Isoxazole hydroxamic acids as histone deacetylase 6 inhibitors

Patent metadata

Field	Value
Publication number	US-12522572-B2
Application number	US-202418618511-A
Country	US
Kind code	B2
Filing date	Mar 27, 2024
Priority date	Mar 29, 2017
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

The present disclosure provides compounds represented by Formula I:

and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein X and n are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat diseases and conditions, e.g., cancer, wherein inhibition of HDAC provides a benefit.

First claim

What is claimed is:

1 . A method of increasing efficacy of or reducing side-effects of a cancer treatment in a subject, said method comprising:
administering a therapeutically effective amount of an HDAC6 inhibitor to a subject in need of a cancer treatment, thereby increasing efficacy of or reducing side-effects of said subject to the cancer treatment,
wherein the cancer treatment comprises a radiotherapy, a chemotherapy, or a combination thereof, and
wherein said HDAC6 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
X is selected from the group consisting of:

R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 2 is selected from the group consisting of optionally substituted C 6 -C 14 aryl and aralkyl;
R 3 is selected from the group consisting of optionally substituted C 6 -C 14 aryl, optionally substituted 5- to 14-membered heteroaryl, and —C(═O)NR d R e ;
R 4a , R 4b , R 4e and R 4f are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;
R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 4c and R 4d taken together form a —C(═O)—with the carbon atom to which they are attached;
R 5a , R 5b , R 5c , and R 5d are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;
Z is selected from the group consisting of —O—, —N(R 8 )—, and —C(═O)—; or
Z is absent;
R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, aralkyl, optionally substituted 5- to 14-membered heteroaryl, and heteroaralkyl;
m is 0, 1, or 2;
n is 1, 2, 3, 4, 5, or 6;
represents a single or double bond;
R a , R b , R d , and R e are independently selected from the group consisting of hydrogen, C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, optionally substituted 5- to 14-membered heteroaryl; or
R a and R b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; or
R d and R e taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; and
R c is C 1-4 alkyl,
with the proviso that when Z is absent, R 3 is a bicyclic or tricyclic C 10-14 aryl, a bicyclic or tricyclic 9- to 14-membered heteroaryl, or —C(═O)NR d R e .

2 . The method of claim 1 , wherein said HDAC6 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 5- or 6-membered heterocyclo;
R a and R b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R a and R b taken together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocyclo;
R c is C 1-4 alkyl; and
n is 1, 2, or 3.

3 . The method of claim 1 , wherein said HDAC6 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 7a , R 7b , R 7c , R 7d , and R 7e , and lee are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 5- or 6-membered heterocyclo;
R a and R b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R a and R b taken together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocyclo;
R c is C 1-4 alkyl; and
n is 1, 2, or 3.

4 . The method of claim 1 , wherein said HDAC6 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 4a and R 4b are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy;
R 4c and R 4d are independently selected from the group consisting of hydrogen and methyl;
m is 0 or 1;
n is 1, 2, or 3; and
represents a single or double bond.

5 . The method of claim 1 , wherein said HDAC6 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 5a and R 5c are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy; and
n is 1, 2, or 3.

6 . The method of claim 1 , wherein said HDAC6 inhibitor is selected from the group consisting of:
5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-dichlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(-3-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(5,6-dichloro-1H-indol-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-3,4-dihydroquinolin-1 (2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-1 (2H)-yl) butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(3-(3,4-dichlorophenoxy) propyl)-N-hydroxyisoxazole-3-carboxamide; 5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzoazepin-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-bromobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; N-hydroxy-5-(2-(4-methoxybenzamido)ethyl) isoxazole-3-carboxamide; 5-(2-(4-(dimethylamino)benzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-cyclopropylbenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3,4-difluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-chloro-4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(4-chloro-3-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide; 5-(2-(3-(dimethylamino)benzamido)ethyl)-N-hydroxy

Assignees

• The George Washington Univ A Congressionally Chartered Not For Profit Corporation
• Univ Illinois

Inventors

• Villagra Alejandro
• Kozikowski Alan P
• Shen sida

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title