Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9617259-B2
Application number	US-201414776320-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 14, 2013
Publication date	Apr 11, 2017
Grant date	Apr 11, 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:
each of the dashed lines indicate a single or double bond, provided that the ring contains one or two double bonds that are non-adjacent;
R 1 is —C(O)NH(OH) or —N(OH)C(O)R 5 wherein R 5 is hydrogen, lower alkyl or lower haloalkyl;
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; and
R 3 is hydrogen, 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 , aryl, heteroaryl, and nitrile;
for each occurrence, R 4 is independently selected from halo, lower alkyl, lower haloalkyl, and hydroxyl;
x and y are independently selected from 1, 2, and 3, provided that the sum of x+y is ≦4,
n is 0, 1, 2 or 3;
R b is hydrogen, C 1 -C 6 alkyl, aryl, or heteroaryl; and
R c is hydrogen or 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, cycloalkyl, 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, Formula III, or Formula IV:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula XI, Formula XII, or Formula XIII:

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(OH)C(O)R 5 .

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or lower alkyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 5 is lower alkyl.

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

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

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

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, for each occurrence, R 4 is independently selected from halo and lower alkyl.

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

14. 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.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, lower alkyl, and haloalkyl.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, 2-fluorophenyl, 3-fluoro-2-methylphenyl or 2-methylphenyl.

17. 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, lower alkyl, and haloalkyl.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridinyl optionally substituted with 1 to 3 substituents independently selected from halo, lower alkyl, and haloalkyl.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 2-methylpyridin-3-yl.

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

21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or alkyl optionally substituted with 1 to 3 substituents independently selected from halo, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

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

23. The compound of claim 20 , 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.

24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, 2-methylphenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4,4-difluoro-1,2,3,4-tetrahydroquinolin-7-yl, or 4,4,8-trifluoro-1,2,3,4-tetrahydroquinolin-6-yl.

25. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

26. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 6-methylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, 5-fluoropyridin-3-yl, 5-(trifluorometh

Assignees

• Chdi Foundation Inc

Inventors

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

Classifications

• C07D213/56

  Amides · CPC title

• C07D241/42

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

• C07D241/12

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

• C07D239/26

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title