PI-kinase inhibitors with broad spectrum 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. 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 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.