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 an alkoxy or a substituted alkoxy;
R 3 is hydrogen, a lower alkyl or a substituted lower alkyl;
Y 3 is N;
Z 2 is absent, CO or SO 2 ;
R 1 is an aryl, a substituted aryl, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocycle, a heteroaryl, a substituted heteroaryl or a substituted heterocycle; and
R 4 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle;
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is of formula (XXII):
wherein:
R 10 is selected from cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle; and
R 51 and R 52 are independently selected from H, halogen, alkyl and substituted alkyl.
3. The compound of claim 2 , wherein the compound is of formula (XXIII):
wherein:
R 31 -R 35 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, acyl, substituted acyl and —CO 2 R, wherein R is H, alkyl or substituted alkyl.
4. The compound of claim 2 , wherein the compound is of formula (XXXI):
wherein:
each (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.
5. The compound of claim 3 , wherein the compound is of formula (XXXII):
R 31 -R 33 and R 35 are independently selected from hydrogen and halogen;
(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; and
R′ is H, alkyl or substituted alkyl.
6. The compound of claim 1 , wherein the compound is of formula (XXXIV):
wherein:
R 2 is an alkoxy or a substituted alkoxy;
R 3 is hydrogen, a lower alkyl or a substituted lower alkyl;
R 1 is an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl a cycloalkyl, a substituted cycloalkyl, a heterocycle or a substituted heterocycle; and
R 4 is selected from cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle.
7. The compound of claim 1 , wherein the compound is of formula (XXXIX):
wherein:
R 41 is hydrogen, a lower alkyl or a substituted lower alkyl; and
R 42 is selected from cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle.
8. The compound of claim 7 , wherein the compound is of formula (XLV):
wherein:
R 31 -R 35 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, acyl, substituted acyl and —CO 2 R, wherein R is H, alkyl or substituted alkyl.
9. The compound of claim 8 , wherein the compound is of formula (XLVII):
wherein:
(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.
10. The compound of claim 1 , wherein the compound is of formula (XLVIII):
wherein R 1 is selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl.
11. The compound of claim 10 , wherein R 4 is methyl, isopropyl, cyclohexyl, substituted cyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl or —CH 2 -4-tetrahydropyran.
12. A new compound of one of the formulae:
wherein:
R 1 is selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl;
R 2 is an alkoxy or a substituted alkoxy;
R 3 is hyrdrogen, a lower alkyl or a substituted lower aryl;
R 4 is a lower alkyl or a substituted lower alkyl;
R 11 is an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloalkyl, a substituted cycloalkyl, a hetercycle or a substituted heterocycle;
R 14 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle;
R 31 -R 35 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, hydroxyl, alkkoxy, substituted alkoxy, acyl, substituted acyl and —CO 2 R′, wherein R′ is H, alkyl or substituted alkyl;
R 41 is hydrogen, a lower alkyl or a substituted lower alkyl; and
R 42 is selected from cycloalkyl, substituted cycloalkyl, alkyl-cycloalkyl, substituted alkyl-cycloalkyl, heterocycle, substituted heterocycle, alkyl-heterocycle and substituted alkyl-heterocycle;
(R) n is one or more optional substitutents each independently selected from alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, halogen, and CO 2 R″ wherein R″ is hydrogen, alkyl or substituted alkyl; and
Y 11 and Y 12 are selected from CR″ 2 , NR″ and O, wherein each R″ is independently H, R, an acyl or a substituted acyl.
13. The compound of claim 12 , wherein the compound is formula (XIX) or (XXX).
14. The compound of claim 12 , wherein the compound is of formula (XLIX), wherein R 14 is methyl, isopropyl, cyclohexyl, substituted cyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl or —CH 2 -4-tetrahydropyran.
15. The compound of claim 12 , wherein the compound is of formula (XXXV) or (XXXVI).
16. The compound of claim 12 , wherein the compound is of formula (XL) or (XLI).
17. The compound of claim 16 , wherein R 42 is a heterocycle or substituted heterocycle.
18. The compound of claim 12 , wherein the compound is of formula (XLIV).
19. The compound of claim 18 , wherein the compound is of formula (XLVI):
wherein:
(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.
20. A compound of formula (III):
wherein:
R 2 is alkoxy or substituted alkoxy;
R 3 is alkoxy or a substituted alkly;
W 1 is —SO 2 —;
W 2 is —NH—;
R 4 is alkyl-heterocyclyl or a substituted alkyl-heterocyclyl;
R 1 is selected from:
wherein:
Z 13 is CR 23 or N, Z 3 is N or CR 11 and Z 4 is N or CR 13 ; and
R 11 to R 15 and R 22 -R 26 are each independently selected from hydrogen, an alkyl, an aryl, hydroxyl, an alkoxy, a heterocycle, cyano, a halogen, an amino, an acyl, an acyloxy, an amido and nitro.