6-Membered heterocyclic compounds useful for selective inhibition of the coagulation cascade

Abstract

The present invention relates to compounds, and prodrugs thereof, compositions and methods useful for preventing and treating thrombotic conditions in mammals. The compounds of the present invention, and prodrugs thereof, selectively inhibit certain proteases of the coagulation cascade.

1 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are each ring atoms defining a 6-membered heterocyclic ring;  
 X 1 , X 3 , and X 4  are independently carbon or nitrogen;  
 X 2 , X 5 , and X 6  are independently carbon, nitrogen, oxygen or sulfur where X 5  and X 6  are optionally substituted with a halogen;  
 provided no more than 4 of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are sp 2  hybridized;  
 L 1 , L 3  and L 4  are linkages through which Z 1 , Z 3 , and Z 4 , respectively, are covalently bonded to different ring atoms of the 6-membered heterocyclic ring defined by X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , wherein Z 1  is covalently bonded to X 1 , Z 3  is covalently bonded to X 3 , and Z 4  is covalently bonded to X 4 , each of L 1 , L 3  and L 4  independently being a covalent bond or comprising one or more atoms through which Z 1 , Z 3 , and Z 4  are covalently bonded to X 1 , X 3  and X 4 , respectively;  
 Z 1  is hydrocarbyl or substituted hydrocarbyl;  
 Z 2  is hydrogen, an electron pair, or a hydrogen bond acceptor covalently or datively bonded to X 2 ;  
 Z 3  comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine or a derivatized amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3  being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, hydroxy, haloalkyl, alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy; and  
 Z 4  comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4  being carbon, nitrogen, oxygen, or sulfur.  
 
   
   
       2 . The compound of  claim 1  wherein Z 2  is a hydrogen bond acceptor covalently or datively bonded to X 2 ; 
 Z 3  comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine or derivatized amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3  being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, hydroxy, haloalkyl, or alkyl; and    X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , L 1 , L 3 , L 4 , Z 1 , and Z 4  are as defined in  claim 1 .    
   
   
       3 . The compound of  claim 1  wherein X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are independently selected from carbon and nitrogen provided at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  is nitrogen.  
   
   
       4 . The compound of claims  1  or  2  wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and Z 2  are selected to provide a heterocyclic ring selected from the group consisting of piperidinone, dihydropyrimidinone, tetrahydropyrimidinone, dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone, tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, and piperazine.  
   
   
       5 . The compound of claims  1  or  2  wherein L 1  is covalently bonded directly to X 6  to form a fused ring.  
   
   
       6 . The compound of claims  1  or  2  wherein L 1  is X 9 NH, wherein X 9  is covalently bonded to Z 1 , and X 9  is a bond or (CH 2 ) m , wherein m is 1 to 5.  
   
   
       7 . The compound of  claim 6  wherein X 9  is a bond.  
   
   
       8 . The compound of claims  1  or  2  wherein L 3  is selected from the group consisting of a glycine derivative, an alanine derivative, an amino derivative, and a sulfonyl derivative.  
   
   
       9 . The compound of  claim 8  wherein L 3  is CH 2 CONHCH 2 .  
   
   
       10 . The compound of  claim 1  wherein L 4  is selected from the group consisting of a bond, methylene, ethylene, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.  
   
   
       11 . The compound of  claim 10  wherein L 4  is a bond.  
   
   
       12 . The compound of  claim 1  wherein Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       13 . The compound of claims  1  or  2  wherein the 5- or 6-membered heterocyclic or aromatic ring comprising Z 3  is substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group.  
   
   
       14 . The compound of  claim 1  wherein Z 3  comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;  
   
   
       15 . The compound of  claim 14  wherein Z 3  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 304  and R 306  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl; and  
 R 305  and R 307  are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy.  
 
   
   
       16 . The compound of  claim 2  wherein the 5- or 6-membered heterocyclic or aromatic ring comprising Z 3  is optionally substituted at any position with fluorine, methyl or hydroxy.  
   
   
       17 . The compound of  claim 1  wherein Z 4  comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z 4  being Z 40 , Z 41 , Z 42 , Z 44  and Z 45  when Z 4  is a 5-membered ring and Z 40 , Z 41 , Z 42 , Z 43 , Z 44  and Z 45  when Z 4  is a 6-membered ring, Z 40 , Z 41 , Z 42 , Z 43 , Z 44  and Z 45 , being carbon, nitrogen, oxygen or sulfur, Z 40  being the ring atom through which Z 4  is attached to the heterocyclic core ring, Z 41  and Z 45  each being in an alpha position relative to Z 40 , Z 42  and Z 44  each being in a beta position relative to Z 40 , Z 43  being in the gamma position relative to Z 40  when Z 4  is a 6-membered ring, Z 4  having a substituent R 42  covalently attached to Z 42 , and a second substituent bonded to one of Z 41 , Z 43 , Z 44 , or Z 45 , the substituent being R 41  when bonded to Z 41 , the substituent being R 43  when bonded to Z 43 , the substituent being R 44  when bonded to Z 44 , and the substituent being R 45  when bonded to Z 45 ; 
 R 42  is amino; and    R 41 , R 43 , R 44  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R 41 , R 43 , R 44  or R 45  is other than hydrogen.    
   
   
       18 . The compound of  claim 17  wherein R 44  is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl.  
   
   
       19 . The compound of  claim 1  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 9  is a bond or (CH 2 ) m  wherein m is 1 or 2; and  
 X 1 , X 2 , X 3  X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , and Z 4  are as defined in  claim 1 .  
 
   
   
       20 . The compound of  claim 19  wherein X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are independently selected from carbon and nitrogen, and at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  is nitrogen.  
   
   
       21 . The compound of claims  1  or  19  wherein X 2  is carbon and Z 2  is hydrogen, fluorine, oxygen, or sulfur.  
   
   
       22 . The compound of claims  1  or  19  wherein X 2  is nitrogen, oxygen or sulfur and Z 2  is hydrogen, an electron pair, or a hydrogen bond acceptor.  
   
   
       23 . The compound of claims  1  or  19  wherein X 2  is nitrogen and Z 2  is hydrogen, oxygen, amino, or acyl.  
   
   
       24 . The compound of claims  1  or  19  wherein X 3  is nitrogen.  
   
   
       25 . The compound of claims  1  or  19  wherein X 2  is carbon and X 3  is nitrogen.  
   
   
       26 . The compound of  claim 19  wherein X 9  is a bond.  
   
   
       27 . The compound of  claim 26  wherein Z 1  is C 1 -C 5  alkyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       28 . The compound of  claim 19  wherein Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       29 . The compound of  claim 19  wherein the 5- or 6-membered heterocyclic or aromatic ring comprising Z 3  is substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination, or any combination thereof, yields an amidine group.  
   
   
       30 . The compound of 19 wherein Z 3  is phenyl substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination, or any combination thereof, under physiological conditions yields an amidine group.  
   
   
       31 . The compound of  claim 19  wherein Z 3  comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy  
   
   
       32 . The compound of  claim 31  wherein Z 3  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 304  and R 306  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl; and  
 R 305  and R 307  are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy.  
 
   
   
       33 . The compound of claims  1  or  19  wherein Z 4  is a substituted, 6-membered, carbocyclic aromatic ring.  
   
   
       34 . The compound of  claim 19  wherein Z 4  is  
     
       
         
         
             
             
         
       
       wherein:  
       R 42  is amino;  
       R 44  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
       R 41 , R43 and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
     
   
   
       35 . The compound of  claim 34  wherein R 41 , R 43  and R 45  are independently hydrogen, halogen, alkoxy, or alkyl, optionally substituted with halogen or alkoxy and R 42  and R 44  are as defined in  claim 34 .  
   
   
       36 . The compound of  claim 34  wherein R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.  
   
