Serine Protease Inhibitors

Abstract

Compounds having the structure shown below are useful to inhibit serine protease enzymes, such as TF/factor VIIa, factor Xa, thrombin and kallikrein. These compounds may be used in methods of preventing and/or treating clotting disorders.

1 . A compound having the structure shown below:  
       
         
           
           
               
               
           
         
       
       where 
 A and B are independently CH, CR 3  or N;  
 X is C═O or (CR 4a R 4b ) m  where m=1 or 2;  
 Y is S(O) n —R 1  where n=1 or 2, S(O) n —NR 2 R 2  where n=1 or 2, S(O) n —OR 2  where n=1 or 2, C(O)R 1 , C(S)R 1 , C(O)—OR 1 , C(O)—NR 2 R 2 ;  
 N 1  and N 2  are nitrogen atoms;  
 Q and R 1  are independently 
 (1) optionally substituted alkyl having 1 to about 10 carbon atoms;  
 (2) optionally substituted aralkyl containing an aryl moiety having 6 to about 10 ring carbon atoms bonded to an alkyl moiety containing 1 to about 10 carbon atoms;  
 (3) optionally substituted heteroaralkyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;  
 (4) optionally substituted carbocycloalkyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;  
 (5) optionally substituted heterocycloalkyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms;  
 (6) optionally substituted alkenyl having 2 to about 10 carbon atoms;  
 (7) optionally substituted aralkenyl containing an aryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;  
 (8) optionally substituted heteroaralkenyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;  
 (9) optionally substituted carbocycloalkenyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;  
 (10) optionally substituted heterocycloalkenyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;  
 (11) optionally substituted aryl having 6 to about 10 ring carbon atoms;  
 (12) optionally substituted heteroaryl having 5 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur;  
 (13) optionally substituted carbocyclyl having 3 to about 10 ring carbon atoms;  
 (14) optionally substituted heterocyclyl having 3 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur;  
 
 each R 2  is, independently, H, alkyl, substituted alkyl, C(O)R 7  or C(NH)R 7 , or N 1 R 2  and N 2 R 2  are together form the group N 1 —CO—N 2 ;  
 R 3  is H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen or OH;  
 R 4a and R 5  are, independently, a member selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxyalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted aryl, alkyl-OR 7 , alkyl-NR 7 R 8 , alkyl-OC(O)R 7 , alkyl-C(O)OR 7 , alkyl-C(O)R 7 , OC(O)R 7 , C(O)OR 7 , C(O)R 7  and members in which the alkyl, R 7  or R 8  is substituted with 1-3 F, Cl, Br, I, OR 7 , SR 7 , NR 7 R 8 , OC(OR 7 ), C(O)OR 7 , C(O)R 7 , C(O)NR 7 R 8 , NHC(NH)NH 2 , PO 3 , unsubstituted or substituted indolyl or unsubstituted or substituted imidazolyl groups;  
 R 4b is H, alkyl, or substituted alkyl;  
 R 6  is selected from the group selected from H, C 1 -C 6  alkyl, C 1 -C 6  alkyl-OR 7 , C 1 -C 6  alkyl-N R 7 R 8 , C 1 -C 6  haloalkyl, halo, cyano, OR 7 , SR 7 , NR 7 R 8 , C(O)OR 7 , C(O)R 7  and OC(O)R 7 ;  
 R 7  and R 8  are independently H or C 1 -C 6  alkyl; and acid and base addition salts and prodrugs thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein Q is phenyl optionally substituted with 1-5, preferably 2-4, more preferably 2-3, substituents selected from the group consisting of halo, nitro, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 1 -C 6  alkyl-C(O)OR 7 , OC 1 -C 6  alkyl-C(O)OR 7 , C 1 -C 6  alkyl-OR 7 , OC 1 -C 6  alkyl-OR 7 , C 1 -C 6  alkyl-NR 7 R 8 , OC 1 -C 6  alkyl-NR 7 R 8 , C 1 -C 6  alkyl-C(O)NR 7 R 8 , OC 1 -C 6  alkyl-C(O)NR 7 R 8 , C 1 -C 6  alkyl-C(O)R 7 , OC 1 -C 6  alkyl-C(O)R 7 , C 1 -C 6  haloalkyl, O-aralkyl (e.g. benzyloxy), C(O)OR 7 , C(O)NR 7 R 8 , OC(O)NR 7 R 8 , NHC(O)R 7 , NHC(O)NR 7 R 8 , NR 7 S(O) n R 1 , NR 7 S(O) n R 7 , S(O) n R 7 , S(O) n NR 7 , where R 7  and R 8  independently are H or C 1 -C 6  alkyl.  
     
