Selective HDAC1 and HDAC2 inhibitors

Patent metadata

Field	Value
Publication number	US-9765066-B2
Application number	US-201615214061-A
Country	US
Kind code	B2
Filing date	Jul 19, 2016
Priority date	Nov 2, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Provided herein are compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with HDAC activity, particularly diseases or disorders that involve activity of HDAC1 and/or HDAC2. Such diseases include cancer, sickle-cell anemia, beta-thalassemia, and HIV.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein
Y 1 is CR 7 or NR 7 ;
Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently CH, CH 2 , N, or C(O), wherein at least one of Y 2 , Y 3 , Y 4 , and Y 5 are CH;
R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted;
R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-OR 6 , aryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
R 4 is H, C 1-6 -alkyl, or C 1-6 -alkyl-OR 6 ;
R 5 is CO 2 R 6 , C 1 -C 6 -alkyl-aryl, or C 1-6 -alkyl-OR 6 ;
R 6 is H or C 1-6 -alkyl;
R 7 is null, H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl;
a line denotes an optionally double bond;
m is 0 or 1; and
n is 0 or 1, provided at least one of m or n is 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 ;
R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-OR 6 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, and C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with C 1-4 -alkyl, CO 2 R 6 , C(O)R 6 , or C 1-6 -alkyl-OR 6 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
R 1 is monocyclic aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halo;
R 2 and R 3 are each independently selected from C 2-6 -alkenyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 4 R 5 , O—C 1-6 -alkyl-OR 6 , or C 1-6 -alkyl-OR 6 ;
R 4 is H or C 1-6 -alkyl;
R 5 is CO 2 R 6 or C 1-6 -alkyl-OR 6 ; and
R 6 is C 1-6 -alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
m is 1; n is 1; Y 1 is N; and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each CH;
m is 0; n is 1; Y 2 is N; Y 1 is CR 7 ; and Y 3 , Y 4 , and Y 6 are each CH;
m is 0; n is 1; Y 1 is CR 7 ; Y 2 is N; Y 3 is C(O); Y 4 is CH 2 ; and Y 6 is CH;
m is 1; n is 1; Y 1 is CR 7 ; Y 2 is N, and Y 3 , Y 4 , Y 5 , and Y 6 are each CH;
m is 0; n is 1; Y 1 is CR 7 ; Y 2 and Y 3 are each N; and Y 4 and Y 6 are each CH;
m is 0; n is 1; Y 1 and Y 2 are N; Y 3 , Y 4 , and Y 6 are each CH; or
m is 1; n is 1; and Y1, Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each CH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, thienyl, or pyridinyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is para to NH 2 in the compound of Formula I.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclopropyl, cyclopentyl, CH 2 -cyclopropyl, CH 2 CH═CH 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, O—C 1-6 -alkyl-OR 6 , or C 1-6 -alkyl-OR 6 , or NR 4 R 5 .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is morpholinyl, piperazinyl, CH 2 CH 2 -morpholinyl, CH 2 -morpholinyl, CH 2 CH 2 -piperazinyl, CH 2 -piperazinyl, OCH 2 CH 2 OCH 3 , OCH 2 OCH 3 , CH 2 CH 2 OCH 3 , or NHCO 2 CH 2 CH 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H or C 3-6 -cycloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is cyclopropyl.

12. The compound claim 1 , having the structure of Formula III:

or a pharmaceutically acceptable salt thereof.

13. A compound selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

14. A compound selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

Assignees

• Acetylon Pharmaceuticals Inc
• Regenacy Pharmaceuticals Llc

Inventors

• Van Duzer John H
• Mazitschek Ralph

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D215/54

  attached in position 3 · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title