ACYLSULFAMIDE INHIBITORS OF FACTOR VIIa

Abstract

Compounds having the general formula I are useful for inhibiting serine protease enzymes, such as Tissue Factor VIIa, factor Xa, thrombin and kallikrein and have improved permeability properties. These compounds may be used in methods of preventing and/or treating clotting disorders.

1 . A compound having the general formula I:  
       
         
           
           
               
               
           
         
       
       wherein I 
 A and B are independently CH, CR 3  or N;  
 Q is: 
 (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 carbocyclic 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 heterocyclic 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 carbocyclic 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 heterocyclic 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 carbocyclic having 3 to about 10 ring carbon atoms;  
 (14) optionally substituted heterocyclic having 3 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur;  
 
 Pr 1  and Pr 2  are independently H, hydroxy, alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, aryloxy, or arylalkoxy;  
 said alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, aryloxy or arylalkoxy are independently and optionally substituted with hydroxy, halogen, carboxyl, alkyl, halosubstituted alkyl, alkoxy, a carbocycle or a heterocycle;  
 said carbocycle and heterocycle are optionally substituted with 1-5 hydroxy, alkoxy, carboxyl, alkyl, or halosubstituted alkyl; and  
 one to three carbon atoms of said alkyl, alkoxy, alkanoyl, alkanoyloxy or alkoxycarbonyl chain are optionally replaced with O, C(O), NH, S, SO 2 , —OC(O)—, C(O)O— or —OC(O)NH—;  
 each R 1  is, independently, H, alkyl, substituted alkyl, aryl, substituted aryl, C(O)R 7  or C(NH)R 7 , or both R 1  form a heterocycle optionally substituted with hydroxy, amino, halogen, carboxy alkyl, alkoxy, alkanoyl or alkanoyloxy;  
 R 2  is H, alkyl or substituted alkyl;  
 R 3  is H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen or OH;  
 R 5  is 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;  
 each R 6  is independently H, C 1 -C 6  alkyl, C 1 -C 6  alkyl-OR 7 , C 1 -C 6  alkyl-NR 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  or OC(O)R 7 ;  
 R 7  and R 8  are independently H or C 1 -C 6  alkyl; and  
 acid and base addition salts, solvates and prodrugs thereof.  
 
     
     
         2 . The compound of  claim 1  wherein Q is phenyl optionally substituted with 1-5 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, 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  claim 1  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 , are each independently 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 1 -C 6  alkyl)-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 , wherein R 7  and R 8  are independently H or unsubstituted or substituted C 1 -C 6  alkyl; R 12  is unsubstituted or substituted C 6 -C 10  aryl or heterocyclic 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  claim 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  claim 3  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  where n is 1 or 2.  
     
     
         6 . The compound of  claim 3  wherein Z 1  and Z 2  are hydrogen, and R 10  is OR 7 , OR 12 , O—(C 7 -C 10 -aralkyl), OC 1 -C 6  alkyl-OR 7  or OC 1 -C 6  alkyl-OR 12 .  
     
     
         7 . The compound of  claim 3  wherein Z 1  or Z 2  is C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen or nitro.  
     
     
         8 . The compound of  claim 3  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  claim 3  wherein R 11  is NR 7 S(O) n —R 7  or NR 7 S(O) n —R 12 , and n is 1 or 2.  
     
     
         10 . The compound of  claim 3  wherein R 10  and Z 2 , or Z 2  and R 11 , are bonded together to form a fused unsubstituted or substituted, carbocyclic or heterocyclic ring.  
     
     
         11 . The compound of  claim 10  wherein Q is a benzofuran heterocyle optionally substituted with hydroxy, halogen, amino, carboxy, alkyl or alkoxy; wherein said alkyl and alkoxy are optionally substituted with hydroxy, halogen, amino, carboxy, alkoxy, a substituted or unsubstituted carbocycle or heterocycle.  
     
     
         12 . The compound of  claim 1  wherein each R 1  is independently 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  is 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  claim 1  wherein A and B are CH.  
     
     
         14 . The compound of  claim 1  wherein both R 6  substituents are H.  
     
     
         15 . The compound of  claim 1  wherein both R 1  substituents are H, methyl or together with the nitrogen atom from which they depend form a morpholino heterocycle.  
     
     
         16 . The compound of  claim 1  wherein Pr 1  is H, hydroxy, alkoxy, alkanoyl, aryloxy or aryl; wherein said alkoxy, alkanoyl, aryloxy and aryl are optionally substituted with halogen; and Pr 2  is H.  
     
     
         17 . The compound of  claim 1  selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . 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 compound of  claim 1 .  
     
     
         19 . 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 compound of  claim 1 .  
     
     
         20 . A method of preventing thrombosis or treating abnormal thrombosis, comprising administering to a mammal in need thereof an effective amount of the compound of  claim 1 .  
     
     
         21 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.  
     
     
         22 . The pharmaceutical composition of  claim 21  formulated in a unit dosage form.  
     
     
         23 . The pharmaceutical composition of  claim 21  administered orally.  
     
     
         24 . The pharmaceutical composition of  claim 21  administered parenterally.  
     
     
         25 . An article of manufacture comprising 
 the pharmaceutical composition of  claim 21;     a container; and    a package insert or label indicating that the pharmaceutical composition can be used to treat a thrombosis disorder.