Biphenylamide derivative hsp90 inhibitors

Patent metadata

Field	Value
Publication number	US-2016272584-A1
Application number	US-201415034957-A
Country	US
Kind code	A1
Filing date	Nov 7, 2014
Priority date	Nov 7, 2013
Publication date	Sep 22, 2016
Grant date	—

Abstract

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.

First claim

What is claimed is:

1 . A compound selected from formulas I, II, III, IV, or V, wherein the formulas are further defined as:

wherein:
X 1 is heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (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) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (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) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (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) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (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

wherein:
A 1 and A 2 are each independently selected from N or CR 15 and A 3 and A 4 are each independently selected from N or CR 14 provided at least one of A 1 , A 2 , A 3 , and A 4 is N;
X 5 is heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , or a substituted version thereof;
Y 5 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 13 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) ;
each R 14 and R 15 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
n 1 and n 2 are each independently 0, 1, or 2;

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) , -alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -amino, -alkanediyl (C≦6) -alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (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;
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;

or a pharmaceutically acceptable salt thereof.

3 . The compound of either claim 1 or claim 2 , 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.

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

wherein:
X 2 is heterocycloalkyl (C≦12) , -alkanediyl (C≦6) -heterocycloalkyl

Assignees

• Univ Kansas
• Univ Kansas

Inventors

• Blagg Brian S J
• Zhao Huiping

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4458

  only substituted in position 2, e.g. methylphenidate · CPC title

• A61K31/4465

  only substituted in position 4 · CPC title