Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10047073-B2
Application number	US-201615148884-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	May 7, 2015
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, compositions thereof, and methods of their use.

First claim

What is claimed:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, an optical isomer, or a mixture of optical isomers thereof;
wherein:
R 1 is selected from: H and C 1 -C 3 alkyl;
p is 0; and R 2 and R 3 , together with the carbon atom to which they are attached, form a 3 to 6-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2 alkyl, C 1 -C 2 haloalkyl or halo; or
p is 1; R 2 is H; and R 3 and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group, wherein said cyclopropyl group is optionally substituted with one or two halo groups;
R 5 is C 0 -C 3 alkylene;
R 6 is selected from: H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and
R 7 is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl, each aromatic moiety of which is optionally substituted with one to five substituents independently selected from: C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 4 alkoxy, amino, cyano, halo, and hydroxyl; or
R 6 and R 7 , together with the nitrogen atom to which they are both attached, form a 5, 6, or 7-membered heteromonocyclic group, or a 6, 7, 8, 9, or 10-membered heterobicyclic group, each of which is optionally substituted with one to five substituents independently selected from: C 1 -C 4 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein the aryl, 3 or 4-membered cycloalkyl, and heteroaryl are optionally further substituted with one to five substituents independently selected from: C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, and halo;
W is N or CR 8 ; X is N or CR 9 ; Y is N or CR 10 ; and Z is N or CR 11 ; provided not more than two of W, X, Y, and Z are N; and
R 8 , R 9 , R 10 and R 11 are each independently selected from: H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and halo.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein the compound is of Formula II:

3. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 2 is H; and R 3 and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group, wherein said cyclopropyl group is optionally substituted with one halo group.

4. A compound according to claim 3 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 3 and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein the compound is of Formula III:

6. A compound according to claim 5 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3 to 5-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2 alkyl, C 1 -C 2 haloalkyl or halo.

7. A compound according to claim 6 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3 or 4-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2 alkyl, C 1 -C 2 haloalkyl or halo.

8. A compound according to claim 7 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3 or 4-membered cycloalkyl group.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein
R 7 is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl, each aromatic moiety of which is optionally substituted with one to three substituents independently selected from: C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 4 alkoxy, amino, cyano, halo, and hydroxyl.

10. A compound according to claim 9 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 is selected from: H and C 1 -C 3 alkyl.

11. A compound according to claim 9 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 7 is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 and R 7 , together with the nitrogen atom to which they are both attached, form a 5, 6, or 7-membered heteromonocyclic group, optionally substituted with one to five substituents independently selected from: C 1 -C 4 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein the aryl, 3 or 4-membered cycloalkyl, and heteroaryl are optionally further substituted with one to five substituents independently selected from: C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, and halo.

13. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 and R 7 , together with the nitrogen atom to which they are both attached, form a pyrrolidin-1-yl or piperidin-1-yl, optionally substituted with one to five substituents independently selected from: C 1 -C 4 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein the aryl, 3 or 4-membered cycloalkyl, and heteroaryl are optionally further substituted with one to five substituents independently selected from: C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, and halo.

14. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 and R 7 , together with the nitrogen atom to which they are both attached, form a pyrrolidin-1-yl or piperidin-1-yl, optionally substituted with one to five substituents independently selected from: C 1 -C 3 alkyl and cyclopropyl.

15. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 and R 7 , together with the nitrogen atom to which they are both attached, form a 6, 7, 8, 9, or 10-membered heterobicyclic group, each of which is optionally substituted with one to five substituents independently selected from: C 1 -C 4 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein the aryl, 3 or 4-

Assignees

• Chdi Foundation Inc
• Chdi Foundation Inc

Inventors

• Maillard Michel C
• Breccia Perla
• Dominguez Celia
• Haughan Alan F
• Jarvis Rebecca E
• Luckhurst Christopher A
• Saville-Stones Elizabeth A
• Stott Andrew J
• Van de Poël Amanda
• Wall Michael
• Wishart Grant

Classifications

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D413/12 Primary

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