Histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-9512143-B2
Application number	US-201514598583-A
Country	US
Kind code	B2
Filing date	Jan 16, 2015
Priority date	Feb 28, 2011
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The compounds provided herein are phenyl analine amides and are useful for inhibiting histone deacteylase (“HDAC”) enzymes, such as HDAC1, HDAC2, and HDAC3.

First claim

We claim:

1. A compound having a structure of formula (II):

wherein:
R 3 is H or F;
R p is Cl or F;
Cy is a saturated heterocyclyl having 4-8 ring atoms, where at least one hetero atom is NH or N(C 1-6 alkyl) to form a secondary amine or tertiary amine, respectively, and optionally one or two additional heteroatoms are independently selected from the group consisting of O, NH, and N(C 1-6 alkyl); wherein a ring atom of Cy is bonded to the exocyclic double bond;
V is C(R y ) 2 ;
each R y is independently selected from the group consisting of H, F, C 1-6 alkyl, and C 3-6 cycloalkyl;
R 1 is H, phenyl, or monocyclic or bicyclic heteroaryl, where the phenyl and heteroaryl are each optionally substituted with 1-3 Rq; and
R q is independently halogen, OH, C 1-6 alkyl, fluoro(C 1-6 alkyl), hydroxy(C 1-4 alkyl), C 1-6 alkoxy, or fluoro(C 1-6 alkoxy);

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 3 is H.

3. The compound of claim 1 , wherein R 3 is F.

4. The compound of claim 1 , wherein Cy is a saturated heterocyclyl having 4-6 ring atoms where at least one heteroatom is NH to form a secondary amine.

5. The compound of claim 1 , wherein Cy is azetindinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.

6. The compound of claim 1 , wherein Cy is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and V—R 1 is CH 2 -pyridyl, CH 2 -indolyl, C 1-6 alkyl, CH 2 -cyclopropyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with C 1-6 alkyl.

7. The compound of claim 1 , wherein Cy is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and V—R 1 is C 1-6 alkyl, CH 2 -cyclopropyl, CH 2 -pyridyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with methyl.

8. The compound of claim 7 , wherein Cy is azetindinyl, and V—R 1 is CH 2 -cyclopropyl, CH 2 -pyridyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with methyl.

9. The compound of claim 7 , wherein Cy is piperidinyl, and V—R 1 is C 1-6 alkyl or CH 2 -cyclopropyl.

10. The compound of claim 7 , wherein Cy is 8-azabicyclo [3.2.1]octanyl and V—R 1 is C 1-6 alkyl.

11. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A method of selectively inhibiting HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

13. A method of selectively inhibiting HDAC1 or HDAC2 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

14. A method of inhibiting HDAC1, HDAC2, and HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

15. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

18. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

Assignees

• Biomarin Pharm Inc

Inventors

• Jacques Vincent
• Rusche James R
• Peet Norton P
• Singh Jasbir

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P29/00

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