Azaindole kinase inhibitors

Abstract

The present invention provides compounds of formula I, and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer 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 
 Z is selected from O, S, N, OH, or Cl, with the provisos that when Z is O or S, R 41  is absent and when Z is OH or Cl, both R 41  and R 42  are absent;  
 X and Y are independently selected from O, OCO, S, SO, SO 2 , CO, CO 2 , NR 10 , NR 11 CO, NR 12 CONR 13 , NR 14 CO 2 , NR 15 SO 2 , NR 16 SO 2 NR 17 , SO 2 NR 18 , CONR 19 , halogen, nitro, cyano, or X or Y are absent;  
 R 1  is hydrogen, CH 3 , OH, OCH 3 , SH, SCH 3 , OCOR 21 , SOR 22 , SO 2 R 23 , S 2 NR 24 R 25 , CO 2 R 26 , CONR 27 R 28 , NH 2 , NR 29 SO 2 NR 30 R 31 , NR 32 SO 2 R 33 , NR 34 COR 35 , NR 36 CO 2 R 37 , NR 38 CONR 39 R 40 , halogen, nitro, or cyano;  
 R 2  and R 3  are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; with the proviso that when X is halo, nitro or cyano, R 2  is absent, and, when Y is halo, nitro or cyano, R 3  is absent;  
 R 6  is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, NR 7 R 8 , OR 9  or halogen;  
 R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 24 , R 25 , R 26 , R 27 R 28 , R 29 R 30 , R 31 , R 32 , R 34 , R 35 , R 36 , R 38 , R 39  and R 40  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, or substituted heterocyclo;  
 R 22 , R 23 , R 33  and R 37  are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, or substituted heterocyclo;  
 R 42  is  
                     
 (R 43 ) n  wherein n equals 0, 1 or 2 and each R 43  is independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; and  
 R 44  is methyl, or hydrogen, with the further provisos that:  
 a. R 2  may not be hydrogen if X is SO, SO 2 , NR 13 CO 2 , or NR 14 SO 2 ; and  
 b. R 3  may not be hydrogen if Y is SO, SO 2 , NR 13 CO 2 , or NR 14 SO 2 ; or an enantiomer, diastereomer, or pharmaceutically acceptable salt, prodrug, or solvate thereof,  
 
   
   
       2 . A compound according to  claim 1  wherein R 1  is hydrogen or methyl; R 6  is hydrogen; R 3  is lower alkyl; and Z is oxygen or nitrogen.  
   
   
       3 . A compound according to  claim 1  wherein R 1  is hydrogen; R 3  is lower alkyl; Y is absent; X is oxygen or nitrogen; R 43  is fluoro or hydrogen; and R 44  is hydrogen or methyl.  
   
   
       4 . A compound according to  claim 1  wherein X is oxygen; R 2  is a substituted alkyl and R 43  is fluoro.  
   
   
       5 . A compound according to  claim 1  wherein X is absent; R 2  is a substituted hetrocyclo, substituted heterocyclo, heteroaryl or substituted heteroaryl, and Z is nitrogen.  
   
   
       6 . A compound selected from the group consisting of 
 4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-ol,    (R)-1-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-propan-2-ol,    (S)-1-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-propan-2-ol,    (R)-1-[4-(4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-propan-2-ol,    (R)-2-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethylamine,    (R)-2-[4-(4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methyl-ethylamine,    2-[4-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-ethylamine,    (4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine,    (4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine,    (4-Fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-[5-isopropyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine, and    [5-Isopropyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-amine.    
   
   
       7 . A pharmaceutical composition comprising at least one of the compounds of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       8 . A pharmaceutical composition comprising at least one of the compounds of  claim 6  and a pharmaceutically acceptable carrier therefor.  
   
   
       9 . A pharmaceutical composition comprising at least one or more compounds of  claim 1  in combination with a pharmaceutically acceptable carrier and at least one additional anti-cancer or cytotoxic agent.  
   
   
       10 . A pharmaceutical composition comprising at least one or more compounds of  claim 6  in combination with a pharmaceutically acceptable carrier and at least one additional anti-cancer or cytotoxic agent.  
   
   
       11 . The pharmaceutical composition of  claim 7 , wherein said anti-cancer or cytotoxic agent is selected from the group consisting of: linomide, inhibitors of integrin αvβ3 function, angiostatin, razoxane, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, herceptin, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine, adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, irinotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers.  
   
   
       12 . A method for producing an antiangiogenic effect which comprises administering to a mammalian species in need thereof, an effective antiangiogenic producing amount of at least one of the compounds of  claim 1 .  
   
   
       13 . A method for producing a vascular permeability reducing effect which comprises administering to a mammalian species in need thereof an effective vascular permeability reducing amount of at least one of the compounds of  claim 1 .  
   
   
       14 . A method of inhibiting protein kinase activity of growth factor receptors which comprises administering to a mammalian species in need thereof, an effective protein kinase inhibiting amount of at least one of the compounds of  claim 1 .  
   
   
       15 . A method of inhibiting tyrosine kinase activity of growth factor receptors which comprises administering to a mammalian species in need thereof, an effective tyrosine kinase inhibiting amount of at least one of the compounds of  claim 1 .  
   
   
       16 . A method for treating proliferative diseases, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of the composition of  claim 7 .  
   
   
       17 . A method for treating cancer, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of the composition of  claim 7 .  
   
   
       18 . A method for treating inflammation, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of the composition of  claim 7 .  
   
   
       19 . A method for treating autoimmune diseases, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of the composition of  claim 7 .  
   
   
       20 . 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 at least one of the compounds of  claim 1.