Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9783488-B2
Application number	US-201414776280-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 14, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 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 is —C(O)NH(OH) or —N(OH)C(O)R 4 ;
R 2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile;
X is absent, —O—, —NR 6 —, or —[C(R 7 R 8 )] p —;
R 3 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, —CONR b R c , alkyl, alkyl substituted with —NR b R c , cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkoxy substituted with —NR b R c , aryl, heteroaryl, and nitrile;
R 4 is hydrogen, lower alkyl or lower haloalkyl;
for each occurrence, R 5 is independently selected from halo, lower alkyl, lower haloalkyl, and hydroxyl; or
R 3 taken together with R 5 , and any intervening atoms, forms a 3- to 7-membered heterocycloalkyl or cycloalkyl ring;
m and m′ are independently selected from 1, 2, and 3, provided that m+m′≦4;
n is 0, 1, 2 or 3;
p is 1 or 2;
R 6 is hydrogen, lower alkyl, cycloalkyl, or lower haloalkyl; and
for each occurrence, R 7 and R 8 are each independently selected from hydrogen, halo, lower alkyl, and lower haloalkyl,
R b is selected from H, C 1 -C 6 alkyl, aryl, and heteroaryl; and
R c is selected from hydrogen and C 1 -C 4 alkyl; or
R b and R c , and the nitrogen to which they are attached, form a heterocycloalkyl group; and
where for R b and R c , each C 1 -C 6 alkyl, aryl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH(C 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), —CO 2 H, —C(O)OC 1 -C 4 alkyl, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —NHC(O)(C 1 -C 4 alkyl), —NHC(O)(phenyl), —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)C(O)(phenyl), —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 phenyl, —C(O)C 1 -C 4 haloalkyl, —OC(O)C 1 -C 4 alkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 4 alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 4 haloalkyl).

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 m is 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 2.

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

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m′ is 1.

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m′ is 2.

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m′ is 3.

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

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

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

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is lower alkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 3.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, for each occurrence, R 5 is independently selected from halo and lower alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 3-fluoro-2-methylphenyl or 2-methylphenyl.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridinyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 2-methylpyridin-3-yl.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 2.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, for each occurrence, R 7 and R 8 are each independently selected from hydrogen, halo, and lower alkyl.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is absent.

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —NR 6 —.

30. The compound of claim 29 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, lower alkyl, or cycloalkyl.

31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, —CONR b R c , alkyl, alkyl substituted with —NR b R c , cycloalkyl, haloalkyl, hydroxyl, alkoxy, alkoxy substituted with —NR b R c , and nitrile.

32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 3 is aryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

33. The compound of claim 32 , or a pharmaceutically acceptable salt the

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Muñoz-Sanjuán Ignacio
• Maillard Michel
• Raphy Gilles
• Haughan Alan F
• Luckhurst Christopher A
• Jarvis Rebecca E
• Bürli Roland W
• Breccia Perla
• Wishart Grant
• Hughes Samantha J
• Allen Daniel R
• Penrose Stephen D

Classifications

• C07D311/96

  spiro-condensed with carbocyclic rings or ring systems · CPC title

• A61P25/14

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

• C07D209/46

  with an oxygen atom in position 1 · CPC title

• C07D215/06

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title

• C07D265/36

  condensed with one six-membered ring · CPC title