Imidazole derivatives as raf kinase inhibitors

Abstract

Novel compounds and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 X is O, CH 2 , CO, S or NH, or the moiety X—R 1  is hydrogen;  
 Y 1  and Y 2  are independently N or CH;  
 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 may be optionally substituted; in addition when X is CH 2  then R 1  may be hydroxy or C 1-6 alkoxy which may be optionally substituted;  
 R 2  is a substituted C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl aryl, wherein the substituent is selected from aryl, heteroaryl, heterocyclyl, C 1-6 alkoxy, C 1-6 alkylthio, arylC 1-6 alkoxy, aryl C 1-6 alkylthio, amino, mono- or di-C 1-6 alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amide, ureido, guanidino, C 1-6 alkylguanidino, amidino, C 1-6 alkylamidino, C 1-6 acyloxy, hydroxy, and halogen or any combinations thereof but must include a heterocyclyl or heteroaryl group, or R 2  is a heterocyclyl, or heteroaryl, either of which may be optionally substituted;  
 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 3  and R 4  are independently selected from hydrogen, halogen, C 1-6 alkyl, aryl, aryl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 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 1-6 alkylcarbamoyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, C 1-6 alkylguanidino, amidino, C 1-6 alkylamidino, sulphonylamino, aminosulphonyl, C 1-6 alkylthio, C 1-6 alkylsulphinyl or C 1-6 alkylsulphonyl;  
 R 15  is O or N—OH;  
 one of X 1  and X 2  is N and the other is NR 6  wherein R 6  is hydrogen or C 1-6 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound of formula (I) according to  claim 1  wherein X is NH or X—R 1  is hydrogen.  
   
   
       3 . A compound of formula (I) according to  claim 1  wherein R 15  is N—OH  
   
   
       4 . A compound of formula (I) according to  claim 1  wherein R 2  is 
 i) —CR 7 R 8 —CH 2 -Z, —CH 2 -Z and heterocyclyl, wherein R 7  and R 8  independently represent hydrogen or optionally substituted C 1-6 alkyl, or R 7  and R 8  together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl or C 5-7 cycloalkenyl ring; and Z is NR 9 R 10 , NR 9 C(Q)NR 9 R 10 , NR 9 COOR 10 , NR 9 SO 2 R 10 , NR 9 C(Q)R 10  or heterocyclyl wherein R 9  and R 10  are independently selected from heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl and heteroarylC 1-6 alkyl, any of which may be optionally substituted or together form a heterocyclic group, when present as NR 9 R 10 ; Q is O or S, preferably O; and when R 2  or Z is heterocyclyl, e.g. piperidyl, piperazine or morpholine, the heterocyclyl group is optionally substituted; or    ii) optionally substituted pyridyl, pyrimidyl and furanyl.    
   
   
       5 . A compound of formula (I) according to  claim 1  wherein R 3  is hydrogen.  
   
   
       6 . A compound of formula (I) according to  claim 1  wherein R 4  is hydrogen.  
   
   
       7 . A compound of formula (I) according to  claim 1  wherein R 6  is hydrogen.  
   
   
       8 . A compound of formula (I) according to  claim 1  which is selected from: 
 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid {2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide;    5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime;    5-[2-(1-{1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-mathanoyl}-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime;    5-[2-(1-Furan-3-ylmethyl-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime;    5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one oxime;    1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid [4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide;    5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime    5-(2-Morpholin-4-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime;    5-(5-Pyridin-4-yl-2-(2,3,5,6-tetrahydro-[1,2′]bipyrazin-4-ylmethyl)-1H-imidazol-4-yl]-indan-1-one oxime;    5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime;    5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl 1-indan-1-one;    5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}1-indan-1-one oxime;    5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one;    5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one oxime;    and pharmaceutically acceptable salts thereof.    
   
   
       9 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       10 . (canceled)  
   
   
       11 . (canceled)  
   
   
       12 . (canceled)  
   
   
       13 . A method of therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a neurotraumatic event which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
   
   
       14 . A method of therapeutic treatment of ischemic stroke which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
   
   
       15 . A method of therapeutic treatment of cancer which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
   
   
       16 . A method of therapeutic treatment of chronic neurogeneration, pain, migraine and cardiac hypertrophy which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.  
   
   
       17 . A method of therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a neurotraumatic event which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (Ia)  
     
       
         
         
             
             
         
       
     
     wherein 
 X is O, CH 2 , CO, S or NH, or the moiety X—R 1  is hydrogen;  
 Y 1  and Y 2  are CH;  
 R 1  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, or arylC 1-6 alkyl, any of which may be optionally substituted; in addition, when X is CH 2  then R 1  may be hydroxy or C 1-6 alkoxy which may be optionally substituted;  
 R 2  is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, or aryl, any of which may be optionally substituted;  
 Ar is a group of the formula a) or b):  
                     
  wherein A represents a fused 5-membered carbocyclic ring which ring is optionally substituted by up to 2 substituents selected from halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy and keto;  
 R 3  and R 4  are independently selected from hydrogen, halogen, C 1-6 alkyl, aryl, aryl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 alkyl, arylC 1-6 alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N—C 1-6 alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carbamoyl, mono- and di-N—C 1-6 alkylcarbamoyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, C 1-6 alkylguanidino, amidino, C 1-6 alkylamidino, sulphonylamino, aminosulphonyl, C 1-6 alkylthio, C 1-6 alkylsulphinyl and C 1-6 alkylsulphonyl;  
 R 15  is O or N—OH;  
 one of X 1  and X 2  is N and the other is NR 6  wherein R 6  is hydrogen or C 1-6 alkyl;  
 wherein the optional substituents for alkyl, alkoxy, alkenyl, cycloalkyl and cycloalkenyl groups are selected from aryl, C 1-6 alkoxy, C 1-6 alkylthio, arylC 1-6 alkoxy, aryl C 1-6 alkylthio, amino, mono- or di-C 1-6 alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy, amide, ureido, guanidino, C 1-6 alkylguanidino, amidino, C 1-6 alkylamidino, C 1-6 acyloxy, hydroxy, halogen, cyano and any combinations thereof;  
 wherein the aryl groups may be optionally substituted by a substituent selected from halogen, hydroxy, C 1-6 alkyl, aryl, arylC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 alkyl, arylC 1-6 alkoxy, nitro, cyano, azido, amino, mono- and di-N—C 1-6 alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carbamoyl, mono- and di-N—C 1-6 alkylcarbamoyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, C 1-6 alkylguanidino, amidino, C 1-6 alkylamidino, urea, carbamate, acyl, sulphonylamino, aminosulphonyl, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, and any combination thereof;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       18 . A method of therapeutic treatment of ischemic stroke which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (Ia) as defined in  claim 17  or a pharmaceutically acceptable salt thereof.  
   
   
       19 . A method of therapeutic treatment of cancer which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (Ia) as defined in  claim 17  or a pharmaceutically acceptable salt thereof.  
   
   
       20 . A method of therapeutic treatment of chronic neurogeneration, pain, migraine and cardiac hypertrophy which method comprises administering to a human or other mammal a therapeutically effective amount of a compound of formula (Ia) as defined in  claim 17  or a pharmaceutically acceptable salt thereof.