Imidazole-2-Carboxamide Derivatives as Raf Kinase Inhibitors

Abstract

The present invention relates to compounds of formula (I): pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, use as Raf Kinase Inhibitors and treatment methods for neurotraumatic diseases and cancer.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, CH 2 , S or NH, or the moiety X—R 1  is hydrogen;  
 Y 1  and Y 2  independently represent CH or N;  
 R 1  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl, any of which except hydrogen may be optionally substituted;  
 R 2  and R 3  independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, or heterocyclylC 1-6 alkyl, or R 2  and R 3  together with the nitrogen atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring;  
 Ar is a group of the formula a) or b):  
                     
 wherein A represents a fused 5- to 7-membered ring optionally containing up to two heteroatoms selected from O, S and NR 5 , wherein R 5  is hydrogen or C 1-6 alkyl, which ring is optionally substituted by up to 2 substituents selected from halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy or keto;  
 R a  and R 4  are independently selected from hydrogen, halogen, C 1-6 alkyl, aryl, arylC 1-6 alkyl, C 1-16 alkoxy, C 1-16 alkoxyC 1-6 alkyl, haloC 1-16 alkyl, arylC 1-6 alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N—C 1-6 alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N—C 1-16 alkylcarbamoyl, C 1-16 alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, C 1-16 alkylguanidino, amidino, C 1-16 alkylamidino, sulphonylamino, aminosulphonyl, C 1-6 alkylthio, C 1-6 alkyl sulphinyl or C 1-6 alkylsulphonyl; and  
 one of X 1  and X 2  is N and the other is NR 6 , wherein R 6  is hydrogen, C 1-6 alkyl, or arylC 1-6 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound of  claim 1  wherein X—R 1  is hydrogen.  
     
     
         3 . A compound of  claim 1  wherein A represents a fused 5 membered ring optionally containing up to two heteroatoms selected from O, S and NR 5 , wherein R 5  is hydrogen or C 1-6 alkyl, which ring is optionally substituted by up to 2 substituents selected from halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy or keto.  
     
     
         4 . A compound of  claim 1  wherein R 2  and R 3  independently represent hydrogen, C 1-6 alkyl, aryl, heteroarylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, any of which, except hydrogen, is optionally substituted; or R 2  and R 3  together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered monocyclic or bicyclic ring.  
     
     
         5 . A compound selected from: 
 4-(1-Hydroxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;    5-(2-{1-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-methanoyl}-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime;    4-(1-Hydroxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-carboxylic acid methyl-(1-methyl-piperidin-4-yl)-amide;    5-{2-[1-(4-Cyclohexyl-piperazin-1-yl)-methanoyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one oxime;    5-[2-(1-[1,4′]-Bipiperidinyl-1′-yl-methanoyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime;    5-(2-{1-[4-(4-Chloro-benzyl)-piperazin-1-yl]-methanoyl}-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime;    4-(1-Hydroxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-carboxylic acid methyl-(3-dimethylaminomethyl-phenyl)-amide;    4-(1-Hydroxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide; or    a pharmaceutically acceptable salt thereof.    
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         7 . A compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein X, Y 1 , Y 2 , R 1 , R a , Ar, X 1  and X 2  are as defined for formula (I) of  claim 1  and R is hydrogen, C 1-6 alkyl or arylC 1-6 alkyl.  
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 5  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         10 . A method for prophylactic or therapeutic treatment of a disease state exacerbated or caused by a neurotraumatic event in a human or other mammal, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A method for prophylactic or therapeutic treatment of cancer in a human or other mammal, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A method for prophylactic or therapeutic treatment of a disease state exacerbated or caused by a neurotraumatic event in a human or other mammal, which comprises administering a therapeutically effective amount of a compound of  claim 5  or a pharmaceutically acceptable salt thereof.  
     
     
         13 . A method for prophylactic or therapeutic treatment of cancer in a human or other mammal, which comprises administering a therapeutically effective amount of compound of  claim 5  or a pharmaceutically acceptable salt thereof.