Hemiasterlin derivatives and uses thereof in the treatment of cancer

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 - 98 . (canceled) 
     
     
         99 . A compound having the structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or salt of an ester thereof; 
         wherein g is 0, 1, 2 or 3; 
         X 2  is C(═O), CR A R B , or —SO 2 —; wherein each occurrence of R A  and R B  is independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, 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; 
         R 5 , R 6  and R 7  are each independently 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, or wherein any two R 5 , R 6  and R 7  groups, taken together, form an alicyclic, heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety; wherein R F  is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; R 8a , R 9a  and R 10a  are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; 
         R L1  and R L2  are each independently hydrogen or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and 
         Q is OR Q′  or NR Q′ R Q″ ; wherein R Q′  is a heteroaliphatic moiety, and R Q″  is hydrogen; or Q is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of r is 0, 1 or 2; 
         wherein R Q1  is a heteroalkyl moiety and R Q2  is hydrogen; 
         or a pharmaceutically acceptable salt, ester or salt of ester thereof. 
       
     
     
         100 . The compound of  claim 99 , wherein R 2  is hydrogen, or linear or branched, cyclic or acyclic, C 1-6  alkyl or benzyl. 
     
     
         101 . The compound of  claim 99  wherein R 2  is C 1-6  alkyl; R 6  is tert-butyl, R 7  and R 10a  are each methyl and R 8a  is iso-propyl; R L1  and R L2  are each independently hydrogen, C 1-6  alkyl, heteroalkyl, aryl or heteroaryl. 
     
     
         102 . The compound of  claim 99  wherein Q is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or salt of ester thereof. 
       
     
     
         103 . The compound of  claim 99  wherein Q is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or salt of ester thereof. 
       
     
     
         104 . The compound of  claim 99  wherein Q is OR Q′ , or a pharmaceutically acceptable salt, ester or salt of ester thereof. 
     
     
         105 . The compound of  claim 99  wherein Q is NR Q′ R Q″ , or a pharmaceutically acceptable salt, ester or salt of ester thereof. 
     
     
         106 . The compound of  claim 99  wherein the heteroaliphatic moiety is an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms in place of carbon atoms; and wherein the heteroaliphatic moiety is optionally substituted by a heteroaryl moiety. 
     
     
         107 . A pharmaceutical composition comprising a compound of  claim 99 , a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent. 
     
     
         108 . The pharmaceutical composition of  claim 107  wherein the compound is present in an amount effective to inhibit cancer cell growth in vitro. 
     
     
         109 . The pharmaceutical composition of  claim 107  wherein the compound is present in an amount effective to cause tumor regression in vivo. 
     
     
         110 . A method for treating cancer comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 99 . 
     
     
         111 . A method for treating cancer comprising: administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 107 . 
     
     
         112 . The method of  claim 111  further comprising the administration of a pharmaceutically acceptable carrier or diluent, and optionally an additional therapeutic agent. 
     
     
         113 . The method of any one of  claim 110 , wherein the cancer is prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma. 
     
     
         114 . The method of any one of  claim 111 , wherein the cancer is prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma. 
     
     
         115 . The method of any one of  claim 112 , wherein the cancer is prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma.