MXPA99000375A

MXPA99000375A - Amidinoindoles, amidinoazoles and analogues of them as inhibitors of the factor xa and the tromb

Info

Publication number: MXPA99000375A
Application number: MXPA/A/1999/000375A
Authority: MX
Inventors: Dominguez Celia; Lifen Quan Mimi; Han Qi; Anita Rossi Karen; Emmett Duffy Daniel; Maria Park Jeongsook; Richmond Wexler Ruth
Original assignee: The Du Pont Merck Pharmaceutical Company
Priority date: 1996-07-08
Filing date: 1999-01-07
Publication date: 2000-02-02

Abstract

The present application describes amidinoindoles, amidinoazoles and analogs of the same of formula (I): wherein W, W1, W2 and W3 is selected from CH and N, provided that one of W1 and W2 is C (C (= NH) NH2) and also two of W, W1, W2 and W3 are N and one of Ja and Jb is substituted by - (CH2) nZAB, which are useful as inhibitors of factor Xa or thrombi

Description

AM DINOINDOLES, AMIDINOAZOLES, AND ANALOGUES OF THEM AS INHIBITORS OF THE FACTOR Xa AND THE THROMBIN FIELD OF THE INVENTION This invention relates generally to amidinoindoles, amidinoazoles and analogs, which are inhibitors of serine protease enzymes similar to trypsin, especially thrombin and factor Xa, pharmaceutical compositions containing the same, and methods of use. of them as anticoagulant agents for the treatment and prevention of thromboembolic diseases.

BACKGROUND OF THE INVENTION EP 0,540,051 and JP 06227971 describe a series of compounds useful as inhibitors of factor Xa or to treat influenza, based on the formula: wherein A is an alkylene linker optionally substituted by hydroxyalkyl, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyl, or carboxyalkyl, X REF. 29233 is a bond, O, S, or carbonyl, n is 0-4, and Y is a 'optionally substituted carbocycle or heterocycle. The present invention does not involve compounds containing the above annotated combination of A, X, n, and Y. Tidwell et al, Throp-juster Research 1981, 24, 73-83, describes factor Xa inhibitory activity of a series of monoamine - and aromatic diamidines. The aromatic amidino moieties include indole, indoline, benzofuran and benzimidazole. Tidwell et al., "Med. Cbem. 1983, 26, 294-298, reports a series of amidinoindoles of the formula: in which one of R1 and R2 is amidine, X can be methyl or ethyl when Y and Z are H, and can be C (0) CH2CH3 when X and Z are H, and Z can be CHO, COCH3 COCF3, or C (0) Ph when X and Y are H. The inhibition constants of thrombin are given for those compounds. EP 0,655,439 describes Ilb / IIIa antagonists of the formula: wherein the central ring is a heterocycle, B is a basic group, A is an acidic group, R1 is an optional substituent, R2 is an optional substituent, and La and L are linkers, which may be optionally substituted. The present invention does not contain the group La-A. Fairley et al, J. Med. Chem. 1993, 36, 1746-1753, illustrates a series of bis (amidinobenzimidazoles) and bis (amidinoindoles) of the formulas: wherein R is an amidine or derivative thereof and X is a linker 'alkylene, alkenylene, phenylene or phenylene ethylene. The binding capacity of these compounds was studied and reported, but the inhibition of trypsin-like enzymes was not discussed. WO 95/08540 describes bis (amidinobenzimidazolyl) alkanes of the formula: wherein Z is an amidine derivative and R and R1 are - selected from a variety of substituents including hydroxyl, amino, and alkoxy. It seems that these compounds are useful in the treatment of viruses, specifically HIV. No mention is made of the inhibition of Xa or thrombin. Trypsin-like enzymes are a group of proteases, which hydrolyse peptide bonds in the basic residues by releasing either an arginyl residue or a C-terminal lysyl residue. Between those enzymes of the blood coagulation and the fibronilitic system required for haemostasis. They are Factors II, X, VII, IX, XII, kallin, tissue plasminogen activators, plasminogen activator similar to urokinase, and plasmin. High levels of proteolysis by these proteases can result in disease states. For example, destructive csagulopathy, a condition marked by decreased levels of enzymes in the blood, both the coagulation system, the fibronilitic system, and the protease inhibitors that accompany it is often fatal. More specifically, proteolysis by thrombin is required for blood coagulation. The inhibition of thrombin results in an effective inhibitor of blood coagulation. The importance of an effective inhibitor of thrombin is highlighted by the observation that conventional anticoagulants such as heparin (and its complex with the protein inhibitor), antithrombin III) are not effective in blocking arterial thrombosis associated with myocardial infarction and other coagulation disorders. However, a thrombin inhibitor, of low molecular weight, which contains a different functionality, was effective in blocking arterial thrombosis (Hanson and Harker, Proc.Nat.Acid.Sci.U.S.A. 85, 3184 1988). Activated factor Xa, whose main practical role in the generation of thrombin by the limited proteolysis of prothrombin, contains a central position that links the mechanisms of intrinsic and extrinsic activation in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the via to generate a fibrin clot, from its precursor, is amplified by the formation of the prothrombinase complex (factor Xa, factor V, Ca2 + and phospholipids). Since it is estimated that a factor Xa molecule can generate 138 thrombin molecules (Elodi, S., Varadi, K.: Optimization of the conditions for the catalytic effect of the Factor IXa -f complex, actor VIII: Probable role of the complex in the amplification of blood coagulation, Thromb Res. 1979, 15, 617-629), the inhibition of factor Xa may be more efficient than the inactivation of thrombin in the interruption of the blood coagulation system.

Therefore, effective and specific inhibitors of factor Xa or thrombin are necessary as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. In this way, it is desirable to discover new inhibitors of thrombin or factor Xa.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, an object of the present invention is to provide novel amidinoindoles and analogs thereof, which are useful as inhibitors of factor Xa or thrombin or pharmaceutically acceptable salts or active proprinciples thereof. Another objective of the present invention is to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable active salt or proprinciple thereof. Another objective of the present invention is to provide a method for treating thromboembolic disorders, which comprises administering to a host in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable active salt or proprinciple. thereof. These and other objects, which will become apparent during the following detailed description, have been achieved by the discovery of the inventors of the compounds of formula (I): or pharmaceutically acceptable salts or active proprinciple forms thereof, wherein D, D, J, Ja, J, W, W1, W2 and W ?, are defined below, are effective inhibitors of factor Xa or thrombin.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: or a stereoisomerically or pharmaceutically acceptable salt form thereof, wherein: W and W3 are selected from CH and N; W and 2 are selected from C, CH, and N; provided that 0-2 of W, W1, 2, and 3 are N; one of D and Da is selected from H, C? _ alkoxy, alkoxy, CN, C (= NR7) NR8R9, NHC (= NR7) NR8R9, NR8CH (= NR7), C (0) NR8R9, and (CH2) tNR8R9, and the other is absent; provided that if one of D and Da is H, then at least one of W, 1, W2, and W3 is N; one of Ja and Jb is substituted by (CH2) n-Z-A-B; J, Ja, and Jb combine to form an aromatic heterocyclic system containing 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R1, provided that Jb can be solely C or N; J, Ja, and Jb can, alternatively, be combined to form a heterocyclic ring, wherein Jb is N and J and Ja are CH 2 substituted with 0-1 R 1; J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring, where Jb is CH, J is NR1 and Ja is CH2, substituted with 0-1 R1; R1 is selected from H, C? -4 alkyl, (CH2) -OR3, (CH2) rNR3R3 ', (CH2) cC (= 0) R2, (CH2) c (CH = CH) (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, (CH2) rNR3S02R4, and (CH) r- 5-membered heterocyclic system, having 1-4 heteroatoms selected from N, O and S; R2 is selected from H, OR3, C? -4 alkyl, NR3R3 ', CF3, and a C3-10 carbocyclic residue substituted with 0-2 R6; R3 and R3 'are independently selected from H, C? _ Alkyl, and a C3-10 carbocyclic residue substituted with 0-2 R6; R4 is selected from C? - / NR3R3 'alkyl, and a C3-10 carbocyclic residue substituted with 0-2 R6; Z is selected from CH = CH, CH ((CH2) mQ (CH2) mR5), CH ((CH2) mQ (CH2) mR5) C (0) NR3, CH ((CH2) mC (0) (CH2) mR5a) N ((CH2) qQ (CH2) mR5), N (Q '(CH2) mR5a) C (0) N ((CH2) mQ '(CH2) mR: 5a < C (O) (CH2) r, C (0) 0 (CH2) r, OC (O) (CH2) r, C (O) (CH2) rNR3 (CH2) NR3C (O) (CH2) r, OC (0) NR3 (CH2) NR3C (0) 0 (CH2) r, NR3C (0) NR3 (CH2) S (0) p (CH2) r, SO2CH2, SCH2C (0) NR3, S02NR3 (CH2) r, NR3S02 (CH2Y NR3S02NR3 CH2; Q is selected from a bond, O, NR3, C (O), C (0) NR3, NR3C (0), S02, NR3S02, and SO? NR-3; Q 'is selected from a link, C (O), C (0) NR3, S02, and S02NRJ; R5 is selected from H, C? -4 alkyl, a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing? ^ 3 heteroatoms selected from the group consisting of N , O and S substituted with 0-2 R6, provided that when Q is S02 or NR3S02, R5 is different from H and when 0 is S02, R5 is different from H; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, phenethyl substituted with 0-2 R6, fenll-CH = substituted with 0-2 R6, a carbocyclic residue of C3-10 substituted with 0-2 R6, and a 5-10 heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; B is selected from: XY, C3-6 alkyl, NR3R3, C (= NR3) NR3R3 ', NR3C (= NR3) NR3R3', benzyl substituted with 0-2 R6, a carbocyclic residue of C3-10 substituted with 0- 2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; A and B can, alternatively, be combined to form a C9-10 carbocyclic residue substituted with 0-2 R6 or a 9-10 member heterocyclic system, containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from C1-4 alkylene, -C (O) -, -C (0) CR3R3'-, -CR3R3'C (0), -S (0) p-, -S (O) PCR3R3'-, -CR3R3'S (0) p '-S (0) 2NR3-, - NR3S (0) 2-, -C (0) NR3-, -NR3C (0) -, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3 '? -, and -OCR3R3'-; Y is selected from: a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0- 2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C1-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3,' NR3C (0) R3 ', NR3C (0) NR3R3 ', CH (= NH) NH2, NHC (= NH) NH2, S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-C1-4 alkyl, and (alkyl) C1-4) tetrazolyl; R7 is selected from H, OH, C? _6 alkyl, C? -6 alkylcarbon, C? _6 alkoxy, C1_4 alkoxycarbonyl, C6_? Aryloxy or C6_? 0 aryloxycarbonyl, C arylmethylcarbonyl IO, C 1 -4 alkylcarbonyloxy, C 1 -4 alkoxycarbonyl, C 6 -α arylcarbonyloxy, C 1 -4 alkoxycarbonyl, C 1 -6 alkylaminocarbonyl, phenylaminocarbonyl, and C 4 -4 phenyl alkoxycarbonyl; R8 is selected from H, C1-6 alkyl and (CH2) n-phenyl; R is selected from H, C? -6 alkyl and (CH2) n-phenyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4; provided that: (a) Z is different from CH2; and, (b) if Z is CH ((CH2) mQ (CH2) mR5) or CH ((CH2) mC (0) (CH2) mR5a), then B is different from XY, a carbocyclic residue of C3-10 or a heterocyclic system of 5-10 members. [2] In a preferred embodiment, the present invention provides the compounds of formula II: II in which: 0-1 of W, 1, 2, and 3 are N; R1 is selected from H, C1-4 alkyl, (CH2) rOR3, (CH2) cNR3R3 ', (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, (CH2) ) rNR3S02R4, and (CH2) r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S; R2 is selected from H, OR3, C? _4 alkyl, NR3R3 ', and CF3; R and R3 are independently selected from H, C? _4 alkyl, and phenyl; R 4 is selected from C 1 -4 alkyl, phenyl and NR 3 R 3 '; Z is selected from CH = CH, CH ((CH2) mQ (CH2) mR5), CH ((CH2) mQ (CH2) mR5) C (0) NR3, CH ((CH2) mC (O) (CH2) mR5a ), N ((CH2) qQ (CH2) mR5), N (Q '(CH2) mR5), C (O) N ((CH2) mQ' (CH2) mR5a), C (O), C (0) CH2, C (0) 0, OC (O), C (O) (CH2) rNR3 (CH2) r, NR3C (O), OC (0) NR3, NR3C (0) 0, NR3C (0) NR3, S (0) p, S02CH2, S02NR3, NR3S02, and NR3S02NR3; B is selected from: XY, C3-β alkyl, benzyl substituted with 0-2 R6, a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; A and B can, alternatively, be combined to form a C9-10 carbocyclic residue substituted with 0-2 R6 or a 9-10 member heterocyclic system containing 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; and, R6 is selected from H, OH, (CH2) nOR3, halo, C1-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-C1-4 alkyl and (C1-4 alkyl) -tetrazolyl. [3] In a more preferred embodiment, the present invention provides compounds of formula II, wherein: J, Ja and Jb combine to form an aromatic heterocyclic system containing 1-2 nitrogen atoms, substituted with 0-1 R1; J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring wherein Jb is N and J and Ja are CH 2 substituted with 0-1 R 1; J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring wherein Jb is CH, J is NR1 and Ja is CH2 substituted with 0-1 R1; R1 is selected from H, C? -4 alkyl, (CH2) rOR3, (CH2) rNR3R3 ', (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, and (CH2) ENR3S02R4; Z is selected from CH ((CH2) mQ (CH2) mR5), CH ((CH2) mQ (CH2) mR5) C (0) NR3, * CH ((CH2) mC (0) (CH2) raR5a), N ((CH2) qQ (CH2) mR5), N (Q '(CH2) mR5), C (0) N ((CH2) mQ' (CH2) mR5a), C (O), C (0) CH2, C (O) (CH2) rNR3 (CH2) r, NR3C (0), NR3C (0) NR3, S (0) 2, S02CH2, S02NR3, NR3S02, and NR3S02NR3; A is selected from: benzyl substituted with 0-2 R6, a carbocyclic residue of C3-? 0 substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, Q, and S substituted with 0-2 R6; B is selected from: X-Y, C3-β alkyl, benzyl substituted with 0-2 R6, a carbocyclic C5-6 residue substituted with 0-2 R6, and a 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from -C (O) -, -C (O) CR3R3'-, -S (0) 2-, -S (0) 2CR3R3'-, -S (0) 2NR3-, -C (0) NR3-, -NR3-, -NR3CR3R3'-, and O; Y is selected from: a C5_6 carbocyclic residue substituted with 0-2 R6, and a 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C? _4 alkyl, CN, N02, (CH) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-alkyl? of C? -4 Y (C? -4) -tetrazolyl alkyl; n is selected from 0 1, and 2; and, r is selected from 0, 1, and 2. [4] In an even more preferred embodiment, the present invention provides compounds of formula II: III wherein: J and Jb combine to form an aromatic heterocyclic system containing 1-2 nitrogen atoms, substituted with 0-1 R1; J and Jb can, alternatively, form a heterocyclic ring wherein Jb is N and J is CH 2 substituted with 0-1 R 1; J and Jb can, alternatively, form a heterocyclic ring wherein Jb is CH and J is NR1; Z is selected from C (0) N (Q'R5a), C (O), C (0) NR3, NR3C (0), and S02NR3; Q 'is selected from C (O) and C (0) NR3; R5 is selected from H and C? -4 alkyl; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-1 R6, phenyl substituted with 0-1 Rd, piperidinyl substituted with 0-1 Rs, piperazinyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6; B is selected from: X-Y, benzyl substituted with 0-1 R6, phenyl substituted with 0-2 R6, cyclohexyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6; X is selected from: -C (O) -, -S (0) 2-, S02CH2, -S (0) 2NR3-, -NR3- and -C (0) NR3-; Y is selected from: phenyl substituted with 0-2 R6, and pyridyl substituted with 0-1 Rs; R6 is selected from H, OH, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2-j rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02- C4-4 alkyl and (C? -4) -tetrazolyl alkyl; n is selected from 0, 1, and 2. [5] In one most preferred embodiment, the present invention provides compounds of formula IV: in which A, B, D, and Z are as defined above. [6] In an even more preferred embodiment, the present invention provides compounds selected from: 3- ((4-cyclohexyl) phenylaminomethylcarbonyl) methyl-5-amidinoindole 3- (4-p-toluenesulsonyl-piperazincarbonyl) methyl-5-amidinoindole 3 - (4- (2-aminosulfonylphenyl) pyridine-2-amino-carbonyl) methyl-5-amidinoindole; 3- (4- [2-tetrazole) phenyl) phenylaminocarbonyl) methyl-5-amidinoindole; 3- (4-biphenylaminocarbsnyl) methyl-5-amidinoindole; 3- (4- (phenylmethylsulfonyl) piperazincarbonyl) methyl-5-a idinoindole; 3- (4-cyclohexylphenylaminocarbonyl) methyl-5-amidino-indole; 3- (4-benzylpiperazincarbonyl) methyl-5-amidinoindole; 3- (3-amidinobenzylamino (methylcarbonylmethoxy) -carbonyl) methyl-5-amidinoindole; 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-5-amidinoindole; 3- (1-benzylpiperidin-4-aminocarbonyl) methyl-5-amidinoindole; 3- (4-phenylpiperazincarbonyl) methyl-5-amidinoindole; 3- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole; 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole; 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-methylaminoindole; 3- (2-fluoro-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindole; 3- (2-chloro-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole; 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminocarbaryl) methyl-5-cyanoindole; 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindole; 3- (2-methyl-4- (2- (t-butylaminosulfonyl)) phenylphenyl-aminocarbonyl) methyl-5-amidinoindole; 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-a- (methylcarboxymethyl ether) -5-amidinoindole; 3- (4- (2-aminosulfonyl.) Phenyl) phenylaminocarbonyl-methyl-a- (benzyl) -5-amidinoindole; 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5- amidinoindole; 3- (4- (2-ethylaminosulfonyl) phenyl) phenylaminocarbonyl-methyl-5-amidinoindole; 3- (4- (2-propylaminosulfonyl) phenyl) phenyl) amino-carbonylmethyl-5-amidinoindole; 2-methyl-3-. { 2-iodo-4- (2-aminosulfonyl) phenyl) phenyl} -aminocarbonylmethyl-5-amidinoindole; 2-methyl-3-. { 4- (2-aminosulfonyl) phenyl) phenyl} amino-carbonylmethyl-5-amidinoindole; 3-. { 4- (2-aminosulfonyl) phenyl) phenyl} -N-methylamino-carbonylmethyl-5-amidinoindole; 2-methyl-3-. { 4- (2-t-butylaminosulfonyl) phenyl) phenyl} -aminocarbonylmethyl-5-methoxyindole; and, 3-. { 4- (2-N-methylaminosulfonyl) phenyl) phenyl} -N-methy1-aminocarbonylmethyl-5-amidinoindole; or a stereoisomer or pharmaceutically acceptable salt thereof. [7] In a more preferred embodiment, the present invention provides compounds of formula IVa: IVa in which A, B, D, and Z are as defined above. [8] In another still more preferred embodiment, the present invention provides compounds selected from: 3-. { 4- (2- (n-butylaminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindoline; 3-. { 4- (2- (n-propylaminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindoline; (-) -3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5-amidinoindoline; 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5-amidinoindoline; 3- (4- (2-dimethylaminosulfonyl) phenyl) phenylamino-carbonylmethyl-5-amidinoindoline; (+) - 3 - (4- (2-t-Butylaminosulfonyl) phenyl) pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; (-) - 3 - (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-yl) to o-carbonylmethyl-5-aminocarboxyindoline; 3-. { 4- (2-t-butylaminosulfonyl) phenyl) phenyl} amino-carbonylmethyl-5-amidinoindoline; and, 3-. { 4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl} α-indocarbonylmethyl-5-amidinoindoline; or a stereoisomer or pharmaceutically acceptable salt thereof. [9] In another more preferred embodiment, the present invention provides compounds of formula IVb: IVb in which A, B, D, and Z are as defined above. [10] In another still more preferred embodiment, the present invention provides compounds selected from: 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-6-amidinoindazole; i 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-1-6-amidinoindazole; 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-6-amidinoindazole; and, 3- (4- (2-t-butylaminosulfonyl) phenyl) phenylamino-carbonylmethyl-6-amidinoindazole; or a stereoisomer or pharmaceutically acceptable salt thereof. [11] In another more preferred embodiment, the present invention provides compounds of formula IVc: IVc in which D, Da, Z, A, and B are as defined above. [12] In another still more preferred embodiment, the present invention provides compounds selected from: [4- (phenyl) phenylcarbonyl] methyl-β-amidino-beneimidazole; [4- (phenyl) phenylcarbonyl] methyl-5-amidino-benzimidazole; [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidino-benzimidazole; [4- (3-aminophenyl) phenylcarbonyl] methyl-5-amidino-benzimidazole; [4- (4-fluorophenyl) phenylcarbonyl] methyl-6-amidino-benzimidazole; [4- (4-formylphenyl) phenylcarbonyl] methyl-6-amidino-benzimidazole; [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole; [4- (2-tert-butylaminosulfonylphenyl) phenylcarbonyl] -methyl-6-amidinobenzimidazole; . { 4- [(2-tetrazolyl) phenyl] phenylcarbonyl} methyl-6-amidinobenzimidazole; [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-6-amidinobenzimidazole; [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-5-amidinobenzimidazole; 1- (4-benzylpiperidincarbonyl) methyl-6-amidino-benzimidazole; 1- (4-benzylpiperidinecarbonyl) methyl-5-amidino-benzimidazole; 1- (4-benzylpiperidincarbonyl) methyl-6-amidino-benzimidazole; 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amidinobenzyl idazole; 2- [4- (2-tert-Butylaminosulfonylphenyl) phenylcarbonyl] -methyl-5-azabenzimidazole; 2S- [4- (2-tert-aminosulfonylphenyl) phenylamino-carbonyl] methyl-thio-lH-imidazo (4,5-C) pyridine; and, 2S- [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] -methylthio-lH-imidazo (4,5-C) pyridine; or a stereoisomer or pharmaceutically acceptable salt form thereof. [13] In a preferred embodiment, the present invention provides compounds of formula V: v wherein one of R and Ra is - (CH2) n-Z-A-B and the other H; W, 2, and W3 are selected from CH and N, provided that at least one of W, W2, and W3 can be N; J is selected from N and C-R1; R1 is selected from H, O, (CH2) r0R3, (CH2) rC (= 0) R2, (CH = CH) C (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, (CH2) rNR3S02R4, and (CH2) r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S; R2 is selected from H, OR3, C? _4 alkyl, NR3R3 ', CF3, and a C3-10 carbocyclic residue substituted with 0-2 R6; R3 and R3 'are independently selected from H, C1-4 alkyl, and a carbocyclic residue of C3_? 0 substituted with 0-2 R6; R 4 is selected from OR 3, C 1-4 alkyl, NR 3 R 3 ', and a C 3-10 carbocyclic residue substituted with 0-2 R 6; Z is selected from CH = CH, CH (CH2) mQ (CH2) mR5, CH. { (CH2) mQ (CH2) mR5) C (0) NR3, CH (CH2) mC (0) (CH2) mR5 N (CH2) qQ (CH2) mR3, NQ '(CH2) mR °, C (O) N ((CH2) mQ' (CH2) mRDa), C (O), C (0) CH2, C (0) 0, 0C (0), C (O) NR3 (CH2) r, NR3C (0), 0C (0) NR3, NR3C (0) 0, NR3C (0) NR3, S (0) p, "S02CH2, S02NR3 , NR3S02, and R3S02NR3; Q is selected from a bond, O, NR3, C (0), C (0) NR3, NR3C (0), S02, NR3S02, 'and S02NR3; Q' is selected from a bond, C (0), C (0) NR, S02, and S02NR3 R5 is selected from H, C? _4 alkyl, a C3-8 carbocyclic residue substituted with 0-2 R6, and a 5-10 membered heterocyclic system which contains from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6, provided that when Q is S02 or NR3S02, R5 is different from H and when Q 'is S02, R5 is different from H; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, a carbocyclic residue of C3_? 0 substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from: H, X-Y, NR3R3 ', C (= NR3) NR3R3', NR3C (= NR3) NR3R3 ', benzyl substituted with 0-2 R6, a carbocyclic residue of C3_? 0 substituted with 0-2 R% Y a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from alkylene of C? -4, -C (O) -, -C (0) CRJR-, -CRJRJC (0), -S (0) p-, -S (0) PCRJRJ -, -CR ) 3JRn3J 'S (O) p-, -S (0) 2NR3-, -NR3S (O) -C (0) NR-, -NRJC (0) -, -NR-, -CRJRJ NR-3-, O, -CR 3JpR3J ', O-, and -; Y is selected from: a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2) nR3, halo, C4-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C ( 0) NR3R3 ', CH (= NH) NH2, NHC (= NH) NH2, C (= 0) R3, S02NR3R3', NR3S02NR3R3 ', and NR3S02-C? -4 alkyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4. [14] In another more preferred embodiment, the present invention provides compounds of formula VI: saw wherein one of R and Ra is - (CH2) n-Z-A-B and the other is H; W and W2 are selected from CH and N, provided that at least one of W and W2 can be N; J is selected from N and C-R1; R1 is selected from H, (CH2) r0R3, (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH = CH) C (= 0) R2, (CH2) rS02R4, and ( CH2) rNR3S02R4; R2 is selected from H, OR3, C? - alkyl, NR3R3 ', and CF3; R3 and R3 'are independently selected from H, C? -4 alkyl, and phenyl; R 4 is selected from OR 3, C 4 alkyl, NR 3 R 3 ', and phenyl; Z is selected from C (0), C (0) CH2, C (0) NR3, NR3C (0), S (0) 2, S02CH2, S02NR3, NR3S02, and NR3S02NR3; A is selected from: a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0 -2 R6; B is selected from: XY, a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from -C (O) -, -C (O) CR3R3'-, -CR3R3'C (0), -S (0) p-, -S (0) pCR3R3'-, -CR3R3'S (0) p-, -S (0) 2NR3-, -NR3S (0) 2-, -C (0) NR3-, -NR3-, -NR3CR3R3'-, and -CR3R3'NR3-; Y is selected from: a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0 -2 R6; R6 is selected from H, OH, (CH2) n0R3, halo, C1-4alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C (0 ) NR3R3 ', C (= 0) R3, S02NR3R3', NR3S02NR3R3 ', and NR3S02-alkyl? of C? _; n is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4. [15] In another still more preferred embodiment, the present invention provides compounds of formula VII: VII in which, W and W2 are selected from CH and N, provided that at least one of W and W2 can be N; R1 is selected from H, (CH2) rOR3, (CH2) rC (= 0) R2 ,, (CH2) rNR3C (= 0) R2, (CH = CH) C (= 0) R2, (CH2) rS02R4, and (CH2) rNR3S02R4; R2 is selected from H, OR3, C? _4 alkyl NR3R3 ', and CF3; R3 and R3 'are independently selected from H, C? _4 alkyl, and phenyl; R 4 is selected from OR 3, C 1 - alkyl, NR 3 R 3 ', and phenyl; Z is selected from C (O), C (0) CH2, C (0) NR3, S (0) 2, S02CH2, S02NR3, and NR3S02NR3; A is selected from: a C3_? 0 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0 -2 R6; B is selected from: X-Y, a carbocyclic residue of C3-? 0 substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from -S (0) p-, -S (0) pCR3R3'-, -S (0) 2NR3-, -NR3S (0) 2-, and -C (0) NR3-; Y is selected from: a C3_? 0 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0 -2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2) rNRJRJ (CH2) rC (0) R3, NR3C (0) R3 NR3C (0) NR3R3 ', C (= 0) R3, S02NR3R3', NR3S02NR3R3 ', and NR3S02-C? N alkyl is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4. [16] In another more preferred embodiment, the present invention provides compounds selected from: 1- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole; 1- (4-benzylpiperidincarbonyl) ethyl-5-amidinoindole; 1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-amidinoindole; 1- (1- (4-amidino) benzyl-N- (methylaceta) aminocarbonyl) methyl-5-amidinoindole; 1- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole-3-methyl propanoate; 1- ((4-benzylpiperidincarbonyl) methyl- (3-ethan-hydroxyl) -5-amidinoindole; 5-amidinoindole 1- (4-benzylpiperidine-1-carbonyl) methyl-3-methylcarboxylic acid; 1- (1-benzylpiperidine) 4-aminocarbonyl) methyl-5-amidinoindole; 1- (4-benzoylpiperidincarbonyl) methyl-5-amidinoindole; 1- (4- (3-fluoro) benzylpiperazincarbonyl) methyl-5-amidinoindole; 1- (4-phenylbenzylaminocarbonyl) methyl- 5-amidinoindole; 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole-3-methyl propanoate; and 1 (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-amidinoindole; or a stereoisomer or pharmaceutically salt form In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically active proprinciple form. acceptable in the same way, in a third modality, the present and invention provides a novel method for treating or preventing a thromboembolic condition, comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable form of proprinciple thereof. .

