Compositions of kinase inhibitors and their use for treatment of cancer and other diseases related to kinases

Abstract

The present invention relates to novel thiazole-substituted indolin-2-ones as inhibitors of CSCPK and related kinases; to methods of inhibiting cancer stem cells by using a kinase inhibitor; to pharmaceutical compositions containing such compounds; and to methods of using such compounds in the treatment of a protein kinase related disorder in a mammal; and to processes of making such compounds and intermediates thereof.

1 . A process for preparing a compound of formula VI or a pharmaceutically-acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: R 1  is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , SR a , S(═O)2R e , S(═O) 2 OR e , C(═O)OR d , C(═O)R a , or C(═O)NR b R c ; 
         R 4,  R 7,  and R 8  are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , SR a , S(═O)R e , S(═O) 2 R e , P(═O) 2 R e , S(═O) 2 OR e , P(═O)OR e , NR b R c , NR b S(═O) 2 R e , NR b P(═O) 2 R e , S(═O) 2 NR b R c , P(═O)2NR b R c , C(═O)OR e , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR e , NR d C(═O)NR b R c , NR d S(═O) 2 NR b R c , NR d P(═O) 2 NR b R c , NR b C(═O)R a , or NR b P(═O) 2 R e ; 
         R 5  is alkyl or substituted alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  is hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, or OR a ; 
         R a  is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; 
         R b , R c  and R d  are independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said R b  and R c  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; and 
         R e  is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, comprising reacting a compound of formula VII, 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 4 , R 7 , and R 8  are defined as hereinabove, and X is a leaving group selected from Cl Br, I, and —OSO 2 R, in which R is alkyl, substituted alkyl, aryl or substituted aryl, with a compound of formula VIII, 
       
       
         
           
           
               
               
           
         
         wherein R 5  is defined as hereinabove, to provide the compound of formula VI. 
       
     
     
         2 . The process of  claim 1 , further comprising reacting the compound of formula IV with a compound of formula IX, 
       
         
           
           
               
               
           
         
         wherein R 2  is heterocycle or substituted heterocycle, aryl or substituted aryl; and 
         R 3  is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         to provide a compound of formula I or a pharmaceutically-acceptable salt thereof, 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , SR a , S(═O) 2 R e , S(═O) 2 OR e , C(═O)OR d , C(═O)R a , or C(═O)NR b R c ; 
         R 2  is heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 3  is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 4 , R 7 , and R 8  are each independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , SR a , S(═O)R e , S(═O) 2 R e , P(═O) 2 R e , S(═O) 2 OR e , P(═O) 2 OR e , NR b R c , NR b S(═O) 2 R e , NR b P(═O) 2 R e , S(═O)2NR b R c , P(═O)2NR b R c , C(═O)OR e , C(═O)R a , C(═O)NR b R c , OC(═O)R a , OC(═O)NR b R c , NR b C(═O)OR e , NR d C(═O)NR b R c , NR d S(═O) 2 NR b R c , NR d P(═O) 2 NR b R c , NR b C(═O)R a , or NR b P(═O) 2 R e ; 
         R 5  is alkyl or substituted alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  is hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, or OR a ; 
         R a  is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; 
         R b , R c  and R d  are independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said R b  and R c  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; and 
         R e  is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl.