Selective HDAC3 inhibitors

• US 10,125,131 B2
• Filed: 12/23/2016
• Issued: 11/13/2018
• Est. Priority Date: 02/01/2013
• Status: Active Grant

• Current Assignee: Regenacy Pharmaceuticals LLC
• Original Assignee: Regenacy Pharmaceuticals LLC
• Inventors: van Duzer, John H., Mazitschek, Ralph
• Primary Examiner(s): Shterengarts, Samantha L
• Application Number:
  US15/389,838
• Publication Number:
  US 20170204094A1
• Time in Patent Office: 690 Days
• Field of Search: None
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 217/26 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/06 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 235/08 : Radicals containing only hydrogen and carbon atoms
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Provided herein are HDAC3 inhibitors, as well as methods of treatment comprising administering these compounds to a subject in need thereof.

Claims

1. A compound of Formula I:

2. The compound of claim 1,

wherein

the heterocycloalkyl or C_1-6-alkyl-heterocycloalkyl groups of R³ are optionally substituted with C_1-4-alkyl;

and

the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups of R⁴ and R⁵ are optionally substituted with C_1-4-alkyl, CO₂R⁸, C(O)R⁸, or C_1-6-alkyl-OR⁸.

3. The compound of claim 1,

wherein

A is a bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of

4. The compound of claim 1,

wherein

A is a bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of

5. The compound of claim 1, wherein R¹ is halo.

6. The compound of claim 1, wherein R¹ is fluoro.

7. The compound of claim 1, wherein R² is halo.

8. The compound of claim 1, wherein R² is chloro.

9. The compound of claim 1, wherein R³ is heterocycloalkyl, or C_1-6-alkyl-heterocycloalkyl wherein the heterocycloalkyl or C_1-6-alkyl-heterocycloalkyl groups are optionally substituted with C_1-4-alkyl.

10. The compound of claim 1, wherein R³ is piperazinyl or piperazinyl-CH₃.

11. The compound of claim 1, wherein R³ is CH₂CH₂-morpholinyl.

12. The compound of claim 1,

wherein

R⁴ is independently selected from H, C_3-6-cycloalkyl, C_1-6-alkyl-C_3-6-cycloalkyl, heterocycloalkyl, or C_1-6-alkyl-heterocycloalkyl.

13. The compound of claim 1, wherein R⁴ is H or C_3-6-cycloalkyl.

14. The compound of claim 1, wherein R⁴ is H.

15. The compound of claim 1, wherein R⁴ is cyclopropyl.

16. The compound of claim 1, wherein R⁵ is H.

17. The compound of claim 1, of Formula III:

18. The compound of claim 17, wherein R¹ is chloro and R² is fluoro.

19. The compound of claim 17, wherein R³ is H, R⁴ is H, and R⁵ is H.

20. The compound of claim 1, selected from the following:

21. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

22. A method of inhibiting the activity of HDAC3 in a subject in need thereof, comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.

23. A method of treating a disease mediated by HDAC3 in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 21.