Selective histone deactylase 6 inhibitors

Patent metadata

Field	Value
Publication number	US-9751832-B2
Application number	US-201414907321-A
Country	US
Kind code	B2
Filing date	Jul 30, 2014
Priority date	Jul 30, 2013
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

Disclosed are selective histone deactylase inhibitors (HDACi) that having Formula I. Specifically, the disclosed subject matter relates to compounds having activity as selective HDAC6 inhibitors, methods of making and using the compounds, and compositions comprising the compounds. In still further aspects, the disclosed subject matter relates to methods for treating oncological disorders in a patient. 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 compound having Formula I:

wherein
A is aryl, heteroaryl, or C 1 -C 8 alkyl, any of which is optionally substituted with one or more groups chosen from 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, halo, hydroxy, thiol, cyano, or nitro; and
R 1 is hydrogen and R 2 is 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; 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 A is phenyl, pyridyl, oxazolidyl, pyrimidyl, pyrimidinyl, or 1H-indazolyl, optionally substituted with C 1 -C 5 alkyl, amino, alkoxy, alkylhydroxy, halo, hydroxy, or thiol.

3. The compound of claim 1 , wherein A is pyrimidinyl or 1H-indazolyl substituted with C 1 -C 5 alkyl, C 1 -C 4 alkoxyl, or halo.

4. The compound of claim 1 , wherein R 2 is 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.

5. 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.

6. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl.

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

Assignees

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

Inventors

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

Classifications

• C07D295/13

  to an acyclic saturated chain · CPC title

• C07D233/74

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title