Biphenylamide derivative Hsp90 inhibitors
Compounds of the formulas are provided: wherein variables Y 1 -Y 5 , X 1 -X 5 , A 1 -A 4 , X, y, n 1 , n 2 , and R 1 -R 15 are as defined herein. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are useful for the treatment of a disease or disorder, including, for example, a proliferative disease, such as cancer.
1. A compound selected from formulas I, II, III, or IV, wherein
the formulas are further defined as:
wherein:
X 1 is heterocycloalkyl (C≤12) or a substituted version thereof;
Y 1 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
R 1 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
each R 2 and R 3 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 0, 1, 2, 3, or 4;
wherein:
X 2 is heterocycloalkyl (C≤12) or a substituted version thereof;
Y 2 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
R 4 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
each R 5 and R 6 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 0, 1, 2, 3, or 4;
wherein:
X 3 is heterocycloalkyl (C≤12) or a substituted version thereof;
Y 3 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
R 7 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
each R 8 and R 9 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 0, 1, 2, 3, or 4;
wherein:
X 4 is heterocycloalkyl (C≤12) or a substituted version thereof;
Y 4 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
R 10 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
each R 11 and R 12 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is further defined as:
wherein:
X 1 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;
Y 1 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
each R 2 and R 3 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is further defined as:
wherein:
X 2 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;
Y 2 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
each R 5 and R 6 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is further defined as:
wherein:
X 3 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;
Y 3 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
each R 5 and R 9 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is further defined as:
wherein:
X 4 is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) ;
Y 4 is cycloalkyl (C≤18) , aryl (C≤24) , heteroaryl (C≤24) , -arenediyl (C≤18) -alkyl (C≤8) , -arenediyl (C≤18) -alkenyl (C≤8) , -arenediyl (C≤18) -alkoxy (C≤8) , or a substituted version of any of these groups;
each R 11 and R 12 are each independently selected from hydrogen, amino, cyano, halo, hydroxy, mercapto, nitro, sulfato, sulfamido, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , acyloxy (C≤12) , substituted acyloxy (C≤12) , amido (C≤12) , or substituted amido (C≤12) ; and
x and y are each independently selected from 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein X 1 , X 2 , X 3 , or X 4 is heterocycloalkyl (C≤12) .
7. The compound of claim 6 , wherein X 1 , X 2 , X 3 , or X 4 is:
8. The compound of claim 1 , wherein Y 1 , Y 2 , Y 3 , or Y 4 is aryl (C≤18) or substituted aryl (C≤18) .
9. The compound of claim 8 , wherein Y 1 , Y 2 , Y 3 , or Y 4 is aryl (C≤18) .
10. The compound of claim 8 , wherein Y 1 , Y 2 , Y 3 , or Y 4 is substituted aryl (C≤18) .
11. The compound of claim 1 , wherein x is 1 or 2.
12. The compound of claim 1 , wherein y is 1 or 2.
13. The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt of any of the above formulas.
14. A compound of the formula:
or a pharmaceutically acceptable salt of any of the above formulas.
15. A pharmaceutical composition comprising a compound of claim 1 and an excipient.
16. A method of treating a breast cancer comprising administering to a patient in need thereof a pharmaceutically acceptable amount of a compound of claim 1 .