JP2002514162A - Amidinoindoles, amidinoazoles, and analogs thereof as factor Xa inhibitors and thrombin inhibitors - Google Patents

Abstract

This application describes amidinoindoles, amidinoazoles, and analogs thereof, represented by formula (I), which are useful as inhibitors of factor Xa or thrombin: , W ¹ , W ² , and W ³ are selected from CH and N, provided that ^one of W ¹ and W ² is C (C (＝ NH) NH ₂ ) and W, W ¹ , W ² , and two at most W ³ is n, and one of J ^a and J ^b - (CH ₂₎ are replaced by _n -Z-a-B.

Description

DETAILED DESCRIPTION OF THE INVENTION Amidinoindoles as factor Xa inhibitors and thrombin inhibitors, amidi Noazoles and their analogs                                Field of the invention   The present invention generally relates to trypsin-like serine protease enzymes, particularly thrombin and Amidinoindoles, amidinoazoles, and inhibitors of factor Xa And analogs, pharmaceutical compositions containing them, and thromboembolic diseases For use as anticoagulants for the treatment and prevention of cancer.                                Background of the Invention   EP 0,540,051 and JP 062277971 are factor Xa inhibitors Or a series of formulas based on the following formula, useful for treating influenza Describes the compound: In the above formula, A is optionally hydroxyalkyl, carboxyl, alkoxycarbo. Substituted by phenyl, alkoxyalkenylalkyl, or carboxyalkyl X is a bond, O, S, or carbonyl , N is 0-4, and Y is an optionally substituted carbocycle or heterocycle. The present invention Does not include compounds containing the above combinations of A, X, n and Y .   Tidwell et al., Thrombosis Research, 198. 1, 24, pp. 73-83, describes a series of aromatic mono- and di-amidines. Describes factor Xa inhibitory activity. Amidino aromatic moiety is indole, ind Including drin, benzofuran and benzimidazole.   Tidwell et al.J.Med.Chem.1983, Volume 26, pp. 294-298 Report a series of amidinoindoles of the formula:In the above formula, R¹And R^TwoIs an amidine and X is a medicament when Y and Z are H. May be tyl or ethyl and Y is C (O) CH when X and Z are H_TwoC H_ThreeZ may be CHO, COCH when X and Y are H_Three, COCF_Three Or C (O) Ph. These compounds have thrombin inhibition constants. Have been.   EP 0,655,439 is an IIb / IIIa antagonist represented by the following formula: Discusses: In the above formula, the central ring is a heterocyclic ring, B is a basic group, A is an acidic group, R₁Is any place Substituent, R_TwoIs an optional substituent, and L_aAnd L_bAre linkers and they are optional It may be substituted. The present invention is L_aDoes not include the -A group.   J. Med.Chem from Fairley et al..1993, 36, 1746-17 On page 53, a series of bis (amidinobenzimidazones represented by the following formula: ) And bis (amidinoindole): In the above formula, R is amidine or a derivative thereof, X is alkylene, alkenylene, It is a phenylene or phenylene methylene linker. The D of these compounds The ability to bind NA has been studied and reported, but the inhibition of trypsin-like enzymes has been discussed. I couldn't.   WO95 / 08540 is a bis (amidinobenzimida) represented by the following formula: Zolyl) alkanes are mentioned: In the above formula, Z is an amidine derivative, and R and R¹Is hydroxyl, amino, And various substituents including alkoxy. These compounds are It is said to be useful for the treatment of mosses, especially HIV. Xa or thrombin Nothing is said about the inhibition.   Trypsin-like enzymes hydrolyze peptide bonds at basic residues and produce C- One group of proteases that release either terminal arginine or lysine residues It is. Among them are enzymes of blood coagulation and fibrinolysis necessary for hemostasis. There is an element. They include Factor II, Factor X, Factor VII, Factor IX, Factor XII, Reclein, tissue plasminogen activator, urokinase-like plasmin Gen activator, and plasmin. By these proteases Elevated levels of proteolysis can cause pathological conditions. For example, consumable coagulopathy, That is, both clotting and fibrinolytic enzymes and their associated proteins Conditions characterized by a decrease in blood levels of zein inhibitors are often fatal. Than More specifically, thrombin proteolysis is required for blood clotting It is. Thrombin inhibition effectively inhibits blood clotting. Heparin (and ta) Conventional anti-thrombin III and heparin). Coagulants effectively prevent arterial thrombosis associated with myocardial infarction and other coagulation disorders The lack of observations underscores the importance of effective thrombin inhibitors. I However, low molecular weight thrombin inhibitors containing different functions effectively prevented arterial thrombosis (Hanson and Harker, Proc. Natl. Acad. Sci. U.S.A., 85 Vol., P. 3184 (1988)).   Activated factor Xa (its primary practical role is in the limited proteolysis of prothrombin Therefore, the production of thrombin) is the ultimate common pathway in blood coagulation. Maintain a central position linking intrinsic and extrinsic activation mechanisms. Fibri Thrombin, the final serine protease in the pathway that produces Of the prothrombinase complex (factor Xa, factor V, Ca²⁺You And phospholipids). According to calculations, one molecule of factor Xa is Since it is possible to produce 138 molecules of thrombin (Elodi, S.) Varadi, K .: Conditions for Catalytic Effect of Factor IXa-Factor VIII Complex Optimization: Putative Role of the Complex in Amplifying Blood Coagulation (Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Com plex: Probable role of the complex in the amplification of blood coagulat Res. 1979, 15, 617-629), inhibition of factor Xa. Harm may be more efficient than thrombin inactivation for disrupting the blood coagulation system I don't know.   Thus, factor Xa is a potentially effective therapeutic for the treatment of thromboembolism Or there is a need for effective and specific inhibitors of thrombin. New thrombi for this It is desirable to find inhibitors or factor Xa inhibitors.                                Summary of the Invention   Accordingly, one object of the present invention is to provide a useful factor Xa or thrombin inhibitor. Novel amidinoindole and its analogues or pharmaceutically acceptable To provide salts or prodrugs.   Another object of the invention is to provide a pharmaceutically acceptable carrier and a therapeutically effective amount of A small amount of the compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. It is to provide a pharmaceutical composition comprising at least one.   Another object of the present invention is to provide a therapeutically effective host for a host in need of thromboembolism treatment. Amount of the compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof Providing a method of treating thromboembolism, comprising administering at least one of the forms It is.   These and other objects will become apparent from the detailed description provided below, D inside, D^a, J, J^a, J^b, W, W¹, W^Two, W^ThreeIs defined by: Compound of (I): Or their pharmaceutically acceptable salts or prodrug forms are Factor Xa or Have been achieved by the present inventors' discovery that they are inhibitors of thrombin.                       Detailed Description of the Preferred Embodiment [1] Accordingly, in a first embodiment, the present invention provides a novel compound of formula (I): Or providing their stereoisomers or pharmaceutically acceptable salt forms; Where:   W and W^ThreeIs selected from CH and N;   W¹And W^TwoIs selected from C, CH and N;   However, W, W¹, W^Two, And W^Three0 to 2 are N,   D and D^aOne of them is H, C_1-4Alkoxy, CN, C (= NR⁷) NR⁸R⁹, N HC (= NR⁷) NR⁸R⁹, NR⁸CH (= NR⁷), C (O) NR⁸R⁹,and (CH_Two)_tNR⁸R⁹And the other does not exist,   Where D and D^aW is W if one of H is H¹, W^Two, And W^ThreeLess of One is N,   J^aAnd J^bIs-(CH_Two)_n-Z-AB,   J, J^a, And J^bTogether form 0-2 R¹N, O, substituted with Aromatic heterocyclic system containing 1-2 heteroatoms selected from the group consisting of With the proviso that J^bOnly can be C or N;   Or J, J^a, And J^bTogether, J^bIs N, J and J^aIs 0 One R¹CH substituted with_TwoCan form a heterocyclic ring,   Or J, J^a, And J^bAre together, J^bIs CH and J is NR¹In J^aIs 0 to 1 R¹CH substituted with_TwoCan form a heterocycle ,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)_rNR^ThreeR^Three', (CH_Two)_rC ( = O) R^Two, (CH_Two)_r(CH = CH) (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeSO_TwoR^Four, And (CH_Two)_r− (N, O And a 5-membered heterocyclic ring system having 1 to 4 heteroatoms selected from S and S And   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three', CF_Three, And 0-2 R⁶ C substituted with_3-10Selected from carbocyclic residues,   R^ThreeAnd R^Three'Is independently H, C_1-4Alkyl, and 0 to 2 R⁶Replaced by C_3-10Selected from carbocyclic residues,   R^FourIs C_1-4Alkyl, NR^ThreeR^Three', And 0 to 2 R⁶C substituted with_3-10Charcoal Selected from elementary ring residues,   Z is CH = CH, CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH ((CH_Two)_mC (O) (CH_Two)_mR^5a), N ((CH_Two)_qQ (CH_Two)_mR^Five ), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O) (CH_Two )_r, C (O) O (CH_Two)_r, OC (O) (CH_Two)_r, C (O) (CH_Two)_rNR^Three(CH_Two)_r, NR^ThreeC (O) (CH_Two)_r, OC (O) NR^Three(CH_Two)_r, NR^ThreeC (O) O (CH_Two)_r, NR^ThreeC (O) NR^Three(CH_Two)_r, S ( O)_p(CH_Two)_r, SO_TwoCH_Two, SCH_TwoC (O) NR^Three, SO_TwoNR^Three(CH_Two)_r, NR^Three SO_Two(CH_Two)_r, And NR^ThreeSO_TwoNR^Three(CH_Two)_rSelected from   Q is a bond, O, NR^Three, C (O), C (O) NR^Three, NR^ThreeC (O), SO_Two, NR^Three SO_Two, And SO_TwoNR^ThreeSelected from   Q ′ is a bond, C (O), C (O) NR^Three, SO_Two, And SO_TwoNR^ThreeSelected from   R^FiveIs H, C_1-4Alkyl, 0-2 R⁶C substituted with_3-10Carbocyclic residues, And 0 to 2 R⁶1 selected from the group consisting of N, O and S substituted with Selected from a 5-10 membered heterocyclic ring system containing up to 3 heteroatoms, Where Q is SO_TwoOr NR^ThreeSO_TwoIf R^FiveIs other than H, Q 'is SO_TwoIf R^FiveIs other than H,   R^5aIs NHR^Five, OR^Five, And R^FiveSelected from   A is   0-2 R⁶A benzyl substituted with   0-2 R⁶Phenethyl substituted with   0-2 R⁶Phenyl-CH = substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue;   0-2 R⁶1 selected from the group consisting of N, O and S, substituted with A 5-10 membered heterocyclic ring system containing up to 3 heteroatoms,   B is   XY, C_3-6Alkyl, NR^ThreeR^Three’, C (= NR^Three) NR^ThreeR^Three’, NR^ThreeC (= N R^Three) NR^ThreeR^Three’, 0 to 2 R⁶Benzyl substituted with 0-2 R⁶C substituted with_3-10A carbocyclic residue, and R⁶N, O substituted with And a 5- to 10-membered group containing 1 to 3 heteroatoms selected from the group consisting of Selected from ring systems,   Alternatively, A and B together form 0-2 R⁶C substituted with_9-10carbon Ring residue or 0-2 R⁶Selected from the group consisting of N, O, and S, Can form a 9-10 membered heterocyclic ring system containing selected 1-3 heteroatoms. ,   X is C_1-4Alkylene, -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three’ C (O), -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^ThreeC (O)-, -NR^Three -, -NR^ThreeCR^ThreeR^Three’-, -CR^ThreeR^Three'NR^Three-, O, -CR^ThreeR^Three'O- and -OCR^ThreeR^Three’-,   Y is 0 to 2 R⁶C substituted with_3-10A carbocyclic residue and 0 to 2 R⁶so 1 to 3 substituted heteroatoms selected from the group consisting of N, O, and S Selected from 5-10 membered heterocyclic ring systems, including   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^ThreeR^Three’, CONHS O_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two-C_1-4Alkyl, and (C_1-4A Alkyl) -tetrazolyl,   R⁷Is H, OH, C_1-6Alkyl, C_1-6Alkylcarbonyl, C_1-6Alkoki Si, C_1-4Alkoxycarbonyl, C_6-10Aryloxy, C_6-10Aryloxy Cicarbonyl, C_6-10Arylmethylcarbonyl, C_1-4Alkyl cal Bonyloxy C_1-4Alkoxycarbonyl, C_6-10Arylcarbonyloxy C_{1 -Four} Alkoxycarbonyl, C_1-6Alkylaminocarbonyl, phenylaminoca Rubonyl and phenyl C_1-4Selected from alkoxycarbonyl,   R⁸Is H, C_1-6Alkyl and (CH_Two)_n-Selected from phenyl;   R⁹Is H, C_1-6Alkyl and (CH_Two)_n-Selected from 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;   r is selected from 0, 1, 2, 3, and 4;   However, (A) Z is CH_TwoOther than, and (B) Z is CH ((CH_Two)_mQ (CH_Two)_mR^Five) Or CH ((CH_Two)_mC (O) (CH_Two)_mR^5a ), Then B is XY, C_3-10Carbocyclic residue or 5- to 10-membered heterocyclic ring Non-system. [2] In a preferred embodiment, the present invention provides a compound represented by formula II: AndWhere W, W¹, W^Two, And W^Three0 to 1 are N,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)_rNR^ThreeR^Three’, (CH_Two)_r C (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeS O_TwoR^Four, And (CH_Two)_r-(Heteroatoms 1-4 selected from N, O and S A 5-membered heterocyclic ring system having   R^TwoIs H, OR^Three, C_1-4Alkyl NR^ThreeR^Three’, CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Selected from alkyl, and phenyl ,   R^FourIs C_1-4Alkyl, phenyl and NR^ThreeR^Three’,   Z is CH = CH, CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH ((CH_Two)_mC (O) (CH_Two)_mR^5a), N ((CH_Two)_qQ (CH_Two)_mR^Five ), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O), C ( O) CH_Two, C (O) O, OC (O), C (O) (CH_Two)_rNR^Three(CH_Two)_r, NR^ThreeC (O), OC (O) NR^Three, NR^ThreeC (O) O, NR^ThreeC (O) NR^Three, S (O)_p, SO_TwoCH_Two, S O_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from   B is XY, C_3-6Alkyl,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶1 selected from the group consisting of N, O and S, substituted with Selected from a 5-10 membered heterocyclic ring system containing up to 3 heteroatoms,   Alternatively, A and B together form 0-2 R⁶C substituted with_9-10Charcoal A ring residue or 0 to 2 R⁶From the group consisting of N, O and S, substituted with Can form a 9-10 membered heterocyclic ring system containing selected 1-3 heteroatoms. Come   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (CH_Two )_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three’ , SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two− C_1-4Alkyl, and (C_1-4Alkyl) -tetrazolyl. [3] In a more preferred embodiment, the present invention provides a compound of formula II: in this case,   J, J^aAnd J^bTogether with 0 to 1 R¹The nitrogen atom substituted with 1 to Form an aromatic heterocyclic ring system containing two,   Or J, J^aAnd J^bTogether, J^bIs N, J and J^aIs 0 One R¹CH substituted with_TwoTo form a heterocyclic ring system,   Or J, J^aAnd J^bTogether, J^bIs CH and J is NR¹And J^a Is 0 to 1 R¹CH substituted with_TwoTo form a heterocyclic ring system,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)_rNR^ThreeR^Three’, (CH_Two)_r C (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^FourAnd (CH_Two)_rN R^ThreeSO_TwoR^FourSelected from   Z is CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five) C (O) NR^Three, CH (CH_Two)_mC (O) (CH_Two)_mR^5a) , N ((CH_Two)_qQ (CH_Two)_mR^Five), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '( CH_Two)_mR^5a), C (O), C (O) CH_Two, C (O) (CH_Two)_rNR^Three(CH_Two)_r, NR^ThreeC (O), NR^ThreeC (O) NR^Three, S (O)_Two, S O_TwoCH_Two, SO_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from   A is   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY, C_3-6Alkyl,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_5-6A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-6 membered heterocyclic ring system containing 3 heteroatoms,   X is -C (O)-, -C (O) CR^ThreeR^Three'-, -S (O)_Two-, S (O)_pCR^ThreeR^Three’ -, -S (O)_TwoNR^Three-, -C (O) NR^Three-, -NR^Three-, -NR^ThreeCR^ThreeR^Three’-, And O,   Y is   0-2 R⁶Replaced by_5-6A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-6 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two-C_1-4Alkyl and (C_1-4Alkyl) -te Selected from tolazolyl,   n is selected from 0, 1, and 2;   r is selected from 0, 1, and 2. [4] In an even more preferred embodiment, the present invention is represented by Formula III below. Providing a compound that is Where:   J and J^bTogether form 0-1 R¹One or two nitrogen atoms substituted with To form an aromatic heterocyclic ring system containing   Or J and J^bIs J^bIs N and J is 0 to 1 R¹CH substituted with_Twoso Can form a heterocycle,   Or J and J^bIs J^bIs CH and J is NR¹Forming a heterocyclic ring that is Can be   Z is C (O) N (Q'R^5a), C (O), C (O) NR^Three, NR^ThreeC (O) and SO_Two NR^ThreeSelected from   Q 'is C (O) and C (O) NR^ThreeSelected from   R^FiveIs H and C_1-4Selected from alkyl,   R^5aIs NHR^Five, OR^Five, And R^FiveSelected from   A is   0 to 1 R⁶Benzyl substituted with   0 to 1 R⁶Phenyl substituted with   0 to 1 R⁶Piperidinyl substituted with   0 to 1 R⁶Piperazinyl substituted with, and   0 to 1 R⁶Selected from pyridyl substituted with   B is   XY,   0 to 1 R⁶Benzyl substituted with   0-2 R⁶Phenyl substituted with   0 to 1 R⁶A cyclohexyl substituted with   0 to 1 R⁶Selected from pyridyl substituted with   X is -C (O)-, -S (O)_Two-, SO_TwoCH_Two, -S (O)_TwoNR^Three-, -NR^Three− And -C (O) NR^Three-Selected from   Y is   0-2 R⁶Phenyl substituted with   0 to 1 R⁶Selected from pyridyl substituted with   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two -C_1-4Alkyl and (C_1-4Alkyl) -tetrazolyl,   n is selected from 0, 1 and 2. [5] In an even more preferred embodiment, the present invention relates to a compound of formula IV Provide things, Wherein A, B, D, and Z are as defined above. [6] In an even more preferred embodiment, the present invention provides a compound comprising Provide selected compounds: 3-((4-cyclohexyl) phenylaminomethylcarbonyl) methyl-5-amido Zinoindole 3- (4-p-toluenesulfonyl-piperazinecarbonyl) methyl-5-amidi Noindore 3- (4- (2-aminosulfonylphenyl) pyridine-2-aminocarbonyl) me Chill-5-amidinoindole 3- (4- [2-tetrazole] phenyl) phenylaminocarbonyl) methyl- 5-amidinoindole 3- (4-biphenylaminocarbonyl) methyl-5-amidinoindole 3- (4- (phenylmethylsulfonyl) piperazinecarbonyl) methyl-5-amido Zinoindole 3- (4-cyclohexylphenylaminocarbonyl) methyl-5-amidinoin Doll 3- (4-benzylpiperazinecarbonyl) methyl-5-amidinoindole 3- (3-amidinobenzylamino (methylcarbonylmethoxy) carbonyl) methyl- 5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- 5-amidinoindole 3- (1-benzylpiperazine-4-aminocarbonyl) methyl-5-amidinoy Ndore 3- (4-phenylpiperazinecarbonyl) methyl-5-amidinoindole 3- (4-benzylpiperazinecarbonyl) methyl-5-amidinoindole 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-methylaminoindole 3- (2-fluoro-4- (2-aminosulfonyl) phenylphenylaminocar Bonyl) methyl-5-amidinoindole 3- (2-chloro-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-amidinoindole 3- (2-methyl-4- (2- (t-butylaminosulfonyl)) phenylphenyl Aminocarbonyl) methyl-5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- α- (methylcarbonyl methyl ether) -5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- α- (benzyl) -5-amidinoindole 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylaminocarboni Rumethyl-5-amidinoindole 3- (4- (2-ethylaminosulfonyl) phenyl) phenylaminocarbonyl Chill-5-amidinoindole 3- (4- (2-propylaminosulfonyl) phenyl) phenyl) aminocarboni Rumethyl-5-amidinoindole 2-methyl-3- (2-iodo-4- (2-aminosulfonyl) phenyl) phenyl ) Aminocarbonylmethyl-5-amidinoindole 2-methyl-3- (4- (2-aminosulfonyl) phenyl) phenyl) aminocar Bonylmethyl-5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenyl) -N-methylaminocar Bonylmethyl-5-amidinoindole 2-methyl-3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl) Aminocarbonylmethyl-5-methoxyindole 3- (4- (2-N-methylaminosulfonyl) phenyl) phenyl) -N-methyl Aminocarbonylmethyl-5-amidinoindole Alternatively, a stereoisomer or a pharmaceutically acceptable salt form of the above compound. [7] In another even more preferred embodiment, the invention is represented by formula IVa: Providing a compound A, B, D, and Z in the formula are as defined above. [8] In another even more preferred embodiment, selected from the following compound group: Provided compounds are provided: 3- (4- (2- (n-butylaminosulfonyl) phenylphenylaminocarboni L) Methyl-5-cyanoindoline 3- (4- (2- (n-propylaminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-amidinoindoline (-)-3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocar Bonylmethyl-5-amidinoindoline 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarbonyl Methyl-5-amidinoindoline 3- (4- (2-dimethylaminosulfonyl) phenyl) phenylaminocarbonyl Methyl-5-amidinoindoline (+)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl Aminocarbonylmethyl-5-amidinoindoline (-)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl Aminocarbonylmethyl-5-amidinoindoline 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-yl) aminocarboni Rumethyl-5-aminocarboxyindoline 3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl) aminocarbo Nylmethyl-5-amidinoindoline 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl) ami Nocarbonylmethyl-5-amidinoindoline Or a stereoisomer or a pharmaceutically acceptable salt form of the above compound. [9] In another even more preferred embodiment, the present invention provides a compound of formula IVb Providing a compound represented by A, B, D, and Z in the formula are as defined above. [10] In another even more preferred embodiment, the present invention provides Provide a compound selected from: 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarbonyl Methyl-6-amidinoindazole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- 6-amidinoindazole 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylamino Carbonylmethyl-6-amidinoindazole 3- (4- (2-t-butylamino Sulfonyl) phenyl) phenylaminocarbonylmethyl-6-amidinoindazo Rule Alternatively, a stereoisomer or a pharmaceutically acceptable salt form of the above compound. [11] In another even more preferred embodiment, the present invention provides a compound of formula IVc: Providing a compound to be exposed, D, D in the formula^a, Z, A and B are as defined above. [12] In another even more preferred embodiment, the present invention provides a method comprising: Provide compounds that are: [4- (phenyl) phenylcarbonyl] methyl-6-amidinobenzimidazo Le [4- (phenyl) phenylcarbonyl] methyl-5-amidinobenzimidazo Le [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidinobenzo Imidazole [4- (3-aminophenyl) phenylcarbonyl] methyl-5-amidinobenzo Imidazole [4- (4-fluorophenyl) phenylcarbonyl] methyl-6-amidinoben Zoimidazole [4- (4-formylphenyl) phenylcarbonyl] methyl-6-amidinoben Zoimidazole [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amido Dinobenzimidazole [4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl] methyl -6-amidinobenzimidazole [4-((2-tetrazolyl) phenyl) phenylcarbonyl] methyl-6-amidi Nobenzimidazole [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-6 -Amidino benzimidazole [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-5 -Amidino benzimidazole 1- (4-benzylpiperidinecarbonyl) methyl-6-amidinobenzimidazo Rule 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinobenzimidazo Rule 2- (4- (2-aminosulfonylphenyl) phenylcarbonyl) methyl-6-a Midino benzimidazole 2- (4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl) methyl Le-5-azabenzimidazole 2S- [4- (2-t-aminosulfonylphenyl) phenylaminocarbonyl] Methyl-thio-1H-imidazo [4,5-C] pyridine 2S- [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl Ru-thio-1H-imidazo [4,5-C] pyridine Or a stereoisomer or a pharmaceutically acceptable salt form of the above compound. [13] In a preferred embodiment, the present invention provides a compound represented by formula V: AndWhere:   R and R^aIs-(CH_Two)_n-ZAB, the other is H,   W, W^Two, And W^ThreeIs selected from CH and N, provided that W, W^Two,and W^ThreeMay be N or less,   J is N and C—R¹Selected from   R¹Is H, O, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH = CH) C (= C ) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeSO_TwoR^Four , And (CH_Two)_r-(Has 1 to 4 heteroatoms selected from N, O and S 5 membered heterocyclic ring system)   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, CF_Three, And 0-2 R⁶C substituted with_3-10Selected from carbocyclic residues,   R^ThreeAnd R^Three’Is independently H, C_1-4Alkyl, NR^ThreeR^Three’And 0- Two R⁶C substituted with_3-10Selected from carbocyclic residues,   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three'And 0 to 2 R⁶Replaced by C_3-10Selected from carbocyclic residues,   Z is CH = CH, CH (CH_Two)_mQ (CH_Two)_mR^Five, CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH (CH_Two)_mC (O) (CH_Two)_mR^5a, N (CH_Two)_qQ (CH_Two)_mR^Five, NQ '(CH_Two)_mR^Five, C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O), C (O) C H_Two, C (O) O, OC (O), C (O) NR^Three(CH_Two)_r, NR^ThreeC (O), OC (O) NR^Three , NR^ThreeC (O) O, NR^ThreeC (O) NR^Three, S (O)_p, SO_TwoCH_Two, SO_TwoNR^Three, NR^Three SO_TwoAnd NR^ThreeSO_TwoNR^ThreeSelected from   Q is a bond, O, NR^Three, C (O), C (O) NR^Three, NR^ThreeC (O), SO_Two, NR^Three SO_Two, And SO_TwoNR^ThreeSelected from   Q ′ is a bond, C (O), C (O) NR^Three, SO_Two, And SO_TwoNR^ThreeSelected from   R^FiveIs H, C_1-4Alkyl, 0-2 R⁶C substituted with_3-8Carbocyclic residues, and And 0 to 2 R⁶Selected from the group consisting of N, O and S, Selected from 5 to 10 membered heterocyclic ring systems containing three heteroatoms, provided that Q is SO_TwoMa Or NR^ThreeSO_TwoIf R^FiveIs other than H, and Q ′ is SO_TwoIs Ki, R^FiveIs other than H,   R^5aIs NHR^Five, OR^FiveAnd R^FiveSelected from   A is   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶1-3 selected from the group consisting of N, O and S substituted with Selected from a 5 to 10 membered heterocyclic ring system comprising   B is   H, XY, NR^ThreeR^Three’, C (= NR^Three) NR^ThreeR^Three’,   NR^ThreeC (= NR^Three) NR^ThreeR^Three’,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10Carbocyclic residue,   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X is C_1-4Alkylene, -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three’ C (O), -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^ThreeC (O)-, -NR^Three -, -NR^ThreeCR^ThreeR^Three’-, -CR^ThreeR^Three'NR^Three-, O, -CR^ThreeR^Three’-, And -OCR^ThreeR^Three’-,   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, CH (= NH) NH_Two, NHC (= NH) NH_Two, C (= O) R^Three, SO_TwoNR^ThreeR^Three ’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^ThreeSO_Two-C_1-4Selected from 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;   r is selected from 0, 1, 2, 3, and 4. [14] In another more preferred embodiment, the present invention is represented by formula VI: Providing a compound, Where:   R and R^aIs-(CH_Two)_n-ZAB, the other is H,   W and W^TwoIs selected from CH and N, provided that W and W^TwoIs N May not be more than one,   J is N and C—R¹Selected from   R¹Is H, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two , (CH = CH) C (= O) R^Two, (CH_Two)_rSO_TwoR^Four, And (CH_Two)_rNR^ThreeSO_TwoR^Four Selected from   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Select from alkyl and phenyl And   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And phenyl,   Z is C (O), C (O) CH_Two, C (O) NR^Three, NR^ThreeC (O), S (O)_Two, SO_TwoCH_Two , SO_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from   A is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY,   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X is -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three'C (O), -S (O)_p -, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S (O)_TwoNR^Three-, -N R^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^Three-, -NR^ThreeCR^ThreeR^Three’-, And- CR^ThreeR^Three'NR^Three-Selected from   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (CH_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^Three R^Three’, C (= O) R^Three, SO_TwoNR^ThreeR^Three’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^Three SO_Two-C_1-4Selected from alkyl,   n is selected from 0, 1, 2, 3, and 4;   p is selected from 0, 1, and 2;   r is selected from 0, 1, 2, 3, and 4. [15] In another even more preferred embodiment, the invention is represented by formula VII: Provide compounds that are:Where:   W and W^TwoIs selected from CH and N, provided that W and W^TwoIs N May not be more than one,   R¹Is H, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two , (CH = CH) C (= O) R^Two, (CH_Two)_rSO_TwoR^Four, And (CH_Two)_rNR^ThreeSO_TwoR^Four Selected from   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Selected from alkyl, and phenyl And   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And phenyl,   Z is C (O), C (O) CH_Two, C (O) NR^Three, S (O)_Two, SO_TwoCH_Two, SO_TwoNR^Three , And NR^ThreeSO_TwoNR^ThreeSelected from   A is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY,   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X is -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, And -C (O) NR^Three-Selected from   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, C (= O) R^Three, SO_TwoNR^ThreeR^Three’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^ThreeSO_Two -C_1-4Selected from alkyl,   n is selected from 0, 1, 2, 3, and 4;   p is selected from 0, 1, and 2;   r is selected from 0, 1, 2, 3, and 4. [16] In another even more preferred embodiment, the present invention provides the following compound Provide a compound selected from the group: 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole 1- (4-benzylpiperidinecarbonyl) ethyl-5-amidinoindole 1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole 1- (1- (4-amidino) benzyl-N- (methyl acetate) aminocarbonyl) Methyl-5-amidinoindole Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Le-3-propanoate 1-((4-benzylpiperidinecarbonyl) methyl- (3-ethanehydroxyl) -5-amidinoindole 1- (4-benzylpiperidine-1-carbonyl) methyl-3-methylcarboxylic acid -5-amidinoindole 1- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-amidinoy Ndore 1- (4-benzoylpiperidinecarbonyl) methyl-5-amidinoindole 1- (4- (3-fluoro) benzylpiperazinecarbonyl) methyl-5-amidino Indole 1- (4-phenylbenzylaminocarbonyl) methyl-5-amidinoindole Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Le-3-propanoate 1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole Alternatively, a stereoisomer of the above compound or a pharmaceutically acceptable salt form thereof.   In a second embodiment, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable carrier. An effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or A novel pharmaceutical composition comprising a prodrug form is provided.   In a third embodiment, the invention provides a therapeutically effective amount of a compound of formula (I), Converts pharmaceutically acceptable salts or prodrug forms of this compound into thromboembolism Treating thromboembolism, including administration to patients in need of treatment or prevention Or a new method of prevention.Definition   The compounds described herein can have asymmetric centers. Asymmetrically substituted Compounds of the present invention that contain an atom are separated in optically active or racemic forms. Optical activity How to make the body is well known to those skilled in the art. For example, resolution of racemate, or optics And synthesis from active starting materials. Geometry of olefins, C = N double bond, etc. There are also a large number of chemical isomers in the compounds described herein. All stable isomers are considered. Cis and trans geometric isomerism of compounds of the invention Are described and separated as a mixture of isomers, It may be separated as a figure. Not specifically designated as a specific stereochemistry or isomeric form As long as all chiral, diastereomeric, racemic and all Geometric isomeric forms are contemplated.   Some variable (eg, R⁶) Occurs multiple times Sometimes, its definition in each occurrence is its definition in any other occurrence Has nothing to do with. For example, if the group is 0-2 R⁶Is replaced by If indicated, said group may optionally have up to two R⁶Can be replaced by R in development⁶Is considered R⁶Independently selected from a clear list of Also , Substituents and / or combinations of variables may make such combinations more stable. Only allowed to bring compound.   "C" used here_1-4Alkyl "refers to branched-and-having the specified number of carbon atoms. It shall contain a straight-chain saturated aliphatic hydrocarbon group. Examples are methyl, ethyl , N-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, And t-butyl, but not limited to; "alkenyl" Chain or branched hydrocarbon chain and any stable point along the chain Ethenyl, propenyl and the like, which include an unsaturated carbon-carbon bond.   As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, And iodine; and "counterion" is a small, negatively charged species, such as Chloride ion, bromide ion, hydroxide, acetate, sulfate, etc. To represent.   As used herein, a “carbocycle” or “carbocyclic residue” is a stable 3- to 7-membered unit. Ring or bicyclic, or 7 to 10 membered bicyclic or tricyclic, shall mean All are saturated, partially unsaturated, or aromatic. Examples of such carbocycles are (But not limited to) cyclopropyl, cyclobutyl, cyclopropyl Pentyl, 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 (tetra Phosphorus).   As used herein, the term “heterocycle” or “heterocycle” refers to a stable 5 to 7 membered monocyclic or bicyclic heterocyclic ring, or 7 to 10 membered bicyclic heterocyclic ring These rings are saturated, partially unsaturated or unsaturated (aromatic) and have carbon atoms and N From 1 to 4 heteroatoms independently selected from the group consisting of And also includes two rings in which any of the above heterocycles is fused to a benzene ring. You. Nitrogen and sulfur may optionally be oxidized. Heterocycles provide stable structures Bond to the pendant group at any heteroatom or carbon atom You may. The heterocycles described herein may be carbon or carbon if the resulting compound is stable. It may be substituted on a nitrogen atom. More specifically, the nitrogen of the heterocycle is It may be optionally quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, These heteroatoms are not adjacent to each other.   The term “aromatic heterocyclic ring system” as used herein refers to a stable 5- to 7-membered monocyclic or bicyclic ring. Ring means a heteroaromatic ring, or a 7-10 membered bicyclic heteroaromatic ring, These rings are independently selected from the group consisting of carbon atoms and N, O, and S Consists of 1 to 4 heteroatoms. Sum of S and O atoms in the aromatic heterocycle Preferably, the number is not greater than one.   Examples of heterocycles include, but are not limited to: Ndazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H -Pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4 H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocy Nil, benzimidazolyl, benzofuranyl, benzothiophenyl, benzotri Azolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazoly , Benzimidazolonyl, carbazolyl, 4aH-carbazolyl, β-carbo Linyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H , 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydro Furan, furanyl, furzanil, imidazolidinyl, imidazolinyl, imidazo Ryl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, i N-dolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoin Drill, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazo Ryl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazo Lysinyl, oxazolyl, oxazolidinyl pyrimidinyl, phenanthridinyl , Phenanthrolinyl, fenalsazinyl, phenazinyl, phenothiazinyl, Phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperi Dinyl, pteridinyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl , Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, Lidoxazole, pyridoimidazole, pyridothiazole, pyrazyl, pirimi Dinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4 H-quinolidinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahi Drofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H- 1,2,5-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thieno Thiazole, thienooxazole, thienoimidazole, thienophenyl, tri Azinyl, xanthenyl. Preferred heterocycles are pyridinyl, furanyl, thienyl, pi Loryl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H- Indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazoly , Oxyindolyl, benzoxazolinyl, or isatinoyl, It is not limited to these. For example, condensed rings containing the above heterocycles and spiro Compounds are also included.   The bond to the substituent has been shown to intersect the bond connecting the two atoms in the ring. In such cases, such substituents may be attached to any atom of the ring. Substituents are indicated , Through which atoms of its substituents to bond to the rest of the compound of the given formula Where is not indicated, such a substituent may be attached through any atom of such a substituent. May be combined. Combinations of substituents and / or variables are Only allowed if the combination results in a stable compound.   The term "substituted" as used herein refers to one or more hydrogens on a specified atom selected. Means substituted with the selected indicated group. In this case specified Substitutions of stable atoms without exceeding the normal valence of the atom That is the condition. When the substituent is keto (ie, = 0), the two waters on the atom Element is replaced.   As used herein, “pharmaceutically acceptable salts” are derivatives of the disclosed compounds. To transform the parent compound by making an acidic or basic salt of the parent compound. Means the resulting derivative. Examples of pharmaceutically acceptable salts include: But not limited to: basic residues such as inorganics such as amines. Acid salts, such as alkali or organic salts such as carboxylic acids; And so on. Pharmaceutically acceptable salts are formed, for example, from non-toxic inorganic or organic acids. And common non-toxic salts or quaternary ammonium salts of the parent compound. For example, this Such common non-toxic salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfa Those derived from minic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid, propio Acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, queer Acid, ascorbic acid, pamoic acid, maleic acid, hydroxymale Acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, And salts formed from ethanedisulfonic acid, oxalic acid, isethionic acid and the like.   The pharmaceutically acceptable salts of the present invention are directed to parent compounds that contain a basic or acidic moiety. Can be synthesized by general chemical methods. Generally, such salts are The free acid or base form of the compound is dissolved with a stoichiometric amount of a suitable base or acid in water or in water. Made by reacting in organic solvent or in a mixture of these two types Generally non-aqueous solvents such as ether, ethyl acetate, ethanol, Sopropanol, acetonitrile and the like are preferred. A list of suitable salts is Remington's Pharmaceutical Sciences, 17th edition, Ma Brook Publishing Company, Easton, PA, 1985, Found on page 1418. This disclosure is incorporated herein by reference. Shall be.   The phrase “pharmaceutically acceptable” is used here to make a sound medical judgment. Can cause undue toxicity, irritation and allergic reactions in contact with human and animal tissues. Response or other problems or complications, with a reasonable benefit / risk ratio Used to indicate compounds, substances, compositions and / or dosage forms that can be used as appropriate. Can be   "Prodrug" refers to the administration of such a prodrug to a test mammal. A covalent carrier which releases the active parent drug according to formula (I) in vivo Means that. Prodrugs of the compounds of formula (I) modify the functional groups present on the compound. Made by shaping, the deformation of which is in daily operation or in  It is performed in such a way that it is cleaved in vivo to produce the parent compound. Prodora Is a compound represented by the formula (I) in which hydroxy, amino, or Includes compounds in which the rufhydryl group is bound to a group such as: Is cleaved off when the prodrug or compound of formula (I) is administered to a mammal. To give free hydroxyl, free amino, or free sulfhydryl groups, respectively. I forgot. Examples of prodrugs are those of the alcohol and amine functions of the compounds of formula (I) Including but not limited to acetate, formate and benzoate derivatives It is not something to be done. Preferred prodrugs are D or D^aIs C (= N H) N (H) R^TenAnd R^TenIs OH, C_1-4Alkoxy, C_6-10Aryloxy, C_{1- Four} Alkoxycarbonyl, C_6-10Aryloxycarbonyl, C_6-10Arylme Tylcarbonyl, C_1-4Alkylcarbonyloxy C_1-4Alkoxycarbonyl, And C_6-10Arylcarbonyloxy C_1-4Selected from alkoxycarbonyl Is an amidine prodrug. More preferred prodrugs are⁷But OH , Methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and And methylcarbonyloxymethoxycarbonyl.   “Stable compounds” and “stable structures” refer to mixtures of useful purity from a reaction mixture. Compounds that are robust enough to withstand the process of isolation and prescribing as an effective therapeutic Means to show.                                   Synthesis   The compounds of the present invention may be any of many compounds well known to those skilled in organic synthesis. Can be made by law. The compounds of the present invention can be prepared by Synthesis methods known to those skilled in the art or modifications thereof as recognized by the skilled It can be synthesized by using them together. Preferred methods include the following: However, it is not limited to these. Each of the following references is a book Shall be incorporated into the invention. All temperatures are reported in ° C.   Compounds of formula I can be made using the following reactions and techniques. Reaction used The reaction is carried out in a solvent which is suitable for the reagents and materials employed and which are suitably modified for practice. Minute The functionalities present in the offspring must not be inconsistent with the transformations intended Those skilled in the art will understand. Therefore, to obtain the desired compound of the present invention, Reorder the stages or select a particular process scheme over others Is sometimes necessary. When planning any synthetic route in this area Another important consideration is the reaction present in the compounds according to the invention. It is also understood that this is a judicious choice of protecting groups to be used for protecting the functional groups. Become skilled Authoritative reports explaining many alternatives to those skilled in the art are available in Green and (Protective Groups In Organic Synthesis) ic Synthesis), Willie and Sons, 1991).   The description below refers to benzimidazoles, indazoles and indoles. General methods for synthesis via various intermediates are described. These methods are based on the above compound It is not intended to represent all possible means of manufacturing goods, It is only a brief description. A skilled person will appreciate all of the compounds shown here Easily understand what starting materials you need to make.   4-amino-3-nitrobenzonitrile (Aldrich Chemical Co., Ltd.) ) In the presence of a base with an acyl chloride (R¹CHO) or anhydride ((R¹CO)_TwoO) The intermediate (1) formed by chilling and subsequent hydrogenation is M 1 is shown. Using borane-pyridine in acetic acid in the presence of (1) the aldehyde ( CHO) can be reductively aminated to give an N-alkylated product (2). Cs_TwoCO_ThreeIn the presence of a base such as_ThreeAlkylation with X) Compound (3) is obtained. Compounds 2 and 3 exhibit a Pinner reaction 6-amidino-benzimidazole derivative (4) and 5-amidino-be Nzoimidazole derivative (5) can be provided respectively (Khanna J. Org. Chem., 1995, 60, 960). Scheme 1: Amidino-benzoimidyl via 4-amino-3-nitrobenzonitrile Dazol   Scheme 2 shows a 3-amino-4-nitrophenyl halide in DMF under reflux And zinc cyanide are coupled with palladium (0) catalyst to give compound (6) (Lawton et al., J. Org. Chem., 1959, vol. 24, p. 26). Di). (6) is acylated with acyl chloride or anhydride in the presence of a base, Compound (7) is formed upon oxidization. Cs_TwoCO_Three(7) in the presence of a base such as Acylation with a ride gives compound (8). Using borane-pyridine in acetic acid Reductive amination of the aldehyde with (7) gives the N-alkylated product (9) . Compounds (8) and (9) are converted to their 6-amidino-benzoyl by a Pinner reaction. Can be converted to midazole or 5-amidino-benzimidazole derivatives, respectively. You. Scheme 2: Amidino-benzo via 3-amino-4-nitrophenyl halide Imidazole  NaHCO_Three4-chloro-3-nitrobenzoni in the presence of a base such as Tolyl and amine (P_ThreeNH_TwoThe Ullmann reaction with the compound (10) shown in Scheme 3 Can be formed. Hydrogenation of (10) followed by a ring using an acid such as formic acid Can give compound (5), which, as described above, has its 5-amidino- Can be converted to benzimidazole derivatives. Further, compound (5) is Br- (CH_Two)_n Derivatized by the addition of -ZAB. The resulting mixture is subjected to a pinner reaction And could be separated by standard methods.        Scheme 3: Amidino-benzimidazole by Ullmann reaction   As described in Scheme 4, 4-amino-benzonitrile was brominated with NBS. And then NaNO in concentrated HCl_TwoAnd Cu_TwoWhen treated with O, compound (1) 1) is obtained (Tsuji et al., Chem. Pharm. Bull., 1992, vol. 40, p. 2399). Di). NaHCO_ThreeUllmann reaction of (11) with amine in the presence of a base such as As a result, compound (12) is formed. Hydrogenation of (11) followed by cyclization with formic acid is a compound (8), which, as described above, has its 6-amidino-benzoimid Can be converted to dazole derivatives.       Scheme 4: Amidino-benzimidazoles by Ullmann reaction   Scheme 5 illustrates the use of 4-amino-3-nitro-benzonitrile or 4-hydroxy 3,4-Diamino-be obtained by hydrogenating c-3-nitrobenzonitrile From zononitrile and 3-amino-4-hydroxybenzonitrile (13) The synthesis of 2-substituted-amidino-benzimidazoles is described. (13) PPA Treatment with acyl chloride or acid in the presence of Walker et al., Synthesis, 1981, 303). Compound (14) is anti-pinner Can be converted to an amidino derivative. Alternatively, when Y is NH, K_TwoC O_ThreeAlkylation of (14) with a halide in the presence of a base such as A mixture of isomers (15) and (16) is obtained. After these are separated, pinner After the reaction, 2-substituted-6-amidino-benzimidazole and 2-substituted-5 To provide amidino-benzimidazole derivatives, respectively.           Scheme 5: 2-Substituted-amidino-benzimidazoles  The 6-hydroxy-indazole is protected with pivalic anhydride in the presence of a base and Followed by treatment with trifluoromethanesulfonic anhydride, as shown in Scheme 6. The compound (17) is obtained. Platinum (0) -catalyzed coupling of (17) with zinc cyanide Provides compound (18). Compound (18) is deprotected under acidic conditions, and then Alkylation with a halide in the presence of a base gives compound (19), which is Can be converted to its 6-amidino-indazole derivative by You. Scheme 6: Amidino-benzoindazole via 6-hydroxy-indazole Kind   1-Substituted-amidino-indoles and -indazoles were added to Scheme 7 Could be made from 5-cyanoindole in the manner outlined. Intermediate (21) ) (20) with Br (CH_Two)_nCan be easily obtained by alkylating with Z. Wear. Peptide coupling with HAB using BOP reagent or alkylation Should give intermediate (22). It is then removed under pinner conditions (23). Scheme 7: 1-Substituted-amidino-indoles from 5-cyanoindole and And -indazoles (J^a= CH or N)   Scheme 8 shows that 3-substituted-amidino-indoles and -indazoles also It shows that it can be derived from 5-cyanoindole. Compound (26) is obtained by converting (24) to R¹ Substitution to form (25), (25) in the presence of oxalyl chloride at room temperature in a stream of nitrogen And acylation. Triturate the compound in trifluoroacetic acid. Selective ketone reduction with ethylsilane for 3 hours, then coupling with HAB can do. Scheme 8: 3-Substituted-amidino-indoles from 5-cyanoindole and And indazoles (J^a= CH or N)  Piperazine phenylsulfonamide, (31), and various other sulfo The amide analog was obtained from commercially available BOC-piperazine as shown in Scheme 9. CH_TwoCl_TwoWith phenylsulfonyl chloride in triethylamine and triethylamine Made by doing Scheme 9: Phenylsulfonylpiperazines from Boc-piperazine   Biphenyl compounds are made by methods known to those skilled in the art. example For example, Scheme 10 shows that BOC protected 4-bromoaniline (or 1-bromo-4- Suzuki coupling with (nitrobenzene) to make substituted biphenyls, A method for obtaining compound (35) will be described.              Scheme 10: Biphenyls from bromoaniline  Compound (38) is represented by R⁶= SO_TwoWhen NH-t-Bu, it is outlined in Scheme 11. As shown, deprotection of the t-butyl group with TFA followed by R^ThreeAlkylation with X Alternatively, it can be obtained by acylation.    Scheme 11: Synthesis of 4'-amino-biphenyl-2-sulfonamides   Scheme 12 describes a method for obtaining intermediates (43)-(45) from the same intermediate (39). Show. After acylation with oxalyl chloride, the addition of methanol gives the ketoester. (40) should be formed, and selective reduction with triethylsilane The acetate (42) is obtained. Alcohol when reduced with sodium borohydride Is obtained and it is R^ThreeIt can be converted to (45) by X. Intermediate (43) is as follows You can get it. POCl in DMF_ThreeFormylation with aldehyde ( 41), which is then Wittig-olefinated to give compound (43). Scheme 12: R to 1-substituted indoles or indazoles¹With substituent Addition  Sulfonyl chloride (49) can be obtained via aldehyde (47). Alde The hydride is reduced with sodium borohydride and sulfonated with methanesulfonyl chloride. Can be replaced by sodium sulfite in ethanol. Sulfonyl chloride ( 49) is then chlorinated with a sulfonyl chloride as detailed in Scheme 13. Should be obtained by doing Scheme 13: 1-R to protected indoles or indazoles¹Addition of      P is a protecting group (for example, a MEM group).   Scheme 14 shows the substitution of indole at position 2 with s-BuLi at -78 ° C. And subsequent R¹A method of obtaining compound (51) by adding X The method is described in detail. Thereafter, compound (51) can be converted to compound (52) by the method described above. .           Scheme 14: 1-R at position 2 of protected indole¹Addition of   In Scheme 15, using sodium methoxide in the presence of nitromethane, Thereafter, the compound (53) is converted into 5-cyanoindole by Zn reduction and condensation. A method for making compound (54) is shown.                     Scheme 15: Formation of indoles  Groups A and B can be obtained from commercial sources as known in the literature, or Alternatively, those skilled in organic synthesis can easily synthesize by applying standard methods known in the art. You. The necessary reactive functional groups added to the analogs of A and B are also commercially available from the literature. Or by standard methods known to those skilled in the art of organic synthesis. Therefore, they are easily synthesized. The table below shows the coupling between A and B The outline of the chemical reaction required for is described. Table 1: Amides, esters, ureas, sulfonamides and sulfamides between AB Preparation of the bond   The chemistry in Table 1 describes aprotic solvents such as chlorocarbons, pyridines, benzenes The reaction is carried out at a temperature from -20 ° C to the reflux temperature of the solvent with toluene or toluene. The lialkylamine base may or may not be present. Table 2: Preparation of ketone bond between AB  The coupling chemistry in Table 2 can be performed in various ways. Necessary for Y Grignard reagents are dry ether, dimethoxyethane, or tetrahydrofuran. Made from halogen analogues of Y in a temperature range from 0 ° C. to the reflux temperature of the solvent . This Grignard reagent is used under very well-controlled conditions, At room temperature (below -20 ° C), a large excess of acid chloride and dimethyl sulfite as solvent A catalytic or stoichiometric amount of copper bromide / dimethyl sulfide complex in the buffer Can react directly with their variants. Other methods that can be used include Grignard The reagent is changed to cadmium reagent, and Carson and Prout Coupling by the method (Org. Syn. Col. 3 (1955) p. 601) Or Fe (acac) by Fiandanese et al._ThreeIntermediary coupling (Tetrahedoron Lett., (1984) p. 4805), or manganese (II) Medium-mediated couplings (Cahiez and Laboue, Tetrahe doron Lett. 33 (31), (1992) 4437).   Table 3: Preparation of ether and thioether bonds between AB  The ether and thioether linkages in Table 3 correspond to polar aprotic solvents such as Potassium carbonate in seton, dimethylformamide or dimethylsulfoxide In the presence of a base such as sodium hydride or potassium t-butoxide By reacting the two components in a temperature range from the temperature to the reflux temperature of the solvent used, Can be made. Table 4: -SO- and -SO from the thioethers of Table 3_Two-Preparation of the bond   The thioethers in Table 3 were used to prepare the sulfoxide and sulfone analogs in Table 4. A convenient starting material. The combination of wet alumina and oxone is A reliable reagent for oxidizing the ether to sulfoxide, while -Oxidation with chloroperbenzoic acid gives the sulfone.   Other features of the present invention will become apparent from the following description of exemplary embodiments. These embodiments are intended to illustrate the invention, but not to limit it. Absent.                                  Example   Hereinafter, the synthesis of representative compounds according to the present invention will be described specifically, but not limited to. This will be described in detail with reference to typical embodiments.   The abbreviations used in the examples are defined as follows: "° C." , "D" is a double line, "dd" is a double line of a double line, "DAST" is a difluoride Ruaminosulfur, "eq" is equivalent (s), "g" is grams (single or Mg) milligram (s), “mL” is milliliter (s) Or "H" is hydrogen (s), "hr" is time (s) , “M” is a multiple line, “M” is mole, “min” is minute (s), “MHz” "" Is megahertz, "MS" is mass spectrometry, "nmr" or "NMR" is nuclear magnetic Resonance analysis, "t" for triplet, "TLC" for thin layer chromatography .   Examples 1 to 15 use K as the base in DMF (10 mL)._TwoCO_Three(2 mmol) 5-cyano-benzimidazole used at 90-110 ° C for 16-25 hours Was added to α, β-unsaturated ester, followed by a pinner reaction Made The mixture of meta- and para-isomers is converted to CH_Two Cl_TwoObtained by purification with 10-20% MeOH. Pure meta- The para-isomers were separated by HPLC.                       5-cyanobenzimidazole   4-amino-3-nitrobenzonitrile containing 5% Pd / C (1 g) (20 mm ol) MeOH (300 mL) solution was hydrogenated at room temperature for 16 hours. The reaction mixture Filtration and concentration gave 3,4-diaminobenzonitrile (2.4 g, 90 yield). %). It was treated directly with formic acid (20 mL) under reflux for 4 hours. Remove excess formic acid After work up, the residue was dissolved in EtOAc, 10% sodium bicarbonate and brine. Wash with MgSO_FourDried on. When concentrated, 5-cyanobenzimidazole ( (2.2 g, 85%). Ethyl 2- (3-cyanophenyl) ethacrylate and ethyl 2- (4-cyano Preparation of (phenyl) ethacrylate   To a stirred suspension of zinc powder (22 mmol) in THF (10 mL) was added 1,2- Dibromoethylene (0.2 g) was added and the mixture was stirred for 30 minutes. THF (25m L), 3-cyanobenzyl bromide or 4-cyanobenzyl bromide (20 m mol) solution was added slowly at a rate of one drop every 5 seconds at 5-10 ° C. Mix 3 And then copper (I) cyanide (20 mmol) in THF (20 mL) and Transferred to a solution of lithium chloride (40 mmol), -78 ° C. Warm the resulting mixture The mixture was stirred at −20 ° C. for 20 minutes and then cooled to −78 ° C. Ethyl 2- (B After slowly adding (lomomethyl) acrylate (20 mmol), the mixture was Stirred at -78 ° C for 2 hours, then warmed to room temperature overnight. Ether (100 mL) And saturated aqueous ammonium chloride solution (50 mL) were added to the mixture, and the mixture was filtered. did. Wash the filtrate with water and brine, and add MgSO_FourDried on. Concentrate and remain A distillate is obtained, which is subjected to column chromatography by means of a gradient system (CH_TwoCl_Two -EtOAc) to give ethyl 2- (3-cyanophenyl) ethanol Rate (1.2 g, 26.2%) and ester ethyl 2- (4-cyanophenyl) Ethacrylate (3.6 g, 78.6%) was obtained.   For ethyl 2- (4-cyanophenyl) ethacrylate:   For ethyl 2- (3-cyanophenyl) ethacrylate:  Method for producing ethyl [3- (4-cyanophenyl) -2-bromomethyl] acrylate   To a solution of 4-cyanobenzylbromide (40 mmol) in xylene (40 mL) Triphenylphosphine (40 mmol) was added, and the resulting solution was left Heated to ° C. After removing xylene, a white solid was obtained. It is THF (4 0 mL) and EtOH (40 mL) and dissolved at room temperature for 1 hour in DBU (40 mL). mmol), and ethyl pyruvate (40 mmol) was added thereto. Generate The mixture was stirred at room temperature overnight, filtered and_ThreePO was removed. Concentrate the filtrate, Dissolve in EtOAc, wash with 1N HCl, water and brine, add MgSO_FourDry on Dried. Upon concentration, cis and trans olefins were obtained almost quantitatively. CCl_Four(200 mL), olefin (5 mmol), NBS (5 mmol), and And AIBN (0.25 mmol) were refluxed under nitrogen for 16 hours, filtered and concentrated. , Gradient solvent system (CH_TwoCl_Two-EtOAc) by column chromatography. To give the title compound as a white solid (1.25 g, 85%). .        