Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9765054-B2
Application number	US-201213981107-A
Country	US
Kind code	B2
Filing date	Jan 23, 2012
Priority date	Jan 24, 2011
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

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, wherein
R 1 and R 2 are independently chosen from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 3 is —C(O)NH(OH); and
R 3 is hydrogen or lower alkyl optionally substituted with halo.

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a is —CF 3 .

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

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I a compound of Formula V:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted with one, two, or three groups independently chosen from —R 21 , —OR 22 , halo, and —NR 23 SO 2 R 21 , wherein
R 21 is chosen from optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
R 22 is chosen from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and
R 23 is chosen from hydrogen and optionally substituted C 1 -C 4 alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclohexyl, thiophen-2-yl, thiazol-5-yl, or phenyl, each of which is optionally substituted with one, two, or three groups independently chosen from —R 21 , —OR 22 , and halo.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophen-2-yl or phenyl, each of which is optionally substituted with one, two, or three groups independently chosen from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, and halo.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 3-fluorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 5-methylthiophen-2-yl, 3-fluoro-5-methylthiophen-2-yl, 5-methyl-3-(trifluoromethyl)thiophen-2-yl, or 5-(trifluoromethyl)thiophen-2-yl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted with one, two, or three groups independently chosen from —R 11 , —OR 12 , halo, —NR 12 R 13 , —C(O)R 12 , —C(O)OR 12 , —C(O)NR 12 R 13 , —OC(O)R 12 , —OC(O)OR 11 , —OC(O)NR 12 R 13 , —NR 13 C(O)R 12 , —NR 13 C(O)OR 11 , —NR 13 C(O)NR 12 R 13 , —S(O)R 11 , —SO 2 —R 11 , —SO 2 NR 12 R 13 , and —NR 13 SO 2 R 11 , wherein
R 11 is chosen from optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, and optionally substituted heteroaryl;
R 12 is chosen from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and
R 13 is chosen from hydrogen and optionally substituted C 1 -C 4 alkyl.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one, two, or three groups independently chosen from —R 11 , —OR 12 , halo, —C(O)R 12 , —NR 12 R 13 , and —NR 13 SO 2 R 11 .

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one, two or three groups independently selected from
halo,
C 1 -C 6 alkyl,
aryl optionally substituted with one or two groups independently chosen from lower alkyl, trifluoromethyl, cycloalkyl, phenyl, and benzyloxy,
heteroaryl optionally substituted with one or two groups independently chosen from lower alkyl, trifluoromethyl, cycloalkyl, and phenyl,
(cycloalkyl)sulfonamido, and
heterocycloalkyl optionally substituted with one or two groups independently chosen from halo, lower alkyl, trifluoromethyl, cycloalkyl, heterocycloalkyl, and phenyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one, two or three groups independently selected from halo, lower alkyl, oxazol-2-yl, oxazol-5-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1H-pyrazol-1-yl, (cycloalkyl)sulfonamido, 1H-imidazol-1-yl, imidazol-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, phenyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, piperidin-1-yl, piperazin-1-yl, and 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl, each of which is optionally substituted with one or two groups independently chosen from halo, lower alkyl, trifluoromethyl, phenyl, cycloalkyl, benzyl, benzyloxy, and pyrrolidin-1-yl.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(5-methylpyrimidin-2-yl)phenyl, 3-(5-fluoropyrimidin-2-yl)phenyl, 4-(5-chloropyrimidin-2-yl)phenyl, 4-(5-fluoropyrimidin-2-yl)phenyl, 4-(4-(trifluoromethyl)pyrimidin-2-yl)phenyl, 4-(5-trifluoromethylpyrimidin-2-yl)phenyl, 4-(5-cyclopropylpyrimidin-2-yl)phenyl, 4-(pyridazin-3-yl)phenyl, 4-(pyridazin-4-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(1-methyl-1H-imidazol-2-yl)phenyl, 4-(5-methyl-1H-imidazol-2-yl)phenyl), 4-(1H-pyrazol-1-yl)phenyl, 4-(3-methyl-1H-pyrazol-1-yl)phenyl, 4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-(oxazol-2-yl)phenyl, 4-(oxazol-5-yl)phenyl, 4-(2-methyloxazol-5-yl)phenyl, 4-(2-cyc

Assignees

• Bürli Roland W
• Stott Andrew J
• Breccia Perla
• Dominguez Celia
• Muñoz-Sanjuàn Ignacio
• Luckhurst Christopher A
• Hughes Samantha J
• Haughan Alan F
• Chdi Foundation Inc

Inventors

• Bürli Roland W
• Stott Andrew J
• Breccia Perla
• Dominguez Celia
• Muñoz-Sanjuàn Ignacio
• Luckhurst Christopher A
• Hughes Samantha J
• Haughan Alan F

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

• C07D265/36

  condensed with one six-membered ring · CPC title