Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10065948-B2
Application number	US-201515315713-A
Country	US
Kind code	B2
Filing date	Jun 1, 2015
Priority date	Jun 2, 2014
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, or pharmaceutically acceptable salts thereof, compositions thereof, and methods of their use. The condition or disorder mediated by HDAC comprises a neurodegenerative pathology. Accordingly, also provided is a method of treating a neurodegenerative pathology mediated by HDAC in a subject in need of such a treatment, comprising administering to the subject a therapeutically effective amount of at least one compound, or pharmaceutically acceptable salt thereof, described herein.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —C(O)NH(OH) or —N(OH)C(O)R 9 ;
R 2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile;
A is aryl or heteroaryl;
R 3 and R 4 are independently chosen from hydrogen, alkyl, halo, —NHSO 2 R 10 , C(O)NR 11 R 12 , NR 11 R 12 , nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino;
for each occurrence, R 5 , R 6 , R 7 , and R 8 are independently chosen from hydrogen and lower alkyl;
R 9 is hydrogen or lower alkyl;
R 10 is lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 11 and R 12 are independently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyl and cycloalkyl, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and
m and m′ are independently chosen from 0, 1, 2, 3 and 4, provided that 2≤(m+m′)≤4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula II:

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl optionally substituted with one or two substituents independently chosen from alkyl, haloalkyl, alkoxy, haloalkoxy, and halo.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-2-fluorophenyl, 2,6-difluorophenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-methylphenyl, 2,4-difluorophenyl, 4-(difluoromethoxy)phenyl, or 3-fluoro-2-methylphenyl.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridin-2-yl, pyridin-4-yl, or pyrazin-2-yl, each of which is optionally substituted with one or two substituents independently chosen from alkyl and halo.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 5-fluoropyridin-2-yl, pyrazin-2-yl, or 3-methylpyridin-4-yl.

7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopropyl or cyclopentyl, each of which is optionally substituted with one or two substituents independently chosen from alkyl and halo.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopropyl or cyclopentyl.

9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is isopropyl.

10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula III:

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl, haloalkyl, or aralkyl optionally substituted with halo.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, 2,2,2,-trifluoroethyl, or 4-fluorobenzyl.

14. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl optionally substituted with one or two substituents independently chosen from alkyl, haloalkyl, alkoxy, haloalkoxy, and halo.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 3 is 2-fluorophenyl, 4-(difluoromethoxy)phenyl, 4-fluoro-2-methylphenyl, or 3-methylphenyl.

16. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridin-2-yl or pyridin-4-yl, each of which is optionally substituted with one or two substituents independently chosen from alkyl and halo.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 3-methylpyridin-4-yl, 3-chloropyridin-2-yl, or 3-fluoropyridin-2-yl.

18. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, cyclopropyl, or phenyl optionally substituted with halo.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

20. A compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C(O)NH(OH) or —N(OH)C(O)R 9 ;
R 2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile;
R 3 and R 4 are independently chosen from hydrogen, alkyl, halo, —NHSO 2 R 10 , C(O)NR 11 R 12 , NR 11 R 12 , nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino;
for each occurrence, R 5 , R 6 , R 7 , and R 8 are independently chosen from hydrogen and lower alkyl;
R 9 is hydrogen or lower alkyl;
R 10 is lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 11 and R 12 are independently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyl and cycloalkyl, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and
m and m′ are independently chosen from 0, 1, 2, 3 and 4, provided that 2≤(m+m′)≤4.

21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

22. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cyclopropyl.

23. A compound of Formula I is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C(O)NH(OH) or —N(OH)C(O)R 9 ;
R 2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile;
R 3 is hydrogen, alkyl, halo, —NHSO 2 R 10 , C(O)NR 11 R 12 , NR 11 R 12 , nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, ha

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Muñoz-Sanjuán Ignacio
• Bürli Roland W
• Luckhurst Christopher A
• Allen Daniel R
• Raphy Gilles
• Breccia Perla
• Haughan Alan F
• Wishart Grant
• Hughes Samantha J
• Jarvis Rebecca E
• Vater Huw D
• Penrose Stephen D
• Wall Michael
• Stott Andrew J
• Saville-Stones Elizabeth A

Classifications

• 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

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/74

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring · CPC title

• C07D239/88

  Oxygen atoms · CPC title