Method for producing ethyl 2- (4-benzyloxyphenyl) methacrylate   4-bromophenol (40 mmol) in DMF (200 mL), benzyl bromide (40 mmol) and Na_TwoCO_ThreeIs stirred at room temperature for 24 hours, and then Poured into water. The solid was collected and recrystallized from hexane to give 4-benzyloxybenzene. Nsenbromide was obtained almost quantitatively. Solution of bromide in THF (100 mL) Was treated with BuLi (44 mmol) at −78 ° C. for more than 30 minutes, then THF ( ZnI in 40mL)_Two(40 mmol) solution for more than 20 minutes. The resulting mixture After warming to room temperature for more than one hour, it was cooled to -78 ° C and sheared in THF (50 mL). A solution of copper (I) chloride (40 mmol) and lithium chloride (80 mmol) slowly added. The resulting mixture was warmed, stirred at -20 ° C for 20 minutes, and cooled to -78 ° C. And ethyl 2- (bromomethyl) acrylate (40 mmol) was added thereto. Generate The resulting mixture was stirred at -78 <0> C for 2 hours, then warmed to room temperature overnight. With ether A saturated aqueous solution of ammonium chloride was added and filtered. Wash the filtrate with water and brine , MgSO_FourDried on. Concentration gave a residue that was eluted with a gradient solvent system (CH_Two Cl_Two-EtOAC) purified by column chromatography. The title compound was obtained (3.6 g, 30.4%): Example 1 Ethyl 2- (3-amidinophenyl) ethyl-3- (5-amidinobenzo Imidazole) propionate and ethyl 2- (3-amidinophenyl) ethyl Method for producing -3- (6-amidinobenzimidazole) propionate   5-cyanobenzimidazole (2 mmol) in DMF (10 mL), ethyl 2- (3-cyanophenyl) ethacrylate (2 mmol) and K_TwoCO_Three(2 mmol) of The mixture was heated to 90 ° C. under nitrogen for 16 hours. Mixture with EtOAc (150 mL) Diluted with 1N HCl, water and brine, and dried over MgSO_FourDried on. Filtration After filtration and concentration, the residue was concentrated in a gradient solvent system (CH_TwoCl_Two-EtOAc) Purification by column chromatography gives ethyl 2- (3-cyanophenyl) ethyl 3- (6-cyanobenzimidazole) propionate and ethyl 2- (3-cy (Anophenyl) methyl-3- (5-cyanobenzimidazole) propionate (0.57 g, 76.4%) as a colorless oil. Examples 2 and 3 Ethyl 2- (3-amidinophenyl) ethyl-3- (5-amidinobenzimida Sol) propionate and ethyl 2- (3-amidinophenyl) ethyl-3- ( Method for producing 6-amidinobenzimidazole) propionate   The mixture of esters obtained in Example 1 was added in absolute ethanol at 0 ° C. for 15 minutes. HCl (gas) and then stirred for 16 h. Excess HCl (gas) and After removing the ethanol, the residue was taken up in anhydrous ethanol (10 mL) (NH_Four)_TwoCO_Three( 5 eq) at room temperature for 24 hours. Concentration gave a residue, which was CH on plate_TwoCl_TwoPurification with 10% MeOH in water affords a mixture of the title compounds. (400 mg, 65.4%): mp 160-165 ° C; ESMS: 204.2 (M + 2H)²⁺. The mixture was subjected to HPLC on a chiral OJ column. By CO_TwoFurther separation with / MeOH / TEA (80/20 / 0.1) gave Example 2, ethyl 2- (3-amidinophenyl) ethyl-3- (5-amidinobenzo Imidazole) propionate and Example 3, ethyl 2- (3-amidinofe Nyl) ethyl-3- (6-amidinobenzimidazole) propionate is obtained. Was.   Example 2:   Example 3 Example 4 Ethyl 2- (4-amidinophenyl) ethyl-3- (5-amidinobenzo Imidazole) propionate and ethyl 2- (4-amidinophenyl) ethyl Method for producing -3- (6-amidinobenzimidazole) propionate   Example 4 uses ethyl 2- (4-cyanophenyl) ethacrylate (2 mmol). Made using the method described in Example 1 except used; (100 mg, 13% in two steps): mp 230 ° C (decomposition); ESMS: 407 (M + H).⁺; HRMS: 407.2200 (analytical value), C_{twenty two}H₂₆N₆O_TwoCalculated value: 407.219 5. Example 4 was further separated to give Examples 5 and 6.                             Examples 5 and 6 Ethyl 2- (4-amidinophenyl) ethyl-3- (5-amidinobenzo Imidazole) propionate and ethyl 2- (4-amidinophenyl) ethyl Method for producing -3- (6-amidinobenzimidazole) propionate   Further separation of the mixture of compounds obtained in Example 4 gives Examples 5 and 6. Obtained.   Example 5, ethyl 2- (4-amidinophenyl) ethyl-3- (5-amidinobe Nzoimidazole) propionate:   Example 6, ethyl 2- (4-amidinophenyl) ethyl-3- (6-amidinobe Nzoimidazole) propionate: Example 7 Ethyl [3- (4-amidinophenyl) -2- (5-amidinobenzo Imidazole) methyl] acrylate   5-cyanobenzimidazole (2 mmol) in DMF (10 mL), ethyl [3 -(4-cyanophenyl) -2-bromomethyl] acrylate (2 mmol) and K_TwoCO_Three(2 mmol) The mixture was heated at 90 ° C. under nitrogen for 24 hours. Mixtures with E Dilute with tOAc (150 mL), wash with 1N HCl, water and brine, add Mg SO_FourDried on. After filtration and concentration, the residue was subjected to column chromatography (CH_Two Cl_Two-EtOAc) to give ethyl [3- (4-cyanophenyl) -2. -(5-cyanobenzimidazole) methyl] acrylate is obtained as a colorless oil. (0.401 g, 56.3%).   The pinner reaction is based on ethyl [3- (4-cyanophenyl) -2- (5-cyanobenzo). [Imidazole) methyl] acrylate (0.42 mmol) was converted to the title compound. (400 mg, 65.4%): Example 8 Ethyl 2- (4-amidinophenyl) methyl-3- (6-amidinobenzo Imidazole) propionate and ethyl 2- (4-amidinophenyl) methyl Method for producing -3- (5-amidinobenzimidazole) propionate   Ethyl [3- (4-cyanophenyl) -2- (5-cyanobenzimidazole) meth Tyl] acrylate in MeOH in the presence of 10% palladium on activated carbon in water When quenched, ethyl 2- (4-cyanophenyl) methyl-3- (6-cyanobenzo Imidazole) propionate and ethyl 2- (4-cyanophenyl) methyl- 3- (5-cyanobenzimidazole) propionate was obtained:   The resulting mixture (1.5 mmol) is subjected to a pinner reaction to give the title compound. (300 mg, 48%):   Examples 51-63 were made by Method A, B or C. All compounds are final HPLC (CH_ThreeCN / H_Two/0.05%TFA).   Method A: Examples 51 to 59 were prepared using THF (H_Two(80% in O, 10 mL / mmol) Inside, Na_TwoCO_Three(2-4 equivalents) and Pd (PPh_Three)_Four(5-10% mmol^-1) Using [(4-bromophenyl) carbonyl] methyl-6-cyano Benzimidazole or [(4-bromophenyl) carbonyl] methyl-5-cy Suzuki coupling between anobenzimidazole and various boronic acids, It was then made by performing a Pinner reaction.   [(4-Bromophenyl) carbonyl] methyl-6-cyanobenzimidazole And [(4-bromophenyl) carbonyl] methyl-5-cyanobenzimidazole Was mixed with NaH (48 mmol) as a base in THF (80 mL). 5-cyano-benzimidazole (36 mmol) is converted to 2,4'-dibromoacetof Made in over 90% yield by alkylation with enone (36 mmol) . The mixture was washed with MeOH / CO_TwoH on a chiral OJ column using (20/80) Separation by PLC gave pure individual compounds.   [(4-Bromophenyl) carbonyl] methyl-6-cyanobenzimidazole :   [(4-bromophenyl) carbonyl] methyl-5-cyanobenzimidazole : Example 51 [(4-phenyl) phenylcarbonyl] methyl-6-amidino Preparation of Benzimidazole Example 52 [(4-phenyl) phenylcarbonyl] methyl-5-amidinobenzo Preparation of imidazole Example 53 [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidino Preparation of Benzimidazole Example 54 [4- (3-aminophenyl) phenylcarbonyl] methyl-5- Preparation of amidinobenzimidazole Example 55 [4- (4-fluorophenyl) phenylcarbonyl] methyl-6 Preparation of amidinobenzimidazole Example 56 [4- (4-Formylphenyl) phenylcarbonyl] methyl-6 Preparation of amidinobenzimidazole Example 57 [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6 Preparation of amidinobenzimidazole Example 58 [4- (2-t-butylaminosulfonylphenyl) phenyl Process for producing carbonyl] methyl-6-amidinobenzimidazole Example 59 ( 4-[(2-tetrazolyl) phenyl] phenylcarbonyl) methyl- Method for producing 6-amidinobenzimidazole   Method B: Examples 60, 61 and 62 convert 5-cyanobenzimidazole to [ 4- (2-t-butylaminosulfonylphenyl) phenylaminocarbonyl] me Tylene chloride or (4-benzylpiperidinecarbonyl) methylene chloride And then subjected to a Pinner reaction.                           Examples 60 and 61 [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl- 6-amidinobenzimidazole (Example 60) and [4- (2-amino Sulfonylphenyl) phenylaminocarbonyl] methyl-5-amidino Preparation of Benzimidazole (Example 61)   [4- (2-t-butylaminosulfonylphenyl) phenylaminocarbonyl ] Methylene chloride is 4-[(o-SO_TwoNHtBu) phenyl] aniline (3m mol) to CH_ThreeΑ-chloroacetyl chloride (4 mmol) in CN (100 mL) And K_TwoCO_Three(4 mmol).   5-cyanobenzimidazole (2 mmol) was added to DMF (10 mL) [4- (2 -T-butylaminosulfonylphenyl) phenyl-aminocarbonyl] methyle N Chloride (2 mmol) and K_TwoCO_Three(4mmol) at room temperature for 16 hours Then, when purified on a thin-layer TLC plate and further separated by HPLC, [4- (2-t-butylaminosulfonylphenyl) phenylaminocarbonyl] methyl -6-cyanobenzimidazole (240 mg, 56%) and [4- (2-t- Butylaminosulfonylphenyl) phenylaminocarbonyl] methyl-5-cy Anobenzimidazole (160 mg, 37%) was obtained.   [4- (2-t-butylaminosulfonylphenyl) phenylaminocarbonyl ] Methyl-6-cyanobenzimidazole was converted to Example 60 by a Pinner reaction. Converted and purified by HPLC: MP: 134-136 ° C;   [4- (2-t-butylaminosulfonylphenyl) phenylaminocarbonyl ] Methyl-5-cyanobenzimidazole was converted to Example 61 by a Pinner reaction. Converted and purified by HPLC: MP: 254 ° C. (dec); Example 62 1- (4-benzylpiperidinecarbonyl) methyl-6-amidinobenzo Imidazole and 1- (4-benzylpiperidinecarbonyl) methyl- Method for producing 5-amidinobenzimidazole   (4-benzylpiperidinecarbonyl) methylene chloride is Lysine (100 mmol) was added to chloroacetyl chloride (10 mL) in THF (250 mL). 0 mmol) and K_TwoCO_ThreeMade by acylation with (100 mL) . 5-Cyanobenzimidazole (2 mmol) was added to DMF (5 mL) in NaH ( (4-benzylpiperidinecarboxyl) at a temperature from 0 ° C. to room temperature in the presence of Alkylation with (bonyl) methylene chloride (2 mmol) for more than 16 hours Purification on an LC plate gave 1- (4-benzylpiperidinecarbonyl) methyl- 6-cyanobenzimidazole and 1- (4-benzylpiperidinecarbonyl) Methyl-5-cyanobenzimidazole (0.4 g, 56% yield) was obtained. This (1.11 mmol) was subjected to a pinner reaction, followed by CLC on a TLC plate. H_TwoCl_TwoPurification with 10% MeOH in MeOH and further purification by HPLC gave the title compound Obtained: MP: 54-56 ° C: MS: 376.4 (M + H).⁺; HRMS: 376.2118 (analytical), 376.2137 (calculated); Analysis: (C_{twenty two}H_{twenty five}N_FiveO₁+1.8 TFA + 0.1 HCl).   Method C: Example 63 uses 4-chloro-3-nitrobenzenenitrile and (4- Udmann coupling reaction with (benzylpiperidinecarbonyl) methylamine, Subsequent 4-[(4-benzylpiperidinecarbonyl) methyl] amino-3-nitto Reduction of lobenzonitrile, cyclization with formic acid, and final pinner reaction made.                                Example 63 1- (4-benzylpiperidinecarbonyl) methyl-6 Preparation of amidinobenzimidazole   (4-benzylpiperidinecarbonyl) methylamine is (4-benzylpiperidi Carbonyl) methylene chloride in aqueous acetone_ThreeAnd then 5 Made by hydrogenation in the presence of% Pd / C. N in DMF (10 mL) aHCO_Three(4-benzylpiperidinecarbonyl) methyl in the presence of (10 mmol) Lumin (8.6 mmol) and 4-chloro-3-nitro-benzonitrile (10 mm ol) at 100 ° C. for 16 hours to give 4-[(4-benzylpiperidinecarboxyl). Bonyl) methyl] amino-3-nitrobenzonitrile (1.6 g, 49.2% yield) was gotten. This is then purified in MeOH in the presence of 5% Pd / C (10% w / w). Hydrogenation yields 1- (4-benzylpiperidinecarbonyl) methyl-6-cyanoben Zoimidazole was formed (1.3 g, 90% yield). 1- (4-benzy (Lupiperidinecarbonyl) methyl-6-cyanobenzimidazole (0.57 mm ol) was then subjected to a pinner reaction, followed by CH2 on a TLC plate._TwoCl_TwoMiddle one Purification by 0% MeOH and further purification by HPLC gave the title compound: m p: 68-70 ° C; Example 64 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6 Preparation of amidinobenzimidazole N-ethylmalonyl-4'-aminobiphenyl-2-t-butylsulfonamide : 4'- in 30 mL of anhydrous methylene chloride and 0.93 mL of triethylamine To a solution of aminobiphenyl-2-t-butylsulfonamide (1.01 g) was added ethyl 0.43 mL of nmalonyl chloride was added dropwise. Stir the reaction mixture at ambient temperature overnight did. Concentration under vacuum gave a residue, which was taken up in 50 mL ethyl acetate . The organic layer was washed with 3 × 20 mL. The formed organic layer is dried over magnesium sulfate. Dry and concentrate under reduced pressure to give the crude product. The crude product is subjected to standard chromatography. Purification by the rough method yields N-ethylmalonyl-4'-aminobiphenyl-2- 0.70 g of t-butylsulfonamide was obtained. 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6 Cyanobenzimidazole:   0.32 g of 3,4-diaminobenzonitrile and N-ethylmalonyl-4'-a A mixture with 0.70 g of minobiphenyl-2-t-butylsulfonamide is mixed with 180 Heated to 20 ° C for 20 hours. The mixture was cooled to ambient temperature. Concentration, coarse by high vacuum 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6 0.09 g of cyanobenzimidazole was obtained. This crude material is used in the next reaction series. Used for LRMS (ES +): 431 (M + H).2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6 Amidinobenzimidazole : 10 mL of 1: 1 anhydrous chloroform: anhydroethanol 2- [4- (2-aminosulfonylphenyl) phenylcarbonyl] in toluene A solution of methyl-6-cyanobenzimidazole was stirred in an ice bath. So Was fed with hydrogen chloride gas for 20 minutes. Then the reaction mixture is To ambient temperature over a period of time. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Emptied. Ethyl imidate formed was dissolved in anhydrous ethanol in 0.30 g of ammonium carbonate. Treated directly with Nium. The reaction mixture was stirred at ambient temperature for 24 hours. Reaction mixture Was concentrated under reduced pressure and the crude product was purified by standard HPLC methods. -[4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-a Midinobenzimidazole was obtained. LRMS (ES +): 449 (m + H). H RMS (FAB): calcd 449.139586 mass 449.13 9273. Example 65 2- [4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl] me Method for producing chill-5-azabenzimidazole N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfone Amide : 4'- in 30 mL of anhydrous THF and 0.93 mL of triethylamine To a solution of aminobiphenyl-2-t-butylsulfonamide (1.01 g) was added ethyl. 0.43 mL of malonyl chloride was added dropwise. The reaction mixture was stirred for 24 hours. true Concentration in air gave a residue, which was taken up in 50 mL of ethyl acetate. Organic The layers were washed with 3 × 20 mL of water. The purified organic layer is dried over magnesium sulfate And concentrated under reduced pressure. The crude product is purified by standard chromatography to give N-ethyl Malonyl-4'-aminobiphenyl-2-t-butylsulfonamide is 0.63. g were obtained. 2- [4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl] me Tyl-5-azabenzimidazole:   0.026 g of 3,4-diaminopyridine And N-ethylmalonyl-4'-aminobiphenyl-2-t-butylsulfonamido The mixture with 0.10 g of the compound was heated to 165 ° C. for 20 hours. Cool mixture to ambient temperature Was. The crude material was purified by standard chromatography to give 2- [4- (2-t -Butylaminosulfonylphenyl) phenylcarbonyl] methyl-6-azabe Nzoimidazole was obtained. LRMS (ES +): 464 (M + H). HRMS (NH_Four-Cl): Mass 464.175637, calculated 464.17 5630. Example 66 2S- [4- (2-t-aminosulfonylphenyl) phenylamino Process for producing carbonyl] methyl-thio-1H-imidazo [4,5-C] pyridine   1H-imidazo [4,5-C] pyridine-2-thiol (in DMF (2.5 mL) To a solution of 37 mg, 0.245 mmol) was added 4- (2-t-butylaminosulfonate). Ruphenyl) phenylaminocarbonyl] methyl chloride (75 mg, 0.197 mmol) and K_TwoCO_Three(58 mg, 0.42 mmol) and the resulting mixture Was heated at 120 ° C. for 1 hour. HCl (Et._Two1N in O, 1m L) and then MeOH (6 mL) were added to give a clear solution. And slowly Et_TwoO (200 ml) was added and a white suspension was observed. Filter it, white solid Collected. The solid was dissolved in DMSO (8 mL). Generated solution for HPLC Therefore H_TwoO-CH_ThreePurification using CN-TFA gave the title compound (60 mg). Was done. HRMS (M + H)⁺  Calculated m / z: 496.1477, analytical value: 496. 1492.                                Example 67 2S- [4- (2-aminosulfonylphenyl) phenylamino Process for producing carbonyl] methyl-thio-1H-imidazo [4,5-C] pyridine   A solution of Example 66 in THF (0.5 mL) was heated for 16 hours. Remove all solvents And remove by HPLC_TwoO-CH_ThreePurification using CN-TFA gives the title compound. (13 mg) was obtained. HRMS (M + H)⁺  Calculation m / z: 440.0851, Analytical value: 440.0831.                               Example 101 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Manufacturing method 5-cyanoindole-1-methyl acetate:   5-Si in 10 mL of dry DMF A stirred solution of anoindole (5.0 g, 35.2 mmol) was added at 0 ° C with N_TwoUnder the atmosphere NaH (1.1 g, 42.2 mmol) was added. The reaction was stirred for 30 minutes and then Add α-bromomethyl acetate (5.4 g, 35.2 mmol) and add room temperature for 2 hours Stirred. Then H_TwoThe reaction was quenched with O, extracted with ethyl acetate (3x),_TwoS O_Four, Filtered and concentrated in vacuo to give a light yellow solid (7.5 g, 35. 2 mmol). 3- (5-cyanoindole) acetic acid: Methyl-5-cyanoindole-1-ace The tate was saponified in MeOH, KOH (3.3 eq) at room temperature for 18 hours. True mixture Concentrate under air, dissolve in water, extract with diethyl ether (2 ×), extract the acidic aqueous layer with 2N  Acidified with HCl. Filter the resulting white solid and dry in a vacuum oven And 6.2 g of the title compound were obtained. LRMS ESI (M + H)⁺  201.1- (4-benzylpiperidinecarbonyl) methyl-5-cyanoindole:   Dry Dry CH_TwoCl_Two3-acetic acid-5-cyanoindole (2.0 g, 0.1 mmol) and And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC) To the stirred complex of 4-benzylpiperidine (1.8 g, 0.01 mmol) was added. . Mixture N_TwoStir under an atmosphere for 18 hours, concentrate in vacuo, dissolve in ethyl acetate 1N HCl (3 ×), NaHCO_Three(3 ×), washed with brine (2 ×), Na_TwoSO_Four , Filtered and concentrated in vacuo to give a white solid (2.8 g). HRMS (M + H)⁺  C_{twenty three}H_{twenty four}N_ThreeO Calculated 358.1919938, Analytical 358.193278.1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole : N-1-acetyl-1-N'-piperidinyl-4-benzyl-5-cyanoindo (500 mg) was cooled to O 0 C and saturated with HCl (g) in dry MeOH (3 0 mL). The resulting solution was warmed to room temperature over 18 hours. True mixture Concentrate in the air, redissolve in dry MeOH and add (NH_Four)_TwoCO_Three(672.0 mg). The Lasco was sealed and stirred at room temperature for 18 hours. The resulting suspension is passed through Celite® Filtered, rinsed with dry MeOH and concentrated in vacuo to give the product (by HPLC 997 mg); 100 mg of which was further purified by preparative HPLC. Purification gave 29 mg (100% pure by HPLC). m. p. 214-215 ° C HRMS (NH_Three−CI) (C_{twenty three}H₂₆N_FourO) (M + H)⁺ Calculated 375.221701, Anal. 375.2218487. Example 102 1- (4-benzylpiperidinecarbonyl) ethyl-5-amidinoindole Recipe Methyl-5-cyanoindole-3-propionate: In acetonitrile 5-cyanoindole (1.0 g, 7.0 mmol), K_TwoCO_Three(0.966 g, 7. 0 mmol) to a stirred solution of 3-bromomethylpropionate (1.17 g, 7.0). mmol) was added. The mixture was stirred at reflux under a nitrogen atmosphere for 18 hours, allowed to cool,_Two Diluted with O, extracted with ethyl acetate, Na_TwoSO_Four, Filtered and concentrated in vacuo. .59 g of product was obtained. 5-cyanoindole-3-propionic acid: Methyl-5-cyanoindole- 3-propionate (200 mg) was added to MeOH (10 mL) / KOH (150 mg, (0.88 mmol) at room temperature for 18 hours. Concentrate the solution under vacuum and dissolve in water Thawed and washed with chloroform. The acidic layer was acidified, extracted with ethyl acetate, Na_Two SO_Four, Filtered and concentrated in vacuo to give 188 mg of product. 1- (4-benzylpiperidinecarbonyl) ethyl-5-amidinoindole:   Manufacturing is performed as in the last two steps of Example 101. 156 mg of TFA salt were obtained. Was. HRMS (M + H)⁺  C_{twenty four}H₂₉N_FourO Calculated 389.2234137, Analytical 3 89.231258.                               Example 103 1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5- Amidinoindole manufacturing method 4- (3-fluorobenzyl) piperidine : 1-benzylpiperidine in THF- A stirred solution of 4-one (0.99 mL, 5.34 mmol) was added at 0 ° C. under a nitrogen atmosphere. Ph_ThreeP = CH- (3-fluoro) phenyl (2.41 g, 5.34 mmol) was added. Was. After stirring at room temperature for 4 hours, the reaction was_TwoStop with O, concentrate in vacuo and filter the residue on silica Chromatography in gel using 1: 1 hexane: ethyl acetate as eluent To give 313 mg of product. LRMS NH_Three-CI (M + H)⁺  2 82. MeO containing the product (330 mg) in a parr shaker H, 10% Pd // C (300 mg) and concentrated HCl (5 mL) at 50 psi Hydrogenated for 8 hours. Filter the reaction through Celite® and concentrate the filtrate in vacuo And 250 mg of the title compound were obtained. LRMS NH_Three-CI (M + H)⁺  194 .1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-cyanoi Ndore : Prepared as described in Example 101. LRMS ESI (M + H)⁺  376.1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole Example 103 was made in the same manner as Example 101. C_{twenty three}H₂₆N_FourHRMS FAB for FO Glycerol matrix (M + H )⁺  Calculated 393.209065, Anal. 393.208858.                               Example 104 1- (1- (4-amidino) benzyl-N- (methyl acetate) aminocarbonyl) Method for producing methyl-5-amidinoindole ( 4-cyano) benzyl-N- (methyl acetate) amine: Α-bromo- Nitrile (2.0 g, 10.5 mmol) was added to CHCl_ThreeGlycine methyl ether Steal (2.64 g, 21.0 mmol) and triethylamine (2.92 mL, 1 (0.5 mmol). The mixture was stirred under a nitrogen atmosphere for 18 hours, concentrated in vacuo. And purified on a silica gel column with 1: 1 hexane: ethyl acetate as eluent. 1.07 g of the title compound were obtained (5.25 mmol). 1- (1- (4-cyano) benzyl-N- (methylacetate) aminocarbonyl) meth Chill-5-cyanoindole : The compound was subjected to the same coupling method as in Example 101. Made using HRMS NH_Three-CI (M + H)⁺  C_{twenty three}H₂₀N_FourO_Three  Calculated value 401.161366, analysis value 401.159527.1- (1- (4-amidino) benzyl-N- (methyl acetate) aminocarbonyl) Methyl-5-amidinoindole : Under the same pinner conditions as in Example 101 Had made. LRMS ESI (M + 2H)⁺²  218.                               Example 105 Methyl 1- (4-benzylpiperidine-1-carbonyl) methyl- Method for producing 5-amidinoindole-3-propanoate Methyl 1- (4-benzylpiperidine-1-carbonyl) methyl-5-cyanoi Ndole-3-propanoate : 1- (4-benzylpiperidine-1-carbo) Nyl) -5-cyanoindole (1.0 g, 2.8 mmol) in dry CH_TwoCl_Two  2 Dissolve in 0 mL, cool to 0 ° C. and add oxalyl chloride (1.07 g, 8.4 mmol). added. The reaction was stirred at room temperature for 3 hours. It is then concentrated in vacuo and dried MeO H (20 mL) and stirred for 18 hours. The resulting yellow solution is concentrated in vacuo, 1.0 g (2.3 mmol) was taken up in TFA (20 mL) at 0 ° C. and triethylsilane was added. (535 mg, 4.6 mmol) was added slowly. The reaction was stirred at 0 ° C. for 3 hours And then concentrate it in vacuo, CH_TwoCl_TwoDissolved in saturated NaHCO_ThreeWash with sulfuric acid Dried over sodium acid, filtered and concentrated. The product residue is purified on silica gel at 7% M OH / CHCl_ThreeChromatography using eluent as eluent 840 mg of the compound were obtained. LRMS ESI (M + H)⁺  430.   1- (4-benzylpiperidine-1-carbonyl) methyl-3-methylacetate To-5-amidinoindole : Amidine was made as described in Example 101 . HRMS NH_Three-CI (M + H)⁺  C₂₆H₃₄N_FourO_Three  Calculated value 447.239 616, analytical value 447.2241907.                               Example 106 1- (4-benzylpiperidinecarbonyl) methyl- (3-ethanehydroxy) -5 -Amidinoindole manufacturing method 1- (4-benzylpiperidine-1-carbonyl) methyl-3-ethanehydroxy -5-cyanoindole : Methyl 1-acetyl- (4-benzylpiperidine- 1-yl) -3-acetate-5-cyanoindole (100 mg, 0.233 m mol) in ethanol, and sodium borohydride (20 mg, 0.51 m mol) was added and the solution was stirred at room temperature for 18 hours. Concentrate the reaction under vacuum and add water , Extracted with methylene chloride (3x), dried over sodium sulfate, filtered, filtered Kuno Reduction yielded 93.0 mg of the title compound. LRMS DCI-NH_Three(M + NH_Four)⁺  419.   1- (4-benzylpiperidine-1-carbonyl) methyl-3-ethanehydroxy C-5-amidinoindole : Amidine was made as in Example 101. HRMS NH_Three-CI (M + H)⁺  C_{twenty five}H₃₁N_FourO_Two  Calculated value 419.2247 02, analysis 419.253383.                               Example 107 1- (4-benzylpiperidine-1-carbonyl) methyl-3-methyl Method for producing carboxylic acid-5-amidinoindole   Methyl 1-acetyl- (4-benzylpiperidin-1-yl) -3-acetate -5-Amidinoindole is converted to TFA / H_TwoHydrolyzed in O for 18 hours. Preparative H Purification by PLC gives the title compound. LRMS (M + H)⁺  433.                               Example 108 1- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-amidinoy Ndole recipe 1- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-cyanoin Doll : N-1-methylenecarbohydroxy-5-cyanoindole (300 mg, 1.5 mmol) and 4-amino-1-benzylpi Peridine and triethylamine (0.209 mL, 1.5 mmol) were added. Anti The reaction was stirred at room temperature for 18 hours. Volatiles are removed in vacuo and the residue is separated on silica gel. 1% MeOH / CH_TwoCl_TwoAnd purified as eluent to give 160 mg of product was gotten. HRMS NH_Three-CI (M + H)⁺  C_{twenty three}H_{twenty four}N_FourO calculated value 373. 204739, Anal. 373.202837.1- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-amidinoy Ndore Amidine was made as described in Example 101 and the title compound 96 mg Gave. HRMS NH_Three-CI calculated value 390.2229386, analytical value 3 90.229386.                               Example 109 1- (4-benzoylpiperidinecarbonyl) methyl-5-amidinoindole Recipe 1- (4-benzoylpiperidinecarbonyl) methyl-5-cyanoindole : The procedure was as described in Example 108, except that 4-benzoylpiperidine was used. Was. HRMS NH_Three-CI (M + H)⁺  C_{twenty three}H_{twenty one}N_ThreeO_TwoCalculated value 372.17 1702, analytical value 372.171620.1- (4-benzoylpiperidinecarbonyl) methyl-5-amidinoindole:   Amidine was made using the same method as in Example 101. HRMS (M + H)⁺  C_{twenty three}H_{twenty four}N_FourO_Three  Calculated value 389.197751, analysis value 389.198109.                               Example 110 1- (4- (3-fluoro) benzylpiperazinecarbonyl) methyl- Method for producing 5-amidinoindole 1- (4- (3-fluoro) benzylpiperazinecarbonyl) methyl-5-amidino Indole : 1-acetyl- (1-piperazine) -5-cy in diethyl ether Anoindole (400 mg, 1.31 mmol), triethylamine (0.036 mL, 2.62 mmol) of 3-fluorobenzyl bromide (0.16 mL). 1 mL, 1.31 mmol) at room temperature._TwoStirred under atmosphere for 18 hours. Anti The reaction was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and vacuum Dark Reduction yielded 438 mg of product. LRMS (M + H)⁺  377.1- (4- (3-fluoro) benzylpiperazinecarbonyl) methyl-5-amidino Indole : Made as described in Example 101. HRMS (M + H)⁺  C_{twenty two}H_{twenty four}N_FiveOF calculated value 394.204314, analytical value   394.204917.                               Example 111 1- (4-phenylbenzylaminocarbonyl) methyl-5- Amidino indole 1- (4-phenylbenzylaminocarbonyl) methyl-5-cyanonoindole : 5-cyanoindole 1-acetate in methylene chloride (250 mg, 1.25 mmol) ) And DEC (239 mg, 1.25 mmol) were added to a stirred complex. Enylbenzylamine (228 mg, 1.25 mmol) was added. Room temperature, nitrogen atmosphere After stirring under ambient for 18 hours, the reaction was concentrated in vacuo, dissolved in ethyl acetate and 1N  Wash with HCl, sodium bicarbonate, and brine and dry over sodium sulfate , Filtered and concentrated in vacuo to give 215 mg of product. HRMS (M + H)⁺   Calculated 366.626037, Analytical 366.160323.1- (4-phenylbenzylaminocarbonyl) methyl-5-amidinoindole : Made as in Example 101. HRMS calc. 383.187187, min Analyzed value 383.189667.                               Example 112 Methyl 1- (4-benzylpiperidineaminocarbonyl) methyl-5 Amidinoindole-3-propenoate Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-cyanoindole -3-propenoate : DMF (15 mL) and POCl at 0 ° C_Three(256mg , 1.7 mmol) was added to 1- (4-benzylpiperidinecarbonyl) methyl Le-5-cyanoindole (199 mg, 0.56 mmol) was added. 3 hours stirring After stirring, the reaction was quenched with 2N sodium hydroxide and stirred for 30 minutes. Then black Extracted with roform, dried over sodium sulfate, filtered and concentrated in vacuo to give the product . LRMS (M + H)⁺  386. The product is then triphenylphosphonated in THF. Reflux for 18 hours under nitrogen atmosphere in the presence of ammonium (methylenecarbomethoxy) ylide did. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography. 7% MeOH / CHCl_ThreePurification using as eluent gives 140 mg of product Obtained.Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Le-3-propenoate : Made as in Example 101. LRMS (M + H)⁺ 459.                               Example 113 1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl- Method for producing 5-amidinoindole 4- (2-fluoro) benzylpiperidine: Trife in -78 ° C dry THF N-buLi () was added to the stirred solution of nylphosphonium-2-fluorobenzylbromide 2.5M (2.13 mL) was added and stirred for 30 minutes. And 1-benzyl-4- Piperidinene (0.99) was added, and the mixture was stirred at room temperature for 4 hours. Stop the reaction with water and Concentrated in the sky. The resulting residue was subjected to silica gel chromatography to give 1: 1 hex. Purification using ethyl acetate as eluent gave 313 mg. LRM S (M + H)⁺  282. The product was washed in a pearl shaker at 50 psi with MeOH ( 10 mL), water in 5.0 mL concentrated HCl and 10% Pd / C (300 mg) for 18 hours Simplification. The mixture is filtered through Celite® and concentrated in vacuo to 250 mg of product were obtained. LRMS (M + H)⁺  194.1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-cyanoi Ndore Using the method described in Example 101, 3-acetic acid-5-cyanoin Made by coupling of Dole with 4- (2-fluoro) benzylpiperidine Was. LRMS (M + H)⁺  376.1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole : Made as in Example 101. HRMS (M + H)⁺  Calculated value 3 93.20965, Anal. 393.208858.Example 201 3-((4-cyclohexyl) phenylaminomethylcarbonyl) methyl- Method for producing 5-amidinoindole.   Methyl 5-cyanoindole-3-acetate. 5-Si in dry methylene chloride To a stirred solution of anoindole (10.0 g) was added oxalyl chloride (3.0 eq, 61.4). 3 mL) was added. After stirring for 1 hour at room temperature under a nitrogen atmosphere, the resulting precipitate was filtered off. , Rinsed with diethyl ether. The solid is then taken up in dry MeOH and stirred for 1 hour did. At this time, the solid was filtered, rinsed with MeOH and diethyl ether, 5.93 g of chill α-ketoacetate 5-cyanoindole were obtained. LRMS ( M + H)⁺  229. Methyl α-ketoacetate (4.90 g) was added in 50 mL at 0 ° C. Dissolve in trifluoroacetic acid and slowly add triethylsilane (5.0 g) from the dropping funnel. (20 min). It was stirred at 0 ° C. for 3 hours. Vacuum the resulting yellow solution Concentrate, neutralize with sodium bicarbonate, extract with diethyl acetate, Dried over cesium, filtered and concentrated in vacuo. On silica gel chromatography 1% MeOH / CH_TwoCl_TwoWhen purified using as eluent, purified product 2.48 was obtained. g was obtained. LRMS (M + H)⁺  232.3- (5-cyanoindole) acetic acid : The above ester in KOH / MeOH at room temperature For 18 hours. Solution 3 is then concentrated in vacuo, dissolved in water and treated with ethyl acetate. And the acetic acid layer was acidified with 1N HCl at 0 ° C. Filter the resulting white solid And dried further under high vacuum to give the product. m. p. 196.5-19 8.5; Calculated C66.00 H4.04 N13.99; Analytical value C65.71.   H4.24 N13.94. 3- (4-cyclohexylphenylaminomethylcarbonyl) methyl-5-cyano Indole : 5-cyanoindoleacetic acid in DMF (312 mg, 1.5 mmol) ) And BOP reagent (1.03 g) were added to 4-cyclohexylphenylacetate. Minomethyl was added. After heating at 50 ° C. for 18 hours under a nitrogen atmosphere, the reaction was brought to room temperature. , Diluted with water, extracted with ethyl acetate, 1N HCl, sat. Wash with helium, and brine, dry over sodium sulfate, filter, and concentrate under vacuum. Shrank. The residue is purified by chromatography using 100% ethyl acetate as eluent This gave 210 mg of product. LRMS (M + H)⁺  372.3- (4-cyclohexyl) phenylaminomethylcarbonyl) methyl-5-amido Zinoindole : Made as described in Example 101. HRMS (M + H)⁺C_{Two Four} H₂₉N_FourO Calculated 389.2234137, Analyzed 389.232086.                               Example 202 3- (4-p-toluenesulfonylpiperazinecarbonyl) methyl-5-amidi Noindole recipe 3- (4-paratoluenesulfonylpiperazinecarbonyl) methyl-5-cyanoi Ndore : 3- (piperazinecarbonyl) methyl-5-cyanoi in chloroform Ndole hydrochloride (200 mg, 0.66 mmol) and triethylamine (134 m g, 185 μL) was added to a stirred solution of toluenesulfonyl chloride (126 mg, 0.1 g). 66 mmol) was added. After stirring at room temperature under a nitrogen atmosphere for 18 hours, the reaction was Stop and extract with chloroform, 1 N HCl, saturated sodium bicarbonate, and Wash with brine, dry over sodium sulfate, filter and concentrate in vacuo to give 237 mg. The product was obtained. LRMS (M + H)⁺  423.3- (4-paratoluenesulfonylpiperazinecarbonyl) methyl-5-amidino Indole :   Made as described in Example 101. HRMS (M + H)⁺, C_{twenty two}H₂₆N_FiveO_ThreeS   Calculated value 440.174611, analyzed value 440.175637.                               Example 203 3- (4- (2-aminosulfonylphenyl) pyridine-2-aminocarbonyl) me Method for producing chill-5-amidinoindole 3- (4-2-aminosulfonylphenyl) pyridine-2-aminocarbonyl) me Chill-5-cyanoindole : 5-cyano-3-acetic acid i in DMF (15 mL) Of indole (400 mg, 2.0 mmol) and BOP (884 mg, 3.0 mmol) Add 4- (2-aminosulfonyl) phenyl-2-aminopyridine (91 2 mg, 3.0 mmol) and heated to 50 ° C. for 3 hours. Dilute the reaction with water , Extracted with ethyl acetate, 10% HCl, sodium bicarbonate, brine and water , Dried over magnesium sulfate, filtered and concentrated in vacuo to give 420m of product g was obtained. LRMS 488. The t-butyl group is removed under TFA reflux for 1 hour And the product is purified on silica gel using 100% ethyl acetate as eluent. 101 mg of the product were obtained. LRMS 432.3- (4- (2-aminosulfonylphenyl) pyridine-2-aminocarbonyl) me Chill-5-amidinoindole . Made as described in Example 101. HRMS (M + H)⁺  C_{twenty two}H_{twenty two}N_FiveO_ThreeS Calculated value 449.139586, analysis value 4 49.139058.                               Example 204 3- (4- [2-tetrazole] phenyl) phenylaminocarbonyl) methyl- Method for producing 5-amidinoindole 3- (4- [2-tetrazole] phenyl) phenylaminocarbonyl) methyl-5 -Cyanoindole : 5-cyanoindole-3-acetic acid is converted to DMF / CH_TwoCl_Two , DEC (382 mg), and DMAP (10 mg), and the reaction mixture was Stirred for minutes. 4-((2-Tetrazol) phenyl) aniline is added and the reaction mixture Was stirred for 2 hours. The reaction was concentrated in vacuo, dissolved in ethyl acetate, water and Washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. silica gel Purification using 1: 1 hexane: ethyl acetate yielded 660 mg of purified product. Obtained. In THF (30 mL) and 4 M HCl in dioxane (0.988 mL), At room temperature, the trityl group was cleaved off for 18 hours. Then basify with NaOH and pH 11, wash with ether, acidify to pH 3 with 10% HCl, collect the precipitate, Drying in high vacuum yielded 250 mg of product. LRMS (M + H)⁺  420.3- (4- [2-tetrazole] phenyl) phenylaminocarbonyl) methyl-5 -Amidinoindole : Made as described in Example 101. HRMS (M + H)⁺  C_{twenty three}H₂₀N₈O Calculated 437.383833, Analytical 43 7.186710.                               Example 205 Preparation of 3- (4-biphenylaminocarbonyl) methyl-5-amidinoindole Law .   The title compound was made as described in Example 101. HRMS (M + H)⁺  C_{twenty three}H₂₀N_FourO Calc. 369.172173, Anal. 36 9.171537.                               Example 206 3- (4- (phenylmethylsulfonyl) piperazinecarbonyl) methyl-5-a How to make midino indole   The title compound was made as described in Example 101. HRMS (M + H)⁺   C_{twenty two}H_{twenty five}N_FiveO_ThreeS Calculated 440.176204, Analytical value 440.175637.                               Example 207 3- (4-cyclohexylphenylaminocarbonyl) methyl-5-amidinoy Ndole recipe   The title compound was made as described in Example 101. HRMS (M + H)⁺C_{Two Three} H₂₆N_FourO Calculated 375.218732, Anal. 375.2218487.                               Example 208 3- (4-benzylpiperazinecarbonyl) methyl-5-amidinoindole Manufacturing method   The title compound was made as described in Example 101. HRMS (M + H)⁺   C_{twenty two}H_{twenty five}N_FiveO Calculated 376.2213722, Analyzed 376.221336.                               Example 209 3- (3-amidinobenzylamino (methylcarbonylmethoxy) carbonyl) me Method for producing chill-5-amidinoindole .   The title compound was made as described in Example 101. HRMS calc. 435.221464, analyzed 435.2216822.                               Example 210 1-methyl-3- (4-amidinobenzylamino (methylcarbonylmethoxy) Process for producing (carbonyl) methyl-5-amidinoindole .   The title compound was made as described in Example 101. HRMS calc. 435.221464, analyzed 435.213247.                               Example 211 1-methyl-3- (4- [2-aminosulfonyl] phenylbenzylaminocar Process for producing (bonyl) methyl-5-amidinoindole   The title compound was made as described in Example 101. LRMS 476, m . 231 ° C.                               Example 212 1-methyl-3- (4-phenylbenzylaminocarbonyl) methyl-5-amido How to make Zinoindole   The title compound was made as described in Example 201. HRMS calc. 397.220237, analytic 397.220420.                               Example 213 1-methyl-3- (4-phenylpiperazinecarbonyl) methyl-5-amidino Indole recipe   The title compound was made as described in Example 201. HRMS calculated 389.2234137, analyzed 389.223435.                               Example 214 3- (4- (2-aminosulfonyl) phenylphenylaminocarbonyl) methyl -5-Amidinoindole production method   The title compound was made as described in Example 203. HRMS calc. 448.144337, analytic 448.143656.                               Example 215 3- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-amidino Indole recipe   The title compound was made as described in Example 201. HRMS calc. 390.2229386, analytic 390.230305.                               Example 216 3- (4-phenylpiperazinecarbonyl) methyl-5-amidinoindole Manufacturing method   The title compound was made as described in Example 201. HRMS calc. 362.198086, Anal. 362.197315.                               Example 217 3- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Manufacturing method   The title compound was made as described in Example 201. HRMS calc. 374.210662, analytic 374.2386.Example 218 1-methyl-3- (5- (2-aminosulfonyl) phenylpyridine-2-amido Production of (carbonyl) methyl-5-amidinoindole   The title compound was made as described in Example 201. HRMS calc. 463.155236, analytic 463.155236.                               Example 219 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-cyanoindole   Anhydrous methyl acetate (15 mL) and anhydrous methanol (0.5 mL, 10.0 eq) in 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylamido Nocarbonyl) methyl-5-cyanoindoline (1.2378 mmol, 0.7 g) The solution was saturated with dry hydrogen chloride at −20 ° C. for 20 minutes. Close the reaction mixture and seal Leave at ambient temperature for 18 hours. The reaction mixture is evaporated and the residual HCl is pumped Removed for several hours. Add this imidate in anhydrous methanol (15 mL) to ammonium carbonate (1.189 g, 10.0 eq) was added. The reaction mixture is left at ambient temperature for 24 hours. While stirring. The final reaction mixture was evaporated and analyzed by HPLC on a C-18 column. Solvent mixture A (water: TFA 99.95: 0.05) and solvent mixture Using mixture B (acetonitrile: TFA 99.95: 0.05), starting with 80% A Finally, purification was performed using a gradient that resulted in 100% B in 60 minutes. After lyophilization, pure raw 0.122 g of product (15%) was obtained (15%); HRMS (M + H)⁺ Calculated 526.05848, Anal. 526.037991 (o-Br compound).                               Example 220 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-methylaminoindole   Absolute ethanol: 3- (2-methyl-4- (2-aminosulfur) in TFA (4: 6) (Honyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole (0.1 To a solution of 5992 ml, 0.3 g) was added palladium hydroxide on carbon (0.06 g, used (20% by weight of the starting material). The reaction mixture is vacuumed (house vacuum) Under agitation at ambient temperature for 10 minutes to remove oxygen. Then 1 by the balloon method atm H_TwoFor 3 hours. The reaction mixture was filtered through celite to remove the catalyst. Removed and washed with ethanol (20 mL). The filtrate is evaporated to give t-butyl sulfone The desired product with the addition of the amide was obtained. The product is treated with trifluorovinegar at 55 ° C. The sulfonamide protecting group was removed by treatment with acid for 2 hours. Reaction mixture Was evaporated, HPLC was performed on a C-18 column for purification, and the solvent mixture A (water: T FA99.95: 0.05) and solvent mixture B (acetonitrile: TFA99.95) : 0.05). At that time, it starts with A80% and changes to B100% in 60 minutes A gradient was used. Purification as above gave 10.0 mg of pure product. (3%, low yield due to low solubility); HRMS (M + H)⁺  Calculated 449.164738, Analyzed 449.165207 .                               Example 221 3- (2-fluoro-4- (2-aminosulfonyl) phenylphenylaminoca Preparation of (rubonyl) methyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS (NH_Three-CI / D EP) (M + H)⁺  C_{twenty three}H_{twenty one}N_FiveSO_ThreeF Calculated 466.134915, analysis 466.133832.                               Example 222 3- (2-chloro-4- (2-aminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-cyanoindole   The title compound was made as described in Example 203. HRMS C_{twenty five}H_{twenty one}N_FiveSO_ThreeCl (M + H)⁺  Calculated 482.105364; analysis Value 482.103835.                               Example 223 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-cyanoindole   The title compound was made as described in Example 203. HRMS C_{twenty three}H_{twenty one}IN_FiveO_ThreeS (M + H)₊  Calculated 574.040989; Analytical 574.042800.                               Example 224 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C_{twenty four}H_{twenty four}N_FiveO_ThreeS (M + H)⁺  Calculated 462.159987; Analytical value 4 62.158553.                               Example 225 3- (2-methyl-4- (2- (t-butylaminosulfonyl) phenylphenyl) Method for producing (aminocarbonyl) methyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C₂₈H₃₂N_FiveO_ThreeS (M + H)⁺  Calculated 518.222587; Analytical value 5 18.221998.Example 226 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl Method for producing -α- (methylcarboxymethyl ether) -5-amidinoindole   The title compound (racemic) was made as described in Example 203. HRMS C₂₆H_{twenty five}N_FiveO_FiveS (M + H)⁺  Calculated value 520.166599; Analyzed value 5 20.165466.                               Example 227 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl Method for producing -α- (benzyl) -5-amidinoindole   The title compound (racemic) was made as described in Example 203. HRMS C₃₀H₂₉N_FiveO_ThreeS (M + H)⁺  Calculated value 538.191287; Analytical value 5 38.191263.                               Example 228 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylaminocarbo Method for producing nilmethyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C_{twenty three}H₂₀N_FiveO₁F_Three(M + H)⁺  438.154170; analysis 438. 152166.                               Example 229 3- (4- (2-ethylaminosulfonyl) phenyl) phenylaminocarbonyl Method for producing methyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C₂₆H₂₇N_FiveO_ThreeS₁(M + H)⁺  Calculated 477.675637; Analytical 476.175892.                               Example 230 3- (4- (2-propylaminosulfonyl) phenyl) phenyl) aminocarbo Method for producing nilmethyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C₂₆H₂₇N_FiveO_ThreeS (M + H)⁺  Calculated 499.0191287; Analytical 4 90.190996.                             Example 231 2-methyl-3- (2-iodo-4- (2-aminosulfonyl) phenyl) phenia Method for producing minocarbonylmethyl-5-amidinoindole   The title compound was made as described in Example 203. HRMS C_{twenty four}H_{twenty three}IN_FiveO_ThreeS₁(M + H)⁺  Calculated 558.056639; analysis Value 558.057057.                               Example 232 2-methyl-3- (4- (2-aminosulfonyl) phenyl) phenyl) amino Method for producing rubonylmethyl-5-amidinoindole   The title compound was made as described in Example 203. LRMS C_{twenty four}H_{twenty three}N_FiveO_ThreeS₁(M + H)⁺  462.                               Example 233 3- (4- (2-aminosulfonyl) phenyl) phenyl) -N-methylaminoca Method for producing rubonylmethyl-5-amidinoindole   The title compound was made as described in Example 203. LRMS C_{twenty four}H_{twenty four}N_FiveO_ThreeS₁(M + H)⁺  462.                               Example 234 2-methyl-3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl ) Method for producing aminocarbonylmethyl-5-methoxyindole   The title compound was made as described in Example 203. LRMS C₂₈H₃₁N_ThreeO_FourS₁(M + H)⁺  506.                               Example 235   3- (4- (2-N-methylaminosulfonyl) phenyl) phenyl) -N-methyl L-aminocarbonylmethyl-5-amidinoindole   The title compound was made as in Example 203. HRMS C_{twenty four}H_{twenty three}N_FiveO_ThreeS (M + H)⁺  Calculated 462.159987; Analytical value 4 62.159054.                               Example 236 3- (4- (2- (n-butylaminosulfonyl) phenylphenylaminocarbo Process for producing (nyl) methyl-5-cyanoindoline   Indoline 3-acetate (0.001 mol, anhydrous acetonitrile (10 mL) 0.2 g) (or indophosphoric acid (0.001 mol, 0.202 g)) Thionyl (0.3 mL, 4.0 eq.) Was added (in the case of indoline, ethyl ether was added). 1.0 M HCl in ter (0.05 mL, 1.0 eq.) Was added before thionyl chloride. ). The reaction mixture was warmed to 50 ° C. for 10 minutes. Then cool to ambient temperature, 2 Stirred for hours. The solvent and excess thionyl chloride are removed under vacuum and the residue is Pong And dried further. The dried residue was added to anhydrous methylene chloride (10 mL). AB (0.338 g, 1.0 eq.) And triethylamine (0.14 mL, 1. 0 eq .; 2.0 eq. For HCl salt. ) Was added. This reaction mixture is Stirred at ambient temperature for 2 hours. The reaction mixture was evaporated and a silica gel column (50 g) Flash chromatography, eluting with 3: 1 hexane: ethyl acetate This gave 0.4 g of pure product with n-butylsulfonamide (51 %).                               Example 237 3- (4- (2- (n-propylaminosulfonyl) phenylphenylaminocar Process for producing (bonyl) methyl-5-amidinoindoline   The title compound was made as in Example 203. HRMS C₂₆H₃₀N_FiveSO_Three(M + H)⁺  Calculated value 492.220637; Analytical value 4 92.207667.                               Example 238 ( -)-3- (4- (2-Aminosulfonyl) phenyl) pyrid-2-ylaminoca Method for producing rubonylmethyl-5-amidinoindoline   The title compound was made as in Example 203. HRMS C_{twenty two}H_{twenty four}N₆O_ThreeS₁(M + H)⁺  Calculated value 451.155236; Analytical value 451.154317.                               Example 239 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarboni Method for producing rumethyl-5-amidinoindoline   The title compound (racemic) was made as in Example 203. HRMS C_{twenty two}H_{twenty four}N₆O_ThreeS₁(M + H)⁺  Calc. 451.155236; analysis Value 451.154317.                               Example 240 3- (4- (2-dimethylaminosulfonyl) phenyl) phenylaminocarboni Method for producing rumethyl-5-amidinoindoline   The title compound (racemic) was made as in Example 203. HRMS C_{twenty five}H₂₆N_FiveO_ThreeS₁(M + H)⁺  Calculated value 450.159987; Analytical value 450.159435.                               Example 241 ( +)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-i Method for producing ruaminocarbonylmethyl-5-amidinoindoline   The title compound was made as in Example 203. HRMS C₂₆H₃₀N₆O_ThreeS₁(M + H)⁺  Calculated value 507.217836; Analytical value 507.217901. 98% ee; rotation (+) 19.23.                               Example 242 ( -)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-i Method for producing ruaminocarbonylmethyl-5-amidinoindoline   The title compound was made as described in Example 203. HRMS C₂₆H₃₀N₆O_ThreeS₁(M + H)⁺  Calculated value 507.217836; Analytical value 507.2217678. 98% ee; rotation-16.28.                               Example 243 3- (4- (2-aminosulfonylphenylphenyl-pyrid-2-yl) amido Method for producing nocarbonylmethyl-5-aminocarboxyindoline   The title compound (racemic) was made as described in Example 203. HRMS C_{twenty two}H_{twenty three}N₆O_ThreeS₁(M + H)⁺  Calculated 451.1552036; analysis Value 451.154691.                               Example 244 3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl) aminocar Process for producing bonylmethyl-5-amidinoindoline   The title compound was made as described in Example 203. LRMS C₂₇H₃₁N_FiveO_ThreeS₁(M + H)⁺  Calculated 506.3; Analytical value 506.4.                               Example 245 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl) a Method for producing minocarbonylmethyl-5-amidinoindoline   The title compound (racemic) was made as described in Example 203. LRMS C₂₆H₃₀N₆O_ThreeS₁(M + H)⁺  Calculated value 507.3; Analytical value 507.4.                               Example 246 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarboni Method for producing methyl-6-amidinoindazole   The title compound was made as described in Example 203. HRMS C_{twenty one}H_{twenty one}N₇O_ThreeS₁  (M + H)⁺  Calculated value 450.34835; Analysis value 450.134725.Example 247 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl -6-Amidinoindazole production method   The title compound was made as described in Example 203. HRMS C_{twenty two}H_{twenty two}N₆O_ThreeS₁(M + H)⁺  Calculated value 499.139586; analytical value 449.138515.Example 248 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylami Method for producing nocarbonylmethyl-6-amidinoindazole   The title compound was made as described in Example 203. HRMS C_{twenty five}H₂₉N₇O_ThreeS₁(M + H)⁺  Calculated value 450.134835; analytical value 450.134725.                               Example 249 3- (4- (2-t-butylaminosulfonyl) phenyl) phenylaminocarbo Method for producing nilmethyl-6-amidinoindazole   The title compound was made as described in Example 203. HRMS C₂₆H₃₀N₆O_ThreeS₁(M + H)⁺  Calculated value 505.2202186; analysis value 505.202031.                                  Usefulness   The compound of the present invention is an anticoagulant for treating or preventing thromboembolic diseases in mammals. Useful as As used herein, the term "thromboembolic disorder" refers to an artery or artery. Or cardiovascular or cerebrovascular thromboembolic disease of the vein or vein Heart disease, initial or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, Atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary Including arterial and cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism. Compound of the present invention The anticoagulant effect of the product may be due to inhibition of factor Xa or thrombin. Have been.   The efficacy of the compound of the present invention as a factor Xa inhibitor depends on purified human factor Xa and total The evaluation was performed using a synthetic substrate. Chromogenic substrate S2222 (Kabi Pharmacia, Frank Factor Xa hydrolysis rates of the compounds of the present invention and non- Measured both in the presence. Hydrolysis of this substrate causes the release of pNA. This is measured by spectrophotometry by measuring the increase in absorbance at 405 nm. I did it. A decrease in the rate of change of absorbance at 405 nm indicates inhibition of the enzyme. This The result of the assay is the inhibition constant, K_iExpressed as   0.10 M sodium phosphate containing 0.20 M NaCl and 0.5% PEG8000 Factor Xa was measured in a lithium buffer (pH 7.5). For hydrolysis of substrates The Michaelis constant, Km, was determined at 25 ° C. using the Lineweaver-Burk method. Was. K_iValues are 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories (South Bent, IN) with substrate (0.20 mM to 1) in the presence of inhibitor. mM). The reaction was continued for 30 minutes and the rate (time Change rate of absorbance) was measured in a time frame of 25 to 30 minutes. Using the following relational expression K_iThe value was calculated. (V_O-V_S) / V_S= I / (K_i(1 + S / K_m))   Where v_OIs the rate of control in the absence of inhibitor,         v_SIs the rate in the presence of the inhibitor,         I is the concentration of the inhibitor;         K_iIs the dissociation constant of the enzyme-inhibitor complex,         S is the concentration of the substrate,         K_mIs the Michaelis constant.   Using the above methodology, many of the compounds of the present invention have_i≦ 5μm Thus, the usefulness of the compound of the present invention as an effective Xa inhibitor was confirmed.   The antithrombotic effect of the compound of the present invention is shown in a rabbit arteriovenous (AV) shunt thrombosis model. Can be In this model, xylazine (10 mg / kg i.m.) and ketami Rabbits weighing 2-3 kg anesthetized with a 50 mg / kg i.m. mixture were used. Menstrual diet A saline-filled AV shunt device was connected between the femoral artery and the femoral vein cannula. The AV shunt device consists of a 6 cm tygon tube, which contains silk. Thigh movement Blood flows from the pulse to the femoral vein via the AV shunt. Blood flow is exposed to silk thread Induces significant thrombus formation. 40 minutes later, remove shunt and covered with thrombus Measure the weight of the silk thread. Give test drug or vehicle before opening AV shunt (i.v., i.p., sc. or orally). Determine percent inhibition of thrombus formation for each treatment group I do. ID50 values (dose that inhibits thrombus formation by 50%) are determined by linear regression.   Compounds of structural formula (I) are useful for serine prostheses, especially human thrombin, plasma potassium. It is also considered to be useful as an inhibitor of crane and plasmin. these Because of their inhibitory action, compounds are catalyzed by enzymes of the aforementioned kind, Have been suggested for use in the prevention or treatment of inflammatory reactions, clotting, and inflammation. Special Compounds are useful in treating diseases caused by increased thrombin activity, such as myocardial infarction. Of blood into plasma as a drug for and for diagnostic and other commercial purposes It has utility as a reagent used as an anticoagulant in processing.   Some of the compounds of the present invention are characterized in that thrombin cleaves small substrates in purification systems. A direct inhibitor of the serine protease thrombin due to its ability to inhibit It turned out. J. Kettner et al., J. Am. Biol. Ch em. No. 265, pages 18289-18297 (1990) In vitro inhibition constants were determined by the method. In such assays, dye production Nature group Thrombin mediation of quality S2238 (Helena Laboratories, Beaumont, TX) Hydrolysis was monitored spectrophotometrically. Add inhibitor to assay mixture This reduces the absorbance, indicating inhibition of thrombin. 0.10M phosphorus Sodium acid buffer (pH 7.5), 0.20 M NaCl, 0.5% PEG 600 Human thrombin at a concentration of 0.2 nM (Enzyme Research Laboratories, Inc.) (South Bend, IN) from 0.20 to 0.02 mM Incubation was carried out using the material concentration. After a 25-30 minute incubation, To monitor the rate of increase in absorbance at 405 nm resulting from hydrolysis of the substrate Therefore, thrombin activity was assayed. Using the standard Lineweaver-Burk method The inhibition constant as a function of substrate concentration was derived from a reciprocal plot of the reaction rate. The aforementioned The method was used to evaluate several compounds of the invention,_iIs less than 5 μm According to the present invention as an effective thrombin inhibitor. The usefulness of the compound was confirmed.   The compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents. Can also be. These include other anticoagulants or anticoagulants, antiplatelet agents or blood Including platelet inhibitors, thrombin inhibitors, or thrombolytic or fibrinolytic agents.   A therapeutically effective amount of the compound is administered to a mammal. A “therapeutically effective amount” is defined as When the compound of formula I is administered to a mammal, alone or in combination with another therapeutic agent; Effective in preventing or ameliorating thromboembolic disease states or disease progression Means quantity.   “Administered in combination” or “combination therapy” refers to a compound of structural formula I and one or more Is administered to the mammal to be treated at the same time. Union When administered at the same time, each component may be administered simultaneously or in any Can be administered. Thus, while each component can be administered separately, Administered sufficiently close in time to achieve the desired therapeutic effect. The present invention Other anticoagulants (or anticoagulants) that can be used in combination with the compound include: Other factor Xa inhibition as described in the publications described in the background of the invention above. Includes warfarin and heparin, as well as drugs.   As used herein, the term antiplatelet agent (or platelet inhibitor) An agent that inhibits platelet function, such as inhibiting aggregation, adhesion, or granule secretion To taste. Such drugs include aspirin, ibuprofen, naproxen, Lindac, indomethacin, mefenamic acid, droxicam, diclofenac, Various known non-steroids such as sulfinpyrazone and piroxicam Anti-inflammatory drugs (NSAIDS) and their pharmaceutically acceptable salts or prodrugs Including, but not limited to. Of NSAIDS, aspirin (acetyl salicy (Rulic acid or ASA) and piroxicam are preferred. Other suitable antiplatelet agents include Including ticlopidine and its pharmaceutically acceptable salts or prodrugs . Ticlopidine is preferred because it is known to be gentle on the digestive tract in use. It is also a compound. Still other suitable platelet inhibitors include IIb / IIIa antagonists, Lomboxane-A2-receptor antagonists and thromboxane-A2-synthase inhibitors and And their pharmaceutically acceptable salts or prodrugs.   As used herein, the term thrombin inhibitor (or antithrombin agent) Means an inhibitor of the serine protease thrombin. Inhibiting thrombin May result in thrombin-mediated platelet activation (ie, eg, platelet aggregation, And / or plasminogen activator inhibitor-1 and / or serotoni Thrombin-mediated processes and / or fibrin secretion Phosphorus formation is prevented. Many thrombin inhibitors are known to those skilled in the art, These inhibitors are contemplated for use in combination with the compounds of the present invention. That's it Such inhibitors, including pharmaceutically acceptable salts or prodrugs thereof, include Loarginine derivatives, boropeptides, heparin, hirudin and argatroban Including, but not limited to. Boroarginine derivatives and boropeptides , Including N-acetyl and peptide derivatives of boronic acids, such as lysine, orni Tin, arginine, homoarginine and their corresponding isothiouronium Includes analog C-terminal α-aminoboronic acid derivatives. Hirudin used here The term is a suitable derivative of hirudin or (such as disulfatohirudin A) Includes analogs of hirudin, referred to herein as hilllogs. Boropepti Dothrombin inhibitors include U.S. Patent No. 5,187,157 to Kettner et al. No. 293 881 A2, the disclosure of which is hereby incorporated by reference. In writing Invite. Other suitable boroarginine derivatives and boropeptide thrombin inhibition The drugs include PCT Application Publication No. 92/07869 and European Patent Application Publication No. 471,651A. No. 2, including those disclosed in No. 2, the disclosure of which is incorporated herein.   The thrombolytic (or fibrinolytic) agent (or thrombolytic agent or The term (fibrinolytic) means an agent that lyses a clot (thrombus). That Such agents include their pharmaceutically acceptable salts or prodrugs, Tissue plasminogen activator, anistreplase, Kinase or streptokinase. Anistreple used here The term is used, for example, in European Patent Application 028,489 (the disclosure of which is incorporated herein by reference). Anisoylated plasminogen streak, as described in Reference is made to the Putkinase activator complex. Urokinase used here The term contemplates both double and single chain urokinase, the latter being It is also referred to herein as prourokinase.   