Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9505736-B2
Application number	US-201314414149-A
Country	US
Kind code	B2
Filing date	Jul 16, 2013
Priority date	Jul 16, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

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

First claim

The invention claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein:
R 1 and R 2 are independently chosen from optionally substituted aryl and optionally substituted heteroaryl;
R 3 is chosen from —C(O)NH(OH) and —N(OH)C(O)R 4 ;
R 3a is halo; and
R 4 is chosen from hydrogen and lower alkyl.

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

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is chosen from compounds of Formula III.

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

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3a is fluoro.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —C(O)NH(OH).

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —N(OH)C(O)R 4 wherein R 4 is hydrogen.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —N(OH)C(O)R 4 wherein R 4 is methyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from aryl and heteroaryl, each of which is optionally substituted with one or two groups independently chosen from lower alkyl, halo, hydroxyl, and lower alkoxy.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from aryl optionally substituted with one or two groups independently chosen from lower alkyl, halo, hydroxyl, and lower alkoxy.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from phenyl, 2-methylphenyl, and 3-fluoro-2-methylphenyl.

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

13. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from heteroaryl optionally substituted with one or two groups independently chosen from lower alkyl, halo, hydroxyl, and lower alkoxy.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from pyridin-3-yl and 6-oxo-1,6-dihydropyridin-2-yl, each of which is optionally substituted with one or two groups independently chosen from lower alkyl, halo, hydroxyl, and lower alkoxy.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from 2-methylpyridin-3-yl and 1-methyl-6-oxo-1,6-dihydropyridin-2-yl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from aryl and heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups independently chosen from
halo,
cyclopropyl,
trifluoromethyl,
lower alkyl optionally substituted with 1, 2 or 3 groups independently chosen from halo, lower alkoxy, and hydroxyl,
phenyl optionally substituted with 1 or 2 groups independently chosen from cyclopropyl, halo, difluoromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, and lower alkyl,
heteroaryl optionally substituted with 1 or 2 groups independently chosen from cyclopropyl, halo, difluoromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, and lower alkyl, and
-L-(CR 5 R 6 ) n —N(R 7 )R 8 where L is chosen from —C(O)NR 9 — and —NR 10 —, n is 1 or 2, each occurrence of R 5 and R 6 is independently selected from hydrogen and lower alkyl, R 7 is hydrogen or lower alkyl, and R 8 is hydrogen or lower alkyl or R 7 and R 8 , taken together with the nitrogen to which they are bound, form an optionally substituted 4- to 8-membered heterocycloalkyl ring, R 9 is hydrogen, and R 10 is selected from hydrogen and lower alkyl.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from 1,2,3,4-tetrahydroquinolin-6-yl, 1H-pyrazol-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-6-yl, chroman-6-yl, phenyl, pyridazin-4-yl, pyridin-3-yl, pyridin-4-yl, and thiazol-5-yl, each of which is optionally substituted with 1, 2, or 3 groups independently chosen from
halo,
cyclopropyl,
lower alkyl optionally substituted with 1, 2, or 3 groups independently chosen from halo, lower alkoxy, and hydroxyl,
phenyl optionally substituted with halo,
oxazol-5-yl optionally substituted with cyclopropyl,
pyrimidin-4-yl optionally substituted with 1 or 2 groups independently chosen from halo, difluoromethoxy, difluoromethyl, trifluoromethoxy, trifluoromethyl and lower alkyl,
pyrimidin-2-yl optionally substituted with 1 or 2 groups independently chosen from halo, difluoromethoxy, difluoromethyl, trifluoromethoxy, trifluoromethyl and lower alkyl,
pyrazin-2-yl optionally substituted with 1 or 2 groups independently chosen from halo, difluoromethoxy, difluoromethyl, trifluoromethoxy, trifluoromethyl or lower alkyl,
pyridin-2-yl optionally substituted with 1 or 2 groups independently chosen from halo, difluoromethoxy, difluoromethyl, trifluoromethoxy, trifluoromethyl or lower alkyl, and
-L-(CR 5 R 6 ) n —N(R 7 )R 8 where L is chosen from —C(O)NR 9 — and —NR 10 —, n is 1 or 2, each occurrence of R 5 and R 6 is independently selected from hydrogen and lower alkyl, R 7 is hydrogen or lower alkyl, and R 8 is hydrogen or lower alkyl or R 7 and R 8 , taken together with the nitrogen to which they are bound, form an optionally substituted 4- to 8-membered heterocycloalkyl ring, R 9 is hydrogen, and R 10 is selected from hydrogen and lower alkyl.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from 1,2,3,4-tetrahydroquinolin-6-yl, 1H-pyrazol-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-6-yl, chroman-6-yl, phenyl, pyridazin-4-yl, pyridin-3-yl, pyridin-4-yl, and thiazol-5-yl, each of which is optionally substituted with 1, 2, or 3 groups independently chosen from
2-(trifluoromethyl)pyrimidin-4-yl,
2-cyclopropyloxazol-5-yl,
2-hydroxypropan-2-yl,
4-(trifluoromethyl)pyrimidin-2-yl,
4-fluorophenyl,
5-(trifluoromethyl)pyridin-2-yl,
5-fluoropyrimidin-2-yl,
5-chloropyrimidin-2-yl,
5-methylpyrimidin-2-yl,
5-(difluoromethoxy)pyrimidin-2-yl,
5-(difluoromethyl)pyrimidin-2-yl,
2-methylpyrimidin-5-yl,
5-fluoropyridin-2-yl,
5-(trifluoromethyl)pyrazin-2-yl,

bromo,
chloro,
cyclopropyl,
fluoro, and
oxazol-5-yl.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from (1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl, 2-(2-(trifluoromethyl)pyrimidin-4-yl)thiazol-5-yl, 2-(2-hydroxypropan-2-yl)benzo[d]oxazol-6-yl, 2-(2-hydroxypropan-2-yl)benzo[d]thiazol-6-yl, 2-(2-hydroxypropan-2-yl)pyridin-4-yl, 2-(2-hydroxypropan-2-yl)thiazol-5-yl, 2-(4-fluorophenyl)thiazol-5-yl, 2-(5-fluoropyrimidin-2-yl)thiazol-5-yl, 2-cyclopropyl-5-fluoropyridin-4-yl, 2-cyclopropylbenzo[d]oxazol-6-yl, 2-cyclopropylpyridin-4-yl, 2-cyclopropylthiazol-5-yl, 3-(2-cyclopropyloxazol-5-yl)phenyl, 3-(5-fluoropyrimidin-2-yl)phenyl, 4-(2-cyclo

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Breccia Perla
• Luckhurst Christopher A
• Bürli Roland W
• Stott Andrew J

Classifications

• A61P43/00

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

• A61P25/14

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

• C07D239/34

  One oxygen atom · CPC title

• C07D401/04

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