Pyrrolotriazine 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 - 20 . (canceled)  
   
   
       21 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, 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 and when Z is N, then R 41  is H; 
 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 2 , SOR 22 , SO 2 R 23 , SO 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 CR 35 ,  
 NR 36 CO 2 R 37 , NR 38 CONR 39 R 40 , halogen, nitro, or cyano;  
 R 2  is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl, or when X is halo, nitro or cyano, R 2  is absent;  
 R 3  is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl, or when Y is halo, nitro or cyano, R 3  is absent, with the proviso that R 3  is not methyl;  
 R 6  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, NR 7 R , 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, 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, heterocyclo, or substituted heterocyclo; and  
                     
 wherein  
 each R 43  is independently selected from fluorine or methyl;  
 n is 0, 1 or2; and  
 R 44  is methyl, ethyl or cyclopropylmethyl;  
 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 .  
 
 
   
   
       22 . The compound according to claim  1 , selected from the group consisting of: 
 5-(1-Methylethyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one-6-carboxylic acid ethyl ester,    4-Chloro-[2,1-f][1,2,4]triazin-5-(1-Methylethyl)pyrrolo-6-carboxylic acid ethyl ester,    4-Chloro-5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin,    4-[[3-[(Methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[[2-Fluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[[2-Fluoro-5-[(methoxyamino)carbonyl]-4-methylphenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[[3-[(Methoxyamino)carbonyl]-4-methylphenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[[4-Fluoro-3-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester,    4-[3-[(Methoxyam ino)carbonyl]phenoxy]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid, ethyl ester,    4-[2-Fluoro-3-[(methoxyamino)carbonyl]phenoxy]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid, ethyl ester,    4-[[2-Fluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid,    N-Ethyl-4-[[2-fluoro-5-[(methoxyam ino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide,    N-[2-(Dimethylamino)ethyl]-4-[[2-fluoro-5-[(methoxyamino)carbonyl] phenyl]am ino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide,    4-[[2-Fluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-N-(2-hydroxyethyl)-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide,    4-[[3-[(Methoxyamino)carbonyl]-4-methylphenyl]amino]-N-methyl-5-(1-methylethyl)pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxam ide,    4-[[3-[(Methoxyam ino)carbonyl]-4-methylphenyl]amino]-5-(1-methylethyl)-N-[2-(1-pyrrolidinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide,    [4-[[3-[(Methoxyam ino)carbonyl]-4-methylphenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(1-methyl-2-pyrrolidinyl)ethyl ester,    4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 3-(methylsulfonyl)propyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 3-(1-piperidinyl)propyl ester,    5-[[6-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-2,4-difluoro-N-methoxybenzamide,    5-[[6-Ethoxy-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]am ino]-4-fluoro-N-methoxy-2-methylbenzamide,    2,4-Difluoro-N-methoxy-5-[[5-(1 -methylethyl)-6-(2-methyl-1 H-1,2,4-triazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    2,4-Difluoro-N-methoxy-5-[[5-(1-methylethyl)-6-(1-methyl-1. H-1,2,4-triazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    2,4-Difluoro-N-methoxy-5-[[5-(1-methylethyl)-6-[5-[(methylsulfonyl)methyl]-1,3,4-oxadiazol-2-yl]pyrrolo[2,1-f][ 1,2,4]triazin-4-yl]amino]benzamide,    5-[[6-[5-[Difluoro(methylsulfonyl)methyl]-1,3,4-oxadiazol-2-yI]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-2,4-difluoro-N-methoxybenzam ide,    5-[[6-[5-(Dimethylamino)-1,3,4-oxadiazol-2-yl]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-2,4-difluoro-N-methoxybenzamide,    [4-[[2 ,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]am ino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(1-methyl-1 H-1,2,4-triazol-5-yl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbam ic acid, (1-methyl-4-piperidinyl)methyl,    [4-[[2,4-Difluoro-5-[(methoxyam ino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, 3-(1 H-1,2,3-triazol-1-yl)propyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, 2-(1 H-1,2,3-triazol-1-yl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, 3-(6-methyl-2-pyridinyl) propyl ester    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(methylsulfonyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid (2-butyl-1H-imidazol-4-yl)methyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(4-pyridinyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(dimethoxyphosphinyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid (6-methyl-2-pyridinyl)methyl ester,    [4-[[2 ,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid [(2S)-1-methyl-2-pyrrolidinyl]methyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid (1-methyl-2-piperidinyl)methyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]am ino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 1-methyl-4-piperidinyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 4-pyridinylmethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 3-pyridinylmethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(2-pyridinyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-pyridinylmethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(4-morpholinyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(1-methyl-2-pyrrolidnyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyam ino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 1-methyl-3-pyrrolidnyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbam ic acid 2-ethoxyethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid [5-[(dimethylamino)methyl]-2-furanyl]methyl ester,    [4-[[2,4-Difluoro-5-[(methoxyamino)carbonyl]phenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 2-(1-piperidinyl)ethyl ester,    [4-[[2,4-Difluoro-5-[(methoxyam ino)carbonyl]phenyl]am ino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid 3-hydroxybutyl ester,    4-Fluoro-N-methoxy-3-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    2,4-Difluoro-N-methoxy-5-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl) pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    2-Fluoro-N-methoxy-5-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    N-Methoxy-2-methyl-5-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    4-Fluoro-N-methoxy-2-methyl-5-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide,    2-Chloro-N-methoxy-5-[[5-(1-methylethyl)-6-(5-methyl-2-oxazolyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzam ide,    2,4-Difluoro-N-methoxy-5-[[5-(1-methylethyl)-6-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide, or a pharmaceutically acceptable salt thereof.    
   
   
       23 . A pharmaceutical composition comprising one or more of the compounds of  claim 21  and a pharmaceutically acceptable carrier.  
   
   
       24 . A pharmaceutical composition comprising one or more of the compounds of  claim 21  in combination with pharmaceutically acceptable carrier and an anti-cancer or cytotoxic agent.  
   
   
       25 . The pharmaceutical composition according to  claim 24 , 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.  
   
   
       26 . A method for producing an antiangiogenic effect which comprises administering to a mammalian species in need thereof, an effective antiangiogenic producing amount of one or more of the compounds of  claim 21 .  
   
   
       27 . 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 one or more of the compounds of  claim 21 .  
   
   
       28 . 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 one or more of the compounds of  claim 21 .  
   
   
       29 . A method for treating proliferative diseases, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of a composition of  claim 23 .  
   
   
       30 . A method for treating cancer, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of a composition of  claim 23 .  
   
   
       31 . A method for treating proliferative diseases, comprising administering to mammalian species in need thereof, a therapeutically effective amount of a composition of  claim 24 .  
   
   
       32 . A method for treating cancer, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of a composition of  claim 24 .  
   
   
       33 . A compound selected from 
 3-Amino-4-fluoro-N-methoxybenzamide,    5-amino-2-methyl-4-fluoro-N-methoxybenzam ide,    5-amino-2-methyl-N-methoxycarboxamide,    5-amino-2,4-difluoro-N-methoxybenzamide,    or a pharmaceutically acceptable salt thereof.