Pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

Abstract

This invention relates to pyrrozolotriazine compounds, pharmaceutical compositions containing such compounds and the use of those compounds and compositions for the prevention and/or treatment of hyper-proliferative disorders and diseases associated with angiogenesis.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of aryl, benzyl, and heteroaryl,
 wherein aryl and heteroaryl can be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of
 (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 heterocyclyl, or 0 or 1 (C 1 -C 3 )alkoxy, wherein
 (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino, 
 
 (C 1 -C 3 )alkoxy, wherein (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino, 
 halogen, 
 trifluoromethyl, 
 trifluoromethoxy, 
 (C 3 -C 6 )cycloalkyl, 
 phenyl optionally substituted with 1 or 2 halogen, 
 
 
       
       
         
           
           
               
               
           
         
       
       wherein X is CH 2 , O, S or NR 1-1 , and wherein R 1-1  is hydrogen or (C 1 -C 6 )alkyl,
     nitro,   cyano,   (C 1 -C 3 )alkylthio,   trifluoromethylthio,   (C 1 -C 3 )alkylcarbonyl,   (C 1 -C 6 )alkoxycarbonyl, and   phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, and halogen,     and   wherein benzyl can be substituted with 0, 1, 2 or 3 groups selected from halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy;   
 R 2  is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy; 
 R 3  is selected from the group consisting of
 carboxyl, 
 formyl, 
 (C 1 -C 6 )alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C 1 -C 6 )alkoxy, and heterocycle, 
 (C 3 -C 6 )cycloalkylcarbonyl, 
 (C 1 -C 6 )alkoxycarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from amino, and (C 1 -C 6 )alkoxycarbonyl, 
 aminocarbonyl, 
 (C 1 -C 6 )alkylamino carbonyl, wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C 3 -C 6 )cycloalkyl, halogen, amino, (C 1 -C 6 )alkylamino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino, and methylsulfonyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with or 0 or 1 heterocyclyl, wherein heterocyclyl can optionally be substituted with 0 or 1 (C 1 -C 6 )alkyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy, 
 heterocyclylcarbonyl optionally substituted with 0 or 1 amino, (C 1 -C 6 )alkylamino, cycloalkyl, or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can optionally be substituted with 0 or 1 amino or (C 1 -C 6 )alkylamino, 
 (C 1 -C 6 )alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of 
 
 a) hydroxyl, 
 b) amino, 
 c) (C 1 -C 6 )alkylamino, wherein (C 1 -C 6 )alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl, 
 d) arylamino, wherein arylamino can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and trifluoromethyl, 
 e) heterocyclyl, wherein heterocyclyl can be substituted with 0, 1 or 2 (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl, 
 f) imidazolyl, 
 g) pyridylamino, 
 h) (C 1 -C 3 )alkoxy optionally substituted by fluoro up to the perfluoro level, or by heterocycle, wherein heterocycle can optionally be substituted by 0 or 1 (C 1 -C 6 )alkyl, 
 i) (C 1 -C 3 )alkoxy(C 2 -C 3 )alkoxy, and 
 j) (C 1 -C 6 )alkoxycarbonyl, 
 k) (C 3 -C 6 )cycloalkyl, 
 l) cyano,
 (C 1 -C 6 )alkoxy optionally substituted with 1, 2 or 3 substituents 
 
 independently selected from the group consisting of amino, (C 1 -C 6 )alkylamino, and heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2 or 3 (C 1 -C 6 )alkyl,
 (C 3 -C 6 )cycloalkylaminocarbonyl optionally substituted with (C 1 -C 3 )alkyl, 
 cyano, 
 heteroaryl, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of 
 
 q) (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be substituted with 0, 1, 2, or 3 halogen, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy, 
 r) halogen, 
 s) amino, 
 t) alkylamino, 
 u) (C 1 -C 6 )alkoxycarbonyl, and 
 v) (C 3 -C 6 )cycloalkyl,
 heteroarylcarbonyl, which can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl and halogen, 
 heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxycarbonyl; and 
 
 R 4  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and halogen; 
 or a pharmaceutically acceptable salt thereof.