Coumarin based HSP90 inhibitors with urea and ether substituents
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 useful for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a proliferative disease such as cancer.
1. A compound of the formula:
wherein:
R 3 is hydrogen, hydroxy, alkoxy (C≤12) , substituted alkoxy (C≤12) , acyloxy (C≤12) , or substituted acyloxy (C≤12) ;
R 4 is alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , or a substituted version of any of these groups;
A is alkanediyl (C≤8) or substituted alkanediyl (C≤8) ; and
Y 1 is heterocycloalkyl (C≤12) , substituted heterocycloalkyl (C≤12) , or —NR 5 R 6 ;
wherein:
R 5 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of the last five groups;
R 6 is substituted alkyl (C≤12) ; or
cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is further defined as:
wherein:
R 3 is hydroxy, acyloxy (C≤12) , or substituted acyloxy (C≤12) ;
A is alkanediyl (C≤8) or substituted alkanediyl (C≤8) ; and
Y 1 is heterocycloalkyl (C≤12) , substituted heterocycloalkyl (C≤12) , or —NR 5 R 6 ;
wherein:
R 5 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of the last five groups; and
R 6 is substituted alkyl (C≤12) ; or
cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 3 is hydroxy.
4. The compound of claim 1 , wherein R 4 is alkenyl (C≤12) .
5. The compound of claim 1 , wherein A is alkanediyl (C≤12) .
6. The compound of claim 1 , wherein Y 1 is —NR 5 R 6 ; wherein: R 5 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of the last five groups; and R 6 is substituted alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , adamantyl (C≤18) , or a substituted version of any of the last four groups.
7. The compound of claim 6 , wherein R 5 is cycloalkyl (C≤12) .
8. The compound of claim 6 , wherein R 5 is adamantyl (C≤12) or substituted adamantyl (C≤12) .
9. The compound of claim 1 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 and an excipient.
11. A method for treating a disease or disorder comprising administering to a patient in need thereof a pharmaceutically acceptable amount of a compound of claim 1 .
12. The method of claim 11 , wherein the disease or disorder is cancer.
13. The compound of claim 1 , wherein Y 1 heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) .
14. A compound of the formula:
or a pharmaceutically acceptable salt thereof.