Inhibitors of farnesyl protein transferase

Abstract

The present invention relates to inhibitors of ras farnesylation of Formula (1), wherein T is of Formula (1) or (2) or (3), A is aryl or heteroaryl; B is aryl or heteroaryl; X and Y represent hydrogen, or both X and Y can represent a single bond (so as to form a double bond); R 1 represents a group of Formula (II) or (III), the group of Formula (II) or Formula (III) (having L or D configuration at the chiral alpha carbon in the corresponding free amino acid); R 2 represents hydrogen, aryl or heteroaryl; Z represents a direct bond, methylene, ethylene, vinylene, oxy, —CH 2 —O— or —O—CH 2 —; and R 3 —R 4 , p and r 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 . An inhibitor of ras farnesylation of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein T is of the formula:  
       
         
           
           
               
               
           
         
         A is aryl or heteroaryl;  
         B is aryl or heteroaryl;  
         X and Y represent hydrogen, or both X and Y can represent a single bond (so as to form a double bond);  
         R 1  represents a group of the Formula II:  
         
           
             
             
                 
                 
             
           
         
         wherein R 7  is hydrogen or C 1-4 alkyl, R 8  is hydrogen or C 1-4 alkyl, R 9  is of the formula —(CH 2 ) q —R 11  wherein q is 0-4 and R 11  is C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, hydroxy, amino, 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 10  is hydroxy, heterocyclylC 1-4 alkoxy, heterocyclyloxy, C 5-7 cycloalkyC 1-4 alkoxy, C 1-4 alkoxy, amino, or —NH—SO 2 —R 13  wherein R 13  represents CF 3 , C 1-4 alkyl, aryl, heteroaryl, aryl C 1-4 alkyl or heteroarylC 1-4 alkyl or R 1  represents a lactone of Formula III:  
         
           
             
             
                 
                 
             
           
         
         wherein R 12  is hydrogen or C 1-4 alkyl;  
         the group of Formula II or III (having  L  or  D  configuration at the chiral alpha carbon in the corresponding free amino acid);  
         R 2  represents hydrogen, aryl or heteroaryl;  
         Z represents a direct bond, methylene, ethylene, vinylene, oxy, —CH 2 —O— or —O—CH 2 ;  
         R 3  represents hydrogen, C 1-4 alkyl, halogen, hydroxy, C 1-4 alkoxy, 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, carbamoyl, C 1-4 alkoxycarbonyl, thiol, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, aminosulfonyl, carbamoylC 1-4 alkyl,  N -(C 1-4 alkyl)carbamoylC 1-4 alkyl,  N -(diC 1-4 alkyl)carbamoyl-C 1-4 alkyl, hydroxyC 1-4 alkyl and C 1-4 alkoxyC 1-4 alkyl;  
         r is 0-3 and R 3  can have the same or different values when r is 2-3;  
         R 4  is hydrogen or C 1-4 alkyl; R 5  is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl; R 6  is hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, arylC 1-4 alkyl, sulfanylC 1-4 alkyl, aminoC 1-4 alkyl, or C 1-4 alkylaminoC 1-4 alkyl;  
         p is 0-3 and R 4  can have the same or different values when p is 2-3;  
         or a pharmaceutically acceptable salt, prodrug or solvate thereof.  
       
     
     
         2 . A compound according to  claim 1  wherein A is phenyl.  
     
     
         3 . A compound according to either  claim 1  or  claim 2  wherein T is of the formula (1) or (2) and R 5  and R 6  are as defined in  claim 1 .  
     
     
         4 . A compound according to any one of  claims 1  to  3  wherein B is thiazolyl or phenyl.  
     
     
         5 . A compound according to anyone of  claims 1  to  4  wherein >C(X)—CH(Y)— is >C═CH—.  
     
     
         6 . A compound according to to any one of  claims 1  to  5  wherein R 2  is phenyl, thienyl or pyridyl.  
     
     
         7 . A compound according to any one of  claims 1  to  6  wherein R 1  is of the formula II.  
     
