Pyrazol-3-ones that activate pro-apoptotic bax

Abstract

This application features pyrazol-3-one compounds that activate pro-apoptotic BAX. Also featured are methods of using such compounds, e.g., for the treatment or prevention of diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., insufficient apoptosis of diseased or damaged cells or essentially the absence of apoptosis of diseased or damaged cells).

What is claimed is: 
     
         1 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is N or CH; 
 X is heteroaryl, which comprises 5 ring atoms and is optionally substituted with 1 R a , wherein 1 or 2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; 
 Y is phenyl optionally substituted by 1 or 2 R b ; 
 R 1  is selected from the group consisting of: 
 (i) heteroaryl comprising from 5-6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S, and the heteroaryl ring is optionally substituted by 1 or 2 R c ; 
 (ii) —C(O)-(heteroaryl), wherein the heteroaryl contains from 5-10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and 
 (iii) hydrogen; 
 R 2  is 
 (i) C 1 -C 8  alkyl; 
 (ii) phenyl optionally substituted with from 1-4 R e ; 
 (iii) heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from the group consisting of N, NH, N(C 1 -C 3  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; wherein the heteroaryl is optionally substituted with from 1-3 R e ; or 
 (iv) C 3 -C 8  cycloalkyl optionally substituted with from 1-4 independently selected C 1 -C 4  alkyl groups; 
 R a  is C 1 -C 8  alkyl; 
 R b  is halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, N(C 1 -C 6  alkyl) 2 , COOH, or C(O)O(C 1 -C 6  alkyl); 
 R c  is halo, phenyl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl, CN, COOH, C(O)O(C 1 -C 6  alkyl), C(O)N(C 1 -C 6  alkyl) 2 , or C 1 -C 6  alkyl optionally substituted with OH; and 
 R e  is halo, CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkoxy. 
 
     
     
         2 . The composition of  claim 1 , wherein A is N. 
     
     
         3 . The composition of  claim 2 , wherein X is unsubstituted heteroaryl. 
     
     
         4 . The composition of  claim 3 , wherein X is thiazolyl. 
     
     
         5 . The composition of  claim 4 , wherein Y is unsubstituted phenyl. 
     
     
         6 . The composition of  claim 5 , wherein R 1  is heteroaryl substituted by 2 R c . 
     
     
         7 . The composition of  claim 6 , wherein R 1  is thiazolyl substituted by 2 R c . 
     
     
         8 . The composition of  claim 7 , wherein each R c  is methyl. 
     
     
         9 . The composition of  claim 8 , wherein R 2  is unsubstituted phenyl. 
     
     
         10 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is N or CH; 
 X is heteroaryl, which comprises 5 ring atoms and is optionally substituted with 1 R a , wherein 1 or 2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; 
 Y is unsubstituted phenyl; 
 R 1  is selected from the group consisting of: 
 (i) heteroaryl comprising from 5-6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S, and the heteroaryl ring is substituted by 1 or 2 R c ; 
 (ii) —C(O)-(heteroaryl), wherein the heteroaryl contains from 5-10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms is independently selected from N, NH, N(C 1 -C 3  alkyl), O, and S; and 
 (iii) hydrogen; 
 R 2  is 
 (i) C 1 -C 8  alkyl; 
 (ii) phenyl optionally substituted with from 1-4 R e ; 
 (iii) heteroaryl containing from 5-6 ring atoms, wherein from 1-4 of the ring atoms is independently selected from the group consisting of N, NH, N(C 1 -C 3  alkyl), NC(O)(C 1 -C 6  alkyl), O, and S; wherein the heteroaryl is optionally substituted with from 1-3 R e ; or 
 (iv) C 3 -C 8  cycloalkyl optionally substituted with from 1-4 independently selected C 1 -C 4  alkyl groups; 
 R a  is C 1 -C 8  alkyl; 
 R c  is halo, phenyl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl, CN, COOH, C(O)O(C 1 -C 6  alkyl), C(O)N(C 1 -C 6  alkyl) 2 , or C 1 -C 6  alkyl optionally substituted with OH; and 
 R e  is halo, CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkoxy. 
 
     
     
         11 . The compound of  claim 10 , wherein A is N. 
     
     
         12 . The compound of  claim 11 , wherein X is unsubstituted heteroaryl. 
     
     
         13 . The compound of  claim 12 , wherein X is thiazolyl. 
     
     
         14 . The compound of  claim 13 , wherein R 1  is heteroaryl substituted by 2 R c . 
     
     
         15 . The compound of  claim 14 , wherein R 1  is thiazolyl substituted by 2 R c . 
     
     
         16 . The compound of  claim 15 , wherein each R c  is methyl. 
     
     
         17 . The compound of  claim 16 , wherein R 2  is unsubstituted phenyl. 
     
     
         18 . A method of treating cancer in a subject, comprising administering the composition of  claim 1  to a subject in need of cancer treatment in an amount effective to treat the cancer, wherein the cancer is leukemia. 
     
     
         19 . The method of  claim 18 , wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). 
     
     
         20 . A method of activating a pro-apoptotic function of BAX in a cell or tissue containing BAX, comprising contacting the cell or tissue with the composition of  claim 1 .