Selective histone deactylase 6 inhibitors

Patent metadata

Field	Value
Publication number	US-9956192-B2
Application number	US-201615231187-A
Country	US
Kind code	B2
Filing date	Aug 8, 2016
Priority date	Mar 7, 2012
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

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.

First claim

What is claimed is:

1. A method of treating melanoma in a subject, comprising: administering to the subject a therapeutically effective amount of 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, hydrogen, or are C 1 -C 8 alkyl, C 1 -C 3 alkylaryl, or C 1 -C 3 alkylheteroaryl optionally substituted with acetyl, C 1 -C 5 alkyl, —NR 6 R 7 , C 1 -C 4 alkoxy, carbonyl, halo, or hydroxy; 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 1 -C 3 alkylaryl, or C 1 -C 3 alkylheteroaryl, any of which is optionally substituted with amino, 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 (i.e., ═O); 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 method of claim 1 , wherein R 1 and R 2 are both hydrogen.

3. The method of claim 1 , wherein A is phenyl.

4. The method 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 method of claim 1 , wherein A is ortho-methoxyl substituted phenyl.

6. The method of claim 1 , wherein A is pyridyl or pyridyl substituted with C 1 -C 5 alkyl, C 1 -C 4 alkoxyl, or halo.

7. The method 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 method of claim 1 , wherein R 1 is hydrogen or C 1 -C 8 alkyl is optionally substituted with C 1 -C 3 alkyl, —NR 6 R 7 , C 1 -C 4 alkoxy, carbonyl, or hydroxy.

9. The method of claim 1 , wherein R 1 is C 1 -C 8 alkyl.

10. The method of claim 1 , wherein R 1 is C 1 -C 8 alkyl optionally substituted with acetyl, NH 2 , N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, carbonyl, halo, or hydroxy.

11. The method of claim 1 , wherein R 1 is hydrogen.

12. The method of claim 1 , wherein R 2 is hydrogen or C 1 -C 8 alkyl optionally substituted with C 1 -C 5 alkyl, —NR 6 R 7 , C 1 -C 4 alkoxy, carbonyl, or hydroxy.

13. The method of claim 1 , wherein R 2 is C 1 -C 5 alkyl, or C 1 -C 5 alkyl substituted with a methoxy, —NR 6 R 7 , carbonyl, or hydroxy.

14. The method of claim 1 , wherein R 2 is C 1 -C 3 alkylheteroaryl.

15. The method of claim 1 , wherein R 2 is C 1 -C 3 alkyl substituted with a phenyl, hydroxy substituted phenyl, methoxy substituted phenyl, halo substituted phenyl, or amino substituted phenyl.

16. The method 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 8 alkyl, C 1 -C 4 alkoxy, or halo, or a pharmaceutically acceptable salt or hydrate thereof.

17. The method 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 method 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′ , and R 2″ , are independently, hydrogen, or are C 1 -C 8 alkyl, C 1 -C 3 alkylaryl, or C 1 -C 3 alkylheteroaryl, any of which is optionally substituted with amino, 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 method of claim 18 , wherein R 1′ and R 1″ or R 2′ and R 2″ are both methyl.

20. The method of claim 18 , wherein R 1′ is hydrogen and R 1″ is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, benzyl, methylphenol, methylphenylmethoxy, or methylphenylamino or R 2′ is hydrogen and R 2″ is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, benzyl, methylphenol, methylphenylmethoxy, or methylphenylamino.

21. The method of claim 1 , wherein R 1′ and R 1″ or R 2′ and R 2″ form a carboxyl group.

22. The method of claim 1 , wherein the compound is chosen from:

23. The method of claim 1 , wherein the compound is Tubstatin A.

24. The method of claim 1 , wherein the compound is administered with one or more of ipilimumab, revlimid, velcade, vemurafenib, ST-3-06, ST-2-92, Tubstatin A, Tubacin.

25. The method of claim 1 , wherein the inhibitor is combined with a STAT3 inhibitor.

Assignees

• H Lee Moffitt Cancer Ct & Res
• Board Of Trustees Of The Univ Of Illinois

Inventors

• Sotomayor Eduardo M
• Bergman Joel
• Kozikowski Alan
• Woan Karrune Veeraprasert
• Villagra Alejandro V

Classifications

• C07C275/34

  having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring · CPC title

• C07C275/28

  having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title