Pi-kinase inhibitors with anti-infective activity

Patent metadata

Field	Value
Publication number	US-9926309-B2
Application number	US-201615055403-A
Country	US
Kind code	B2
Filing date	Feb 26, 2016
Priority date	Oct 5, 2011
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

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-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.

First claim

What is claimed is:

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 form

Assignees

• Univ Leland Stanford Junior
• Univ California

Inventors

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

Classifications

• C07D277/44

  Acylated amino or imino radicals · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D277/46

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

• C07D277/42

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