Imidazole derivatives and their use as farnesyl protein transferase inhibitors

Abstract

The present invention relates to compound of formula (1), wherein Ar 1 represents (A), or (B), or (C); R 12 and R 13 are independently hydrogen or C 1-4 alkyl; Ar 2 is phenyl or heteroaryl; p is 0 or 1; Ar 3 is phenyl, pyridinyl, pyridazinyl, pyrirmidyl or pyrazynyl the ring being substituted on ring carbon atoms by R 2 and —(CH 2 ) n R 3 and wherein Ar 3 is attached to Ar 1 C(R 12 )R 13 CH(Ar 2 )O— by a ring carbon atoms; R 2 is a group of formula (2), or R 2 represents a lactone of formula (3), the group of formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; n is 0, 1 or 2; R 3 is phenyl or heteroaryl; and R 5 -R 9 , m and n are as defined in the specification; or a pharmaceutically acceptable salt, prodrug or solvate thereof. Processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them. A particular use is in cancer therapy.

1 . A compound of Formula (1):  
       
         
           
           
               
               
           
         
         wherein Ar 1  represents:  
         
           
             
             
                 
                 
             
           
         
         R 5  is hydrogen, C 1-4 alkyl, phenylC 1-4 alkyl;  
         R 6  is hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, dihaloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, sulfanylC 1-4 alkyl, aminoC 1-4 alkyl, N-(C 1-4 alkyl)aminoC 1-4 alkyl, N N-di(C 1-4 alkyl)aminoC 1-4 alkyl or phenylC 1-4 alkyl; m is 0, 1 or 2;  
         R 12  and R 13  are independently hydrogen or C 1-4  alkyl;  
         Ar 2  is phenyl or heteroaryl;  
         p is 0 or 1;  
         Ar 3  is phenyl, pyridinyl, pyridazinyl, pyrimidyl or pyrazinyl, the ring being substituted on ring carbon atoms by R 2  and —(CH 2 ) n R 3  and wherein Ar 3  is attached to Ar 1 C(R 12 )R 13 CH(Ar 2 )O— by a ring carbon atom;  
         R 2  is a group of the Formula (2):  
         
           
             
             
                 
                 
             
           
         
         wherein R 7  is hydrogen or C 1-4 alkyl, R 8  is —(CH 2 ) q —R 10  wherein q is 0-4 and R 10  is C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, hydroxy, C 1-4 alkoxy, carbamoyl, N-C 1-4 alkyl carbamoyl, N,N-(diC 1-4 alkyl)carbamoyl, C 1-4 alkyl, phenyl, thienyl, or C 1-4 alkanoylamino, R 9  is hydroxy, C 1-6 alkoxy, C 3-9 cycloalkyloxy, heterocyclyloxy, heterocyclylC 1-4 alkoxy or —NH—SO 2 —R 11  wherein R 11  represents, trifluoromethyl, C 1-4 alkyl, phenyl, heteroaryl, arylC 1-4 alkyl or heteroarylC 1-4 alkyl;  
         or R 2  represents a lactone of Formula (3):  
         
           
             
             
                 
                 
             
           
         
         the group of Formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid;  
         n is 0, 1 or 2;  
         R 3  is phenyl or heteroaryl;  
         phenyl and heteroaryl rings in R 3 , R 5 , R 6 , R 9 , R 11  and Ar 2  are independently optionally substituted on ring carbon atoms in by up to three substituents selected from C 1-4 alkyl, halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkanoyl, C 1-4 alkanoyloxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkanoylamino, nitro, cyano, carboxy, thiol, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkanesulphonamido, N-(C 1-4 alkylsulphonyl)-N-C 1-4 alkylamino, aminosulfonyl, N-(C 1-4 alkyl)aminosulfonyl, N,N-di(C 1-4 alkyl)aminosulfonyl, carbamoyl, N-(C 1-4 alkyl)carbamoyl, N,N-(diC 1-4 alkyl)carbamoyl, carbamoylC 1-4 alkyl, N-(C 1-4 alkyl)carbamoylC 1-4 alkyl, N,N-(diC 1-4 alkyl)carbamoylC 1-4 alkyl, hydroxyC 1-4 alkyl and C 1-4 alkoxyC 1-4 alkyl and on ring NH groups (replacing hydrogen) by C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkylsulfonyl, haloC 1-4 alkyl, difluoromethyl or trifluoromethyl;  
         or a pharmaceutically-acceptable salt, prodrug or solvate thereof.  
       
