Synthesis of small molecule histone deacetylase 6 degraders, compounds formed thereby, and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-11059815-B2
Application number	US-202016800514-A
Country	US
Kind code	B2
Filing date	Feb 25, 2020
Priority date	Jul 23, 2018
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

Histone deacetylase (“HDAC”)-selective inhibitors covalently bonded to a linker covalently bonded to an E3 ubiquitin ligase ligand, and salts thereof; pharmaceutical compositions containing them; methods of using the composition to inhibit neoplastic cell growth in mammals, including humans.

First claim

What is claimed is:

1. A compound comprising a histone deacetylase 6 (“HDAC6”)-selective inhibitor covalently bonded to a linker, covalently bonded to an E3 ubiquitin ligase ligand:

wherein:
the HDAC6-selective inhibitor is selected from the group consisting of:

wherein each Z is independently selected from —N— or —(CH)—;
the linker is a C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene, —O—(CH 2 ) m —, or —NH—(CH 2 ) m , wherein “m” is an integer of from 1 to 12; and
the E3 ubiquitin ligase ligand is selected from:

wherein “p” is an integer of from 1 to 12; and
salts thereof.

2. The compound of claim 1 , wherein the linker is C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene.

3. The compound of claim 2 , wherein each Z is —N—.

4. The compound of claim 2 , wherein each Z is —(CH)—.

5. The compound of claim 1 , wherein the linker is —O—(CH 2 ) m —.

6. The compound of claim 5 , wherein each Z is —N—.

7. The compound of claim 5 , wherein each Z is —(CH)—.

8. The compound of claim 1 , wherein the linker is —NH—(CH 2 ) m .

9. The compound of claim 8 , wherein each Z is —N—.

10. The compound of claim 8 , wherein each Z is —(CH)—.

11. The compound of claim 1 , wherein the HDAC6-selective inhibitor is:

the linker is —O—(CH 2 ) m —; and
the E3 ubiquitin ligase ligand is:

12. The compound of claim 11 , wherein each Z is —N—.

13. The compound of claim 11 , wherein each Z is —(CH)—.

14. The compound of claim 11 , wherein “p” is 3, 4, or 5.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Tang Weiping
• Yang Ka
• Wu Hao
• Zhang Zhongrui

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title