Multikinase inhibitors for use in the treatment of cancer

Abstract

The present invention provides compounds, pharmaceutical compositions and methods for the treatment of specific cancers. Such compositions may generally comprise a compound of formula (I): wherein R 1 -R 3 are as defined herein, or pharmaceutically acceptable salts or esters thereof; and a pharmaceutically acceptable carrier.

1 - 41 . (canceled) 
     
     
         42 . A method for treating a FLT3 mutated cancer in a subject, wherein the FLT3 mutated cancer comprises an internal tandem duplication, comprising administering to the subject a composition comprising at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H 
 R 2  is a moiety selected from the group consisting of H and trifluoromethylcarbonyl; or R 1  and R 2  are taken together with the core structure to form a heterocyclydiyl moiety of formula (a): 
 
       
       
         
           
           
               
               
           
         
         
           R 3  is a moiety selected from the group consisting of —OR a  and —NR b R c ; 
           R a  is a C 1-4  alkyl group optionally substituted with an imidazolyl; 
           R b  is a moiety selected from the group consisting of a C 1-4  alkyl group and a C 1-4  alkoxy group, wherein R b  is substituted with 0, 1 or 2 groups each independently selected from the group consisting of —OCH 3 , —C(O)OH, —C(O)NR′R″, —NH(C 1-3  alkyl), —NH(CH 2 CH 2 O) n CH 3 , wherein n is 2-4, piperazinyl, N-methylpiperazinyl, piperidinyl, N-methylpiperidinyl, N-morpholinyl, imidazolyl, pyrrolidinyl, —OPO 3 H 2  and hydroxyl; wherein the —NH(C 1-3  alkyl) group is substituted with 0, 1 or 2 hydroxyl moieties and wherein R′ and R″ are each independently selected from —H or —CH 3 ; and 
           R c  is H, or R b  and R c  are taken together with the nitrogen to which they are attached to form a heterocyclyl moiety selected from the group consisting of formula (b) and formula (c): 
         
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or ester thereof; in an amount effective for treating the FLT3 mutated cancer. 
         
       
     
     
         43 . The method of  claim 42 , wherein the FLT3 mutated cancer is a hematologic cancer. 
     
     
         44 . The method of  claim 43 , wherein the hematologic cancer is leukemia. 
     
     
         45 . The method of  claim 44 , wherein the leukemia is acute myeloid leukemia. 
     
     
         46 . The method of  claim 42 , wherein 
       
         
           
           
               
               
           
         
       
       represents a double bond. 
     
     
         47 . The method of  claim 42 , wherein R 3  is —NR b R c , and wherein R c  is H and R b  is an unsubstituted C 1-4  alkyl. 
     
     
         48 . The method of  claim 47 , wherein R c  is H and R b  is methyl or ethyl. 
     
     
         49 . The method of  claim 42 , wherein the compound of formula (I) is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein
 R 3  is —NHR b , and R b  is C 1 -C 3  alkyl substituted with 0, 1, or 2 hydroxyl moieties; 
 
         or a pharmaceutically acceptable salt or ester thereof. 
       
     
     
         50 . The method of  claim 49 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts and esters thereof. 
       
     
     
         51 . The method of  claim 50 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts and esters thereof. 
       
     
     
         52 . The method of  claim 51 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         53 . The method of  claim 52 , wherein the compound is a pharmaceutically acceptable salt of: 
       
         
           
           
               
               
           
         
       
     
     
         54 . The method of  claim 52 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 42 , further comprising administration of a second chemotherapeutic drug. 
     
     
         56 . The method of  claim 42 , wherein the composition is administered intravenously. 
     
     
         57 . The method of  claim 42 , wherein the composition is administered at a dosage between about 0.10 mg/kg to about 25 mg/kg of body weight. 
     
     
         58 . A method for treating a FLT3 mutated cancer in a subject, wherein the FLT3 mutated cancer comprises an internal tandem duplication, the method comprising:
 a) determining if the subject's cancer comprises an internal tandem duplication; and   b) if the cancer is determined to carry an internal tandem duplication, administering to the subject a composition comprising at least one compound of formula (I):   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H 
 R 2  is a moiety selected from the group consisting of H and trifluoromethylcarbonyl; or R 1  and R 2  are taken together with the core structure to form a heterocyclydiyl moiety of formula (a): 
 
       
         
           
           
               
               
           
         
         R 3  is a moiety selected from the group consisting of —OR a  and —NR b R c ; 
         R a  is a C 1-4  alkyl group optionally substituted with an imidazolyl; 
         R b  is a moiety selected from the group consisting of a C 1-4  alkyl group and a C 1-4  alkoxy group, wherein R b  is substituted with 0, 1 or 2 groups each independently selected from the group consisting of —OCH 3 , —C(O)OH, —C(O)NR′R″, —NH(C 1-3  alkyl), —NH(CH 2 CH 2 O) a CH 3 , wherein n is 2-4, piperazinyl, N-methylpiperazinyl, piperidinyl, N-methylpiperidinyl, N-morpholinyl, imidazolyl, pyrrolidinyl, —OPO 3 H 2  and hydroxyl; wherein the —NH(C 1-3  alkyl) group is substituted with 0, 1 or 2 hydroxyl moieties and wherein R′ and R″ are each independently selected from —H or —CH 3 ; and 
         R c  is H, or R b  and R c  are taken together with the nitrogen to which they are attached to form a heterocyclyl moiety selected from the group consisting of formula (b) and formula (c): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof; in an amount effective for treating the FLT3 mutated cancer.