Deacetylase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9434686-B2
Application number	US-201313861519-A
Country	US
Kind code	B2
Filing date	Apr 12, 2013
Priority date	Jul 23, 2008
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

The present invention provides novel compounds of formula (I) and pharmaceutical compositions thereof. The inventive compounds are useful as deacetylase inhibitors (e.g., histone deacetylase inhibitors) and may be useful in the treatment of proliferative diseases such as cancer. In particular, the inventive compounds are HDAC6 inhibitors. The invention also provide synthetic methods for preparing the inventive compounds.

First claim

What is claimed is:

1. A method of treating a histone deacetylase-associated cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable form thereof;
wherein:
n is an integer between 1 and 10, inclusive;
m is an integer between 0 and 5, inclusive;
k is an integer between 0 and 5, inclusive;
p is an integer between 0 and 5, inclusive;
R 2 is an optionally substituted acyl moiety;
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(═O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety;
R 4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N(R D ) 2 ; —NHC(═O)R D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety;
R 5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR E ; —C(═O)R E ; —CO 2 R E ; —CN; —SCN; —SR E ; —SOR E ; —SO 2 R E ; —NO 2 ; —N(R E ) 2 ; —NHC(═O)R E ; or —C(R E ) 3 ; wherein each occurrence of R E is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety; and
wherein the histone deacetylase-associated cancer is selected from the group consisting of leukemia, multiple myeloma, lymphoma, and skin cancer.

2. The method of claim 1 , wherein n is 4 to 7, inclusive.

3. The method of claim 2 , wherein n is 6.

4. The method of claim 1 , wherein m is 0, 1, or 2.

5. The method of claim 1 , wherein p is 0, 1, or 2.

6. The method of claim 1 , wherein k is 0, 1, or 2.

7. The method of claim 1 , wherein R 2 is —C(═O)R B , wherein R B is —OR′ or —N(R″) 2 , wherein R′ is hydrogen or an optionally substituted alkyl moiety, and R″ is hydrogen, —OH, an optionally substituted aryl moiety, or an optionally substituted heteroaryl moiety.

8. The method of claim 7 , wherein R 2 is —CO 2 H.

9. The method of claim 7 , wherein R B is —OR′; and R′ is an optionally substituted alkyl moiety.

10. The method of claim 7 , wherein R B is —NHR″, and R″ is —OH, an optionally substituted aryl moiety, or an optionally substituted heteroaryl moiety.

11. The method of claim 10 , wherein R″ is —OH.

12. The method of claim 10 , wherein R″ is an optionally substituted aryl moiety.

13. The method of claim 12 , wherein the aryl moiety is of the structure:

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

and pharmaceutically acceptable forms thereof,
wherein n is 4, 5, 6, or 7.

15. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable form thereof.

16. The method according to claim 1 , wherein the subject is a mammal.

17. The method according to claim 16 , wherein the subject is human.

18. The method according to claim 1 , wherein the cancer is skin cancer.

19. The method according to claim 1 , wherein the step of administering comprises administering the compound orally or intravenously.

20. The method according to claim 1 , wherein the cancer is leukemia.

21. The method according to claim 1 , wherein the cancer is multiple myeloma.

22. The method according to claim 18 , wherein the skin cancer is malignant melanoma.

23. The method according to claim 1 , wherein the cancer is lymphoma.

24. The method according to claim 23 , wherein the lymphoma is cutaneous T-cell lymphoma.

Assignees

• Harvard College
• Dana Farber Cancer Inst Inc

Inventors

• Tang Weiping
• Bradner James E
• Schreiber Stuart L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title