Deubiquitinase inhibitors and methods for use of the same

Patent metadata

Field	Value
Publication number	US-9868736-B2
Application number	US-201415027714-A
Country	US
Kind code	B2
Filing date	Oct 10, 2014
Priority date	Oct 10, 2013
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

Disclosed herein are methods of inhibiting a deubiquitinase (DUB) by contact with a compound of formula (I).

First claim

What is claimed:

1. A compound having a formula (I):

wherein
R 1 and R 2 together form an optionally substituted aryl ring or heteroaryl ring, and R 3 is halo or hydrogen;
R 4 is C 2 -C 6 alkyl or C 1 -C 6 alkylenearyl; and
(a) one of R 5 and R 5 ′ is hydrogen and the other substituted alkoxy, or (b) each of R 5 and R 5 ′ is substituted alkoxy, or (c) when the ring formed by R 1 and R 2 together is an aryl ring which is substituted, or is a heteroaryl ring which is optionally substituted, then R 5 and R 5 ′ can each be hydrogen;

or a salt or solvate thereof.

2. The compound of claim 1 , wherein R 1 and R 2 together form a nitrogen-containing heteroaryl ring which is optionally substituted.

3. The compound of claim 2 , wherein the compound of formula (I) has a structure

4. The compound of any one of claim 1 , wherein R 4 is propyl or isopentyl.

5. The compound of claim 1 , wherein R 5 ′ is hydrogen and R 5 is a heterocyclyl substituted alkoxy.

6. The compound of claim 5 , wherein R 5 is —Oalkyleneheterocyclyl.

7. The compound of claim 1 , wherein R 5 is hydrogen and R 5 ′ is a heterocyclyl substituted alkoxy.

8. The compound of claim 7 , wherein R 5 ′ is —Oalkyleneheterocyclyl.

9. The compound of any one of claim 5 , wherein the heterocyclyl is morpholinyl, sulfoxymorpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

10. The compound of claim 9 , wherein the heterocyclyl is morpholinyl.

11. The compound of claim 1 , wherein R 5 or R 5 ′ is —O(CH 2 ) m N(Me)(CH 2 ) 2 NMe 2 ; —O(CH 2 ) m N(Me)(CH 2 ) 2 NHMe; —O(CH 2 ) m N(Me)(CH 2 ) 2 NEt 2 ; —O(CH 2 ) m N(Me)(CH 2 ) 2 NHEt; —O(CH 2 ) m O(CH 2 ) 2 NMe 2 ; —O(CH 2 ) m O(CH 2 ) 2 NHMe; —O(CH 2 ) m O(CH 2 ) 2 NEt 2 ; or —O(CH 2 ) m O(CH 2 ) 2 NHEt, and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

12. The compound of claim 1 , wherein R 3 is chloro.

13. The compound of claim 1 , wherein R 3 is fluoro.

14. A compound of having a structure

or a salt or solvate thereof.

15. A compound having a structure

or a salt or solvate thereof.

16. A method of inhibiting proliferation in a cancer cell, the method comprising contacting the cancer cell with the compound of claim 1 in an amount effective to inhibit proliferation, wherein the cancer cell is plasma cell leukemia, melanoma, or myeloma.

17. A method of inhibiting a deubiquitinase (DUB), the method comprising contacting a DUB with the compound of claim 1 , wherein the DUB is Usp24 or Usp9x.

18. A compound having the structure

or a salt or solvate thereof.

19. A method of inhibiting proliferation in a cancer cell, the method comprising contacting the cancer cell with the compound of claim 18 in an amount effective to inhibit proliferation, wherein the cancer cell is plasma cell leukemia, melanoma, or myeloma.

20. A method of inhibiting a deubiquitinase (DUB), the method comprising contacting a DUB with the compound of claim 18 , wherein the DUB is Usp24 or Usp9x.

21. A method of treating a viral infection, the method comprising contacting a cell infected with a virus with the compound of claim 18 in an amount effective to treat the viral infection, wherein the virus is a single stranded RNA virus.

22. A method of treating a viral infection, the method comprising contacting a cell infected with a virus with the compound of claim 18 in an amount effective to treat the viral infection, wherein the virus is a selected from the group consisting of: Tulane virus, Sindbis virus, LaCrosse virus, or Norwalk virus.

Assignees

• Univ Michigan Regents

Inventors

• Donato Nicholas J
• Talpaz Moshe
• Peterson Luke
• Young Matthew
• Showalter Hollis D
• Wobus Christiane
• O'Riordan Mary Xuan Dziem
• Ermann Monika

Classifications

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• C07D213/57

  Nitriles · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title