PI-kinase inhibitors with broad spectrum anti-infective activity

Patent metadata

Field	Value
Publication number	US-9309236-B2
Application number	US-201214348864-A
Country	US
Kind code	B2
Filing date	Oct 5, 2012
Priority date	Oct 5, 2011
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Compounds and methods are provided for the treatment of pathogen infections. In some embodiments, the anti-infective compounds have broad spectrum activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of inhibiting a PI4-kinase and methods of inhibiting viral infection. In some embodiments, the compound is a PI4-kinase inhibiting compound that is a 5-aryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribivarin, and the like.

First claim

What is claimed is:

1. A compound of the structure:

wherein:
R 1 is selected from an aryl, a heterocycle, and a cycloalkyl;
R 2 is selected from hydrogen, a halogen, an alkyl and an alkoxy;
R 3 is an alkyl;
R 4 is an alkyl, an alkyl-cycloalkyl, or an alkyl-heterocyclyl;
W 1 is —SO 2 —; and
W 2 is —NHCO—.

2. The compound of claim 1 , wherein R 1 is selected from an aryl and a cycloalkyl.

3. The compound of claim 1 , wherein R 4 is —(CH 2 ) n —R 10 , wherein n is 1, 2 or 3 and R 10 is a cycloalkyl or a heterocycle.

4. The compound of claim 3 , wherein the compound is of the structure:

wherein:
R 1 is an aryl, or a cycloalkyl;
R 2 is an alkoxy;
R 3 is an alkyl;
W 2 is —NHCO—;
n is 1; and
R 10 is a cyclopropyl, a cyclopentyl, a cyclohexyl, a piperidinyl or a pyrrolidinyl.

5. The compound of claim 4 wherein R 1 is of the structure:

wherein A is a 6-membered aryl, or cycloalkyl ring, wherein Z 11 -Z 16 are independently selected from CR′, and CR′R″, wherein each R′ and R″ are independently selected from hydrogen, an alkyl, an aryl, a hydroxy, an alkoxy, an aryloxy, a heterocycle, a cyano, a halogen, an amino, an acyl, an acyloxy, an amido, and a nitro.

6. The compound of claim 1 , wherein R 2 is lower alkoxy.

7. The compound of claim 1 , wherein R 3 is lower alkyl.

8. The compound of claim 1 , wherein R 1 is a cycloalkyl.

9. The compound of claim 1 , wherein R 1 is of one of the following structures:

wherein R 44 -R 46 are independently selected from hydrogen, an alkyl, an aryl, a hydroxy, an alkoxy, an aryloxy, a heterocycle, a cyano, a halogen, an amino, an acyl, an acyloxy, an amido, and a nitro.

10. The compound of claim 1 , wherein the compound is selected from one of the following compounds

11. An anti-infective pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Univ Leland Stanford Junior
• Univ California

Inventors

• Glenn Jeffrey S
• Gelman Michael A
• Tavshanjian Brandon
• Shokat Kevan
• Choong Ingrid

Classifications

• C07D277/40

  Unsubstituted amino or imino radicals · CPC title

• C07D277/44

  Acylated amino or imino radicals · CPC title

• C07D277/42

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D277/46

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title