Coumarin based Hsp90 inhibitors with urea and ether substituents

Patent metadata

Field	Value
Publication number	US-10030006-B2
Application number	US-201415035610-A
Country	US
Kind code	B2
Filing date	Nov 11, 2014
Priority date	Nov 11, 2013
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

Compounds of the formulas: wherein: R 1 -R 4 , X 1 , Y 1 , and A are as defined herein are provided. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are are useful for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a proliferative disease such as cancer.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
R 1 and R 2 are each independently selected from hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is hydrogen, alkyl (C≤12) , aralkyl (C≤12) , substituted alkyl (C≤12) , or substituted aralkyl (C≤12) ; or R 3 and Y 1 are taken together as defined below;
R 4 is hydrogen, alkyl (C≤12) , alkoxy (C≤12) , substituted alkyl (C≤12) , or substituted alkoxy (C≤12) ;
X 1 is -alkanediyl (C≤8) -heterocycloalkyl (C≤12) , -alkanediyl (C≤8) -amino (C≤12) , -alkanediyl (C≤8) -alkylamino (C≤12) , -alkanediyl (C≤8) -dialkylamino (C≤12) , heterocycloalkyl (C≤12) , or a substituted version of any of these groups; and
Y 1 is alkyl (C≤12) , cycloalkyl (C≤12) , adamantyl (C≤18) , aryl (C≤18) , aralkyl (C≤18) , acyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -arenediyl (C≤12) -alkene (C≤8) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -aralkyl (C≤12) , -arenediyl (C≤12) -aryloxy (C≤12) , or a substituted version of any of these groups; or R 3 and Y 1 are taken together and are alkanediyl (C≤8) , alkylaminodiyl (C≤8) , alkoxydiyl (C≤8) , or a substituted version of any of these groups; or

wherein the compound is not selected from:

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 further defined as:

wherein:
R 1 and R 2 are each independently selected from hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is hydrogen, alkyl (C≤12) , aralkyl (C≤12) , substituted alkyl (C≤12) , or substituted aralkyl (C≤12) ; or R 3 and Y 1 are taken together as defined below;
X 1 is -alkanediyl (C≤8) -heterocycloalkyl (C≤12) , -alkanediyl (C≤8) -amino (C≤12) , -alkanediyl (C≤8) -alkylamino (C≤12) , -alkanediyl (C≤8) -dialkylamino (C≤12) , heterocycloalkyl (C≤12) , or a substituted version of any of these groups; and
Y 1 is alkyl (C≤12) , cycloalkyl (C≤12) , adamantyl (C≤18) , aryl (C≤18) , aralkyl (C≤18) , acyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -arenediyl (C≤12) -alkene (C≤8) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -aralkyl (C≤12) , -arenediyl (C≤12) -aryloxy (C≤12) , or a substituted version of any of these groups; or R 3 and Y 1 are taken together and are alkanediyl (C≤8) , alkylaminodiyl (C≤8) , alkoxydiyl (C≤8) , or a substituted version of any of these groups; or

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 further defined as:

wherein:
R 2 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is hydrogen, alkyl (C≤12) , aralkyl (C≤12) , substituted alkyl (C≤12) , or substituted aralkyl (C≤12) ; or R 3 and Y 1 are taken together as defined below;
X 1 is -alkanediyl (C≤8) -heterocycloalkyl (C≤12) , -alkanediyl (C≤8) -amino (C≤12) , -alkanediyl (C≤8) -alkylamino (C≤12) , -alkanediyl (C≤8) -dialkylamino (C≤12) , heterocycloalkyl (C≤12) , or a substituted version of any of these groups; and
Y 1 is alkyl (C≤12) , cycloalkyl (C≤12) , adamantyl (C≤18) , aryl (C≤18) , aralkyl (C≤18) , acyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -arenediyl (C≤12) -alkene (C≤8) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -aralkyl (C≤12) , -arenediyl (C≤12) -aryloxy (C≤12) , or a substituted version of any of these groups; or R 3 and Y 1 are taken together and are alkanediyl (C≤8) , alkylaminodiyl (C≤18) , alkoxydiyl (C≤8) , or a substituted version of any of these groups; or

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 further defined as:

wherein:
R 3 is hydrogen, alkyl (C≤12) , aralkyl (C≤12) , substituted alkyl (C≤12) , or substituted aralkyl (C≤12) ; or R 3 and Y 1 are taken together as defined below;
X 1 is -alkanediyl (C≤8) -heterocycloalkyl (C≤12) , -alkanediyl (C≤8) -amino (C≤12) , -alkanediyl (C≤8) -alkylamino (C≤12) , -alkanediyl (C≤8) -dialkylamino (C≤12) , heterocycloalkyl (C≤12) , or a substituted version of any of these groups; and
Y 1 is alkyl (C≤12) , cycloalkyl (C≤12) , adamantyl (C≤18) , aryl (C≤18) , aralkyl (C≤18) , acyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -arenediyl (C≤12) -alkene (C≤8) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -aralkyl (C≤12) , -arenediyl (C≤12) -aryloxy (C≤12) , or a substituted version of any of these groups; or R 3 and Y 1 are taken together and are alkanediyl (C≤8) , alkylaminodiyl (C≤8) , alkoxydiyl (C≤8) , or a substituted version of any of these groups; or

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 further defined as:

wherein:
R 3 is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , aralkyl (C≤12) , or substituted aralkyl (C≤12) ; or R 3 and Y 1 are taken together as defined below;
X 1 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ; and
Y 1 is alkyl (C≤12) , cycloalkyl (C≤12) , adamantyl (C≤18) , aryl (C≤18) , aralkyl (C≤18) , acyl (C≤12) , -alkanediyl (C≤8) -cycloalkyl (C≤12) , -arenediyl (C≤12) -alkene (C≤8) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -aralkyl (C≤12) , -arenediyl (C≤12) -aryloxy (C≤12) , or a substituted version of any of these groups; or R 3 and Y 1 are taken together and are alkanediyl (C≤8) , alkylaminodiyl (C≤8) , alkoxydiyl (C≤8) , or a substituted version of any of these groups; or

or a pharmaceutically acceptable salt thereof.

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

7. The compound of claim 1 , wherein R 3 is alkyl (C≤6) .

8. The compound of claim 1 , wherein X 1 is heterocycloalkyl (C≤8) or substituted heterocycloalkyl (C≤8) .

9. The compound of claim 8 , wherein X 1 is:

10. The compound of claim 1 , wherein Y 1 is aryl (C≤18) or substituted aryl (C≤18) .

11. The compound of claim 10 , wherein Y 1 is aryl (C≤12) .

12. The compound of claim 10 , wherein Y 1 is biphenyl (C≤12) .

13. The compound of claim 10 , wherein Y 1 is substituted aryl (C≤12) .

14. The compound of claim 10 , wherein Y 1 is substituted biphenyl (C≤18) .

15. The compound of claim 1 , wherein Y 1 is aralkyl (C≤18) or substituted aralky (C≤18) .

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

Assignees

• Univ Kansas

Inventors

• Blagg Brian S J
• Zhao Huiping

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/12 Primary

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

• A61K31/453

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• G16H50/50

  for simulation or modelling of medical disorders · CPC title