The combined administration of a compound of structural formula I of the present invention with another such therapeutic agent comprises the compound and the therapeutic agent. May be superior to the efficacy of the agent alone and can be achieved using lower doses of each. it can. Lower doses minimize potential side effects, thereby increasing the margin of safety. Can be.   The compounds of the invention may be used, for example, in tests or assays related to the inhibition of factor Xa. Also available as a standard or reference compound, such as as a quality standard or control It is for. Such compounds can be provided in commercial kits, for example, It can be used for pharmaceutical research related to factor Xa. For example, the compound of the present invention An analyte is a reference in an assay to compare its known activity to a compound of unknown activity. It can also be used as a control substance. This is especially true for testers, especially for test compounds. If is a derivative of the reference compound, the analysis was performed properly and the basis for comparison is It is guaranteed to be provided. New analytical methods or protocols Use compounds according to the invention to test their effectiveness when developing be able to.   The compounds of the present invention can also be used in diagnostic methods involving factor Xa. For example The presence of factor Xa in an unknown sample tested the chromogenic substrate S2222 To By adding to the series of solutions containing and optionally one of the compounds of the invention Can be determined. A solution containing a test sample but no compound of the invention If pNA production is observed in the fluid, it is possible to conclude the presence of factor Xa. it can.                               Dosage and formulation   The compounds of the present invention include tablets and capsules (each including a sustained release formulation or a sustained release formulation). Pills), pills, powders, granules, elixirs, tinctures, suspensions, syrups, And can be administered as oral dosage forms, such as emulsions. The compound is administered intravenously (Bolus injection or infusion), also administered as intraperitoneal, subcutaneous, or intramuscular injection Using all dosage forms known to those of ordinary skill in the pharmaceutical arts. I have. The compound can be administered alone, but may be administered by a selected route of administration. And is usually administered with a pharmaceutical carrier, selected based on standard pharmaceutical practice. You.   The dosage regimen of the compound of the present invention will, of course, depend on the particular agent and its type and route of administration. Pharmacodynamic properties of the recipient; species, age, gender, health, medical condition and Weight; nature and severity of symptoms; type of combination therapy; frequency of treatment; It depends on known factors such as kidney and liver function, and the desired effect. Doctor Or veterinarian to prevent, stop, or stop the progression of thromboembolic disease Can determine and prescribe the effective amount of the drug required for the drug.   As a general guideline, the daily oral dose of each active ingredient should be used for the indicated effect. Between about 0.001 and 1000 mg / kg body weight, preferably 1 kg between about 0.01 and 100 mg per day per gram, and most preferably between about 1.0 and 20 mg / Kg / day. Intravenously, the most preferred dose is a constant rate infusion Between about 1 to about 10 mg / kg / min. Daily dose of the compound of the present invention A single dose or a total daily dose of 2, 3, or 4 doses daily Can be   The compounds of the invention may be administered in the nasal form through topical use of a suitable nasal vehicle; Can be administered by the transdermal route using a skin patch. Transdermal delivery When administered in the form of a stem, the dose is administered intermittently, Rather than continuous.   The compound may be administered in the intended dosage form (ie, oral tablet, capsule, elixir). Agents, syrups, etc.) and are inconsistent with conventional pharmaceutical practice No suitable pharmaceutical diluent, excipient, or carrier (here (Referred to as an active carrier).   For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be formulated with ease. Toose, starch, sucrose, glucose, methylcellulose, mug stearate Nesium, dicalcium phosphate, calcium sulfate, mannitol, sorbitol In combination with pharmaceutically acceptable inert carriers that are non-toxic orally, such as Can be made. For oral administration in liquid form, the oral pharmaceutical ingredients are ethanol, Any orally non-toxic, pharmaceutically acceptable, such as lyserol, water, etc. It can be combined with a functional inert carrier. More desirable or necessary When appropriate, incorporate appropriate binders, lubricants, disintegrants, and colorants into the mixture. Can also. Suitable binders include starch, gelatin, glucose or beta- Natural sugars such as lactose, corn sweeteners, gum arabic, tragacanth, Or natural and synthetic gums such as sodium alginate, Includes lulose, polyethylene glycol, wax and the like. Used in these dosage forms Lubricants include sodium oleate, sodium stearate, Contains gnesium, sodium benzoate, sodium acetate, sodium chloride, etc. . Disintegrators include starch, methylcellulose, agar, bentonite, xantha But not limited to xanthan gum.   The compounds of the present invention can be used in small unilamellar vesicles, large unilamellar vesicles, It can also be administered in the form of a liposome delivery system, such as a vesicle. Liposomes can be cholesterol, stearylamine, or phosphatidylcholine. Can be formed from various phospholipids, such as   The compounds of the present invention may be used as soluble polymers as targetable pharmaceutical carriers. Can also be combined. Such polymers include polyvinylpyrrolidone, Pyran copolymer, polyhydroxypropyl methacrylamide-phenol, Replace with a hydroxyethyl aspartamide phenol or palmitoyl residue Exchange Polyethylene oxide-polylysine. Furthermore, the present invention The compound is a biodegradable polymer useful for achieving sustained release of the drug (eg, , Polylactic acid, polyglycolic acid, polylactic acid, and copolymers of polyglycolic acid ー, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoester , Polyacetals, polydihydropyrans, polycyanoacrylates and hydrides (Crosslinked or amphiphilic block copolymer of Rogel) it can.   Dosage forms (pharmaceutical compositions) suitable for administration may comprise from about 1 milligram to about 1 milligram per unit dose. It can contain 00 milligrams of active ingredient. In these pharmaceutical compositions, The active ingredient is usually present in an amount of about 0.5-95% by weight, based on the total weight of the composition.   Gelatin capsules contain the active ingredient and powder carrier (eg, lactose, starch). , Cellulose derivatives, magnesium stearate, stearic acid, etc.) be able to. Compressed tablets can be made with similar excipients. Capsules for tablets Must also be manufactured as a sustained release product that releases the drug continuously over an extended period of time. Can be. Compressed tablets, as dragees or film-coated tablets, have an unpleasant taste. Can block or protect tablets from outside air, or selectively in the gastrointestinal tract Into enteric-coated tablets that disintegrate.   Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. Can be included.   Generally, water, suitable oils, saline, dextrose (glucose) solutions, And related sugar solutions and propylene glycol or polyethylene glycol Such glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration are preferred. Preferably a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffers. Including. Such as sodium bisulfite, sodium sulfite, or ascorbic acid Antioxidants, alone or in combination, are suitable stabilizers. Que Acids and salts thereof, and sodium EDTA are also used. In addition, parenteral Solution is benzalkonium chloride, methyl or propyl paraben and chloro A preservative such as butanol can be included.   Suitable pharmaceutical carriers are standard reference books in the art, Mack Publishing Company's Remington's Pharmaceutical Sciences.   Representative pharmaceutical forms effective for administration of the compounds of the present invention can be shown as follows: .   capsule   Many unit capsules contain standard two-piece hard gelatin capsules, 100 milligrams powdered active ingredient, 150 milligrams lactose, 50 milligrams Fill with rum cellulose and 6 milligrams magnesium stearate Prepared.Soft gelatin capsule   Mixing active ingredients in digestible oils such as soybean oil, cottonseed oil or olive oil The product was prepared and pumped into the gelatin by positive displacement pump to obtain 100 milligrams of activity. Form a soft gelatin capsule containing the active ingredient. The capsule is washed and dried.   tablet   Many tablets are prepared by conventional methods and have a unit dose of 100 milligrams of active Ingredients, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of stearin Magnesium oxide, 275 milligrams of microcrystalline cellulose, 11 milligrams of den Pun and 98.8 milligrams of lactose. Increased palatability Or can be provided with an appropriate coating to delay absorption .   Injection   Parenteral compositions suitable for administration by injection include 10% by volume propylene glycol. It is prepared by stirring 1.5% by weight of the active ingredient in an aqueous solution. The solution is chlorided Make isotonic with sodium and sterilize.   Suspension   Aqueous suspensions were prepared for oral administration, and 100 mg finely divided into 5 mL each. Active ingredient, 200 mg sodium carboxymethylcellulose, 5 mg Sodium benzoate, 1.0 g sorbitol solution (U.S.P) and 0.025 Include mL of vanillin.   When a compound of the present invention is combined with another anticoagulant, for example, the daily dose may vary from the patient's body. About 0.1 to 100 milligrams of the compound of formula I per kilogram of And about 2 to 7.5 milligrams of the second anticoagulant. Usually for tablet dosage forms , The compound of the invention may be present in an amount of about 5 to 10 milligrams per dose unit, and a second The anticoagulant is present in an amount of about 1 to 5 milligrams per dose unit.   When a compound of formula I is used in combination with an antiplatelet agent, general guidance is provided. Typically, the daily dose is about 0.1 mg of a compound of formula I per kilogram of patient body weight. 01 to 25 milligrams and about 50 to 150 milligrams of the antiplatelet agent, preferably Or about 0.1 to 1 milligram of the compound of structural formula I and about 1 3 milligrams.   When a compound of structural formula I is used in combination with a thrombolytic agent, typically the daily dose will be About 0.1 to 1 milligram of the compound of structural formula I per kilogram of body weight and In the case of a thrombolytic agent, the usual dose when the thrombolytic agent is administered alone is determined by using the compound of structural formula I When administered with a substance, it can be reduced by about 70-80%.   When two or more of the foregoing second therapeutic agents are administered with a compound of structural formula I, The typical daily dose and the amount of each component in a typical dosage form may Or reduced due to synergistic effects compared to normal dose when administered alone. Can be made.   Especially when provided as a single dosage unit, the Interaction may occur. For this reason, compounds of structural formula I and When the second and the second therapeutic agents are combined in a single dosage unit, the multiple active ingredients Even when combined in a single dose unit, physical contact between the active ingredients is minimized (e.g., (I.e., reduced). For example, one active ingredient may be You may also Combination by enteric coating one of the active ingredients Not only minimizes the contact between active ingredients, but also one of these ingredients Are not released in the stomach but rather in the intestine, The release of one of these components can be controlled. Sustained release effect throughout the digestive tract A substance that has the role of minimizing contact between active ingredients used in combination. , One of the active ingredients can also be coated. In addition, sustained release components Enteric coating to ensure that release of this component occurs only in the intestine. Wear. In order to further separate the active ingredients, one ingredient is controlled release and / or enteric coated. Coat with rimer and separate components with low viscosity grade hydroxypropyl methylcellulose Le Polymers such as loin (HPMC) or other suitable materials known in the art Yet another method is used to formulate combination products. Polymer Co As a further barrier to interaction with other components work.   These methods of minimizing contact between the components of the combination product of the present invention and the methods thereof Other methods include administration in a single dosage form, or separate dosage forms but at the same time, Irrespective of whether they are administered in the same manner, those skilled in the art It will be obvious.   It is self-evident that many variations and modifications of the present invention are possible in light of the above teachings. It is clear. Therefore, within the scope of the claims set forth below, It should be understood that the method can be implemented in a manner different from that described above.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4439 A61K 31/4439 31/454 31/454 31/496 31/496 A61P 7/02 A61P 7 / 02 43/00 111 43/00 111 C07D 209/14 C07D 209/14 209/16 209/16 209/18 209/18 231/12 231/12 231/56 231/56 AZ 235/06 235/06 401 / 06 401/06 401/12 401/12 403/06 403/06 403/10 403/10 403/12 403/12 405/14 405/14 471/04 107 471/04 107 (81) Designated country EP ( AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AM, AU, AZ, BR, BY, CA, CN, CZ, EE, HU, IL, P, KG, KR, KZ, LT, LV, MD, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, UA, VN (72) Inventor Han, Ki. 19810 Wilmington Merhill Drive, Delaware 2609 (72) Inventor Duffy, Daniel, Emmet. United States 19803 Wilmington Pascal Road, Delaware 42 (72) Inventor Park, Jeonsk, Maria. United States 19701 Bear Cornwell Drive, Delaware 241 (72) Inventor Kuan, Mimi, Leifen. United States 19711 Newark Venus Drive, Delaware 113 (72) Inventor Rossi, Karen, Anita. United States 19808 Wilmington Valley Green, Delaware 5414 Apartment Dee 3 (72) Inventor Wexler, Ruth, Rich Command. United States 19810 Wilmington, Delaware Patowin load 2205

Claims (1)

[Claims] 1. Compounds of formula (I) below: Or their stereoisomers or pharmaceutically acceptable salts, Where:   W and W^ThreeIs selected from CH and N;   W¹And W^TwoIs selected from C, CH and N;   However, W, W¹, W^Two, And W^Three0 to 2 are N,   D and D^aOne of them is H, C_1-4Alkoxy, CN, C (= NR⁷) NR⁸R⁹, N HC (= NR⁷) NR⁸R⁹, NR⁸CH (= NR⁷), C (O) NR⁸R⁹, And (CH_Two)_t NR⁸R⁹And the other does not exist,   Where D and D^aW is W if one of H is H¹, W^Two, And W^ThreeLess of One is N,   J^aAnd J^bIs-(CH_Two)_n-Z-AB,   J, J^a, And J^bTogether form 0-2 R¹N, O, substituted with Aromatic heterocyclic system containing 1-2 heteroatoms selected from the group consisting of With the proviso that J^bOnly can be C or N;   Or J, J^a, And J^bTogether, J^bIs N, J and J^aIs 0 One R¹CH substituted with_TwoCan form a heterocyclic ring,   Or J, J^a, And J^bAre together, J^bIs CH and J is NR¹In J^aIs 0 to 1 R¹CH substituted with_TwoCan form a heterocycle ,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)^rNR^ThreeR^Three', (CH_Two)_rC ( = O) R^Two, (CH_Two)_r(CH = CH) (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeSO_TwoR^Four, And (CH_Two)_r− (N, O And a 5-membered heterocyclic ring system having 1 to 4 heteroatoms selected from S and S And   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three', CF_Three, And 0-2 R⁶ C substituted with_3-10Selected from carbocyclic residues,   R^ThreeAnd R^Three'Is independently H, C_1-4Alkyl, and 0 to 2 R⁶Replaced by C_3-10Selected from carbocyclic residues,   R^FourIs C_1-4Alkyl, NR^ThreeR^Three', And 0 to 2 R⁶C substituted with_3-10Charcoal Selected from elementary ring residues,   Z is CH = CH, CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH ((CH_Two)_mC (O) (CH_Two)_mR^5a), N ((CH_Two)_qQ (CH_Two)_mR^Five ), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O) (CH_Two )_r, C (O) O (CH_Two)_r, OC (O) (CH_Two)_r, C (O) (CH_Two)_rNR^Three(CH_Two)_r, N R^ThreeC (O) (CH_Two)_r, OC (O) NR^Three(CH_Two)_r, NR^ThreeC (O) O (CH_Two)_r, NR^ThreeC (O) NR^Three(CH_Two)_r, S (O)_p(CH_Two)_r, SO_TwoCH_Two, SCH_TwoC (O) NR^Three, SO_Two NR^Three(CH_Two)_r, NR^ThreeSO_Two(CH_Two)_r, And NR^ThreeSO_TwoNR^Three(CH_Two)_rChoose from Selected,   Q is a bond, O, NR^Three, C (O), C (O) NR^Three, NR^ThreeC (O), SO_Two, NR^Three SO_Two, And SO_TwoNR^ThreeSelected from   Q ′ is a bond, C (O), C (O) NR^Three, SO_Two, And SO_TwoNR^ThreeSelected from   R^FiveIs H, C_1-4Alkyl, 0-2 R⁶C substituted with_3-10Carbocyclic residues, And 0 to 2 R⁶1 selected from the group consisting of N, O and S substituted with Selected from a 5-10 membered heterocyclic ring system containing up to 3 heteroatoms, Where Q is SO_TwoOr NR^ThreeSO_TwoIf R^FiveIs other than H, Q 'is SO_TwoIf R^FiveIs other than H,   R^5aIs NHR^Five, OR^Five, And R^FiveSelected from   A is   0-2 R⁶A benzyl substituted with   0-2 R⁶Phenethyl substituted with   0-2 R⁶Phenyl-CH = substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue;   0-2 R⁶1 selected from the group consisting of N, O and S, substituted with A 5-10 membered heterocyclic ring system containing up to 3 heteroatoms,   B is   XY, C_3-6Alkyl, NR^ThreeR^Three’, C (= NR^Three) NR^ThreeR^Three’, NR^ThreeC (= N R^Three) NR^ThreeR^Three’, 0 to 2 R⁶Substituted with 0 to 2 R⁶Replaced by C_3-10A carbocyclic residue, and R⁶The group consisting of N, O, and S, substituted with Selected from a 5 to 10 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from:   Alternatively, A and B together form 0-2 R⁶C substituted with_9-10Charcoal A ring residue or 0 to 2 R⁶From the group consisting of N, O, and S, substituted with Can form a 9-10 membered heterocyclic ring system containing selected 1-3 heteroatoms. Come   X is C_1-4Alkylene, -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three’ C (O), -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^ThreeC (O)-, -NR^Three -, -NR^ThreeCR^ThreeR^Three’-, -CR^ThreeR^Three'NR^Three-, O, -CR^ThreeR^Three'O- and -OCR^ThreeR^Three’-,   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶1 selected from the group consisting of N, O and S, substituted with Selected from a 5-10 membered heterocyclic ring system containing up to 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^ThreeR^Three’, CONHS O_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two-C_1-4Alkyl, and (C_1-4A Alkyl) -tetrazolyl,   R⁷Is H, OH, C_1-6Alkyl, C_1-6Alkylcarbonyl, C_1-6Alkoki Si, C_1-4Alkoxycarbonyl, C_6-10Aryloxy, C_6-10Aryloxy Cicarbonyl, C_6-10Arylmethylcarbonyl, C_1-4Alkylcarbonyl Kishi C_1-4Alkoxycarbonyl, C_6-10Arylcarbonyloxy C_1-4Arco Xycarbonyl, C_1-6Alkylaminocarbonyl, phenylaminocarbonyl And phenyl C_1-4Selected from alkoxycarbonyl,   R⁸Is H, C_1-6Alkyl and (CH_Two)_n-Selected from phenyl;   R⁹Is H, C_1-6Alkyl and (CH_Two)_n-Selected from 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;   r is selected from 0, 1, 2, 3, and 4;   However, (A) Z is CH_TwoOther than, and (B) Z is CH ((CH_Two)_mQ (CH_Two)_mR^Five) Or CH ((CH_Two)_mC (O) (CH_Two)_mR^5a ), Then B is XY, C_3-10Carbocyclic residue or 5- to 10-membered heterocyclic ring Non-system A compound comprising: 2. 