   
       37 . The compound of  claim 36  wherein R 44  is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl, sulfonamido, or alkoxycarbonyl.  
   
   
       38 . The compound of  claim 37  wherein R 44  is sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.  
   
   
       39 . The compound of  claim 34  wherein R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl, and carboxamidoalkylaryl.  
   
   
       40 . The compound of  claim 39  wherein each of R 41 , R 43  and R 45  is hydrogen.  
   
   
       41 . The compound of  claim 36  wherein Z 41 , Z 43  or Z 45  is substituted with fluorine or chlorine.  
   
   
       42 . The compound of  claim 19  wherein Z 4  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 42  is amino;  
 R 43  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41 , R 44  and R 45  are independently hydrogen, halogen or alkoxy.  
 
   
   
       43 . The compound of  claim 19  wherein Z 4  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 42  is amino;  
 R 45  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41 , R 43  and R 44  are independently hydrogen, halogen or alkoxy.  
 
   
   
       44 . The compound of  claim 19  wherein Z 4  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 42  is amino;  
 R 41  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 43 , R 44  and R 45  are independently hydrogen, halogen or alkoxy.  
 
   
   
       45 . The compound of  claim 19  wherein Z 4  has the following structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 Z 40 , Z 41 , Z 42 , Z 44 , and Z 45  are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
 R 42  is amino;  
 R 44  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
 
   
   
       46 . The compound of  claim 45  wherein R 41  and R 45  are independently hydrogen, halogen, alkoxy, or alkyl, optionally substituted with halogen or alkoxy and R 42  and R 44  are as defined in  claim 45 .  
   
   
       47 . The compound of  claim 45  wherein R 44  is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl, sulfonamido, or alkoxycarbonyl.  
   
   
       48 . The compound of  claim 47  wherein R 44  is sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.  
   
   
       49 . The compound of claims  1  or  19  wherein X 9  is a bond, Z 1  is selected from the group consisting of cyclopropyl, isopropyl, cyclobutyl, isobutyl, sec-butyl, methyl, ethyl, and phenyl, and Z 3  is phenyl substituted with an amidine group.  
   
   
       50 . The compound of claims  1  or  19  wherein X 9  is a bond, Z 4  is a substituted, 6-membered, carbocyclic aromatic ring, Z 3  is phenyl substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination under physiological conditions yields an amidine group, and Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, sec-butyl, and phenyl.  
   
   
       51 . The compound of claims  1  or  19  wherein X 9  is a bond, Z 1  is selected from the group consisting of optionally substituted C 1 -C 6  cycloalkyl, C 1 -C 6  alkyl and phenyl, Z 3  is phenyl substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination under physiological conditions yields an amidine group, and Z 4  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 42  is amino;  
 R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41 , R 43  and R 45  are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
 
   
   
       52 . The compound of  claim 51  wherein R 44  is selected from the group consisting of hydroxy, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboxamidoalkyl, and carboxamidoalkylaryl.  
   
   
       53 . The compound of  claim 51  wherein each of R 41 , R 43  and R 45  is hydrogen.  
   
   
       54 . The compound of  claim 51  wherein R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine; and each of Z 41 , Z 43  and Z 45  is optionally substituted with fluorine or chlorine.  
   
   
       55 . The compound of  claim 54  wherein R 44  is sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.  
   
   
       56 . The compound of any of claims  1  or  19  wherein the 6-membered heterocyclic ring defined by X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and Z 2  is selected from the group consisting of piperidinone, dihydropyrimidinone, tetrahydropyrimidinone, tetrahydrotriazinone, piperidine, and piperazine.  
   
   
       57 . The compound of  claim 1  having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1 , X 4 , X 5  and X 6  are independently carbon or nitrogen;  
 Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted with fluorine, hydroxy, carboxy, or alkoxycarbonyl;  
 R 440  is C 1 -C 6  alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein said alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine; and  
 R 310  and R 311  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, alkoxy, and carboxy.  
 
