Compounds for treating infectious diseases

Patent metadata

Field	Value
Publication number	US-9505735-B2
Application number	US-201314408605-A
Country	US
Kind code	B2
Filing date	Jun 21, 2013
Priority date	Jun 21, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present invention provides compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting fungal or parasitic growth. The compounds are useful as inhibitors of glycosylphosphatidylinositol (GPI)-anchor biosynthesis, in particular, as inhibitors of fungal Gwt1 activity. The present invention further provides methods of using the compounds described herein for treating fungal or parasitic infections. The compounds can also be used as biological probes to study the effects of inhibiting Gwt1 activity.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof, wherein:
each one of R 1 and R 5 is hydrogen;
each one of R 3 and R 4 is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —OC(═O)R A , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —OC(═O)OR A , —NR B C(═O)OR A , —OC(═O)N(R B ) 2 , —SC(═O)R A , —C(═NR B )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;

each occurrence of R A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R B groups are joined to form an optionally substituted heterocyclic ring;
R 2 is —O—R x ;
R x is optionally substituted C 3-8 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl;
or R x and R 3 are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
Y is —O— or —S—;
each instance of R 11 is independently hydrogen or optionally substituted alkyl;
each instance of R 12 is independently hydrogen or optionally substituted alkyl;
L is —C(═O)NR 13 —;
R 13 is hydrogen or C 1-6 alkyl;
E is of the formula

s is 1, 2, 3, 4, 5, or 6;
each instance of V 1 , V 2 , and V 3 is independently N or C, provided that at least one of V 1 , V 2 , and V 3 is N;
each instance of R E is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —OC(═O)R A , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —OC(═O)OR A , —NR B C(═O)OR A , —OC(═O)N(R B ) 2 , —SC(═O)R A , —C(═NR B )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; and
p is 0, 1, 2, 3, or 4, as valency permits.

2. The compound of claim 1 , wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof.

3. The compound of claim 1 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof,
wherein:
each of R xa and R xb is independently hydrogen, halogen, or optionally substituted alkyl.

4. The compound of claim 1 , wherein Y is —O—.

5. The compound of claim 1 , wherein at least one of R 11 and R 12 is hydrogen.

6. The compound of claim 1 , wherein R 11 and R 12 are hydrogen.

7. The compound of claim 1 , wherein R 11 is methyl and R 12 is hydrogen.

8. The compound of claim 1 , wherein L is —C(═O)NH—.

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

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof.

10. The compound of claim 1 , wherein the compound is of formula III-b:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof.

11. The compound of claim 1 , wherein the compound is of formula III-b1:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof.

12. The compound of claim 11 , wherein Y is —O—.

13. The compound of claim 11 , wherein each one of R 3 and R 4 is hydrogen.

14. The compound of claim 11 , wherein R X is optionally substituted C 3-8 alkyl.

15. The compound of claim 11 , wherein R A is optionally substituted C 1-6 alkyl.

16. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer thereof.

17. The compound of claim 1 , wherein R 3 is halogen, optionally substituted C 1-6 alkyl, or —OR A .

18. The compound of claim 1 , wherein R 4 is halogen or optionally substituted C 1-6 alkyl.

19. The compound of claim 1 , wherein R 3 is hydrogen.

20. The compound of claim 1 , wherein R 4 is hydrogen.

21. The compound of claim 1 , wherein R X is optionally substituted C 3-8 alkyl.

22. The compound of claim 1 , wherein R X is optionally substituted aryl.

23. The compound of claim 1 , wherein R X is optionally substituted heteroaryl.

24. The compound of claim 1 , wherein R X is optionally substituted aralkyl.

25. The compound of claim 1 , wherein R X and R 3 are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.

26. The compound of claim 1 , wherein s is 1.

27. The compound of claim 1 , wherein V 1 is N, and V 2 and V 3 are C.

28. The compound of claim 1 , wherein V 2 is N, and V 1 and V 3 are C.

29. The compound of claim 1 , wherein V 3 is N, and V 1 and V 2 are C.

30. The compound of claim 1 , wherein the compound is of formula 111-c:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, or diastereomer ther

Assignees

• Whitehead Inst Biomedical Res
• Massachusetts Gen Hospital

Inventors

• Mclellan Catherine
• Mazitschek Ralph
• Whitesell Luke
• Lindquist Susan L

Classifications

• C07D213/643

  2-Phenoxypyridines; Derivatives thereof · CPC title

• C07D311/08 Primary

  not hydrogenated in the hetero ring · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• A61P31/10

  Antimycotics · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title