl, C 1 -C 3 alkylheteroaryl, or heteroaryl, any of which is optionally substituted with acetyl, C 1 -C 5 alkyl, amino, —NR 6 R 7 , —C(O)NR 6 R 7 , C 1 -C 4 alkoxy, C 1 -C 4 alkylhydroxy, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, aryl, heteroaryl, carbonyl, halo, hydroxy, thiol, cyano, or nitro; or
R 1 and R 2 are joined such that together they form an alkylene bridge comprising 2 atoms so that a 5-membered ring is formed with the —NC(O)N— moiety, in which case A is as defined above or hydrogen, and which 5-membered ring is optionally substituted with R 1 ′, R 2 ′, R 1 ″, and R 2 ″, which are independently, hydrogen, or are C 1 -C 8 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, C 1 -C 3 alkylaryl, aryl, C 1 -C 3 alkylheteroaryl, or heteroaryl any of which is optionally substituted with amino, aryl, C 1 -C 4 alkoxy, halo, or hydroxy; or R 1 ′and R 1 ″ together or R 2 ″ and R 2 ′ together form a carbonyl; or R 1 ′ and R 2 ′ are null and R 1 ″and R 2 ″ together form a fused phenyl group; and
R 6 and R 7 are independently H, C 1 -C 4 alkyl, or are joined such that together they form an alkylene bridge comprising 4 or 5 atoms so that a 5 or 6-membered ring is formed with the nitrogen;
or a pharmaceutically acceptable salt or hydrate thereof.
2. The compound of claim 1 , wherein R 1 and R 2 are both hydrogen.
3. The compound of claim 1 , wherein A is phenyl.
4. The compound of claim 1 , wherein A is phenyl substituted with one or more C 1 -C 5 alkyl, C 1 -C 4 alkoxyl, or halo.
5. The compound of claim 1 , wherein A is ortho-methoxyl substituted phenyl.
6. The compound of claim 1 , wherein A is pyridyl or pyridyl substituted with one or more C 1 -C 5 alkyl, C 1 -C 4 alkoxyl, or halo.
7. The compound of claim 1 , wherein A is n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, i-butyl, n-pentyl, i-pentyl, or s-pentyl group.
8. The compound of claim 1 , wherein R 1 is hydrogen, C 1 -C 8 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with C 1 -C 3 alkyl, amino, —NR 6 R 7 , C 1 -C 4 alkoxy, C 1 -C 4 alkylhydroxy, carbonyl, hydroxy, thiol, or cyano.
9. The compound of claim 1 , wherein R 1 is C 1 -C 8 alkyl.
10. The compound of claim 1 , wherein R 1 is C 1 -C 8 alkyl which is optionally substituted with acetyl, NH 2 , N(C 1 -C 4 ) 2 C 1 -C 4 alkoxy, C 1 -C 4 C 5 -C 6 heterocycloalkyl, carbonyl, halo, or hydroxy.
11. The compound of claim 1 , wherein R 1 is hydrogen.
12. The compound of claim 1 , wherein R 2 is hydrogen, C 1 -C 8 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with C 1 -C 5 alkyl, amino, —NR 6 R 7 , C 1 -C 4 alkoxy, C 1 -C 4 alkylhydroxy, carbonyl, hydroxy, thiol, or cyano.
13. The compound of claim 1 , wherein R 2 is C 1 -C 5 alkyl, or C 1 -C 5 alkyl substituted with a methoxy, amino, —NR 6 R 7 , alkylhydroxy, carbonyl, hydroxy, cyano.
14. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl substituted with a heteroaryl.
15. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl substituted with a phenyl, hydroxy substituted phenyl, methoxy substited phenyl, halo substituted phenyl, or amino substituted phenyl.
16. The compound of claim 1 , wherein the compound has Formula I-A:
wherein each W is CH or any one or two W is N and the others are CH; and R 5 is hydrogen, C 1 -C 5 alkyl, C 1 -C 4 alkoxy, or halo, or a pharmaceutically acceptable salt or hydrate thereof.
17. The compound of claim 1 , wherein the compound has Formula I-B:
wherein each W is CH or any one or two W is N and the others are CH; and R 5 is C 1 -C 5 alkyl, C 1 -C 4 alkoxy, or halo, or a pharmaceutically acceptable salt or hydrate thereof.
18. The compound of claim 1 , wherein the compound has Formula I-C:
wherein
A is C 1 C 8 alkyl, phenyl, pyridyl, oxazolidyl, or pyrimidyl optionally substituted with one or more groups chosen from C 1 -C 5 alkyl, C 1 -C 4 alkoxy, or halo; and
R 1 ′, R 2 ′, R 1 ″, and R 2 ″, are independently, hydrogen, or are C 1 -C 8 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, C 1 -C 3 alkylaryl, aryl, C 1 -C 3 alkylheteroaryl, or heteroaryl any of which is optionally substituted with amino, aryl, C 1 -C 4 alkoxy, halo, or hydroxy; or R 1 ′ and R 1 ″ together or R 2 ″ and R 2 ′ together form a carbonyl; or R 1 ′ and R 2 ′ are null and R 1 ″ and R 2 ″ together form a fused phenyl group, or a pharmaceutically acceptable salt or hydrate thereof.
19. The compound of claim 18 , wherein R 1 ′ and R 1 ″ or R 2 ′ and R 2 ″ are both methyl.
20. The compound of claim 18 , wherein R 1 ′ is hydrogen and R 1 ″ is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, benzyl, tosyl, hydroxyphenyl, C 1 -C 4 alkoxyphenyl, or aminophenyl or R 2 ′ is hydrogen and R 2 ″ is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, benzyl, tosyl, hydroxyphenyl, C 1 -C 4 alkoxyphenyl, or aminophenyl.
21. The compound of claim 18 , wherein R 1 ′and R 1 ″ or R 2 ′ and R 2 ″ form a carboxyl group.
22. The compound of claim 1 , wherein the compound is chosen from: