Triazole modified coumarin and biphenyl amide-based HSP90 inhibitors

Patent metadata

Field	Value
Publication number	US-9994556-B2
Application number	US-201515318351-A
Country	US
Kind code	B2
Filing date	Jun 12, 2015
Priority date	Jun 13, 2014
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Provided herein are compounds of the formulas: which are 90-kDa heat shock protein inhibitors. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds may be used for the treatment of diseases, including cancer, e.g., cancers of the breast, the prostate, and the head & neck.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
R 1 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups;
R 2 is hydrogen, hydroxy, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , cycloalkoxy (C≤12) , or substituted cycloalkoxy (C≤12) ;
R 3 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ; and
X 1 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ; or

a compound of the formula:

wherein:
R 4 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups;
R 5 and R 6 are each independently:
amino, cyano, halo, hydroxy, nitro, hydroxysulfonyl, or sulfonamide; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , alkoxy (C≤12) , acyl (C≤12) , amido (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkylsulfonyl (C≤12) , or a substituted version of any of these groups;

n 1 and n 2 are each independently 0, 1, 2, 3, or 4; and
X 2 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is further defined as:

wherein:
R 1 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , alkanediyl (C≤8) cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups;
R 3 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ; and
X 1 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is further defined as:

wherein:
R 1 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is further defined as:

wherein:
R 4 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups; and
X 2 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is further defined as:

wherein:
R 4 is alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , cycloalkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -alkanediyl (C≤8) -cycloalkenyl (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 1 is aryl (C≤12) or substituted aryl (C≤12) .

7. The compound of claim 1 , wherein R 1 is aralkyl (C≤12) or substituted aralkyl (C≤12) .

8. The compound of claim 1 , wherein R 1 is -alkanediyl (C≤8) -cycloalkyl (C≤12) or a substituted version of this group.

9. The compound of claim 1 , wherein R 3 is alkyl (C≤12) or substituted alkyl (C≤12) .

10. The compound of claim 1 , wherein X 1 is a nitrogen containing heterocycloalkyl (C≤12) or a substituted nitrogen containing heterocycloalkyl (C≤12) .

11. The compound of claim 1 , wherein R 4 is aryl (C≤12) or substituted aryl (C≤12) .

12. The compound of claim 1 , wherein R 4 is aralkyl (C≤12) or substituted aralkyl (C≤12) .

13. The compound of claim 1 , wherein R 4 is -alkanediyl (C≤8) -cycloalkyl (C≤12) or a substituted version of this group.

14. The compound of claim 1 , wherein n 1 and n 2 are each independently 0 or 1.

15. The compound of claim 1 , wherein X 2 is a nitrogen containing heterocycloalkyl (C≤12) or a substituted nitrogen containing heterocycloalkyl (C≤12) .

16. The compound of claim 1 , wherein X 1 or X 2 is:

17. The compound of claim 1 , wherein the compound is further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

18. The compound of claim 1 , wherein the compound is further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

19. A pharmaceutical composition comprising:
(A) a compound of claim 1 ; and
(B) a pharmaceutically acceptable carrier.

20. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1 .

Assignees

• Univ Kansas
• Univ Kansas

Inventors

• Zhao Jinbo
• Zhao Huiping
• Blagg Brian S J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title