Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10053434-B2
Application number	US-201615148907-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	May 7, 2015
Publication date	Aug 21, 2018
Grant date	Aug 21, 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, an optical isomer, or a mixture of optical isomers thereof;
wherein:
W is N or CR 5 ; X is N or CR 6 ; Y is N or CR 7 ; and Z is N or CR 8 ; provided not more than two of W, X, Y, and Z are N;
R 1 is selected from H and C 1 -C 3 alkyl;
R 2 is C 2 -C 3 alkylene optionally substituted with C 1 -C 2 haloalkyl or 3 or 4-membered cycloalkyl;
R 3 and R 4 , together with the nitrogen atom to which they are attached, form:
a 4 or 7-membered heteromonocyclic group optionally substituted with one to five substituents independently selected from: C 1 -C 3 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, carboxy, aryl, cyano, halo, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halo; or
a 5 or 6-membered heteromonocyclic group optionally substituted with one to five substituents independently selected from: C 1 -C 3 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, carboxy, aryl, cyano, halo, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents each independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halo; or
a 6, 7, 8, 9, or 10-membered heterobicyclic group, which is optionally substituted with one to five substituents independently selected from: C 1 -C 3 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, carboxy, aryl, cyano, halo, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halo;

R 5 , R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and halo;
provided that if R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 5 or 6-membered heteromonocyclic group, then:
R 2 is C 2 -C 3 alkylene substituted with C 1 -C 2 haloalkyl or 3 or 4-membered cycloalkyl.

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 C 2 -C 3 alkylene optionally substituted with 3 or 4-membered cycloalkyl.

4. A compound of Formula III:

or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein:
R 1 , R 5 , R 6 , R 7 and R 8 are each H; and
R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 5 or 6-membered heteromonocyclic group substituted with one to two substituents each independently selected from 3 or 4-membered cycloalkyl and heteroaryl.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 6 is H.

6. 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 V:

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 is C 2 -C 3 alkylene optionally substituted with 3 or 4-membered cycloalkyl.

8. A compound according to claim 7 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein the compound is of Formula VI:

9. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 5 is H.

10. 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 H.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 8 is selected from H, halo, and methyl.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 1 is selected from H and methyl.

13. A compound according to claim 12 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 1 is H.

14. A compound according to claim 1 , or a pharmaceutically acceptable salt, an optical isomer, or a mixture of optical isomers thereof, wherein R 3 and R 4 , together with the nitrogen atom to which they are attached, form a 4 or 7-membered heteromonocyclic group selected from
3-phenylazetidin-1-yl, and
azepan-1-yl.

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

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

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

18. A compound according to claim 1 , or a pharmaceutically accept

Assignees

• Chdi Foundation Inc

Inventors

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

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title