Pyrrolotriazine compounds as kinase inhibitors

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 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl; 
         R 2  is aryl, substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl; 
         R 3  is hydrogen, alkyl or substituted alkyl; 
         X is a direct bond, —NR 3 — or —O—; 
         Y is a direct bond, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl; 
         or a pharmaceutically acceptable salt or stereoisomer thereof, 
         with the proviso that R 2  is not indazolyl or substituted indazolyl. 
       
     
     
         2 . A compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         X is a direct bond, —NR 3 — or —O—; 
         Z is 
       
       
         
           
           
               
               
           
         
       
       or —NR 7 —;
 R 2  is aryl or substituted aryl, heteroaryl or substituted heteroaryl, 
 R 3 , R 4  and R 5  are independently selected from hydrogen, alkyl and substituted alkyl; 
 R 6 , R 6a  and R 6b  are independently selected from the group consisting of one or more hydrogen, halogen, alkyl, alkoxy, aryloxy, —CN, —NH 2 , —OH, —COOH, —CH 2 OR 5 , —CONHSO 2 R 5 , —CONR 4 R 5 , —NHalkyl, —NHCOalkyl, —NR 4 SO 2 alkyl, —NR 4 SO 2 NR 4 R 5 , —OCONR 4 R 5 , —CF 3  and —OCF 3 , two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable; 
 R 7  is hydrogen, alkyl or —NH 2 , and 
 n is 0, 1, 2 or 3; 
 
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         3 . A compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         X is a direct bond, —NR 3 — or —O—; 
         R 2  is aryl or substituted aryl, heteroaryl or substituted heteroaryl, 
         R 3 , R 4  and R 5  are independently selected from hydrogen, alkyl and substituted alkyl; 
         R 6 , R 6a  and R 6b  are independently selected from the group consisting of one or more hydrogen, halogen, alkyl, alkoxy, aryloxy, —CN, —NH 2 , —OH, —COOH, —CH 2 OR 5 , —CONHSO 2 R 5 , —CONR 4 R 5 , —NHalkyl, —NHCOalkyl, —NR 4 SO 2 alkyl, —NR 4 SO 2 NR 4 R 5 , —OCONR 4 R 5 , —CF 3  and —OCF 3 , two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable; and 
         n is 0, 1, 2 or 3; 
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         4 . The compound according to  claim 3  wherein
 R 2  is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, oxazole, substituted oxazole, thiazole, substituted thiazole, pyrazinyl or substituted pyrazinyl; 
 R 6 , R 6a  and R 6b  are independently selected from the group consisting of one or more hydrogen, —NH 2 , OH, alkoxy, —CONR 4 R 5 , —NR 4 SO 2 alkyl, —NR 4 SO 2 NR 4 R 5 , —OCONR 4 R 5 , —NHalkyl and —NHCOalkyl; 
 X is —NH—; and 
 n is 1 or 2. 
 
     
     
         5 . A pharmaceutical composition comprising one or more compounds of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         6 . A pharmaceutical composition comprising one or more compounds of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         7 . A pharmaceutical composition comprising one or more compounds of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         8 . A pharmaceutical composition comprising one or more compounds of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         9 . A pharmaceutical composition comprising one or more compounds according to  claim 1  in combination with a pharmaceutically acceptable carrier and one or more other anti-cancer or cytotoxic agent. 
     
     
         10 . The pharmaceutical composition according to  claim 9  wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, trastuzumab, erlotinib, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridol, bortezomib and biological response modifiers. 
     
     
         11 . A method for treating a proliferative disease, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of one or more compound according to  claim 1 . 
     
     
         12 . The method of  claim 11  wherein the proliferative disease is selected from the group consisting of cancer, psoriasis and rheumatoid arthritis. 
     
     
         13 . The method of  claim 12  wherein the proliferative disease is cancer. 
     
     
         14 . The method of  claim 13  further comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of one or more other anti-cancer or cytotoxic agent in combination with one or more compound according to  claim 1 . 
     
     
         15 . The method of  claim 14  wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, trastuzumab, erlotinib, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers. 
     
     
         16 . A method of modulating receptor tyrosine kinase activity which comprises administering to a mammalian species in need thereof, an effective amount of one or more compound according to  claim 1 . 
     
     
         17 . The method of  claim 16  wherein said receptor tyrosine kinase is selected from the group consisting of HER1, HER2 and HER4. 
     
     
         18 . A method for treating diseases associated with signal transduction pathways operating through growth factor receptors, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of one or more compound according to  claim 1 . 
     
     
         19 . A method for identifying kinase ATP-competitive inhibitors which comprises selecting a compound as defined in  claim 1 , that binds in the adenine pocket, the ribose pocket, the phosphate binding pocket, specificity region 1 and specificity region 2 of the kinase as shown in  FIG. 2 , wherein the group occupying the ribose and/or the phosphate binding pocket can interact with one or more of the absolutely conserved residues involved in phosphate binding. 
     
     
         20 . The method according to  claim 19  wherein the group interacts with residues Asn818 and/or Asp 831 (HER1 numbering) or the corresponding residues in a different kinase of the ribose/phosphate binding pockets.