PI4-Kinase Inhibitors and Methods of Using the Same

1 . A compound of formula (I):

wherein:

Y 1 is selected from CH or N;

Y 2 is selected from S, O or NR 19 , wherein R 19 is selected from hydrogen, alkyl, and substituted alkyl;

R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle;

R 2 is selected from alkoxy and substituted alkoxy;

R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl;

R 4 and R 5 are each independently selected from lower alkyl and substituted lower alkyl; or R 4 and R 5 together with the carbon to which they are attached provide a cyclic group selected from cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and

R 6 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl; or

R 4 , R 5 and R 6 together with the carbon to which they are attached provide a bridged cyclic group selected from bridged cycloalkyl, substituted bridged cycloalkyl, bridged heterocycle and substituted bridged heterocycle;

or a prodrug thereof or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is not

2 . The compound of claim 1 , wherein the compound is of formula (II):

wherein:

A is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle; and

B is a ring system selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle.

3 . The compound of claim 2 , wherein the B ring system is selected from B2-B9:

wherein:

Y 3 and Y 5 are each independently selected from N and CR 11 , wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxyamide, substituted carboxyamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide;

Y 4 is selected from CR 11 2 , NR 11 , SO 2 and O;

Y 6 is selected from CR 11 2 and NR 11 ;

each R 10 is selected from, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen;

n is an integer from 0 to 5;

m is an integer from 0 to 3;

p is an integer from 0 to 4;

q is an integer from 0 to 8

q′ is an integer from 0 to 6; and

r is an integer from 0 to 2.

4 . The compound of claim 2 , wherein the A ring is selected from:

wherein:

Y 3 is selected from N and CR 11 , wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxyamide, substituted carboxyamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide;

Y 4 is selected from CR 11 2 , NR 11 SO 2 and O;

R 10 is one or more optional substituents independently selected from, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen;

n is an integer from 0 to 5;

m is an integer from 0 to 3;

p is an integer from 0 to 4; and

q is an integer from 0 to 8.

5 . The compound of claim 2 , wherein the compound is of one of the following formulae:

6 . The compound of claim 5 , wherein the compound is of any one of the formulae (IIG1a)-(IIG1i) or (IIK1a)-(IIK1i), and R 11 is an acyl group.

7 . The compound of claim 1 , wherein R 4 and R 5 are both methyl.

8 . The compound of claim 1 , wherein Y 2 is S.

9 . The compound of claim 1 , wherein the compound is of formula (II):

wherein:

is absent or a covalent bond:

R 7 and R 8 are each independently selected from hydrogen, halogen, alkyl and substituted alkyl; and

R 9 is selected from substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl.

10 . The compound of claim 1 , wherein R 1 is selected from aryl, di-substituted aryl, tri-substituted aryl, tetra-substituted aryl, penta-substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle.

11 . The compound of claim 1 , wherein the compound is selected from any one of the compounds of Table 1, Table 2 or Table 3, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

12 . A pharmaceutical composition comprising:

a compound of claim 1 ; and

a pharmaceutically acceptable excipient.

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

14 . The method of claim 13 , wherein the PI4-kinase is a PI4-III kinase.

15 . 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 a 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.

16 . A method of treating cancer, the method comprising:

administering to a subject with cancer a therapeutically effective amount of a compound of claim 1 .

17 . The method of claim 16 , further comprising:

measuring the expression level or activity level of PI4KIIIβ in cancer cells of a biological sample obtained from the subject; and

determining whether the expression level or activity level of PI4KIIIβ in the cancer cells is elevated relative to one or more control cells.

18 . The method of claim 16 , further comprising co-administering an effective amount of an additional agent to the subject.

19 . A method of inhibiting proliferation of a cancer cell, the method comprising:

contacting a cancer cell with an effective amount of a compound of claim 1 .

20 . An anti-cancer kit, comprising:

an effective dose of a compound of claim 1 ;

an effective dose of an additional anticancer agent; and

instructions for use in treating cancer.