Oxazole and thiazole compounds as beta-catenin modulators and uses thereof

Abstract

A series of oxazole and thiazole compounds are shown herein to be small molecule inhibitors of the Wnt pathway that specifically target the activity of the stabilized pool of β-cat oxazole and thiazole compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, cancer, and others.

1 . A method for preventing, treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the Wnt signaling pathway in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula I: 
       
         
           
           
               
               
           
         
       
       wherein A is A 1 , A 2  , or A 3  ; 
       
         
           
           
               
               
           
         
       
       A 1  is 
       
         
           
           
               
               
           
         
       
       A 2  is 
       
         
           
           
               
               
           
         
       
       A 3  is
 x is 1, when A is A 1  or A 2 ; or x is 0, when A is A 3 ; 
 L 1  is S, SO or SO 2 ; 
 m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5; 
 L 2  is substituted or unsubstituted C 1 -C 7  alkylene or heteroalkylene; 
 each R 1 , R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halo, and substituted or unsubstituted C 1 -C 6  alkyl; 
 R 2  is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R 4 ; 
 R 3  is hydroxy, alkoxy, substituted or unsubstituted amino or cycloheteroalkyl; or when A is A 3 , R 3  is R 5 ; 
 each R 4  and R 5a  is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and 
 R 5  is selected from aryl or heteroaryl, unsubstituted or substituted with one or more R 5a ; 
 or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
 and stereoisomers, isotopic variants and tautomers thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein the compound is according to formula IIa, IIb or IIc: 
       
         
           
           
               
               
           
         
         and wherein L 1 , L 2 , m1, n, R 1 , R 2a , R 2b , R 2c , R 2d , R 2 , R 3 , R 4 , and R 5  are as in claim 
       
     
     
         3 - 23 . (canceled) 
     
     
         24 . The method according to  claim 2 , wherein the compound is according to formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein n and R 4  are as stated, and each R 3a  and R 3b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a  and R 3b  loin together to form a cycloheteroalkyl heteroaryl ring; and m is 0 or 1. 
       
     
     
         25 . The method according to  claim 2 , wherein the compound is according to formula IVa, IVb, or IVc: 
       
         
           
           
               
               
           
         
         wherein n, R 4 , and R 5  are as stated, and each R 3a  and R 3b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a  and R 3b  join together to form a cycloheteroalkyl heteroaryl ring. 
       
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method according to  claim 1 , wherein the compound is according to formulae Va, Vb, Vc, Vd, Ve or Vf: 
       
         
           
           
               
               
           
         
         wherein each R 3a  and R 3b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a  and R 3b  join together to form a cycloheteroalkyl heteroaryl ring; and m is 0 or 1. 
       
     
     
         31 - 47 . (canceled) 
     
     
         48 . The method according to  claim 1 , wherein the compound is according to formula VIa, VIb, or VIc: 
       
         
           
           
               
               
           
         
         and m is 0 or 1. 
       
     
     
         49 - 50 . (canceled) 
     
     
         51 . The method according to  claim 2 , wherein the compound is according to formula VIIa, VIIb, VIIc or VIId: 
       
         
           
           
               
               
           
         
         wherein R 3b  is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3b  is joined together with R 3a  to form a cycloheteroalkyl heteroaryl ring. 
       
     
     
         52 - 53 . (canceled) 
     
     
         54 . The method according to  claim 1 , wherein the compound is according to formula VIIIa, VIIIb, VIIIc, or VIIId: 
       
         
           
           
               
               
           
         
       
       wherein Cy is 
       
         
           
           
               
               
           
         
         and wherein R 3c  is H or alkyl. 
       
     
     
         55 . The method according to  claim 1 , wherein the compound is according to formula IXa, IXb, IXc or IXd: 
       
         
           
           
               
               
           
         
       
     
     
         56 . The method according to  claim 1 , wherein the compound is according to formula Xa, Xb, Xc or Xd: 
       
         
           
           
               
               
           
         
       
     
     
         57 . The method according to  claim 1 , wherein the compound is according to formula XIa, XIb, XIc or XId: 
       
         
           
           
               
               
           
         
       
     
     
         58 . The method according to  claim 1 , wherein the compound is according to formula XIIa, XIIb, XIIc or XIId: 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method according to  claim 1 , wherein the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId: 
       
         
           
           
               
               
           
         
       
     
     
         60 . The method according to  claim 1 , wherein the compound is according to formula XIVa, or XIVb: 
       
         
           
           
               
               
           
         
       
       wherein each R 4  and R 5a  is independently selected from alkyl, alkoxy, haloalkyl, halo, hydroxy, carboxy, carbalkoxy, or nitro; and each n and t is independently 0, 1 or 2. 
     
     
         61 - 64 . (canceled) 
     
     
         65 . The method according to  claim 1 , wherein the compound is according to formula XVa or XVb: 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method according to  claim 1 , wherein the compound is selected from Tables 1-6. 
     
     
         67 . The method according to  claim 1 , wherein the compound is selected from Tables 7-10. 
     
     
         68 . The method of  claim 1 , wherein the disease or condition is cancer. 
     
     
         69 . The method of  claim 68 , wherein the cancer is hepatic cancer, colorectal cancer, breast cancer, or skin cancer. 
     
     
         70 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
         71 . The pharmaceutical composition of  claim 70  wherein the carrier is a parenteral carrier, oral or topical carrier. 
     
     
         72 - 75 . (canceled)