BENZOFURAN INHIBITORS OF FACTOR VIIa

Abstract

Compounds of Formula I are useful for inhibiting serine protease enzymes, such as TF/factor VIIa, factor Xa, thrombin and kallikrein and have improved pharmacokinetic properties. These compounds may be used in methods of preventing and/or treating clotting disorders.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 A and B are independently CH, CR 3  or N;  
 X is C═O or (CR 4a R 4b ) m  where m is 1 or 2;  
 Y is S(O) n —R 1 , S(O) n —NR 2 R 2 , S(O) n —OR 2 , C(O)R 1 , C(S)R 1 , C(O)—OR 1 , or C(O)—NR 2 R 2 , where n is 1 or 2;  
 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—;  
 R′ and R″ are each independently H, carboxyl, alkyl, alkoxy, alkanoyl, alkanoyloxy or alkoxycarbonyl; wherein said alkyl, alkoxy, alkanoyl, alkanoyloxy and alkoxycarbonyl groups are optionally substituted with amino, hydroxy, alkoxy, acyl, acyloxy, a substituted or unsubstituted carbocycle or heterocycle; 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—;  
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, naphthyl, benzyl or heteroaryl;  
 each R 2  is, independently, H, alkyl, substituted alkyl, aryl, substituted aryl, C(O)R 7  or C(NH)R 7 , or the two NR 2  and NR 2  groups together form a heterocycle;  
 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-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  and OC(O)R 7 ;  
 R 7  and R 8  are independently H or C 1 -C 6  alkyl;  
 R 9  is H, halogen, hydroxy, alkyl, alkoxy, alkanoyl, NR 7 R 8  or SR 7 ; wherein said alkyl, alkoxy, and alkanoyl are optionally substituted with halogen, amino, hydroxy, carboxyl, alkoxy or alkoxycarbonyl;  
 R 11  is 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 12  is unsubstituted or substituted C 6 -C 10  aryl or heterocycle and n is 1 or 2; and  
 acid and base addition salts and prodrugs thereof.  
 
   
   
       2 . The compound of  claim 1  wherein R 9  is H, halogen alkyl, alkoxy, halo, nitro, cyano, wherein said alkyl and alkoxy are optionally substituted with hydroxy, halogen, alkoxy, aryl and aryloxy; and R 11  is H.  
   
   
       3 . The compound of  claim 2  wherein R 9  is H, methoxy, ethoxy, ethyl, propyl, ethynyl, Cl, I, propyn-1-yl or 1-chlorovinyl.  
   
   
       4 . The compound of  claim 3  wherein R 9  is ethyl.  
   
   
       5 . The compound of  claim 1  wherein R′ is H, halogen alkyl, alkoxy, halo, nitro, cyano, wherein said alkyl and alkoxy are optionally substituted with hydroxy, halogen, alkoxy, aryl and aryloxy; and R 11  is H.  
   
   
       6 . The compound of  claim 5  wherein R′ is Cl, methyl, ethyl, propyl, hydroxyethyl or benzoyloxyethyl.  
   
   
       7 . The compound of  claim 6  wherein R′ is methyl.  
   
   
       8 . The compound of  claim 1  wherein R″ is alkyl, optionally substituted with amino, hydroxy, alkoxy, acyl, acyloxy, a carbocycle or heterocycle; alkanoyl, alkoxycarbonyloxyalkyl, alkanoyloxyalkyl, acyloxyalkyl or a heterocycle; wherein said carbocycle or heterocycle is optionally substituted with halogen, haloalkyl, alkoxy or carboxyl)  
   
   
       9 . The compound of  claim 8  wherein R″ is H, ethyl, propyl, t-butyl, hydroxymethyl, hydroxyethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, methoxymethyl, aminomethyl, N-dimethylaminomethyl, N-acetylaminomethyl, N-acetyl-N-methylaminomethyl, acetylethyl, propanoyl, acetyl, ethyloxycarbonyloxyemethyl, acetyloxyethyl, t-butylcarbonyloxyethyl, benzoyloxyethyl, 3,5-diCF 3 -benzoyloxyethyl, trichloroacetyloxyethyl, propanoyloxyethyl, N-morpholino or imidazole-1-yl.  
   
   
       10 . The compound of  claim 9  wherein R″ is H.  
   
   
       11 . The compound of  claim 1  wherein Y is S(O) n —NR 2 R 2  wherein both R 2  are H or alkyl.  
   
