Substituted 5-membered polycyclic 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 comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being X 1 , X 2 , X 3 , X 4 , and X 5 , wherein X 1 , X 3 , and X 4 , are independently carbon or nitrogen and X 2  and X 5  are independently carbon, nitrogen, oxygen or sulfur;  
 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 5-membered heterocyclic or carbocyclic ring of X, 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 3  comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with 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, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, alkyl or hydroxy; 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: 
 each of X 1 , X 2 , X 3 , X 4 , and X 5  are as defined in  claim 1;     L 1  is —X 9 NH— wherein X 9  is covalently bonded directly to Z 1  and X 9  is a direct bond or —(CH 2 ) m — wherein m is 1 to 5;    L 3  is a glycine derivative;    L 4  is a direct bond;    Z 1  is selected from the group consisting of C 1 -C 8  alkyl, C 2 -C 8  alkenyl, and C 2 -C 8  alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;    Z 3  comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;    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 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 an optionally substituted 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.    
   
   
       3 : The compound of  claim 2  wherein: 
 X 9  is a direct bond;    L 3  is —CH 2 CONHCH 2 — and Z 3  is covalently bonded to the methylene bonded to the amine nitrogen of L 3 ;    Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;    Z 3  comprises a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;    Z 4  comprises a phenyl or thienyl ring having two substituents, R 42  and R 44 , and two ring atoms each of which is in the beta position relative to the ring atom of Z 4  through which Z 4  is covalently bonded to X, wherein one of R 42  and R 44  is covalently bonded to one of the beta positions and the other of R 42  and R 44  is covalently bonded to the other of the beta positions;    R 42  is amino; and    R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.    
   
   
       4 : The compound of  claim 1  wherein L 1  is —X 9 NH— wherein X 9  is covalently bonded directly to Z 1  and X 9  is a direct bond or —(CH 2 ) m — wherein m is 1 to 5.  
   
   
       5 : The compound of  claim 1  wherein L 3  is selected from the group consisting of a glycine derivative, an alanine derivative, an amino derivative, and a sulfonyl derivative.  
   
   
       6 : The compound of  claim 5  wherein L 3  is a glycine derivative.  
   
   
       7 : The compound of  claim 6  wherein L 3  is —CH 2 CONHCH 2 — and Z 3  is covalently bonded to the methylene bonded to the amine nitrogen of L 3 .  
   
   
       8 : The compound of  claim 1  wherein L 4  is selected from the group consisting of a direct bond, methylene, ethylene and an optionally substituted heteroatom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.  
   
   
       9 : The compound of  claim 8  wherein L 4  is a direct bond.  
   
   
       10 : The compound of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
     wherein: 
 X 2  and X 5  are as defined in  claim 1;   
 X 1 , X 3  and X 4  are independently carbon or nitrogen;  
 X 9  is a direct bond or —(CH 2 ) m — where m is 1 or 2; and  
 Z 1 , Z 3  and Z 4  are as defined in  claim 1 .  
 
   
   
       11 : The compound of  claim 10  wherein: 
 X 9  is selected from the group consisting of a direct bond, methylene, and ethylene;    Z 1  is selected from the group consisting of C 1 -C 8  alkyl, C 2 -C 8  alkenyl, and C 2 -C 8  alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;    Z 3  comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;    Z 4  comprises a phenyl or thienyl ring having two substituents, R 42  and R 44 , and two ring atoms each of which is in the beta position relative to the ring atom of Z 4  through which Z 4  is covalently bonded to X, wherein one of R 42  and R 44  is covalently bonded to one of said beta positions and the other of R 42  and R 44  is covalently bonded to the other of said beta positions;    R 42  is amino; and    R 44  is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.    
   
   
       12 : The compound of  claim 11  wherein: 
 X 9  is a direct bond;    Z 1  is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;    Z 3  is a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;    Z 4  is a substituted phenyl ring; and    R 44  is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p-fluorobenzylamide, cyclobutylamide, -fluorobenzylamide, 1-methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1-carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy.    
   
   
       13 - 16 . (canceled)  
   
   
       17 : The compound of  claim 1  wherein X 1 , X 2 , X 3 , X 4 , and X 5  are selected to provide a heterocyclic or carbocyclic ring selected from the group consisting of pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino, pyrazole, 1,3,4-triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2-amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine.  
   
   
       18 - 19 . (canceled)  
   
   
       20 : The compound of  claim 2  wherein X 9  is a direct bond.  
   
   
       21 : The compound of  claim 2  wherein X 9  is methylene or ethylene.  
   
   
       22 : The compound of  claim 1  wherein Z 1  is selected from the group consisting of C 1 -C 8  alkyl, C 2 -C 8  alkenyl, and C 2 -C 8  alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen.  
   
   
       23 - 25 . (canceled)  
   
   
       26 : The compound of  claim 1  wherein Z 3  comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy.  
   
   
       27 - 31 . (canceled)  
   
   
       32 : The compound of  claim 1  wherein Z 4  is a substituted, 6-membered, carbocyclic aromatic ring.  
   
   
       33 - 53 . (canceled)  
   
   
       54 : A method for substantially inhibiting thrombotic conditions in blood comprising adding to blood a composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       55 - 63 . (canceled)