Indazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9738610-B2
Application number	US-201314430308-A
Country	US
Kind code	B2
Filing date	Sep 24, 2013
Priority date	Sep 24, 2012
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

The present invention provides novel compounds (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, solvates, hydrates, 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 protozoon, or inhibiting the growth of a fungus or protozoon. The fungus may be a Candida species, Aspergillus species, or other pathogenic fungal species. The compounds of the invention may inhibit the activity of fungal or protozoan cytochrome b and/or fungal or protozoan Hsp90. The present invention also provides synthetic methods of the inventive compounds.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is phenyl
each instance of R A is independently 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 , or —OC(═O)N(R A1 ) 2 , or optionally two R A groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
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, or optionally two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring; provided that when R A is —OR A1 , R A1 is substituted or unsubstituted acyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
k is 1, 2, 3, 4, or 5;
each instance of Z is CR B ;
each instance of R B is independently hydrogen, 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 B1 , —N(R B1 ) 2 , —SR B1 , —CN, —SCN, —C(═NR B1 )R B1 , —C(═NR B1 )OR B1 , —C(═NR B1 )N(R B1 ) 2 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O)N(R B1 ) 2 , —NO 2 , —NR B1 C(═O)R B1 , —NR B1 C(═O)OR B1 , —NR B1 C(═O)N(R B1 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , or —OC(═O)N(R B1 ) 2 , or optionally two R B groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
each instance of R B1 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, or optionally two R B1 groups are joined to form a substituted or unsubstituted heterocyclic ring;
X is —(C(R x ) 2 ) n —;
each instance of R x is independently hydrogen, or substituted or unsubstituted alkyl;
n is 1;
R C is —C(═O)OR C1 ; and
R C1 is methyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B is halogen, substituted or unsubstituted alkyl, —OR B1 , —N(R B1 ) 2 , —SR B1 , —C(═O)OR B1 , or —C(═O)N(R B1 ) 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. A method of treating a fungal infection caused by Candida albicans, Aspergillus terreus , or Saccharomyces cerevisiae in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

10. A method of inhibiting the activity of Candida albicans, Aspergillus terreus , or Saccharomyces cerevisiae cytochrome b in a subject in need thereof, or biological sample, the method comprising:
administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

11. A method of killing or inhibiting the growth of Candida albicans, Aspergillus terreus , or Saccharomyces cerevisiae , the method comprising:
contacting the fungus with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one R A is halogen, substituted or unsubstituted alkyl, —OR A1 , —CN, or —NO 2 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one R A is of the formula:

wherein:
each instance of R A2 is independently hydrogen, or substituted or unsubstituted alkyl, or two or three R A2 groups are joined to form a substituted or un

Assignees

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

Inventors

• Vincent Benjamin
• Whitesell Luke
• Lindquist Susan L
• Youngsaye Willmen
• Buchwald Stephen L
• Langlois Jean-Baptiste
• Nag Partha P
• Ting Amal
• Morgan Barbara J
• Munoz Benito
• Dandapani Sivaraman
• Tidor Bruce
• Srinivas Raja R

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/04

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

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title