Tubulin-binding compounds, compositions and uses related thereto

Abstract

This disclosure relates to antimitotic compounds, compositions comprising therapeutically effective amounts of these compounds, and methods of using those compounds and compositions in treating hyperproliferative disorders, e.g., cancers and myelodysplastic syndromes.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is —NH—, —O— or S; 
         Y is —CH═ or —N═; 
         n is selected from 0-5; 
         m is selected from 0-5; 
         A is a ring selected from (C6-C10)-aryl and 5-10-membered heteroaryl; 
         L is a C1-C3 straight or branched carbon chain that may be fully saturated, or have one or more units of unsaturation, and links A to the central ring, wherein one or more methylene units of L are optionally and independently replaced by —O— —S—, —S(O)—, —S(O) 2 —, —N═, or —NH—, wherein L is optionally further substituted with one or more R 4 ; 
         each occurrence of R 1  is independently selected from: halogen, nitro, cyano, hydroxyl, thiol, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioether, ester, amide, thioester, carboxy, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, sulfate, acyl, acyloxy, and acylamino; 
         each occurrence of R 2  is independently selected from alkyl and halogen; 
         R 3  is hydrogen or alkyl; 
         each occurrence of R 4  is independently selected from:
 cyano, halogen, nitro, hydroxyl, thiol, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioether, ester, amide, thioester, carboxy, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, sulfate, acyl, acyloxy, and acylamino. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound has the structure of formula IA: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound according to  claim 2 , wherein both occurrences of R 4  are hydrogen. 
     
     
         4 . The compound according to  claim 1 , wherein Y is —N═. 
     
     
         5 . The compound according to  claim 1 , wherein X is —S—. 
     
     
         6 . The compound according to  claim 1 , wherein A is unsubstituted or substituted phenyl. 
     
     
         7 . The compound according to  claim 6 , wherein the compound has the structure of formula IA-1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 - 21 . (canceled) 
     
     
         22 . The compound according to  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         24 . A method for treating cancer or a myelodysplastic syndrome in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 1 . 
     
     
         25 - 27 . (canceled) 
     
     
         28 . A method of destabilizing microtubules in a cell, comprising contacting the cell with a compound of  claim 1 . 
     
     
         29 . A compound of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 2  is —N═; 
         Z 2  is —NH—, —O—, or —S—; 
         R 21 , independently for each occurrence, is selected from hydroxyl, halogen, cyano, substituted or unsubstituted amido, amino, acyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, acylamino, alkylamino, carbamate, ester, heteroaryl, heteroaralkyl, carbamate, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; 
         R 22 , R 23 , R 24 , R 25  independently for each occurrence, are selected from H, hydroxyl, halogen, cyano, substituted or unsubstituted amido, amino, acyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, acylamino, alkylamino, carbamate, ester, heteroaryl, heteroaralkyl, carbamate, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; 
         L 2  is absent or selected from —S—, substituted or unsubstituted alkyl, alkenyl, alkynyl, and heteroaryl; 
         A 2  is a ring selected from substituted or unsubstituted aryl or heteroaryl; and 
         m is selected from 0-5. 
       
     
     
         30 . The compound according to  claim 29 , wherein L 2  is substituted or unsubstituted alkenyl. 
     
     
         31 . The compound according to  claim 29 , wherein R 22  and R 25  are both hydrogen. 
     
     
         32 . The compound according to  claim 29 , wherein Z 2  is S. 
     
     
         33 . The compound according to  claim 29 , wherein A 2  is pyridyl, such as pyridin 3 yl. 
     
     
         34 . The compound according to  claim 29 , wherein R 23  and R 24  are both substituted or unsubstituted alkyl. 
     
     
         35 . The compound according to  claim 29 , wherein m is 0. 
     
     
         36 . A pharmaceutical composition comprising a compound according to  claim 29 , and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         37 . A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 29 . 
     
     
         38 - 43 . (canceled)