PI-kinase inhibitors with anti-infective activity
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-hetereoaryl-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.
1. A compound of the formula (XXI)
wherein:
R 2 is alkoxy or substituted alkoxy;
R 3 is hydrogen, lower alkyl or substituted lower alkyl;
Y 3 is CH;
Z 2 is absent;
R 1 is aryl, substituted aryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle or substituted heterocycle; and
R 4 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, alkyl-aryl, substituted alkyl-aryl, aryl, substituted aryl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle, wherein the substituted alkyl, the substituted cycloalkyl, and the substituted alkyl-cycloalkyl are not substituted with an oxo or a thioketo;
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. A method of inhibiting a PI4-kinase, the method comprising contacting a sample comprising the PI4-kinase with the compound of claim 1 .
3. The method of claim 2 , wherein the PI4-kinase is a PI4-III kinase.
4. A method of treating a subject in need thereof for an infective disease condition, by inhibiting, relieving or causing regression of said 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 having a basic amino acid PIP-2 pincer (BAAPP) domain and is susceptible to PI4-kinase inhibition.
5. The method of claim 4 , wherein the infective disease condition results from infection with a virus selected from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae and Coronavirinae families.
6. The method of claim 5 , wherein the infective disease condition results from infection with a virus from the Flaviviridae family.
7. The method of claim 5 , wherein the infective disease condition results from infection with a pathogen selected from hepatitis C virus (HCV), rhinovirus, P. falciparum , ebola virus, francisella tularensis , hantavirus, SARS virus, MERS virus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus (HAV), influenza virus, norovirus, polio virus, enterovirus, hepatitis E virus (HEV), EV71, EV68, West Nile Virus, cytomegalovirus, P. aeruginosa , and Dengue virus.
8. The method of claim 7 , wherein the pathogen is HCV.
9. The method of claim 7 , wherein the pathogen is HAV.
10. The method of claim 7 , wherein the pathogen is EV71 or EV68.
11. The method of claim 7 , wherein the pathogen is human rhinovirus.
12. The method of claim 7 , wherein the pathogen is norovirus.
13. The method of claim 7 , wherein the pathogen is ebola virus.
14. The compound of claim 1 , wherein R 4 is alkyl-aryl or substituted alkyl-aryl.
15. The compound of claim 1 , wherein R 4 is alkyl-heterocycle or substituted alkyl-heterocycle.
16. The compound of claim 1 , wherein R 1 is aryl, substituted aryl, heterocycle, or substituted heterocycle.
17. The compound of claim 16 , wherein R 1 is aryl or substituted aryl.
18. The compound of claim 16 , wherein R 1 is of the formula:
wherein Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 are each independently selected from N and CR′;
wherein each R′ is independently selected from hydrogen, alkyl, substituted alkyl, cyano, and halogen.
19. The compound of claim 18 , wherein Z 11 , Z 12 , Z 13 , and Z 15 are each CR′.
20. The compound of claim 18 , wherein:
R 2 is alkoxy;
R 3 is lower alkyl; and
R 4 is alkyl-aryl or substituted alkyl-aryl.
21. The compound of claim 18 , wherein:
R 2 is alkoxy;
R 3 is lower alkyl; and
R 4 is alkyl-heterocycle or substituted alkyl-heterocycle.