Hemiasterlin Derivatives and Uses Thereof

Abstract

The present invention provides compounds having formula (I): and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R 1 -R 7 , X 1 , X 2 , R, Q, and n are as defined herein.

1 - 45 . (canceled) 
     
     
         46 . An intermediate having the structure: 
       
         
           
           
               
               
           
         
         wherein g is 1, 2, 3 or 4; 
         R 2  is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety; 
         R 6  is substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; 
         L is CR L1 R L2 , S, O or NR L3 , wherein each occurrence of R L1 , R L2  and R L3  is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; 
         each occurrence of R G1 , R M1  and R M2  is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
       
       wherein any two adjacent R L1 , R L2 , R L3 , R G1 , R M1  or R M2  groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety. 
     
     
         47 - 52 . (canceled) 
     
     
         53 . The intermediate of  claim 46  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         54 - 61 . (canceled) 
     
     
         62 . An intermediate having the structure: 
       
         
           
           
               
               
           
         
         wherein R x1  and R x2  are independently hydrogen, aliphatic, alicyclic or aryl; 
         g is 1, 2, 3 or 4; 
         L is CR L1 R L2 , S, O or NR L3 , wherein each occurrence of R L1 , R L2  and R L3  is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; 
         each occurrence of R G1 , R M1  and R M2  is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
         wherein any two adjacent R L1 , R L2 , R L3 , R G1 , R M1  or R M2  groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety; 
         R 2  is hydrogen, —(C═O)R C  or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein each occurrence of R c  is independently hydrogen, OH, OR D , or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein R D  is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
         R 6  is hydrogen, —(C═O)R E  or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of R E  is independently hydrogen, OH, OR F , or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; wherein R F  is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety. 
       
     
     
         63 . The intermediate of  claim 62  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The intermediate of  claim 63  wherein R x1  and R x2  are independently hydrogen, alkyl or aryl. 
     
     
         65 . The intermediate of  claim 63  wherein R x1  and R x2  are each hydrogen. 
     
     
         66 . The intermediate of  claim 53  or  63  wherein R 2  is hydrogen, or a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety. 
     
     
         67 . The intermediate of  claim 66  wherein R 2  is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH 3 )Et, —CH(CH 3 )CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —C(CH 3 ) 2 Et, —CH(CH 3 )cyclobutyl, —CH(Et) 2 , —C(CH 3 ) 2 C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. 
     
     
         68 . The intermediate of  claim 66  wherein R 2  is methyl, ethyl, propyl or i-propyl. 
     
     
         69 . The intermediate of  claim 53  or  63  wherein R 6  is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; and R 2  is methyl, ethyl, propyl, butyl, pentyl, tert-butyl, i-propyl, —CH(CH 3 )Et, —CH(CH 3 )CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —C(CH 3 ) 2 Et, —CH(CH 3 )cyclobutyl, —CH(Et) 2 , —C(CH 3 ) 2 C≡CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. 
     
     
         70 . The intermediate of  claim 69  wherein R 6  is tert-butyl. 
     
     
         71 . The intermediate of  claim 53  or  63  wherein R G1  is hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl. 
     
     
         72 . The intermediate of  claim 71  wherein R G1  is hydrogen, methyl or phenyl. 
     
     
         73 . The intermediate of  claim 71  wherein R G1  is hydrogen. 
     
     
         74 . The intermediate of  claim 53  or  63  wherein R M1  and R M2  are each independently hydrogen, hydroxyl, a substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl moiety; a substituted or unsubstituted phenyl moiety, or R M2  is absent when R M1  and the substitutents on L, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety. 
     
     
         75 . The intermediate of  claim 74  wherein R M1  and R M2  are each hydrogen. 
     
     
         76 . The intermediate of  claim 53  or  63  wherein L is CR L1 R L2  wherein R L1  and R L2  are each independently hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl or substituted or unsubstituted phenyl. 
     
