Histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-10851058-B2
Application number	US-201615740437-A
Country	US
Kind code	B2
Filing date	Jul 1, 2016
Priority date	Jul 2, 2015
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

Provided herein are compounds and methods for inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).

First claim

What is claimed is:

1. A compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof

wherein
ring A is a 4-7 membered saturated heterocycle containing one nitrogen ring atom or a 7-9 membered saturated bicyclic heterocycle containing one nitrogen ring atom;
Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C(O)C 1-6 alkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or saturated C 0-3 alkylene-C 2-5 heterocycle having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl);
R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.

2. The compound of claim 1 , wherein ring A is a 4-7 membered saturated heterocycle containing one nitrogen ring atom or a 7-9 membered bicyclic saturated heterocycle containing one nitrogen ring atom; Z is O, NR 3 , S, or SO 2 ; R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-7 cycloalkyl; R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is H, C 1-6 -alkyl, C 1-6 hydroxyalkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or saturated C 0-3 alkylene-C 2-5 heterocycle having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-10 cycloalkyl.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is methyl, isopropyl, sec-butyl, CH 2 C(CH 3 ) 3 , or

6. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is cyclopropyl, cyclobutyl, cyclohexyl, adamantanyl, CH 2 cyclopropyl, (1-methylcyclopropyl)methyl, CH 2 cyclobutyl, CH 2 cyclohexyl, CH 2 -adamantanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
ring A is selected from the group consisting of:

Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,

R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from the group consisting of

Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,

and R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl.

9. The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is selected from the group consisting of

10. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is H.

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is selected from the group consisting of

12. The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is selected from the group consisting of

Z is O or NR 3 ; and R 1 is selected from the group consisting of

13. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III), or a pharmaceutically acceptable salt thereof

wherein Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of

R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is O, NR 3 , S, or SO 2 ; and R 1 is selected from the group consisting of

15. The compound of claim 1 having a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 selected from the group consisting of

Assignees

• Biomarin Pharm Inc

Inventors

• Bhagwat Shripad
• Luedtke Gregory
• BRIDGES Alexander

Classifications

• C07D211/54

  Sulfur atoms · CPC title

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D223/08

  Oxygen atoms · CPC title

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title