DEFINITIONS The compounds described herein may have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be substituted in optically active or racemic form. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic and all geometric isomeric forms of a structure are intended, unless the specific stereochemical or isometric form is specifically indicated.

When any variable (for example, R6) occurs more than once in any constituent or formula of a compound, its definition each time it occurs is independent of its definition at another time it occurs. Thus, for example, if a group is substituted with 0-2 R6, then such a group can be optionally substituted with up to two R6 and R6 each time it occurs, it is independently selected from the defined list of possible R6. Also, combinations of substituents and / or variables are allowed only if such combinations result in stable compounds. As used herein, 'Cl-4 alkyl' is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl , ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl; it is intended that the 'lkenyl' include hydrocarbon chains of straight or branched configuration and one or more unsaturated carbon-carbon bonds, which may be at any stable point along the chain, such as ethenyl, propenyl, and the like "Halo" or "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine, and "counterion" was used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate , sulfate, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any unicycle or bicyclo of 3 to 7 members or bicyclo or tricycle of 7 to 10 members, any of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin) , [2.2.2] bicyclooctane, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a 5- to 7-membered monocyclic or bicyclic heterocyclic or 7- to 10-membered bicyclic ring, which is saturated, partially unsaturated or unsaturated (aromatic) and which consists of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and includes any bicyclic group in which any of the heterocyclic rings identified I above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein can be substituted on the carbon atom or one of nitrogen, if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be in its quaternary form. It is preferred that, when the total number of S atoms and 0 in the heterocycle exceeds 1, then those heteroatoms are not adjacent to each other. As used herein, the term "aromatic heterocyclic system" is intended to mean a 5- to 7-membered monocyclic or bicyclic heterocyclic or 7- to 10-membered bicyclic heterocyclic ring, which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group which consists of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. Examples of heterocycles include, but are not limited to lH-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolicinyl, 6H-1, 2, 5-thiadiacinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranoyl, benzothiophenyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, anilyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2, 3-b ] tetrahydrofuran, furanyl, furazanyl, imidazoli dichloridyl, imidazolyl, 1H-indazolyl, indolenyl, indolenyl, indolinyl, indolicinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, fenarsazinilo, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl / 4H-quinolicinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6iT-1, 2,5-thiadiazinyl, thiantrenyl, thiazolyl, thienyl, thienothiazole, thienooxazole, thienoimidazole, thiophenil, triazinyl, xanthenyl . Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused and spiro ring compounds, which contain, for example, the above heterocycles. When a bond for a substituent is shown by crossing the bond connecting two atoms in a ring, then such a substituent may be attached to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is attached to the rest of the compound of a given formula, then such a substituent may be attached via any atom in such a substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The term 'substituted', as used herein, means that any one or more hydrogens on the designated atom are replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded, and that substitution of resulting in a stable compound When a substituent is keto (ie, = 0), then 2 hydrogens are replaced on the atom As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds, wherein the Original compound was modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues, such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymalonic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acidic or basic portion by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of those compounds in a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms, which are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication commensurate with the reasonable benefit / risk ratio "Active principles" are intended to include any covalently bonded carrier that releases the original active principle according to formula (I) in vivo when such active proprinciple is administered to a mammalian subject. The active proprinciples of a compound of formula (I) are prepared by modifying the functional groups present in the compound, such that the modifications are cleaved, either in routine manipulation or in vivo, the parent compound. Active proprinciples include compounds of formula (I), wherein a hydroxy, amino, or sulfanyl group is attached to any group which, when the active proprinciple or compound of formula (I) is administered to a mammalian subject, is cleaved to form a free hydroxyl group, free amino, or free sulfhydryl, respectively. Examples of active proprinciples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I) and the like. Preferred active proprinciples are the active proprinciples of amidine, wherein either D or Da is C (= NH) N (H) R 10, and R 10 is selected from OH, d-4 alkoxy, C 6 -aryloxy or, C6- [alpha] 4-aryloxycarbonyl, C6_ [alpha] aryloxycarbonyl, C6_ [alpha] 0- arylmethylcarbonyl, C [beta] 4-alkylalkanoyloxy, C [beta] -4-alkoxycarbonyl, and C6- [alpha] 4-arylcarbonyloxy, or C [beta] 4-alkoxycarbonyl. The most preferred active principles are, wherein R7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyl-xethoxycarbonyl. "Stable compound" and "stable structure" mean that they indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture, and formulation into an effective therapeutic agent.

SYNTHESIS The compounds of the present invention can be prepared in numerous ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below, therefore, are incorporated herein by reference. All temperatures were reported here in degrees Celsius. The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions were carried out in a suitable solvent for the reagents and materials used and suitable for the transformations carried out. It is understood by those skilled in the art of organic synthesis that the functionality present on the molecule must be consistent with the proposed transformations. This will sometimes require a judgment to modify the order of the synthetic steps or to select a particular process scheme over another to obtain a desired compound of the invention. It should also be recognized that another major consideration in the planning of any synthetic route in this field is the careful choice of the protecting groups used for the protection of the reactive functional groups present in the compounds described in this invention. An alternative that describes the many alternatives to a trained practitioner is Greene and uts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). The following descriptions give the details of the general methods for producing benzimidazoles, indazoles and indoles through a variety of intermediates. It is not intended that these methods represent all possible means to produce the above compounds, simply a broad representation. One skilled in the art would readily understand that starting groups would be necessary to produce all of the compounds herein. Intermediate 1, which can be formed via the acylation of 4-amino-3-nitrobenzonitrile (Aldrich Chemical Co.) with an acyl chloride (R1CH0) or an anhydride ((RaC0) 20) in the presence of a base, followed by the hydrogenation is shown in Scheme 1. The reductive amination of an aldehyde (RCHO) in the presence of 1 using boran-pyridine in acetic acid can give the N-alkylated product 2. The alkylation of 1 with a halide (P3X) in the presence of a base, such as Cs2C03, can provide compound 3. Compounds 2 and 3 can be subjected to the Pinner reaction, to give the 6-amidino-benzimidazole derivative 4 and the 5-amidino-benzimidazole derivative 5, respectively (see Khanna et al J. Org. Chem. 1995, 60, 960).

Scheme 1: Amidino-benzimidazoles, via 4-amino-3-nitrobenzonitrile Scheme 2 shows that palladium (0) catalyzed coupling of the 3-amino-4-nitrophenyl halides with zinc cyanide in low DMF or reflux can provide compound 6 (see Lawton et al J. Org Chem. 1959, 24, 26). Acylation of 6 with an acyl chloride or anhydride in the presence of a base, followed by hydrogenation can form compound 7. Alkylation of 7 with a halide in the presence of a base, such as Cs2CO3, can provide compound 8. Reductive amination of an aldehyde with 7, using boran-pyridine in acetic acid can give the N-alkylated product 9. Compounds 8 and 9 can be converted to its 6-amidino-benzimidazole or 5-amidino-benzimidazole derivative, respectively via the Pinner reaction.

Scheme 2: Amidino-benzimidazoles via the 3-ap-ino- ^ 4-nitrophenyl halides The Ullmann reaction of 4-chloro-3-nitrobenzonitrile with an amine (P3NH2) in the presence of a base, such as NaHC03, can form the compound 10 shown in Scheme 3. Hydrogenation of 10, followed by acid cyclization, such as formic acid, can give compound 5, which can be converted to its derivatives. -amidino-benzimidazole as described above. In addition, compound 5 could be derivatized by the addition of Br- (CH 2) n-Z-A-B and the resulting mixture subjected to the Pinner reaction and separated by standard techniques.

\ Scheme 3: Amidino-benzimidazoles via the Ullmann Reaction As described in Scheme 4, the bromination of the 4-aminobenzonitrile with NBS, followed by treatment with NaN02 and Cu20 in concentrated HCl, can provide compound 11 (see Tsuji et al Chem. Pharm. Bull, 1992, 40, 2399). Reaction of Ullma n of 11 with an amine in the presence of a base, such as NaHCO 3, can form compound 12. Hydrogenation of 11, followed by cyclization with formic acid can give compound 8, which can be converted to its 6-amidino-benzimidazole derivative as described above.

Scheme 4: Amidino-benzimidazoles via the Ullmann Reaction Scheme 5 gives the details of the synthesis of the amidino-benzimidazoles substituted in the 2-position from 3,4-diamino-benzonitrile and 3-amino-4-hydroxybenzonitrile 13, which are obtained by the hydrogenation of the 4-amino -3-nitro-benzonitrile or 4-hydroxy-3-nitrobenzonitrile. Treatment of 13 with an acyl chloride or an acid in the presence of PPA can form compound 14 (see Walker et al Synthesis 1981, 303). Compound 14 can be converted to its amidino derivative via the Pinner reaction. Alternatively, when Y is NH, the alkylation of 14 with a halide in the presence of a base, such as K2C03, can give a mixture of two regioisomers 15 and 16, which can, after being separated, be subjected to the Pinner reaction to give the substituted 6-amidino-benzimidazole derivatives at position 2 and substituted 5-amidino-benzimidazoles at position 2, respectively.

Scheme 5: Amidino-benzimidazoles substituted at position 2 Protection of 6-hydroxy-indazole with pivalic anhydride in the presence of a base, followed by treatment with triflic anhydride can give compound 17, as shown in Scheme 6. - Palladium-catalyzed coupling (O) of 17 with Zinc cyanide can provide compound 18. Deprotection of compound 18 under acidic conditions, followed by alkylation with a halide in the presence of a base can be compound 19, which can be converted to its 6-amidino-indazole derivative via the Pinner reaction.

Scheme 6: Amidino-benzimidazoles via 6-hydroxy-indazole The amidino-indoles and indazoles substituted at position 1, could be made from 5-cyanoindole as set forth below in Scheme 7. Intermediate 21 can be easily obtained via the alkylation of 20 with Br (CH2) nZ. Peptide coupling with H-A-B using a BOP reagent or alkylation gives the intermediate 22, which can then be converted to arr-idino 23 under Pinner conditions.

Scheme 7: Amidino-indoles and indazoles substituted at position 1 from 5-cyanoindazole (- ^ "CH or N) alkylation 22 H-A.-B Scheme 8 shows that amidino-indoles and substituted indazoles at the 3-position of 5-cyanoindole are also derivable. Compound 26 can be obtained by substituting R1 on 24 to form 25 and acylating 25 in the presence of oxalyl chloride at normal temperature under a nitrogen atmosphere. The compound can be subjected to selective ketonic reduction with triethylsilane in trifluoroacetic acid for 3 h and then coupled with H-A-B.

Scheme 8: Amidino-indoles and indazoles substituted in position 3 from 5-cyanoindole (J * = CH or N) Piperazin phenylsulfonamide, 31, and various other sulfonamide analogues can be prepared from commercially available BOC-piperazine, via sulfonation with phenylsulfonyl chloride in CH2C12 and triethylamine, as indicated in Scheme 9.

Scheme 9: Phenyl sulphonylpiperazines from Bocipaperazine The biphenyl compounds can be prepared by methods known to those skilled in the art. For example, Scheme 10 shows how to obtain substituted biphenyls via a Suzuki coupling with 4-bromoaniline (or 1-bromo-4-nitrobenzene) protected with BOC to give compound 35.

Scheme 10: Biphenyls and bromoaniline Compound 38 can be obtained via the deprotection of the t-butyl group when R -S02NH-t-Bu, with TFA followed by alkylation or acylation with R3X as set forth in Scheme 11.

Scheme 11: Preparation of 4'-amino-biphenyl-2-sulfonamides Scheme 12 shows how intermediates 43-45 can be obtained via the same intermediate 39. Acylation with oxalyl chloride followed by the addition of methanol should produce the ketoester 40 and selective reduction with triethylsilane can give methyl acetate 42. The reduction with sodium borohydride, can give the alcohol, which can then be converted to 45 with R3X. Intermediate 43 can be obtained via formylation with P0C13 in DMF to give aldehyde 41, which could then be subjected to an olefination of Wittig to give compound 43.

Scheme 12: Addition of R 1 substituted to indoles or substituted indazoles in position 1 The sulfonyl chloride 49 can be obtained via aldehyde 47. The aldehyde can be reduced with sodium borohydride, sulfonated with methane sulfonyl chloride, and displaced with sodium sulfite in ethanol. Sodium chloride 49 will then be obtained via chlorination with sulfonyl chloride as detailed in Scheme 13.

Scheme 13: Addition of R1 to protected indoles or indazoles in position 1 P is a protective group, for example, a MEM group. Scheme 14 gives details of how the substitution at position 2 of indole can be carried out via lithiation with s-BuLi at -78 ° C followed by the addition of 'RXX to give the compound 51. The compound 51 can then be converted to the compound 52 by the aforementioned methodology.

Scheme 14: Addition of two R1 'to the indole protected in 1: position 1 In Scheme 15, it is shown how the compound 5-cyanoindole 54 can be prepared via compound 53 using sodium methoxide in the presence of nitromethane, followed by reduction with zinc and condensation.

Scheme 15: Formation of Índoles "° x" and I H Groups A and B are available either from commercial sources, known in the literature or are easily synthesized by adapting standard procedures known to those skilled in the art of organic synthesis. Required reactive functional groups appended to analogs of A and B, are also available, either through commercial sources r known in the literature, or can be easily synthesized by adapting standard procedures known to those skilled in the art. Organic synthesis. In the following tables, the chemical parameters required to effect the coupling from A to B are exposed.

Table 1: Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamide bonds between A and B.

Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) The chemical process of Table 1 can be carried out in aprotic solvents such as chlorocarbide, pyridine, benzene or toluene, at temperatures ranging from -20 ° C to the point of reflux of the solvent and with or without a trialkylamine base.

Table 2: Preparation of ketone link between A and B The chemical coupling procedure of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from an analogous Y halogen in dry ether, dimethoxyethane or tetrahydrofuran at 0 ° C to the point of the reflux of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, ie at low temperature (-20 ° C or less) and with a large excess of hydrochloric acid or with copper bromide complex »catalytic or stoichiometric dimethyl sulphide in sulfur of dimethyl as a solvent or with a variant thereof. Other available methods include transforming the Grignard reagent to the cadmium reagent and coupling according to the Carson and Prount procedure (Org Syn. Col. Vol. (1955) 601) or a coupling mediated by Fe (acac) 3 according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboune, Tetrahedron Lett., 33 (31), (1992) 4437).

Table 3: Preparation of ether and thioether bonds between A and B Table 3 (Continued) The ether and thioether bonds of Table 3 can be prepared by reacting the two components in an aprotic polar solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide. at a temperature that fluctuates from the ambient temperature to the reflux point of the solvent used.

Table 4: Preparation of bonds -SO- and -S02- from the thioethers of Table 3.

The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulphone analogs of Table 4. A combination of alumina and wet oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while the oxidation with m-chloroperbenzoic acid will give the sulfone. Other features of the invention will be apparent in the course of the following descriptions of the exemplary embodiments which are given to illustrate the invention and are not intended to limit the same.

EXAMPLES The synthesis of the representative compounds according to the invention is described in more detail below with reference to the following specific examples, but not limiting. The abbreviations used in the Examples are defined as follows: * ° c "for degrees Celsius, * d" for doublet, 'dd "for doublet of doublets,' DAST" for trifluoride of diethylaminosulfide, 'eq "for equivalent or equivalents,' g "for gram or grams, 'mg" for milligram or milligrams,' mL 'for milliliter or milliliters,? "for hydrogen or hydrogens,' hr" for hour or hours, * m "for multiplet, 'M" for molar, 'min' for minute or minutes, 'MHz' for megahertz, 'M' for mass spectroscopy, 'nmr' or 'NMR' for nuclear magnetic resonance spectroscopy, * t "for triplet, 'CCF' for thin layer chromatography Examples 1-15 were prepared by the addition of Michael 5-cyano-benzimidazole to the α, β-unsaturated esters using K 2 CO 3 (2 mmol) as a base in DMF (10 mL) at 90-110 ° C for 15 minutes. -24 hours, followed by the Pinner reaction, a mixture of meta and para isomers was obtained by purification on TLC plates with 10-20% MeOH in CH2C12. or for pure, separated by CLAP.

-Cyanobenzimidazole A solution of 4-amino-3-nitrobenzonitrile (20 mmol) in MeOH (300 mL) in the presence of 5% Pd / C (1 g) was treated with hydrogen at room temperature for 16 hours. The reaction mixture was filtered and concentrated to give 3,4-diaobenzonitrile (2.4 g, 90% yield), which was treated directly with formic acid (20 mL) under reflux for 4 hours. After removing the excess formic acid, the residue was dissolved in EtOAc, washed with 10% sodium bicarbonate and brine, and dried over MgSO4. The concentration gave 5-cyanobenzimidazole (2.2 g, 85%). XH NMR (CD3OD) d 8.39 (s, ÍH), 8.05 (s, ÍH), 7.76 (d, J = 8.4 Hz, ÍH), 7.59 (dd, J = 8.4 Hz, J = 1.1 Hz, ÍH); MS: 144 (M + H) +.

Preparation of ethyl 2- (3-cyanoyl) ethacrylate and ethyl 2- (4-phenytophenyl) ethacrylate. To a stirred suspension of zinc powder (22 mmol) in THF (10 mL) was added 1,2-dibromoethylene (0.2 g) at room temperature and the mixture was stirred for 30 minutes. A solution of 3-cyanobenzylbromide or 4-cyanobenzylbromide (20 mmol) in THF (25 mL) was slowly added at a rate of one drop for every five seconds at 5-10 ° C. The mixture was stirred for 3 hours, and then transferred to a solution of copper (I) cyanide (20 mmol) and lithium chloride (40 mmol) in THF (20 mL) at -78 ° C. The resulting mixture was heated and stirred at -20 ° C for 20 minutes, and then cooled to -78 ° C. After slowly adding ethyl 2- (bromomethyl) acrylate (20 mmol) the mixture was stirred at -78 ° C for 2 hours, and then warmed to room temperature overnight. Ether (100 L) and aqueous saturated ammonium chloride (50 mL) were added to the mixture, and the mixture was filtered. The filtrate was washed with water and brine, and dried over MgSO4. The concentration gave a residue, which was purified by column chromatography with the gradient solvent system (CH2Cl-EtOAc) to give ethyl 2- (3-cyanophenyl) ethacrylate (1.2 g, 26.2%) and the ethyl ester. Ethyl 2- (4-cyanophenyl) ethacrylate (3.6 g, 78.6%). For ethyl 2- (4-cyanophenyl) ethacrylate: * H NMR (CDC13) d 7.58 (dd, J = 8.4 Hz, J = 1.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.17 (d, J = 1.1 Hz, HH) 5.48 (dd, J = 2.6 Hz, J = 1.1 Hz, HH), 4.22 (c, J = 7.3 Hz, 2H), 2.86 (dd, J = 8.6 Hz, J = 7.1 Hz, 2H), 2.61 (dd, J = 8.6 Hz, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); MS: 247 (M + NH4) +. For 2- (3-cyanophenyl) ethacrylate. of ethyl: 1 H NMR (CDCl 3) d 7.51-7.36 (, 4H), 6.17 (s, ÍH), 5.48 (d, J = 1.1 Hz, ÍH), 4.22 (c, J = 7.3 Hz, 2H), 2.84 ( dd, J = 8.4 Hz, J = 7.0 Hz, 2H), 2.61 (dd, J = 8.4 Hz, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); 13C NMR (CDC13) d 166.80, 142.85, 139.41, 133.14, 132.05, 129.85, 129.17, 118.94, 112.43, 60.79, 34.50, 33.57, 14.22; MS 247 (M + NH4) +.

Preparation of ethyl [3- (4-sianof nyl) -2-bromomethyl] acrylate To a solution of 4-cyanobenzylbromide (40 mmol) in xylene (40 mL) was added triphenylphosphine (40 mmol) and the resulting solution was heated to 110 ° C for 2 hours. After removal of the xylene, a white solid was obtained, which was dissolved in a mixture of THF (40 mL) and EtOH (40 mL), treated with DBU (40 mmol) at room temperature for one hour, and then ethyl pyruvate (40 mmol) was added. The resulting mixture was stirred at room temperature overnight and filtered to remove the Ph3PO.The filtrate was concentrated, dissolved in EtOAc, washed with IN HCl, water and brine, and dried over MgSO4. mixture of cis and trans olefins in an almost quantitative yield A solution of the olefins (5 mmol), NBS (5 mmol), and AIBN (0.25 mmol) in CC14 (200 mL) was refluxed under nitrogen for 16 hours, it was filtered, concentrated and purified by column chromatography with the gradient solvent system (CH2Cl2-Et0Ac) to give the title compound (1.25 g, 85%) as a white solid, XH NMR (CDC13) d 7.71 ( d, J = 1.4 Hz, ÍH), 7.68 (d, J = 8.8 Hz, 2H), 7.58 (J = 8.5 Hz, 2H), 4.29 (c, J = 7.3 Hz, 2H), 4.23 (s, 2H) , 1.32 (t, J = 7.3 Hz, 3H).

Preparation of ethyl 2- (4-benzyloxyphenyl) methacrylate A mixture of 4-bromophenol (40 mmol), benzyl bromide (40 mmol) and Na 2 CO 3 in DMF (200 mL) was stirred at room temperature for 24 hours and then poured in water A solid was collected and further recrystallized from hexane to give 4-benzyloxybenzene bromide in an almost quantitative yield. A solution of the bromide in THF (100 L) was treated with BuLi (44 mmol) at -78 ° C for 30 minutes and then with a solution of Znl2 (40 mmol) in THF (40 mL) for 20 minutes. After the resulting mixture was warmed to room temperature for one hour, it was cooled to -78 ° C and a solution of copper (I) cyanide (40 mmol) and lithium chloride (80 mmol) in THF ( 50 mL). The resulting mixture was heated and stirred at -20 ° C for 20 minutes, cooled to -78 ° C, and ethyl 2- (bromomethyl) acrylate (40 mmol) was added thereto. The resulting mixture was stirred at -78 ° C for 2 hours and then warmed to room temperature overnight. Ether and saturated aqueous ammonium chloride were added and filtered. The filtrate was washed with water and brine, and dried over MgSO4. The concentration gave a residue, which was purified by column chromatography with the gradient solvent system (CH2Cl2-Et0Ac) to give the title compound (3.6 g, 30.4%): XH NMR (CDC13) d 7.44-7.26 ( , 5H), 7.12 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.20 (s, ÍH), 5.92 (s, ÍH), 5.07 (s, 2H), 4.18 (c, J = 7.4 Hz, 2H), 3.57 (s, 2H), 1.27 (t, J = 7.4 Hz, 3H); MS: 314 (M + NH4) +.

EXAMPLE 1 Preparation of ethyl 2- (3-apylinophenyl) ethyl-3- (5-amidinobenzimidazole) propionate and ethyl 2- (3-amidinophenyl) ethyl-3- (6-amidinobenzimidazole) propionate A mixture of -cyanobenzimidazole (2 mmol), ethyl 2- (3-cyanophenyl) ethacrylate (2 mmol) and K2CO3 (2 mmol) in DMF (10 L) was heated at 90 ° C under nitrogen for 16 hours. The mixture was diluted with EtOAc (150 mL), washed with IN HCl, water, and brine, and dried over MgSO4. After filtration and concentration, the residue was purified by column chromatography with the gradient solvent system - (CH2Cl2-EtOAc) to give a mixture of 2- (3-cyanophenyl) ethyl-3- (6-cyano-benzimidazole ethyl propionate and ethyl 2- (3-cyanophenyl) methyl-3- (5-cyanobenzimidazole) propionate (0.57 g, 76.4%) as a colorless oil. XH NMR (CDC13) d 8.13-7.36 (m, 8H) 4.55 (dd, J = 14.3 Hz, J = 9.2 Hz, 1H), 4. 28 (dd, J = 14.3 Hz, J = 5.5 Hz, ÍH), 4.07 (c, J = 7.0 Hz, 2H), 3.00-2.91 (m, ÍH), 2.80-2.64 (m, 2H), 2.18-2.07 (m, ÍH), 1.92-1.82 (m, ÍH), 1.12 (t, J = 7.0, 3H).

Examples 2 and 3 Preparation of ethyl 2- (3-amidinophenyl) ethyl-3- (5-amidinobenzimide-zol) propionate and ethyl 2- (3-amidinophenyl) ethyl-3- (d-amidinobenzimidazole) propionate The mixture of esters obtained in Example 1 was treated with HCl (gas) in anhydrous ethanol (10 mL) for 15 minutes at 0 ° C and then stirred for 16 hours.

After removing the excess HCl (gas) and ethanol, the residue was treated with (NH) 2 CO 3 (5 equivalents) in anhydrous ethanol (10 mL) at room temperature for 24 hours. Concentration gave a residue, which was purified on TLC plates with 10% MeOH in CH2C12 to give a mixture of the title compounds (400 mg, 65.4%): p. F. 160-165 ° C; ESEM: 204.2 (M + 2H) 2+. The mixture was further separated by CLAP on a chiral OJ column csn C02 / MeOH / TEA (30/20 / 0.1) to give Example 2, ethyl 2- (3-amidinophenyl) ethyl-3- (5-amidinobenzimidazole) propionate, and Example 3, Ethyl 2- (3-amidinophenyl) ethyl-3- (6-amidinobenzimidazole) propionate. Example 2: H NMR (CD3OD) d 8.36 (s, 1H), 8.17 (s, ÍH), 7.75-7.72 (, 2H) 7.63 (broad s, 2H), 7.50-7.43 (, 2H), 4.66 (dd, J = 9.5 Hz, J = 14.3 Hz, HH), 4.55 (dd, J = 5.5 Hz, J = 14.2 Hz, HH), 4.02-3.92 (m, 2H), 3.14-3.03 (m, HH), 2.81 ( t, J = 7.0 Hz, 2H), 2.19-1.93 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H); ESEM: 204.2 (M + 2H) 2+. Example 3: tE NMR (CD3QD) d 8.37 (s, ÍH), 8.10 (s, ÍH), 7.84 (d, J = 8.4 Hz, ÍH), 7.72 (d, J = 2.4 Hz, 1H), 7.65-7.62 (m, 2H), 7.55-7.46 (m, 2H), 4.68 (dd, J = 9.5 Hz, J = 14.3 Hz, ÍH), 4.56 (dd, J = 5.5 Hz, J = 34.2 Hz, 1H), 4.04 -3.94 (m, 2H), 3.24-3.18 (, ÍH), 2.83 (t, J = 7.0 Hz, 2H), 2.19-1.95 (m, 2H), 1.05 (t, J = 7.0 Hz, 3H); ESEM: 204.2 (M + 2H) 2 + Example 4 Preparation of ethyl 2- (-amidinophenyl) ethyl-3- (5-amidinobenzimidazole) propionate and ethyl 2- (4-amidino-enyl) ethyl-3- (6-amidinobenzimidazole) propionate Example 4 was made using the same method as that described for Example 1, except that ethyl 2- (4-cyanophenyl) ethacrylate (2 mmol) (100 mg, 13% for two steps) was used: p. f. 230 ° C (With decomposition); ESEM: 407 (M + H) +; HREM: 407.2200 (obs.), 407.2195 (calculated) for C22H26N6O2. Example 4 was further separated to give Examples 5 and 6.

Examples 5 and 6 Preparation of ethyl 2- (4-amidinophenyl) tyl-3- (5-arnidinobenzimidazole) propionate and 2- (4- to idinophenyl) ethyl-3- (β-amidinobenzimidazole) ethyl propionate The mixture of the compounds obtained in the Example 4 was further separated to give Examples 5 and 6. Example 5 Ethyl 2- (4-amidinophenyl) ethyl-3- (5-amidinobenzimidazole) propionate: 1 H NMR (DMSO-d 6): d 9.43-9.08 (m, 6H), 7.74-7.65 (, 2H), 7.40-7.38 (, 2H), 7.35-7.00 (m, 4H), 4.67-4.55 (m, 2H), 4.06 (s broad, 2H), 3.48 (s broad, 2H), 3.20 (s broad, ÍH), 2.70 (s broad, 2H), 1.00 (s broad, 3H); ESEM: 407 (M + H) +. Example 6, ethyl 2- (4-amidinophenyl) ethyl-3- (6-amidinobenzimidazole) propionate: XH NMR (DMS0-d6): d 9.23-9.12 (m, 6H), 8.41 (s, .IH), 8.21 (s, ÍH), 7.84-7.82 (m, ÍH), 7.74 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.24 (s broad, ÍH), 4.58-4 : 56 (, 2H), 3.95-3.89 (m, 2H), 3.10-3.00 (m, ÍH), 2.73-2.71 (m, 2H) 1.90-1.88 (m, 2H), 0.98-0.96 (m, 3H); ESEM: 407 (M + H) +.

Example 7 Preparation of Ethyl [3- (4-amidinophenyl) -2- (5-amidinobenzipiidazole) methyl] methacrylate A mixture of 5-cyanobenzimidazole (2 mmol), [3- (4-cyanophenyl) -2-bromomethyl] acrylate of ethyl (2 mmol) and K2CO3 (2 mmol) in DMF (10 mL) was heated at 90 ° C under nitrogen for 24 hours. The mixture was diluted with EtOAc (150 L), washed with 1N HCl, water, and brine, and dried over MgSO4. After filtration and concentration, the residue was purified by column chromatography (CH2Cl2-Et0Ac) to give ethyl [3- (4-cyanophenyl) -2- (5-cyanobenzimidazole) -methyl] acrylate (0.401 g, 56.3%) as a colorless oil. * H NMR (CDC13) d 8.10-8.00 (m, 4H), 7.83-7.77 (m, 2H), 7.52-7.44 (m, 2H), 7.01-6.98 (m, ÍH), 5.20 (s, 2H), 4.24 (c, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H); MS: 357 (M + H) +. The Pinner reaction converted ethyl [3- (4-cyanophenyl) -2- (5-cyanobenzimidazole) methyl] acrylate (0.42 mmol) to the title compound (400 mg, 65.4%): XH NMR (CD30D) d 8.19-8.12 (m, 2H), 7.92-7.88 (m, 3H), 7.74-7.69 (m, 4H), 4.22-4.19 (, 2H), 1.24-1.20 (m, 3H); ESEM: 196.2 (M + 2H) 2+; HREM: 391.1889 (obs.), 391.1882 (calculated).

