Plasma Carboxypeptidase B Inhibitors

Abstract

Compounds of the following formula (I), for example: wherein R 1 , R 2 , R 3 , and R 4 are described herein, are useful as inhibitors of plasma carboxypeptidase B. Pharmaceutical compositions containing these compounds, methods of using these compounds as antithrombotic agents and processes for synthesizing these compounds are also described herein.

1 .- 25 . (canceled) 
     
     
         26 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, alkyl, alkenyl, aryl or aralkenyl; 
 R 2  is —P(O)(OR 5 ) 2 , —P(O)(OR 5 )R 6 , —P(O)(OR 5 )—R 7 —N(R 6 ) 2 , —P(O)(OR 5 )—R 7 —C(O)—R 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—S(O) 2 —R 9 , or —P(O)(OR 5 )—R 7 —N(R 5 )—C(S)—N(R 6 ) 2 ; 
 R 3  is tetrazole, —C(O)OR 6 , —C(O)O—R 7 —OC(O)R 5 , —S(O)OR 5 , —S(O) 2 OR 5 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )R 6 , or —B(OR 5 ) 2 ; 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, mercapto, alkylthio, phenyl, cycloalkyl, nitro, cyano, —OR 6 , —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
 or R 4  is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  or —N(R 5 )—C(O)—R 7 —N(R 6   2 ), or wherein a nitrogen atom in the N-heterocyclyl may be optionally substituted by —C(NR 5 )—N(R 5 ) 2 , —C(NR 5 )—R 6 , —C(O)—N(R 6 ) 2  or —C(O)—R 7 —N(R 6 ) 2 ; 
 each R 5  is independently hydrogen, alkyl or aralkyl; 
 each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
 each R 7  is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); 
 each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl; and 
 R 9  is —R 7 N(R 6 )C(O)OR 8 , haloalkyl, alkyl (optionally substituted by hydroxy, alkoxy, aralkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), alkenyl (optionally substituted by hydroxy, alkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aryl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkenyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), or N-heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ); 
 provided that when R 3  is —C(O)OH or when R 4  is a substituted aryl or substituted N-heterocyclyl, R 2  can not be —P(O)(OR 5 )—R 7 —N(H)—C(O)OR 8  or —P(O)(OR 5 )—R 7 —N(H)—C(O)—R 7 —N(R 5 )—C(O)OR 8 ; 
 as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
 
     
     
         27 . The compound of  claim 26  wherein:
 R 1  is hydrogen; 
 R 2  is —P(O)(OR 5 )R 6 , —P(O)(OR 5 )—R 7 —N(R 6 ) 2 , or —P(O)(OR 5 )—R 7 —N(R 5 )—C(S)—N(R 6 ) 2 ; 
 R 3  is tetrazole, —C(O)OR 6  or —C(O)O—R 7 —OC(O)R 5 ; 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
 each R 5  is independently hydrogen, alkyl or aralkyl; 
 each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
 each R 7  is a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); and 
 each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl. 
 
     
     
         28 . The compound of  claim 27  selected from the group consisting of the following:
 2-(3-guanidinophenyl)-2-((1-(2-phenylethyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-aminophenyl)-2-((phenyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; and 
 2-(3-guanidinophenyl)-2-((1-(benzylaminothiocarbonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid. 
 
     
     
         29 . The compound of  claim 26  wherein:
 R 1  is hydrogen; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—S(O) 2 —R 9 ; 
 R 3  is tetrazole, —C(O)OR 6  or —C(O)O—R 7 —OC(O)R 5 ; 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
 each R 5  is independently hydrogen, alkyl or aralkyl; 
 each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
 each R 7  is a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); 
 each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl; and 
 R 9  is alkyl (optionally substituted by hydroxy, alkoxy, aralkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), alkenyl (optionally substituted by hydroxy, alkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), or aralkenyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ). 
 
     
     
         30 . The compound of  claim 29  selected from the group consisting of the following:
 2-(3-guanidinophenyl)-2-((1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyloxy)ethanoic acid; and 
 2-(3-guanidinophenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid. 
 