   
   
       58 . The compound of  claim 1  having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1,  X 4 , X 5  and X 6  are independently carbon or nitrogen;  
 Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted with fluorine, hydroxy, carboxy, or alkoxycarbonyl;  
 R 440  is C 1 -C 6  alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein said alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine; and  
 R 310  and R 311  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, alkoxy, and carboxy.  
 
   
   
       59 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1 , X 2 , X 5 , and X 6  are members of a heterocyclic ring;  
 X 1 , X 2  and X 3  are independently carbon or nitrogen;  
 X 5  and X 6  are independently selected from the group consisting of nitrogen, oxygen, sulfur, carbon, C(F) and C(Br);  
 provided no more than 4 of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are sp 2  hybridized;  
 T 3 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, and substituted amino;  
 T 4  is selected from the group consisting of —Cl, —Br, —I, —S(CH 3 ), and —OSO 2 (CF 3 );  
 Z 1  is hydrocarbyl, or substituted hydrocarbyl; and  
 Z 2  is a hydrogen bond acceptor covalently or datively bonded to X 2 .  
 
   
   
       60 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1 , X 2 , X 5 , and X 6  are members of a heterocyclic ring;  
 X 1 , X 2  and X 3  are independently carbon or nitrogen;  
 X 5  and X 6  are independently selected from the group consisting of nitrogen, oxygen, sulfur, carbon, C(F) and C (Br);  
 provided no more than 4 of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are sp 2  hybridized;  
 Z 4  comprises hydrocarbyl, substituted hydrocarbyl or a 5 or 6 membered heterocyclic or carbocyclic ring, the ring atoms of the 5 or 6 membered heterocyclic or carboxylic ring of Z 4  being carbon, nitrogen, oxygen, or sulfur;  
 Z 1  is hydrocarbyl, or substituted hydrocarbyl; and  
 Z 2  is a hydrogen bond acceptor covalently or datively bonded to X 2 .  
 
   
   
       61 . The compound of  claim 1  having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 Z 1 , Z 2 , Z 3,  Z 4 , L 3 , X 1 , X 2 , X 3 , X 4 , and X 5  are as defined in  claim 1;   
 X 6  is carbon or nitrogen;  
 X 7  and X 8  are independently carbon, nitrogen, oxygen or sulfur;  
 R 70  and R 80  are independently selected from the group consisting of hydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, phenyl optionally substituted by hydroxy, amino, C 1 -C 8  alkyl, or halogen provided that R 70  is not present when X 7  is a bond and R 80  is not present when X 8  is a bond; or R 70  and R 80 , along with the ring atoms to which each is attached, form a 5- or 6-membered saturated ring; and  
 n is 0 to 2.  
 
   
   
       62 . The compound of  claim 61  having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Z 1 , Z 3 , Z 4 , R 70 , R 80  and n are as defined in  claim 61 .  
 
   
   
       63 . The compound of  claim 62  wherein X 7  and X 8  are carbon.  
   
   
       64 . The compound of  claim 62  wherein Z 4  is  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 42  is amino;  
 R 44  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41 , R 43  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
 
   
   
       65 . The compound of  claim 62  wherein Z 1  is methyl, ethyl, isopropyl, cyclopropyl, sec-butyl, tert-butyl, and cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       66 . The compound of  claim 62  wherein Z 3  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 304  and R 306  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy, and alkoxycarbonyl; and  
 R 305  and R 307  are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy, and carboxy.  
 