EXAMPLE 8 Preparation of ethyl 2- (4-amidinophenyl) methyl-3- (6- to idinobenzimidazole) propionate and ethyl 2- (4-amldinophenyl) methyl-3- (5-amidinobenzimidazole) propionate Hydrogenated [3 - (4-cyanophenyl) -2- (5-cyanobenzimidazole) methyl] ethyl acrylate in MeOH in the presence of 10% palladium on activated carbon to give 2- (4-cyanophenyl) ethyl-3- (6-cyanobenzimidazole) ethyl propionate and 2- (4-cyanophenyl) methyl-3- (5-cyanobenzimidazole) ethyl propionate: 2H NMR (CDC13) d 8.24-8.02 (m, 2H), 7.87-7.50 (m, 4H), 7.34 -7.28 (m, 2H), 4.58-4.55 (m, ÍH), 4.32-4.27 (m, ÍH), 4.12-3.93 (m, 2H), 3.20-2.91 (m, 2H), 2.79-2.72 (m, ÍH), 1.10-0.95 (m, 3H). The obtained mixture (1.5 mmol) was subjected to the Pinner reaction to obtain the title compound (300 mg, 48%): 2 H NMR (CD30D): d 8.63 (broad s, HI), 8.27-7.96 (, 7H) , 4.98-4.54 (m, 2H), 3.98-3.80 (, 2H), 3.53-3.45 (m, ÍH), 3.37-3.09 (m, 2H), 1.00-0.96 (m, 3H); ESEM: 197 (M + 2H) 2+. Examples 51-63 were prepared by Method A, B, or C. All compounds were finally purified by CLAP (CH3CN / H2 / 0.05% TFA). Method A: Examples 51-59 were made by Suzuki coupling reactions of [(4-bromophenyl) carbonyl] methyl-6-cyanobenzimidazole or [(4-bromophenyl) carbonyl] methyl-5-cyanobenzimidazsl with a variety of boronic acids using Na2C03 (2-4 equivalents) and Pd (PPh3) 4 (5-10% mol "1) as a catalyst in THF (80% in H20, 10 mL / mmol), followed by Pinner reactions. of [(4-bromophenyl) carbonyl] methyl-6-cyanobenzimidazole and [(4-bromophenyl) carbonyl] methyl-5-cyanobenzimidazole with a yield greater than 90% by the alkylation of 5-cyano-benzyl idazole (36 mmol) with 2, 4'-dibromoacetophenone (36 mmol) using NaH (48 mmol) as a base in THF (80 mL) The mixture was isolated by CLAP on an OJ quiracel column with MeOH / C02 (20/80) to give the compounds single ([4-Bromophenyl) carbonyl] methyl-6-cyanobenzimidazole: tE NMR (CDC13) d 8.35 (s, 1H), 8.11 (dd, J = 1.1 Hz, J = 0.7 Hz, 1H), 8.08 (d , J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.56, J = 8.4 Hz, J = 1.8 Hz, ÍH), 6.16 (s, ÍH); ESEM: 340/342 (M + H) +. [(4-Bromophenyl) carbonyl] methyl-5-cyanobenzimidazole: X H NMR (CDCl 3) d 8.31 (s, ÍH), 8.13 (t, J = 0.7 Hz, ÍH), 8.07 (d, J = 8.8 Hz, 2H) , 7.81 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 4 Hz, J = 0.7 Hz, ÍH), 7.57 (dd, J = 8.4 Hz, J = 1.1 Hz, 1H), 6.15 (s) , ÍH); ESEM: 340/342 (M + H) +.

Example 51 Preparation of [4- (phenyl) enylcarbonyl] methyl-6-amidi-obencimidazole P.F .: 155-157 ° C; XH NMR (CD30D) d 8.44 (s, ÍH), 8.23 (d, J = 8.4 Hz, ÍH), 8.07 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 8.8 Hz, ÍH), 7.88 (dd, J = 8.4, 2H), 7.72 (dd, J = 8.4 Hz, J = 1.1 Hz, 3H), 7.52-7.41 (m, 3H), 6.10 (s, 2H); MS: 355 (M + H) +, HREM: 355. 1554 (obs.), 355. 1559 (calculated); Analysis: (C22H? 8N40 + 0 .9 TFA 1.2. HCl + 0.5 H20) C, H, N, F, Cl.

Example 52 Preparation of [4- (phenyl) phenylcarbonyl] methyl-5-amidinobenzimidazole P. F .: 260-261 ° C; aH NMR (CD30D) d 8.41 (s, 1H), 8.22 (s, ÍH), 8.20 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.73-7.70 (m, 4H), 7.51-7.41 (m, 3H), 6.10 (s, 2H); MS: 355.2 (M + H) +; HREM: 355.1538 (obs.), 355.1559 (calculated); Analysis: (C22H18N40? + 1.5 TFA + 0.08 HCl + 1H20) C, H, N, Cl.

Example 53 Preparation of [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidinobenzyl idazole XH NMR (DMS0-d6) d 9.22 (s, 1.5 H) 9.04 (s, 1.5 H), 8. 48 (s, 1H), 8.22 (d, J = 1.4 Hz, ÍH), 8.18 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.5 Hz, ÍH), 7.84 (d, J »8.5 Hz, 2H) 7.69 (dd, J« 8.6 Hz, 1.7 Hz, ÍH), 7.21 (t, J = 1.8 Hz, ÍH), 7.04 (s, ÍH), 7.00 (d, J = 8.4 Hz, ÍH), 6.73 (d, J = 8.1 Hz, ÍH), 6. 14 (s, 2H); 13C NMR (DMSO-d6) d 192.4, 165.9, 148.6, 147.6, 146. 7, 146.2, 139.3, 134.3, 132.9, 129.7, 128.8, 126.8, 121. 8, 121.3, 119.7, 115.6, 115-.1, 113.0, 111.8, 51.0; MS: 370 (M + H) +; HREM: 370.1664 (obs.), 370.1668 (calculated) Example 54 Preparation of [4- (3-aminophenyl) phenylcarbonyl] methyl-5-amidinobenzimidazole XH NMR (CD3OD) d 8.48 (s, ÍH), 8.32 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 845 Hz, 2H), 7.74 (s, 2H), 7.62-7.56 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 7.4 Hz, ÍH), 6.12 (s, 2H); MS: 370 (M + H) +, HREM: 370.1664 (obs.), 370.1668 (calculated).

Example 55 Preparation of [4- (4-fluorophenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole P.F .: 102-105 ° C .; XH NMR (CD3OD) d 8.54 (broad s, ÍH), 8.23 (d, J = 8.8 Hz, 2H), 8.10 (s broad, ÍH), 7.92 (s broad, 1H), 7.86 (d, J = 8.4 Hz, 2H); 19F NMR d -116.3, -77.65 (TFA); 13C NMR (CD30D) d 192.9, 168.6, 165.0, 163.5, 147. 2, 137.1, 134.3, 130.3, 130.2, 130.1, 128.5, 124.7, 123.4, 120.8, 117.1, 116.9, 112.9, 52.5; MS: 373.2 C (M + H) +; HREM: 373. 1481 (obs.), 373. 1465 (calculated); Analysis : (C22H17N-1O1F1 + 1 .9 TFA + 0.1 HCl + 2 H20) C, H, N, F, Cl.

Example 56 Preparation of [4- (4-formylphenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole P.F .: 125-128 ° C; XH NMR (CD30D) d 10.05 (s, 1H) t 8.48 (s, ÍH), 8.27 (d, J = 8.4 Hz, ÍH), 8.07 (s broad, ÍH), 8.05 (d, J = 8.4 Hz, 2H ), 7.97 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 8.4 Hz, J = 1.8 Hz, ÍH), 6.12 (s, 2H); 13C NMR (CD30D) d 192.99, 168. 67, 147.86, 140.90, 140.15, 134.44, 130.10, 128.64, 128. 57, 128".09, 124.63, 123.41, 120.75, 112.87, 104.26, 54. Four. Five; MS: 192.2 (M + 2H) 2+; HREM: 383.1531 (obs.), 383.1508 (calculated).

Example 57 Preparation of [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole P.F .: 126-128 ° C; H NMR (CD30D) d 8.55 (s broad, ÍH), 8.18 (d, J = 8.4 Hz, 2H), 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, ÍH), 8.09 (s, ÍH), 7.94 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.4 Hz, J = 1.4 Hz, 1H) 7.67 (d, J = 7.8 Hz, ÍH) ), 7.65 (d, J = 8.1 Hz, 2H) 7.60 (dd, J = 7.8 Hz, J = 1.4 Hz, ÍH), 7.36 (dd, J = 7.3 Hz, J = 1.4 Hz, ÍH), 6.13 (s, 2H); MS: 217.7 (M + 2H) 2+; HREM: 434.1303 (obs.), 434.1287 (calculated).

Example 58 Preparation of [4- (2-tert.-butylaminosul onyl) nyl) enylcarbonyl] methyl-6-amidinobenzimidazole. F.: 118-120 ° C; H NMR (CD3OD) d 8.60 (broad s, ÍH), 8.19 (d, J = 8.4 Hz, 2H), 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, ÍH), 8.09 (s, 1H), 7.95 (d, J = 8.8 Hz, ÍH) , 7.76 (dd, J = 8.4 Hz, J = 1.4 Hz, HI), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.60 (dd) , J = 7.7 Hz, J = 1.4 Hz, HH), 7.34 (dd, J = 7.7 Hz, J = 1.4 Hz, HH), 6.14 (s, 2H), 1.Q9 (s, 9H); 13C NMR (CD3OD) d 193.25, 168.78, 149.52, 147.86, 143.50, 140.87, 134.76, 133.27, 133.07, 132.83, 131.58, 130.45, 129.77, 129.49 128.76, 127.34, 124.45, 123.22, 120.99, 112.68, 55.30, 52.38, 30.22; Analysis: (C26H27N5O-3S1 + 1 .9 TFA + 1H20) C, H, N, F, S, Cl.

Example 59 Preparation of. { 4- (2-tetrazolyl) phenyl] phenylcarbonyl} methyl-6-amidinobenzimidazole P. F .: 144-145 ° C; XH NMR (CD3OD) d 8.56 (s broad, 1H), 8.11-8.09 (m, 3H), 7.93 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5 Hz, J = 1.7 Hz, ÍH), 7.73 (d, J = 7.3 Hz, 2H), 7.67- 7.62 (m, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.09 (s, 2H) ); 13C NMR (CD3OD) d 192.97, 168.66, 156.91, 149.40, 147.07, 146.51, 142.32, 135.60, 134.66, 132.64, 131.79, 131.71, 130.90, 129.88, 129.47, 124.56, 123.43, 120.75, 112.87, 52.45; MS: 212.2 (M + 2H) 2+; HREM: 423.1686 (obs.), 423.1682 (calculator-Analysis: (C23H? 8N80? + 1.9 TFA + 1 HCl + 0.5 H20) C, H, N, F, S, Cl. Method B: Examples 60, 61 and 62 were made by the alkylation of 5-cyanobenzimidazole with [4- (2-tert-butylaminosulfonylphenyl) phenylaminocarbonyl] methylene chloride, or (4-benzylpiperidinecarbonyl) methylene chloride, followed by the Pinner reactions.

Examples 60 and 61 Preparadon of [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-6- to idinobenzimidazole (Example 60) and [4- (2-amidinosulfonylphenyl) enylaminocarbonyl] methyl-5-amidinobenzimidazole (Example 61) [4- (2-tert-butylaminosulfonylphenyl) phenylaminocarbonyl) ethylene by acylation of 4 [(o-S02NHtBu) phenyl] aniline (3 mmol) with a-dichloroacetyl chloride (4 mmol) in CH3CN (100 mL) and K2C03 (4 mmol). Alkylation of 5-cyanobenzimidazole (2 mmol) with [4- (2-tert-butylaminosulfonylphenyl) phenylaminocarbonyl] methylene chloride (2 mmol) in DMF (10 mL) and K2CO3 (4 mmol) at normal temperature for 16 hours, followed by purification on thin layer chromatography plates, and additional isolation by CLAP gave [4- (2-tert-buminosulfonylphenyl) phenylaminocarbonyl] methyl-6-cyanobenzimidazole (240 mg, 56%) and the [4- (2-tert-buminosulfonylphenyl) phenylaminocarbonyl] methyl-5-cyanobenzimidazole (160 mg, 37%). [4- (2-tert-Buminosulfonylphenyl) phenylaminocarbonyl] methyl-6-cyanobenzimidazole was converted to Example 60, via the Pinner reaction and purified by CLAP: P.F .: 134-136 ° C; 1E NMR (CD30D) d 8.73 (s broad, ÍH), 8.15 (s, ÍH), 8.10 (dd, J = 8.6 Hz, J = 1.2 Hz, ÍH), 7.93 (d, J = 8.3 Hz, ÍH), 7.75 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 7.6 Hz, J = 1.2 Hz, ÍH), 7.52 (td, J = 7.6, J = 1.4 Hz, ÍH), 7.40 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 7. 6 Hz, J = 1.2 Hz, 1H), 5.36 (s, 2H); 13C NMR (CD30D) d 168.79, 166.75, 143.05, 141.48, 138.93, 137.50, 133.63, 132.92, 131.28, 128.75, 128.59, 124.63, 123.35, 120.96, 120.53, 112.80, 47.51; MS: 449.3 (M + H) +; HREM: 449.1401 (obs.), 449.1396 (calculated); Analysis: (C22H2oN603S? + 1.8 TFA + 0.25 HCl +1 H20) C, H, N, F, S, Cl. [4- (2-tert-Butylaminosulfonylphenyl) phenylaminocarbonyl] methyl-5-cyanobenzimidazole was converted to Example 61 via the Pinner reaction and purified by CLAP: P.F .: 254 ° C (with decomposition); H NMR (CD30D) d 8.55 (s, ÍH), 8.22 (s, 1H), 8.08 (d, J = 6.6 Hz, ÍH), 7.83-7.75 (m, 2H), 7.62 (d, J = 8.8, 2H ), 7.59-7.52 (m, 2H), 7.39 (d, J = .4 Hz, 2H), 7.31 (d, J = 7.4 Hz, ÍH), 5.33 (s, 2H); 3C NMR (DMSO-dβ) d 165.73, 164.97, 147.72, 142.58, 142.19, 139.43, 138.17, 137.63, 135.23, 132.31, 131.35, 129.69, 127.39, 127. 23, 122.20, 121.03, 120.96, 120.17, 118.21, 118.12, 111. 24, 47.51; MS: 449.3 (M + H) +; HREM: 449.1414 (obs.), 449.1396 (calculated); Analysis: (C22H20N603S1 + 2 TFA + 0.15 HCl + 1.5 H20) C, H, N, F, S, Cl.

EXAMPLES 62 Preparation of 1- (4-benzylpiperidincarbonyl) methyl-6-amidinobenzimidazole and 1- (4-benzylpiperidincarbonyl) methyl-5-amidinobenzimidazole (4-benzylpiperidincarbonyl) ethylene chloride was prepared by acylation of 4-benzylpiperidine (100 mmol) with chloroacetyl chloride (100 mmol) in THF (250 mL) and K2C03 (100 L). The alkylation of 5-cyanobenzimidazole (2 mmol) with (4-benzylpiperidinecarbonyl) methylene chloride (2 mmol) in DMF (5 mL) in the presence of NaH (3 mmol) at 0 ° C at room temperature for 16 hours, followed by purification on TLC plates gave 1- (4-benzylpiperidinecarbonyl) methyl-6-cyanobenzimidazole and 1- (4-benzylpiperidinecarbonyl) methyl-5-cyanobenzimidazole (0.4 g, 56% yield). This mixture (1.11 mmol) was then brought to the Pinner reaction, followed by purification on TLC plates with 10% MeOH CH2C12, and purification by additional CLAP to give the title compounds: MP: 54-54 ° C; MS: 376.4 (M + H) +; HREM: 376.2118 (obs.), 376.2137 (calculated); Analysis: (Cz? H? SNsOi + 1.8 TFA + 0.1 HCl). Method C: Example 63 was made by the Ullman coupling reaction of 4-chloro-3-nitrobenzenetritrile with (4-benzylpiperidincarbonyl) ethylamine, followed by the reduction of 4- [(4-benzylpiperidincarbonyl) methyl] amino-3 -Nitrobenzonitrile, cyclization with formic acid and finally the Pinner reaction.

Example 63 Preparation of 1- (4-benzylpiperidinesarbonyl) methyl-6- to idinobenzimidazole (4-benzylpiperidincarbonyl) ethylamine was prepared by treatment of (4-benzylpiperidinecarbonyl) methylene chloride with NaN3 in aqueous acetone, followed by hydrogenation with Pd 5% / C. The reaction of (4-benzylpiperidinecarbonyl) methylamine (8.6 mmol) with 4-chloro-3-nitro-benzonitrile (10 mmol) in DMF (10 mL) in the presence of NaHCO 3 (10 mmol) at 100 ° C for 16 hours, gave 4- [(4-benzylpiperidincarbonyl) methyl) amino-3-nitrobenzonitrile (1.6 g, 49.2% yield), which was then hydrogenated in MeOH in the presence of 5% Pd / C (10% w / w weight) to produce l- (4-benzylpiperidinecarbonyl) methyl-6-cyanobenzimidazole (1.3 g, 90% yield). The 1- (4-benzylpiperidinecarbonyl) methyl-6-cyanobenzimidazole (0.57 mmol) was then brought through the Pinner reaction, followed by purification on TLC plates with 10% MeOH in CH2C12, and additional purification by CLAP. to give the title compound: p. F.: 68-70 ° C; 1 H NMR (CD30D) d 8.52 (s, ÍH), 8.20 (s, 1H), 7.75 (s, 2H), 7.29-7.24 (m, 2H), 7.18-7.16 (m, 3H), 5.43 (dd, J = 17.2 Hz, J = 24.5 Hz, 2H), 4.40 (d, J = 12.8 Hz, ÍH), 4.00 (d, J = 12.8 Hz, 1H), 3.18 (t, J = 12.8 Hz, ÍH), 2.68 ( t, J = 12.8 Hz, ÍH), 2.59 (d, J = 7.00 Hz, 2H), 1.87-1.78 (m, 2H), 1.72-1.68 (m, ÍH), 1.42-1.35 (m, ÍH), 1.22 -1.15 (m, ÍH); 13C NMR (CD30D) d 168.76, 166.06, 148.73, 141.23, 139.50, 130.17, 129.45, 129.33, 127.35, 127.11, 124.04, 120.40, 113.19, 47.38, 46.36, 43.93, 43.73, 39.15, 33.35, 32.73; MS: 188.8 (M + 2H) 2+; HREM: 376. 2130 (obs.), 376. 2137 (calculated); Analysis: (Cz? HzsNsOi + 1.85 TFA + 0.18 HCl + 0.5 H20).

Example 64 Preparation of 2- [4- (2-aminosul onyl) phenylsarbonyl] methyl-6-amidinobenzimidazole N-ethylmalonyl-4'-aminobiphenyl-2-tert-butyl sulfonamide. To a solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide in 30 mL anhydrous methylene chloride and 0. 93 mL of triethylamine 0.43 mL of ethyl alonyl chloride was added by dropwise addition. The reaction mixture was allowed to stir overnight at room temperature. It was concentrated in vacuo to give the residue, which was extracted in 50 mL of ethyl acetate. The organic fractions were washed 3x20 mL of water. The resulting organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified via a standard chromatographic technique to give 0.70 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. LREM (NH3-CI): 436 (M + NH4: H NMR (CDC13, 300 MHz): d 9.42 (s, ÍH), 8.18 (d, ÍH), 7.79 (d, 2H), 7.52 (m, 3H), 7.49 (d, ÍH), 7.30 (d, ÍH), 4.30 (c, 2H), 3.60 (s, ÍH), 3.50 (s, 2H ), 1.35 (t, 3H), 1.0 (s, 9H). 2- [4- (2-Aminosulfonylphenyl) phenylcarbonyl] methyl-6-sianobenzimidazole. A mixture of 0.32 g of 3,4-diaminobenzonitrile and 0.70 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide was heated at 180 ° C for 20 h. The mixture was allowed to cool to room temperature. Concentration to high vacuum gave 0.09 g of crude 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl) methyl-6-cyanobenzimidazole. The crude material was carried through the following reaction sequence. LREM (ES +): 431 (M + H). 2- [4- (2-aminosulfonylphenyl) phenylissarbonyl] methy1-6-amidinobensimidazole. A solution of the crude 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] ethyl-6-cyanobenzimidazole in 10 L of anhydrous chloroform to 1: 1 anhydrous ethanol was stirred in an ice bath. Hydrogen chloride gas was bubbled into the reaction vessel for 20 minutes. Then, the reaction mixture is <allowed to warm to room temperature for 15 h. The reaction mixture was concentrated under reduced pressure and the crude product was placed under high vacuum. The resulting ethyl imidate was treated directly with 0.30 g of ammonium carbonate and anhydrous ethanol. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified via the standard CLAP technique to give the purified 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole. LREM (ES +): 449 (m + H). HREM (BAR): calculated 449.139586 mass 449.139273. X H NMR (DMSQ, d 6, 300 MHz): d 10.50 (s, ÍH), 9.20 (broad s, 2H), 8.67 (broad s, 2H), 7.79 (d, 2H), 7.55 (m, 4H), 7.25 (m, 4H), 4.05 (s, 2H).

Example 65 Preparation of 2- [4- (2-tert-butylaminosulfonylphenyl) phenylcarbonylmethyl-5-azabenzimidazole N-ethylmalonyl-4'-aminobiphenyl-2-tert-butyl sulfone ida. To a solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide in 30 mL of anhydrous THF and 0.93 mL of triethylamine was added 0.93 mL of ethyl malonyl chloride by dropwise addition. The mixture was allowed to stir for 24 h. Concentrate in vacuo to give a residue, which was extracted with 50 L ethyl acetate. The organic fractions were washed 3x20 mL with water. The resulting organic fractions were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified via a standard chromatographic technique to give 0. 63 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. LREM (NH3-CI): 436 (M + NH4). X H NMR (CDC13, 300 MHz): d 9.42 (s, 1H), 8.18 (d, ÍH), 7.79 (d, 2H), 7.52 (, 3H), 7.49 (d, ÍH), 7.30 (d, ÍH). 2- [4- (2-tert-Butylaminosulfonylphenyl) phenylcarbonyl] -methyl-5-azabenzimidazole. A mixture of 0.026 g of 3, 4-diaminopyridine and 0.10 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide was heated at 165 ° C for 20 h. The mixture was allowed to cool to room temperature. The crude material was purified by a standard chromatographic technique to give 2- [4- (2-tert-butylaminosulfonylphenyl) -phenylcarbonyl] methyl-6-azabenzimidazole. LREM (ES +): 464 (M + H). HREM (NH4-CI): Mass 464.175637 Calculated 464.175630. 2H NMR (CDC13, 300 MHZ): d 9.49 (s, ÍH), 8.40 (s, ÍH), 8.15 (d, ÍH), 7.98 (s, ÍH), 7.47 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H), 4.30 (s, 2H), 1.0 (s, 9H).

Example 66 Preparation of 2S- [4- (2-tertiary-aminosulfonylphenyl) phenylcarbonyl] methyl-thio-lH-imidazo (4, 5-C) pyridine To a solution of 1H-imidazo (4, 5-C) pyridine 2-thiol (37 mg, 0.245 mmol) in DMF (2.5 mL) was added 4- (2-tert-butylaminosulfopylphenyl) phenylaminocarbonyl] methyl chloride (75 mg, 0.197 mmol) and then K2C03 (58 mg, 0.42 mmol), and the resulting mixture was heated at 120 ° C for 1 hour. To the mixture at room temperature was added HCl (IN in Et20, 1 mL) and then MeOH (6 mL), a clear solution was obtained. To this was added Et20 (200 ml) directly, and a white suspension was observed, which was filtered and a white solid (120 mg) was collected. The solid was soluble in DMSO (8 mL), and the resulting solution was purified by CLAP with H20-CH3CN-TFA to give the title compound (60 mg). HREM (M + H) + calculated m / z: 496.1477, obs: 496.1492.

Example 67 Preparation of 2S- [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-thio-lH-imidazo (4, 5-C) pyridine A solution of Example 66 (26 mg) in TFA (0.5 mL) was heated for 16 hours. All the solvent was removed and purified by CLAP with H20-CH3CN-TFA to give the title compound (13 mg). HREM (M + H) + calculated m / z: 440.0851, obs .: 440.0831.

Example 101 Preparation of 1- (4-benzylpiperidinecarbonyl) methyl-5- to idinoindole 5-Cyanoindole-1-methylacetate. To a stirred solution of 5-cyanoindole (5.0 g, 35.2 mmol) in 10 L of dry DMF at 0 ° C under an N 2 atmosphere was added NaH (1.1 g, 42.2 mmol). The reaction was stirred for 30 minutes, and then a-bromomethyl acetate (5.4 g, 35.2 mmol) was added and stirred at room temperature for 2 h. This was then quenched with H20, extracted with ethyl acetate (3x), dried with Na2SO4, filtered and concentrated in vacuo to give a light yellow solid (7.5 g, 35.2 mmol). XH NMR (CDC13) d ppm 3.2 (s, 2H), 3.8 (s, 3H), 7.03 (s, ÍH), 7.32 (d, 1H, J = 7.5 Hz), 7.41 (d, ÍH, J = 7.5 Hz), 7.61 (s, ÍH), 7.81 (s, ÍH). LREM NH3-CI m / z (M + H) + 229, (M + NH4) + 246. 3- (5-Cyanoindole) acetic acid. Methyl 5-cyanoindole-1-acetate was saponified in MeOH, KOH (3.3 eq) at normal temperature for 18 h. The mixture was concentrated in vacuo, dissolved in water, extracted with diethyl ether (2x) and the aqueous acid layer was acidified with 2N HCl. The resulting white solid was filtered and dried in a vacuum oven to give 6.2 g of the title compound. LREM ESI (M + H) + 201. 1- (4-Bensylpiperidincarbonyl) methyl-5-cyanoindole. To a stirred complex of 3-acetic acid-5-cyanoindole (2.0 g, 0.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC) in dry CH 2 C 12 was added 4-benzylpiperidine (1.8 g, 0.01 mmol). The mixture was stirred under an N2 atmosphere for 18 h, then concentrated in vacuo, dissolved in ethyl acetate, washed with 1N HCl (3x), NaHCO3 (3x), brine (2x), dried with Na2SO4. , filtered and concentrated in vacuo to give a white solid (2.8g). HREM for C 23 H 24 N 30 (M + H) + calculated 358.191938, found 358.193278. 1- (4-Benzylpiperidinesarbonyl) methyl-5-amidinoindole. N-1-acetyl-l-N '-piperidinyl-4-benzyl-5-cyanoindole (500 mg) was dissolved in dry MeOH (30 mL), cooled to 0 ° C and saturated with HCl (g). The resulting solution was allowed to warm to normal temperature for 18 h. The mixture was concentrated in vacuo, redissolved in dry MeOH and (NH4) 2CO3 (672.0 mg) was added, the flask was sealed and stirred for 18 at normal temperature. The resulting suspension was filtered through Celite®, rinsed with dry MeOH, concentrated in vacuo to give 997 mg of product (89% by CLAP); 100 mg of which were further purified via preparative CLAP to give 29 mg (100% purity by CLAP). P. f. 214-215 ° C. HREM (NH3-C1) for C23H26N40 (M + H) + calculated 375.217601, found 375.218487. X H NMR (CD3OD) d ppm 1.05 (cd, ΔH, J = 7.5 Hz, J = 2.5 Hz), 1.25 (cd, ΔH, J = 7.5, J = 2.5 Hz), 1.65 (bd, ΔH, J = 7.5 Hz ), 1.76 (bd, ÍH, J = 7.5 Hz), 1.83 (m, ÍH), 2.58 (d, 2H, J = 6.0 Hz), 2.63 (t, ÍH, J = 75 Hz), 3.07 (t, ÍH , J = 7.5 Hz), 4.03 (bd, ÍH, J = 7.5 Hz), 4.2 (bd, ÍH, J = 7.5 Hz), 5.21 (cd, 2H J = 7.5 Hz), 6.63 (s, ÍH), 7.18 (, 3H), 7.23 (m, 2H), 7.38 (s, 1H), 7.51 (d, ÍH, J = 5.0 Hz), 7.58 (d, ÍH, J = 5.0 Hz), 8.05 (s, ÍH).

Example 102 Preparation of methyl 1- (4-bensylpiperidinearbonyl) ethyl-5-amidinoindole 5-cyanoindole-3-propionate. To a stirred solution of 5-cyanoindole (1.0 g, 7.0 mmol), K2CO3 (0.966 g, 7.0 mmol) in acetonitrile was added 3-bromomethylpropionate (1.17 g, 7.0 mmol). The mixture was stirred at reflux for 18 h under a nitrogen atmosphere, cooled, diluted with H20, extracted with ethyl acetate, dried with Na2SO4, filtered and concentrated in vacuo to give 1. 59 g of the product. : H NMR (CD30D) d ppm 2.85 (t, 2H, J = 6.6 Hz), 3.61 (s, 3H), 4.58 (t, 2H, J = 6.6 Hz), 6.61 (s, ÍH), 7.42, (m , 3H), 7.62 (d, ÍH, J = 8.4 Hz), 7.99 (s, 1H). Asido 5-aianoindol-3-propioniso. The methyl 5-cyanoindole-3-propionate (200 mg) was saponified in MeOH (10 L) / KOH (150 mg, 0.88 mmol) at normal temperature for 18 h. The solution was concentrated in vacuo, dissolved in water and washed with chloroform. The acid layer was acidified and extracted with ethyl acetate, dried with Na 2 SO 4, filtered and concentrated in vacuo to give 188 mg of the product. XH NMR (CD30D) d ppm 2.83 (t, 2H, J = 6.6 Hz), 4.43 (t, 2H, J = 6.6 Hz), 6.6 (nd, 1H, J 3.2 Hz), 7.42 (d, 2H, J = 7.3 Hz ), 7.43 (s, 1H), 7.61 (d, ÍH, J = 7.3 Hz), 7.99 (s, ÍH); LREM ESI (M + H) + 215. 1- (4-Benzylpiperidincarbonyl) ethyl-5-amidinoindole. The preparation followed the last two steps of Example 101. It gave 156 mg of the TFA salt. X NMR (DMSO-d6) d ppm 2.42 (, 4H), 2.89 (m, 4H), 3.21 (d, 2H, J = 5.0 Hz), 3.72 (bd, 1H, J = 10.0 Hz), 4.12 (m, ÍH), 4.38 (bd, 1H, J = 10 Hz), 4.51 (m, 2H), 6.62 (s, ÍH), 7.1-7.31 (m, 5H), 7.62 (m, 2H), 7.72 (d, ÍH) , J = 6.0 Hz), 8.21 (broad s, ÍH); HREM (M + H) + for C 24 H 29 N 40 calculated 389.234137, found 389.231258.

Example 103 Preparation of 1- (4- (3-Fluoro) benzylpiperidinesarbonyl) methyl-5-amidinoindole 4- (3-Fluorobenzyl) piperidine. To a stirring solution of l-benzylpiperidin-4-one (0.99 mL, 5.34 mmol) in THF, Ph3P = CH- (3-fluoro) phenyl (2.41 g, 5.34 mmol) was added at 0 ° C under an atmosphere of nitrogen. After stirring for 4 h at normal temperature, the reaction was quenched with H20, concentrated in vacuo and the residue sex subjected to chromatography on silica gel using hexane: ethyl acetate 1: 1 as the eluent to give 313 mg of product. LREM NH3-C1 (M + H) + 282. The product (330 mg) was hydrogenated in MeOH, 10% Pd / C (300 mg) and concentrated HCl (5 mL) in a 50 psi shaker for 18 hours. h. The reaction was filtered through Celite® and the filtrate was concentrated in vacuo to give 250 mg of the title compound. LREM NH3-C1 (M + H) + 194. 1- (4- (3-Fluoro) bensylpepyridinosarbonyl) methyl-5-cyanoindole. Prepared as in Example 101. LREM ESI (M + H) + 376. 1- (4- (3-Fluoro) benzylpepyridinocarbonyl) methyl-5-amidinoindole. Example 103 was prepared via the same method as in Example 101. HREM FAB glycerol matrix for C23H26N4FO (M + H) + calculated 393.209065, found 393.208858.

EXAMPLE 104 Preparation of 1-1- (4-amidino) benzyl-N- (methylacetate) aminocarbonyl) methyl-5-amidinoindole (4-Cyano) bensyl-N- (methylasetate) amine. Α-Bromo-tolunitrile (2.0 g, 10.5 mmol) was dissolved in CHC13 and glycine methyl ester (2.64 g, 21.0 mmol) and triethyl amine (2.92 mL, 10.5 mmol) was added. The mixture was stirred for 18 h under an atmosphere of nitrogen, concentrated in vacuo and purified via a column of silica gel using hexane: ethyl acetate 1: 1 as the eluent to give 1.07 g of the title compound (5.25 mmol ) LREM ESI (M + H) + 205. H NMR (CDCl 3) d ppm 3.42 (s, 2H), 3.78 (s, 3H), 3.91 (s, 2H), 7.42 (d, 2H, J = 8.0 Hz) , 7.62 (d, 2H, J = 8.0 Hz). 1- (1- (4-Cyano) bensyl-N- (methylasetate) aminoaarbonyl) -methyl-5-sianoindole. The compound was prepared using the same coupling procedure as in Example 101. HREM NH3-CI for C23H2oN4? 3 (M + H) + calculated 401.161366, found 401.159527. 1- (1- (4-Amidino) bensyl-N- (methylated tato) ammonno-sarbonyl) methyl-5-amidinoindole. It was prepared by the same Pinner conditions as in Example 101. LREM ESI (M + 2HT2 218.

Example 105 Preparasión 1- (4-bensilpiperidin-l-carbonyl) methyl-5- amidinoindol-3-propanoate 1- (4-Benailpiperidin-l-sarbonil) methyl-5-sianoindol-3-propanoate. 1- (4-Benzylpiperidin-1-carbonyl) -5-cyanoindole (1.0 g, 2.8 mmol) was dissolved in 20 mL of dry CH2C12, cooled to 0 ° C and oxalyl chloride (1.07 g, 8.4 mmol) was added. The reaction was stirred for 3 h at normal temperature. It was then concentrated in vacuo and dissolved in dry MeOH (2 mL) and stirred for 18 h. The resulting yellow solution was concentrated in vacuo and 1.0 g (2.3 mmol) in TFA (20 mL) was taken at 0 ° C and triethylsilane (535 mg, 4.6 mmol) was slowly added. The reaction was stirred at 0 ° C for 3 h and then concentrated in vacuo, dissolved in CH2C12 and washed with saturated NaHCO3, dried with sodium sulfate, filtered and concentrated. The resulting residue was subjected to chromatography via silica gel using 7% MeOH / CHCl 3 as the eluent to give 840 mg of the title compound. LREM ESI (M + H) + 430. 1- (4-Bensylpiperidin-1-sarbonyl) methyl-3-methyl-asetate-5-amidinoindole. Amidine was prepared as in example 101. HREM NH3-C1 for C26H34N403 (M + H) + calculated 447.239616, found 447.241907.

Example 106 Preparasión 1- ((4-bensilpiperidinaarbonil) methyl- (3- etanhidroxil) -5-amidinoindol 1- (4-Bensilpiperidin-1-carbonyl) methyl-3-etanhidroxil-5-sianoindol. Methyl 1- dissolved acetyl- (4-benzylpiperidin-1-yl) -3-acetate-5-cyanoindole (100 mg, 0.233 mmol) in ethanol and sodium borohydride (20 mg, 0.51 mmol) was added and the solution was stirred at normal temperature for 18 h. the reaction was concentrated in vacuo diluted with water and extracted with methylene chloride (3x), dried over sodium sulfate, filtered and in vacuo concentrated to give 93.0 mg of the title compound. LRMS DCI-NH3 (M + NH4) + 419. 1- (4-Bensilpiperidin-l-sarbonil) methyl-3-etanhidroxil-5-amxdinoindol. the amidine is prepared as in example 101. HRMS NH3-C1 to C25H3? N402 (M + H) + calculated 419.244702, found 419.245383.

Example 107 5-Preparasión of Asido amidinoindol 1- (4-benzylpiperidine-l- sarbonil) methyl-3-methyl metilsarboxíliso 1-acetyl- (4-benzyl-piperidin-1-yl) -3-ethyl-5-amidinoindol was hydrolyzed in TFA / H20 for 18 h. It was purified via preparative CLAP to give the title compound. LREM (M + H) + 433.

Example 108 Preparation of 1- (1-Benzylpiperidin-4-aminocarbonyl) methyl-5-amidinoindole 1- (1-Benzylpiperidin-4-aminocarbonyl) methyl-5-cyanoindole. To a complex of N-l-methylenecarbohydroxy-5-cyanoindole (300 mg, 1.5 mmol) and DEC with stirring, 4-amino-1-benzylpiperidine and triethylamine (0.209 mL, 1.5 mmol) were added. The reaction was stirred at normal temperature for 18 h. The volatiles were removed in vacuo and the residue was purified via silica gel using 1% MeOH / CH2C12 as the eluent to give 160 mg of the product. HREM NH3-C1 for C23H24N40 (M + H) + calculated 373.204.204739, found 373.202837. 1- (1-Benzylpxperidin-4-ammocarbonyl) metxl-5-amidinoindole. Amidine was prepared as in Example 101 to give 96 mg of the title compound. HREM NH3-C1 calculated 390.229386, found 390.229386.

Example 109 Preparation of 1- (4-benzoylpjperidinsarbonyl) methyl-5-amidinoindole 1- (4-Benzoylpiperidinecarbonyl) methyl-5-sianoindole.

Prepared as in example 108, except that 4-benzoylpiperidine was used. HREM NH3-CI (M + H) "1" for C23H21N3O2 calculated 372.171702, found 372.171620. 1- (4-Benzoxlpiperxdinsarbonil) metxl-5-amidinoindol.

Amidine was prepared using the same method as in Example 101. HREM (M + H) + for C23H24N403 calculated 389.197751, found 389.198109.

EXAMPLE 110 Preparation of 1- (4- (3-fluoro) bensylpiperasinearbonyl) methyl-5-amidinoindole 1- (4- (3-Fluoro) bensylpiperaainsarbonyl) methyl-5-cyanoindole. To a stirred solution of l-acetyl- (l-piperazin) -5-cyanoindole (400 mg, 1.31 mmol), triethylamine (0.0.36 L, 2.62 mmol) in diethyl ether 3-fluorobenzyl bromide (0.161 mL was added , 1.31 mmol) and stirred at normal temperature under an N2 atmosphere for 18 h. The reaction was quenched with water, extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated in vacuo to give 438 mg of the product. LREM (M + H) + 377. 1- (4- (3-Fluoro) bensylpiperasinsarbonyl) methyl-5-amidinoindole. Prepared as in Example 101. HREM (M + H) + for C 22 H 24 N 5 OF calculated 394.204314, found 394.204917.

Example 111 Preparation of l- (4-phenylbensilaminosarbonyl) methyl-5-amidinoindole 1- (4-phenylbensilaminosarbonyl) methyl-5-cxanoindole.

To a complex of 1-acetic acid-5-cyanoindole (250 mg, 1.25 mmol) and DEC (239 mg, 1.25 mmol) in methylene chloride with stirring, 4-phenylbenzylamine (228 mg, 1.25 mmol) was added.

After stirring at normal temperature for 18 h under a nitrogen atmosphere, the reaction was concentrated in vacuo, dissolved in ethyl acetate, washed with 1N HCl, sodium bicarbonate and brine, dried with sodium sulfate, filtered and concentrated in vacuo to give 215 mg of the product. HREM (M + H) + calculated 366.260637, found 366.160323. 1- (4-phenylbenzylaminosarbonyl) methyl-5-amidinoindole. Prepared as in Example 101. Calculated HREM 383.187187, found 383.189667.

EXAMPLE 112 Preparation of Methyl 1- (4-benzylpxperidxncarbonyl) methyl-5-amidinoindol-3-propanoate 1- (4-Benzylpiperidinesarbonyl) methyl-5-sianediol-3-propanoate. To a stirred solution of DMF (15 mL) and P0C13 (256 mg, 1.7 mmol) at 0 ° C was added 1- (4-benzylpiperidine-carbonyl) methyl-5-cyanoindole (199 mg, 0.56 mmol). After stirring for 3 h, the reaction was quenched with 2N sodium hydroxide and stirred for 30 minutes. This was then extracted with chloroform, dried with sodium sulfate, filtered and concentrated in vacuo to give the product. LREM (M + H) + 386. The product was then refluxed in the presence of (methylenecarbomethoxy) triphenyl phosphonium hilide in THF under a nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and the residue was purified via chromatography on silica gel using 7% MeOH / CHCl3 as the eluent to give 140 mg of product. Methyl 1- (4-Bensylpiperidinsarbonyl) methyl-5-amxdinoindol-3-propenoate. Prepared as in Example 101. LREM (M + H) + 459.

Example 113 Preparation of l- (4- (2-fluoro) bensylpiperidinesarbonyl) methyl-5-amidinoindole 4- (2-Fluoro) bensylpiperidine. To a stirring solution of triphenylphosphonium-2-fluorobenzyl bromide in Dry THF at -78 ° C was added n-BuLi (2.5 M, 2.13 L) and stirred for 30 minutes. To this, l-benzyl-4-piperidinene (0.99 L) was then added and the mixture was stirred at normal temperature for 4 h. The reaction was quenched with water and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using hexane: ethyl acetate 1: 1 as the eluent to give 313 mg. LREM (M + H) + 282. The product was hydrogenated on a 50 psi stirrer in MeOH (10 mL), 5.0 mL concentrated HCl and 10% Pd / C (300 mg) for 18 h. The mixture was filtered through Celite and concentrated in vacuo to give 250 mg of the product. LREM (M + H) + 194. 1- (4- (2-Fluoro) bensylpiperidinesarbonyl) methyl-5-sianoindole. Prepared by coupling 3-acetic acid-5-cyanoindole with 4- (2-fluoro) benzylpiperidine using the method described in Example 101. LREM (M + H) + 376. 1- (4- (2-Fluoro) bensylpiperidinsarbonyl ) methyl-5-amidinoindole. Prepared as in Example 101. HREM (M + H) + calculated 393.209065, found 393.208858.

EXAMPLE 201 Preparation of methyl 3- ((4-cislohexyl) phenylaminomethylsarbonyl) methyl-5-amxdinoindole 5-cyanoindole-3-aselate. To a stirred solution of 5-cyanoindole (10.0 g) in dry methylene chloride was added (3.0 eq, 61.43 mL) of oxalyl chloride. After stirring for 1 h under a nitrogen atmosphere at normal temperature, the resulting precipitate was filtered and washed with diethyl ether. The solids were then extracted in dry MeOH and stirred for 1 h. At this time, the solids were filtered and washed with MeOH and diethyl ether to give 5.93 g of methyl α-ketoacetate 5-cyanoindole. LREM (M + H) + 229. Methyl α-ketoacetate (4.90 g) was dissolved in 50 mL of trifluoroacetic acid at 0 ° C and triethyl silane (5.0 g) was slowly added via a dropping funnel (20 minutes). This was then stirred at 0 ° C for 3 h. The resulting yellow solution was concentrated in vacuo, neutralized with sodium bicarbonate, extracted with ethyl diacetate, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification was carried out via chromatography on silica gel using 1% MeOH / CH2C12 as the eluent to give 2.48 g of the product. LREM (M + H) + 232. Asido 3- (5-sianoindole) aaetiso. The above ester was saponified in KOH / MeOH at normal temperature for 18 h. The solution 3 was then concentrated in vacuo, dissolved in water, extracted with ethyl acetate and the acid layer then acidified with IN HCl at 0 ° C. The resulting white solids were filtered and dried further under high vacuum to give the product. P. f. 196.5-198.5; Calculated C 66.00, H 4.04, N 13.99, found C 65. 71, H 4.24, N 13.94. aH NMR (CD3OD) d ppm 3.78 (s, 2H), 7.28 (s, 1H), 7.38 (d, H, J = 8.6 Hz), 7.45 (d, H, J = 8.6 Hz), 7.89 (s, 1H) ); LREM (M +) + 199. 3- (4-Cyclohexylphenylaminomethylsarbonyl) methyl-5-sianoindole. To a stirred complex of 5-cyanoindole acetic acid (312 mg, 1.5 mmol) and BOP reagent (1.03 g) in DMF, 4-cyclohexylphenylaminomethyl was added. After heating at 50 ° C under a nitrogen atmosphere for 18 h, the reaction was cooled to normal temperature by diluting with water and extracted with ethyl acetate, washed with IN HCl, saturated sodium bicarbonate and brine, dried with Sodium sulfate, filtered and concentrated in vacuo. The residue was purified via chromatography using 100% ethyl acetate as the eluent to give 210 mg of product. LREM (M + H) + 372. 3- ((4-Cxalohexyl) phenylaminomethylsarbonyl) methyl-5-amidinoindole. It was prepared as in example 101. HREM (M + H) + for C 24 H 29 N 4 O calculated 389.234137, found 389.232086.

Example 202 Preparation of 3- (4-p-toluenesulfonylpeperasinsarbonyl) methyl-5-amxdxnoindole 3- (4-Paratoluenesulfonylpiperazincarbonyl) methyl-5-sianoindole. To a stirred solution of 3- (piperazincarbonyl) methyl-5-cyanoindole hydrochloride (200 mg, 0.66 mmol) and triethylamine (134 mg, 185 μL) in chloroform was added toluenesulfonyl chloride (126 mg, 0.66 mmol). After stirring for 18 h at normal temperature under a nitrogen atmosphere, the reaction was quenched with water, extracted with chloroform, washed with IN HCl, saturated sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to give 237 mg of the product. LREM (M + H) + 423. 3- (4-Paratoluenesulfonylpiperasinsarbonyl) ethyl-5-amidinoindole. Prepared as in Example 101. HREM (M + H) + for C22H26N503S, calculated 440.174611, found 440.175637.

EXAMPLE 203 Preparation of 3- (4- (2-aminosulfonylphenyl) pyridin-2-aminocarbonyl) ethyl-5-amxdinoindole 3- (4- (2-Aminosulfonylphenyl) pyridin-2-ammon-sarbonyl) methyl-5-cyanoindole. To a stirring solution of 5-cyano-3-acetic acid indole (400 mg, 2.0 mmol), BOP (884 mg, 3.0 mmol) in DMF (15 mL), 4- (2-aminosulfonyl) phenyl-2 was added -aminopyridine (912 mg, 3.0 mmol) and I was heated at 50 ° C for 3 h. The reaction was diluted with water, extracted with ethyl acetate, washed with 10% HCl, sodium bicarbonate, brine, and water, dried with magnesium sulfate, filtered and concentrated in vacuo to give 420 mg of the product LREM 488. The t-butyl group was refluxed in TFA for 1 h and the product was purified via silica gel using 100% ethyl acetate as the eluent to give 101 mg of the product. LREM 432. 3- (4 - (2-Aminosulfonylphenyl) pyridine-2-amino-carbonyl) methyl-5-amidinoindole. It was prepared as in example 101. HREM (M + H) 'for calculated C22H22N503S 449. 139586, found 449. 139058.

EXAMPLE 204 Preparadon of 3- (4- [2- tetrazol] phenyl) phenylaxnosarbonyl) methyl-5-amidinoindole. 3- (4- [2-Tetrazole] phenyl) phenylaminosarbonyl) methyl-5-sianoindole. The 5-cyanoindole-3-acetic acid was dissolved in DMF / CH2C12, DEC (382 mg), and DMAP (10 mg) and the reaction mixture was stirred for 15 minutes. 4 - ((2-Tetrazol) phenyl) aniline was added and the reaction mixture was stirred for 2 h. The reaction was concentrated in vacuo, dissolved in ethyl acetate and washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification was done via silica gel using hexane: ethyl acetate 1: 1 to give 660 mg of product. The trityl group was separated in THF (30 mL) and 4M dioxane HCl (0.988 mL) at normal temperature for 18 h. It was then basified with NaOH to pH 11, washed with ether, acidified to pH 3 with 10% HCl and the precipitate was collected and dried under high vacuum to give 250 mg of product. LREM (M + H) + 420. 3- (4- [2-Tetrazol] enyl) enylaminosarbonyl) methyl-5-amidinoindole. Prepared as in Example 101. HREM for C23H20N80 (M + H) + calculated 437.183833, found 437.186710.

Example 205 Preparation of 3- (4-biphenylaminosarbonyl) metxl-5- to idinoindole The title compound was prepared as in Example 101. HREM (M + H) + for C23H20N4? calculated 369,172173, found 369.171537.

Example 206 Preparation of 3- (4- (phenylmethylsulfonyl) piperasinsarbonil) methyl-5-amidinoindol The title compound was prepared as in Example 101. HRMS (M + H) + calculated 440.176204 503S C22H25, found 440.175637.

Example 207 Preparation of 3- (4-scylohexylphenollaminosarbonyl) methyl-5-axdxnoindole The title compound was prepared as in Example 101. HREM (M + H) + C23H26N4? calculated 375. 218732, found 375.218487.

Example 208 Preparation of 3- (4-bensylpiperasinarbonyl) methyl-5-amidinoindole The title compound was prepared as in Example 101. HREM (M + H) + for C22H25N50 calculated 376.213722, found 376.213736.

Example 209 Preparation of 3- (3-amidinobenzylamino (methylcarbonylmethoxy) sarbonyl) methy1-5-amidinoindole The title compound was prepared as in Example 101. Calculated HREM 435.214464, found 435.216822.

Example 210 Preparation of 1-methyl-3- (4-amidinobenzylamino (methylsarbonylmethoxy) sarbonyl) myl-5-amidinoindole The title compound was prepared as in example 101. Calculated HREM 435.214464, found 435.213247.

Example 211 Preparation of 1-methyl-3- (4- [2-aminosulfonyl] phenylbenzylamidocarbonyl) methyl-5-amidinoindole The title compound was prepared as in example 201. LREM 476, p. F. 231 ° C.

Example 212 Preparation of 1-methyl-3- (4-phenylbensilaminosarbonyl) methyl-5-amidinoindole The title compound was prepared as in example 201. Calculated HREM 397.202837, found 397.204520.

Example 213 Preparation of 1-methyl-3- (4-phenylpiperacinsarbonyl) methyl-5-amidinoindole The title compound was prepared as in example 201. Calculated HREM 389.234137, found 389.234635.

Example 214 Preparation of 3- (4- [2- aminosul onyl) phenylphenylaminocarbonyl) methyl-5-amxdinoindole The title compound was prepared as in Example 203. Calculated HREM 448.144337, found 448.143656.

Example 215 Preparation of 3- (l-benzylpiperidin-4-aminocarbonyl) methyl-5-amidinoindole The title compound was prepared as in example 201. Calculated HREM 390.229386, found 390.230305.

Example 216 Preparation of 3- (4-enyl) -peracinsarbonyl) methyl-5-amidinoindole The title compound was prepared as in Example F 201. HREM calculated 362.198086, found 362.197315.

Example 217 Preparation of 3- (4-bensylpiperidinsarbonyl) methyl-5-amidinoindole The title compound was prepared as in example 201. Calculated HREM 374.210662, found 374.210386.

Example 218 Preparation of l-methyl-3- (5- (2-aminosulfonyl) enilpiperidin- 2-aminoaarbonil) methyl-5-amidin indole The title compound was prepared as in Example 201. HRMS calculated 463.155236, found 463.155236.

Example 219 Preparing the 3-. { 2-bromo-4- (2-inosulfonyl) enylphenylaminocarbonyl) methyl-5-cyanoindole A solution of 3- (2-bromo-4- (2-anedosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindoline (1.2378 mmol, 0.7 g) in anhydrous ethyl acetate (15 L) and anhydrous methanol (0.5 mL, 10.0 eq.) Was saturated with dry hydrogen chloride gas at -20 ° C for 20 minutes. The reaction mixture was sealed and left at normal temperature for 18 h. This reaction mixture was evaporated and pumped for several hours to remove any residual HCl. To this anhydrous methanol imidate (15 L) was added ammonium carbonate (1189 g, 10.0 eq.). This reaction mixture was allowed to stir at normal temperature for 24 h. This final reaction mixture was evaporated and purified by CLAP on a C-18 column eluted with a mixture of solvent A (water: TFA 99.95: 0.05) and mixture of solvent B (acetonitrile: TFA 99.95: 0.05) using a gradient starting with A at 80% and changing to B at 100% for 60 minutes. After lyophilization, 0.122 g of the pure product (15%) were obtained; HREM (M + H) + calculated 526.054848, found 526.053791 for the o-Br compound.

EXAMPLE 220 Preparation of 3- (2-methyl-4- (2-aminosulfonyl) phenyl-enylsarbonyl) methyl-5-methylamino indole To the solution of 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl- 5-cyano indole (0.5992 mmol, 0.3 g) in absolute ethanol: TFA 4: 6, palladium hydroxide on carbon (0.06 g, 20% by weight equivalent of the starting material used) was added. This reaction mixture was stirred under vacuum for 10 minutes at normal temperature to remove oxygen. It was then subjected to 1 atm of H2 via the balloon method for 3 h. The reaction mixture was filtered through celite to remove the catalyst and washed with ethanol (20 mL). The filtrate was evaporated to give the desired product with t-butyl sulfonamide. This product was treated with trifluoroacetic acid at 55 ° C for 2 h for the deprotection of the sulfonamide. The reaction mixture was evaporated and purified by CLAP on a C-18 column eluted with solvent mixture A (water: TFA 99.95: 0.05) and mixture of solvent B (acetonitrile: FA 99.95: 0.05) using a gradient starting with 80% A and changing to 100% B for 60 minutes to give 10.0 mg of the pure product (3%, poor yield due to poor solubility); HREM (M + H) + calculated 449.164738, found 449.165207.

Example 221 Preparation of 3- (2-fluoro-4- (2-aminosul onyl) phenyl-enylaminosarbonyl) methyl-5-amidinoindole The title compound was prepared as in Example 203. HREM (NH3-C1 / DEP) (M + H) + for C23H21N5S03F calculated 466.134915; found 466.133832.

Example 222 Preparing the 3-. { 2-Chloro-4- (2-aminosulfonyl) enylphenylaminosarbonyl) methyl-5-sianoindole The title compound was prepared as in Example 203. HREM for C25H21N5S03C1 (M + H) + calculated 482.105364; found 482.103835.

Example 223 Preparation of 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminosarbonyl) methyl-5-sianoindole The title compound was prepared as in Example 203. HREM for C23H2? IN503S (M + H) + calculated 574.040989; found 574.042800.

Example 224 Preparing the 3-. { 2-Methyl-4- (2-aminosulfonyl) phenylphenylaminosarbonyl) methyl-5-amidinoindole The title compound was prepared as in Example 203. HREM for C24H24N503S (M + H) + calculated 462. 159987; found 462. 158553.

Exeptplo 225 Preparadón del 3- (2-methyl-4- (2- (t-butylaminosulfonxl)) phenylphenylaminocarbonyl) methyl-5-amidnoindole The title compound was prepared as in Example 203. C28H32N5? 3S (M + H) + calculated 518.222587; found 518.221998.

Ejepplo 226 Preparadón del 3-. { 4- (2-aminosulfonyl) phenyl) phenylaminosarbonylmethyl-a- (methylaarboxymethylether) -5-amidinoindole The title compound (racemic) was prepared as in Example 203. HREM for CzgHss sOsS (M + H) + calculated 520.166599; Found 520.165466.

EXAMPLE 227 3- (4- (2-Aminosulfonyl) phenyl) phenylaminosarbonylmethyl-a- (bensyl) -5- amidinoindole compound Preparadon of the title (racemic) was prepared as in Example 203. HREM for C3oH29N5? 3S (M + H) + calculated 538.191287; found 538.191263.

Example 228 Preparation of 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylaminoaarbonylmethyl-5-amidinoindole The title compound was prepared as in Example 203. HREM for C23H2oN5O? F3 (M + H) + 438.154170; found 438.152166.

Example 229 Preparadón del 3-. { 4- (2-ethylaminosulfonyl) phenyl) fe lamino < -arphaonylmethyl-5-amidnoindole The title compound was prepared as in Example 203. HREM for C26H27N503S? (M + H) + calculated 476.175637; found 476.175892.

Example 230 Preparadón del 3-. { 4- (2-prspilaminosulfonyl) phenyl) phenyl) aminoc-arbon lme -yl-5-amidinoindole The title compound was prepared as in Example 203. HREM for C26H27N503S (M + H) + calculated 490.191287; found 490.190996.

Example 231 Preparation of 2-methyl-3- (2-iodo-4- (2-aminosulfonyl) enxl) phenyl) aminocarbonylmethyl-5-amidoxindole The title compound was prepared as in Example 203. HREM for C24H23IN5O3S-1 ( M + H) + calculated 558.056639; found 558.057057.

Example 232 Preparation of 2-methyl-3-. { 4- (2- aminosul fonyl) phenyl) phenyl) apinocarbonylmethyl-5-amidinoxandol The title compound was prepared as in Example 203. LREM for (M + H) + 462.

Example 233 Preparation of 3-. { 4- (2-aminosulfonyl) phenyl) phenyl) -N-methylamino-aarbonylmethyl-5-amidinoindole The title compound was prepared as in Example 203. LREM for C24H24N503S? (M + H) + 462.

Example 234 Preparadon of 2-methyl-3-. { 4- (2- t-butylaminosul onyl) enyl) enxl) aminocarbonylmethyl-5-methoxyindole The title compound was prepared as in Example 203. LREM for C28H3iN304S? (M + H) + 506.

Example 235 Preparation of 3- (4- (2-N-methylaminosulfonyl) phenyl) phenyl) -N-methylaminosarbonylmethyl-5-amidinoindole The title compound was prepared as in Example 203. HREM for calculated C24H23N503S (M + H) + 462.159987; found 462.159054.

Example 236 Preparing the 3-. { 4- (2- (n-butylaminosulfonyl) f-nylphenylaminocarbonyl) methyl-5-sianoindoline To a solution of 3-acetic acid indoline (0.001 mol, 0.2 g) [or acid indoline (0.001 mol, 0.202 g)] in anhydrous acetonitrile ( 10 L) thionyl chloride (0.3 mL, 4.0 eq.) Was added [for indoline, 1.0 M HCl in ethyl ether (0.05 mL, 1.0 eq.) Was added before thionyl chloride]. This reaction mixture was heated to 50 ° C for 10 minutes, then cooled to normal temperature and stirred for 2 h. The solvent and extra thionyl chloride were removed in vacuo and the residue pumped for several hours to dry further. To this dry residue was added to the reaction mixture of A-B (0.338 g, 1.0 equivalents) and triethyl amine (0.14 mL, 1.0 equivalents, 2.0 equivalents for HCl salt) in anhydrous methylene chloride (10 mL). This reaction mixture was allowed to stir at normal temperature for 2 h. The reaction mixture was evaporated and purified by flash chromatography on a column of silica gel (50 g) eluting with 3: 1 hexane: ethyl acetate to give 0.4 g of the pure product with n-butyl sulfonamide (51%).

Example 237 Preparing the 3-. { 4- (2- (n-propylaminosul onyl) enylphenylaminocarbonyl) methyl-5- to idinoindoline The title compound was prepared as in Example 203. HREM for C 26 H 3 o N 5 S 0 3 (N + H) + calculated 492.206937; found 492.207667.

Example 238 Preparation of (-) - 3 - (4- (2-aminosul onxl) phenyl) pyrxd-2-ylaminocarbonylmethyl-5-amidxnoindoline The title compound was prepared as in Example 203. HREM for C22H24N603S? (M + H) + calculated 451.155236; found 451.154317.

Example 239 Preparation of the 3-. { 4- (2-aminosul onyl) phenyl) pyrid-2-ylaminosarbonylmethyl-5-amidinoindoline The title compound (racemic) was prepared as in Example 203. HREM for C22H24N603S? (M + H) + calculated 451.155236; found 451.154317.

Example 240 Preparation of the 3-. { 4- (2-Dimethylaminosulfonyl) phenyl) phenylaminocarbonylmethyl-5-amidinoindoline The title compound (racemic) was prepared as in Example 203. HREM for C25H26N503S? (M + H) + calculated 450. 159987; Found 450 159435.

Example 241 Preparation of (+) - 3 -. { 4- (2-t-butylaminessulonyl) enyl) pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline The title compound was prepared as in Example 203. HREM for C26H3oN603S? (M + H) + calculated 507.217836; found 507.217901. 98% ee; rotation (+) 19.23.

Example 242 Preparation of (-) - 3 - (4- (2-t-butylaminosulfonyl) pyrxd-2-ylaminosarbonylmethyl-5-amidinoindoline The title compound was prepared as in Example 203. HREM for CseHsoNeOsSi (M + H) + calculated 507.217836, found 507.217678. 98% ee; rotation -16.28.

Example 243 Preparation of 3- (4- (2-aminosulfonyl) pheny1) pyrid-2-yl) aminosarbonylmethyl-5-aminocarboxyindoline The title compound (racemic) was prepared as in Example 203. HREM for C22H23N603S? (M + H) + calculated 451.1552036; found 451.154691.

Example 244 Preparasion of 3- (4- (2-t-butylaminosulfonyl) phenyl) enyl) aminosarbonylmethyl-5-amidinoindoline The title compound was prepared as in Example 203. LREM for C27H3? N503S? (M + H) + calculated 506.3; Found 506.4.

Example 245 Preparing the 3-. { 4- (2-t-butylaminosulfonyl) phenxl) pyrid-2-yl} amnnoaarbonylmethyl-5-amidxnoindolxane The title compound (racemic) was prepared as in Example 203. LREM for C26H3oN6? 3S? (M + H) + calculated 507.3; found 507.4.

Example 246 Preparation of 3- (4- (2-ammonosulfonyl) enyl) pyrid-2-ylaminosarb-nylmethyl-6-amidinoindazole The title compound was prepared as in Example 203. HREM for C2? H2? N703S? (M + H) + calculated 450.134835; found 450.134725.

EXAMPLE 247 Preparation of 3- (4- (2-ammonosulfonyl) enxl) phexlamxnosarbonxlmetxl-6-amxdinoindazole The title compound was prepared as in Example 203. HREM for C22H22N603S? (M + H) + calculated 449.139586; found 449.138515.

Preparation of 3- (4- (2-t-butylap-inosulf onyl) phenyl) pyr-2-ylaminocarbonylmethyl-6-amidinoipdazole The title compound was prepared as in Example 203. H EM for C25H29N7? 3S? (M + H) + calculated 450.134835; 450.134725.

Example 249 Preparation of 3- (4- (2-t-butylaminosul onyl) phenyl) phenylaminocarbonylmethyl-6-amidinoindazole The title compound was prepared as in Example 203. C26H3oN603S? (M + H) + calculated 505.202186; found 505.202631.

Table 5 Table 6a * Example 65 contains the group CH2-Z-A-B in position 2 Table 6b Table 7 Table 8a * * For all the Examples, but 226 and 277, n =. For Examples 226 and 227, n = 0. i TQ Table 8b Table 8c Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 1211 C (O) CH2CH2OH 4- (2,3-difluorobenzyl) piperidine 1212 C (O) CH2CH2OH 4- (2-chloro-4-fluorobenzyl) piperidine 1213 CÍO) CH2OCH3 4-benzylpiperidine 1214 C (O) CH2OCH3 3-acetyl-4-benzylpiperidine 1215 C (O) CH2OCH3 4- (3-fluorobenzyl) piperidine 1216 C (O) CH2OCH3 4- (4- fluorobenzyl) piperidine 1217 C (O) CH2OCH3 4- (2,3-difluorobenzyl) piperidine 1218 C (O) CH2OCH3 .4- (2-Chloro-4-fluorobenzyl) piperidine 1219 C (O) CH2CH2-tetrazolyl 4-benzylpiperidine 1220 C (O) CH2CH-tetrazolyl 3-acetyl-4-benzylpiperidine 1221 C (O) CH2CH2-tetrazolyl 4- (3-fluorobenzyl) piperidine 1222 CÍO) CH2CH2-tetrazolyl 4- (4-fluorobenzyl) piperidine 1223 C (O) CH2CH2-tetrazolyl 4- (2,3-difluorobenzyl) piperidine Table 19 • • 10 fifteen twenty Table 20 Table 21 O 10 -I twenty Utility The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic conditions" as used herein includes arterial or venous or cardiovascular or cerebrovascular thromboembolic conditions, including, for example, unstable angina, first • myocardial infarction or recurrent, sudden ischemic death, transient ischemic attack, stroke, arteriosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism and pulmonary embolism It is believed that the anticoagulant effect of the compounds of the present invention is due to the inhibition of factor Xa or thrombin The affectivity of the compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and a synthetic substrate The rate of hydrolysis of factor Xa from the chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in absence and in the presence of the compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was verified spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of change of absorbance at 405 nM in the presence of inhibitor is indicative of enzyme inhibition. The results of this test were expressed as the inhibition constant, Ki. The determinations of factor Xa were made in 0.10 M sodium phosphate buffer, pH 7.5, with a content of 0.20 M NaCl, and 05% PEG 8000. The Michaelis constant, Km, for hydrolysis of the substrate was determined at 25 ° C using the Lineweaver and Burk method. Ki values were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) reacted with the substrate (0.20 mM - 1 mM) in the presence of inhibitor. The reactions were allowed to proceed for 30 minutes and the velocities (velocity of the absorbance change versus time) were measured in the 25-30 minute time interval. The following relationship was used to calculate the values of Ki: (v0-vs) / vs = I / (Ki (1 + S / K) where: v0 is the speed of the control in the absence of inhibitor, vs is the velocity in presence of inhibitor, I is the inhibitor concentration, Ki is the dissociation constant of the enzyme: inhibitor complex; S is the concentration of the substrate; E-m is the Michaelis constant. Using the methodology described above, it was found that a number of compounds of the present invention exhibit a Kx of < 5 μm, thus conforming the utility of the compounds of the present invention as effective Xa inhibitors. The antithrombotic effect of the compounds of the present invention can be demonstrated in rabbit arteriovenous (AV) thrombosis models. In this model, rabbits weighing 2-3 kg were anesthetized with a mixture of xylasin (10 mg / kg i) and ketamine (50 mg / kg i). An AV shunt device filled with saline was connected between the femoral and venous femoral arterial cannulas. The AV shunt device consists of a 6 cm piece of tygon tube which contains a piece of silk thread. Blood will flow from the femoral artery via the AV shunt to the femoral vein. The exposure of blood flowing to the silk strand will induce the formation of a significant thrombus. Forty minutes later, the shunt is disconnected and the silk thread covered with the thrombus is weighed. Agents or test vehicles (i.v., i.p., s.c., or orally) will be given prior to the opening of the AV shunt. The percentage inhibition of thrombus formation was determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) were estimated by linear regression. The compounds of formula (I) are also considered useful as inhibitors of serine proteases, particularly human thrombin, plasma kallikrein and plasmin. Due to their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the class of enzymes mentioned above. Specifically, the compounds have utility as active ingredients for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and commercial purposes. . Some compounds of the present invention showed to be inhibitors of direct action of serine professes thrombin for their ability to inhibit the cleavage of substrates of small molecules by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in < -7. Biol. Chem. 265, 18289-18297 (1990), incorporated herein by reference. In those assays, thrombin-mediated hydrolysis of chromogenic substrate S2238 (Helena Laboratories, 'Beaumont, TX) was verified spectrophotometrically. The addition of an inhibitor to the assay mixture results in a decrease in absorbance and is indicative of the inhibition of thrombin. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, the activity of the thrombin was tested by verifying the rate of increase of the absorbance 405 nm which rises due to the hydrolysis of the substrate. The inhibition constants were derived from the reciprocal graphs of the reaction rate as a function of the substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K-. of less than 5 μm, thereby confirming the usefulness of the compounds of the invention as effective thrombin inhibitors. The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anticoagulant or coagulation inhibitor agents, or antiplatelet agents or platelet inhibitors, thrombin inhibitors or thrombolytic or fibrinolytic agents. The compounds are administered to a mammal in a therapeutically effective amount. By "effective therapeutic amount" is meant an amount of a compound of Formula I which, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or alleviate that condition of thromboembolic disease or the progress of the disease By "administered in combination" or "combination therapy" means that the compound of form I and one or more additional therapeutic agents are administered concurrently to the mammal being treated.When administered in combination each component can be administered at the same time. or sequentially in any order at different points in time.Thus, each component can be administered separately but sufficiently close in relation to time to provide the desired therapeutic effect.Other anticoagulant agents (or coagulation inhibitors) which can be used in combination with the compounds of this The invention includes warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under the Background of the Invention.

The term antiplatelet agents (or platelet inhibiting agents), as used herein, denotes agents that inhibit platelet function such as inhibition of aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the different active ingredients or known nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone and piroxicam, including the salts or pharmaceutically acceptable active principles thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), or piroxicam are preferred. Other suitable antiplatelet agents include ticlopidine, including the pharmaceutically acceptable active salts or proprinciples thereof. Ticlopidine is also a preferred compound since its use is known to be gentle on the gastrointestinal tract. Still other suitable platelet inhibiting agents include the Ilb / IIIa antagonists, thromboxane A2 receptor antagonists and thromboxane-A2 synthetase inhibitors, as well as the pharmaceutically acceptable active salts or proprinciples thereof. The term thrombin inhibitors (or antithrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By thrombin inhibition, the different thrombin-mediated processes, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation, and / or granular secretion of thrombin activator inhibitor 1) plasminogen and / or serotonin) and / or fibrin formation are interrupted. Numerous thrombin inhibitors are known to those skilled in the art and those inhibitors were contemplated to be used in combination with the compounds herein. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable active salts and proprinciples thereof. The boroarginine and boropeptide derivatives include the N-acetyl and peptide derivatives of "boronic acid, such as the C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and the corresponding isothiouronium analogues of the The term hirudin, as used herein, includes suitable derivatives or analogues of hirudin, which are referred to herein as analogs, such as disulfatohirudin.Rubbrominated thrombin inhibitors include the compounds described in Kettner et al. US Patent 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are incorporated herein by reference.Any other suitable boroarginine derivatives and inhibitors of the boropeptide thrombin include those described in PCT Application Publication No. 92/07869 and European Patent Application Publication Number 471, 651 A2, the descriptions of the ales are incorporated here as a reference. The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable active salts or proprinciples thereof. The term "anistreplase", as used herein, refers to the anisolated plasminogen activator plasminogen activator complex, as described, for example, in European Patent Application No. 028, 489, the disclosure of which is incorporated herein by reference. The term urokinase, as used herein, is intended to denote a single double chain of urokinase, as also referred to herein as pruorokinase. The administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, can give an advantage in the effectiveness over the compounds and agents alone, and can thus also allow the use of lower doses of each. A lower dose minimizes the potential for side effects, thus providing a greater margin of safety. The compounds of the present invention are also useful as standard or reference compounds, for example as a standard or quality control, in tests or assays involving the inhibition of factor Xa. Such compounds can be provided in a commercial kit, for example for use in the pharmaceutical search involving the ---. 10 factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity with a compound with an unknown activity. It would also assure the experimenter that the trial was carried out properly and provided a basis for comparison, especially if the test compound was a derivative of the reference compound. When new assays or protocols are developed, the compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by adding the chromogenic substrate S2222 to a series of solutions containing test samples and optionally one of the compounds of the present invention. If the production of pNA is observed in the solutions containing the test sample, but not the compound of the present invention, then it would be concluded that factor Xa was present.

Dosage and Formulation The compounds of this invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or synchronized release formulations), pills, powders, granules, elixirs, dyes, suspensions, syrups and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration in standard pharmaceutical practice. The dosage regimen for the compounds of the present invention, of course, will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and degree of the symptoms; type of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the active ingredient or drug required to prevent, counteract or arrest the progress of thromboembolic disease. As a general guideline, the daily oral dose of each active ingredient, when used for the indicated purposes, will range from about 0.001 to 1000 mg / kg of body weight, preferably between about 0.01 to 100 mg / kg of body weight per day, and more preferably between about 1.0 to 20 mg / kg / day. Intravenously, the most preferred dose will range from about 1 to about 10 mg / kg / minute during an infusion at constant speed. The compounds of this invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times a day. The compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the administration of the dose, of course, will be continuous rather than intermittent through the dosing regimen. The compounds are typically administered in a mixture with pharmaceutically acceptable diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended administration form, i.e., oral tablets, capsules, elixirs, syrups and the like, and in a manner consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral active ingredient component can be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as ethanol, glycerol, water, and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like . The lubricants used in those dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds of the present invention can also be coupled with soluble polymers as carriers of the objective active ingredient. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving the controlled release of an active ingredient, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxy acid butyric, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphatic block copolymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per unit dose. In those pharmaceutical compositions the active ingredient will commonly be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and pulsed carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of the drug over a period of hours. Compressed tablets can be sugar coated or coated with a film to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, "either alone or in combination, are suitable stabilizing agents, citric acid and its salts and sodium EDTA are also used, and parenteral solutions may contain preservatives. , such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol Suitable pharmaceutical carriers are described in Remingto, s Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative, useful pharmaceutical dosage forms for the administration of the compounds of this invention may be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules, each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate.

Soft Gelatin Capsules A mixture of active ingredient is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil and is injected by means of a positive displacement pump into the gelatin to form gelatin capsules soft that contain 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional procedures, so that the dosage unit is 100 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.9 milligrams of lactose. Appropriate coatings may be applied to increase the taste or delayed absorption.

Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension An aqueous suspension is prepared for oral administration so that each 5 mL contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, USP, and 0.025 mL of vanillin. Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dose may be from about 0.1 to 100 milligrams of the compounds of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient's body weight. . For a tablet dosage form, the compounds of this invention may generally be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit. Where the compounds of Formula I are administered in combination with an antiplatelet agent, in the manner of a general guide, typically a daily dose may be from about 0.01 to 25 milligrams of the compounds of Formula I and from about 50 to 150 milligrams. of the antiplatelet agent, preferably from about 0.1 to 1 milligram of the compound of Formula I and about 1 to 3 milligrams of the antiplatelet agents, per kilogram of the patient's body weight. Where the compounds of Formula I are administered in combination with thrombolytic agent, a typical daily dose may be from about 0.1 to 1 milligrams of the compounds of Formula I, per kilogram of patient's body weight and, in the case of thrombolytic agents, the usual dose of the thrombolytic agent when administered alone can be reduced by about 70-80% when administered with a compound of Formula I. When two or more of the above second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dose and typical dosage form can be reduced relative to the usual dose of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination. Particularly when they are provided as a single dosage unit, there is the potential for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated so that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (ie, reduced). For example, an active ingredient can be enterically coated. By the enteric coating of one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but also, it is possible to control the release of one of those components in the gastrointestinal tract so that one of the those components are not released into the stomach but are released into the intestine. One of the active ingredients may also be coated with a material that effect a sustained release through the gastrointestinal tract and also serve to minimize the physical contact between the combined active ingredients.

In addition, the sustained release component can be enterically coated additionally so that the release of that component occurs only in the intestine. Yet another method would involve the formulation of a combined product in which one component is coated with a sustained release and / or enteric polymer, and the other component is also coated with a polymer such as a low hydroxypropyl methylcellulose (HPMC) grade. viscosity or other suitable materials known in the art, to further separate the active components. The polymeric coating serves to form an additional barrier "to interaction with the other component, as well as other ways of minimizing contact between the components of the combined products of the present invention, whether administered in a single dosage form. or administered in separate forms but at the same time and in the same manner, will be readily apparent to those skilled in the art, once armed with the description herein, Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings It should therefore be understood that within the scope of the appended claims, the present invention may be practiced otherwise than specifically described herein.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following: J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring, wherein Jb is CH, J is NR1 and Ja is CH2, substituted with 0-1 R1; R1 is selected from H, alkyl of C? _4, (CH2) rOR3, (CH2) rNR3R3 ', (CH2) rC (= 0) R2, (CH2) r (CH = CH) (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2 / (CH2) rS02R4, (CH2) rNR3S02R4, and (CH2) E-5-membered heterocyclic system, having 1-4 heteroatoms selected from N, 0 and S; R2 is selected from H, OR3, C? -4 alkyl, NR3R3 ', CF3, and a C3-10 carbocyclic residue substituted with 0-2 R6; R3 and R3 'are independently selected from H, C? -4 alkyl, and a C3-? 0 carbocyclic residue substituted with 0-2 R6; R 4 is selected from C 4 -4 alkyl, NR 3 R 3 ', and a C 3-10 carbocyclic residue substituted with 0-2 R 6; Z is selected from CH = CH, CH ((CH2) mQ (CH2) mR5), CH ((CH2) mQ (CH2) mR5) C (0) NR3, CH ((CH2) mC (O) (CH2) mR5a ), N ((CH2) qQ (CH2) mR5), N (Q '(CH2) raR5), C (O) N ((CH2) mQ' (CH2) mR5a), C (0) (CH2) r, C ( 0) 0 (CH2) r, OC (O) (CH2) r, C (O) (CH2) rNR3 (CH2) r, NR3C (0) (CH2) r, OC (0) NR3 (CH2) r, NR3C (0) 0 (CH2) r, NR3C (0) NR3 (CH2) r, S (0) p (CH2) r, S02CH2, SCH2C (0) NR3, S02NR3 (CH2) r, NR3S02 (CH2) r, and NR3S02NR3 (CH2) r; Q is selected from a bond, 0, NR3, C (0), C (0) NR3, NR3C (0), S02, NR3S02, and S02NR3; Q 'is selected from a link, CIO), C (0) NR3, S02, and 'S02NR R5 is selected from H, C? _4 alkyl, a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R6, provided that when Q is S02 or NR3S02, R5 is different from H and when Q 'is S02, R5 is different from H; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, phenethyl substituted with 0-2 R6, phenyl-CH = substituted with 0-2 R6, a carbocyclic residue of C3_? 0 substituted with 0-2 R6, and a heterocyclic system of 5-10 members containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; B is selected from: X-Y, C3-6 alkyl, NR3R3, C (= NR3) NR3R3 ', NR3C (= NR3) NR3R3 ', benzyl substituted with 0-2 Rs, a carbocyclic residue of C3-10 substituted with 0-2 • R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; A and B can, alternatively, be combined to form a Cg-1o carbocyclic residue substituted with 0-2 R6 or a 9-10 member heterocyclic system, containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from alkylene of C? -4, -C (0) -, -C (0) CR3R3'-, -CR3R3'C (0) -S (0) p-, -S (0) pCR3R3 -CR3R3'S (O) p.