     
         77 . The intermediate of  claim 76  wherein L is CH 2 . 
     
     
         78 . A method for preparing a compound of formula VI A : 
       
         
           
           
               
               
           
         
         said method comprising steps of: 
         (a) reacting two compounds having the structures: 
       
       
         
           
           
               
               
           
         
         under suitable conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
         (b) oxidizing the compound formed in step (a) under suitable conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
         (c) subjecting the compound formed in step (b) to suitable olefin-forming conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
         (d) subjecting the compound formed in step (c) to suitable diversification reactions to generate the desired compound having the structure: 
       
       
         
           
           
               
               
           
         
         wherein g is 1 or 2; 
         R Q′  is hydrogen, lower alkyl or an oxygen protecting group; 
         R 2  and R 6  are independently substituted or unsubstituted linear or branched lower alkyl; 
         R 10a  is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; 
         L is CR L1 R L2 , S, O or NR L3 , wherein each occurrence of R L1 , R L2  and R L3  is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; 
         each occurrence of R G1 , R M1  and R M2  is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
       
       wherein any two adjacent R L1 , R L2 , R L3 , R G1 , R M1  or R M2  groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety. 
     
     
         79 . The method of  claim 78  wherein, in the step of oxidizing, the conditions comprise Swern or Dess Martin oxidizing conditions. 
     
     
         80 . The method of  claim 78  wherein, in step (c), the olefin-forming conditions comprise Ph 3 P═C(R 10a )CO 2 R Q′ ; wherein R Q′  is hydrogen, lower alkyl or an oxygen protecting group; and R 10a  is as defined generally above and in classes and subclasses herein. 
     
     
         81 . A method for preparing a compound of formula VI A : 
       
         
           
           
               
               
           
         
         said method comprising steps of: 
         (a) reacting two compounds having the structures: 
       
       
         
           
           
               
               
           
         
         under suitable conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
         wherein R x1  and R x2  are independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; 
         (b) converting the compound formed in step (a) under suitable conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
         (c) subjecting the compound formed in step (b) to suitable diversification reactions to generate the desired compound having the structure: 
       
       
         
           
           
               
               
           
         
         wherein g is 1 or 2; 
         R Q′  is hydrogen, lower alkyl or an oxygen protecting group; 
         R 2  and R 6  are independently substituted or unsubstituted linear or branched lower alkyl; 
         R 10a  is hydrogen or substituted or unsubstituted, linear or branched, cyclic or acyclic, or saturated or unsaturated lower alkyl; 
         L is CR L1 R L2 , S, O or NR L3 , wherein each occurrence of R L1 , R L2  and R L3  is independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; 
         each occurrence of R G1 , R M1  and R M2  is each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
       
       wherein any two adjacent R L1 , R L2 , R L3 , R G1 , R M1  or R M2  groups, taken together, form a substituted or unsubstituted alicyclic or heteroalicyclic moiety containing 3-6 atoms or an aryl or heteroaryl moiety. 
     
     
         82 . The method of  claim 81  wherein the step of converting comprises steps of:
 (i) subjecting the compound having the structure:   
       
         
           
           
               
               
           
         
         to ozonolysis conditions to form an aldehyde having the structure: 
       
       
         
           
           
               
               
           
         
         (ii) subjecting the compound formed in step (i) to suitable olefin-forming conditions to form a compound having the structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         83 . The method of  claim 81  wherein, in step (ii), the olefin-forming conditions comprise Ph 3 P═C(R 10a )CO 2 R Q′ ; wherein R Q′  is hydrogen, lower alkyl or an oxygen protecting group; and R 10a  is as defined generally above and in classes and subclasses herein. 
     
     
         84 . The method of  claim 81  wherein, the step of converting comprises a step of:
 subjecting the compound having the structure:   
       
         
           
           
               
               
           
         
         to cross-olefin-metathesis conditions in the presence of CH 2 ═C(R 10a )CO 2 R Q′  to form a compound having the structure: