PI-kinase inhibitors with anti-infective activity

Patent metadata

Field	Value
Publication number	US-11884657-B2
Application number	US-202117371653-A
Country	US
Kind code	B2
Filing date	Jul 9, 2021
Priority date	Feb 26, 2016
Publication date	Jan 30, 2024
Grant date	Jan 30, 2024

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 or a 5-heteroaryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribavirin, and the like.

First claim

What is claimed is:

1. A compound having one of formulae (XLVIa)-(XLVId) and (XLVIIa)-(XLVIId):

wherein:
R 2 is an alkoxy or a substituted alkoxy;
R 3 is hydrogen, a lower alkyl or a substituted lower alkyl;
(R) n is one or more optional substituents each independently selected from alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, halogen and CO 2 R″ wherein R″ is hydrogen, alkyl or substituted alkyl;
n is 0, 1, 2, 3, or 4;
Y 4 is O;
R 41 is lower alkyl; and
R 31 -R 35 are independently selected from hydrogen, methyl, halogen and hydroxy;

or a pharmaceutically acceptable salt thereof.

2. A compound selected from

or a pharmaceutically acceptable salt thereof.

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

4. A method of inhibiting a PI4-kinase, the method comprising contacting a sample comprising the PI4-kinase with the compound of claim 1 .

5. The method of claim 4 , wherein the PI4-kinase is a PI4-III kinase.

6. The method of claim 5 , wherein the PI4-III kinase is a PI4KIIIα- or PI4KIIIβ-kinase.

7. A method of treating a subject for an infective disease condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.

8. The method of claim 7 , wherein the infective disease condition results from infection with a virus selected from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae and Coronavirinae families.

9. The method of claim 7 , wherein the infective disease condition results from infection with a pathogen selected from HCV, rhinovirus, P. falciparum , ebola virus, Francisella tularensis , hantavirus, SARS virus, MERS virus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus, and influenza virus, Norovirus, PolioVirus, Enterovirus, HEV, EV71, EV68, West Nile Virus, cytomegalovirus, P. aeruginosa , and Dengue Virus.

10. The method of claim 9 , wherein the pathogen is selected from EV71, EV68, human rhinoviruses, hepatitis A virus, HCV, norovirus and ebola virus.

11. The method of claim 7 , wherein the compound has activity against two or more pathogens.

12. A compound having the structure:

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

14. A method of inhibiting a PI4-kinase, the method comprising contacting a sample comprising the PI4-kinase with the compound of claim 12 .

15. The method of claim 14 , wherein the PI4-kinase is a PI4-III kinase.

16. The method of claim 15 , wherein the PI4-III kinase is a PI4KIIIα- or PI4KIIIβ-kinase.

17. A method of treating a subject for an infective disease condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.

18. The method of claim 17 , wherein the infective disease condition results from infection with a virus selected from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae and Coronavirinae families.

19. The method of claim 17 , wherein the infective disease condition results from infection with a pathogen selected from HCV, rhinovirus, P. falciparum , ebola virus, Francisella tularensis , hantavirus, SARS virus, MERS virus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus, and influenza virus, Norovirus, PolioVirus, Enterovirus, HEV, EV71, EV68, West Nile Virus, cytomegalovirus, P. aeruginosa , and Dengue Virus.

20. The method of claim 19 , wherein the pathogen is selected from EV71, EV68, human rhinoviruses, hepatitis A virus, HCV, norovirus and ebola virus.

Assignees

• Univ Leland Stanford Junior
• Univ California

Inventors

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

Classifications

• C07D417/12 Primary

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

• A61P31/14

  for RNA viruses · CPC title

• C07D277/42

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

• C07D277/44

  Acylated amino or imino radicals · CPC title

• C07D277/46

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