-S (0) 2NR3-, -NR3S (0) 2-, -C (0) NR3-, -NR3C (0) -, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, 0, -CR3R3 '? -, and -0CR3R3'-; Y is selected from: a C3-? 0 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0 -2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C3-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (0) R3, NR3C (0) R3', NR3C (0) NR3R3 ', CH (= NH) NH2, NHC (= NH) NH2, S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-C? -4 alkyl, and (alkyl) C? -4) tetrazolyl; R7 is selected from H, OH, C? -6 alkyl, C? _6 alkylcarbonyl, C? -6alkoxy, C? - alkoxycarbonyl, C6_? Aryloxy, C6-? Aryloxycarbonyl or, aryl ethylcarbonyl C6-? O, C? -4 alkoxycarbonylcarbonyloxycarbonyl, C6-? Arylcarbonyloxy or C? _4alkoxycarbonyl, C? -6alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C4- alkoxycarbonyl; R8 is selected from H, C? -6 alkyl and (CH2) n-phenyl; R9 is selected from H, C? _6 alkyl and (CH2) n-phenyl; n is selected from 0, 1, 2, 3, and 4; is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4; provided that: (a) Z is different from CH2; and, (b) if Z is CH ((CH2) mQ (CH2) mR5) or CH ((CH2) mC (O) (CH2) mR5a), then B is different from XY, a carbocyclic residue of C3-10 or a heterocyclic system of 5-10 members. 2. The compound according to claim 1, characterized in that the compound is of the formula II: or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: 0-1 W, W1, W2, and W3 are N; R1 is selected from H, C ?4 alkyl, (CH2) rOR3, (CH2) rNR3R3 ', (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, (CH2) ) rNR3S02R4, and (CH2) r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S; R2 is selected from H, OR3, C? _4 alkyl, NR3R3 ', and CF3; R3 and R3 'are independently selected from H, C? _4 / alkyl and phenyl; R 4 is selected from C 1 - alkyl, phenyl and NR 3 R 3 '; Z is selected from CH = CH, CH ((CH2) mQ (CH2) mR5), CH ((CH2) mQ (CH2) mR5) C (0) NR3, CH ((CH2) mC (0) (CH2) mR5a ), N ((CH2) qQ (CH2) mR5), N (Q '(CH2) mR5), C (0) N ((CH2) mQ' (CH2) mR5a), CIO), C (0) CH2, C ( 0) 0, OC (O), C (O) (CH2) rNR3 (CH2) r, NR3C (O), OC (0) NR3, NR3C (0) 0, NR3C (0) NR3, S (0) p , S0CH.-, S02NR3, NR3S02, and NR3S02NR3; B is selected from: X-Y, C3-6 alkyl, benzyl substituted with 0-2 R6, a carbocyclic residue of C3-10 substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; A and B can, alternatively, be combined to form a C9-10 carbocyclic residue substituted with 0-2 R5 or a 9-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O , and S substituted with 0-2 R6; and, R6 is selected from H, OH, (CH2) nOR3, halo, d-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C (0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-C1-4 alkyl and (C1-4 alkyl) -tetrazolyl. 3. The compound according to claim 2, characterized in that: J, Ja and Jb combine to form an aromatic heterocyclic system containing 1-2 nitrogen atoms, substituted with 0-1 R1; J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring wherein Jb is N and J and Ja are CH 2 substituted with 0-1 R 1; J, Ja and Jb can, alternatively, be combined to form a heterocyclic ring wherein Jb is CH, J is NR1 and Ja is CH2 substituted with 0-1 R1; R1 is selected from H, C? - alkyl, (CH2) rOR3, INCH2) rNR3R3 ', (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH2) rS02R4, and (CH2) rNR3S02R4; Z is selected from CH ((CH2) mQ (CH2) mR: >), CH ((CH2) mQ (CH2) mR5) C (0) NR3 CH ((CH2) mC (0) (CH2) mR5a), N ((CH2) qQ (CH2) mR3), N (Q '(CH2) mR °), C (O) N ((CH2) mQ' (CH2) mRSa), C (0), C (0) CH2 , C (0) (CH2) rNR3 (CH2) r, NR3C (O), NR3C (0) NR3, S (0) 2, S02CH2, S02NR3, NR3S02, and NR3S02NR3; A is selected from: benzyl substituted with 0-2 R6, a carbocyclic residue of C3_? 0 substituted with 0-2 Rb, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from: XY, C3_6 alkyl, benzylated substituted with 0-2 R6, a carbocyclic C5-6 residue substituted with 0-2 R6, and a 5-6 member heterocyclic system containing from 1-3 selected heteroatoms from the group consisting of N, 0, and S substituted with 0-2 R6; X is selected from -C (0) -, -C (O) CR3R3'-, -S (0) 2-, - S (0) 2CR3R3'-, -S (0) 2NR3-, -C (0) NR3-, -NR3-, -NR3CR3R3'-, and O; Y is selected from: a C-e carbocyclic residue substituted with 0-2 Rb, and a 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2) nR3, halo, C4-4 alkyl, CN, N02, (CH) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C ( 0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ', NR3S02-C? -4 alkyl and (C? -4) alkyl-tetrazolyl; n is selected from 0 1, and 2; and, r is selected from 0, 1, and 2. 4. The compound according to claim 3, characterized in that the compound is of formula II: III or a stereoisomer or a pharmaceutically acceptable salt form thereof, wherein: J and Jb combine to form an aromatic heterocyclic system containing 1-2 nitrogen atoms, substituted with 0-1 R1; J and J can, alternatively, form a heterocyclic ring wherein Jb is N and J is CH2 substituted with 0-1 R1; J and Jb can, alternatively, form a heterocyclic ring wherein Jb is CH and J is NR1; Z is selected from C (0) N (Q'R5a), C (O), C (0) NR3, NR3C (0), and S02NR3; Q 'is selected from C (0) and C (0) NR3; R5 is selected from H and C? -4 alkyl; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-1 R6, phenyl substituted with 0-1 Rs, piperidinyl substituted with 0-1 R6, piperazinyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6; B is selected from: X-Y, benzyl substituted with 0-1 R6, phenyl substituted with 0-2 R6, cyclohexyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6; X is selected from: -C (O) -, -S (0) 2-, S02CH2, -S (0) 2NR3-, -NR3- and -C (0) NR3-; Y is selected from: phenyl substituted with 0-2 R6, and pyridyl substituted with 0-1 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3C (0) R3', NR3C ( 0) NR3R3 ', S02NR3R3', CONHS02R4, NR3S02NR3R3 ',' NR3S02- C4-4alkylaryl and (Cx-) alkyl-tetrazolyl; n is selected from 0, 1, and 2. 5 . The compound according to claim 4, characterized in that the compound is of formula IV: IV or a stereoisomer or a pharmaceutically acceptable salt form thereof thereof, wherein A, B, D, and Z are as defined above. 6. The compound according to claim 1, characterized in that the compound is selected from: 3- ((4-cyclohexyl) phenylaminomethylcarbonyl) methyl-5-amidinoindole 3- (4-p-toluensulsonyl-piperazincarbonyl) methyl-5-amidinoindole 3- (4- (2-aminosulfonylphenyl) pyridine-2-amino-carbonyl) methyl-5-amidinoindole; 3- (4- [2-tetrazole) phenyl) phenylaminocarbonyl) methyl-5-amidinoindole; 3- (4-biphenylaminocarbonyl) methyl-5-amidinoindole; 3- (4- (phenylmethylsulfonyl) piperazincarbonyl) methyl-5-amidinoindole; 3- (4-cyclohexylphenylaminocarbonyl) methyl-5-amidino-indole; 3- (4-benzylpiperazincarbonyl) methyl-5-amidinoindole; 3- (3-amidinobenzylamino (methylcarbonylmethoxy) -carbonyl) methyl-5-amidinoindole; 3- (4- (2-aminosulfonyl) phenylphenylaminocarbonyl) -methyl-5-amidinoindole; 3- (1-benzylpiperidin-4-aminocarbonyl) methyl-5-amidinoindole; 3- (4-phenylpiperazincarbonyl) ethyl-5-amidinoindole; 3- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole; 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole; 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-methylaminoindole; 3- (2-fluoro-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindole; 3-2-chloro-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole; 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole; 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindole; 3- . { 2-methyl-4- (2- (t-butylaminosulfonyl)) phenylphenyl-aminocarbonyl) methyl-5-amidinoindole; 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-a- (methylcarboxymethyl ether) -5-amidinoindole; 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-a- (benzyl) -5-amidinoindole; 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5-amidinoindole; 3- (4- (2-ethylaminosulfonyl) phenyl) phenylaminocarbonyl-methy1-5-amidinoindole; 3- (4- (2-propylaminosulfonyl) phenyl) phenyl) to n-carbonylmethyl-5-amidinoindole; 2-methyl-3-. { 2-iodo-4- (2-aminosulfonyl) phenyl) phenyl} -aminocarbonylmethyl-5-amidinoindole; 2-methyl-3-. { 4- (2-aminosulfonyl) phenyl) phenyl lamino-carbonylmethyl-5-amidinoindole; 3- (4- (2-aminosulfonyl) phenyl) phenyl} -N-methylamino-carbonylmethyl-5-amidinoindole; 2-methyl-3-. { 4- (2-t-butylaminosulfonyl) phenyl) phenyl} -aminocarbonylmethyl-5-methoxyindole; and, 3-. { 4- (2-N-methylaminosulfonyl) phenyl) phenyl} -N-methy1-aminocarbonylmethyl-5-amidinoindole; or a stereoisomer or pharmaceutically acceptable salt form thereof. 7. The compound according to claim 4, characterized in that the compound is of formula IVa: IVa or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein A, B, D, and Z are as defined above. 8. The compound according to claim 1, characterized in that the compound is selected from: 3-. { 4- (2- (n-butylaminosulfonyl) phenylphenylaminocarbonyl) methyl-5-cyanoindoline; 3- . { 4- (2- (n-propylaminosulfonyl) phenylphenylaminocarbonyl) methyl-5-amidinoindoline; (-) -3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5-amidinoindoline; 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-5-amidinoindoline; 3- (4- (2-dimethylaminosulfonyl) phenyl) phenylamino-carbonylmethyl-5-amidinoindoline; (+) - 3 - (4- (2-t-Butylaminosulfonyl) phenyl) pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; (-) - 3 - (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-yl) aminocarbonylmethy1-5-aminocarboxyindoline; 3- . { 4- (2-t-butylaminosulfonyl) phenyl) phenyl} amino-carbonylmethy1-5-amidinoindoline; and, 3-. { 4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl} -aminocarbonylmethyl-5-amidinoindoline; or a stereoisomer or a pharmaceutically acceptable salt form thereof thereof. 9. The compound according to claim 4, characterized in that the compound is of formula IVb: IVb or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A, B, D, and Z are as defined above. The compound according to claim 1, characterized in that the compound is selected from: 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-6-amidinoindazole; 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonyl-methyl-6-amidinoindazole; 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylamino-carbonylmethyl-6-amidinoindazole; and, 3- (4- (2-t-butylaminosulfonyl) phenyl) phenylamino-carbonylmethyl-6-amidinoindazole; or a stereoisomer or a pharmaceutically acceptable salt form * thereof. 11. The compound according to claim 4, characterized in that the compound is of formula IVc: IVc or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein D, Da, Z, A, and B are as defined above. The compound according to claim 1, characterized in that the compound is selected from: [4- (phenyl) phenylcarbonyl] methyl-6-amidino-benzimidazole; [4- (phenyl) phenylcarbonyl] ethyl-5-amidino-benzimidazole; [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidino-benzimidazole; [4- (3-aminophenyl) phenylcarbonyl] methyl-5-amidino-benzimidazole; [4- (4-fluorophenyl) phenylcarbonyl] methyl-6-amidino-benzyl idazole; [4- (4-formylphenyl) phenylcarbonyl] methyl-6-amidino-eneimidazo1; [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amidinobenzimidazole; [4- (2-tert-butylaminosulfonylphenyl) phenylcarbonyl] -methyl-6-amidinobenzimidazole; . { 4- [(2-tetrazolyl) phenyl] phenylcarbonyl} methyl-6-amidinobenzimidazole; [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-6-amidinobenzimidazole; [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-5-amidinobenzimidazole; 1- (4-benzylpiperidincarbonyl) methyl-6-amidino-benzimidazole; 1- (4-benzylpiperidinecarbonyl) methyl-5-amidino-benzimidazole; 1- (4-benzylpiperidincarbonyl) methyl-6-amidino-benzimidazole; and 2- [4- (2-tert-butylaminosulfonylphenyl) phenylcarbonyl] -methyl-5-azabenzimidazole; 2S- [4- (2-tert-aminosulfonylphenyl) phenylaminocarbonyl] methyl-thio-lH-imidazo (4,5-C) pyridine; and, 2S- [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] -methylthio-lH-imidazo (4,5-C) pyridine; or a stereoisomer or a pharmaceutically acceptable salt form thereof. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is of formula V: or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein one of R and Ra is - (CH2) n-Z-A-B and the other H; W, W2, and W3 are selected from CH and N, provided that at least one of W, W2, and W3 can be N; J is selected from N and C-R1; R1 is selected from H, O, (CH2) rOR3, (CH2) rC (= 0) R2, (CH = CH) C (= 0) R2, (CH2) JNR3C (= 0) R2, (CH2) rS02R4, (CH2) rNR3S02R4, and (CH2) r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S; R2 is selected from H, OR3, C? -4 alkyl, NR3R3 ', CF3, and a C3-? Carbocyclic residue or substituted with 0-2 R6; R3 and R3 'are independently selected from H, C? _4 alkyl, and a C3-10 carbocyclic residue substituted with 0-2 R6; R 4 is selected from OR 3, C 4 alkyl, NR 3 R 3 ', and a carbocyclic residue of C 3 - α or substituted with 0-2 R 6; Z is selected from CH = CH, CH (CH2) mQ (CH2) mR5, CH ((CH2) mQ (CH2) mR5) C (0) NR3, CH (CH2) mC (0) (CH2) mR5a, N (CH2) qQ (CH2) mR5, NQ '(CH2) mR5, C (O ) N ((CH2) mQ '(CH2) mR5a), C (O), C (0) CH2, CIO) O, OC (O), C (0) NR3 (CH2) r, NR3C (0), OC (0) NR3, NR3C (0) 0, NR3C (0) NR3, S (0) p, S02CH2, S02NR3, NR3S02, and NR3S02NR3; Q is selected from a bond, O, NR3, C (0), C (0) NR3, NR3C 0), S02, NR3S02, and S02NR3 0 is selected from a bond, C (0), C (0) NR3, S02 S02NR3; R5 is selected from H, C? - alkyl, a C3-8 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6, provided that when Q is S02 or NR3S02, R5 is different from H and when 0 is S02, R5 is different from H; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, a carbocyclic residue of C3-10 substituted with 0-2 a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; B is selected from: H, X-Y, NR3R3 ', C (= NR3) NR3R3', NR3C (= NR3) NR3R3 ', benzyl substituted with 0-2 R6, a carbocyclic residue of C3-10 substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from alkylene of C? _4, -C (O) -, -C (0) CR3R3'-, -CR3R3'C (0), -S (0) p-, -S (0) pCR3R3'- , -CR3R3'S (O) p-, -S (0) 2NR3-, -NR3S (0) 2-, -C (0) NR3-, -NR3C (0) -, -NR3-, -NR3CR3R3'-, - CR3R3'NR3-, O, -CR3R3 ', O-, and -0CR3R3'-; Y is selected from: a C3-? 0 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C4-4 alkyl, CN, N02, (CH2) rNR3R3 ', (CH2) rC (O) R3, NR3CÍO) R3', NR (O) NRJRJ, CH (= NH) NH2, NHC (= NH) NH2, C (= 0) RJ, SOzNR ^ R-3, NR3S02NR3R3 ', and NR3S02-C? _4 alkyl; n- is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 1 and 2; and, r is selected from O, 1, 2, 3, and 4. 14. The compound according to claim 13, characterized in that the compound is of formula VI: v or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein one of R and Ra is - (CH2) n-Z-A-B and the other is H; W and W2 are selected from CH and N, provided that at least one of W and W2 can be N; J is selected from N and C-R1; R1 is selected from H, (CH2) rOR3, (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH = CH) C (= 0) R2, (CH2) rS02R4, and ( CH2) rNR3S02R4; R2 is selected from H, OR3, C? -4 alkyl, NR3R3 ', and CF3; R3 and R3 'are independently selected from H, C? -4 alkyl, and phenyl; R 4 is selected from OR 3, C 4 alkyl, NR 3 R 3 ', and phenyl; Z is selected from C (0), C (0) CH2, C (0) NR3, NR3C (0), S (0) 2, S02CH2, S02NR3, NR3S02 and NR3S02NR3; A is selected from: a C3-10 carbocyclic residue substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from: X-Y, a carbocyclic residue of C3_? 0 substituted with 0-2 • R% and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from -C (O) -, -C (O) CR3R3'-, -CR3R3'C (0), -S (0) p-, -S (0) pCR3R3'-, -CR3R3'S (0) p-, -S (0) 2NR3-, -NR3S (0) 2-, -C (0) NR3-, -NR3-, -NR3CR3R3'-, and -CR3R3'NR3-; Y is selected from: a carbocyclic residue of C3_? 0 substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0 -2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C? -4 alkyl, CN, N02, (CH2) 'rNR3R3', (CH2) rC (0) R3, NR3C (0) R3 ', NR3C (0) NR3R3 ', C (= 0) R3, S02NR3R3', NR3S02NR3R3 ', and NR3S02-C? - alkyl; n is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4. 15. The compound according to claim 14, characterized in that the compound is of formula VII: Vl. or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, W and W2 are selected from CH and N, provided that at least one of W and W2 can be N; R1 is selected from H, (CH2) rOR3, (CH2) rC (= 0) R2, (CH2) rNR3C (= 0) R2, (CH = CH) C (= 0) R2, (CH2) rS02R4, and ( CH2) rNR3S02R4; R2 is selected from H, OR3, C? -4 alkyl, NR3R3 ', and CF3; R3 and R3 'are independently selected from H, C- alkyl, and phenyl; R is selected from OR, C? -4 alkyl, NR R, and phenyl; Z is selected from C (O), C (0) CH2, C (0) NR3, S (O) S02CH2, S02NR3, and NR3S02NR3; A is selected from: a carbocyclic residue of C3_? 0 substituted with 0-2 R6, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from:? - ?, a carbocyclic residue of C3 -? _ Substituted with 0-2 Rb, and a 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from -S (0) p-, -S (OpCR-'R-3 -, -CR3R3 S (0) p-, -S (0) 2NR-, -NR3S (0) 2-, and -C (0) NR3-; Y is selected from: a C3-? 0 carbocyclic residue substituted with 0-2 R6, and a 5-10 member heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2) nOR3, halo, C3-4 alkyl, CN, N02, (CH2) 'rNR3R3', (CH2) rC (O) R3, NR3C (0) R3 ', NR3C (0) NR3R3 ', C (= 0) R3, SOsNR > 3-'tR-, 3-3 '', NR-3S02NR > 3-3tR-, 3-3", and NR-SOS-alkyl of C? _4; n is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4. 16. The compound according to claim 13, characterized in that the compound is selected from: 1- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole; 1- (4-benzylpiperidincarbonyl) ethyl-5-amidinoindole; 1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-amidinoindole; 1- (1- (4-amidino) benzyl-N- (methylacetate) amino-carbonyl) methyl-5-amidinoindole; 1- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole-3-methyl propanoate; 1- ((4-benzylpiperidincarbonyl) methyl- (3-ethan-hydroxyl) -5-amidinoindole; 5-amidinoindole 1- (4-benzylpiperidine-1-carbonyl) methyl-3-methylcarboxylic acid; 1- (1-benzylpiperidine) 4-aminocarbonyl) methyl-5-amidinoindole; 1- (4-benzoylpiperidincarbonyl) methyl-5-amidinoindole; 1- (4- (3-fluoro) benzylpiperazincarbonyl) methyl-5-amidinoindole; 1- (4-phenylbenzylaminocarbonyl) methyl- 5-amidinoindole; 1- (4-benzylpiperidincarbonyl) methyl-5-amidinoindole-3-methyl propanoate; and, 1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-amidinoindole; or a stereoisomer or a salt form Pharmaceutically acceptable thereof 17. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof 18. A pharmaceutical composition, characterized in that comprises: a pharmaceutically acceptable carrier and a can The pharmaceutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof. A method for treating or preventing a thromboembolic condition, characterized in that it comprises: administering to a patient in need thereof, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. A method for treating or preventing a thromboembolic condition *, characterized in that it comprises: administering to a patient in need thereof, a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION The present application describes amidinoinols, amidinoazoles and analogues thereof of formula (I): wherein W, W1, W2 and W3 are selected from CH and N, provided that one of W1 and W2 is C (C (= NH) NH2) and in addition two of W, W1, W2 and W3 are N and one of Ja and Jb is substituted by - (CH2) nZAB, which are useful as inhibitors of factor Xa or thrombin.

Claims

211 CLAIMS

1. A compound of formula I: or a stereoisomer or a pharmaceutically acceptable salt form thereof, characterized in that: W and W3 are selected from CH and N; W1 and W2 are selected from C, CH, and N; provided that 0-2 of W, W1, W2, and W3 are N; one of D and Da is selected from H, C? _4 alkoxy, CN, C (= NR7) NR8R9, NHC (= NR7) NR8R9, NR8CH (= NR7), C (0) NR8R9, and (CH2) tNR8R9, and the other is absent; provided that if one of D and Da is H, then at least one of W, W1, W2, and W3 is N; one of Ja and Jb is substituted by (CH2) n-Z-A-B; J, Ja, and Jb combine to form an aromatic heterocyclic system containing 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R1, provided that Jb can be solely C or N; J / a / and Jb can, alternatively, be combined to form a heterocyclic ring, wherein Jb is N and J and Ja are CH 2 substituted with 0-1 R 1;