2-(2-Hydroxybiphenyl-3-yl)-1H-Benzoimidazole-5-Carboxamidine Derivatives as Factor VIIA Inhibitors

Abstract

The present invention relates to novel inhibitors of 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 . (canceled) 
   
   
       2 . (canceled) 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . A method of treating a disease in an animal mediated by Factor VIIa which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 3  is —CONR 7 R 8  (where R 7  is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl and R 8  is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH 2 CH 2 ) n  R b  (where n is an integer from 1 to 6 and R b  is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl or R 7  and R 8  together with the nitrogen atom to which they are attached form heterocycloalkylamino), -(alkylene)-CONR 9 R 10  (where R 9  is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl and R 10  is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH 2 CH 2 ) n  R b  (where n is an integer from 1 to 6 and R b  is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl or R 9  and R 10  together with the nitrogen atom to which they are attached form heterocycloalkylamino), —CONHSO 2 R 11  (where R 11  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl), or -(alkylene)-CONHSO 2 R 11  (where R 11  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); and 
 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, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, 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 or R 14  and R 15  together with the nitrogen atom to which they are attached from heterocycloamino), -(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 or R 14  and R 15  together with the nitrogen atom to which they are attached from heterocycloamino), —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 2 OR 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 from 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 from 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 from heterocycloamino), -(alkylene)-NR 29 SO 2 NR 31 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 from 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 pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
 
   
   
       6 - 10 . (canceled) 
   
   
       11 . The method of  claim 5 , wherein the compound of Formula I is selected from: 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamic;
 ({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-carboxymethyl-amino)-acetic acid; 
 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinic acid; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2-carboxamide; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hydroxy-pyrrolidine-2-carboxylic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-acetamide; 
     {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-acetic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-carbamoylmethyl-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-acetamide; 
     3-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-propionic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(S,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,21-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-acetamide; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-acetamide; 
     (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethyl)-phosphonic acid; 
     {2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamic acid; 
     ({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-carboxymethyl-amino)-acetic acid; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinic acid; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-pyrrolidine-2-carboxamide; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-4-hydroxy-pyrrolidine-2-carboxylic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-isobutyramide; 
     {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-acetic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-carbamoylmethyl-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-isobutyramide; 
     3-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-propionic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5-sulfamoyl-biphenyl-3-yl]-N-methyl-isobutyramide; 
     2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide; 
     (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionylamino}-ethyl)-phosphonic acid; 
     {2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-2-methyl-propionyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamic acid; 
     ({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-carboxymethyl-amino)-acetic acid; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinic acid; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-pyrrolidine-2-carboxamide; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-4-hydroxy-pyrrolidine-2-carboxylic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N,N-dimethyl-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-isobutyramide; 
     {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-acetic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-carbamoylmethyl-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-dimethylamino-ethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-isobutyramide; 
     3-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-propionic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-methyl-isobutyramide; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-succinamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide; 
     (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionylamino}-ethyl)-phosphonic acid; 
     {2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid; 
     2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-succinamic acid; 
     {[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-carboxymethyl-amino}-acetic acid; 
     2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-succinic acid; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2-carboxylic acid; 
     1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hydroxy-pyrrolidine-2-carboxylic acid; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-N,N-dimethyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-hydroxy-1-hydroxymethyl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     {[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-acetic acid; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-N-carbamoylmethyl-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-dimethylamino-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     3-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-propionic acid; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-5′-sulfamoyl-biphenyl-3-carboxamide; 
     (2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethyl)-phosphonic acid; 
     {2-[[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N,N-bis-(2-hydroxy-ethyl)-5′-methyl-biphenyl-3-carboxyamide; 
     (2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethyl)-trimethyl-ammonium; 
     2-{5-[4-(2-amino-ethyl)-piperazine-1-carbonyl]-2,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine; 
     2-amino-6-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-hexanoic acid; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-hydroxy-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N,N-dimethyl-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxamide; 
     1-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxamide; 
     2-[2,2′-dihydroxy-5-(morpholine-4-carbonyl)-5′-sulfamoyl-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine; 
     1-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxylic acid; 
     [(2-{4-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-piperazin-1-yl}-ethylamino)-dimethylamino-methylene]-dimethyl-ammonium; 
     2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethanesulfonic acid; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide; 
     2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetamide; 
     2-amino-6-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-hexanoic acid; 
     2-{2,2′-dihydroxy-5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-5′-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine; 
     (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethyl)-trimethyl-ammonium; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-carbamoylmethyl-methyl-5′-sulfamoyl-biphenyl-3-carboxamide; 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-(2-piperazin-1-yl-ethyl)-5′-sulfamoyl-biphenyl-3-carboxamide; and 
     5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-N-methyl-5′-sulfamoyl-biphenyl-3-carboxamide. 
   
   
       12 . The method of  claim 5  wherein the compound of Formula I has the structure:
 R 3  is —CONR 7 R 8  (where R 7  is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R 8  is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH 2 CH 2 ) n  R b  (where n is an integer from 1 to 6 and R b  is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or hetereocycloalkylalkyl or R 7  and R 8  together with the nitrogen atom to which they are attached form heterocycloalkylamino), -(alkylene)-CONR 9 R 10  (where R 9  is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl and R 10  is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH 2 CH 2 ), R b  (where n is an integer from 1 to 6 and R b  is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl or R 9  and R 10  together with the nitrogen atom to which they are attached form heterocycloalkylamino), —CONHSO 2 R 11  (where R 11  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclalkyl, or heterocycloalkylalkyl), or -(alkylene)-CONHSO 2 R 11  (where R 11  is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl), wherein any rings comprising R 3  are optionally substituted with one to six groups independently selected from hydroxy, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminoalkyl, guanidinoalkyl, alkyl or —CONR a R b  where R a  and R b  are independently hydrogen or alkyl; and   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, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, 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 or R 14  and R 5  together with the nitrogen atom to which they are attached from heterocycloamino), -(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 or R 14  and R 15  together with the nitrogen atom to which they are attached from heterocycloamino), —NR 18 R 19  (where R 12  is hydrogen or alkyl and R 19  is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR 2 OR 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 from 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 from 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 from heterocycloamino), -(alkylene)-NR 29 SO 2 NR 3 OR 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 from 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, acyl, or haloalkyl; or   
     a pharmaceutically acceptable salt thereof. 
   
   
       13 . The method of  claim 12 , wherein the compound of Formula I has the structure:
 R 3  is —CONR 7 R 8 , —CH 2 CONR 9 R 10  or —C(CH 3 ) 2 CONR 9 R 10 ;   R 7  and R 8  or R 9  and R 10  both are hydrogen, carboxymethyl, 2-hydroxyethyl or 2-phosphonoethyl; or   R 7  and R 9  is hydrogen or methyl and R 8  and R 10 , respectively, is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminomethyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-dicarboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl or R 7  and R 8  or R 9  and R 10  together with the nitrogen atom to which they are attached form 2-aminocarbonylpyrrolidin-1-yl, 2-carboxy-4-hydroxypyrrolidin-1-yl or 4-methylpiperazin-1-yl;   and R z  is aminosulfonyl or ureidomethyl; or a pharmaceutically acceptable salt thereof.   
   
   
       14 . The method of  claim 5 , wherein the compound of Formula I has the structure: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 3  is —CONR 7 R 8 , —CH 2 CONR 9 R 10  or —C(CH 3 ) 2 CONR 9 R 10 ; 
 R 7  is hydrogen or methyl; 
 R 9  is hydrogen or methyl; 
 R 8  is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminomethyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-dicarboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl; 
 R 10  is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminomethyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-dicarboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl; 
 R z  is aminosulfonyl or ureidomethyl; 
 R 13  is hydrogen; or 
 a pharmaceutically acceptable salt thereof. 
 
   
   
       15 . The method of  claim 14 , wherein the compound of Formula I has the structure:
 R 3  is —CONR 7 R 8 , —CH 2 CONR 9 R 10  or —C(CH 3 ) 2 CONR 9 R 10 ;   R 7  is hydrogen;   R 9  is hydrogen;   R 8  is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl;   R 10  is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl;   R z  is aminosulfonyl; or   a pharmaceutically acceptable salt thereof.   
   
   
       16 . The method of  claim 15 , wherein the compound of Formula I has the structure: 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetylamino}-succinic acid. 
   
   
       17 . The method of  claim 5 , wherein the disease is cancer. 
   
   
       18 . The method of  claim 5 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       19 . The method of  claim 11 , wherein the disease is cancer. 
   
   
       20 . The method of  claim 11 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       21 . The method of  claim 12 , wherein the disease is cancer. 
   
   
       22 . The method of  claim 12 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       23 . The method of  claim 13 , wherein the disease is cancer. 
   
   
       24 . The method of  claim 13 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       25 . The method of  claim 14 , wherein the disease is cancer. 
   
   
       26 . The method of  claim 14 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       27 . The method of  claim 15 , wherein the disease is cancer. 
   
   
       28 . The method of  claim 15 , wherein the disease is a thromboembolic disorder associated with cancer. 
   
   
       29 . The method of  claim 16 , wherein the disease is cancer. 
   
   
       30 . The method of  claim 16 , wherein the disease is a thromboembolic disorder associated with cancer.