     
         3 . The compound of any one of claims  1 - 2 , wherein Q has the structure  
       
         
           
           
               
               
           
         
         wherein  
         R 9  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, hydroxy, NR 7 R 8 , SR 7  or OR 7 , where R 7  and R 8 , independently, are H or unsubstituted or substituted C 1 -C 6  alkyl;  
         R 10 , R 11  and Z 2 , independently, are each selected from the group consisting of H, halo, nitro, cyano, C 1 -C 6  alkyl, C 6 -C 10  aryl, NR 7 R 8 , OR 7 , SR 7 , C 1 -C 6  alkyl-C(O)R 7 , C 1 -C 6  alkyl-C(O)NR 7 R 8 , C 1 -C 6  alkyl-C(O)OR 7 , C 1 -C 6  alkyl-OC(O)R 7 , C 1 -C 6  alkyl-OR 7 , OC 1 -C 6  alkyl-C(O)R 7 , OC 1 -C 6  alkyl-C(O)OR 7 , OC 1 -C 6  alkyl-OC(O)R 7 , O—C 1 -C 6  alkyl-OR 7 , OC 1 -C 6  alkyl-C(O)NR 7 R 8 , C 1 -C 6  haloalkyl, OR 12 , C 1 -C 6  alkyl-R 12 , O—C 1 -C 6  alkyl-R 12 , C(O)OR 7 , C(O)OR 12 , C(O)NR 7 R 8 , OC(O)NR 7 R 8 , NR 7 C(O)R 7 , NR 7 C(O)R 12 , NR 7 C(O)—NR 7 R 8 , NR 7 C(O)OR 7 , NR 7 C(O)OR 12 , NR 7 S(O)n-R 1 , NR 7 S(O)n-R 7  and NR 7 S(O)n-R 12 , where R 7  and R 8 , independently, are H or unsubstituted or substituted C 1 -C 6  alkyl, R 12  is unsubstituted or substituted C 6 -C 10  aryl or heterocycl as defined above and n is 1 or 2;  
         Z 1  is H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen or nitro.  
       
     
     
         4 . The compound of any one of claims  1 - 3 , wherein R 10  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  aminoalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, phenyl, phenoxy, benzyl, benzyloxy, as well as phenoxy- and benzyloxy-substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  aminoalkyl, OC(O)—C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl and C(O)OH.  
     
     
         5 . The compound of any one of claims  3 - 4 , wherein R 11  is NR 7 C 1 -C 6  alkyl-C(O)NR 7 R 8 , NR 7 S(O)n-R 7  or NR 7 S(O)n-R 12 , n is 1 or 2 and/or where Z, =Z 2 =H and/or where R 10  is OR 7 , OR 12 , OC 7 -C 10 -aralkyl, OC 1 -C 6  alkyl-OR 7  or OC 1 -C 6  alkyl-OR 12 .  
     
     
         6 . The compound of any one of claims  3 - 5 , wherein Z 1  and Z 2  are hydrogen; Z 1 , Z 2  and R 11  are hydrogen; or Z 1 , R 10  and R 11  are hydrogen.  
     
     
         7 . The compound of any one of claims  3 - 6 , wherein Z 1  or Z 2  is C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen or nitro.  
     
     
         8 . The compound of any one of claims  3 - 7 , wherein R 10  is OR 7 , OR 12 , C 1 -C 6  alkyl-OR 7  or C 1 -C 6  alkyl-OR 12 .  
     
     
         9 . The compound of any one of claims  3 - 8 , wherein Y is S(O) n R 1  where n=1 or 2 and R 11  is NR 7 S(O) n —R 7  or NR 7 S(O) n —R 12 , n is 1 or 2.  
     
     
         10 . The compound of any one of claims  3 - 9 , wherein R 10  and Z 2  or Z 2  and R 11  are bonded together to form a fused unsubstituted or substituted, carbocyclic or hetercyclic ring.  
     
     
         11 . The compound of any one of claims  1 - 10 , wherein X is a carbonyl group;  
     
     
         12 . The compound of any one of claims  1 - 11 , wherein R 1  is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, naphthyl, benzyl and heteroaryl having 5-6 ring atoms selected from carbon atoms and 1-2 heteroatoms, where the heteroatoms are N, S, or O, and R 1  optionally substituted with 1-3 substituents selected from the group consisting of halo, nitro, C 1 -C 6  alkyl, NR 7 R 8 , OR 7 , SR 7 , C 1 -C 6  alkyl-C(O)OR 7 , C 1 -C 6  alkyl-OC(O)R 7 , C 1 -C 6  alkyl-C(O)R 7 , C 1 -C 6  alkyl-OR 7 , C 1 -C 6  haloalkyl, C 1 -C 6  alkyl-NR 7 R 8 , C(O)OR 7 , OC(O)R 7 , C(O)NR 7 R 8 , OC(O)NR 7 R 8 , NHC(O)R 7 , and NHC(O)NR 7 R 8 , where R 7  and R 8  independently are H or C 1 -C 6  alkyl.  
     
     
         13 . The compound of any one of claims  1 - 12 , wherein A and B are CH.  
     
     
         14 . The compound of any one of claims  1 - 13 , wherein R 6  is H.  
     
     
         15 . The compound of any one of claims  1 - 14 , wherein Y is S(O) n R 1  where n=1 or 2.  
     
     
         16 . A composition, comprising the compound of any one of claims  1 - 15  and a carrier or excipient.  
     
     
         17 . A method of inhibiting TF/factor VIIa, factor Xa, thrombin or kallikrein activity, comprising contacting TF/factor VIIa factor Xa, thrombin or kallikrein with an effective amount of the composition of  claim 16 .  
     
     
         18 . A method of treating a TF/factor VIIa, factor Xa, thrombin or kallikrein mediated disorder, comprising administering to a mammal in need thereof an effective amount of the composition of  claim 16 .  
     
     
         19 . A method of preventing thrombosis or treating abnormal thrombosis, comprising administering to a mammal in need thereof an effective amount of the composition of  claim 16.