Ubiquitination inhibitors

Patent metadata

Field	Value
Publication number	US-10040766-B2
Application number	US-201514826281-A
Country	US
Kind code	B2
Filing date	Aug 14, 2015
Priority date	Aug 14, 2014
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

Disclosed are sulfonamidoquinoline compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , R 2 , R 3 and R 4 are as described herein. In certain embodiments, a compound disclosed herein inhibits ubiquitination, and can be used to treat disease by blocking the degradation of tumor suppressors.

First claim

What is claimed:

1. A compound having structural formula (Ia),

or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
R 1 is -hydrogen, —O—Ar, or —O-Het, wherein —O—Ar and —O-Het are each optionally substituted with one or more —(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN;
R 2 is -hydrogen, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN, wherein —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), and —O—(C 1 -C 6 haloalkyl) are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN;
R 3 is -hydrogen, —Ar, or -Het, wherein —Ar and -Het are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkyl)—Ar, -halogen, —NO 2 or —CN; and
R 4 is —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het or —(C 0 -C 6 alkyl)-Cak, wherein —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het and —(C 0 -C 6 alkyl)-Cak are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), N(R 5 )(R 6 ), -halogen, —NO 2 or —CN, wherein R 5 and R 6 are independently -hydrogen, —(C 1 -C 6 alkyl) or —C(O)—(C 1 -C 6 alkyl),
provided that at least one of R 1 and R 3 is not hydrogen.

2. The compound of claim 1 ,
wherein
R 1 is optionally substituted —O—Ar.

3. The compound of claim 1 ,
wherein
R 3 is optionally substituted —Ar.

4. The compound of claim 1 ,
wherein
R 1 is optionally substituted —O-Het.

5. The compound of claim 1 ,
wherein
R 3 is optionally substituted -Het.

6. The compound of claim 1 , wherein
R 2 is -hydrogen, —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN.

7. The compound of claim 1 , wherein
R 2 is —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN.

8. The compound of claim 1 , wherein R 2 is hydrogen.

9. The compound of claim 1 , wherein R 2 is halogen.

10. The compound of claim 1 , having the structure of formula (II),

wherein R 1 is —O—Ar or —O-Het.

11. The compound of claim 1 , having the structure of formula (III),

wherein R 3 is —Ar, or -Het.

12. The compound of claim 1 having structural formula (IV),

or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
R 1 is -hydrogen or optionally substituted —O—Ar,
R 4 is optionally substituted —(C 0 -C 6 alkyl)-Ar or —(C 0 -C 6 alkyl)-Het.

13. The compound of claim 1 , wherein
R 1 is —O—Ar.

14. The compound of claim 1 , wherein
R 1 is —O-Het.

15. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, carrier, or excipient and a compound according to claim 1 .

16. A method for inhibiting Cks1-Skp2 PPI, comprising administering an effective Cks1-Skp2 PPI inhibiting amount of a compound according to claim 1 .

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Carroll David
• Sran Arvinder
• Singh Rajinder
• Huang Jianing
• Tsvetkov Lyuben
• Issakani Sarkiz
• Payan Donald
• Shaw Simon

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title