C-5 Modified indazolylpyrrolotriazines

Abstract

The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4 thereby making them useful as antiproliferative agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.

1 - 11 . (canceled)  
     
     
         12 . The method of  claim 17  further comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of at least one other anti-cancer or cytotoxic agent in combination with a compound of formula 1.  
     
     
         13 . The method of  claim 12  wherein said anti-cancer or cytotoxic agent is selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan and an epothilone.  
     
     
         14 . A method of modulating receptor tyrosine kinase activity which comprises administering to a warm blooded species in need thereof, an effective amount of a compound of formula 1.  
     
     
         15 . The method of  claim 14  wherein said receptor tyrosine kinase is selected from the group consisting of HER1, HER2 and HER4.  
     
     
         16 . A method for treating diseases associated with signal transduction pathways operating through growth factor receptors, which comprises administering to a warm-blooded species in need thereof a therapeutically effective amount of a compound of formula 1.  
     
     
         17 . A method for treating cancer comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       its enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein 
 R is selected from the group consisting of SR 2 , SOR 2 , SO 2 R 2 , OR 2 , and NR 3 R 4 ;  
 R 1  is selected from the group consisting of aryl, substituted aryl, heterocyclo, and substituted heterocyclo;  
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heterocyclo, and substituted heterocyclo;  
 R 3  and R 4  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, and substituted heterocyclo; or  
 R 3  and R 4  may together form an optionally substituted monocyclic 4-8 membered saturated or unsaturated carbocyclic or heterocyclic ring, or an optionally substituted bicyclic 7 to 12 membered saturated or unsaturated carbocyclic or heterocyclic ring.