   
   
       67 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 Z 1  is selected from the group consisting of an optionally substituted C 2  to C 8  alkyl, optionally substituted C 3  to C 6  cycloalkyl and optionally substituted phenyl;  
 Z 3  comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine or a derivatized amidine group which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3  being carbon, sulfur, nitrogen, or oxygen;  
 Z 4  comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z 4  being Z 40 , Z 41 , Z 42 , Z 44  and Z 45  when Z 4  is a 5-membered ring and Z 40 , Z 41 , Z 42 , Z 43 , Z 44  and Z 45  when Z 4  is a 6-membered ring, Z 40 , Z 41 , Z 42 , Z 43 , Z 44  and Z 45 , being carbon, nitrogen, oxygen or sulfur, Z 40  being the ring atom through which Z 4  is attached to the heterocyclic core ring, Z 41  and Z 45 each being in an alpha position relative to Z 40 , Z 42  and Z 44  each being in a beta position relative to Z 40 , Z 43  being in the gamma position relative to Z 40  when Z 4  is a 6-membered ring, Z 4  having a substituent R 42  covalently attached to Z 42 , and a second substituent bonded to one of Z 41 , Z 43 , Z 44 , or Z 45 , the substituent being R41 when bonded to Z 41 , the substituent being R 43  when bonded to Z 43 , the substituent being R 44  when bonded to Z 44 , and the substituent being R 45  when bonded to Z 45 ;  
 R 42  is amino; and  
 R 41 , R 43 , R 44  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R 41 , R 43 , R 44  or R 45  is other than hydrogen.  
 
   
   
       68 . The compound of  claim 67  wherein Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       69 . The compound of  claim 68  wherein Z 1  is cyclopropyl or isopropyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.  
   
   
       70 . The compound of  claim 67  wherein Z 3  comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy.  
   
   
       71 . The compound of  claim 70  wherein Z 3  is  
     
       
         
         
             
             
         
       
     
     wherein 
 R 304  and R 306  are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl; and  
 R 305  and R 307  are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy.  
 
   
   
       72 . The compound of  claim 70  wherein the 5- or 6-membered heterocyclic or aromatic ring comprising Z 3  is substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination, or any combination thereof, yields an amidine group.  
   
   
       73 . The compound of  claim 67  wherein Z 4  has the following structure:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 42  is amino;  
 R 44  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
 R 41 , R 43  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
 
   
   
       74 . The compound of  claim 73  wherein R 41 , R 43  and R 45  are independently hydrogen, halogen, alkoxy, or alkyl, optionally substituted with halogen or alkoxy and R 42  and R 44  are as defined in  claim 73 .  
   
   
       75 . The compound of  claim 73  wherein R 44  is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl, sulfonamido, or alkoxycarbonyl.  
   
   
       76 . The compound of  claim 75  wherein R 44  is sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.  
   
   
       77 . The compound of  claim 67  wherein Z 4  has the following structure:  
     
       
         
         
             
             
         
       
       wherein Z 40 , Z 41 , Z 42 , Z 44 , and Z 45  are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
       R 42  is amino;  
       R 44  is hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and  
       R 41  and R 45  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.  
     
   
   
       78 . The compound of  claim 77  wherein R 41  and R 45  are independently hydrogen, halogen, alkoxy, or alkyl, optionally substituted with halogen or alkoxy and R 42  and R 44  are as defined in  claim 77 .  
   
   
       79 . The compound of  claim 77  wherein R 44  is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl, sulfonamido, or alkoxycarbonyl.  
   
   
       80 . The compound of  claim 79  wherein R 44  is sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.  
   
   
       81 . A composition for substantially inhibiting thrombotic conditions in blood comprising a compound of claims  1  or  19  and a pharmaceutically acceptable carrier.  
   
   
       82 . A method for substantially inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of the composition of  claim 81 .  
   
   
       83 . A method for substantially inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of the composition of  claim 81 .  
   
   
       84 . A method for substantially inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of the composition of  claim 81 .  
   
   
       85 . A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       86 . A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       87 . A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       88 . A method for treating or preventing thromboembolic stroke in mammals comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       89 . A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in mammals comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       90 . A method for treating or preventing unstable angina in mammals comprising administering to the mammal a therapeutically effective amount of the composition of  claim 81 .  
   
   
       91 . A method for substantially inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of the composition of  claim 81  with a therapeutically effective amount of fibrinogen receptor antagonist.  
   
   
       92 . The method of any of claims  85 - 91  wherein the mammal is a human.