Factor Viia Inhibitor

Abstract

The present invention relates to novel inhibitors or Factors VIIa, IXa, Xa, XIa, in particular Factor VIIa, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing thromboembolic disorders, cancer or rheumatoid arthritis. Processes for preparing these inhibitors are also disclosed.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , X 3 , and X 4  are independently —N— or —CR 4 — wherein R 4  is hydrogen, alkyl, or halo with the proviso that not more than three of X 1 , X 2 , X 3  and X 4  are —N—; 
 R 1  is hydrogen, alkyl, halo, carboxy or aminocarbonyl; 
 R 2  is hydrogen, alkyl, or halo; 
 R 3  is dicarboxyalkylaminocarbonylalkyl or dicarboxyalkylaminocarbonyl-cycloalkyl; 
 R x  is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, or nitro; 
 R y  is hydrogen, alkyl, or halo; 
 R z  is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, carbamimidoyl, hydroxy-carbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-alkyl, heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkyl-alkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR 12  (where R 12  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR 12  (where R 12  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), —CONR 14 R 15  (where R 14  is hydrogen or alkyl and R 15  is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-CONR 16 R 17  (where R 16  is hydrogen, alkyl or hydroxyalkyl and R 17  is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), —NR 18 R 19  (where R 18  is hydrogen or alkyl and R 19  is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR 20 R 21  (where R 20  is hydrogen, alkyl, or hydroxyalkyl and R 21  is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), —SO 2 NR 22 R 23  (where R 22  is hydrogen or alkyl and R 23  is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 22  and R 23  together with the nitrogen atom to which they are attached form heterocycloamino), -(alkylene)-SO 2 NR 24 R 25  (where R 24  is hydrogen or alkyl and R 25  is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl or R 24  and R 25  together with the nitrogen atom to which they are attached form heterocycloamino), —NR 26 SO 2 NR 27 R 28  (where R 26  and R 27  are independently hydrogen or alkyl, and R 28  is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 27  and R 28  together with the nitrogen atom to which they are attached form heterocycloamino), -(alkylene)-NR 29 SO 2 NR 30 R 31  (where R 29  and R 30  are independently hydrogen or alkyl, and R 31  is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl or R 30  and R 31  together with the nitrogen atom to which they are attached form heterocycloamino), —CONH-(alkylene)-NR 32 R 33  where R 32  is hydrogen or alkyl and R 33  is alkyl), or aralkyl; and 
 R 13  is hydrogen, hydroxy, (C 1-10 )alkoxy, —C(O)R 35  where R 35  is alkyl, aryl, haloalkyl, or cyanoalkyl, or —C(O)OR 36  where R 36  is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, or haloalkyl; or 
 
       a zwitterion thereof; or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound of  claim 1  having the structure of Formula Ib or Ic: 
       
         
           
           
               
               
           
         
       
       or a zwitterion thereof or a pharmaceutically acceptable salt thereof. 
     
     
         3 . (canceled) 
     
     
         4 . An intermediate of formula (II): 
       
         
           
           
               
               
           
         
       
       where PG 1  is a suitable oxygen-protecting group and PG 2  is a suitable amino-protecting group. 
     
     
         5 . A process of preparing a compound of Formula I where R 3  is dicarboxyalkylaminocarbonylalkyl comprising:
 (i) reacting a compound of formula:   
       
         
           
           
               
               
           
         
         
           where R 1 , R 2 , R 13 , R x , R y , R z , X 1 —X 4  are as defined in the Summary of the Invention or a suitably protected derivative thereof; with dicarboxyalkylamino where the carboxy groups are optionally protected; 
         
         (ii) optionally deprotecting any protected carboxy group(s); 
         (iii) optionally modifying any of the R 1 , R 2 , R 13 , R x , R y , and R z  groups; 
         (iv) optionally converting the product from step (ii) or (iii) above, to an acid addition salt; 
         (v) optionally converting the product from step (ii) or (iii) above, to a free base; 
         (vi) optionally converting the product from step (ii) or (iii) above, to a zwitterions; and 
         (vii) optionally deprotecting any protected carboxy group(s). 
       
     
     
         6 . A process of preparing a compound of Formula Ib or Ic comprising:
 (i) reacting a compound of formula:   
       
         
           
           
               
               
           
         
         
           with (R) or (S) aspartic acid respectively, where the carboxy groups are optionally protected; 
         
         (ii) optionally deprotecting any protected carboxy group(s); 
         (iii) optionally converting the product from step (i) or (ii) above, to an acid addition salt; 
         (iv) optionally converting the product from step (i) or (ii) above, to a free base; 
         (v) optionally converting the product from step (i) or (ii) above, to a zwitterion; 
         (vi) optionally deprotecting any protected carboxy group(s). 
       
     
     
         7 . A method of preparing an intermediate of formula (II): 
       
         
           
           
               
               
           
         
         where PG 1  is a suitable oxygen-protecting group and PG 2  is a suitable amino-protecting group comprising: 
         (i) reacting a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         where PG 1  and PG 2  is are as defined above and X is halo; with one equivalent of an organometallic agent of formula RLi or RMgX 1  where R is alkyl or aryl and X 1  is halo to deprotonate the —SO 2 NHPG 2  group; 
         (ii) transmetallating the compound generated in Step (i) above with one equivalent of an organometallic agent of formula RLi or RMgX 1  where R is alkyl or aryl; 
         (iii) treating the compound generated in Step (ii) above with trialkylborate to generate a compound of formula (II).