     
     
         31 . The compound of  claim 26  wherein:
 R 1  is hydrogen; 
 R 2  is —P(O)(OR 5 ) 2 , —P(O)(OR 5 )R 6 , —P(O)(OR 5 )—R 7 —N(R 6 ) 2 , —P(O)(OR 5 )—R 7 —C(O)—R 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—S(O) 2 —R 9 , or —P(O)(OR 5 )—R 7 —N(R 5 )—C(S)—N(R 6 ) 2 ; 
 R 3  is tetrazole; 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
 or R 4  is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  or —N(R 5 )—C(O)—R 7 —N(R 6   2 ), or wherein a nitrogen atom in the N-heterocyclyl may be optionally substituted by —C(NR 5 )—N(R 5 ) 2 , —C(NR 5 )—R 6 , —C(O)—N(R 6 ) 2  or —C(O)—R 7 —N(R 6 ) 2 ; 
 each R 5  is independently hydrogen, alkyl or aralkyl; 
 each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
 each R 7  is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); 
 each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl; and 
 R 9  is —R 7 N(R 6 )C(O)OR 8 , haloalkyl, alkyl (optionally substituted by hydroxy, alkoxy, aralkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), alkenyl (optionally substituted by hydroxy, alkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aryl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkenyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), or N-heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ). 
 
     
     
         32 . The compound of  claim 31 , that is 2-methyl-1-[1-(3-guanidinophenyl)-1-tetrazolylmethoxy](hydroxy)phosphinoyl-propylcarbamic acid, benzyl ester. 
     
     
         33 . A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —CH 2 — or —O—; 
 R 1  is hydrogen, alkyl, alkenyl, aryl or aralkenyl; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)R 6 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8  or —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 , 
 R 3  is —C(O)OH; 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, mercapto, alkylthio, phenyl, cycloalkyl, nitro, cyano, —OR 6 , —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
 or R 4  is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  or —N(R 5 )—C(O)—R 7 —N(R 6   2 ), or wherein a nitrogen atom in the N-heterocyclyl may be optionally substituted by —C(NR 5 )—N(R 5 ) 2 , —C(NR 5 )—R 6 , —C(O)—N(R 6 ) 2  or —C(O)—R 7 —N(R 6 ) 2 ; 
 each R 5  is independently hydrogen, alkyl or aralkyl; 
 each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
 each R 7  is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); and 
 each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl; 
 as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
 
     
     
         34 . The compound of  claim 33  wherein:
 X is —O—; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8 ; and 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—N(R 6 )—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ). 
 
     
     
         35 . The compound of  claim 34  selected from the group consisting of the following:
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)aminoethyl)(hydroxy)-phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-(((benzyloxycarbonyl)aminomethyl)(hydroxy)-phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)aminohexyl)-(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-aminophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-3-methylbutyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(2-chloro-3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-1-phenylmethyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(2-fluoro-3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-1-cyclohexylmethyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(2-methyl-3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(amino)methylphenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(guanidinomethyl)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(1-iminoethylaminophenyl))-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(t-butoxycarbonylamino)methylphenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(ethoxycarbonylamino)methylphenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(isopropoxycarbonylamino)methylphenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-(2,2-dimethylpropylcarbonylamino)methylphenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; 
 2-(3-guanidinophenyl)-2-((1-(2-phenylethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid; and 
 2-(3-guanidinophenyl)-2-((1-(2-phenylethenylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid. 
 
     
     
         36 . The compound of  claim 33  wherein:
 X is —O—; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 ; and 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—N(R 6 )—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ). 
 
     
     
         37 . The compound of  claim 36  selected from the group consisting of the following:
 2-(3-guanidinophenyl)-2-[(1-(1-benzyloxycarbonylamino-2-(4-hydroxyphenyl)-ethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; 
 2-(3-guanidinophenyl)-2-[(1-(1-benzyloxycarbonylamino-2-phenylethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; 
 2-(2-fluoro-3-guanidinophenyl)-2-[(1-(1-benzyloxycarbonylamino-2-phenylethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; 
 2-(3-guanidinophenyl)-2-[(1-(1-phenylcarbonylamino-2-phenylethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; 
 2-(3-guanidinophenyl)-2-[(1-(1-ethoxycarbonylamino-2-phenylethylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; 
 2-(3-guanidinophenyl)-2-[(1-(1-benzyloxycarbonylamino-3-phenylpropylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid; and 
 2-(3-(amino)methylphenyl)-2-[(1-(1-benzyloxycarbonylamino-3-phenylpropylcarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy]ethanoic acid. 
 
     
     
         38 . The compound of  claim 33  wherein:
 X is —CH 2 —; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)R 6  or —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8 ; and 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—N(R 6 )—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ). 
 
     
     
         39 . The compound of  claim 38  selected from the group consisting of the following:
 2-(3-(amino)methylphenyl)-3-((1-(methylcarbonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid; 
 2-(3-(hydrazinocarbonyl)phenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyl)propanoic acid; 
 2-(3-guanidinophenyl)-3-((1-(benzyloxycarbonyl)aminoethyl)(hydroxy)phosphinoyl)-propanoic acid; 
 2-(3-guanidinophenyl)-3-((1-(benzyloxycarbonyl)amino-3-methylbutyl)(hydroxy)phosphinoyl)propanoic acid; 
 2-(3-guanidinophenyl)-3-(((benzyloxycarbonyl)aminomethyl)(hydroxy)phosphinoyl)-propanoic acid; 
 2-(3-guanidinophenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid; 
 2-(2-chloro-5-guanidinophenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyl)propanoic acid; 
 2-(3-(amino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid; and 
 2-(3-(amino)methylphenyl)-3-((1-(2-phenylethylcarbonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyl)propanoic acid. 
 
