Thiohydantoin derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9944607-B2
Application number	US-201314435790-A
Country	US
Kind code	B2
Filing date	Oct 16, 2013
Priority date	Oct 16, 2012
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present invention provides novel compounds (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, solvates, hydrate, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits comprising the inventive Compounds, or compositions thereof, for treating and/or preventing a fungal or protozoan infection, inhibiting the activity of a fungal or protozoan enzyme, killing a fungus or protozoan, or inhibiting the growth of a fungus or protozoan. The fungus may be a Candida species, Sacchawmyces species, or other pathogenic fungal species. The compounds of the invention may inhibit the activity of fungal or protozoan mitochondrial phosphate carrier protein.

First claim

What is claimed is:

1. An inhibitor of fungal or protozoan mitochondrial phosphate carrier protein Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:

R A is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 ,—CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , or a nitrogen protecting group when attached to a nitrogen atom;
each instance of R A1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
m is 0;
n is 1 or 2;
R C is —C(═O)R C1 , —C(═O)OR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C1 , —S(═O) 2 OR C1 , or —S(═O) 2 N(R C1 ) 2 ; and
each instance of R C1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom;
provided that the Compound of Formula (I) is not

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, —OR A1 , or —CN.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is F, Cl, Br, —CH 2 F, —CHF 2 , —CF 3 , Me, Et, Pr, Bu, Ph, —OMe, —OEt, —OPr, —OBu, or —CN.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is F, Cl, or —CN.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is F.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or an oxygen protecting group.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is —C(═O)Me, —C(═O)Et, —C(═O)Pr, —C(═O)Bu, —C(═O)OMe, —C(═O)OEt, —C(═O)OPr, —C(═O)OBu, —C(═O)OBn, —C(═O)OPh, —C(═O)NH 2 , —C(═O)NHMe, —C(═O)N(Me) 2 , —S(═O) 2 Me, —S(═O) 2 CF 3 , —S(═O) 2 OMe, —S(═O) 2 OEt, —S(═O) 2 NH 2 , —S(═O) 2 NHMe, or —S(═O) 2 N(Me) 2 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is —C(═O)OMe, —C(═O)OEt, or —C(═O)OPr.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is —C(═O)OEt.

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

or a pharmaceutically acceptable salt thereof.

Assignees

• Whitehead Inst Biomedical Res
• Massachusetts Inst Technology
• Broad Inst Inc

Inventors

• Vincent Benjamin
• Whitesell Luke
• Lindquist Susan L
• Youngsaye Willmen
• Buchwald Stephen L
• Langlois Jean-Baptiste
• Pu Jun
• Munoz Benito
• Dandapani Sivaraman

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A01N43/653

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A01N43/52

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A01N47/20

  N-Aryl derivatives thereof · CPC title