     
         8 . A compound according to  claim 1  which is: 
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenylbenzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-propyl]-2-phenyl-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{4-[( Z )-3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl]-2-phenyl-benammido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl)]-benzamido}-4-carbamoylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfanyl- N -(trifluoromethylsulfonyl)-butanamide;  
 (2 S )-2-{3-[( Z )-2-(4-fluorophenyl)-4-(imidazol-1-yl)-but-1-enyl-]-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{3-[( E )-2-4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-hydroxybutyric acid;  
 (2 S )-2-{3-[( Z )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfonylbutyric acid;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenylbenzamido}-4-carbamoylbutyric acid;  
 (2 S )-2-{3-[( Z )-3-(imidazol-1-yl)-2-thiazol-2-yl)-prop-1-enyl]-benzamido}-4-carbamoylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{3-[( Z )-3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl]-benzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-methylsulfanylbutanoate;  
 tert-butyl (2 S )-2-{-3-[( E )-2-(4-fluorophenyl)-3-imidazol-1-yl)-prop-1-enyl]-benzamido}-4-carbamoylbutanoate;  
 (2 S )-2-{4-( Z )-3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl]-2-phenyl-benzamido}-4-carbamoylbutyric acid;  
 (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-4-(imidazol-1-yl)-but-1-enyl]-benzamido}-4-methylsulfanylbutyric acid;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl]-benzamido}-4-carbamoylbutyric acid;  
 methyl (2 S )-2-{-[( E )-2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenylbenzamido}-4-methylsulfanylbutanoate;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl )-3-(imizidazol-1-yl)prop-1-enyl]-2-phenylbenzamido}-4-methylsullanytbutyric acid;  
 methyl (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-phenyl-benzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
 t-butyl (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)-benzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)-benzamido}-4-methylsulfonylbutyric acid;  
 methyl (2 S )-2-{-4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfonylbutyrate;  
 t-butyl(2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfonylbutyrate;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)-benzamido}-4-methylsulfinylbutyric acid;  
 methyl (2 S )-4-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfinylbutyrate;  
 N-methylpiperidin-4-yl(2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
 1-(morpholin-4-yl)prop-2-yl-(2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)-benzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 S )-4-{[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
 tert-butyl(2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{4-[( Z )-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)-benzamido}-4-methylsulfonylbutyric acid;  
 methyl (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenylbenzamido}-4-methylsulfonylbutyrate;  
 tert-butyl (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfonylbutyrate;  
 N-methylpiperidin-4-yl(2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methysufanylbutyrate;  
 (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(thien-3-yl)benzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(thien-3-yl)benzamido}-4-methylsulfanylbutyrate;  
 methyl (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-2-(pyrid-3-yl)benzamido}-4-methylsulfanylbutyrate;  
 methyl (2 S )-2-{4-[(Z)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(pyrid-3-yl)benzamido}-4-methylsulfanylbutyric acid;  
 N-(3,5-dimethylisoxazol-4-ylsulfonyl (2 S )-2-{4-[(Z)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyramide;  
   N -(4-chlorophenylsulfonyl)(2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamnido}-4-methylsulfanylbutyramide;  
 (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyric acid;  
 methyl(2 S )-2-{4-[( E )-2-(4-fluorophenyl )-3-(imidazol-1-yl)prop-1-enyl]-2-4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
   N -benylsulfonyl(2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamnido}-4-methylsulfanylburtyramide;  
 (2 S )-2-{4-[( E )-2-4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}propanoic acid;  
 methyl (2 S )-2-{4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-propanoate;  
 (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-3-phenylbenzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 S )-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-enyl]-3-phenylbenzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{-4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyric acid;  
 methyl(2 S )-2-{-4-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate;  
 (2 S )-2-{5-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-2-(2-(4-fluorophenyl)ethyl)benzamido}-4-methylsulfanylbutyric acid;  
 methyl (2 R )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyrate;  
 methyl (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyrate;  
 methyl (2 S )-2-{3-[( R / S )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]benzamido}-3-(thien-2-yl)propanoate  
 methyl (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-6-aminohexanoate,  
 (2 S )-2-{-3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyramide;  
 trifluoromethanesulfonyl (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyramide;  
 methanesulfonyl (2 S )-2-{3-[( E )-2-(4-fluorophenyl)-3-imidazol-1-yl)prop-1-enyl]-benzamido}-4-methylsulfanylbutyramnide; or a pharmaceutically acceptable salt thereof.  
 
     
     
         9 . A pharmaceutical composition which comprises a compound according to any one of  claims 1  to  8  and a pharmaceutically-acceptable carrier.  
     
     
         10 . 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 of the Formula I or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A compound according to any one of  claims 1  to  8  for use as a medicament.  
     
     
         12 . A compound according to any one of  claims 1  to  8  for use in the preparation of a medicament for treatment of a disease mediated through farnesylation of mutant ras.  
     
     
         13 . A process for preparing a compound of the Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises: 
 reacting a compound of the Formula IV:                          with a compound of the Formula V   H 2 N—X 1   Formula V   under standard amide bond forming conditions, wherein:    A, B, T, Z, r, p and R 2  R 4 , are as defined in  claim 1  and X 1  is of the formula —C(R 8 )R 9 C(O)R 10  or 2-oxotetrahydrofuran-3-yl    wherein R 8 —R 10  are as defined in  claim 1  and wherein any functional group is protected, if necessary, and thereafter: 
 i. removing any protecting groups;  
 ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.