     
     
         40 . The compound of  claim 33  wherein:
 X is —CH 2 —; 
 R 2  is —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 ; and 
 R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—N(R 6 )—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ). 
 
     
     
         41 . The compound of  claim 40  selected from the group consisting of the following:
 2-(3-guanidinophenyl)-3-(((1-benzyloxycarbonylamino-2-phenylethyl)carbonylaminomethyl)(hydroxy)phosphinoyl)propanoic acid; 
 2-(3-guanidinophenyl)-3-(((1-benzyloxycarbonylamino-2-phenylethyl)carbonylaminomethyl)(hydroxy)phosphinoyl)propanoic acid. 
 
     
     
         42 . (canceled) 
     
     
         43 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II) according to  claim 26 , 
       as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (III) according to  claim 33 , 
       as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method of treating a disease-state characterized by thrombotic activity, which method comprises administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         R 1  is hydrogen, alkyl, alkenyl, aralkyl, or aralkenyl; 
         R 2  is —SH, —S—C(O)—R 8 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )R 6 , —P(O)(OR 5 )—R 7 —N(R 6 ) 2 , —P(O)(OR 5 )—R 7 —C(O)—R 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—C(O)—R 7 —N(R 5 )—C(O)OR 8 , —P(O)(OR 5 )—R 7 —N(R 5 )—S(O) 2 —R 9 , or —P(O)(OR 5 )—R 7 —N(R 5 )—C(S)—N(R 6 ) 2 ; 
         R 3  is tetrazole, —C(O)OR 6 , —C(O)O—R 7 —OC(O)R 5 , —S(O)OR 5 , —S(O) 2 OR 5 , —P(O)(OR 5 ) 2 , —P(O)(OR 5 )R 6 , or —B(OR 5 ) 2 ; 
         R 4  is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, mercapto, alkylthio, phenyl, cycloalkyl, nitro, cyano, —OR 6 , —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  and —N(R 5 )—C(O)—R 7 —N(R 6   2 ); 
         or R 4  is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R 6 ) 2 , —R 7 —N(R 6 ) 2 , —N(R 6 )—C(O)OR 8 , —R 7 —N(R 6 )—C(O)OR 8 , —N(R 6 )—C(O)—R 6 , —R 7 —N(R 6 )—C(O)—R 6 , —C(O)—N(R 6 ) 2 , —C(O)—R 7 —N(R 6 ) 2 , —N(R 5 )—C(NR 5 )—N(R 5 ) 2 , —N(R 5 )—C(O)—N(R 6 ) 2  or —N(R 5 )—C(O)—R 7 —N(R 6   2 ), or wherein a nitrogen atom in the N-heterocyclyl may be optionally substituted by —C(NR 5 )—N(R 5 ) 2 , —C(NR 5 )—R 6 , —C(O)—N(R 6 ) 2  or —C(O)—R 7 —N(R 6 ) 2 ; 
         each R 5  is independently hydrogen, alkyl or aralkyl; 
         each R 6  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl; 
         each R 7  is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R 6 ) 2 , —C(O)OR 6 , or —C(O)N(R 6 ) 2 ); 
         each R 8  is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl; and 
         R 9  is —R 7 N(R 6 )C(O)OR 8 , haloalkyl, alkyl (optionally substituted by hydroxy, alkoxy, aralkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), alkenyl (optionally substituted by hydroxy, alkoxy, haloalkoxy, cyano, nitro, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aryl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), aralkenyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ), or N-heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R 6 ) 2 , —C(O)OR 6 , —C(O)N(R 6 ) 2  or —N(R 6 )C(O)R 6 ); 
         provided that when R 3  is —C(O)OH or when R 4  is a substituted aryl or substituted N-heterocyclyl, R 2  can not be —P(O)(OR 5 )—R 7 —N(H)—C(O)OR 8  or —P(O)(OR 5 )—R 7 —N(H)—C(O)—R 7 —N(R 5 )—C(O)OR 8 ; 
         as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . A method of treating a disease-state characterized by thrombotic activity, which method comprises administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (II) according to  claim 26 , 
       as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A method of treating a disease-state characterized by thrombotic activity, which method comprises administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (III) according to  claim 33 , 
       as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.