     
     
         2 . A compound according to  claim 1  wherein Ar 1  is of the formula (A) or (B):  
       
         
           
           
               
               
           
         
       
       wherein R 5  is hydrogen or methyl; R 6  is hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, fluoroC 1-4 alkyl, difluoroC 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkoxyC 1-4 alkyl and m is as defined in  claim 1 .  
     
     
         3 . A compound according to either  claim 1  or  claim 2  wherein Ar 2  is phenyl, thiazolyl, pyridyl, triazolyl, pyrimidyl, pyrazinyl or pyridazinyl optionally substituted on ring carbon atoms by C 1-4 alkyl, halo, nitro, cyano or C 1-4 alkoxyC 1-4 alkyl.  
     
     
         4 . A compound according to either  claim 1  or  claim 2  wherein Ar 2  is phenyl or thiazolyl optionally substituted on ring carbon atoms by C 1-4 alkyl, halo, nitro, cyano or C 1-4 alkoxyC 1-4 alkyl.  
     
     
         5 . A compound according to any one of  claims 1  to  4  wherein Ar 3  is phenyl or pyridyl, the ring being substituted on ring carbon atoms by R 2  and —(CH 2 ) n R 3  and wherein Ar 3  is attached to Ar 1 C(R 12 )R 13 CH(Ar 2 )O— by a ring carbon atom.  
     
     
         6 . A compound according to  claim 5  wherein, when n is 0, the phenyl or pyridyl ring is substituted by R 2  in the 4-position and —CH 2 ) n R 3  in the 3- or 5-position and when n is 1 or 2, the phenyl or pyridyl ring is substituted by R 2  in the 3- or 5-position and —CH 2 ) n R 3  in the 4-position and wherein the positions indicated are relative to the point of attachment of Ar 3  to —(CH 2 ) p —.  
     
     
         7 . A compound according to any one of  claims 1  to  6  wherein R 2  is of the formula (2):  
       
         
           
           
               
               
           
         
       
       wherein R 7  is hydrogen or methyl; 
 R 8  —(CH 2 ) q —R 10  wherein q is 1 or 2; R 10  is C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, hydroxy or C 1-4 alkoxy;  
 R 9  is hydroxy, C 1-4 alkoxy, C 3-9 cycloalkyloxy, heterocyclyloxy or heterocyclylC 1-4 alkoxy or of the formula —NHSO 2 R 11  wherein R 11  is phenyl; wherein NH groups in heterocyclic groups in R 9  are optionally substituted by methyl, ethyl, acetyl, propionyl, fluoromethyl, difluoromethyl or trifluoromethyl and ring carbon atoms in phenyl or heteroaryl groups in R 11  are optionally substituted by methyl, halo, C 1-4 alkanoyl, nitro, cyano, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, C 1-4 alkylcarbamoyl or diC 1-4 alkylcarbamoyl;  
 or wherein R 2  is of the formula (3) as defined in  claim 1 .  
 
     
     
         8 . A compound according to any one of  claims 1  to  7  wherein R 3  is phenyl, pyridyl or thiazolyl and ring carbon atoms in R 3  are optionally substituted by C 1-4 alkyl, halo, C 1-4 alkoxy, nitro, cyano or C 1-4 alkoxyC 1-4 alkyl and a ring NH group in a heteroaryl group in R 3  is optionally subtituted by C 1-4 alkyl.  
     
     
         9 . A compound according to any one of  claims 1  to  8  wherein R 11  and R 12  are independently hydrogen or methyl.  
     
