Histone deacetylase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10106535-B2
Application number	US-201715482327-A
Country	US
Kind code	B2
Filing date	Apr 7, 2017
Priority date	Mar 14, 2013
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

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 method for treating a patient suffering from a condition or disorder mediated by at least one histone deacetylase, wherein the condition or disorder is cancer, amyotrophic lateral sclerosis (ALS), diabetes, a cardiovascular condition, epilepsy, depression, viral infection, or fungal infection, and wherein the method comprises administering to the patient a therapeutically effective amount of 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, 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 method of claim 1 , wherein the compound of Formula I is a compound of Formula II, Formula III, or Formula IV:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound of Formula I is a compound of Formula XI, Formula XII, or Formula XIII:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein R 1 is —C(O)NH(OH).

5. The method of claim 1 , wherein R 1 is —N(OH)C(O)R 5 .

6. The method of claim 1 , wherein R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

7. The method of claim 1 , wherein R 2 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

8. The method of claim 1 , 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.

9. A method for treating a patient suffering from a condition or disorder mediated by at least one histone deacetylase, wherein the condition or disorder is cancer, amyotrophic lateral sclerosis (ALS), diabetes, a cardiovascular condition, epilepsy, depression, viral infection, or fungal infection, wherein the method comprises administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from:
(R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide;
(R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide;
(R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide;
(R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide;
(R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide;
(S)-3-(5-chloropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinoxalin-6-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide;
(S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxamide;
(S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxamide;
(S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxamide;
(S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide;
N-hydroxy-1-phenylcyclopent-3-enecarboxamide;
1-(2-fluorop

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

• C07D231/12

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

• C07D241/42

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

• C07C259/08

  having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D275/04

  condensed with carbocyclic rings or ring systems · CPC title