Selective hdac6 inhibitors

Patent metadata

Field	Value
Publication number	US-2016347732-A1
Application number	US-201415107272-A
Country	US
Kind code	A1
Filing date	Dec 23, 2014
Priority date	Dec 23, 2013
Publication date	Dec 1, 2016
Grant date	—

Abstract

The present invention provides a compound having the structure:

wherein
R 1 is halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 ) R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 6 , and R7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

Ar 1 is phenyl or thiophene;
wherein when Ar 1 is phenyl, then R 1 is other than —O(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is hydroxyalkyl, or where one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H; and
wherein when Ar 1 is phenyl, then R 1 is other than —NR 5 —C(═O)—R 6 , where one of R 5 is H and R 6 is quinoline,

or a pharmaceutically acceptable salt thereof.

First claim

1 . A compound having the structure:

wherein
R 1 is halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—R 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ) P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

Ar 1 is phenyl or thiophene;
wherein when Ar 1 is phenyl, then R 1 is other than —C(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is —CH 2 CH 2 OH, or where one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H; and
wherein when Ar 1 is phenyl, then R 1 is other than —NR 5 —C(═O)—R 6 , where R 5 is H and R 6 is quinoline,

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 ,
wherein Ar 1 is

3 . The compound of claim 1 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl.

4 . The compound of claim 3 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, hydroxyalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl.

5 . The compound of claim 4 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein
R 5 is C 1-5 alkyl, hydroxyalkyl, aryl or heteroaryl;
R 6 is C 1-5 alkyl, hydroxyalkyl, aryl or heteroaryl; and
R 7 is alkyl, hydroxyalkyl, aryl, heteroaryl, or C 1-5 alkyl-NH-aryl.

6 . The compound of claim 4 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein R 5 , R 6 , and R 7 and are each, independently, phenyl, —CH 2 CH 2 OH, —CH 2 -phenyl, or —CH 2 CH 2 N(H)-phenyl.

7 . The compound of claim 6 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —COR 2 R 7 ,
wherein R 5 , R 6 , and R 7 and are each, independently,

or
R 1 is —C(═O)—NR 5 R 6 ,
wherein R 5 is

and R 6 is

or
R 1 is —NR 5 —C(═O)—R 6 ,
wherein R 5 is

and R 6 is

or
R 1 is —CO 2 R 7 ,
wherein R 7

8 . The compound of claim 1 having the structure:

wherein
R 1 is halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S) R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 5 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 5 , and R 7 and are each, independently, H, alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

wherein R 1 is other than —C(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is —CH 2 CH 2 OH, or where one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H; and
wherein R 1 is other than —NR 5 —C(═O)—R 6 , where R 5 is H and R 6 is quinoline,

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 having the structure:

wherein
R 1 is halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S) R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl,

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 ,
wherein R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein
R 5 is C 1-5 alkyl, hydroxyalkyl, aryl or heteroaryl;
R 6 is C 1-5 alkyl, hydroxyalkyl, aryl or heteroaryl; and
R 7 is C 1-5 alkyl, hydroxyalkyl, aryl, heteroaryl, or C 1-5 alkyl-NH-aryl; and
Ar 1 is phenyl or thiophene,
or a pharmaceutically acceptable salt thereof.

11 . (canceled)

12 . The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

13 . (canceled)

14 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

15 . A method of inhibiting the activity of a histone deactylase in a cell comprising contacting t he histone deacetylase with the compound of claim 1 so as to inhibit the activity of the histone deacetylase.

16 . The method of claim 15 , wherein the histone deacetylase is HDAC6.

17 . A method of treating a neurodegenerative disease in a subject afflicted therewith comprising administering an effective amount of the compound of claim 1 to the subject so as to treat the neurodegenerative disease in the subject, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Huntin ton's disease or Niemann-Pick type C disease.

18 . (canceled)

19 . A method of treating a disease associated with defective lipid t ransport in a subject afflicted t herewith comprising administering an effective amount of the compound of claim 1 to the subject so as to treat the disease in the subject, wherein the disease associated with defective lipid transport is Stargardt disease, macular degeneration, Harlequin ichthyosis or Tan ier disease.

20 . (canceled)

21 . A method of treating cancer in a subject afflicted therewith comprising administering an effective amount of the compound of claim 1 to the subject so as to treat the cancer in the subject.

22 . A method of treating HIV in

Assignees

• Breslow Ronald
• Marks Paul
• Mahendran Adaickapillai
• Yao Yuanshan
• Univ Columbia
• Memorial Sloan Kettering Cancer Center

Inventors

• Breslow Ronald
• Marks Paul
• Mahendran Adaickapillai
• Yao Yuanshan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07C233/69

  of an acyclic saturated carbon skeleton · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K45/06

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

• C07C237/42

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated · CPC title