     
         10 . A compound according to  claim 1  which is: 
 methyl (2S)-2-{2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethyl]benzylamino]-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethylbenzoylamino}-4-methylsulfanylbutyrate;  
 methyl (2S)-2-(2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(thiazol-2-yl)ethoxymethyl]benzoylamino}-4-methylsulfanyl butyric acid;  
 (2S)-2-{-2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(thiazol-2-yl)ethoxymethyl]benzoylamino}-4-methylsulfanyl butyric acid;  
 methyl (2S)-2-{2-(4-fluorophenethyl)-5-[2-(imidazol-1-yl)-1-(4-fluorophenyl)-ethoxymethyl]benzoylamino}-4-methylsulfanyl butyrate;  
 (2S)-2-{2-(4-fluorophenethyl)-5-{2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyric acid;  
 methyl (2S)-2-{2-(4-(fluorobenzyl)-5-[1-(4-fluorophenyl)2-(imidazol-1-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{2-(4-fluorobenzyl)-5-[1-(4-fluorophenyl)-2-imidazol-1-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyric acid;  
 methyl (2S)-2-{2-phenyl4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate; or  
 (2S)-2-{2-phenyl-4-[1-(4-fluorophenyl)2-imidazol-1-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyric acid;  
 methyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethyl]benzoylamino}-2-methyl-4-methylsulfanylbutyrate;  
 (2S)-2-{2-(4-fluorophenyl)[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethyl]benzoylamino}-2-methyl4-methylsulfanylbuyric acid;  
 N-(4-chlorobenzenesulfonyl)-(2S)-2-{2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyramide;  
 2-(morpholinomethyl)prop-2-yl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxymethylbenzoylamino}-4-methylsulfanylbutyrate;  
 methyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 cyclopentyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyrate;  
 2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyric acid;  
 methyl (2S)-2-{5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyrate;  
 (2S)-2-{5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyric acid;  
 methyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{5-[1-(4-fluorophenyl)2-(2-methylimidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenyl)benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenyl)benzoylamino)-4-methylsulfonylbutyrate;  
 2-{4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenyl)benzoylamino}-4-methylsulfonylbutyric acid;  
 methyl (2S)-2-{5-[2-(4-methylimidazol-1-yl)i -(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{5-(2-(4-methylimidazol-1-yl)i-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyrate;  
 (2S)-2-{5-[2-(4-methylimidazol-1-yl)- -(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfonylbutyrate;  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfonylbutyrate;  
 (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]pyrid-3-oylamino}-4-methylsulfanylbutyric acid;  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]pyrid-3-oylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate;  
 cyclopentyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate;  
 (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino)-4-methylsulfanylbutyric acid;  
 (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfonylbutyric-acid;  
 tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate;  
 tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfonylbutyrate;  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate; and  
 tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfonylbutyrate;  
 or a pharmaceutically-acceptable salt thereof.  
 
     
     
         11 . A pharmaceutical composition which comprises a compound according to any one of  claims 1  to  10  and a pharmaceutically-acceptable carrier.  
     
     
         12 . A method of treating a disease or medical condition mediated through farnesylation of ras which comprises administering to a warm-blooded animal an effective amount of a compound according to any one of  claims 1  to  10 .  
     
     
         13 . A compound according to any one of  claims 1  to  10  for use as a medicament.  
     
     
         14 . A compound according to any one of  claims 1  to  10  for use in the preparation of a medicament for treatment of a disease mediated through farnesylation of mutant ras.  
     
     
         15 . A process for preparing a compound of the Formula I or a pharmaceutically acceptable salt, prodrug or solvate thereof, which process comprises: 
 deprotecting a compound of the formula (4):                          wherein Ar 1 ′ is Ar 1  as defined in  claim 1  or protected Ar 1 , Ar 2 ′ is Ar 2  as defined in  claim 1  or protected Ar 2  and Ar 3 ′ is Ar 3  as defined in  claim 1  or protected Ar 3 ; wherein at least one protecting group is present; and thereafter if necessary:    (i) forming a pharmaceutically-acceptable salt,    (ii) forming a prodrug, and/or    (iii) forming a solvate.    
     
     
         16 . A process for preparing a compound of the Formula I or a pharmaceutically-acceptable salt, prodrug or solvate thereof, which process comprises: 
 (i) reacting a compound of the formula (5) with a compound of the formula (6):                          or (iii) converting one value of R 9  in R 2  into another value of R 9 ;    or (iii) reacting a compound in which R 2  in Ar 3 ′ is carboxy with a compound of the formula 7):                          wherein p, R 7  and R 8  are as defined in  claim 1 , Ar 1 ′, Ar 2 ′, Ar 3 ′, R 7  and R 8  are as defined in  claim 15 , R 21  is R 9  as defined in claim I or a carboxy protecting group and when p is 1, L is a leaving group, and when p is 0, L is hydroxy; and thereafter if necessary:    (i) removing any protecting groups;    (ii) forming a pharmaceutically-acceptable salt, prodrug or solvate thereof.