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 compound of formula I, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         R 1  is hydrogen; 
         R 2  is substituted heterocycle; 
         R 3  is hydrogen; 
         R 4 , R 7 , and R 8  are each independently hydrogen; 
         R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  is hydrogen. 
       
     
     
         2 . A compound of formula II, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         Het is a 5-membered aromatic ring containing at least one N heteroatom; 
         R 1  is hydrogen; 
         R 3  and R 10  are each independently hydrogen or alkyl; 
         R 4 , R 7 , and R 8  are each independently hydrogen; 
         R 5  is alkyl heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  and R 9  are each independently hydrogen or alkyl; 
         R 14  and R 15  are independently hydrogen substituted alkyl or said R 14  and R 15  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle. 
       
     
     
         3 . A compound of formula III, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         Het is a 5-membered aromatic ring containing at least one N heteroatom; 
         R 1  is hydrogen; 
         R 3  and R 10  are each independently hydrogen or alkyl; 
         R 4 , R 7 , and R 8  are each independently hydrogen; 
         R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  and R 9  are each independently hydrogen or alkyl; 
         R 11  is hydrogen; 
         R 12  and R 13  are independently alkyl; 
         n is 2. 
       
     
     
         4 . A compound of formula IV, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         Het is a 5-membered aromatic ring containing at least one N heteroatom; 
         R 1  is hydrogen; 
         R 3  and R 10  are each independently hydrogen or alkyl; 
         R 4 , R 7 , and R 8  are each independently hydrogen; 
         R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  and R 9  are each independently hydrogen or alkyl; 
         R 14  and R 15  are independently hydrogen, substituted alkyl, or said R 14  and R 15  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle. 
       
     
     
         5 . A compound of formula V, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         R 1  is hydrogen; 
         R 3  and R 10  are each independently hydrogen or alkyl; 
         R 4 , R 7 , and R 8  are each independently hydrogen; 
         R 5  is heterocycle or substituted heterocycle, aryl or substituted aryl; 
         R 6  and R 9  are each independently hydrogen or alkyl; 
         R 11  is hydrogen; 
         R 12  and R 13  are independently alkyl; 
         n is 2. 
       
     
     
         6 . A pharmaceutical composition comprising a compound or a pharmaceutically-acceptable salt thereof selected from the group consisting of:
 (a) a compound of formula I,   
       
         
           
           
               
               
           
         
         
           or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
           R 1  is hydrogen; 
           R 2  is substituted heterocycle; 
           R 3  is hydrogen; 
           R 4 , R 7 , and R 8  are each independently hydrogen; 
           R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
           R 6  is hydrogen; 
         
         (b) a compound of formula II, 
       
       
         
           
           
               
               
           
         
         
           or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
           Het is a 5-membered aromatic ring containing at least one N heteroatom; 
           R 1  is hydrogen; 
           R 3  and R 10  are each independently hydrogen or alkyl; 
           R 4 , R 7 , and R 8  are each independently hydrogen; 
           R 5  is alkyl heterocycle or substituted heterocycle, aryl or substituted aryl; 
           R 6  and R 9  are each independently hydrogen or alkyl; 
           R 14  and R 15  are independently hydrogen substituted alkyl or said R 14  and R 15  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; 
         
         (c) a compound of formula III, 
       
       
         
           
           
               
               
           
         
         
           or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
           Het is a 5-membered aromatic ring containing at least one N heteroatom; 
           R 1  is hydrogen; 
           R 3  and R 10  are each independently hydrogen or alkyl; 
           R 4 , R 7 , and R 8  are each independently hydrogen; 
           R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
           R 6  and R 9  are each independently hydrogen or alkyl; 
           R 11  is hydrogen; 
           R 12  and R 13  are independently alkyl; 
           n is 2; 
         
         (d) a compound of formula IV, 
       
       
         
           
           
               
               
           
         
         
           or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
           Het is a 5-membered aromatic ring containing at least one N heteroatom; 
           R 1  is hydrogen; 
           R 3  and R 10  are each independently hydrogen or alkyl; 
           R 4 , R 7 , and R 8  are each independently hydrogen; 
           R 5  is alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; 
           R 6  and R 9  are each independently hydrogen or alkyl; 
           R 14  and R 15  are independently hydrogen, substituted alkyl, or said R 14  and R 15  together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; and 
         
         (e) a compound of formula V, 
       
       
         
           
           
               
               
           
         
         
           or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
           R 1  is hydrogen; 
           R 3  and R 10  are each independently hydrogen or alkyl; 
           R 4 , R 7 , and R 8  are each independently hydrogen; 
           R 5  is heterocycle or substituted heterocycle, aryl or substituted aryl; 
           R 6  and R 9  are each independently hydrogen or alkyl; 
           R 11  is hydrogen; 
           R 12  and R 13  are independently alkyl; 
           n is 2; 
         
         and a pharmaceutically-acceptable excipient, carrier, or diluent. 
       
     
     
         7 . A method of treating cancer in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as claimed in  claim 6 . 
     
     
         8 . A method of inhibiting/reducing/diminishing cancer stem cell survival and/or proliferation in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as claimed in  claim 6 . 
     
     
         9 . A method of modulating the catalytic activity of a protein kinase, comprising contacting said protein kinase with a pharmaceutical composition as claimed in  claim 6 . 
     
     
         10 . The pharmaceutical composition of  claim 6 , wherein the pharmaceutically-acceptable excipient, carrier, or diluent is a solution mixture or a suspension mixture comprising, by weight, about 12.5% of DMA, about 52.5% of PEG400, and about 35% of 20% Vitamin E. 
     
     
         11 . The pharmaceutical composition of  claim 6 , further comprising at least one other anti-cancer therapy agent. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said anti-cancer therapy agent is at least one agent selected from the group consisting of radiotherapy (XRT) agents, cytotoxic agents, targeted agents, and adjunctive agents. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein said anti-cancer therapy agent is selected from gemcitabine, erlotinib, paclitaxel docetaxel, carboplatin cisplatin, 5-fluorouracil, doxorubicin, sorafenib, imatinib, bevacizumab, cetuximab, and trastuzumab. 
     
     
         14 . A method of treating cancer in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as claimed in any one of  claims 11 .