Isoxazole hydroxamic acids as histone deacetylase 6 inhibitors

Patent metadata

Field	Value
Publication number	US-2022153709-A1
Application number	US-202217590503-A
Country	US
Kind code	A1
Filing date	Feb 1, 2022
Priority date	Mar 29, 2017
Publication date	May 19, 2022
Grant date	—

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

1 - 25 . (canceled)

26 . A method of treating a disease or condition, the method comprising administering a therapeutically effective amount of a compound having Formula I:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to an individual in need 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, and 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 ;
and wherein the disease or condition is cancer, a neurological disease, a neurodegenerative disorder, a peripheral neuropathy, a psychiatric illness, a traumatic brain injury, a stroke, an inflammation or an autoimmune disease, Charcot-Marie-Tooth disease, an autism spectrum disorder, depression, or bipolar disorder.

27 . (canceled)

28 . The method of claim 26 further comprising administering a therapeutically effective amount of a second therapeutic agent.

29 - 30 . (canceled)

31 . The method of claim 26 , wherein the disease or condition is a cancer.

32 . The method of claim 28 , wherein the second therapeutic agent is one or more of a chemotherapeutic agent, radiation, and an immunotherapy.

33 . (canceled)

34 . The method of claim 26 , wherein the disease or condition is a neurological disease, a neurodegenerative disorder, a peripheral neuropathy, a psychiatric illness, or a traumatic brain injury.

35 . The method of claim 26 , wherein the disease or condition is a stroke.

36 . The method of claim 26 , wherein the disease or condition is an inflammation or an autoimmune disease.

37 . The method of claim 26 , wherein the disease or condition is Charcot-Marie-Tooth disease, an autism spectrum disorder, depression or bipolar disorder.

38 - 66 . (canceled)

67 . The method of claim 26 , the method comprising administering a therapeutically effective amount of a compound having Formula II:

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.

68 . The method of claim 67 , wherein R 6a , R 6b , R 6c , R 6d , and R 6c 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 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl.

69 . The method of claim 68 , wherein R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

70 . The method of claim 26 , the method comprising administering a therapeutically effective amount of a compound having Formula III:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 7a , R 7b , R 7c , R 7d , and R 7e 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.

71 . The method of claim 70 , wherein R 7a , R 7b , R 7c , R 7d , and R 7e 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 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl.

72 . The method of claim 71 , wherein R 7a , R 7b , R 7C , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

73 . The method of claim 26 , the method comprising administering a therapeutically effective amount of a compound having Formula IV:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 4a and R 4b

Assignees

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

Inventors

• Villagra Alejandro
• Kozikowski Alan P
• Shen sida

Classifications

• A61K45/06 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D261/18 Primary

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07D413/06

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

• A61K31/42

  Oxazoles · CPC title