Dihydropyrancarboxamides and uses thereof

Abstract

The present invention provides novel dihydropyrancarboxamide compounds of formula (I): and collections of these compounds, and provides methods for the synthesis of these compounds; wherein R 1 -R 6 are as defined herein. Additionally, the present invention provides pharmaceutical compositions and methods for treating disorders such as proliferative diseases, and cancer, to name a few.

1 . A compound having the structure:  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 4  are each independently hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;  
         R 3  is hydrogen or an aliphatic, heteroaliphatic alkylaryl, heteroaryl or alkylheteroaryl moiety;  
         R 5  and R 6  are each independently hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein R 6  and R 7 , taken together, may form a cyclic aliphatic, heteroaliphatic, aliphatic(aryl), heteroaliphatic(aryl), aliphatic(heteroaryl) or heteroaliphatic(heteroaryl) moiety, or an aryl or heteroaryl moiety;  
         wherein each of the foregoing aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, saturated or unsaturated or linear or branched; and each of the foregoing aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted; and  
         pharmaceutically acceptable derivatives thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein the compound has the structure (II):  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 4  are each independently hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;  
         R 3  is hydrogen or an aliphatic, heteroaliphatic, alkylaryl, heteroaryl or alkylheteroaryl moiety;  
         R 5  and R 6  are each independently hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein R 6  and R 7 , taken together, may form a cyclic aliphatic, heteroaliphatic, aliphatic(aryl), heteroaliphatic(aryl), aliphatic(heteroaryl) or heteroaliphatic(heteroaryl) moiety, or an aryl or heteroaryl moiety;  
         wherein each of the foregoing aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, saturated or unsaturated or linear or branched; and each of the foregoing aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted; and  
         pharmaceutically acceptable derivatives thereof.  
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is hydrogen or an alkyl, heteroalkyl, aryl or heteroaryl moiety substituted with Z, wherein Z is hydrogen, —(CH 2 ) q OR Z , —(CH 2 ) q SR Z , —(CH 2 ) q N(R Z ) 2 , —(C═O)R Z , —(C═O)N(R Z ) 2 , or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R Z  is independently hydrogen, a protecting group, a solid support unit, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         4 . The compound of  claim 3 , wherein R 1  is hydrogen, lower alkyl, a substituted or unsubstituted phenyl or -(lower alkyl)phenyl moiety, —(CH 2 ) n OR z , —[(CH 2 ) n O] m R z , —(CH 2 ) n —Ar—(CH 2 ) m OR z ; wherein n and m are each independently integers from 1-6, Ar represents a substituted or unsubstituted aryl or heteroaryl moiety, and R z  is independently hydrogen, a protecting group, a solid support unit, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         5 . The compound of  claim 4 , wherein R 1  is hydrogen, ethyl, or has one of the structures:  
       
         
           
           
               
               
           
         
         wherein R z  is as defined in  claim 4 .  
       
     
     
         6 . The compound of  claim 1 , wherein R 2  is hydrogen or an alkyl, heteroalkyl, aryl or heteroaryl moiety substituted with Z, wherein Z is hydrogen, —(CH 2 ) q OR Z , —(CH 2 ) q SR Z , —(CH 2 ) q N(R Z ) 2 , —(C═O)R Z , —(C═O)N(R Z ) 2 , or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R z  is independently hydrogen, a protecting group, a solid support unit, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         7 . The compound of  claim 6 , wherein R 2  is hydrogen, lower alkyl, a substituted or unsubstituted phenyl or -(lower alkyl)phenyl moiety, —(CH 2 ) n OR z , —[(CH 2 ) n O] m R z , —(CH 2 ) n —Ar—(CH 2 ) m OR z ; wherein n and m are each independently integers from 1-6, Ar represents a substituted or unsubstituted aryl or heteroaryl moiety, and R z  is independently hydrogen, a protecting group, a solid support unit, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(aliphatic)aryl, -(aliphatic)heteroaryl, -(heteroaliphatic)aryl, or -(heteroaliphatic)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         8 . The compound of  claim 6 , wherein R 2  is hydrogen or has one of the structures:  
       
         
           
           
               
               
           
         
         wherein R z  is as defined in  claim 6 .  
       
     
     
         9 . The compound of  claim 1 , wherein R 3  is an alkyl, heteroalkyl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         10 . The compound of  claim 9 , wherein R 3  has one of the structures:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein R 4  is hydrogen or an alkyl heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         12 . The compound of  claim 11 , wherein R 4  is hydrogen alkyl or heteroalkyl.  
     
     
         13 . The compound of  claim 1 , wherein R 5  and R 6  are each independently hydrogen or an alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; or wherein R 5  and R 6 , taken together, form a substituted or unsubstituted, saturated or unsaturated cyclic moiety comprising 5-12 carbon atoms, 0-5 oxygen atoms, 0-5 sulfur atoms and 1-5 nitrogen atoms; and wherein each of the foregoing alkyl or heteroalkyl moieties may be substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated; and wherein each of the foregoing aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moieties may be substituted or unsubstituted.  
     
     
         14 . The compound of  claim 1 , wherein —NR 5 R 6  is one of the following the structures:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . (canceled)  
     
     
         16 . (canceled)  
     
     
         17 . (canceled)  
     
     
         18 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         22 . (canceled)  
     
     
         23 . A library of compounds comprising a plurality of library members, wherein at least two library members are a compound of  claim 1 .  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . The library of  claim 23 , wherein the library comprises at least 100 compounds.  
     
     
         27 . The library of  claim 23 , wherein the library comprises at least 1,000 compounds.  
     
     
         28 . The library of  claim 23 , wherein the library comprises at least 2,000 compounds.  
     
     
         29 . The library of  claim 23 , wherein the library comprises at least 10,000 compounds.  
     
     
         30 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         31 - 39 . (canceled)