   
       12 . The compound of claims  11  wherein both R 2  substituents are H.  
   
   
       13 . The compound of any one of claims  1  wherein X is a carbonyl group.  
   
   
       14 . The compound of any one of claims  1  wherein Y is S(O) n —R where n is 2; and 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.  
   
   
       15 . The compound of  claim 1  wherein A and B are both CH.  
   
   
       16 . The compound of  claim 1  wherein both R 6  are H.  
   
   
       17 . The compound of  claim 1  selected from:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 1  selected from:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       19 . The compound of claims  1  wherein Pr1 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.  
   
   
       20 . 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 a compound of  claim 1 .  
   
   
       21 . 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 a compound of  claim 1 .  
   
   
       22 . A method of preventing thrombosis or treating abnormal thrombosis, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 .  
   
   
       23 . The compound of  claim 1  having formula II:  
     
       
         
         
             
             
         
       
     
   
   
       24 . The compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       25 . The compound of  claim 24  having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       26 . The compound of  claim 25  wherein R 2  is independently H or C 1 -C 6  alkyl, and R 11  is H.  
   
   
       27 . The compound of  claim 26  wherein R′, R″, R 9  are independently H or C 1 -C 6  alkyl, and Pr1 and Pr2 are H.  
   
   
       28 . The compound of  claim 26  wherein R′, R″, R 9  are independently H or C 1 -C 6  alkyl; Pr 1  is H; and Pr 2  is hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkanoyl, C 1 -C 6  alkanoyloxy, C 1 -C 6  alkoxycarbonyl, aryloxy, or arylalkoxy.  
   
   
       29 . The compound of  claim 26  wherein Pr 2  is benzyloxy (OBn) or substituted benzyloxy.  
   
   
       30 . A compound of formula III:  
     
       
         
         
             
             
         
       
     
     wherein 
 A and B are independently CH, CR 3  or N;  
 R′ and R″ are each independently H, carboxyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkanoyl, C 1 -C 6  alkanoyloxy or C 1 -C 6  alkoxycarbonyl; wherein said alkyl, alkoxy, alkanoyl, alkanoyloxy and alkoxycarbonyl groups are optionally substituted with amino, hydroxy, alkoxy, acyl, acyloxy, a substituted or unsubstituted carbocycle or heterocycle; 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—;  
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, naphthyl, benzyl or heteroaryl;  
 each R 2  is, independently, H, alkyl, substituted alkyl, aryl, substituted aryl, C(O)R 7  or C(NH)R 7 , or the two NR 2  and NR 2  groups together form a heterocycle;  
 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 C 1 -C 6  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, T, 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 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-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  and OC(O)R 7 ;  
 R 7  and R 8  are independently H or C 1 -C 6  alkyl;  
 R 9  is H, halogen, hydroxy, C 1 -C 6  alkyl, alkoxy, alkanoyl, NR 7 R 8  or SR 7 ; wherein said alkyl, alkoxy, and alkanoyl are optionally substituted with halogen, amino, hydroxy, carboxyl, alkoxy or alkoxycarbonyl;  
 R 11  is 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 12  is unsubstituted or substituted C 6 -C 10  aryl or heterocycle and n is 1 or 2;  
 R 12  is selected from H, Cl, Br, I, CN, C(═NPr 2 )(NHPr 1 ), COOH, C(O)—NR 7 R 8  and COOR 1 ;  
 Pr 1  and Pr 2  are independently H, hydroxy, alkyl, alkoxy, alkanoyl, alkanoyloxy or alkoxycarbonyl;  
 said alkoxycarbonyl is 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—;  
 acid and base addition salts and prodrugs thereof.  
 
   
   
       31 . The compound of  claim 30  having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       32 . The compound of  claim 31  wherein R 12  is CN.  
   
   
       33 . The compound of  claim 31  wherein R 12  is C(═NPr 2 )(NHPr 1 ).  
   
   
       34 . 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.  
   
   
       35 . The pharmaceutical composition of  claim 34  formulated in a unit dosage form.  
   
   
       36 . The pharmaceutical composition of  claim 34  administered orally.  
   
   
       37 . The pharmaceutical composition of  claim 34  administered parenterally.  
   
   
       38 . An article of manufacture comprising 
 the pharmaceutical composition of  claim 34;     a container; and    a package insert or label indicating that the pharmaceutical composition can be used to treat a thrombosis disorder.