Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016031863-A1
Application number	US-201414776058-A
Country	US
Kind code	A1
Filing date	Mar 10, 2014
Priority date	Mar 14, 2013
Publication date	Feb 4, 2016
Grant date	—

Abstract

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

First claim

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
X is CR 4 or N;
R is chosen from —C(O)NH(OH) and —N(OH)C(O)R 7 ;
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is chosen from hydrogen, C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, and nitrile;
R 3 is chosen from —OR 5 , NR 5 R 6 , optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkenyl and optionally substituted cycloalkyl;
R 4 is chosen from hydrogen, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
R 5 and R 6 are independently chosen from hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aralkyl and optionally substituted heteroaralkyl; or R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl; and
R 7 is chosen from hydrogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is aryl or heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, and nitrile; R 3 is chosen from —OR 5 , —NR 5 R 6 , alkyl, aralkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkenyl and cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkenyl or cycloalkyl is optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, nitrile, heteroaryl, phenyl, heterocycloalkyl, cycloalkyl, aralkyl and heteroaralkyl; and R 5 and R 6 are independently chosen from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, heteroaryl, heterocycloalkyl, cycloalkyl, aryl, aralkyl and heteroaralkyl, wherein the heteroaryl, heterocycloalkyl, cycloalkyl, aryl, aralkyl or heteroaralkyl is optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, and nitrile; or R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl comprising one or two heteroatoms.

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

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

5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 7 is chosen from hydrogen and C 1 -C 4 alkyl.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 4 alkyl.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 4 .

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or C 1 -C 4 alkyl.

9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

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

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, and nitrile.

12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with 1 or 2 substituents independently chosen from C 1 -C 4 alkyl and halo.

13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from hydrogen, C 1 -C 4 alkyl, halo, and C 1 -C 4 haloalkyl.

15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

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

17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, C 1 -C 4 alkyl, or aralkyl.

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —NR 5 R 6 .

19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl comprising one or two heteroatoms.

20 . The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl chosen from pyrrolidin-1-yl, piperazin-1-yl, piperidine-1-yl, and morpholin-4-yl, each of which is optionally substituted with 1 or 2 substituents independently chosen from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cycloalkyl, halo, and phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents chosen from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and halo.

21 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl optionally substituted with 1 or 2 substituents chosen from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and halo.

22 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 6 is phenyl optionally substituted with 1 or 2 substituents chosen from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and halo.

23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted aryl.

24 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 3 is aryl optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, C 3 -C 6 cycloalkyl and nitrile.

25 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, chroman-8-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, and 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, C 3 -C 6 cycloalkyl and nitrile.

26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted heteroaryl.

27 . The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 3 is heteroaryl optionally substituted with 1 to 3 substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, alkoxy, C 3 -C 6 cycloalkyl and nitrile.

28 . The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridin-3-yl, benzofuran-7-yl, benzo[b]thiophen-7-yl, and benzo[d]thiazol-4-yl, each

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Muñoz-Sanjuán Ignacio
• Maillard Michel
• Vater Huw D
• Jarvis Rebecca E
• Luckhurst Christopher A
• Bürli Roland W
• Wishart Grant
• Stott Andrew J

Classifications

• A61P25/14

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

• C07D207/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D231/14

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D403/04

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title