2. A compound according to claim 1 having the structure of formula II: Or their stereoisomers or pharmaceutically acceptable salts, Where W, W¹, W^Two, And W^Three0 to 1 are N,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)_rNR^ThreeR^Three’, (CH_Two)_r C (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Three, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeS O_TwoR^Four, And (CH_Two)_r-(Heteroatoms 1-4 selected from N, O and S A 5-membered heterocyclic ring system having   R^TwoIs H, OR^Three, C_1-4Alkyl NR^ThreeR^Three’, CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Selected from alkyl, and phenyl ,   R^FourIs C_1-4Alkyl, phenyl and NR^ThreeR^Three’,   Z is CH = CH, CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH ((CH_Two)_mC (O) (CH_Two)_mR^5a), N ((CH_Two)_qQ (CH_Two)_mR^Five ), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O), C ( O) CH_Two, C (O) O, OC (O), C (O) (CH_Two)_rNR^Three(CH_Two)_r, NR^ThreeC (O), OC (O) NR^Three, NR^ThreeC (O) O, NR^ThreeC (O) NR^Three, S (O)_p, SO_TwoCH_Two, S O_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from   B is XY, C_3-6Alkyl,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶1 selected from the group consisting of N, O and S, substituted with Selected from a 5-10 membered heterocyclic ring system containing up to 3 heteroatoms,   Alternatively, A and B together form 0-2 R⁶C substituted with_9-10carbon A ring residue, or 0 to 2 R⁶Selected from the group consisting of N, O and S To form a 9-10 membered heterocyclic ring system containing selected 1-3 heteroatoms. Come   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (CH_Two )_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three’ , SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two− C_1-4Alkyl, and (C_1-4Alkyl) -tetrazolyl A compound comprising: 3. A compound according to claim 2, here,   J, J^aAnd J^bTogether with 0 to 1 R¹The nitrogen atom substituted with 1 to Form an aromatic heterocyclic ring system containing two,   Or J, J^aAnd J^bTogether, J^bIs N, J and J^aIs 0 One R¹CH substituted with_TwoTo form a heterocyclic ring system,   Or J, J^aAnd J^bTogether, J^bIs CH and J is NR¹And J^a Is 0 to 1 R¹CH substituted with_TwoTo form a heterocyclic ring system,   R¹Is H, C_1-4Alkyl, (CH_Two)_rOR^Three, (CH_Two)_rNR^ThreeR^Three’, (CH_Two)_r C (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^FourAnd (CH_Two)_rN R^ThreeSO_TwoR^FourSelected from   Z is CH ((CH_Two)_mQ (CH_Two)_mR^Five), CH ((CH_Two)_mQ (CH_Two)_mR^Five) C (O) NR^Three, CH (CH_Two)_mC (O) (CH_Two)_mR^5a) , N ((CH_Two)_qQ (CH_Two)_mR^Five), N (Q '(CH_Two)_mR^Five), C (O) N ((CH_Two)_mQ '( CH_Two)_mR^5a), C (O), C (O) CH_Two, C (O) (CH_Two)_rNR^Three(CH_Two)_r, NR^ThreeC ( O), NR^ThreeC (O) NR^Three, S (O)_Two, SO_TwoCH_Two, SO_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from A is   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY, C_3-6Alkyl,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_5-6A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-6 membered heterocyclic ring system containing 3 heteroatoms,   X is -C (O)-, -C (O) CR^ThreeR^Three'-, -S (O)_Two-, S (O)_pCR^ThreeR^Three’ -, -S (O)_TwoNR^Three-, -C (O) NR^Three-, -NR^Three-, -NR^ThreeCR^ThreeR^Three’-, And O,   Y is   0-2 R⁶Replaced by_5-6A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-6 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two -C_1-4Alkyl and (C_1-4Alkyl) -tetrazolyl,   n is selected from 0, 1, and 2;   r is selected from 0, 1, and 2 A compound comprising: 4. 4. A compound according to claim 3 having the structure of formula III: Or their stereoisomers or pharmaceutically acceptable salts, Where:   J and J^bTogether form 0-1 R¹One or two nitrogen atoms substituted with To form an aromatic heterocyclic ring system containing   Or J and J^bIs J^bIs N and J is 0 to 1 R¹CH substituted with_Two Can form a heterocyclic ring,   Or J and J^bIs J^bIs CH and J is NR¹Forming a heterocyclic ring that is Can be   Z is C (O) N (Q'R^5a), C (O), C (O) NR^Three, NR^ThreeC (O) and SO_Two NR^ThreeSelected from   Q 'is C (O) and C (O) NR^ThreeSelected from   R^FiveIs H and C_1-4Selected from alkyl,   R^5aIs NHR^Five, OR^Five, And R^FiveSelected from   A is   0 to 1 R⁶Benzyl substituted with   0 to 1 R⁶Phenyl substituted with   0 to 1 R⁶Piperidinyl substituted with   0 to 1 R⁶Piperazinyl substituted with, and   0 to 1 R⁶Selected from pyridyl substituted with   B is   XY,   0 to 1 R⁶Benzyl substituted with   0-2 R⁶Phenyl substituted with   0 to 1 R⁶A cyclohexyl substituted with   0 to 1 R⁶Selected from pyridyl substituted with   X is -C (O)-, -S (O)_Two-, SO_TwoCH_Two, -S (O)_TwoNR^Three-, -NR^Three− And -C (O) NR^Three-Selected from   Y is   0-2 R⁶Phenyl substituted with   0 to 1 R⁶Selected from pyridyl substituted with   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, SO_TwoNR^ThreeR^Three’, CONHSO_TwoR^Four, NR^ThreeSO_TwoNR^ThreeR^Three’, NR^ThreeSO_Two -C_1-4Alkyl and (C_1-4Alkyl) -tetrazolyl,   n is selected from 0, 1 and 2 A compound comprising: 5. A compound according to claim 4 having the structure of formula IV: Or their stereoisomers or pharmaceutically acceptable salts, Wherein A, B, D, and Z are as defined above. A compound comprising: 6. The compound according to claim 1, wherein the compound is selected from the following compound group: 3-((4-cyclohexyl) phenylaminomethylcarbonyl) methyl-5-amido Zinoindole 3- (4-p-toluenesulfonyl-piperazinecarbonyl) methyl-5-amidi Noindore 3- (4- (2-aminosulfonylphenyl) pyridine-2-aminocarbonyl) me Chill-5-amidinoindole 3- (4- [2-tetrazole] phenyl) phenylaminocarbonyl) methyl- 5-amidinoindole 3- (4-biphenylaminocarbonyl) methyl-5-amidinoindole 3- (4- (phenylmethylsulfonyl) piperazinecarbonyl) methyl-5-amido Zinoindole 3- (4-cyclohexylphenylaminocarbonyl) methyl-5-amidinoin Doll 3- (4-benzylpiperazinecarbonyl) methyl-5-amidinoindole 3- (3-amidinobenzylamino (methylcarbonylmethoxy) carbonyl) methyl Le-5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- 5-amidinoindole 3- (1-benzylpiperazine-4-aminocarbonyl) methyl-5-amidinoy Ndore 3- (4-phenylpiperazinecarbonyl) methyl-5-amidinoindole 3- (4-benzylpiperazinecarbonyl) methyl-5-amidinoindole 3- (2-bromo-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-methylaminoindole 3- (2-fluoro-4- (2-aminosulfonyl) phenylphenylaminocar Bonyl) methyl-5-amidinoindole 3- (2-chloro-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-iodo-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-cyanoindole 3- (2-methyl-4- (2-aminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-amidinoindole 3- (2-methyl-4- (2- (t-butylaminosulfonyl)) phenylphenyl Aminocarbonyl) methyl-5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- α- (methylcarbonyl methyl ether) -5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- α- (benzyl) -5-amidinoindole 3- (4- (2-trifluoromethyl) phenyl) pyrid-2-ylaminocarboni Rumethyl-5-amidinoindole 3- (4- (2-ethylaminosulfonyl) phenyl) phenylaminocarbonyl Chill-5-amidinoindole 3- (4- (2-propylaminosulfonyl) phenyl) phenyl) aminocarboni Rumethyl-5-amidinoindole 2-methyl-3- (2-iodo-4- (2-aminosulfonyl) phenyl) phenyl ) Aminocarbonylmethyl-5-amidinoindole 2-methyl-3- (4- (2-aminosulfonyl) phenyl) phenyl) aminocar Bonylmethyl-5-amidinoindole 3- (4- (2-aminosulfonyl) phenyl) phenyl) -N-methylaminocar Bonylmethyl-5-amidinoindole 2-methyl-3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl) Aminocarbonylmethyl-5-methoxyindole 3- (4- (2-N-methylaminosulfonyl) phenyl) phenyl) -N-methyl Aminocarbonylmethyl-5-amidinoindole Alternatively, a stereoisomer or a pharmaceutically acceptable salt form of the above compound. 7. A compound according to claim 4, having the structure of formula IVa: Or their stereoisomers or pharmaceutically acceptable salts, A, B, D, and Z in the formula are as defined above. A compound comprising: 8. The compound according to claim 1, wherein the compound is selected from the following compound group: 3- (4- (2- (n-butylaminosulfonyl) phenylphenylaminocarboni L) Methyl-5-cyanoindoline 3- (4- (2- (n-propylaminosulfonyl) phenylphenylaminocarbo Nyl) methyl-5-amidinoindoline (-)-3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocar Bonylmethyl-5-amidinoindoline 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarbonyl Methyl-5-amidinoindoline 3- (4- (2-dimethylaminosulfonyl) phenyl) phenylaminocarbonyl Methyl-5-amidinoindoline (+)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl Aminocarbonylmethyl-5-amidinoindoline (-)-3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl Aminocarbonylmethyl-5-amidinoindoline 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-yl) aminocarboni Rumethyl-5-aminocarboxyindoline 3- (4- (2-t-butylaminosulfonyl) phenyl) phenyl) aminocarbo Nylmethyl-5-amidinoindoline 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-yl) ami Nocarbonylmethyl-5-amidinoindoline Or a stereoisomer or a pharmaceutically acceptable salt form of the above compound. 9. A compound according to claim 4 having the structure of formula IVb: Or their stereoisomers or pharmaceutically acceptable salts, Wherein A, B, D, and Z are as defined above. A compound comprising: 10. The compound according to claim 1, wherein the compound is selected from the following compound group: 3- (4- (2-aminosulfonyl) phenyl) pyrid-2-ylaminocarbonyl Methyl-6-amidinoindazole 3- (4- (2-aminosulfonyl) phenyl) phenylaminocarbonylmethyl- 6-amidinoindazole 3- (4- (2-t-butylaminosulfonyl) phenyl) pyrid-2-ylamino Carbonylmethyl-6-amidinoindazole 3- (4- (2-t-butylaminosulfonyl) phenyl) phenylaminocarboni Lemethyl-6-amidinoindazole Alternatively, a stereoisomer or a pharmaceutically acceptable salt form of the above compound. 11. 5. A compound according to claim 4, having the structure of formula IVc: Or their stereoisomers or pharmaceutically acceptable salts, D, D in the formula^a, Z, A and B are as defined above A compound comprising: 12. The compound according to claim 1, wherein the compound is selected from the following compound group: [4- (phenyl) phenylcarbonyl] methyl-6-amidinobenzimidazo Le [4- (phenyl) phenylcarbonyl] methyl-5-amidinobenzimidazo Le [4- (3-aminophenyl) phenylcarbonyl] methyl-6-amidinobenzo Imidazole [4- (3-aminophenyl) phenylcarbonyl] methyl-5-amidinobenzo Imidazole [4- (4-fluorophenyl) phenylcarbonyl] methyl-6-amidinoben Zoimidazole [4- (4-formylphenyl) phenylcarbonyl] methyl-6-amidinoben Zoimidazole [4- (2-aminosulfonylphenyl) phenylcarbonyl] methyl-6-amido Dinobenzimidazole [4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl] methyl -6-amidinobenzimidazole [4-((2-tetrazolyl) phenyl) phenylcarbonyl] methyl-6-amidi Nobenzimidazole [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-6 -Amidino benzimidazole [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl-5 -Amidino benzimidazole 1- (4-benzylpiperidinecarbonyl) methyl-6-amidinobenzimidazo Rule 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinobenzimidazo Rule 2- (4- (2-aminosulfonylphenyl) phenylcarbonyl) methyl-6-a Midino benzimidazole 2- (4- (2-t-butylaminosulfonylphenyl) phenylcarbonyl) methyl Le-5-azabenzimidazole 2S- [4- (2-t-aminosulfonylphenyl) phenylaminocarbonyl] Methyl-thio-1H-imidazo [4,5-C] pyridine 2S- [4- (2-aminosulfonylphenyl) phenylaminocarbonyl] methyl Ru-thio-1H-imidazo [4,5-C] pyridine Or a stereoisomer or a pharmaceutically acceptable salt form of the above compound. 13. 2. A compound according to claim 1 having the structure of formula V: Is a sex or pharmaceutically acceptable salt, Where:   R and R^aIs-(CH_Two)_n-ZAB, the other is H,   W, W^Two, And W^ThreeIs selected from CH and N, provided that W, W^Two,and W^ThreeMay be N or less,   J is N and C—R¹Selected from   R¹Is H, O, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH = CH) C (= C ) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two, (CH_Two)_rSO_TwoR^Four, (CH_Two)_rNR^ThreeSO_TwoR^Four , And (CH_Two)_r-(Has 1 to 4 heteroatoms selected from N, O and S 5 membered heterocycle)   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, CF_Three, And 0-2 R⁶C substituted with_3-10Selected from carbocyclic residues,   R^ThreeAnd R^Three’Is independently H, C_1-4Alkyl, NR^ThreeR^Three’And 0- Two R⁶C substituted with_3-10Selected from carbocyclic residues,   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three'And 0 to 2 R⁶Replaced by C_3-10Selected from carbocyclic residues,   Z is CH = CH, CH (CH_Two)_mQ (CH_Two)_mR^Five, CH ((CH_Two)_mQ (CH_Two)_mR^Five ) C (O) NR^Three, CH (CH_Two)_mC (O) (CH_Two)_mR^5a, N (CH_Two)_qQ (CH_Two)_mR^Five, NQ '(CH_Two)_mR^Five, C (O) N ((CH_Two)_mQ '(CH_Two)_mR^5a), C (O), C (O) C H_Two, C (O) O, OC (O), C (O) NR^Three(CH_Two)_r, NR^ThreeC (O), OC (O) NR^Three , NR^ThreeC (O) O, NR^ThreeC (O) NR^Three, S (O)_p, SO_TwoCH_Two, SO_TwoNR^Three, NR^Three SO_TwoAnd NR^ThreeSO_TwoNR^ThreeSelected from   Q is a bond, O, NR^Three, C (O), C (O) NR^Three, NR^ThreeC (O), SO_Two, NR^Three SO_Two, And SO_TwoNR^ThreeSelected from   Q ′ is a bond, C (O), C (O) NR^Three, SO_Two, And SO_TwoNR^ThreeSelected from   R^FiveIs H, C_1-4Alkyl, 0-2 R⁶C substituted with_3-8Carbocyclic residues, and And 0 to 2 R⁶Selected from the group consisting of N, O and S, Selected from 5 to 10 membered heterocyclic ring systems containing three heteroatoms, provided that Q is SO_TwoMa Or NR^ThreeSO_TwoIf R^FiveIs other than H, and Q ′ is SO_TwoIs Ki, R^FiveIs other than H,   R^5aIs NHR^Five, OR^FiveAnd R^FiveSelected from   A is   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶1-3 selected from the group consisting of N, O and S substituted with Selected from a 5 to 10 membered heterocyclic ring system comprising   B is   H, XY, NR^ThreeR^Three’, C (= NR^Three) NR^ThreeR^Three’,   NR^ThreeC (= NR^Three) NR^ThreeR^Three’,   0-2 R⁶Benzyl substituted with   0-2 R⁶C substituted with_3-10Carbocyclic residue,   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X is C_1-4Alkylene, -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three’ C (O), -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^ThreeC (O)-, -NR^Three -, -NR^ThreeCR^ThreeR^Three’-, -CR^ThreeR^Three'NR^Three-, O, -CR^ThreeR^Three’-, And -OCR^ThreeR^Three’-,   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, CH (= NH) NH_Two, NHC (= NH) NH_Two, C (= O) R^Three, SO_TwoNR^ThreeR^Three ’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^ThreeSO_Two-C_1-4Selected from 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;   r is selected from 0, 1, 2, 3, and 4 A compound comprising: 14． 14. A compound according to claim 13 having the structure of formula VI: Or their stereoisomers or pharmaceutically acceptable salts, Where:   R and R^aIs-(CH_Two)_n-ZAB, the other is H,   W and W^TwoIs selected from CH and N, provided that W and W^TwoIs N May not be more than one,   J is N and C—R¹Selected from   R¹Is H, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two , (CH = CH) C (= O) R^Two, (CH_Two)_rSO_TwoR^Four, And (CH_Two)_rNR^ThreeSO_TwoR^Four Selected from   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Selected from alkyl, and phenyl And   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And phenyl,   Z is C (O), C (O) CH_Two, C (O) NR^Three, NR^ThreeC (O), S (O)_Two, SO_TwoCH_Two , SO_TwoNR^Three, NR^ThreeSO_Two, And NR^ThreeSO_TwoNR^ThreeSelected from   A is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY,   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X represents -C (O)-, -C (O) CR^ThreeR^Three’-, -CR^ThreeR^Three'C (O), -S (O)_p -, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S (O)_TwoNR^Three-, -N R^ThreeS (O)_Two-, -C (O) NR^Three-, -NR^Three-, -NR^ThreeCR^ThreeR^Three’-, And- CR^ThreeR^Three'NR^Three-Selected from   Y is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, C (= O) R^Three, SO_TwoNR^ThreeR^Three’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^ThreeSO_Two -C_1-4Selected from alkyl,   n is selected from 0, 1, 2, 3, and 4;   p is selected from 0, 1, and 2;   r is selected from 0, 1, 2, 3, and 4 A compound comprising: 15. 15. The compound of claim 14, having the structure of formula VII: Or their stereoisomers or pharmaceutically acceptable salts, Where:   W and W^TwoIs selected from CH and N, provided that W and W^TwoIs N May not be more than one,   R¹Is H, (CH_Two)_rOR^Three, (CH_Two)_rC (= O) R^Two, (CH_Two)_rNR^ThreeC (= O) R^Two , (CH = CH) C (= O) R^Two, (CH_Two)_rSO_TwoR^Four, And (CH_Two)_rNR^ThreeSO_TwoR^Four Selected from   R^TwoIs H, OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And CF_ThreeSelected from   R^ThreeAnd R^Three’Is independently H, C_1-4Selected from alkyl, and phenyl And   R^FourIs OR^Three, C_1-4Alkyl, NR^ThreeR^Three’, And phenyl,   Z is C (O), C (O) CH_Two, C (O) NR^Three, S (O)_Two, SO_TwoCH_Two, SO_TwoNR^Three , And NR^ThreeSO_TwoNR^ThreeSelected from   A is   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   B is   XY,   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   X is -S (O)_p-, -S (O)_pCR^ThreeR^Three’-, -CR^ThreeR^Three'S (O)_p-, -S ( O)_TwoNR^Three-, -NR^ThreeS (O)_Two-, And -C (O) NR^Three-Y is selected from ,   0-2 R⁶C substituted with_3-10A carbocyclic residue, and   0-2 R⁶Selected from the group consisting of N, O and S, Selected from a 5-10 membered heterocyclic ring system containing 3 heteroatoms,   R⁶Is H, OH, (CH_Two)_nOR^Three, Halo, C_1-4Alkyl, CN, NO_Two, (C H_Two)_rNR^ThreeR^Three’, (CH_Two)_rC (O) R^Three, NR^ThreeC (O) R^Three’, NR^ThreeC (O) NR^ThreeR^Three ’, C (= O) R^Three, SO_TwoNR^ThreeR^Three’, NR^ThreeSO_TwoNR^ThreeR^Three’, And NR^ThreeSO_Two -C_1-4Selected from alkyl,   n is selected from 0, 1, 2, 3, and 4;   p is selected from 0, 1, and 2;   r is selected from 0, 1, 2, 3, and 4 A compound comprising: 16. 14. The compound according to claim 13, wherein the compound is selected from the following compound group: object: 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole 1- (4-benzylpiperidinecarbonyl) ethyl-5-amidinoindole 1- (4- (3-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole 1- (1- (4-amidino) benzyl-N- (methyl acetate) aminocarbonyl) Methyl-5-amidinoindole Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Le-3-propanoate 1-((4-benzylpiperidinecarbonyl) methyl- (3-ethanehydroxyl) − 5-amidinoindole 1- (4-benzylpiperidine-1-carbonyl) methyl-3-methylcarboxylic acid -5-amidinoindole 1- (1-benzylpiperidine-4-aminocarbonyl) methyl-5-amidinoy Ndore 1- (4-benzoylpiperidinecarbonyl) methyl-5-amidinoindole 1 -(4- (3-fluoro) benzylpiperazinecarbonyl) methyl-5-amidinoy Ndore 1- (4-phenylbenzylaminocarbonyl) methyl-5-amidinoindole Methyl 1- (4-benzylpiperidinecarbonyl) methyl-5-amidinoindole Le-3-propanoate 1- (4- (2-fluoro) benzylpiperidinecarbonyl) methyl-5-amidino Indole Alternatively, a stereoisomer of the above compound or a pharmaceutically acceptable salt form thereof. 17． A pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1. Or a pharmaceutically acceptable salt thereof. 18. A pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 2. Or a pharmaceutically acceptable salt thereof. 19. A therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable thereof. Including administering to a patient in need of treatment or prevention of thromboembolism A method for treating or preventing thromboembolism, characterized in that: 20. A therapeutically effective amount of the compound of claim 2 or a pharmaceutically acceptable thereof. Including administering to a patient in need of treatment or prevention of thromboembolism A method for treating or preventing thromboembolism, characterized in that: