MXPA00005706A - Indole derivatives as inhibitors or factor xa - Google Patents

Abstract

The present invention relates to the inhibition of blood clotting proteins, and more particularly, to indole derivatives of formula (I), in which R1a, R1b, R1c R1d, R2, R3, R4 and A are defined as indicated in the claims. The compounds of formula (I) are inhibitors of the blood clotting enzyme factor Xa. The invention also relates to processes for the preparation of the compounds of formula (I), to methods of inhibiting factor Xa activity and of inhibiting blood clotting, to use of the compounds of formula (I) in the treatment and prophylaxis of diseases which can be cured or prevented by the inhibition of factor Xa activity such as thromboembolic diseases, and to the use of the compounds of formula (I) in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing a compound of formula (I) in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of formula (I) together with pharmaceutically acceptable carrier substances and/or auxiliary substances.

Description

INDOL DERIVATIVES AS DEFAULT INHIBITORS XA The present invention relates to the inhibition of blood coagulation proteins, and more particularly to indole derivatives of the formula I, where Rla, Rlb, Rlc, Rld, R2, R3, R4, and A are in accordance with what is indicated below. The compounds of formula I are inhibitors of blood coagulation enzyme factor Xa. The invention also relates to processes for the preparation of the compounds of the formula I, to methods for inhibiting the activity of factor Xa and to the inhibition of blood coagulation, to the use of the compounds of the formula I in the treatment and prophylaxis of diseases that can be cured or prevented by inhibiting factor Xa activity, such as, for example, thromboembolic diseases, and the use of the compounds of formula I for the preparation of drugs to be applied in diseases of this type. The invention further relates to compositions containing a compound of formula I in admixture or in association of another type with an inert carrier, particularly pharmaceutical compositions containing a compound of formula I together with pharmaceutically acceptable carriers and / or auxiliaries. The ability to form blood clots is vital for survival. In certain stages of disease, however, the formation of blood clots within the circulatory system itself is a source of morbidity. However, it is not desirable, in these disease states, to totally inhibit the coagulation system because this could cause dangerous hemorrhages. In order to reduce the cases of intravascular formation of blood clots, those skilled in the art have attempted to develop an effective inhibitor of factor Xa, or pro-thrombinase, the enzyme that is incorporated into the pro-thrombinase complex where it serves to activate thrombin during the formation of clots. Appropriate concentrations of such an inhibitor would increase the level of prothrombinase-forming agents required to initiate coagulation, but would unduly prolong the clotting process once a threshold concentration of thrombin was obtained. Blood coagulation is a complex process that involves a progressively amplified series of enzymatic activation reactions in which plasma zymogens are activated sequentially by limited proteolysis. Mechanically, the cascade of blood coagulation has been divided into intrinsic and extrinsic pathways that converge on the activation of factor X; The subsequent generation of thrombin is carried out through a single common route (see diagram 1). Intrinsic Extrinsic XII XHa Vil + TF * XI > -XIa IX IXa I platelet aggregation Xa / / / Prothrombin ». thrombin I Fibrinogen fibrin Scheme 1: Cascade of blood coagulation Current evidence suggests that the intrinsic pathway plays an important role in the maintenance and growth of fibrin formation, while the extrinsic pathway is critical in the coagulation initiation phase blood It is generally accepted that blood coagulation is initiated physically by forming a tissue factor / Vlla factor complex. Once formed, this complex rapidly initiates coagulation by activating factors IX and X. Activated factor X, newly generated, that is, factor Xa, then forms a one-to-one complex with factor Va and phospholipids for form a prothrombinase complex, which is responsible for the conversion of soluble fibrinogen into insoluble fibrin through the activation of thrombin from its precursor, prothrombin. As time passes, the activity of the factor VlIIa complex / tissue factor (extrinsic pathway) is suppressed by a Kunitz-type protease inhibitor protein, TFPI, which, when complexed with factor Xa, can directly inhibit the proteolytic activity of factor Vlla / tissue factor. In order to maintain the coagulation process in the presence of an inhibited extrinsic system, additional factor Xa is produced through the thrombin-mediated activity of the intrinsic pathway. Thus, trsmbina plays a double autocatalytic function, mediating its own production and the conversion of fibrinogen into fibrin. The autocatalytic nature of the generation of thrombin is an important protection against uncontrolled bleeding and ensures that, once a given threshold level of prothrombinase is present, blood coagulation will be carried out until its culmination, achieving, for example, stopping a hemorrhage. Thus, it is desirable to develop agents that inhibit coagulation without directly inhibiting thrombin. However, despite the long-standing recognition of the desirable character of such an inhibitor, at present we do not have an effective specific inhibitor of Xa in clinical use. In many clinical applications, there is a great need to prevent the formation of intravascular blood clots or of some type of anticoagulant treatment. Currently available drugs are not satisfactory in many specific clinical applications. For example, almost 50% of patients undergoing total hip replacement develop deep vein thrombosis (DVT). The currently approved therapies are a fixed dose of low molecular weight heparin (LMWH) and variable dose heparin. Even with these pharmacological regimens, from 10% to 20% of patients develop deep vein thrombosis and from 5 to 10% develop bleeding complications. Another clinical situation for which better anticoagulants are required refers to patients undergoing transluminal coronary angioplasty and patients at risk of myocardial infarction or patients suffering from increasing angina. The conventionally accepted therapy today, which consists of the administration of heparin and aspirin, is associated with an abrupt vessel closure rate of 6% to 8% within 24 hours of the procedure. The rate of bleeding complications that require transfusion therapy due to the use of heparin is also approximately 7%. In addition, even when the delayed closures are significant, the administration of heparin after the end of the procedures is of little value and may be negative. The most widely used blood coagulation inhibitors are heparin and related sulfated polysaccharides, LMWH and heparin sulfate. These molecules exert their anticoagulation effects by promoting the binding of a natural regulator of the coagulation process, antithrombin III, to thrombin and factor Xa. The activity of heparin inhibition is primarily focused towards thrombin, which is deactivated approximately 100 times more rapidly than factor Xa. Even when compared to heparin, heparin sulfate and LMWH are relatively more potent inhibitors of Xa than of thrombin, in vitro differences are mild (3 to 30 times) and in vivo effects can be without consequences. Hirudin and hirulog are two additional thrombin-specific anticoagulants currently in clinical trials. However, these anticoagulants, which inhibit thrombin, are also associated with bleeding complications. Pre-clinical studies in baboons and dogs have shown that specific inhibitors of factor Xa prevent the formation of clots, without producing the side effects of bleeding observed with direct thrombin inhibitors. Such factor Xa inhibitors include, for example, 2,7-bis (4-amidinobenzylidene) -cycloheptanone and N- (alpha) -tosyl-glycyl-3-amidinophenylalanine methyl ester. { "ENSTOP"), which have effective inhibitory concentrations (Ki's) of approximately 20 nM and 800 nM, respectively (+) - (2S) -2 (4- ( { (3S) -l-acetimidoyl-3) -pyrrolidinyl.} oxy) phenyl) -3- (7-amidino-2-naphthyl) propanoic is also representative of a class of factor Xa inhibitors (Katakura et al., Biochem. Biophys. Res. Comm. 197 (1993), 965-972). To date, however, these compounds have not been developed clinically. Several specific factor Xa inhibitors were reported. Both synthetic factor Xa inhibitors and proteins have been identified including, for example, antiestasin ("ATS") as well as tick anticoagulant peptide ("TAP"). ATS that is isolated from the leech, Haementerin officinalis, contains 119 amino acids and has a Ki for factor Xa of 0.05 nM. TAP, isolated from the tick, OrnitJiodoros moubata, contains 60 amino acids and has a Ki for factor Xa of approximately 0.5 nM. The effectiveness of ATS and TAP produced recombinantly has been studied in several animal model systems. Both inhibitors decrease the bleeding time compared to other anticoagulants, and prevent the formation of clots in a model of thrombosis of deep vein of jugular vein ligand, induced by thromboplastin. The results achieved in this model correlate with the results obtained using the drug of choice, heparin. It was also found that subcutaneous AT was an effective treatment in a disseminated intravascular coagulation (DIC) thromboplastin-induced model. TAP effectively prevents "high shear" arterial thrombosis and "reduced flow" caused by the surgical placement of a polyester graft ("DACRON") at levels A that produced a clinically acceptable prolongation of activated partial thromboplastin time ( aPTT), that is, less than approximately a double extension. In In comparison, standard heparin, even in doses that cause a fivefold increase in aPTT, did not prevent thrombosis or reduce flow within the graft. The aPTT is a clinical coagulation assay that is especially sensitive to thrombin inhibitors. ATS and TAP have not been, developed clinically. A major disadvantage of these two inhibitors is that the administration of the required repeat doses causes the generation of neutralizing antibodies, which limits their -potential clinical use. In addition, the sizes of TAP and ATS make oral administration impossible, further limiting the number of patients who can benefit from these agents.

Other compounds that have an inhibitory activity of factor Xa have been described. WO-A-95/29 189, for example, exhibits factor Xa inhibitors having a peptide-like structure, and WO-A-97/08 165 presents cyclic guanidines that inhibit factor Xa. WO-A-97/21 437 discloses naphthyl-substituted benzimidazoles which have an inhibitory activity against factor Xa and factor lyo and which can be used as anticoagulants, and in WO-A-97/30 971 m-amidinophenyl analogs that inhibit factor Xa are described. But there remains a need for additional factor Xa inhibitors that have improved properties that have a favorable profile of pharmacological activity. A specific factor Xa inhibitor must have a substantial practical value in the practice of medicine. Particularly, a factor Xa inhibitor should be effective under circumstances in which the current drugs of choice, heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Thus, there is a need for a specific blood coagulation inhibitor for low molecular weight factor Xa that is effective, but does not cause unwanted side effects. The present invention meets this need by providing indole derivatives that inhibit novel factor Xa activity of formula I and providing related advantages as well. As used herein, the term "factor Xa activity" refers to the ability of factor Xa, either alone or in the set of subunits known as the prothrombinase complex, to catalyze the conversion of prothrombin to thrombin. When used with reference to factor Xa activity, the term "inhibition" includes both direct and indirect inhibition of factor Xa activity. The direct inhibition of factor Xa activity can be achieved, for example, by the binding of a compound of formula I with a factor Xa or prothrombinase in such a way that the binding of prothrombin with the active site of prothrombinase complex is avoided. . The indirect inhibition of factor Xa activity can be accompanied, for example, by the binding of a compound of the invention with a soluble factor Xa in such a way that its binding in the prothrombinase complex is avoided. As used herein, the term "specific" when employed with reference to the Xa activity factor inhibitor means that a compound of formula I can inhibit factor Xa activity without substantially inhibiting the activity of other specific proteases, including plasmin and thrombin (using the same inhibitor concentration). Such proteases are involved in blood regulation and in the fibrinolysis cascade. The present invention offers novel compounds that inhibit factor Xa activity but do not substantially inhibit the activity of other proteases involved in the blood coagulation pathway. Thus, an object of the present invention relates to indole derivatives of the formula I, where two of the radicals Rla, Rlb, Rlc and Rld independently of each other, are hydrogen, F, Cl, Br, I, alkyl (C? ~ C4), CF3, phenyl, phenylalkyl (C, -C4), alkoxy ( C? -C4), phenyloxy, phenylalkoxy (C1-C4), OH, N02, -NR5aR5b, -NR5b-S02-R6a, -S-R6b, - SOn-R6c where n is 1 or 2, -S02-NR5aR5b , -CN or -CO-R7, and they are identical or different, and the others - two of the radicals Rla, Rib, Rlc and Rld are hydrogen; 5a is hydrogen, (C? -C4) alkyl, phenyl, f? Nylalkyl (d.C4), formyl, ((C? -C4) alkyl) carbonyl-, phenylcarbonyl-, phenyl- (C? -C4 alkyl) )) carbonyl- or phenyl (C 4 -C 4) alkoxycarbonyl-; R5b is hydrogen, (C? -C4) alkyl, phenyl or phenylalkyl (C? -C4); R6a is alkyl (C? -C4), phenyl, phenylalkyl (C? -C4) - or phenyl- NH- is (C1-C4) alkyl, phenyl or phenylalkyl (C1-C4) R c is hydroxy, alkyl (C1- C4) C4), phenyl or phenylalkyl (C1-C4); R7 is hydroxy, (C1-C4) alkoxy, phenylalkoxy (C? -C4) or -NR5aR5b; where all radicals R5a, R5b, R6a, R6b, R6c and R7 if present more than once in the molecule, are independent of each other and can be identical or different; and where the phenyl present in the radicals Rla, Rlb, Rlc, Rld, R5a, R5b, R6a, R6b, R6c and R7 represents an unsubstituted phenyl radical or a phenyl radical substituted by one or two identical or different substituents selected from the series consisting of alkyl (C? -C4), F, Cl, Br , CF3, (C1-C4) alkoxy, N02, OH, NH2 and CN; one of the radicals R2 and R3 is - (CH2) p-CO-R8 and the other is hydrogen, F, Cl, Br, alkyl (C? ~ C4) or - (CH2) P) -CO-R8, or R2 and R3 together form a group of the formula -CH2-CH2-N (-CO-Rzu) -CH2- where > 20 is phenyl, phenyl (C? -C4) pyridyl or pyridylalkyl (C1-C4) and wherein each phenyl residue is unsubstituted or substituted by R15a and each pyridyl residue is unsubstituted or substituted at the nitrogen atom by R14; p is 0, 1 or 2; R8 is -NR9R10, or -OR10 or -S- (C1-C4) alkyl, where radicals R8, if present more than once in the molecule, are independent of each other and can be identical or different; R9 is hydrogen, (C? -C4) alkyl, hydroxycarbonylalkyl (Ci- C) -, (C1-C4) alkoxycarbonyl-(C1-C4) alkyl or aminocarbonylalkyl (C1-C4) -; R10 is hydrogen, (C1-C10) alkyl-, phenyl, naphthyl, phenylalkyl (C? -C4), naphthylalkyl (C? -C4), pyridyl or the radical Het, wherein the alkyl radical (C1-C10) and each radical phenyl and naphthyl is unsubstituted or substituted by one, two or three identical or different radicals R11, and where the pyridyl radical is unsubstituted or substituted at the nitrogen atom by R? , and where Het is unsubstituted or substituted for R, 15a or R9 and R10 together with the nitrogen atom where they are attached form a 5 or 6 membered saturated heterocyclic ring which may contain an additional nitrogen atom in the ring and which is unsubstituted or substituted by R15a or -CO-R7; Het is the radical of a saturated heterocyclic ring of 5 or 6 members containing 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; , 11 is -N (R12) 2, -OR12, -CO-N (R13) 2, -CO-R7, R15b, alkyl (C? Cu), phenyl unsubstituted or substituted by one, two three different R 15b identical radicals, naphthyl unsubstituted or substituted by one, two or three identical or different radicals R15, quinolinyl unsubstituted or substituted by one, two or three identical or different radicals, R15b and / or substituted on the nitrogen atom by R14, unsubstituted isoquinolinyl or substituted by one, two or three radicals R 15b identical or different and / or substituted at the nitrogen atom by R, 14, unsubstituted pyridyl either substituted on the nitrogen atom by R 14, or Het unsubstituted or substituted by R 15a, where the R 11 radicals are present more that once in the molecule, they are independent of each other and can be identical or different; each radical R12 independently of the denotation of another radical R12 is hydrogen, (C 1 -C 4) alkyl, phenyl, phenyl (C 1 -C 4) alkyl, naphthyl, naphthylalkyl (C 1 -C 4) -, pyrrolidinyl, piperidinyl, pyrrolidinyl (C 1 -C 4) alkyl - or piperidinylalkyl (C1-C4) -, wherein each pyrrolidinyl radical and each piperidinyl radical is unsubstituted or substituted on the nitrogen atom by phenylalkyl (C1-C4) or R15a; each radical R13 independently of the denotation of another radical R13 is hydrogen, (C? -C4) alkyl, phenyl, phenylalkyl (O.-C4), naphthyl or naphthylalkyl (C1-C4), or the two radicals R13 together with the The nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclic ring which may contain an additional nitrogen atom or an additional oxygen atom in the ring where the additional nitrogen atom in the ring is unsubstituted or substituted by alkyl ( C1-C4), or phenylalkyl (C1-C4); R 14 is (C 1 -C 6) alkyl, alkenyl (Ci-Ce), alkynyl (C 1 -C 6), phenylalkyl (Ci-Cß) - or (C 1 -C 6 alkoxy) carbonylalkyl (O-C 6) wherein the phenyl present in R14 refers to an unsubstituted phenyl radical, the substitution by these radicals in the nitrogen atom of the heterocyclic radical causes a positively charged group having X "as counter ion, or R14 is oxide, this substitution in the nitrogen atom of the heterocyclic radical causing an N-oxide, and where the radicals R14 if present more than once in the molecule, are independent of each other and can be identical or different, R15a is alkyl (C? -C6), ( alkyl (C? -C6) -C (= NH) -, - (CH2) t- N (R16) 2, - (CH2) t-N + (R16a) 2 (-0-), - (CH2) t- N + (R16a) 3X ", - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, wherein ((C? -C6) -C (= NH) - is attached to a ring nitrogen atom, and where the R15a radicals, if they are present s that once in the molecule, they are independent of each other and can be identical or different; R 15b is alkyl (C? -C6), hydroxy, (C1-C4) alkoxy, F, Cl, Br, I, N02, - (CH2) t-N (R16) 2, - (CH2) t-N + (R16a) 2 (-0-), - (CH2) t ~ + (R16a) 3X " (CH2) t-NHR > 1A7 - (CH2) t-C0-0R, 118B, - (CH2) t-CO-N (R1B) 2, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where alkyl may be substituted 1, 2, 3, 4, 5, 6 or 7 times per fluoro, and where the radicals R 1: 5b SI are present more than once in the molecule, are independent of each other and can be identical or different; t is 0, 1, 2 or 3, where the numbers t, if present more than once in the molecule, are independent of each other and may be identical or different; each radical R16a independently of the denotations of another radical R16 is hydrogen, alkyl (C? -C6), alkenyl (C6C6), alkynyl (C? -C6), phenylalkyl (C? -C6), or (alkoxy) (C? -C6)) carbonylalkyl (C? -C6) wherein the phenyl present in R16 represents an unsubstituted phenyl radical, and where groups containing radicals R16 if present more than once in the molecule, are independent of each other and can be identical or different; each radical R16a, independently of the denotations of another radical R16a is alkyl (C? -C6), alkenyl (C? -C6), alkynyl (C? -C6), phenylalkyl (C? -C6), or (alkoxy) Ci-C6) Jcarbonylalkyl (C? -C6), wherein the phenyl present in R16a refers to an unsubstituted phenyl radical, and where groups containing R16a radicals, if present more than once in the molecule, are independent of each other and they can be identical or different; each radical R independent of the denotation of another radical R17 is hydrogen, alkyl (C6C6), alkylcarbonyl (C6C6), alkoxycarbonyl (C6C6), alkylcarbonyloxy (C6C6), alkoxycarbonyl (Ci-Cß) -, phenylcarbonyl-, phenoxycarbonyl-, phenylalkoxycarbonyl (Ci-Ce), hydroxy, (C? -C6) alkoxy, phenylalkoxy (C? -C6) - or amino, and also in the - (CH2) groups t-C (= NR17) -NHR17 and - (CH2) t-NH-C (= NR17) -NHR17 the two radicals R17 together with the group C (= N) -NH to which they are attached, can form a ring 5 or 6 membered heterocyclic and wherein the phenyl present in R17 refers to an unsubstituted phenyl radical, and where groups containing R17 radicals if present more than once in the molecule, are independent of each other and may be identical or different; each radical R18 independent of the denotation of another radical R18 is hydrogen or (C1-C4) alkyl; A is a direct bond, a radical-saturated (C? -C4) -divalent alkyl or containing a double bond or a triple bond, -CO-, -Sor-, where r is 1 or 2, -CO-alkyl (C1-C4) -, -alkyl (C? -C4) -C0- or -alkyl (O.-C4) -CO-NH- where the nitrogen is attached to R4; R 4 is phenyl substituted by a radical R 15c and which may additionally be substituted by one or two substituents of the series consisting of (C 1 -C 4) alkyl, F, Cl and Br, or R 4 is unsubstituted or substituted pyridyl at the atom ) of nitrogen by R, 14, or R is the radical Het substituted by R15d; R15c is - (CH2) t-N (R16) 2, - (CH2) t-N + (R16a) 2 (-0"), - (CH2) t-N + (R16a) 3X", (CHa -NHR »117 - (CH2) t-CN, - (CH2) t-CS-N (R1B.} 2, - (CH2) tC (= NR17) - NHR1 'or - (CH2) t- NH-C (= NR p1 /). -NHR > 17 R 15d is (alkyl (d-Ce)) -C (= NH) -, - (CH 2) tN (R 16) 2, - (CH 2) t- N + (R 16a) 2 (-0 '), - (CH 2) t-N + (R16a) 3? -, - (CH2) t-NHR17r - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR1) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where ((C? -C6) alkyl) -C (= NH) - is attached on a ring nitrogen atom; X "is a physiologically acceptable anion, in all its stereoisomeric forms and mixtures thereof in any proportion, and its physiologically acceptable salts In general, residues or substituents which may occur more than once in the compounds of the formula I may all independently of one another have the indicated meanings, and can in all cases be identical or different.The alkyl radicals present in the compounds of the formula I can be straight or branched.This also applies in the case where they carry substituents or they occur as substituents in other radicals such as, for example, in alkoxy radicals, alkylcarbonyl radicals, alkoxycarbonyl radicals, or phenylalkyl radicals. alkyl radical such as alkyl (Ci-Ce) comprises alkyl radicals having 1, 2, 3, 4, 5 or 6 carbon atoms, an alkyl radical such as alkyl (Ci-Cio), furthermore alkyl radicals having 1, 8, 9 or 10 carbon atoms, an alkyl radical such as (C 1 -C 14) alkyl, furthermore alkyl radicals having 11, 12, 13 or 14 carbon atoms. Examples of alkyl radicals are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n -tridecyl, n-tetradecyl, isopropyl, isobutyl, isopentyl, isohexyl, isooctyl, neopentyl. 3-methylpentyl, sec-butyl, tert-butyl and tert-pentyl. A preferred group of alkyl radicals is formed from the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl radicals. Examples of fluorosubstituted alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl or 2,2,2-trifluoroethyl, particularly trifluoromethyl. In addition, as used herein, the term alkyl comprises acyclic alkyl residues such as alkyl residues that contain one or more acyclic ring systems. Thus, in addition to acyclic alkyl residues, the term "alkyl" also expressly comprises cycloalkyl radicals attached through a ring carbon atom, and cycloalkyl-alkyl radicals attached through a carbon atom in an acyclic subunit. This also applies when the alkyl radicals carry substituents or occur as substituents on other radicals such as, for example, alkoxy radicals, alkylcarbonyl radicals, alkoxycarbonyl radicals or phenylalkyl radicals. Cycloalkyl radicals representing the alkyl radicals or contained in alkyl radicals can be monocyclic or polycyclic, for example, monocyclic, bicyclic or tricyclic. Obviously, the term alkyl comprises only the cyclic radicals which are stable taking into account the number of carbon atoms present in the alkyl radical in question. As monocyclic alkyl, the radicals must contain at least three carbon atoms in the ring, an alkyl radical (C? -C), for example, also comprises monocycloalkyl radicals (C3-C4), an alkyl radical (C? -C6) it also comprises monocycloalkyl radicals (C3-Cß), an alkyl radical (O.-C10), also comprises monocycloalkyl radical (C3-C10) or an alkyl radical (C? -Cj.4) also comprises monocycloalkyl radicals (C3-C14) . Bicyclic and tricyclic alkyl radicals preferably contain 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Thus, (C1-C10) radical, for example, also comprising radicals bicycloalkyls (C6-C? O) and tricycloalkyl radicals (C6-C? O), or an alkyl (C1-C14) also comprising radicals bicycloalkyl (C6-C1) and tricycloalkyl radicals (Ce-Cu), both preferably comprising bicycloalkyl radicals and tricycloalkyl radicals having 7 or more carbon atoms. Examples of radicals or cyclic alkyl radicals alkyl substituted by alkyl, wherein the alkyl group regarded as a substituent is a cyclic radical, are cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclopropylhexyl, ciclopropilheptilo, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, Cyclobutyl butyl, cyclobutylpentyl, cyclobutylhexyl, cyclopentyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptyl, cyclooctyl, octahydroindenyl, bicyclo [4.2.0] octyl, octahydropentanyl, bicyclo [3.3.1] nonyl, tetradecahidrofenantrilo, dodecahidrofenalenilo, octahydro-1,4-ethano-indenyl, adamantyl or adamantylmethyl, wherein the ethyl, propyl, butyl, pentyl, hexyl and heptyl groups carrying the cyclic may be straight chain or branched in accordance with what is described above. The cyclic groups can be linked through any suitable carbon atoms. The radicals derived from bridged hydrocarbons may be linked through bridgehead carbon atoms or carbon atoms in the bridges. Adamantyl, for example, can be 1-adamantyl or 2-adamantyl.

The alkenyl radicals and alkynyl radicals can also be straight chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, 2-propenyl (= allyl), butenyl, 3-methyl-2-butenyl, pentenyl and hexenyl, examples of alkynyl radicals are ethynyl, 1-propynyl, 2-propynyl (= propargyl ), butynyl, pentynyl and hexynyl. The above observations relate to alkyl, alkenyl and alkynyl radicals and are correspondingly applied to alkyl radicals, alkenyl radicals and divalent alkynyl radicals, i.e. to alkylene radicals or alkandiyl radicals, alkenylene radicals, or alkenyl radicals and alkylenium radicals or radicals alkandiyl occurring, for example, in radical A which may be a saturated divalent alkyl radical or which contains a double bond or a triple bond. Examples of divalent alkyl radicals are methylene (CH2-), ethylmethylene (-CH (CH3) -), dimethylmethylene (-C (CH3) 2-), ethylene (-CH-> -CH2-), methylethylene (-CH ( CH3) -CH2- and -CH2-CH (CH3) -), trimethylene - (CH2) 3- or tetramethylene - (CH2) 4-, examples of unsaturated radicals are vinylene (-CH = CH-), 1-propenylene and 2-propenylene (-CH = CH-CH2- and -CH2-CH = CH-), 2-butylene (-CH2-CH = CH-CH2-), 2,3-dimethyl-2-butylene (-CH2-C) (CH3) = C (CH3) -CH2-), 1-propynylene and 2-propynylene (-C = C-CH2- and -CH2-C = C-), or 2-butynylene (-CH2-C = C -CH2-). In monosubstituted phenyl radicals, the substituent may be located in the 2-position, the 3-position or the 4-position, with 3 and 4 being preferred. If the phenyl is "doubly substituted, the substituents may be in the 2,3-position. , position 2,4, position 2,5, position 2,6, position 3,4, or position 3,5. In phenyl radicals bearing three substituents, the substituents may be in the position 2,3,4, position 2,3,5, position 2,3,6, position 2,4,5, position 2,4,6, or position 3,4,5. The naphthyl radicals can be 1-naphthyl and 2-naphthyl. In substituted naphthyl radicals, the substituents can be in any position, ie in 1-naphthyl radicals monosubstituted in the 2, 3, 4, 5, 6, 7, or 8 position and in 2-naphthyl radicals monosubstituted in the 1-position. , 3, 4, 5, 6, 7, or 8. Examples of pyridyl radicals are 2-pyridyl, 3-pyridyl and 4-pyridyl. Also a pyridyl radical present in a compound of the formula I is substituted at the nitrogen atom by an oxide -O "group, that is, if a pyridine N-oxide radical is present in a compound of the formula I it can be linked through position 2, position 3 or position 4 of the pyridine ring.This also applies to the pyridyl residues where the nitrogen atom is replaced by an alkyl group, etc., this substitution to a positively charged pyridinium group The quinolinyl and isoquinolinyl radicals can be 2-, 3-, 4-, 5-, 6- 7-, or 8-quinolinyl and 1, 3, 4, 5, 6, 7, or 8 isoquinolinyl, respectively The substituted quinolinyl and isoquinolinyl radical, the substituents may be present in any desired position, for example, in a monosubstituted 4-quinolinyl radical in the 2, 3, 5, 6, 7 or 8 position and in a radical 1 -isoquinolinium monosubstituted in the 3, 4, 5, 6, 7 u position 8. Likewise, if a quinolinyl or isoquinolinyl radical present in a compound of the formula I is substituted on the nitrogen atom by an oxide -O "group, that is, if a quinoline or isoquinoline N-oxide radical is present. it is present in a compound of formula I, it can be attached in any desired position. This also applies to quinolinyl and isoquinolinyl radicals wherein the nitrogen atom is replaced by an alkyl group, etc., this substitution causing the conformation of a quinolinium or isoquinolinium group positively charged. Groups of the type alkyl groups, phenyl groups, naphthyl groups, quinolinyl groups or isoquinolinyl groups occurring in groups of type R10 or R11 or representing groups of type R15b, they can preferably carry no more than two, particularly not more than one of the following groups - (CH2) tN (R16) 2, (CH2) t-N + (R16a) 2 (-0-), - (CH2) t -N + (R16a) 3? -, - (CH2) t-NHR17, - (CH2) t- CO-OR18, - (CH2) t-CO-N (R18) 2, - (CH2) t-CN, - (CH2) tC (= NR17) -NHR17 and - (CH2) t-NH-C (= NR17) -NHR17. Of the groups of alkyl (C6-C6), hydroxy, (C-C4) alkoxy, F, Cl, Br, I, N02, and alkyl substituted by fluoro which may be present as substituents on alkyl groups, phenyl groups, etc., of this type, may also be present more than one or more than two groups, for example, one, two or three identical or different groups, either in addition to the first groups listed - (CH2) tN (R16) 2 etc., or without one of the first listed groups present. Unless otherwise indicated, aryl groups such as phenyl or naphthyl present in the compounds of formula I can generally be unsubstituted or substituted in any of the desired positions by one or more, for example, one, two or three identical or different substituents, for example substituents such as (C 1 -C 4) alkyl such as methyl, or tert-butyl, hydroxy, (C 1 -C 4) alkoxy such as methoxy, ethoxy or tert-butoxy, methylenedioxy, ethylenedioxy, F, Cl, Br, I, cyano, nitro, trifluoromethyl, hydroxymethyl, formyl, acetyl, amino, monoalkylamino (C 1 -C 4) or dialkylamino (C 1 -C 4), (C 1 -C 4) alkylcarbonylamino, hydroxycarbonyl, (C 1 -C 4 alkoxy) -C4) carbonyl, carbamoyl, phenyl, benzyl, phenoxy or benzyloxy In general, no more than two nitro groups may be present in the compounds of the formula I.

Examples of the 5- or 6-membered saturated heterocyclic rings which can be formed by R9 and R10 together with the nitrogen atom to which they are attached are pyrrolidine, piperidine, pyrazolidin, imidazolidine, hexahydropyrimidine and piperazine. Substituents present in this ring may be attached at any position unless otherwise indicated. Examples of the 5 or 6 membered saturated heterocyclic rings which can be formed by the two radicals R13 together with the nitrogen atom to which they are attached are pyrrolidine, piperidine, piperazine or morpholine. Examples of Het are pyrrolidine, piperidine, perhydroazepine, tetrahydrofuran, perhydropyran, tetrahydrothiophene, perhydrothiopyran, pyrazolidine, imidazolidine, hexahydropyridazine, hexahydropyrimidine, piperazine, dioxolane, perhydrodioxane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, perhydro-1, 2-oxazine, perhydro- 1,3-oxazine, perhydro-1,4-oxazine (morpholine), perhydro-1,3-thiazine and perhydro-1,4-thiazine (thiomorpholine). Preferred Het groups include, for example, groups containing a nitrogen atom as a ring hetero atom such as pyrrolidine or piperidine. Substituents present in Het may be attached in any position unless otherwise indicated. A nitrogen atom present in Het can carry one or two substituents. When a ring nitrogen atom carries two substituents, that is, when it is quaternized, it is positively charged, and the compound of formula I also comprises therefore an anion X "as counterion In general, a Het group can carry one or more than one substituents, for example, one, two, three, four or five identical or different substituents, of the groups representing R15a which may be present as substituents in a Het group, preferably only one or two, particularly not more than one, of the groups (alkyl (C? -C6) -C (= H) -, - (CH2) tN (R16) 2, - (CH2) t-N + (R16a) 2 { -O "), ~ (CH2) t-N + (R16a) 3X ", - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t" CS-N (R18) 2, (CH2) tC (= NR17) -NHR17 and - (CH2) t-NH-C (= NR17) -NHR17 may be present as a substituent on Het while, for example, alkyl substituents (Ci-Cß) may be present once or more than once in Het, for example, one, two, three or four times, either without a substituent of the first group present or in addition to substituents of the first group. Similarly, a Het group representing R4 preferably bears only one of the radicals representing R15d. These comments apply correspondingly to substituents on other heterocyclic rings. Het groups and similar heterocyclic groups can, in general, be substituted by substituents such as for example alkyl (Ci-Cß) groups and also other substituents, for example, phenyl (C 1 -C 4) alkyl groups such as a benzyl group.

Examples of 5- or 6-membered heterocyclic rings which may be formed by two radicals R17 together with the group C (= N) -NH to which they are attached are 4,5-dihydro-1H-imidazole and 1,, 5, 6 tetrahydropyrimidine. Examples of the substituent (alkyl (Ci-Cß) -C (= NH) - attached on the ring nitrogen atom of a heterocycle are the acetimidoyl radical, ie the radical CH3-C (= NH) -, or radicals CH3-CH2-C (= NH) -, CH3-CH2-CH2-C (= NH) - or (CH3) 2CH-C (= NH) - The following is a list of some groups containing the substituent (alkyl (Ci-Cß) -C (= NH) - which may be present on the radicals R 2 and / or R 3 Similar groups may be present on the radical R *. The following groups correspond to the group R 8 in the definition of the compounds of the formula I and are attached to the group CO in the group - (CH2) p-CO-R8 through a nitrogen atom or an oxygen atom having a free bond which is indicated in the following formulas to through the line starting from an oxygen atom or an NH group In the following formulas, the substituent (alkyl (C? -C6)) -C (= NH) -is abbreviated as Aim-.

A radical represented by the formula (CH 2) 2 (-O ") is the radical of an amine oxide: X" physiologically acceptable anions present in the compounds of the formula I when a positively charged group is present as a quaternary ammonium group or a pyridinium, quinolinium or isoquinolinium group, may be anions derived from inorganic acids, organic carboxylic acids or suitable sulfonic acids. Suitable acids are, in particular, non-toxic acids or which can be used in a pharmaceutical field. Examples of such acids are those given below as examples of acids which can form physiologically acceptable salts with compounds of the formula I containing basic groups. If a compound of formula I contains an anion X "and is present simultaneously as an acid addition salt formed in a basic group, the anion X" may be the same or may be an anion other than the anion introduced by formation of Salt . Physiologically acceptable salts of the compounds of the formula I are, in particular, salts that are non-toxic or can be used in the pharmaceutical field. Such salts are formed, for example, from compounds of the formula I which contain acid groups, for example carboxylic acid or sulfonic acid groups. Examples of such salts are salts containing alkali metal or alkaline earth metal cations such as, for example, sodium, potassium, magnesium or calcium salts, or salts containing the unsubstituted ammonium anion NH4 + or organic ammonium cations, the latter including cations obtained from physiologically acceptable organic amines such as for example methylamine, ethylamine, triethylamine, ethanolamine, tris (2-hydroxyethyl) amine or amino acids by protonation, and suitable quaternary ammonium cations such as for example tetramethylammonium. Compounds of formula I which contain basic groups, for example one or more amino groups and / or amidino groups and / or guanidino groups, form acid addition salts with, for example, inorganic acids, organic carboxylic acids and organic sulfonic acids. Examples of such acids whose anions can be present in physiologically acceptable salts of the compounds of the formula I are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, maleic acid , fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acids. The present invention also encompasses internal salts, zwitterions or betaines of the compounds of the formula I.

Physiologically acceptable salts of the compounds of the formula I can be prepared according to standard procedures, for example, by combining the compound of the formula I with the desired base, for example, with an alkali metal hydroxide or carbonate or hydrogen carbonate or a amine, or with the desired acid in a solvent or diluent. A physiologically acceptable salt of a compound of the formula I can also be prepared from another salt by cation exchange or exchange of anions through standard procedures. In addition, the present invention also encompasses salts of the compounds of the formula I which are obtained, for example, during the chemical synthesis of the compounds and which are less suitable for the desired use of the compounds of the formula I but which can be used as starting materials for the subsequent preparation of a desired physiologically acceptable salt. The present invention also encompasses solvates of the compounds of the formula I, for example hydrates or alcoholates. The compounds of the present invention may be present in stereoisomeric forms. The present invention encompasses all possible stereoisomers. For example, the compounds of formula I according to the invention may contain optically active carbon atoms which, independently of each other, may have an R configuration or an S configuration. The compounds of formula I may therefore be present in the form of individual enantiomers or individual diastereomers or in the form of enantiomeric mixtures including racemates or diastereomeric mixtures. The present invention relates to both pure enantiomers and mixtures of enatomers in all proportions, and to pure diastereomers and to mixtures of diastereomers in all proportions. The invention encompasses mixtures of two stereoisomers as well as mixtures of more than two stereoisomers, and all proportions of stereoisomers in the mixtures. The compounds of the formula I can also be present as E isomers or Z isomers (cis isomers or trans isomers). The present invention relates both to pure E isomers and to pure Z isomers and to mixtures of E isomers and Z isomers, in all ratios. Diastereomers, including E / Z isomers, can be separated into the individual isomers, for example, by chromatography. Mixtures of enatomers, including racemates can be separated into the two enantiomers by chromatography in chiral phases or by resolution in accordance with standard procedures such as for example crystallization of diastereomeric salts obtained with auxiliary agents. Stereochemically pure compounds, for example pure enantiomers can also be obtained by The use in the synthesis of optically active initial materials, or by the use of stereoselective reactions. The compounds of the formula I according to the present invention can also contain mobile hydrogen atoms, that is, they can be present in various tautomeric forms. The present invention relates to all these tautomers. The present invention also encompasses derivatives of the compounds of formula I wherein functional groups are masked or protected by suitable groups, for example, by common protecting groups. Such functional groups are, for example, carboxylic acid groups which may be present as ester groups or amide groups, or groups containing acylatable nitrogen which may be present as acyl derivatives. The present invention also encompasses other derivatives and prodrugs of the compounds of the formula I which can be designed to increase the property profile of the compounds of the formula I and which can be prepared in accordance with techniques well known to a person skilled in the art. , and encompasses active metabolites of the compounds of the formula I. A specific group of compounds of the formula I is formed by the compounds where two of the residues Rla, Rlb, Rlc and Rld independently of each other are hydrogen, F, Cl, Br , I, alkyl (C? -C4), CF3, phenyl, phenylalkyl (C1-C4), alkoxy (d-? C4), phenyloxy-phenylalkoxy (C? -C4), OH, N02, -NR5aR5b, -NR5b-S02-R6b, -SOn-R6c where n is 1 or 2, -S02-NR5aR5b, -CN or - CO-R7 and the other two of the residues Rla, Rlb, Rlc and Rld are hydrogen; Rsa is hydrogen, (C 1 -C 4) alkyl, phenyl, phenylalkyl (C 4 -C 4), formyl, (alkyl, {C 1 -C 4)) carbonyl-, phenylcarbonyl-, phenyl (C 1 -C 4) alkylcarbonyl-, (C 1 -C 4) alkoxycarbonyl- or phenyl- ((C 1 -C 4) alkoxycarbonyl-; R 5b is hydrogen, (C 1 -C 4) alkyl, phenyl or phenyl (C 1 -C 4) alkyl; > 6a is (C 1 -C 4) alkyl, phenyl, phenyl (C 1 -C 4) alkyl- or phenyl- NH-; R6 * "is (C1-C4) alkyl, phenyl or phenylalkyl (C? -C4); r6c is hydroxy, (C1-C4) alkyl, phenyl or phenyl (C1-C4) alkyl; R7 is hydroxy, (C1-C4) alkoxy, phenyl (C1-C4) alkoxy- or -NR5aR5b; where all residues R5a, R5b, R6a, R6b, R6c and R7 if present more than once in the molecule, are independent of each other and can each be identical or different; the phenyl present in the radicals Rla, Rl, Rlc, Rld, R5a, R5b, R6a, R615, R6c and R7 denotes an unsubstituted phenyl radical or a phenyl radical substituted by one or more substituents selected from the series consisting of alkyl (dC4), F, Cl, Br, CF3, alkoxy. { C1-C4), N02, OH, NH2 and CN; one of the radicals R2 and R3 is - (CH2) p-CO-R8 and the other is hydrogen, F, Cl, Br, (C1-C4) alkyl or - (CH2) p-CO-R8, or R2 and R3 together form a group of the formula -CH2-CH2- \ N (-CO-R20.} -CH- where R20 is phenyl, phenyl (C1-C4) alkyl, pyridyl or pyridylalkyl (C1-C4) and where each phenyl radical is unsubstituted or substituted by R15a and each pyridyl radical is unsubstituted or substituted on the nitrogen atom by R14, p is 0, the right 2, R8 is -NR9R10 or -OR10, where radicals R8 if present more than once in the molecule, are independent of each other and can be be identical or different; R9 is hydrogen, (d-C4) alkyl, hydroxycarbonylalkyl (Ci- C4) -, (C1-C4 alkoxy) carbonylalkyl (C1-C4) or aminocarbonylalkyl (C1-C4); is hydrogen, alkyl (C? ~ C8), phenyl, naphthyl, phenylalkyl (d-C4) -, naphthylalkyl (d-C4) -, pyridyl or the radical Het, where the alkyl radical (C? -C8) and each phenyl and naphthyl radical is unsubstituted or substituted by one or two identical or different R11 radicals, and wherein the pyridyl radical is unsubstituted or substituted at the nitrogen atom by R14, and The Het is unsubstituted or substituted by R15a; or R9 and R10, together with the nitrogen atom where they are attached, form a 5- or 6-membered saturated heterocyclic ring which may contain an additional nitrogen atom in the ring and which is unsubstituted or substituted by R15a or -CO-R7; \ l.

Het is the residue of a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; R11 is -NHR12, -OR12, -CO-N (R13) 2, -CO-R7, R15fc, cyclohexyl, phenyl which is unsubstituted or substituted by R15b, unsubstituted naphthyl or substituted by R1 £ c, unsubstituted pyridyl or substituted at the nitrogen atom by R14, or Het is unsubstituted or substituted by R15a, where the R11 radicals, if present more than once in the molecule, are independent of each other and may be identical or different; R12 is hydrogen, pyrrolidinyl, piperidinyl, pyrrolidinylalkyl (C? -C) or piperidinylalkyl (C1-C4), wherein each pyrrolidinyl radical and each piperidinyl radical is unsubstituted or substituted on the nitrogen atom by phenylalkyl (C1-C4) or good R15a; each radical R13 independently of the denotation of another radical R13 is hydrogen, (C1-C4) alkyl or phenylalkyl (Ci-C4), or the two radicals R13 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 5 or 6 members which may contain an additional nitrogen atom or an oxygen atom in the ring where the additional nitrogen atom in the ring is unsubstituted or substituted by (C1-C4) alkyl or phenylalkyl (d-) \ C4) -; R 14 is alkyl (C? -C6), alkenyl (C? -C6), alkynyl (C? -C6) phenylalkyl (d-Ce), or (alkoxy (Ci-C?)) Carbonylalkyl (C? ~ Cß) ~ where the phenyl present in R14 indicates an unsubstituted phenyl radical, the substitution by these radicals in the nitrogen atom of the pyridyl radical leads to the formation of a pyridinium group having X ~ as counter ion; or R14 is this oxidation at the nitrogen atom of the pyridyl radical leading to a pyridine N-oxide; and where the R14 radicals if present more than once in the molecule, are independent of each other and can be identical or different; R15a is alkyl (d-C6), (alkyl (d-C6)) -C (= NH) -, - (CH2) tN (R16) 2, - (CH2) t-N + (R16a) 2 (-0- ), - (CH2) t-N + (R16a) 3-X ", - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2 ) t ~ C (= NR17) -NHR17 ~ or - (CH2) t-NH-C (= NR17) -NHR17, where (alkyl (C? -C6)) -C (= NH) - is attached to a ring nitrogen atom and where the radicals R 15a if present more than once in the molecule are independent of each other and may be identical different; R 15b is alkyl (d-C6), hydroxy, F, Cl, Br, - (CH2) t-N (Ri) 2, (CH2) t-N + (R16a) 2 (-0-), - (CH2) t-N + (R16a) 3XJ - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS -N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where the radicals R15b if present more than once in the molecule , they are independent among them and can be identical or different; t is 0, 1, 2 or 3, where the numbers t, if present more than once in the molecule, are independent of each other and may be identical or different; each radical R16, independently of the denotations of other radicals R16 is hydrogen, alkyl (Ci-Cß), alkenyl (C? -C6), alkynyl (C? -C6), phenylalkyl (Ci-Ce) or (alkoxy (C ? -C6)) carbonylalkyl (Ci-Ce), wherein the phenyl present in R16 refers to an unsubstituted phenyl residue and where groups containing R16 radicals if present more than once in the molecule, are independent of each other and can be identical or different; each radical R16a independently of the denotations of another radical R 16a is alkyl (d-Cß), alkenyl (Ci-Cß), alkynyl (C? -C6), phenylalkyl (Ci-Ce) or alkoxy (C? -C6) ) carbonylalkyl (C? -C6), where the phenyl present in R16a refers to an unsubstituted phenyl radical, and where groups containing R16s radicals if present more than once in the molecule are independent of each other and can be identical or different; each radical R17, independently of the denotation of another radical R17 is hydrogen, alkyl (C? -C6) -, alkylcarbonyl (Ci-Cß) -, alkoxycarbonyl (C? -C6) -, alkylcarbonyloxy (d-C6) -alkoxycarbonyl (C? -C6) -, phenylcarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl (C ? -C6) -, hydroxy, (C? -C6) alkoxy, phenylalkoxy (C? -C6), or amino, and furthermore in the groups - (CH2) t- C (= NR1) -NHR17 and - (CH2) t-NH-C (= NR17) -NHR17 the two radicals R17 together with the group C (= N) -NH to which they are attached can form a 5- or 6-membered heterocyclic ring and where the phenyl present in R17 refers to an unsubstituted phenyl radical, and wherein groups containing radicals R17 if present more than once in the molecule are independent of each other and may be identical or different; each radical R18 independently of the denotation of another radical R18 is hydrogen or (C1-C4) alkyl; A is a direct bond, -alkyl (C1-C4) -, saturated or containing a double bond or a triple bond, -CO-, -S0r ~, where r is 1 or 2, -CO-alkyl (C1-) C4) -, -alkyl (C1-C4) -CO or -alkyl (C1-C4) -CO-NH-, where the nitrogen is attached to R4; R 4 is phenyl substituted by R 15c and which may further be substituted by one or two substituents of the series consisting of (C 1 -C 4) alkyl, F, Cl and Br, or R 4 is unsubstituted or substituted pyridyl at the nitrogen atom by R14, or R4 is the residue Het substituted by R15d; R15c is - (CH2) tN (R16) 2, - (CH2) t-N + (R16a) 2 (-0"), - (CH2) t -N + (R16a) 3X", - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17; R 15d is. { alkyl (d-C6)) -C (= NH) -, - (CH2) tN (R16) 2, - (CH2) t- N * (R16a) 2 (-0-), - (CH2) t-N + (R16a) 3X ", - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS-N (RlS) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where ((C? -C6) alkyl) -C (= NH) - is attached to a ring nitrogen atom; X "is a physiologically acceptable anion; in all its stereoisomeric forms and mixtures thereof in any ratio and their physiologically acceptable salts. As in the case of any group of structurally related compounds possessing a particular generic utility, certain groups and configurations are preferred in the case of compounds of formula I in their end-use application. Preferred compounds of the formula I are the compounds wherein the radicals R > lb R and R independently from each other, are selected from the series consisting of hydrogen, methyl, F, Cl, Br, I, hydroxy, (C1-C4) alkoxy, (C1-C4) phenylalkoxy- and -NR5aR5b, particularly of the series consisting of hydrogen, methyl, F, Br, hydroxy, methoxy, benzyloxy and -NHR5a. Preferred compounds of the formula I are the compounds wherein three or the four radicals Rla, 1b > lc and R, lida are hydrogen. Preferred compounds of the formula I are the compounds wherein the radicals Rlc and Rlb are hydrogen.

Preferred compounds of the formula I are also the compounds wherein the radicals Rla and Rlb are hydrogen or one or two of the radicals Rla and Rlb are different from hydrogen. Especially preferred compounds of the formula I are the compounds wherein one of the radicals Rla and Rlb is hydrogen and the other of the radicals Rla and Rlb is hydrogen or is different from hydrogen. Especially preferred are compounds of formula I wherein one of the radicals R a and , 1b is selected from the series consisting of hydrogen, methyl, F, Br, hydroxy, methoxy, benzyloxy and -NHR5a and the other of the radicals Rla and Rlb as well as the radicals Rlc and Rld are hydrogen. Preferred compounds of the formula I are the compounds wherein the radical R5a is hydrogen or ((C 1 -C 4) alkoxy) carbonyl-, particularly hydrogen or tert-butyloxycarbonyl. Preferred compounds of the formula I are the compounds wherein the radical R5b is hydrogen. Preferred compounds of the formula I are the compounds in which one of the radicals R2 and R3 is - (CH2) p-C0-R8 and the other is hydrogen, F, Cl, Br, (C1-C4) alkyl or - (CH2) p) -CO-R8. Particularly preferred compounds of the formula I are the compounds wherein R3 is - (CH2) p-CO-R8, very particularly -CO-R8. Particularly preferred compounds of the formula I are also the compounds wherein R2 is hydrogen, Cl or Br. Especially preferred compounds of the formula I are the compounds wherein R 2 is hydrogen, Cl or Br and R 3 is - (CH 2) p-CO-R 8, particularly where R 3 is -C0-R 8. Preferred compounds of formula I are also compounds wherein p is 0 or 1, particularly 0. Preferred compounds of formula I are also compounds wherein R8 is -NR9R10 or -OR10, particularly -NR9R10. Preferred compounds of formula I are also compounds wherein R9 is hydrogen. Particularly preferred compounds of the formula I are the compounds wherein R2 is hydrogen, Cl or Br and R3 is -CO- NR3R ?? or -CO-ORlü, especially R3 is -C0-NR9R10, more especially R3 is -CO-NHR10. Preferred compounds of the formula I are the compounds in which R10 is alkyl (Ci-Cio), phenylalkyl (C1-C4) - or naphthylalkyl (C1-C4) -, where the alkyl radical (C1-C10), the phenyl radical and the naphthyl radical are unsubstituted or substituted by one, two or three identical or different R11 radicals, and particularly the (C1-C10) alkyl radical and the phenyl radical are substituted by one, two, three identical or different R11 radicals, and the naphthyl radical is unsubstituted or substituted by one, two or three radicals > n identical or different, and more particularly the radical [C1-C10] alkyl and the phenyl radical are substituted by one, two or three identical or different R11 radicals and the naphthyl radical is unsubstituted. Preferred compounds of the formula I are the compounds wherein R 11 is R 15b, (C 1 -C 14) alkyl, quinolinyl, isoquinolinyl or pyridyl, wherein quinolinyl, isoquinolinyl, and pyridyl are unsubstituted or substituted at the nitrogen atom by R 14. A (C1-C14) alkyl radical that represents > preferably has up to 12, more preferably up to 10 carbon atoms. Preferred compounds of the formula I are the compounds wherein R 14 is alkyl. . Preferred compounds of the formula I are the compounds wherein R15 is alkyl (Ci-Ce) where the alkyl radical may be substituted 1, 2, 3, 4, 5, 6 or 7 times per fluoro, or R15b is F, Cl , I, - (CH2) t-N + (RlßaJsX "or - (CH2) tC (= NR17) -NHR17 Preferred compounds of formula I are also compounds wherein t is 0 or 1, particularly 0, where the numbers t, if they are present more than once in the molecule, are independent of each other and are identical or different Preferred compounds of the formula I are the compounds wherein R? ea is alkyl (C? -C6), alkynyl ( d-C6) or phenylalkyl (C? -C6).

Preferred compounds of formula I are also compounds wherein R17 is hydrogen. Preferred compounds of formula I are also compounds wherein A is a divalent (C 1 -C 4) alkyl radical, particularly a saturated divalent (C 1 -C 4) alkyl radical. Particularly preferred compounds of the formula I are the compounds wherein A is the methylene radical -CH 2 -, Preferred compounds of the formula I are also the compounds wherein R 4 is phenyl substituted by a radical R 15c and which may be further substituted by one or two substituents of the series consisting of (C 1 -C 4) alkyl, F, Cl, and Br or R 4 is unsubstituted pyridyl or substituted on the nitrogen atom by R 14. Particularly preferred compounds of formula I are also compounds wherein R 4 is phenyl substituted by a radical R 15c, especially by a radical R 15c in the meta position or in the para position. Preferred compounds of formula I are also compounds wherein R15c is - (CH2) t-C (= NR17) -NHR17, particularly -C (= NR17) -NHR17. Further preferred are compounds wherein R15c is - (CH2) t-C (= NH) -NH2, particularly -C (= NH) -NH2. Particularly preferred compounds of the formula I are the compounds wherein R4 is phenyl substituted by -C (= NR19) -NHR17, especially the compounds of the formula I wherein R4 is phenyl substituted by -C (= NR17) -NHR17 at the position goal or \ in the position for, especially those substituted in the meta position. A preferred denotation of the radical R17 present in these groups R4 is hydrogen. Especially preferred compounds of formula I are compounds wherein two or more radicals are defined in accordance with that indicated above for preferred compounds of formula I, or the radicals may have one or more of the specific denotations of the radicals that are provide in their general definitions or in the definitions of the preferred compounds mentioned above. All possible combinations of given definitions for preferred definitions and specific denotations of radicals are explicitly a subject of the present invention. Also in relation to all the preferred compounds of the formula I, all their stereoisomeric forms and mixtures thereof in any ratio and their physiologically acceptable salts are explicitly a subject of the present invention, as well as their prodrugs. Similarly, also in all preferred compounds of formula I, all the radicals present more than once in the molecule are independent of each other and can be identical or different. The compounds of the formula I can be prepared by the use of methods and techniques known per se and which a person with ordinary skill in the art will be able to determine. Starting materials or building blocks for use in general synthetic procedures that can be applied to the preparation of the compounds of formula I are readily available to a person with ordinary knowledge in the art. In other cases they are commercially available or have been described in the literature. Otherwise, they can be prepared from readily available precursor compounds analogously to the processes described in the literature, or through procedures analogous to the methods described in this application. In general, compounds of the formula I can be prepared as, for example, in the course of a convergent synthesis, by linking two or more fragments that can be derived retrosynthetically from the formula I. More specifically, substituted indole derivatives suitably substituted are used as building blocks in the preparation of the compounds of the formula I. If they are not commercially available, such indole derivatives can be prepared in accordance with standard procedures either known for the formation of the indole ring system as for example by the synthesis of Fisol indole, the synthesis of Madelung indole, the synthesis of indole starting from N-chloroanilines and β-keto-sulphides described by Gassman et al., the synthesis of indole by Bischler, the synthesis of indole by Reissert, or the synthesis of indole by Nenitzescu. By choosing suitable precursor molecules, this indole synthesis allows the introduction of several substituents in the various positions of the indole system which can then be chemically modified in order to finally reach the molecule of the formula I having the desired pattern of substituent We make reference to the volume 25"índoles, Part \ One "(índoles, parte uno), WJ Houlihan (ed.), 1972, from the series" The Chemistry of Heterocyclic Compounds "(the chemistry of heterocyclic compounds), A. Weissberger and E. C. Taylor (ed.) , John Wiley &Sons, as one of the complete reviews where you can find numerous details and references of the literature on the chemistry of Indoles and on synthetic procedures for their preparation.Examples of the many indole derivatives available in the trade as appropriate Starting materials for the preparation of the compounds of the formula I are the following: The acids listed are commercially available in the form of free acids per se and / or as methyl or ethyl esters: acid indole-2-carboxylic acid, indole-3-carboxylic acid, indole-3-acetic acid, 3- (3-indolyl) -propionic acid, indole-2,3-dicarboxylic acid, 3-ethoxycarbonylmethyl-indole-2-carboxylic acid , 3-methyl-indole-2-carboxylic acid, ac 5-fluoroindole-2-carboxylic acid, 5-chloro-indole-2-carboxylic acid, 5-bromo-indole-2-carboxylic acid, 5-chloro-indole-2-carboxylic acid, 5-bromo-indole-2 acid - carboxylic, 5-methoxy-indole-2-carboxylic acid, 5- hydroxy-indole-2-carboxylic acid, 5,6-dimethoxy-indole-2-carboxylic acid, 4-benzyloxy-indole-2-carboxylic acid, acid 5- benzyloxy-indole-2-carboxylic acid, 6-benzyloxy-5-methoxy-indole-2-carboxylic acid, 5-methyl-indole-2-carboxylic acid, 5-ethyl-indole-2-carboxylic acid, methyl-indole-2-carboxylic acid, 4-methoxy-indole-2-carboxylic acid, 6-methoxy-indole-2-carboxylic acid, 4,6-dimethoxy-indole-2-carboxylic acid, 4,6-dichloro- indole-2-carboxylic acid, 5- nitro-indole-2-carboxylic acid, 5-methylsulfonyl-indole-2-carboxylic acid, 7-nitro-indole-2-carboxylic acid, 7-tert-butylcarbonylamino-indole-2-acid carboxylic acid, 7- (3-trifluoromethylbenzoylamino) -indol-2-carboxylic acid, 7- (4-methoxyphenylsulfonylamino) -indoic acid l-2-carboxylic acid, 5-bromo-3-methyl-indole-2-carboxylic acid, (3- (2-carboxyethyl) -6-chloroindole-2-carboxylic acid. If the initial indole derivatives are to be synthesized, this can be carried out for example, in accordance with the well-known indole synthesis mentioned above. The following are briefly explained, however, are standard procedures discussed widely in the literature, and are known to those skilled in the art.

The synthesis of Fischer indole comprises the cyclization of acid of phenylhydrazones, for example of the general formula which can be obtained through various methods and where R30, R31 and R32 and n can have a wide range of denotations. In addition to hydrogen and alkyl, R31 and R32 may especially indicate ester groups or methyl or ethyl groups bearing an ester group as a substitute, thus allowing the introduction into the indole molecule of the (CH2) P-CO portion occurring in the groups R2 and / or R3 in the compounds of the formula I. As examples of the many literature references describing the synthesis of indole derivatives in accordance with the Fischer synthesis, in addition to the book mentioned above published by Houlihan, the following are mentioned articles: FG Salituro et al., J. Med. Chem. 33 (1990), 2944; N.M. Gray et al., J. Med. Chem. 34 (1991); 1283; J. Sh. Chikvaidze et al., Khim. Geterotsikl. Soedin (1991), 1508, S.P. Hiremath et al., Indian J. Chem. 19 (1980), 770; J. Bornstein, J. Amer. Chem. Soc. 79 (1957), 1745. The synthesis of indole from Reissert comprises the reductive cyclization of o-nitrophenylpyrubic acids or esters thereof, for example of the general formula III, wherein the R30 groups may have a wide range of denotations and may be present in all positions of the benzene ring. The synthesis of indole by Reissert involves the formation of indole-2-carboxylic acid derivatives. The pyruvic acid derivatives of the formula III can be obtained by condensation of oxalic acid esters with substituted o-nitrotoluenes. As reference of literature, in addition to the book mentioned above edited by Houlihan and the literature articles mentioned here, mention is made, for example, of articles by H.G. Lindwall and G.J. Mantell, J. Org. Chem. 18 (1953), 345 or H. Burton and J. L. Stoves, J. Chem. Soc. (1937), 1726. According to Bischler's indole synthesis, alpha-anilinoketones, for example of the general formula IV, they can be cycled in indole derivatives. The indole synthesis of Nenitzescu offers a valuable route to indole-3-carboxylic acid derivatives bearing a hydroxy group in the 5-position. It comprises the reaction of para-benzoquinone with a β-aminocrotonate, for example of the compounds of the formulas V and VI.

SAW An additional route to specifically substituted indole derivatives proceeds through 2; 3-dihydroindoles (indolines) which can be easily obtained by reducing the indoles, for example by hydrogenation, or by cyclization of suitable phenylethylamine derivatives. The indolines can be subjected to several electrophilic aromatic substitution reactions that allow the introduction of several substituents into the benzene nucleus which can not be introduced directly by such reactions into the benzene nucleus of the indole molecule. The indolines can then be dehydrogenated in the corresponding indoles, as for example, with reagents such as chloranil or palladium together with a hydrogen acceptor. Again, details of this synthesis can \ found in the aforementioned book edited by Houlihan. Depending on the substituents of the initial materials, in a certain synthesis of indole, it is possible to obtain mixtures of positional isomers which, however, can be separated by modern separation techniques, such as for example HPLC preparation. Furthermore, in order to obtain the desired substituents in the benzene nucleus and in the heterocyclic nucleus of the indole ring system of the formula I, the functional groups introduced into the ring system during the synthesis of indole can be chemically modified. For example, indoles carrying a hydrogen atom in the 2-position or the 3-position can also be obtained by saponification and subsequent decarboxylation of the indoles carrying an ester group in the respective position. Groups of carboxylic acid and acetic acid groups in the 2-position and in the 3-position can be converted into their homologues by customary reactions for chain elongation of carboxylic acids. Halogen atoms can be introduced in position 2 or position 3, for example, by reacting the respective indolinone with a halogenating agent such as for example phosphorus pentachloride analogously to the method described by J. C. Poers, J. Org. Chem. 31 (1996), 2627. The initial indolinones for a synthesis of this type can be obtained from 2-aminophenylacetic acids. The starting indole derivatives for the preparation of the compounds of the formula I bearing a halogen substituent in the 3-position can also be obtained according to procedures described in the literature as the following. Chlorination of the ethyl ester of lH-indole-2-carboxylic acid in the 3-position by reaction with sulfuryl chloride in benzenes provides 3-chloro-lH-indole-2-carboxylic acid ethyl ester (Chem. Abstr. 1962, 3441i - 3442b). Ethyl ester of 3-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid can be synthesized analogously to J Het. Chem 33 (1996), 1627 by reaction of l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester with pyridinium bromide perbromide in pyridine. Especially the groups present in the benzene nucleus of the indole ring system can be modified by various reactions and consequently the desired Rla, Rlb, Rlc and Rld radicals can be obtained. For example, nitro groups can be reduced in amino group with various reducing agents such as for example sulfides, dithionites, complex hydrides or by catalytic hydrogenation. A reduction of a nitro group can also be carried out at a later stage of the synthesis of a compound of the formula I, and a reduction of a nitro group to an amino group can also occur simultaneously with a reaction performed in another functional group, for example when a cyano group type group reacts with hydrogen sulfide or when a group is subjected to hydrogenation. In order to introduce the radicals R5a, R5b and R6a-S02, amino groups can then be modified in accordance with standard procedures for alkylation, for example, by reaction with alkyl halides (substituted) or by reductive amination of carbonyl compounds , in accordance with standard procedures for acylation, for example, by reaction with activated carboxylic acid derivatives such as acid chlorides, anhydrides, activated esters or others either by reaction with carboxylic acids in the presence of an activating agent, or in accordance with standard procedures for sulfonylation, for example, by reaction with sulfonyl chlorides. Ester groups present in the benzene nucleus can be hydrolyzed in the corresponding carboxylic acids which after activation can react with amines or alcohols under standard conditions. Ether groups present in the benzene nucleus, for example, benzyloxy groups or other readily dissociable ether groups can be dissociated to provide hydroxy groups which can then react with various agents, for example, etherification agents or activating agents that allow the \ replacement of the hydroxy group by other groups. Sulfur-containing groups can react accordingly. The reactions mentioned above for the conversion of functional groups are generally described extensively in books on organic chemistry and in treaties such as Houben-Weyl, "Methodes der Organischen Chemie" (organic chemistry methods), Georg Thieme Verlag, Stuttgart , Germany, or "Organic Reactions" (organic reactions), John Wiley & Sons, New York, where you can find details about the reactions and primary source literature. Due to the fact that in the present case the functional groups are linked on an indole ring, in some cases it may be necessary to adapt the reaction conditions specifically or to choose specific reagents from several reagents that can be used in principle in a reaction of conversion, or otherwise take specific measures to achieve a desired conversion, for example, using protection group techniques. However, finding suitable reaction variants as well as suitable reaction conditions in such cases does not pose any difficulty to a person skilled in the art. The structural elements present in the radicals in the 1-position of the indole ring in the compounds of the formula I and in the group COR8 present in the 2-position and / or in the 3-position of the indole ring can be introduced in the initial indole derivative which is obtained in accordance with that indicated above by consecutive reaction steps such as those mentioned below using methods per se which are well known to a person skilled in the art. The radicals R8 which may be present in R2 and / or R3 may be introduced, for example, by the condensation of a corresponding carboxylic acid of the formula VII or a derivative thereof with a compound or with several compounds of the formula HR8, is say, with an amine of the formula HNR9'R10 'and / or with an alcohol of the formula HOR10' and / or with a mercaptan of the formula HS-(C1-C4) alkyl to provide a compound of the formula VIII. The compound of the formula VIII obtained in this way can easily contain the desired end groups, that is, groups R8 and R40 can be the groups R8 and RA- defined for the formula I, or optionally in the compound of the formula VIII obtained in this way, subsequently the radical or the radicals R8 and the radical R40 are converted to the radicals R8 and R4-A-, respectively, to provide the desired compound of the formula I.

Vile Thus, the radicals R and the radicals R and R 10 'contained herein may have the denotations of R, R and R10, respectively, given above or alternatively in the radicals R8', R9 and R10 'functional groups may also be present. in the form of groups which can subsequently be transformed into the final groups R8, R9 and R10, that is, functional groups can be present in the form of precursor groups or in the form of derivatives, for example, in protected form. Examples of precursor groups are cyano groups, which, in a subsequent step, can be transformed into carboxylic acid derivatives or by reduction into the aminomethyl groups, or nitro groups which can be transformed by reduction as catalytic hydrogenation into amino groups. The radical R40 in the compounds of formulas VII and VIII may indicate the group -A-R4 according to the above defined which must ultimately be present in the desired target molecule of formula I, or may represent a group which may subsequently be transformed into the group -A-R4, for example, a precursor group or a derivative. of the group -A-R4 wherein functional groups are present in protected form, or R40 may represent a hydrogen atom or a protective group for the nitrogen atom in the indole ring. Similarly, the radicals Rla, Rlb, Rle and Ria and the numbers p in formulas VII and VIII in accordance with that defined above, however for the synthesis of the compounds of formula I, these radicals can also in principle be present in the condensation step of a compound of Formula VII with a compound of formula HR8 to give a compound of formula VIII in the form of precursor groups or in protected form. The R41 radicals in the compounds of the formula VII which can be identical or different, can be, for example, hydroxy or (C1-C4) alkoxy, ie the COR41 groups present in the compounds of the formula VII can be, for example, example, the free carboxylic acids or esters thereof such as for example alkyl esters such as the groups COR8 in the compounds of the formula I. The groups COR41 may also be any other activated derivative of a carboxylic acid which allows the formation of amides, formation of esters or formation of thioesters with a compound of the formula HR8. The group COR41 can be, for example, an acid chloride, an activated ester such as, for example, a substituted phenyl ester, un-azole such as, for example, an imidazolide, an azide or a mixed anhydride, such as, for example, an anhydride mixed with an ester of carbonic acid or with a sulfonic acid, said derivatives can all be prepared from the carboxylic acid by standard procedures and can react with an amine, an alcohol or a mercaptan of the formula HR8 under standard conditions. A carboxylic acid group COOH representing COR41 in a compound of formula VII can be obtained, for example, from an ester group introduced into the indole system during an indole synthesis by standard hydrolysis procedures. Compounds of the formula I wherein a group COR8 is an ester group can also be prepared from compounds of the formula VII wherein COR41 is a carboxylic acid group by common esterification reactions such as by reaction of the acid with a low alcohol acid catalysis conditions, or alkylation of a salt of the carboxylic acid with an electrophile such as, for example, alkyl halide, or by transesterification with another ester. Compounds of the formula I wherein a group COR8 is an amide group can be prepared from amines and compounds of the formula VII wherein COR41 is a carboxylic acid group or an ester thereof through common amination reactions. Especially in the case of amide preparation, the compounds of formula VII wherein COR41 is a carboxylic acid group can be condensed under standard conditions with compounds of the formula HR8 which are amines through common coupling reagents employed in the synthesis of the peptides. Such coupling reagents are, for example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonyldiazoles such as for example carbonyldiimidazole and similar reagents, propylphosphonic anhydride, tetrafluoroborate of 0- ((cyano- (ethoxycarbonyl) -methylene) amino) -N, N, N ', N' -tetramethyluronium (TOTU) and many others. If in the compounds of the formula VII two identical groups COR41, for example two groups COOH, are present and only one of them must be condensed with the compound HR8 ', or if the two groups must be condensed with two different compounds HR8 , the condensation reaction must be adapted appropriately. Said adaptation is not a problem for an expert in the field. As reference on these reactions, we can mention, for example, Y. Miki, H. Hachiken and I. Yoshikawa, Heterocycles (Heterocycles) 45 (1997), 1143. The desired result can be achieved, for example, by the use of reagents and / or reaction conditions that allow a selective reaction of the two groups, or through the application of a strategy of protection groups. On this last case, one of the groups is protected selectively, for example, by transformation into an appropriate ester or in another protected form of a carboxylic acid, then the other group is condensed with the compound of the formula HR8, and then the first group it is unprotected and, if desired, reacts with a second compound of the formula HR8. However, different COR41 groups, for example an ester group and a free carboxylic acid group, can, however, be initially present in the initial indole derivative of formula VII used in the condensation reaction. If the radical R4-A- present in an indole of the formula I or the radical R40 present in an indole of the formula VII, or a radical in which functional groups within the radical R4-A- or R40 are present either in protected form or in the form of a precursor group, they have not already been introduced during a preceding step, for example during a synthesis of the indole nucleus, these radicals can, for example, be introduced into position 1 of the indole system by means of conventional in the literature well known to one skilled in the art of N-alkylation, N-arylation, N-acylation or N-sulfonylation of ring nitrogen atoms of heterocycles. The initial indole derivative to be used in such a reaction has a hydrogen atom in the 1-position. The alkylation N of a ring nitrogen atom can be carried out, for example, under standard conditions, preferably in presence of a base, using an alkylation compound of the formula R4-A-LG or of the formula R40-LG, where the atom in group A or in the group R40 linked to the group LG in this case is an atom aliphatic carbon of an alkyl moiety and LG is a labile group for example halogen such as chlorine, bromine or iodine, or a sulfonyloxy group, such as for example tosyloxy, mesyloxy or trifluoromethylsulfonyloxy. LG can also be, for example, a hydroxy group which, to achieve the alkylation reaction, is activated by a conventional activation agent. For the preparation of compounds wherein A is a direct bond and an aromatic group is directly attached at the 1-position of the indole system, conventional arylation procedures can be employed. For example, allyl fluoride, such as, for example, nitroaryl fluorides or cyanoaryl fluoride, can be used as arylating agents that advantageously allow the subsequent formation of an amino group. Such procedures are described, for example, in Tetrahedron Lett. 37 (1996), 299; Tetrahedron Lett. 36 (1995), 8387; Synth Common. 25 (1995), 2165; J. Med. Chem. 28 (1985), 66. A guanidino function present in a compound of the formula I can be introduced by conversion of an amino function which, for example, can be obtained by reducing a nitro function or a cyano function, using the following reagents: 1. O-methylisourea (S. Weiss and H. Krommer, Chemiker-Zeitung 98 (1974), 617-618) 2. S-methylisothiourea (RF Borne, ML Forrester and IW Waters, J. Med. Chem. 20 (1997), 771-776) 3. Nitro-S-methylisothiourea (LS Hafner and RE Evans, J. Org. Chem. 24 (1959), 1157) 4. formamidinosulfonic acid (K. Kim , Y.-T.L and HS Mosher, Tetra, Lett.29 (1988), 3183-3186) 5. 3,5-dimethyl-l-pyrazolylformamidinium nitrate (FL Scott, DG O'Donovan and J. Reilly, J. Amer. Chem. Soc. 75 (1953), 4053, 4054) 6. N, N'-di-tert-butyloxycarbonyl-S-methylisothiourea (RJ Bergeron and JS McManis, J. Org. Chem. 52 (1987) , 1700-1703) 7. N-alkoxycarbonyl-, N, N'-dialkoxycarbonyl-, N- alkylcarboni- and N, N'-dialkyl carbonyl-S-methylisothiourea (H. Wollweber, H. Kdlling, E. Niemers, A. Widdig, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim. Forsch./Drug Res. 34 (1984), 531-542). The amidines can be prepared from the corresponding cyano compounds with addition of alcohols, for example methanol or ethanol, in an anhydrous acidic medium, for example dioxane, methanol or ethanol, and by subsequent aminolysis, for example, treatment with ammonia in alcohols such as, for example, isopropanol, methanol or ethanol (G. Wagner, P. Richter and Ch. Garbe, Pharmazie (29 (1974), 12-55) .Additional methods of preparation of amidines are the addition of hydrogen sulfide. to a cyano group, followed by alkylation, for example, by methylation with a methyl iodide type agent, of the resulting thioamide and the subsequent reaction with ammonia (GDR Patent No. 235 866), or the addition of hydroxylamine which can be obtained from a hydroxylammonium salt with a base, to the cyano group followed by conversion of amidoxime to amidine, for example, by catalytic hydrogenation (see, for example, RP Mull et al., J. Med. Pharm. Ch em 5 (1962), 651; B. J. Broughton et al., J. Med. Chem. 18 (1975), 1117). Compounds of the formula I wherein a (C 1 -C 6) - C (= NH) - (C 1 -C 6) -alkyl group attached to a nitrogen atom is present can be prepared from a parent compound containing said nitrogen atom as a group NH, for example, through the following methods. The precursor compound containing the NH group reacts with a protected mono- or bis-benzyloxycarbonyl (Z) alkylamidine of the formulas ((C? -C6) alkyl) -C (= NH) -NH-Z or (C) alkyl ? -C6)) -C (= NZ) -NH-Z of which the bis-protected reagent is more reactive than the monoprotected reagent (Y. Sugimura et al., Heterocycles 24 (1986), 1331-1345; J. Eustache already.

Grob, Tetrahedron Lett. 36 (1995), 2045-2046). In another method, the precursor compound containing the NH group reacts with an imino ether such as, for example, of the formula ((C? -C6) alkyl) -C (= NH) -O- (C? -C alkyl) )) which in turn is available under standard conditions for a nitrile of the formula (alkyl (C? -C6)) -CN by addition of an alcohol in the presence of an acid. If two or more of the NH groups are present in the compound that is to react with the imino ether or the protected Z-alkylamidine protecting group, strategies can be employed to achieve the desired result, as the experts in the art know. The matter. An imino ether which can be considered as an active nitrile is also a versatile intermediate product in the case where it is prepared from a cyano group present in a compound which already contains the indole system and which has been obtained as an intermediate product during the synthesis of a compound of the formula I. For example, a cyano group present in the radical R40 is a compound of the formulas VII or VIII or another radical can be reacted according to standard procedures to provide an ester of imino. Said imino ester can be reacted, for example, with hydroxylamine to provide an amidoxime group, or it can be reacted with 1,2-diaminoethane to provide an imidazoline group, i.e., a substituent of 4,5-dihydro-lH-imidazole -2-ilo that is in place of the previous cyano group. Again, in reactions of this type as in all reactions used in the synthesis of the compounds of the formula I, depending on the individual case it may be favorable to avoid unwanted reactions by secondary reactions to apply protection group techniques and temporarily block such groups as, for example, amino groups or carboxylic acid groups through suitable protecting groups for the specific synthesis problem. Compounds of the formula I wherein a portion of amine oxide or a portion of pyridine N-oxide, portion of quinoline N-oxide or portion of isoquinoline N-oxide can be obtained by oxidation of the amines or of the nitrogen heterocycles according to standard procedures as described, for example, in J. March. Advanced Organic Chemistry, 3rd. edition, page 1088. The compounds of the formula I can also be prepared, for example, by the synthesis of the compounds, step by step, in a solid phase in accordance with customary methods of solid-phase chemistry, well-known on the from an expert in the art and which are illustrated in the following examples. Compounds of the formula wherein R2 and R3 in the formula I together form a group of the formula -CH2-CH2-N (-CO-R20) -CH2- can be prepared in accordance with the above procedures from appropriately substituted compounds of the formula IX commercially available or that can be prepared according to syntheses described in the literature or analogously to syntheses described in the literature. In the formulas la and IX, the radicals have the meanings defined above.

I As demonstrated in the pharmacological tests described below, the compounds of formula I inhibit the activity of factor Xa. They can therefore be used advantageously as pharmaceutical agents, especially when it is desired to reduce the activity of factor Xa or to produce effects that can be achieved by inhibiting the activity of factor Xa in a system, as for example by influencing the coagulation or inhibition of blood coagulation. Thus, the present invention also relates to the compounds of the formula I for use as pharmaceutical agents as well as to compounds of the formula I for use for 1-a production of drugs, especially drugs for the treatment or prophylaxis of conditions and diseases mentioned below and above. further, the present invention provides a method for specifically inhibiting factor Xa activity by contacting factor Xa with a compound of formula I, wherein a compound of the present invention inhibits the catalytic activity of factor Xa either directly, within of the prothrombinase complex either as a soluble subunit, or indirectly, by inhibiting the assembly of factor Xa in the prothrombinase complex. A preferred embodiment of the present invention comprises compounds of the formula I which can inhibit the activity of factor Xa with a Ki less than or equal to 100 μM, and, more preferably, a Ki less than or equal to 2 μM in accordance with that determined in the factor Xa assay described below. The inhibition of factor Xa activity or the production of effects achieved by said inhibition is carried out, for example, in vivo, that is, in an individual. As used herein, the term "individual" refers to a vertebrate, including a mammal such as a mouse, a rat, a rabbit, a dog, a pig and especially a human being, wherein factor Xa is involved in the coagulation cascade. It can also be carried out outside the body of an individual, for example, in an extracorporeal circulation or in the treatment of blood samples from an individual and generally in vitro. The in vitro uses of the compounds of the formula I are, for example, the use as a biochemical or reactive tool in scientific or analytical investigations or the use in in vitro diagnostics. In addition, a compound of the formula I can be used advantageously as an anticoagulant which can be brought into contact with a blood sample to prevent coagulation. For example, an effective amount of a compound of the formula I can be contacted with a freshly obtained blood sample to avoid coagulation of the blood sample. As used herein, the term "effective amount" when employed in this ratio means an amount of a compound of formula I that inhibits factor Xa activity to the extent desired. The person skilled in the art will recognize that an effective amount of a compound of the present invention can be determined using the methods disclosed herein or otherwise known in the art. Taking into account the disclosed utility of the compounds of the formula I, the person skilled in the art will also recognize that an agent such as for example heparin can be replaced with a compound of the invention. Said use of a compound of the formula I can result, for example, in an economic saving in comparison with other anticoagulants, or in a smaller number of side effects. In a further embodiment, the present invention provides a method for inhibiting factor Xa in a patient that requires such inhibition, comprising administering to said patient an effective inhibitory amount of factor Xa of a compound of formula I. used herein, the term "patient" refers especially to a warm-blooded animal that includes a mammal, and particularly a human being. A patient requires treatment to inhibit factor Xa when the patient suffers from a disease state that can be beneficially influenced by inhibition. of the activity of factor Xa or of which is expected "by the doctor who will be beneficially influenced by the inhibition of factor Xa activity." The identification of these patients who require treatment for the inhibition of factor Xa is found within The ability and knowledge of a person skilled in the art can be easily identified by a skilled physician, for example through the use of clinical tests, physical examination as well as medical / family history, patients who require such treatment. compound of the formula I can inhibit the activity of factor Xa, said compound can be used to reduce or inhibit blood coagulation in an individual. Thus, the present invention further provides a method for reducing or inhibiting the formation of blood clots in an individual, especially in a patient requiring such inhibition, by administering a therapeutically effective amount of a compound of formula I. "therapeutically effective amount" refers to the production in an individual of an inhibition or reduction effect of blood coagulation or an "effective factor Xa inhibitory amount" of a compound of formula I refers to the amount or dose of a compound of the formula I that must be administered to an individual in order to achieve or maintain the desired effect, or to inhibit the factor Xa activity in the individual to the extent desired. Said effective amount or dose to be administered must be adjusted to the individual circumstances in each case. It can be easily determined through the use of conventional techniques using the methods described herein or else methods known on the other hand, and by observing the results obtained in analogous circumstances. In determining the effective dose, numerous factors are considered including, but not limited to, the patient's species; your size, age, and general health status; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the pharmaceutical preparation administered; the selected dose regimen; and the use of concomitant medication. An appropriate dosage can be established employing clinical approaches well known in medicine. In general, taking into account the above factors, it is evident that the effective inhibitory amount of factor Xa or the therapeutically effective amount of a compound of the formula I will vary and can be varied within wide limits. Usually, an effective amount of a compound of formula I will vary from about 0.01 milligrams per kilogram of body weight per day (mg / kg per "" day) to about 20 mg / kg per day. A daily dose of about 0.1 mg / kg to about 10 mg / kg is usually preferred. These data refer to an adult human being of approximately 75 kg of body weight. However, depending on the individual circumstances, it may be necessary to move up or down in relation to these given doses. Particularly, when relatively large amounts are administered, it may be favorable to subdivide the daily dose into several, for example 2, 3 or 4 sub-doses. A compound of the formula I can be administered to an individual for the treatment of various clinical conditions including, for example, the treatment and prophylaxis of cardiovascular disorders or associated complications, for example, with infection or surgical intervention. Examples of cardiovascular disorders include restenosis, for example restenosis after angioplasty, reocclusion prophylaxis, including reocclusion prophylaxis after lysis or dilatation (PTCA), conditions after coronary bypass operations, arterial, venous and microcirculatory disease states, cardiac infarction, angina pectoris including unstable angina pectoris, thromboembolic diseases, thrombosis, embolism, respiratory depression syndrome of adults, multiorgan failure, stroke as well as disseminated disorders of intravascular coagulation. Examples of related complications associated with the surgical intervention include, for example, deep vein thrombosis and proximal vein, which may occur after surgical intervention. In general, a compound of the present invention is useful as a drug to reduce or inhibit or prevent unwanted blood coagulation or the formation of clots or thrombi in an individual. The compounds of the formula I, their physiologically acceptable salts and other suitable derivatives thereof such as for example prodrugs can be administered as drugs or pharmaceutical substances in the aforementioned methods of treatment or prophylaxis on their own, in mixtures with each other or in the form of of pharmaceutical compositions comprising, as an active ingredient, an effective amount of at least one compound of formula I and / or a physiologically acceptable salt and / or other suitable derivative thereof in admixture or in association of another type with a vehicle pharmaceutically acceptable. In treating a patient, compounds of the formula I or pharmaceutical compositions comprising them may be administered in any manner or mode which renders the compounds of the formula I bioavailable in effective amounts, including oral and parenteral routes. For example, they can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like. Oral administration is generally preferred but depending on the specific case, other modes of administration may also be favorable, for example, in the case of an acute stage of a disease, an intravenous administration through injection or infusion. A person skilled in the art will readily select the appropriate form and mode of administration according to the condition of the disease to be treated, the stage of the disease, and other relevant circumstances. Pharmaceutical compositions or drugs comprising a compound of the formula I and / or a physiologically acceptable salt and / or other suitable derivative can be made by the combination through standard procedures of the compounds of the formula I and / or their physiologically acceptable salts and / or other suitable derivatives thereof with one or more substances which are pharmaceutically acceptable carriers and / or auxiliary substances whose proportion and nature are determined according to the chosen administration route and standard pharmaceutical practice. The pharmaceutical compositions or drugs are prepared in a manner well known in the pharmaceutical industry. The pharmaceutical compositions will, in general, contain an effective amount of one or more compounds of the formula I * and / or their physiologically acceptable salt and / or other suitable derivatives, together with a suitable amount of a vehicle to form the appropriate dosage for administration to an individual. The pharmaceutical compositions can be adapted for oral or parenteral use and can be administered to the patient in the form, for example, of tablets, capsules, suppositories, solutions, suspensions, ointments, paints, nasal sprays, aerosol mixtures, implants, microcapsules or the like, as well , together with the claimed compounds of the formula I, the present invention offers useful pharmaceutical compositions or medicaments for inhibiting the activity of factor Xa, for inhibiting blood coagulation and for the treatment and prophylaxis of the aforementioned diseases in an individual. The present invention also encompasses a process for the preparation of pharmaceutical compositions or medicaments comprising at least one compound of the formula I and / or a physiologically acceptable salt and / or other suitable derivative, as well as encompasses the use of the compounds of the formula I and / or physiologically acceptable salts and / or other derivatives suitable for the preparation of drugs, especially drugs for the treatment or prophylaxis of the aforementioned diseases. A pharmaceutically acceptable carrier and auxiliary substances are known as substances or compositions that are not toxic to an individual or have an acceptable toxicity as determined by the appropriate regulatory agency. The carrier substance or excipient may be a solid, semi-solid, or liquefied material that can serve as a vehicle or medium for the active ingredient. As used herein, the term "pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutical carriers such as, for example, liquid carriers, eg, water, saline, phosphate buffered saline, emulsion such as for example oil / water emulsion or water / oil, or solid or semi-solid vehicles such as lactose, corn starch, fats, waxes, etc. Acceptable pharmaceutical carriers and their formulations are well known in the art and are described, for example, by Martin in Remington Pharmaceutical Sciences, 15th. edition, Mack Publishing Co., Easton 1975, which is incorporated herein by reference also with regard to other aspects of the ingredients and the preparation of pharmaceutical compositions. Examples of auxiliary substances are fillers, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors, flavoring agents, thickeners, diluents, regulatory substances, solubilizing agents, agents to achieve a release effect prolonged, salts to alter the osmotic pressure, coating agents, antioxidants, etc. X For the purpose of oral administration, the compounds of the formula I and / or their physiologically acceptable salts and / or other suitable derivatives can be incorporated with inert excipients or diluents or edible carriers and used in the form, for example, of tablets, coated tablets, tablets with films, pills , capsules, granules, solutions, suspensions, emulsions, elixirs, syrups, wafers, chewing gums and the like, or they can be enclosed in a gelatin capsule. The pharmaceutical compositions for oral administration may vary according to the particular form. Typically, such pharmaceutical compositions contain at least 1% of the active ingredient in the formula I and / or of a physiologically acceptable salt and / or other suitable derivative and can conveniently contain up to about 90% of the unit's weight. Preferably, the content of the compounds of the formula I and / or their physiologically acceptable salts and / or other suitable derivatives is from about 4% to about 70% by weight. Preferably, the amount of the active ingredient present in the compositions is such that a unit dosage form suitable for administration can be obtained. Tablets, pills, capsules, and the like may also contain, for example, one or more of the following vehicles and auxiliaries: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as for example starch or lactose, disintegrating agents such as for example alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide. In addition, sweetening agents such as sucrose or saccharin may be added or flavoring agents such as, for example, peppermint, methyl salicylate, and orange flavor. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other forms of dosage units may contain various other materials that modify the physical form of the dosage unit, for example, as a coating. Thus, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, for example, sucrose as a sweetening agent and certain preservatives, colorants and flavorings. For the purpose of parenteral administration, for example, the compounds of the formula I and / or physiologically acceptable salts and / or other suitable derivatives can be incorporated into a solution or a suspension. The solutions or suspensions may also include, for example, one or more of the following vehicles and auxiliaries: sterile diluents such as, for example, water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, and other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as, for example, ethylenediaminetetraacetic acid; regulators such as acetates, citrates or phosphates; agents for adjusting toxicity such as sodium chloride or dextrose. The content of the compounds of the formula I and / or their physiologically acceptable salt and / or other suitable derivatives in the parenteral administration preparations can \ vary. They usually contain at least 0.1% by weight of the compound of the formula I and / or of a physiologically acceptable salt and / or other suitable derivative and up to 90% by weight. Preferably, the content of the compound of the formula I and / or the physiologically acceptable salts thereof and / or other suitable derivatives thereof is from about 0.1% to 50%. Parenteral preparations can be enclosed, for example, in ampoules, disposable syringes, multi-dose vials made of glass or plastic, or infusion bottles. Suitable excipients for microcapsules, implants and rods are, for example, mixed polymers of glycolic acid and lactic acid. Generally, the amount of the compounds of the formula I and / or physiologically acceptable salts thereof and / or other suitable derivatives thereof present in a pharmaceutical composition is from about 0.5 mg to about 1, preferably about 1 mg a approximately 500 mg. In addition, one or more compounds of the formula I and / or one or more physiologically acceptable salts and / or one or more other suitable derivatives of the same active compounds of the pharmaceutical compositions according to the present invention may also contain one or more other compounds pharmacologically active. Any material used in the preparation of the various pharmaceutical compositions must be pharmaceutically pure \ and non-toxic in the amounts used. In another more general embodiment, the present invention offers compositions comprising at least one compound of the formula I and / or a salt thereof and / or another suitable derivative in mixture or in association of another type with one or more inert carriers. These compositions are useful, for example, as test standards, as convenient means for making bulk shipments, as pharmaceutical compositions or as starting materials for the production of pharmaceutical compositions. The amount of a compound of formula I in a composition of this type will generally vary from about 0.001% to about 90% by weight. Inert carriers can be any material that does not degrade or otherwise react covalently with a compound of formula I. Examples of suitable inert carriers are water; aqueous regulators, such as, for example, regulators generally useful in analysis High Performance Liquid Chromatography (HPLC); organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; as well as pharmaceutically acceptable vehicles and / or auxiliary substances. The compounds of the formula I can also be used as starting materials or as chemical intermediates in the preparation of other compounds, especially in the preparation of other pharmacologically active compounds. Examples of such conversions of compounds of the invention in other compounds of the invention are discussed above and are provided in detail below. For this use, in addition to the compounds of the formula I and their physiologically acceptable salts, other salts of the compounds of the formula I which are not suitable or which are less suitable for use as pharmaceutical agents may also be useful. Thus, the present invention also relates to compounds of the formula I and their salts in general as intermediate chemical products, especially as intermediates in the preparation of pharmacologically active compounds. An object of the present invention also relates to intermediates which are used in the synthesis of the compounds of the formula I described above and below, and to their use as intermediate chemical products, especially as intermediates in the preparation of pharmacologically active compounds. The following tests can be used to investigate the pharmacological activity and to illustrate the utility of the compounds of the present invention as factor Xa inhibitors. Test 1: In Vitro Inhibition of Selected Purified Coagulation Enzymes and other Serin Proteases. The ability of a compound of formula I to inhibit the Factor Xa, combine plasmin, elastase and trypsin can be evaluated by determining the concentration of the compound of formula I which inhibits the enzymatic activity by 50% (IC50) • Purified enzymes are used in chromogenic assays. To determine the inhibition constant Ki, the IC50 value is corrected for competition with substrate using the formula Ki = IC50 x (1 / (1 + ((substrate concentration) / substrate Km.).) Where km is the Michaelis constant -Menten (Chen and Prusoff, Biochem Pharmacol 22 (1973), 3099-3018 which is incorporated herein by reference, a) Factor Xa assay A TBS-PEG regulator (50 mM Tris-Cl, pH 7.8, 200 is used mM NaCl, 0.05% (weight / volume) PEG-8000, 0.02% (weight / volume) NaN3) for this assay IC50 is determined by combining in appropriate wells a medium-cost Costar microtiter plate of 25 μl of human factor Xa (Enzyme Research Laboratories, Inc., South Bend, IN) in TBS-P0EG, 40 μl 10% (volume / volume) DMSO in TBS-PEG (control not inhibited) or various concentrations of the compound to be tested diluted in 10% (volume / volume) ie DMSO in TBS-PEG, and substrate S-2765 (N (a) -benzyloxycarbonyl-D-Arg-Gli-L-Arg-p-nitroanilide; Kabi Pharmacia, Inc Franklin OH) in TBS-PEG. The assay was carried out by preincubation of the compound of formula I plus enzyme for 10 minutes. The assay is then started by the addition of substrate to obtain a final volume of 100μl. The initial velocity of the substrate chromogenic hydrolysis is measured by the change in absorbance at 405 nm using a Biotek Instruments kinetic plate reader (Ceres UV900HDÍ) at a temperature of 25 ° C during the linear portion of the temporal development (usually 1.5 minutes after of the addition of the substrate). The concentration of inhibitor causing a 50% decrease in substrate hydrolysis rate is predicted by linear regression after plotting the relative hydrolysis rates (as compared to the uninhibited control) versus the logarithm of the concentration of the compound of formula I. The enzyme concentration is 0.5 nM and the substrate concentration is 40 μM. b. Thrombin assay A TBS-PEG regulator is used for this assay. The IC50 is determined as above in the case of the factor Xa assay, except that the substrate is S-2366 (L-PyroGlu-L-Pro-L-Arg-p-nitroanilide, Kabi) and the enzyme is human thrombin (Enzyme Research Laboratories, Inc., South Bend IN). The enzymatic concentration is 175 μM. c. Plasmin assay For this assay, a TBS-PEG regulator is employed. IC 50 is determined in accordance with that described above for the factor Xa assay, except that the substrate is S-2251 (D-Val-L-Leu-L-Lys-p-nitroanilide, Kabi) and the enzyme is human plasmin ( Kabi). The enzyme concentration is 5nM and the substrate concentration is 300 μM. d. Trypsin Assay A TBS-PEG regulator containing lOnM CaC12 is used for this assay. The IC5o is determined in accordance with that described above in the factor Xa assay, except that the substrate is BAPNA (benzoyl-L-Arg-p-nitroanilide, Sigma Chemical Co., St. Louis MO) and the enzyme is pancreatic trypsin. bovine (Type XIII, treated with TPCK, Sigma). The enzyme concentration is 50nM and the substrate concentration is 300 μM. and. Elastase test For this test, a Tris-Cl buffer (pH 7.4, 300 mM NaCl, 2% (volume / volume) N-ethyl-pyrrolidone, 0.01% (weight / volume) NaN3) is used. The IC50 is determined in accordance with that described above for the assay for factor Xa, except that the substrate is succinyl-Ala-Ala-Ala-p-nitroanilide (Calbiochem-Nova Biochem Corp., San Diego CA) and the enzyme is human neutrophil elastase (Athens Research and Techonology, Inc., Athens GA). The enzyme concentration is 75nM and the substrate concentration is 600 μM. The control compound is "TENSTOP" methyl ester (N (a) -tosyl-Gly-p-amidinophenylalanine; American Diagnostica, Inc.; Greenwish CT), which is a reversible factor Xa inhibitor (Sturzebecher et al., Thromb Res. 54 (1989), 245-252; Hauptmann et al., Thromb. Haem. 63 (1990), 220-223, which are incorporated herein by reference). Test 2: Assays to Determine Coagulation Inhibition The effectiveness of the compounds of formula I can be evaluated by the in vitro prothrombin time (PT) assay using combined plasmas from human donors. An ex vivo assay can also be used where plasma is collected at various times after intravenous (iv) administration of a compound of formula I to rats or rabbits, or after intraduodenal (id) administration to rats, and using the analysis of the PT assay to determine the plasma half-life. The PT assay is initiated with a selected thromboplastin dilution to obtain an extended and highly replicated coagulation endpoint, known as the "diluted PT assay" as described below. The effectiveness of the compounds can also be determined using a rat arteriovenous thrombosis model in vivo, a. In Vitro Diluted Protombrine Time Assay 100 μl of preheated combined low human platelet (PPP) plasma (37 ° C) is added to a fibrometer cup (Baxter Diagnostics, Inc., McGaw Park IL). Add 50 μl of various concentrations of a compound of formula I in TBS-BSA with calcium (50 mM Tris-Cl, 100 mM NaCl, 0.1% (w / v) bovine serum albumin (BSA), 20 mM CaCl2) • In control experiments, TBS-BSA is added with calcium but without test compound of formula I for the measurement of coagulation time without inhibition. 150 μl of diluted preheated rabbit thromboplastin (Baxter) with calcium is added to the fibrometer cup and the fibrometer timer is started. A rabbit thromboplastin dilution curve is obtained before treatment with the compound and is used to choose a thromboplastin dilution that allows a PT time of approximately "30 seconds for non-inhibited controls. The experimental concentration that provides an inhibition of 50 % of coagulation (EC50) is calculated from the dilution curve times Alternatively, the diluted prothrombin time assay can be carried out using the "investigation" mode in an automated coagulation instrument Instrumentation Laboratories (IL) ACL3000 -plus (IL, Milan, Italy) Thromboplastin is diluted until a coagulation time of 30-35 seconds is reached.This coagulation time is taken as a 100% activity.A standard calibration curve is established by diluting the double series of diluted thromboplastin reagent (rabbit brain IL thromboplastin). e 50 μl (plasma separated by centrifugation) with 100 μl of thromboplastin reagent and nephelometric readings are taken in 169 seconds. The coagulation time is determined from the maximum light scatter exchange rate calculated by the instrument. Inhibition is expressed as a percentage activity as determined by comparison with the calibration curve. b. Ex vivo Live Diluted Prothrombin Time Assay A test compound of formula I is administered iv either through the tail vein (rat) or through the ear vein (rabbit) in accordance with a approved protocol. Blood samples of 1 volume of 1 ml are removed at measured intervals after administration of the test compound from a cannulated carotid artery (rat) or atrial artery (rabbit). After centrifugation to obtain PPP, the plasma is immediately stored on ice or frozen. For the determination of the diluted prothrombin time, the plasma is preheated and tested in accordance with what is described above. Percent inhibition is calculated from the thromboplastin dilution curve, which is handled with each series of samples, and which is used to determine the time in which approximately 50% of the initial anticoagulant activity remains in plasma (T? / 2). The test compound of formula I can also be administered to rats using an intraduodenal dosing protocol. Male Sprague-Dawley rats weighing approximately 300 g are anesthetized with a ketamine / xylazine combination administered subcutaneously following an approved protocol. The right carotid artery is cannulated to take blood samples. A laparotomy is performed and the duodenum is cannulated with a ball point needle and held in place to ensure that the suture is distal relative to the insertion site. An additional tie is placed near the insertion point to avoid leaking of gastric contents. The effectiveness of the suture to prevent a compound from reaching the site of the test insertion by pressure testing at the end of each experiment The insertion point at the end of each experiment The insertion point is at a distance of approximately 4 cm from the duodenal-gastric junction The compound is administered in 1 ml of normal saline A 0.7 ml blood sample is extracted before administration of the test compound of formula I and 15, 30, 60, 90 and 120 minutes after administration The plasma is separated by centrifugation and assayed for coagulation inhibition using the diluted prothrombin time assay. c. Rat Arteriovenous Bypass Thrombosis Model The antithrombotic efficacy of the compounds of the present invention can be evaluated using rat extracorporeal arteriovenous (AV) deviation. The AV deviation circuit consists of a 20 cm segment of polyethylene (PE) 60 tube inserted into the right carotid artery, a 6 cm segment of PE 160 tube containing a 6.5 cm segment of mercerized cotton thread (5). cm exposed to blood flow), and a second segment of PE 60 tube (20 cm) that completes the circuit in the left jugular vein. The entire circuit is filled with a normal saline solution before insertion. A test compound of formula I is administered by continuous infusion into the tail vein using a syringe pump and a butterfly-type catheter (infusion volume 1.02 ml / hour). The compound is administered for 30 minutes, then the detour is opened and the blood can flow for a period of 15 minutes (total of 45 minutes of infusion). At the end of the 15-minute period, the detour is stapled and the thread carefully removed and weighed on an analytical balance. Percent inhibition of thrombus formation is calculated using the thrombus weight obtained from control rats, which received the saline solution. Table 1 shows some inhibition constants Ki for the inhibition of factor Xa by example compound of the present invention. Inhibition constants were determined in accordance with what was described above (Test 1, a., Factor Xa Assay). Table 1: Ki values for factor Xa inhibition Example Ki (Xa) (μM) Example Ki (Xa) (μM) 2 0.10 97 1.60 4 0.090 101 7.9 6 0.40 103 1.7 13 55 106 0.04 13 110 1.1 21 (4) 4.8 112 0.013 23 7.0 115 0.009 24 0.11 \ 117 0.015 27 0.61 120 0.0048 0.009 121 0.13 39 0.007 124 0.025 47 0.007 125 0.009 56 0.082 132 2.0 58 0.014 133 0.05 77 0.009 137 0.011 78 0.21 141 0.72 81 63 146 0.013 84 0.90 149 3.3 87 110 loin is used here, the following terms have the indicated ignited ones: "g" refers to grams. v 'mmol "refers to millimoles," mM "refers to millimolar," ml "refers to milliliters," pf "refers to melting point," desc "refers to decomposition;" ° C "refers to degrees Celsius, "μl" refers to microliters, "nM" refers to non-molar, and "μM" refers to micromolar Examples The following examples present typical syntheses of the compounds of formula I. These examples are illustrative only and are not intended limit the scope of the present in any way The compounds of the examples were characterized by mass spectra (MS) and / or NMR spectra and / or melting points Example 1: Trifluoroacetic acid salt of 4- (trifluoroacetate { [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino.} - methyl) -1- ethylpyridinium 1. ) 1- (3-Cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester A solution of 1.9 g (10 mmol) of 1H-indole-2-carboxylic acid ethyl ester in 15 ml of dimethylformamide was treated with 1.2 g (10.5 mmol) of potassium tert-butoxide. The mixture was stirred at room temperature for 10 minutes to provide a clear solution. 2 g (10 mmol) of 3-cyano-benzyl bromide were added and the mixture was slowly heated to 100 ° C, cooled, acidified with acetic acid and poured into ice water. The precipitated product was removed by filtration and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized from methylene chloride / methanol to provide 2.5 g of colorless crystals with a melting point of 93-95 ° C. 2.) Acid - (3-Cyano-benzyl) -lH-indole-2-carboxylic acid A mixture of 0.61 g (2 mmol) of the ethyl ester of 1- (3-cyano-benzyl) -lH-indole-2- carboxylic acid, 25 ml of methanol, 2.5 ml of water, and 0.6 g of sodium hydroxide was heated at reflux for 15 minutes. The solvent was evaporated and the residue was partitioned between methylene chloride and 1 N hydrochloric acid. The organic phase was dried and evaporated. Recrystallization from methylene chloride / hexane gave 0.53 g of colorless crystals with a melting point of 226-228 ° C (decomposition). 3.) 1- (3-Cyano-benzyl) -N- [(4-pyridyl) methyl] -lH-indole-2-carboxamide A mixture of 300 mg of 1- (3-cyano-benzyl) -lH acid -indole-2-carboxylic previous, 20 ml of methylene chloride and 10 ml of thionyl chloride was heated to reflux for 4 hours. The solvent and excess reagent were evaporated, eventually azeotropically with toluene. The residue was dissolved in methylene chloride and the solution was treated with 0.3 ml of 4-aminomethylpyridine. The mixture was layered with a 10% aqueous sodium carbonate solution and vigorously stirred for 15 minutes. The organic layer was dried and evaporated and the residue was crystallized from ethyl acetate / ether to give 280 mg of colorless crystals with a melting point of 154-156 ° C. 4.) N- [(4-pyridyl) methyl] -1- [(3-thiocarbamoyl-phenyl) ethyl] -1H-indole-2-carboxamide. Hydrogen sulphide was introduced for 15 minutes in a solution cooled with ice water of 250 mg of the l- (3-cyano-benzyl) -N- [(4-pyridyl) methyl] -lH-indole-2-carboxamide above in 5 ml of pyridine and 4 ml of triethylamine. The mixture was stirred at room temperature for 18 hours in a sealed flask and then divided between toluene / pyridine and an aqueous solution of 10% sodium carbonate. The organic layer was dried and evaporated and the residue was crystallized from acetone / ether to provide 220 mg of light yellow crystals with a melting point of 197-200 ° C (decomposition).

. ) Trifluoroacetic acid salt of 4- (. {[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -methyl) -1-methylpyridinium trifluoroacetate A mixture of 220 mg of N- [(4-pyridyl) methyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 2 ml of dimethyl sulfoxide, 5 ml of acetone, and 0.5 ml of iodide of methyl was stirred in a sealed jar for 20 hours. The reaction mixture was diluted with toluene and evaporated. The residue was dissolved in acetone and the product was precipitated with ether. The solvents were decanted and the residue was stirred with fresh acetone / ether. The solids were separated and dried in vacuo. This material was dissolved in 20 ml of methanol and the solution was treated with 0.3 ml of acetic acid and 0.4 g of ammonium acetate. The mixture was heated at a temperature of 55-60 ° C for 2 hours in a sealed flask. The solvent was evaporated and most of the ammonium acetate was removed under high vacuum. The residue was lyophilized from acetonitrile / water 1: 1 containing 1% trifluoroacetic acid. Final purification by reverse phase HPLC gave the product with a retention time of 16.14 minutes and a correct molecular weight. Example 2: Trifluoroacetic acid salt of (RS) -4- (l- { [3-Amidino-benzyl] -lH-indole-2-carbonyl] -amino trifluoroacetate} -ethyl) -1-methylpyridinium 1. ) (RS) -1- (3-Cyano-benzyl) -N- [1- (4-pyridyl) -1-ethyl] -1H-indole-2-carboxamide A mixture of 280 mg of 1- (3-) acid cyano-benzyl) -lH-indole-2-carboxylic acid (example 1/2), 10 ml of methylene chloride, and 4 ml of thionyl chloride were heated at reflux for 4 hours. The solvent and excess reagent were evaporated, eventually azeotropically with hexane. This acid chloride was dissolved in methylene chloride and added to a mixture of 0.3 g of (RS) -1- (4-pyridyl) ethylamine hydrochloride, 20 ml of methylene chloride, and 0.5 ml of diisopropylethylamine. After stirring for 15 minutes, the reaction mixture was layered with 10% aqueous sodium carbonate and vigorously stirred for an additional 15 minutes. The organic layer was dried and evaporated and the residue was crystallized from ethyl acetate / ether to provide 300 mg of a colorless product with a melting point of 176-180 ° C. 2. ) (RS) -N- [1- (4-Pyridyl) -1-ethyl] -l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide. Hydrogen sulfide was introduced for 15 minutes in a solution cooled with ice water of 250 mg of the (RS) -l- (3-cyano-benzyl) -N- [1- (4-pyridyl) -1-ethyl] -lH-indole-2-carboxamide above in 5 ml of pyridine and 4 ml of triethylamine. The mixture was stirred at room temperature for 18 hours in a sealed flask and then evaporated. The residue was crystallized from acetone / ether to provide 220 mg of light yellow crystals with a melting point of 197-200 ° C (decomposition). 3.) Trifluoroacetic acid salt of (RS) -4- (1- {[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino trifluoroacetate} -ethyl) - 1-methylpyridinium A mixture of 200 mg of (RS) -N- [1- (4-pyridyl) -1-ethyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 1.5 ml of dimethyl sulfoxide, 5 ml of acetone, and 0.8 ml of methyl iodide was stirred in a sealed flask for 18 hours. The reaction mixture was diluted with toluene and evaporated. The residue was dissolved in acetone and the product was precipitated with ether. The solvents were decanted and the residue was stirred with fresh acetone / ether. The solids were separated, dried in vacuo, and dissolved in 20 ml of methanol. After the addition of 0.3 ml of acetic acid and 0.65 g of ammonium acetate, the mixture was heated to a temperature of 55 ° C in a sealed jar for 3 hours. The excess ammonium solvent and acetate were removed in vacuo and the residue was lyophilized from acetonitrile / water containing 1% trifluoroacetic acid. The crude material was purified by reverse phase HPLC to provide the desired product with 16.6 minute retention time and correct molecular weight. Example 3: 1- (3-Amidino-benzyl) -N- (4-amidino-benzyl) -lH-indole-2-carboxamide trifluoroacetic acid salt 1. ) 1- (3-Cyano-benzyl) -N- (4-cyano-benzyl) -lH-indole-2-carboxamide A mixture of 275 mg (1 mmol) of 1- (3-cyano-benzyl) -1H acid -2-carboxylic acid (example 1/2), 350 mg of diphenylphosphoryl azide, 200 mg of 4-cyano-benzylamine hydrochloride, 5 ml of dimethylformamide, and 0.4 ml of diisopropylethylamine was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was dissolved in methylene chloride. The solution was washed with IN hydrochloric acid and 10% aqueous sodium carbonate, dried and evaporated. The residue was passed on 10 g of silica gel using methylene chloride for elution. Crystallization from methylene chloride / hexane gave 310 mg of colorless crystals with a melting point of 160-162 ° C. 2.) 1- [(3-thiocarbamoyl-phenyl) methyl] -N- [4- (thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide A solution of 150 mg of the 1- (3-cyano- benzyl) -N- (4-cyano-benzyl) -lH-indole-2-carboxamide in 4 ml of pyridine and 2 ml of triethylamine was cooled in ice water and saturated with hydrogen sulphide. After stirring in a sealed container for 18 hours at room temperature, the solvent was evaporated and the residue was crystallized from acetone / methylene chloride / ether to give 180 mg of pale yellow crystals with a melting point of 225 -230 ° C (decomposition). 3.) Salt of trifluoroacetic acid 1- (3-Amidino-benzyl) -N- (4-amidino-benzyl) -lH-indole-2-carboxamide A mixture of 160 mg of 1- [(3-thiocarbamoyl-phenyl) ) methyl] -N- [4- (thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 5 ml of acetone, 1 ml of dimethyl sulfoxide, and 0.4 ml of methyl iodide was stirred at room temperature during 18 hours.

It was diluted with toluene and evaporated. The residue was stirred with acetone / ether and the solvent was decanted. The residue was dissolved in acetone / methanol and the product was precipitated by the addition of ether. The solids were removed by filtration, dried, and dissolved in 20 ml of methanol. The solution was treated with 0.3 ml of acetic acid and 0.6 g of ammonium acetate and the mixture was heated in a sealed flask for 3 hours at a temperature of 55 ° C. The solvent was evaporated and most of the ammonium acetate was removed under high vacuum. The residue was lyophilized from acetonitrile and water containing 1% trifluoroacetic acid. Purification by HPLC gave the title compound with a retention time of 17.46 minutes and the correct molecular weight. Example 4: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethyl-3-trifluoroacetate ammonium 1. ) 1- [3-Cyano-benzyl] -N- [4- (dimethylaminofenyl) methyl] -1H-indole-2-carboxamide A mixture of 275 mg (1 mmol) of 1- (3-cyano-benzyl) acid -1H-indole-2-carboxylic acid (example 1/2), 350 mg of diphenylphosphoryl azide, 250 mg of 4- (dimethylamino) benzylamine dihydrochloride, 5 ml of dimethylformamide, and 0.5 ml of diisopropylethylamine was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was dissolved in methylene chloride. The solution was washed with % aqueous sodium carbonate, dried and evaporated. Crystallization of the residue from methylene chloride / hexane gave 330 mg of colorless crystals with a melting point of 153-155 ° C. 2.) N- [4- (Dimethylaminophenyl) methyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide. Hydrogen sulfide was introduced into a solution cooled with ice water of 200 mg. 1- (3-Cyano-benzyl) -N- [4- (dimethylaenophenyl) ethyl] -lH-indole-2-carboxamide above in 5 ml of pyridine and 4 ml of triethylamine. The mixture was stored in a sealed bottle in the refrigerator for 3 days. The solvents were evaporated and the residue was crystallized from methylene chloride / ether / hexane to give 170 mg of a yellowish product with a melting point of 152-154 ° C. 3.) Trifluoroacetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -methyl) -phenyl] -trimethyl- trifluoroacetate. Ammonium A mixture of 160 mg of N- [4- (dimethylaminophenyl) methyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 5 ml of acetone, and 0.4 ml of methyl iodide, was stirred in a sealed flask for 18 hours at room temperature. The product was precipitated by the addition of ether and collected by filtration. The solids were washed with acetone / ether and dried. This material was dissolved in 10 ml of methanol and the solution was treated with 0.25 ml of acetic acid and 0.5 g of ammonium acetate. The mixture was heated at a temperature of 55 ° C for 3 hours in a sealed flask. The solvent was evaporated and the residue was lyophilized from acetonitrile and water containing 1% trifluoroacetic acid. Purification by HPLC gave the title compound with a retention time of 17.38 minutes and correct molecular weight. Example 5: Trifluoroacetic acid salt of 4- (. {[[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -ethyl-amino} -methyl) -1-methyl- trifluoroacetate pyridinium 1. 1- (3-Cyano-benzyl) -N-ethyl-N- [(4-pyridyl) methyl] -1H-indole-2-carboxamide A mixture of 276 mg of 1- (3-cyano-benzyl) - 1H-indole-2-carboxylic acid (example 1/2), 10 ml of methylene chloride, and 5 ml of thionyl chloride were heated at reflux for 4 hours. The solvent and excess reagent were evaporated, eventually azeotropically with hexane. The crystalline residue was dried in vacuo and dissolved in 20 ml of methylene chloride. (4-Etylaminomethyl) pyridine, 0.3 ml was added, and the mixture was layered with a 10% aqueous sodium carbonate solution and vigorously stirred for 15 minutes. The organic phase was dried and evaporated and the residue was subjected to chromatography on 13 g of silica gel using 30% acetone in methylene chloride for elution. The product (240 mg) was obtained in the form of a colorless viscous oil which was used in the next step. 2.) N-Ethyl-N- [(4-pyridyl) methyl] -l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide The above material was dissolved in 8 ml of pyridine and ml of triethylamine. The solution was saturated with hydrogen sulfide while it was cooled in ice water. The mixture was stirred in a sealed flask for 24 hours and then divided between toluene and an aqueous solution of 10% sodium carbonate. The organic layer was dried and evaporated and the residue was crystallized from acetone / hexane to provide 215 mg of light yellow crystals with a melting point of 180-184 ° C. 3.) Trifluoroacetic acid salt of 4- ( { [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -ethyl-amino} -methyl) -1-methyl- trifluoroacetate. pyridinium A mixture of 200 mg of N-ethyl-N- [(4-pyridyl) methyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 5 ml of acetone, 1 ml of dimethyl sulfoxide, and 0.7 ml of methyl iodide was stirred in a sealed flask for 20 hours at room temperature. The solvents were evaporated and the residue was stirred with ether. The solvent was decanted and the gum-like residue was stirred with acetone / ether. The solids were separated and dried. This material was dissolved in 20 ml of methanol and the solution was treated with 0.25 ml of acetic acid and 0.6 g of ammonium acetate. The mixture was heated at a temperature of 55 ° C for 3 hours in a sealed flask. The solvent was evaporated and the residue was lyophilized from acetonitrile and water containing 1% trifluoroacetic acid. Purification by HPLC provided a pure product with a retention time of 16.80 minutes and a correct molecular weight. Example 6: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino] -methyl) -benzyl] -trimethyl-ammonium trifluoroacetate 1.) 1- (3-Cyano-benzyl) -N-. { [4- (dimethylaminomethyl) phenyl] -methyl} -lH-indole-2-carboxamide A mixture of 275 mg (1 mmol) of 1- (3-cyano-benzyl) -1H-indole-2-carboxylic acid (example 1/2), 350 mg diphenylphosphoryl azide, 250 mg of 4- (dimethylaminomethyl) benzylamine dihydrochloride, 5 ml of dimethylformamide, and 0.2 ml of diisopropylethylamine was stirred at room temperature for 3 days. The solvent was evaporated and the residue was partitioned between methylene chloride and an aqueous solution of 10% sodium carbonate. The organic phase was dried and evaporated. The residue was stirred with ether / hexane to provide 240 mg of colorless crystals with a melting point of 127-128 ° C. 2.) N-. { [4- (Dimethylaminomethyl) phenyl] methyl} -l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide A solution of 240 mg of the 1- (3-cyano-benzyl) -N-. { [4- (dimethylaminomethyl) phenyl] -methyl} -IH-indole-2-carboxamide above in 5 ml of pyridine and 3 ml of triethylamine was saturated with hydrogen sulphide while cooling with ice water. The mixture was allowed to settle for 20 hours at room temperature in sealed jars. The solvents were evaporated and the residue was stirred with ether to give 200 mg of yellow crystals with a melting point of 120-125 ° C. 3.) Trifluoroacetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -methyl) -benzyl] -trimethyl- trifluoroacetate. Ammonium A mixture of 200 mg of N-. { [4- (dimethylaminomethyl) phenyl] -methyl} -l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 6 ml of acetone, 1 ml of dimethyl sulfoxide, and 0.8 ml of methyl iodide was stirred in a sealed flask for 20 hours. After evaporation, the residue was dissolved in acetone and the product was precipitated with ether. The solids were again precipitated from acetone with ether. After drying, the product was dissolved in 20 ml of methanol. The solution was treated with 0.3 ml of acetic acid and 0.6 g of ammonium acetate and the mixture was heated to a temperature of 55 ° C for 3 hours. The solvent was evaporated and the residue was lyophilized from acetonitrile / water containing 1% trifluoroacetic acid. The crude product was purified by HPLC to give the title compound with a retention time of 17.96 minutes and the correct molecular weight. Example 7: Trifluoroacetic acid salt of 4- (. {[[1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -ethyl) -1-methyl-pyridinium trifluoroacetate 1. ) 1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid methyl ester A solution of 0.96 g (5 mmol) of 5-fluoro-lH-indole-2-methyl acid methyl ester The carboxylic acid in 20 ml of dimethylformamide was treated with 0.6 g (5.25 mmol) of potassium tert-butoxide. The mixture was stirred at room temperature for 10 minutes to provide a clear solution. 1 g (5 mmol) of 3-cyano-benzyl bromide was added and the mixture was slowly heated to 100 ° C, cooled, acidified with acetic acid and poured into ice water. The precipitated product was removed by filtration and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized from methanol to give 1.3 g of colorless crystals with a melting point of 148-148 ° C. 2.) 1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid A mixture of 1 g of the methyl ester of l- (3-cyanobenzyl) -5-fluoro- 1H-indole-2-carboxylic acid, 30 ml of methanol, 3 ml of water, and 0.5 g of sodium hydroxide was heated at reflux for 20 minutes. The solvent was partially evaporated and the residue was acidified with 2N hydrochloric acid. The precipitated crystals were removed by filtration and dissolved in methylene chloride / 2-propanol. The solution was dried and evaporated and the residue was crystallized from acetone / hexane to give 0.9 g of colorless crystals with a melting point of 247-250 ° C (decomposition). 3.) 1- (3-Cyano-benzyl) -5-fluoro-N - [(4-pyridyl) ethyl] -1H-indole-2-carboxamide This compound was precipitated by the conversion of the above carboxylic acid into the acid and by its reaction with 4-aminomethylpyridine in accordance with that described in the case of the defluoro analogue in Example 1/3. It was crystallized from ethyl acetate / ether / hexane to give colorless crystals with a melting point of 160-162 ° C. 4.) 5-Fluoro-N- [(4-pyridyl) methyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide This thioamide was obtained by reaction of the above nitrile with sulfide of hydrogen in accordance with that described in example 1/4 for the defluoro analogue. It was obtained as a yellow crystalline solid from acetone with a melting point of 220-223 ° C. 5.) Trifluoroacetic acid salt of 4- ( { [1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) -1- methyl-pyridinium This compound was prepared in a similar manner by the treatment of 5-fluoro-N- [(4-pyridyl) methyl] -lH-indole-2-carboxamide with methyl iodide and subsequently with ammonium acetate in accordance with described in example 1/5. The product was purified by HPLC and had a retention time of 16.64 minutes and the correct molecular weight. Example 8: Trifluoroacetic acid salt of 4- (2. {[[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] amino] -ethyl-1-methyl-pyridinium trifluoroacetate 1. ) 1- (3-Cyano-benzyl) -N- [2- (4-pyridyl) ethyl] -lH-indole-2-carboxamide 1- (3-Cyano-benzyl) -lH-indole-2-carboxylic acid ( Example 1/2), .280 mg, was converted to the acid chloride through thionyl chloride in accordance with that described in Example 1/3. This acid chloride was added to a mixture of 300 mg of 2- (4-pyridyl) ethylamine dihydrochloride and 0.4 ml of diisopropylethylamine in methylene chloride. After stirring for 10 minutes, the mixture was layered with 10% aqueous sodium carbonate and stirred for an additional 10 minutes. The organic layer was dried and evaporated and the residue was subjected to chromatography on 12 g of silica gel using methylene chloride / acetone 1: 1 to provide 280 mg of resinous product. 2.) N- [2- (4-Pyridyl) ethyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide 1- (3-cyano-benzyl) -N- [2- (4-pyridyl) ethyl] -lH-2-carboxamide above was reacted with hydrogen sulphide in accordance with that described in Example 1/4. Crystallization from acetone / hexane gave 290 mg of yellowish crystals with a melting point of 208-210 ° C. 3.) Trifluoroacetic acid salt of 4- (2- {[[1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -ethyl) -1-methyl- trifluoroacetate. pyridinium A mixture of 250 mg of N- [2- (4-pyridyl) ethyl] -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 2 ml of dimethyl sulfoxide, 10 ml of acetone, and 1 ml of methyl iodide was stirred in a sealed flask for 20 hours. The reaction mixture was diluted with toluene and evaporated. The residue was dissolved in acetone and the product was precipitated with ether. The solvents were decanted and the residue was precipitated again from methanol with ether. The solids were separated and dried in vacuo. This material was dissolved in 25 ml of methanol and the solution was treated with 0.4 ml of acetic acid and 0.8 g of ammonium acetate. The mixture was heated at a temperature of 55-60 ° C for 2 hours in a sealed flask. The solvent was evaporated and most of the ammonium acetate was removed under high vacuum. The residue was lyophilized from acetonitrile / water 1: 1 containing 1% trifluoroacetic acid. Final purification by reverse phase HPLC gave the product with a retention time of 16.23 minutes and correct molecular weight. Example 9: Trifluoroacetic acid salt of 4 - [(. {L- [3- (Amino-phenyl) -2-propynyl] -lH-indole-2-carbonyl} -amino) -methyl trifluoroacetate] -1-methyl-pyridinium 1. ) 1- (2-Propynyl) -lH-indole-2-carboxylic acid methyl ester 1.25 g of potassium tert-butoxide was added to a solution of 1.75 g (10 mmol) of 1H-indole-2-methyl ester -carboxylic acid in 20 ml of dimethylformamide cooled to a temperature of 0 ° C. The mixture was stirred at this temperature for 10 minutes and treated with 2 ml of an 80% solution of propargyl bromide in toluene. After stirring for 1 hour at room temperature, the mixture was poured into ice water. The precipitated crystals were removed by filtration and dissolved in methylene chloride. The solution was dried and filtered on a plug of silica gel. The filtrate was evaporated and the residue was crystallized from hexane to provide 1.9 g of colorless crystals with a melting point of 88-90 ° C. 2.) 1- (2-Propynyl) -lH-indole-2-carboxylic acid A mixture of 1065 g (5 mmol) of 1- (2-propynyl) -lH-2-carboxylic acid methyl ether, 30 ml of methanol, 3 ml of water, and 0.4 g of sodium hydroxide was heated to reflux for 40 minutes. The solvent was partially evaporated and the residue was acidified with acetic acid and diluted with water. The precipitate was removed by filtration and partitioned between methylene chloride / ether and 1 N hydrochloric acid. The organic phase was dried and evaporated and the residue was crystallized from methylene chloride / hexane to give 0.87 g of colorless crystals with a spot of fusion of 190-193 ° C. 3.) 1- (2-Propinyl) -N- (4-pyridyl) ethyl-lH-indole-2-carboxamide A mixture of 0.5 g of the above 1- (2-propynyl) -lH-indole-2-carboxylic acid , 20 ml of methylene chloride, and 3 ml of thionyl chloride was heated at reflux for 3 hours. The solvent and excess reagent were evaporated, eventually azeotropically with hexane. The residue was dissolved in methylene chloride and added to a solution of 0.45 ml of 4-aminomethylpyridine in methylene chloride. The mixture was layered with 10% aqueous sodium carbonate and stirred for 15 minutes at room temperature. The organic layer was dried and evaporated, and the residue was passed on 15 g of silica gel using methylene chloride / ethyl acetate 1: 1 for elution. Crystallization from acetone / hexane gave 410 mg of crystals with a melting point of 147-148 ° C. 4. ) 1- . { 3- [4- (N-tert-butoxycarbonyl-amidino) phenyl] -2-propynyl} -N- [(4-pyridyl) methyl] -lH-indole-2-carboxamide A mixture of 290 mg (1 mmol) of 1- (2-propynyl) -N- (4-pyridyl) ethyl-1H-indole The above -2-carboxamide, 350 mg (1 mmol) of 4- (N-tert-butoxycarbonyl-amidino) -iodobenzene, 15 ml of acetonitrile, 1 ml of triethylamine, and 10 mg of cuprous iodide was degassed with nitrogen. Then 20 mg of palladium bistriphenylphosphine dichloride were added and the mixture was stirred in a sealed flask at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and an aqueous solution of 10% sodium carbonate. The organic layer was dried and evaporated and the residue was subjected to chromatography on 15 g of silica gel using methylene chloride / acetone 1: 1 for elution. The combined homogeneous fractions were evaporated to provide 225 mg of a yellowish resin that was employed in the next step. The 4- (N-tert-butoxycarbonyl-amidino) iodobenzene required for the coupling reaction was obtained in the following manner. 4-iodothiobenzamide A mixture of 2.1 g of 4-iodobenzamide, 30 ml of tetrahydrofuran, and 2 g of Lawesson's reagent was heated to reflux for 1 hour. It was divided between toluene and an aqueous solution of 10% sodium carbonate. The organic phase was dried and evaporated. The crude product was passed into a plug of silica gel using acetone / hexane 1: 1 for elution. Crystallization from methylene chloride / hexane chloride afforded 1.75 g of yellow crystals with a melting point of 163-165 ° C. 4- (N-tert-butoxycarbonyl-amidino) iodobenzene A mixture of the above 4-iodothiobenzamide, 20 ml of acetone and 0.7 ml of methyl iodide was stirred at room temperature for 18 hours. The precipitated crystals were collected and washed with ether to provide 2.7 g of yellow crystals of the iodide salt of the S-methylated thiobenzamide with a melting point of 213-215 ° C (decomposition). A mixture of 2.43 g (6 mmol) of this iodide salt, 1 ml of acetic acid, 50 ml of methanol, and 5 g of ammonium acetate was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was stirred with an aqueous solution of 10% sodium carbonate of 1 N sodium hydroxide. The precipitated crystals were collected and dried to provide 1.8 g of 4-iodobenzamide. A part of this material, 1 g, was dissolved in 20 ml of acetonitrile and stirred with 1 g of di-tert-butyl-dicarbonate and 5 ml of a 10% aqueous sodium carbonate solution for 1 hour at room temperature. The mixture was partitioned between methylene chloride. and water. The organic phase was dried and evaporated and the residue was crystallized from 2-propanol / water to leave 0.95 g of product with a melting point of about 185-190 ° C (decomposition) and resolidification with a melting point of >260 ° C. 5.) Trifluoroacetic acid salt of 4- [(. {1- [3- (4-Amidino-phenyl) -2-propynyl] -lH-indole-2-carbonyl} - a) - methyl] -1-methyl-pyridinium A mixture of 125 mg of l-. { 3- [4- (N-tert-butoxycarbonyl-amidino) phenyl} -2-propynyl] -N- [(4-pyridyl) methyl] -lH-indole-2-carboxamide, 5 ml of acetone, and 0.4 ml of methyl iodide was heated at a temperature of 55 ° C for 30 minutes. The solvent and excess reagent were evaporated and the residue was stirred with ether. The solids were collected and dried to provide 130 mg of product. Part of the material, 70 mg, was combined with 2 ml of trifluoroacetic acid. After standing at room temperature for 15 minutes, the solvents were evaporated and the residue was dissolved in 2-propanol and the solution was filtered. The filtrate was evaporated and the residue was stirred with ether. The separated solids were collected and dried to give 75 mg of the title compound having a retention time according to HPLC of 17.3 minutes and the correct molecular weight. Example 10: Trifluoroacetic acid salt of 4- (. {N- [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -N- (methoxycarbonylmethyl) -amino} -methyl) - 1-methyl-pyridinium 1. N- (4-Pyridylmethyl) glycine methyl ester dihydrochloride A mixture of glycine methyl ester hydrochloride (2.5 g, 20 mmol), 10 ml of acetic acid, 20 ml of 2-propanol, and 1.8 g (17 mmol) of 4-pyridinecarboxaldehyde was stirred at room temperature for 15 minutes. A sodium borohydride gel was added in small portions in a period of 15 minutes. After the addition, the mixture was stirred for an additional 30 minutes and then diluted with methylene chloride and made alkaline through the addition of concentrated ammonia and a 1 N sodium hydroxide solution. The organic phase was dried and evaporated. The residue was dissolved in methanol and the solution was treated with 4 N hydrogen chloride in dioxane. The separated crystals were collected, washed with ethanol and ether, and dried to provide 1.72 g of the product with a melting point of 194-196 ° C (decomposition). 2.) 1- (3-Cyano-benzyl) -N- (methoxycarbonylmethyl) -N- (4-pyridylmethyl) -1H-indo1-2-carboxamide 280 mg of 1- (3-cyano-benzyl) -lH- acid indole-2-carboxylic acid were converted to the acid chloride by thionyl chloride in accordance with that described in example 1/3.

This acid chloride was added to a mixture of 340 mg (1.5 mmol) of N- (4-pyridylmethyl) glycine methyl ester dihydrochloride and 0.4 ml of diisopropylethylamine in 20 ml of methylene chloride. After stirring for 10 minutes, the mixture was layered with 10% aqueous sodium carbonate and stirred for an additional 10 minutes. The organic layer was dried and evaporated and the residue was subjected to chromatography on 13 g of silica gel using methylene chloride / acetone 1: 1 to provide 300 mg of resinous product. 3.) N- (methoxycarbonylmethyl) -N- (4-pyridylmethyl) -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide 300 mg of 1- (3-cyano-benzyl) -N- (methoxycarbonylmethyl) -N- (4-pyridylmethyl) -lH-indole-2-carboxamide resinous was dissolved in 6 ml of pyridine and 3 ml of triethylamine. The solution was saturated with hydrogen sulfide while it was cooling in ice water. After stirring at room temperature overnight, the solvents were evaporated and the residue was dissolved in acetone and the product was precipitated by the addition of ether and hexane. The solvents were removed and the solids were dried under vacuum to provide approximately 300 mg of a yellow amorphous powder that was further reacted without purification. 4.) Trifluoroacetic acid salt of 4- (. {N- [1- (3-Amidino-benzyl) -lH-indole-2-carbonyl] -N- (methoxycarbonylmethyl) -amino} -methyl trifluoroacetate. pyridinium A mixture of 300 mg of crude N- (methoxycarbonylmethyl) -N- (4-pyridylmethyl) -1 - [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 10 ml of acetone, and 0.8 ml of methyl iodide was stirred in a sealed flask for 20 hours.The reaction mixture was diluted with toluene and evaporated.The residue was dissolved in acetone and the product was precipitated with ether.The solvents were decanted and the residue The mixture was stirred with acetone / fresh ether, the solids were separated and dried in vacuo, this material was dissolved in 20 ml of methanol and the solution was treated with 0.3 ml of acetic acid and 0.6 g of ammonium acetate. a temperature of 55 ° C for 2.5 hours in a sealed bottle.The solvent was evaporated and most of the ammonium acetate was removed in high vacuum. The residue was lyophilized from acetonitrile / water 1: 1 containing 1% trifluoroacetic acid. Final purification by reverse phase HPLC gave the product with a retention time of 16.75 minutes and correct molecular weight. Example 11: Trifluoroacetic acid salt of 4- (. {[[1- (3-Amidino-benzyl) -3-methoxycarbonyl-1H-indole-2-carbonyl] -amino} -methyl) -1- trifluoroacetate. methyl-pyridinium 1. ) Dimethyl ester of 1- (3-cyano-benzyl) -IH-indol-2,3-dicarboxylic acid A solution of 0.47 g (2 mmol) of lH-indole-2,3-dicarboxylic acid dimethyl ester in 10 ml of dimethylformamide was treated with 0.23 g (2 mmol) of potassium tert-butoxide. After stirring for 5 minutes, 0.4 g (2r mmol) of 3-cyano-benzyl bromide was added and the mixture was heated to a temperature of 95 ° C. After cooling, the mixture was partitioned between methylene chloride / hexane and an aqueous solution of sodium bicarbonate. The organic phase was dried and evaporated and the residue was subjected to chromatography on 15 g of silica gel using 10% ether in methylene chloride for elution. The clean fractions were combined and evaporated to leave 0.6 g of colorless resin. 2.) 1- (3-Cyano-benzyl) -3-methoxycarbonyl-1H-indole-2-carboxylic acid A mixture of 0.4 g of l- (3-cyanobenzyl) -lH-indole-2-dimethyl ester , 3-dicarboxylic acid, 20 ml of methanol, 2 ml of water, and 0.4 g of sodium hydroxide, which was heated to reflux for 5 minutes. The solvent was partially removed and the residue was diluted with water and acidified with 2 N hydrochloric acid. The precipitated acid was extracted with methylene chloride. The extracts were dried and evaporated. Crystallization of the residue from methylene chloride / ether / hexane gave 370 mg of colorless crystals. 3.) 1- (3-Cyano-benzyl) -3-methoxycarbonyl-N- (4-pyridylmethyl) -lH-indole-2-carboxamide A mixture of 200 mg of 1- (3-cyano-benzyl) -3 acid -methoxycarbonyl-1H-indole-2-carboxylic acid, 110 mg of 4-aminomethylpyridine, 210 mg of diphenylphosphoryl azide, 4 ml of dimethylformamide, and 0.3 ml of diisopropylethylamine were allowed to settle at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and an aqueous solution of 10% sodium carbonate. The organic layer was dried and evaporated and the residue was subjected to chromatography on 12 g of silica gel using 2: 2: 1 methylene chloride / ethyl acetate / acetone for elution. Crystallization from ethyl acetate / ether / hexane gave 170 mg of colorless crystals with a melting point of 152-154 ° C. 4.) 3-Methoxycarbonyl-N- [(4-pyridyl) methyl] -l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide A solution of 150 mg of 1- (3-cyano) -benzyl) -3-methoxycarbonyl-N- (4-pyridylmethyl) -lH-indole-2-carboxamide in 4 ml of pyridine and 2 ml of triethylamine was cooled in ice water and saturated with hydrogen sulphide. After settling in a sealed flask for 4 hours at room temperature, the solvents were evaporated, finally azeotropically with ethyl acetate. The residue was crystallized from methylene chloride / ether / hexane to leave 160 mg of a light yellow product which was used in the subsequent step. 5.) Trifluoroacetic acid salt of 4- ( { [1- (3-Amidino-benzyl) -3-methoxycarbonyl-1H-indole-2-carbonyl] -amino} -methyl) -1- methyl-pyridinium A mixture of 150 mg of 3-methoxycarbonyl-N- (4-pyridylmethyl) -1- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide, 10 ml of acetone, 1 ml of Dimethyl sulfoxide, and 0.6 ml of methyl iodide was stirred at room temperature for 18 hours. It was then diluted with ethyl acetate and evaporated. The residue was stirred with ether and the solvent was decanted.

The residue was precipitated from ethyl acetate with ether, collected and dried in vacuo. This material was dissolved in 15 ml of methanol, treated with 0.15 ml of acetic acid and 0.3 g of ammonium acetate, and heated to a temperature of 55 ° C for 2 hours. The solvent was evaporated and the residue was lyophilized from water containing 1% trifluoroacetic acid and acetonitrile (1: 1). HPLC purification afforded the title compound with a retention time of 16.2 minutes and the correct molecular weight. Example 12: Trifluoroacetic acid salt of 4- (. {[[1- (4-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -methyl) -1-methyl-pyridinium trifluoroacetate The starting material was prepared analogously to the isomer of position 3 described in example 1. 1.) 1- (4-Cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester This compound was obtained in the form of colorless crystals from methanol with a melting point of 106-107 ° C by alkylation of 1H-indole-2-carboxylic acid ethyl ester with 4-cyano-benzyl bromide 2.) 1- (4-Cyano- benzyl) -lH-indole-2-carboxylic acid This compound was prepared by alkaline hydrolysis of the above ester with methanol aqueous sodium hydroxide. Crystallization from methylene chloride / hexane provided colorless crystals with a melting point of 185-187 ° C. 3.) 1- (4-Cyano-benzyl) -N- (4-pyridylmethyl) -lH-indole-2-carboxamide This compound was obtained by reaction of the above acid with thionyl chloride and subsequently with 4- aminomethylpyridine and purified by chromatography on silica gel using methylene chloride / acetone 1: 1. Crystallized from ethyl acetate / hexane, the colorless crystals had a melting point of 128-131 ° C. 4.) N- [(4-Pyridyl) methyl] -l- [(4-thiocarbamoyl-phenyl) ethyl] -1H-indole-2-carboxamide This compound resulted from the reaction of the above nitrile with hydrogen sulfide and was obtained in the form of yellowish crystals from acetone / ethyl acetate / ether with a melting point of 176/180 ° C (decomposition). 5.) Trifluoroacetic acid salt of 4- ( { [1- (4-Amidino-benzyl) -lH-indole-2-carbonyl] -amino} -methyl) -1-methyl-pyridinium trifluoroacetate The compound was prepared according to the procedure of Example 1/5 by the reaction of N- (4-pyridylmethyl) -1- [(4-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide with methyl iodide and Subsequently with ammonium acetate. The product was purified by HPLC and had a retention time of 15.4 minutes and the correct molecular weight. Example 13: 1- [4-Amidino-benzyl] -lH-indole-2-carboxylic acid ethyl ester hydrochloride 1. ) Ethyl 1- (4-thiocarbamoyl-phenyl) ethyl-lH-indole-2-carboxylic acid ethyl ester A solution of 300 mg of l- (4-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester in 8 ml of pyridine and 4 ml of triethylamine was saturated with hydrogen sulfide while cooling in ice water. After stirring at room temperature overnight in a sealed flask, the reaction mixture was partitioned between toluene and 10% aqueous sodium carbonate. The organic phase was dried and evaporated. Crystallization of the residue from ether gave 0.3 g of yellow crystals with a melting point of 187-189 ° C. 2.) 1- [4-Amidino-benzyl] -lH-indole-2-carboxylic acid ethyl ester hydrochloride A mixture of 250 mg of l- (4-thiocarbamoyl-phenyl) methyl-lH-indole ethyl ester -2-carboxylic acid, 10 ml of acetone, and 1 ml of methyl iodide was stirred at room temperature for 20 hours. The precipitated crystals were removed by filtration, washed with ether, and dissolved in 10 ml of methanol. The solution was treated with 0.2 ml of acetic acid and 0.5 g of ammonium acetate, and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between methylene chloride / 2-propanol and a 1 N sodium hydroxide solution. The organic phase was dried and evaporated. The residue was treated with hydrogen chloride in ether and crystallized from ethanol / ether to leave colorless crystals with a melting point of 240-241 ° C. Example 14: 1- [3-Amidino-benzyl] -lH-indole-2-carboxylic acid ethyl ester hydrochloride 1. ) Ethyl 1- (3-thiocarbamoyl-phenyl) methyl-lH-indole-2-carboxylic acid ester This compound was obtained by the standard reaction (see example 13/1) of l- (3-cyanobenzyl) -lH-indole-2-carboxylic acid ethyl ester (example 1/1) with hydrogen sulfide. It was crystallized from ether / hexane to provide crystals yellow with a melting point of 124-126 ° C. 2.) 1- [3-Amidino-benzyl] -lH-indole-2-carboxylic acid ethyl ester hydrochloride This compound was prepared in a similar manner to example 13/2 by the reaction of ethyl ester of l- (3 -thiocarbamoyl-phenyl) methyl-lH-indole-2-carboxylic acid with methyl iodide and subsequently with ammonium acetate. The hydrochloride was crystallized from 2-propanol / ethyl acetate / ether to give colorless solvated crystals with a melting point of 136-140 ° C (decomposition). This compound had a retention time according to HPLC of 23.95 minutes and the correct molecular weight.

Example 15: 1- [3-Amidino-benzyl] methyl ester hydrochloride - fluoro-l-indol-2-carboxylic acid The starting material 5-fluoro-1- (3-thiocarbamoyl-phenyl) methyl-1H-indole-2-carboxylic acid methyl ester was obtained, similarly to example 13/1 from the acid methyl ester reaction. 1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (example 7/1) with hydrogen sulfide. It was crystallized from ether / hexane to provide a yellow crystalline powder that was directly converted to amidine in a manner analogous to Example 1/5. The title compound was prepared analogously to Example 1. The hydrochloride was crystallized from methanol / ether and yielded colorless crystals with a melting point of 235-237 ° C (decomposition). Example 16: Trifluoroacetic acid salt of 1- [3-Amidino-benzyl] -lH-indole-2,3-dicarboxylic acid dimethyl ester The initial material of l- (3-thiocarbamoylphenyl) methyl-1H-indole dimethyl ester -2,3-dicarboxylic acid was prepared analogously to example 13/1 by the reaction of 1- (3-cyano-benzyl) -1H-indole-2,3-dicarboxylic acid dimethyl ester (Example 11/1) with hydrogen sulfide. It was crystallized from ether / hexane to give yellow crystals with a melting point of 176-178 ° C. The product was converted to amidine analogously to example 1/5. Amidine was lyophilized from acetonitrile / water / trifluoroacetic acid and had a retention time in HPLC of 20.9 minutes and the correct molecular weight. Example 17: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -4-methoxy-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium 1) ncyl) -4-methoxy-1H-indole-2-carboxylic acid A solution of 1.025 g (5 mmol) of 4-methoxy-1H-indole-2-carboxylic acid methyl ester in 20 ml of dimethylformamide was treated with 0.6 g (5.25 mmol) of potassium tert-butoxide. The mixture was stirred at room temperature for 10 minutes to provide a clear solution. 1 g (5 mmol) of 3-cyano-benzyl bromide was added and the mixture was slowly heated to 90 ° C, cooled, acidified with acetic acid and poured into ice water and stirred to crystallize. The crystals were removed by filtration, washed with water and dissolved in methylene chloride. The solution was washed with a saturated solution of sodium bicarbonate, dried and evaporated and the residue was crystallized from methanol to give 1.3 g of colorless crystals with a melting point of 135-136 ° C. 2) 1- (3-Cyano-benzyl) -1,4-methoxy-1H-indole-2-carboxylic acid A mixture of 0.96 g (3 mmol) of 1- (3-cyano-benzyl) -4-methyl ester The above methoxy-lH-indole-2-carboxylic acid, 20 ml of methanol, 2 ml of water, and 0.5 g of sodium hydroxide were heated to reflux for 40 minutes. The mixture was diluted with water and extracted with ether / hexane. The aqueous phase was acidified with 2N hydrochloric acid and extracted with methylene chloride. The extracts were dried and evaporated. Crystallization of the residue from methylene chloride / hexane gave 0.87 g of colorless crystals with a melting point of 222-224 ° C (decomposition). 3) 1- (3-cyano-benzyl) -4-methoxy-N- [(4-dimethylaminophenyl) methyl] -lH-indole-2-carboxamide A mixture of 306 mg (lmmol) of acid 1- (3. cyano) -benzyl) -4-methoxy-1H-indole-2-carboxylic acid, 250 mg (1.12 mmol) of 4- (dimethylamino) benzylamine hydrochloride, 350 mg of difelnilphosphoryl azide, 0.5 ml of diisopropylethylamine, and 5 ml of dimethylformamide were stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between methylene chloride and an aqueous solution of 10% sodium carbonate. The organic layer was washed with dilute acetic acid and sodium bicarbonate. Dried and evaporated. The residue was passed on a plug of silica gel using 10% ethyl acetate in dichloromethane. Crystallization from ethyl acetate / hexane gave 330 mg (75%) of colorless crystals with a melting point of 138-140 ° C. 4) N- [4-dimethylaminophenyl) methyl] -4-methoxy-l- [(3-thiocarbamoyl-phenyl) ethyl] -lH-indole-2-carboxamide. Hydrogen sulphide was introduced for 15 minutes in a water-cooled solution. frost of 200 mg of l- (3-cyanobenzyl) -4-methoxy-N- [(4-dimethylaminophenyl) ethyl] -1H-indo1-2-carboxamide above in 65 ml of pyridine and 3 ml of tietrilamine. The mixture was stirred at room temperature for 18 hours in a sealed flask and then evaporated. The residue was passed on 10 g of silica gel using 20% acetate in dichloromethane and crystallized from ethyl acetate / hexane to give 150 mg (70%) of light yellow crystals with a melting point of 192. -193 ° C. 5) Trifluoroacetic acid salt of [4- ( { [1- (3-amidino-benzyl) -4-methoxy-lH-indole-2-carbonyl] -amino} - ethyl) -phenyl] trifluoroacetate] -trimethyl ammonium A mixture of 125 mg of N- [4-dimethylaminophenyl) methyl] -4-methoxy-1- [(3-thiocarbamoyl-phenyl) -methyl] -lH-indole-2-carboxamide, 10 ml of acetone, 1 ml of dimethyl sulfoxide, and 0.6 ml of methyl iodide was stirred in a sealed flask for 24 hours at room temperature. The mixture was diluted with ethyl acetate and evaporated. The residue was stirred with acetone / ether the solvent was decanted. The residue was dissolved in a small amount of methanol and the product was precipitated with ether, collected and dried. This material was dissolved in 15 ml of methanol and the solution was treated with 0.2 ml of acetic acid and 0.4 g of ammonium acetate. The mixture was heated at a temperature of 55 ° C for 3 hours in a sealed flask. The solvent was evaporated and the residue was lyophilized from acetonitrile and water containing 1% trifluoroacetic acid. Purification by HPLC gave the title compound with retention time of 17.6 minutes and a correct molecular weight. Example 18: Trifluoroacetic acid salt of [4- (. {[[1- (3-amidino-benzyl) -6-methoxy-1H-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium The starting material was prepared following the procedures described in Example 17. 1) 1- (3-Cyano-benzyl) -6-methoxy-1H-indo-1-carboxylic acid methyl ester This compound was obtained in a yield of 86%. % by alkylation of 6-methoxy-1H-indole-2-methyl ester. carboxylic acid with 3-cyano-benzyl bromide, and had a melting point of 152-153 ° C, was crystallized from methanol. 2) 1- (3-cyano-benzyl) -6-methoxy-1H-indole-2-carboxylic acid This compound was obtained in a 91% yield by means of alkaline hydrolysis of the above methyl ester and had a melting point of 225-227 ° C (decomposition), was crystallized from dichloromethane / hexane. 3) 1- (3-cyano-benzyl) -N- [(4-dimethylaminophenyl) methyl] -6-methoxy-lH-indole-2-carboxamide This compound was prepared in a 78% yield by coupling the above acid with 4-dimethylaminobenzylamine using diphenylphosphoryl azide and having a melting point of 156-158 ° C, was crystallized from ethyl acetate / hexane. 4) N- [(4-dimethylaminophenyl) methyl] -6-methoxy-l- [(3-thiocarbamoyl-phenyl) methyl] -lH-indole-2-carboxamide This compound was obtained in 93% yield by reaction of the anterior nitrile with hydrogen sulfide. It was crystallized from ethyl acetate / hexane to give yellow crystals with a melting point of 190-192 ° C. 5) Trifluoroacetic acid salt of [4- ( { [1- (3-amidino-benzyl) -6-methoxy-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] trifluoroacetate] -trimethyl ammonium A mixture of 150 mg of N- [4- (dimethylamphenyl) methyl] -6-methoxy-1- [(3-thiocarbamoyl-phenyl) -methyl] -lH-indole-2-carboxamide, 10 ml of acetone, 1 ml of dimethyl sulfoxide, and 0.7 ml of methyl iodide was stirred in a sealed flask for 20 hours at room temperature. The mixture was diluted with ethyl acetate and evaporated. The residue was dissolved in acetone / ethyl acetate and precipitated with ether. The solvent was decanted and the residue was dissolved in a small amount of methanol and the product was precipitated with ether, collected, and dried. This material was dissolved in 20 ml of methanol and the solution was treated with 0.2 ml of acetic acid and 0.4 g of ammonium acetate. The mixture was heated at a temperature of 55 ° C for 2.5 hours in a sealed flask. The solvent was evaporated and the residue was lyophilized from acetonitrile and water containing 1% trifluoroacetic acid. Purification by HPLC gave the title compound with retention time of 17.5 minutes and a correct molecular weight. Example 19: Trifluoroacetic acid salt of 4- (dimethylamino) -benzylamide of 1- (3-amidino-benzyl) -lH-indole-3-carboxylic acid 1) 1- (3-cyano-benzyl) -lH-indole-3-carboxylic acid To a solution of 9 g (0.055 mol) of 3-indolecarboxylic acid in 200 ml of tetrahydrofuran, 3 g (0.122 mol) were added. of sodium hydride at a temperature of 0 ° C in portions. After 75 minutes at a temperature of 0 ° C, 10.7 g (0.055 mol) of 3-cyanobenzyl bromide were added. After stirring for 16 hours at room temperature, the precipitate was removed by filtration, dissolved in water, and precipitated by the addition of hydrochloric acid to provide 13 g (86%) of the desired product. Melting point: 226-228 ° C. MS: 277.2 (M + H +). 2) 1- (3-cyano-benzyl) -1H-indole-3-carboxylic acid 4- (dimethylamino) -benzylamide The compound was prepared from l- (3-cyano-benzyl) -lH-indole- 3-carboxylic acid, 4-dimethylaminobenzylamine, diphenylphosphoryl azide and diisopropylethylamine according to that described in example 3/1. The crude material was purified by chromatography on silica gel with toluene / ethyl acetate 5: 1 to provide the desired product in 32% yield. Melting point: 126- 128 ° C. MS: 409.3 (M + H +). 3) trifluoroacetic acid salt of 4- (dimethylamino) -benzylamide of 1- (3-amidino-benzyl) -lH-indole-3-carboxylic acid In a solution of 250 mg (0.612 mmol), 1- (3-cyano-benzyl) -1H-indole-3-carboxylic acid 4-dimethylamino-benzyl amide was bubbled in 10 ml of ethanol hydrogen chloride gas at a temperature of 0 ° C for 4 hours. The mixture was warmed to room temperature overnight and evaporated. The residue was dissolved in 10 ml of ethanol and liquid ammonia was added. The mixture was warmed to room temperature with stirring and evaporated. The crude material was purified by reversed phase chromatography on RPis material with water / ethanol / trifluoroacetic acid 6.5: 3.5: 0.1 to provide 180 mg (36%) of the desired product. Melting point 92-96 ° C. MS: 426.3 (M + H +). Example 20: Trifluoroacetate trifluoroacetic acid salt of [4-. { . { [1- (3-amidino-benzyl) -1H-indole-3-carbonyl] -amino} -methyl) -phenyl] -trimethyl-ammonium 1) [4- ( { [1- (3-cyano-benzyl) -lH-indole-3-carbonyl] -α-phenyl} -methyl) -iodide. phenyl] -trimethylammonium In a solution of 240 mg (0.611 mmol) of 1- (3-cyano-benzyl) -1H-indole-3-carboxylic acid (4-dimethylaminobenzyl) -amide (example 19/2) in 20 ml of acetone, 384 μl (6.11 mmol) of methyl iodide was added and stirred for 4 days at room temperature. The mixture was evaporated to provide 350 mg (quantitative yield) of the desired product. MS: 423.2 (M +). 2) trifluoroacetic acid salt of [4- (. {[[1- (3-amidino-benzyl) -1H-indole-3-carbonyl] -amino] -methyl) -phenyl] -trimethyl-ammonium trifluoroacetate. This compound was prepared from [4- (. {[[1- (3-cyano-benzyl) -lH-indole-3-carbonyl] -amino] -methyl) -phenyl] -triramethyl-ammonium iodide. by the use of hydrogen chloride and liquefied ammonia in accordance with that described in example 19/3. The crude material was purified by reverse phase chromatography on RPiß material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 to provide the desired product in a yield of 39%. Melting point: 177 ° C.

MS: 440.3 (M +). Example 21: Acetic acid salt of (R) -1- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid (1-phenyl-ethyl) -amide 1) 5-benzyloxy-l- (3-cyano-benzyl) -1H-indole-2-carboxylic acid ethyl ester 10 g (0.034 mol) of 5-benzyloxy-1H-indol-2-ethyl ester carboxylic acid in 100 ml of dimethylformamide and 976 mg (0.04 mol) of sodium hydride were added in portions. After 1 hour of stirring at room temperature, 797 mg (0.04 mol) of 3-cyano-benzyl bromide was added. The mixture was stirred at room temperature for 1.5 hours, neutralized with 2N hydrochloric acid, and extracted with methyl tert-butyl ether. The organic phase was dried and evaporated. The crude material was purified by flash chromatography on silica gel with heptane / methyl tert-butyl ether 12: 8 to provide the desired product in 84% yield. Melting point 98-102 ° C. MS: 441.2 (M + H +). 2) 5-benzyloxy-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 5-benzyloxy-l- (3-cyano-benzyl) -lH ethyl ester -indole-2-carboxylic acid and sodium hydroxide according to that described in example 1/2. The crude material was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 0.25 to provide the desired product in 83% yield. 1 H-NMR (MSO-de, 200HMz): lambda-5.11 (s, 2H, OCH 2); 5.88 (s, 2H, N-CH2); 7.04 (dd, 1H, aromatic H); 7.20-7.60 (m, llh, aromatic H); 7.70 (d, 1H, aromatic H). MS: 383.2 (M + H +). 3) (R) -5-benzyloxy-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid (1-phenyl-ethyl) -amide This compound was prepared from 5-benzyloxy-1-acid - (3-cyano-benzyl) -lH-indole-2-carboxylic acid and (R) (1-phenyl-ethyl) amide by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane to provide the desired product in 73% yield. Melting point: 169-170 ° C. MS: 486.3 (M + H +). 4) (R) -5-benzyloxy-1- (3-thiocarbamoyl-benzyl) -1H-indo-1-carboxylic acid (1-phenyl-ethyl) -amide The compound was prepared from (1-phenyl-ethyl) ) - (R) -5-benzyloxy-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid amide and hydrogen sulfide according to that described in example 1/4 to provide the desired product in a 55% yield. Melting point: 146-148 ° C. MS: 520.3 (M + H +). 5) Acetic acid salt of (R) -1- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid (1-phenyl-ethyl) -amide This compound was prepared from ( 1-Phenyl-ethyl) -amide of (R) -5-benzyloxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid, methyl iodide, and ammonium acetate in accordance with that described in example 1/5, but for methylation acetone was used as solvent and in the last step methanol and acetone were used as solvents. The crude material was purified by flash chromatography on silica gel with dichloromethane / methane / acetic acid 9: 0.25: 0.5 to provide the desired product in 28% yield. Melting point 72 ° C. MS: 503.3 (M + H +). Example 22: Acetic acid salt of 1- (3-amidino-benzyl) -lH-indole-2-carboxylic acid benzylamide 1) 1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid benzylamide The compound was prepared from l- (3-cyanobenzyl) -lH-indole-2-carboxylic acid (example / 2) and benzyl amine by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in Example 3/1. The crude material was purified by flash chromatography on silica gel with toluene / ethanol 19: 0.5 to provide the desired product in 97% yield. Melting point: 129-131 ° C. MS: 366.2 (M + M +). 2) 1- (3-amidino-benzyl) -lH-indole-2-carboxylic acid benzylamide acetic acid salt The compound was prepared from 1- (3-cyano-benzyl) -lH-indole benzylamide -2-carboxylic acid by using hydrogen chloride and liquid ammonia in accordance with that described in example 19/2. The crude material was purified by reverse phase chromatography on RP? 8 material with water / acetonitrile / ammonium acetate 6: 4: 0.1 to provide the desired product in a yield, 40%. Melting point: 266-268 ° C (decomposition). MS: 383.2 (M + H +). Example 23: Trifluoroacetic acid salt of (RS) -1- (3-amidino-benzyl) -lH-indole-2-carboxylic acid (4-pyridyl) benzylamide acid 1) (RS) -1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid- (4-pyridyl) -benzylamide This compound was prepared from l- (3-cyano-benzyl) ) -lH-indole-2-carboxylic acid (example "-s) and (RS) -alpha- (4-pyridyl) -benzyl amine by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in example 3/1 The crude material was purified by flash chromatography on silica gel with dichloromethane / ethanol 19: 0.25 to provide the desired product in a 43% yield, melting point 90-110 ° C. MS: 443.2 (M + H +). 2) trifluoroacetic acid salt of (RS) -1- (3-amidino-benzyl) -1H-indole-2-carboxylic acid α- (4-pyridyl) benzylamide This compound was prepared from alpha- ( 4-pyridyl) -benzylamide of (RS) -1- (3-cyano-benzyl) -1H-indole-2-carboxylic acid by the use of hydrogen chloride and liquid ammonia as described in example 19/3. raw material was purified by reverse phase chromatography in a RPis material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 to provide 13% of the desired product. Melting point: 88-92 ° C. MS: 460.3 (M + H +). Example 24: Trifluoroacetic acid salt of (RS) -4- ( { [1- (3-amidino-benzyl) -4-methoxy-1H-indole-2-carbonyl] amino] -phenyl-3-trifluoroacetate. methyl) -1-methyl-pyridinium 1) (RS) -1- (3-cyano-benzyl) -4-methoxy-lH-indole-2-carboxylic acid- (4-pyridyl) -benzylamide acid ester. This compound was prepared from acid (4). pyridyl) -benzylamide of (RS) -1- (3-cyano-benzyl) -1- (3-cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (example 17/2) and ( RS) -alpha- (4-pyridyl) -benzylamine by the use of diphenylformamide azide and diisopropylethylamine in accordance with that described in Example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 0.3 to provide the desired product in an 18% yield. MS: 473.2 (M + H +). 2) (RS) -4- (methoxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid- (4-pyridyl) benzylamide The compound was prepared from alpha (4) acid. (pyridyl) -benzylamide of (RS) -1- (3-cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid and hydrogen sulfide in accordance with that described in example 1/4 to provide the desired product with a yield of 78% MS: 507.1 (M + H +). 5) Trifluoroacetic acid salt of 4- (. {[1- (3-amidino-benzyl) -4-methoxy-lH- indole-2-carbonyl] -amino.}.-phenyl-methyl) -1-methyl-pyridine This compound was prepared from alpha- (4-pyridyl) -benzylamide of (RS) -4-methoxy-l- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid, methyl iodide, and ammonium acetate according to that described in example 1/5. The crude material was purified by flash chromatography on silica gel first using dichloromethane / methanol / trifluoroacetic acid 9: 1: 0.2 to provide a product described in example 54 and second 5: 1: 0.2 to provide the desired product (yield 20). %). Melting point 135 ° C. MS: 504.2 (M + H '). Example 25: Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (2- (4-hydroxy-phenyl) -ethyl) -amide 1. ) (1- (3-Cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (2- (4-hydroxy-phenyl) -ethyl) -amide This compound was prepared from l- (3 -cyano-benzyl) -4-methoxy-lH-indole-2-carboxylic acid (example 17/2) and 4- (2-aminoethyl) -phenol by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in the example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 0.1 to provide the desired product in the form of an oil with a yield of 74%. (M + H +). 2.) trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (2- (4-hydroxy-phenyl) -ethyl) a * nide compound was prepared from 1- (3-cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (2- (4-hydroxy-phenyl) -ethyl-amide by the use of hydrogen chloride and liquid ammonia in accordance with that described in Example 19/3. The crude material was purified by reverse phase chromatography on RPis material with dichloromethane / methanol / trifluoroacetic acid 14: 1.4: 0.1 to provide the desired product in 62% yield. % Melting point: 140-142 ° C. MS: 443.3 (M + H +) Example 26: Trifluoroacetic acid salt of 3-amidino-benzyl ester of 1- (3-Amidino-benzyl) -lH-indole -2-carboxylic 1. 3-cyano-benzyl ester of 1- (3-cyano-benzyl) -1H-indole-2-carboxylic acid This compound was prepared from ethyl ester of 1H-indole-2-carboxylic acid and 3-cyano-benzyl bromide by the use of sodium hydride in accordance with that described in Example 21/1, but this was carried out at a temperature of 100 ° C instead of being carried out at room temperature. The crude material was purified by flash chromatography on silica gel with heptane / ethyl acetate 5: 1 to provide 67% l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester (fraction 1). ) and 10% of the title compound (fraction 2). 10% yield. Melting point 119-120 ° C. MS: 392.1 (M + H +). 2.) Trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -lH-indole-2-carboxylic acid 3-amidino-benzyl ester This compound was prepared from 3-cyano-benzyl ester of 1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid by the use of hydrogen chloride and liquid ammonia in accordance with that described in example 19/3. The crude material was purified MPLC in RPis material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 to provide the desired product with a yield of 12%. Melting point: 258 ° C. MS: 426.2 (M + H +). Example 27: Trifluoroacetic acid salt of ((6-chloro-2-naphthyl) thl-methyl-piperidin-4-yl) -methyl) acid amide RS) -1- (3-Amidino-benzyl) -lH-indole-2- carboxylic 1. ) ((6-chloro-2-naphyl) - (l-methyl-piperidin-4-yl) -methyl) -amido acid (RS) -1- (3-Cyano-benzyl) -lH-indole-2- carboxylic This compound was prepared from l- (3-cyanobenzyl) -lH-indole-2-carboxylic acid (example 1/2) and amine from (RS) - (6-chloro-2-naphthyl) - (l) -methyl-piperidin-4-yl) -methyl by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in Example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 2 to provide the desired product in 58% yield. Melting point 141-145 ° C. MS: 547.2 (M + H +). 2.) Trifluoroacetic acid salt of ((6-chloro-2-naphthyl) - (1-methyl-piperidin-4-yl) -methyl) -amide acid (RS) -l- (3-Amidino-benzyl) - lH-Indole-2-carboxylic acid This compound was prepared from ((6-chloro-2-naphthyl) - (l-methyl-piperidin-4-yl) -methyl) acid (RS) -1- (3- cyanobenzyl) -lH-indole-2-carboxylic acid by the use of hydrogen chloride and liquid ammonia in accordance with that described in example 19/3. The crude material was purified by reverse phase chromatography on RPiß material with water / ethanol / trifluoroacetic acid 5: 5: 0.1 to provide the desired product in a 31% yield. Melting point 110-120 ° C. MS: 564.2 (M + H +). Example 28: Trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -lH-indole-2-carboxylic acid 4-chloro-benzylamide 1 . ) 1- (3-Cyano-benzyl) -1H-indo 1-2 -carboxylic acid 4-chloro-benzylamide This compound was prepared from l- (3-cyano-benzyl) -lH-indole-2- carboxylic acid (example 1/2) and 4-chloro-benzylamine by the use of diphenylphosphoryl azide and diisopropylethylamine in accordance with that described in example 3/1. The crude material was purified by flash chromatography on silica gel with toluene / ethanol 19: 0.065 to provide the desired product in 80% yield: melting point: 147-149 ° C. MS: 400.1 (M + H +) 2.) Trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -lH-indole-2-carboxylic acid 4-chloro-benzylamide This compound was prepared from 4-chloro-benzylamide of 1- ( 3-cyano-benzyl) -lH-indole-2-carboxylic acid by using hydrogen chloride and liquid ammonia in accordance with that described in Example 19/3 The crude material was purified by reverse phase chromatography in RPis material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 in the desired product in a yield of 74% Melting point 230 ° C (decomposition) MS: 439.3 (M + H +) Example 29: trifluoroacetic acid salt of trifluoroacetate of 4- ( { [l- (3-Amidino-benzyl) -4-methyl-lH-indole-2-carboxylic acid] -amino.} - methyl) -phenyl] -benzyl-dimethyl-am onio 1. ) 1- (3-Cyano-benzyl) -4-methyl-1H-indole-2-carboxylic acid ethyl ester This compound was prepared from 4-methyl-1H-indole-2-carboxylic acid ethyl ester and bromide of 3-cyanobenzyl by the use of sodium hydride in accordance with that described in example 21/1 to provide the desired product in a 70% yield. A-NMR (DMSO-de, 200 MHz): d = 1.29 (t, 3H, OCH2CH3); 2.52 (s, 3H, CH3); 4.29 (q, 2H, OCH2CH3); 5.88 (s, 2H, N-CH2); 6.97 (d, 1H, aromatic H); 7.12-7.32 (m, 2H, aromatic H); 7.34-7.55 (m, 4H, aromatic H); 7.69 (d, 1H, aromatic H). 2.) 1- (3-Cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid This compound was prepared from ethyl 1- (3-cyano-benzyl) -4-methyl- ethyl ester lH-indole-2-carboxylic acid and sodium hydroxide according to that described in example 1/2 to provide the desired product in 99% yield. Melting point 227-229 ° C. MS: 291.1 (M + H +). 3. ) (1- (3-Cyano-benzyl) -4-methyl-1H-indo-1-carboxylic acid (4-dimethylamino) -benzylamide. This compound was prepared from l- (3-cyanobenzyl) -4 -methyl-lH-indole-2-carboxylic acid and 4- (dimethylamino) -benzylamine by the use of diphenylphosphoryl azide and diisopropylamine in accordance with that described in example 3/1. The crude material was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 0.05 to provide the desired product with a yield of 78%. A-NMR (DMSO-de, 200 MHz): d = 2.50 (s, 3H, CH 3); 2.85 (s, 6H, N (CH3) 2); 4.32 (d, 2H, NH-CH2); 5.92 (s, 2H, N-CH2); 6.68 (m, 2H, AA 'BB' -System); 6.91 (d, 1H, aromatic H); 7.09 (m, 2H, AA'BB '-System); 7.15 (m, 2H, aromatic H); 7.27-7.40 (m, 3H, H ~ aromatic); 7.48 (t, 1H, aromatic H); 7.50 (s, 1H, aromatic H); 7.69 (d, 1H, aromatic H); 9.01 (t, 1H, NH). 4.) benzyl- [4- ( { [1- (3-cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid] -amino.} - methyl) -phenyl] -di ethyl-ammonium This compound was prepared from 1- (3-cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide and benzyl bromide in accordance with what was described in Example 20/1 to provide the desired product with a 90% yield. MS: 513.3 (M +). 5.) Trifluoroacetic acid salt of 4- ( { [1- (3-Amidino-benzyl) -4-methyl-lH-indole-2-carbonyl] -amino-} -methyl) -phenyl ] -benzyl-dimethyl-ammonium This compound was prepared from benzyl- [4- ( { [1- (3-cyano-benzyl) -4-methyl-lH-indole-2-carbonyl] -amino .) - methyl) -phenyl] -dimethyl-ammonium by the use of hydrogen chloride and liquid ammonia in accordance with that described in Example 19/3. The crude material was purified by reverse phase chromatography on RPis material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 in the desired product in 60% yield. Melting point 113 ° C (decomposition). MS: 530.2 (M +). Example 30: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -ethyl-dimethyl-ammonium 1. ) 1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid ethyl ester This compound was prepared from 5-fluoro-lH-indole-2-carboxylic acid ethyl ester (5g) , 24 mmol), sodium hydride (695 mg, 29 mmol), 3-cyano-benzyl bromide (5,678 g, 29 mmol) and N, -dimethylformamide (50 ml). The indole was dissolved in N, N-dimethylformamide and sodium hydride was added in portions and the reaction mixture was stirred for 90 minutes. Then nitrile was added. After stirring for 3 hours and after resting overnight the mixture was divided between a solution of sodium bicarbonate (5% in water) and methyl tert-butyl ether. The root layer was dried, evaporated, and purified by flash chromatography on silica gel with dichloroethane / heptane 1: 1 to provide 5,524 g (71%) of the desired product. Melting point: 94.96 ° C. MS: 323.1 (M + H +). 2.) 1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid This compound was prepared from ethyl 1- (3-cyano-benzyl) -5-fluoro- lH-Indole-2-carboxylic acid (5.48 g, 17 mmol), sodium hydroxide (7.9 g, 198 mmol), methanol (600 mL), and water (33.4 mL) in a manner analogous to Example 1/2. The crude material obtained after drying and evaporation of the organic layer was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 1 to provide 4679 (94%) of the desired product. Melting point 253 ° C (decomposition). MS: 295.0 (M + H +). 3.) (1- (3-Cyano-benzyl) -5-fluoro-1H-indole-2-carboxylic acid (4-dimethylamino) -benzylamide This compound was prepared from l- (3-cyanobenzyl) -5-fluoro-lH-indole-2-carboxylic acid (1.0 g, 3.4 mmol), diphenylphosphoryl azide (955 μl, 1.3 equivalents), N, N-diisopropylethylamine (2.02 ml, 3.5 equivalents), 4- (dimethylamino) dihydrochloride ) -benzylamine (849 mg, 1.1 equivalents), and N, N-dimethylformamide (40 ml) in accordance with that described in example 3/1. Purification was carried out by flash chromatography on silica gel with dichloromethane / methanol 19: 0.1. Yield: 1.22 g (84%). A-NMR (DMSO-de, 200 MHz): d = 2.85 (s, 6H, N (CH3) 2); 4.32 (d, 2H, NH-CH2); 5.91 (s, 2H, N-CH2); 6.65 (m, 2H, AA'BB'-System a); 7.13-7.00 (, 2H, AA 'BB' -System); 7.15 (d, 1H, aromatic H); 7.20 (s, 1H, aromatic H); 7.32 (d, 1H, aromatic H); 7.53-7.40 (m, 3H, aromatic H); 7.58 (, 1H, aromatic H); 7.71 (m, 1H, aromatic H); 9.10 (t, 1H, NH). 4.) [4- ( { [1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -ethyl-dimethyl-iodide ammonium This compound was prepared from 1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide and ethyl iodide in accordance with that described in Example 20/1 to provide the desired product in a 74% yield. MS: 455.3 (M +). 5.) Trifluoroacetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) -phenyl trifluoroacetate. ] -ethyl-dimethyl-ammonium This compound was prepared from [4- (. {[[1- (3-Cyano-benzyl) -5-fluoro-1H-indole-2-carbonyl] -amino] iodide. .methyl) -phenyl] -ethyl-dimethyl-ammonium by the use of hydrogen chloride and liquid ammonia in accordance with that described in example 19/3. The crude material was purified by reverse phase chromatography on RPi8 material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 to provide the desired product in 28% yield. Melting point 73-75 ° C (decomposition). MS: 472.3 (M +). Example 31: Trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -5-fluoro-1H-indole-2-carboxylic acid (4-dimethylamino) -benzylamide acid salt This compound was prepared from 1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide (example 30/3), hydrogen chloride, ammonia liquid in a manner analogous to example 19/3. Yield: 59%.

Melting point: 90 ° C (decomposition). MS: 444.2 (M + H +). Example 32: Acetic acid salt of [4- ( { [1 - (3-Amidino-benzyl) -5- f-loro-l-indol-2-carbonyl] -amino} -methyl ester. phenyl] - trimethyl ammonium 1. ) Yodide [4- ( { [1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino}. -methyl-phenyl] -trimethyl-ammonium Starting from 5-Fluoro-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide (example 30/3), the compound was prepared by alkylation with methyl iodide in a manner Analogous to example 20/1 Yield: 90% Melting point 203-205 ° C. MS: 441.2 (M +) 2.) Acetic acid salt of [4- (. {[1- (3 -Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino.} - methyl) -phenyl] -trimethyl-ammonium This compound was prepared from iodide of [4- ( { [ l- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino.} - methyl) -phenyl] -trimethyl-ammonium, hydrogen chloride, and liquid ammonia in a manner analogous to. 3/19 Instead of trifluoroacetic acid, acetic acid was used for chromatography. Performance: 74%. Melting point 172 ° C (decomposition). MS: 458.2 (M +). Example 33: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium Acetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) -phenyl] -trimethyl ester -ammonium (32/2) was dissolved in water / ethanol / trifluoroacetic acid 1: 1: 0.1. The product was separated by flash chromatography on RP18 material with water / ethanol / trifluoroacetic acid 1: 1: 0.1 to provide the trifluoroacetic acid salt in 100% yield. Melting point: 120-124 ° C. MS: 458.2 (M +). Example 34: Trifluoroacetic acid salt of 1- (3-Amidino-benzyl) -4-methyl-1H-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide The starting material (4-dimethylamino) -benzylamide of 1- (3-cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid (example 29/3) was treated analogously to example 19/3. Yield: 46% Melting point: 106 ° C (decomposition). MS: 440.3 (M + H +). Example 35: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -4-methyl-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium The starting material was 1- (3-cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid (4-dimethylamino) -benzyl amide (example 29/3). All the steps were prepared analogously to example 20/1 and 19/3. Performance (last step): Four. Five%. Melting point: 81 ° C (decomposition). MS: 454.3 (M +).

Example 36: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -5-nitro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium The starting material was ethyl ester of 5-nitro-lH-indole-2-carboxylic acid. All steps were prepared analogously to examples 21/1, 1/2, 3/1, 20/1 and 19/3. Performance (last step): 52%. Melting point: 120 ° C (decomposition). MS: 485.3 (M +). Example 37: Trifluoroacetic acid salt of [4- (. {[[1- (3-Amidino-benzyl) -5-amino-1H-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate. ] -trimethyl-ammonium This compound was prepared from the trifluoroacetic acid salt of [4- (. {[1- (3-amidino-benzyl) -5-nitro-lH-indole-2-carbonyl] -amino trifluoroacetate]. methyl) -phenyl] -trimethyl-ammonium (example 36) by hydrogenation in ethanol with 3 equivalents of acetic acid was catalyzed by Pd / C (10%). Yield: 70%. Melting point: 114 ° C (decomposition). MS: 455.3 (M +). Example 38: [4- (. {[[1- (3- Amidino-benzyl) -5-methylsulfonyl-1H-indole-2-carbonyl] -α-n-yl] -methyl) -phenyl] - trifluoroacetate. trimethyl ammonium The starting material was 5-methylsulfonyl-1H-indole-2-carboxylic acid methyl ester. All steps were prepared analogously to examples 21/1, 1/2, 3/1, /1 and 19/3. Performance (last step): 83%. Melting point: 70 ° C (decomposition). MS: 518.2 (M +). Example 39: Acetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -5-hydroxy-lH-indole-2-carbonyl] -amino} -methyl) -phenyl acetate ] -trimethyl-ammonium The starting material was ethyl ester of 4-benzyloxy-l-indole-2-carboxylic acid. All intermediates were prepared analogously to examples 21/1, 1/2, 3/1 and 20/1. In the last step, hydrogen chloride gas was bubbled into a solution of 4-benzyloxy-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester and ethanol for 4 hours at a temperature of 0 ° C. The mixture was warmed to room temperature overnight and evaporated. The residue was dissolved in 10 ml of ethanol and liquid ammonia was added. The mixture was warmed to room temperature during stirring and concentrated. The crude material was purified by flash chromatography on RP18 material with water / ethanol / acetic acid 7: 3: 0.1. Performance (last step): 57%. Melting point: 113 ° C (decomposition). MS: 456.3 (M +). Example 40: Acetic acid salt of [4- ( { [1- (3-Amidino-benzyl) -5-methoxy-lH-indole-2-carbonyl] -amino} -methyl) -phenyl acetate; trimethyl ammonium The starting material was 5-methoxy-1H-indole-2-carboxylic acid ethyl ester. All steps were prepared analogously to examples 21/1, 1/2, 3/1, 20/1 and 19/3. Performance (last step): 74%. Melting point: 94 ° C (decomposition). MS: 470 (M +). Example 41: Trifluoroacetic acid salt of [4- (2. {[1- (3-Amidino-benzyl) -4-methoxy-1H-indole-2-carbonyl] -amino trifluoroacetate. 1-methyl-pyridinium The starting material was 1- (3-cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (example 17/2). All steps were prepared analogously to examples 3/1, 20/1 and 19/3, but the amine in step 3/1 was 4- (2-aminoethyl) -pyridine instead of 4- (4-dihydrochloride. dimethylamino) -benzylamine and dimethyl sulfoxide was added to the solvent in step 20/1.

Performance (last step): 83%. Melting point: 164 ° C (decomposition). MS: 442.3 (M +). Example 42: Acetic acid salt of 1- (3-Amidino-benzyl) -4-methyl-1H-indole-2-carboxylic acid ethyl ester 1. 3-Cyano-benzyl ester of 4-Methyl-lH-indole-2-carboxylic acid The starting material was 4-methyl-lH-indole-2-carboxylic acid.

Alkylation with 3-cyano-benzyl bromide (analogously to Example 19/1, but the solvent was dimethyl 5-formamide instead of tetrahydrofuran) gave 3-cyano-benzyl ester of 4-methyl-1H-indole-2-carbsylic acid . Performance: 75%. MS: 291.1 (M + H +). 3-Cyano-benzyl ester of 1- (3-Cyano-benzyl) -4-methyl-1H-indole-2-carboxylic acid The alkylation of 3-cyano-benzyl ester of 4-methyl-1H-indole-2-acid carboxylic acid with 3-cyano-benzyl bromide was prepared analogously to Example 21/1. Performance: 90% MS: 406.1 (M + H +). 2.) Acetic acid salt of l- (3-Amidino-benzyl) -4-methyl-lH-indole-2-carboxylic acid ethyl ester This compound was prepared from 3-cyano-benzyl ester of acid 1- (3-cyano-benzyl) -4-methyl-1H-indole-2-carboxylic acid by the use of hydrogen chloride and liquid ammonia in accordance with that described in example 19/3. The crude material was purified by flash chromatography on RP? 8 material with water / ethanol / acetic acid 4: 1: 0.2 to provide a fraction containing in a yield of 7% the compound described in Example 63 and a fraction containing a yield of 16% of the title compound of this example. Melting point: 187 ° C (decomposition). MS: 336.2 (M + H +). Example 43: 1- (4-Amidino-benzyl) -lH-indole-2-carboxylic acid benzyl amide hydrochloride A solution of 10 g (53 mmol) 1H-indole-2-carboxylic acid ethyl ester in 80 ml of dimethylformamide was treated with 10.95 g (79 mmol) of potassium carbonate. The mixture was stirred at room temperature for 10 minutes. 15.47 g (79 mmol) of 3-Cyano-benzyl bromide were added and the mixture was heated to 100 ° C. After 4 hours at this temperature, it was cooled to room temperature, acidified with acetic acid (pH 5-6) and emptied into ice water. The product was extracted with methylene chloride. The organic layer was dried and evaporated. The residue was crystallized from 2-propanol to provide 9.8 g of the desired product. Yield: 61% Melting point: 214 ° C. MS: 305.1 (M + H +).

The following steps were prepared analogously to examples 1/2, 3/1 and 19/3, but the amine in step 3/1 was benzylamine instead of 4- (dimethylamino) -benzylamine dihydrochloride. Performance (last step): 35%. Melting point: 266-268 ° C (decomposition). MS: 383.2 (M + H +). Example 44: Trifluoroacetic acid salt of (RS) -1- (4-Amidino-benzyl) -lH-indole-2-carboxylic acid a- (4-pyridyl) -benzylamide This compound was prepared from ethyl ester of lH-indole-2-carboxylic acid analogously to example 43. All the steps were prepared analogously to examples 1/2, 3/1 and 19/3 but the amine in step 3/1 was (RS) -a- (4-pyridyl) -benzylamine dihydrochloride instead of 4- (dimethylamino) -benzylamine dihydrochloride. Performance (last step): 70%. Melting point: 150 ° C. MS: 460.3 (M + H +). Example 45: Salt of tr - if luoroacetic acid amide of l -. (3-Amidino-benzyl) -lH-indole-2-carboxylic acid This compound was isolated in Example 26/2 as a by-product in a 3% yield. Melting point: 278 ° C (decomposition). MS: 293.1 (M + H +). Example 46: Trifluoroacetic acid salt of 4-chloro-benzylamide acid 1- (4-Amidino-benzyl) -lH-indole-2-carboxylic acid The starting material ethyl ester of lH-indole-2-carboxylic acid was alkylated with 4-cyano-benzyl bromide analogously to example 43. The following steps were prepared analogously to examples 1/2, 3/1 and 19/3, but the amine in step 3/1 was 4-chloro-benzylamine instead of 4- (dimethylamino) -benzylamine dihydrochloride. Performance (last step): 20%. Melting point 268 ° C (decomposition). MS: 417.2 (M + H +). Example 47: Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -4-methyl-1H-indole-2-carboxylic acid 3-amidino-benzylamide This compound was prepared from l- (3-cyano-benzyl) -4-methyl-lH-indole-2-carboxylic acid (example 29/2) analogously to examples 3/1 and 19/3, but the amine in step 3/1 was 3-cyano-benzylamine hydrobromide instead of 4- (dimethylamino) -benzylamine dihydrochloride. Performance (last step): 25%. Melting point: 242-243 ° C. MS: 439.3 (M + H +). Example 48: Acetic acid salt of acetate of. { 4- [( { 1- [3- (4, 5-Dihydro-lH-imidazol-2-yl) -benzyl] -5-fluoro-lH-indole-2-carbonyl} - - methyl] - phenyl.}. -trimethyl-ammonium The starting material, iodide of [4- ( { [-1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino.} - methyl) -phenyl] -trimethylammonium (example 32/1) reacted with hydrogen chloride and ethylenediamine (instead of liquid ammonia) in a manner analogous to example 19/3 to provide the imidazoline derivative. Performance: 30%. Melting point: 51 ° C (decomposition). MS: 484.3 (M +). Example 49: 1- (3-hydroxyamidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid 2- (4-pyridyl) -ethyl-amide The starting material, l- (3-cyano-benzyl) -4-methoxy-lH-indole-2-carboxylic acid 2- (4-pyridyl) -ethyl-amide ester (example 41) was dissolved in ethanol, 2.4 equivalents of hydrochloride of hydroxylamine and 2.4 equivalents of triethylamine were added and the mixture was refluxed for 6.5 hours. The precipitate was removed by filtration to provide 54% of the desired product. Melting point: 220-222 ° C. MS: 444.3 (M + H +). Example 50: 1- (3-Hydroxyamidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid 2- (4-pyridyl) -ethyl amide bishydrochloride The starting material, l- (3-hydroxyamidino-benzyl) -4-methoxy-lH-indole-2-carboxylic acid 2- (4-pyridyl) -ethyl-amide (Example 49), was dissolved in 0.1 N hydrochloric acid, Concentrate in vacuum, dissolved in water again and lyophilized. Yield: 66%. Melting point 215-217 ° C. MS: 444. 3 (M + H +). Example 51: 1- (3-hydroxyamidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid 2- (4-hydroxy-phenyl) -ethyl-amide The starting material 1- (3-cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid 2- (4-hydroxyphenyl) -ethyl-amide (Example /1) was dissolved in ethanol and hydroxylamine hydrochloride and triethylamine were added. After refluxing for 5 hours, the reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 1 to provide 63% of the desired product, which solidified under water. Melting point 173-175 ° C (decomposition). MS: 459. 3 (M + H +). Example 52: 1- (3-Hydroxyamidino-benzyl) -5-chloro-1H-indole-2-carboxylic acid (4-dimethylamino) -benzylamide The starting material, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was treated analogously to Example 21/1.

All intermediate products were prepared analogously to examples 1/2 and 3/1. The title compound was prepared analogously to example 49. Purification by flash chromatography on silica gel with dichloromethane / methanol 19: 0.6 provided a mixture of two compounds, the title compound and an unknown compound that were separated by HPLC. Performance (last step): 6%. Melting point 200 ° C (decomposition). MS: 476.1 (M + H +). Example 53: 1- (3-hydroxyamidino-benzyl) -lH-indole-2-carboxylic acid (3-hydroxyamidino-benzyl) ester 3-cyano-benzyl ester of l- (3-cyano-benzyl) -iH-indole-2-carboxylic acid (Example 26/1) was dissolved in ethanol, three equivalents of hydroxylamine were added, and the mixture was refluxed during 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The compound was purified by flash chromatography on silica gel with dichloromethane / methanol 20: 1 to provide 76% of the desired product. Melting point 114- 116 C (decomposition) MS 458.2 (M + H *). Example 54: Trifluoroacetic acid salt of alpha- (4-pyridyl-benzyl) (RS) -1- (3-amidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid amide This compound was a by-product of the reactions described in Example 24. Purification by flash chromatography on silica gel with dichloromethane / methanol / trifluoroacetic acid 9: 1: 0.2 gave 3% of the title compound. Melting point 105 ° C. MS: 490 (M + M +). Example 55: Trifluoroacetate trifluoroacetate acid salt [4- (. {[[1- (3-amidino-benzyl) -5-chloro-lH-indole-2-carbonyl] -amino] -methyl-phenyl] - trimethyl ammonium The starting material, 5-chloro-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid (4-dimethylamino) -benzylamide (Example 52) was reacted analogously to Example 1/4 and example 1/5. Performance (last two steps): 8%. Melting point: 112 ° C (decomposed): MS: 474.2 (M +). Example 56: Trifluoroacetic acid trifluoroacetate salt [4- ( { [5-benzyloxy-1- (3-amidino-benzyl) -lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethyl-ammonium This compound was prepared from 5-benzyloxy- 1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid (example 21/2), 4- (dimethylamino) -benzylamine dihydrochloride, diphenylphosphoryl azide, and diisopropylethylamine analogously to example 3/1, hydrogen sulphide analogously to example 1/4, and methyl iodide in acetone analogously to example 1/5. Performance (last step): 52%. Melting point 60 ° C (decomposition). MS: 546.3 (M +). Example 57: Trifluoroacetic acid salt of trifluoroacetate [4- ( { [1- (3-amidino-benzyl) -5-hydroxy-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethyl-ammonium The starting material Trifluoroacetic acid trifluoroacetate salt [4- ( { [5-benzyloxy-1- (3-amidino-benzyl) -1H-indole-2-carbonyl] -amino} -methyl) -phenyl] -trimethyl ammonium (example 56) was dissolved in ethanol, 2 equivalents of trifluoroacetic acid and Pd / C (10%) were added and the mixture was hydrogenated. The reaction mixture was concentrated and purified by flash chromatography on silica gel with dichloromethane / methanol / trifluoroacetic acid in 9: 1: 0.1. The product was concentrated and lyophilized to provide 53% of the desired product. Melting point 78 ° C (decomposition). MS: 456.4 (M +). Example 58: Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -5-tert-butoxycarbonylamino-lH-indole-2-carbonyl] -amino} -methyl) - phenyl] -trimethyl-ammonium 1) 5- (tert-butoxycarbonylamino) -1- (3-thiocarbamoyl) -benzyl) -lH-indole-2-carboxylic acid 4- (dimethylamino) -benzylamide The initial material1- (3-Cyano-benzyl) -5-nitro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzylamide (Example 36) was treated with hydrogen sulfide gas analogously to Example 1 / Four. The resulting compound was dissolved in ethanol, 2 equivalents of di-tert-butyl dicarbonate, and 3 equivalents of sodium bicarbonate were added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and then divided between dichloromethane and citric acid (0.1% in water). The organic layer was dried over concentrated magnesium sulfate and purified by flash chromatography on silica gel with dichloromethane / methanol 20: 0.2 to provide 43% of the desired product. MS: 558.4 (M + H +). 2) Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -5-tert-butoxycarbonylamino-lH-indole-2-carbonyl] -amino} -methyl) -phenyl ester ] -trimethyl ammonium This compound was prepared analogously to the example 1/5, but the solvent for the methylation was pure acetone. The pure product was purified by flash chromatography on RPIS material with ethanol / water / trifluoroacetic acid 1: 1: 0. 1 to provide 55% of the desired product. Melting point 146 ° C (decomposition). MS: 555 (M +). Example 59: 1- (3-amidino-benzyl) -5-benzyloxy-H-indole-2-carboxylic acid 3-amidino-benzylamide dihydroiodide 1) 3-cyano-benzylamide of 5-benzyloxy-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 5-benzyloxy-l- (3-cyano-benzyl) ) -lH-indole-2-carboxylic acid (500 mg, 1.3 mmol, example 21/2), diphenylphosphoryl azide (370 μl, 1.7 mmol), N, N-diisopropylethylamine (440 μl, 2.6 mmol), as well as hydrobromide 3-cyano-benzyl amine (312 mg, 1.5 mmol) in N, N-dimethylformamide (10 ml) in accordance with that described in example 3/1. Purification by flash chromatography on silica gel was carried out with dichloromethane to provide 451 mg (69%) of the desired product. 2) 3-thiocarbamoyl-benzylamide of 5-benzyloxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 3-cyano-benzylamide of 5-benzyloxy-l- (3-Cyano-benzyl) -lH-indole-2-carboxylic acid (451 mg, 0.9 mmol), pyridine (6.67 mL, 83 mmol), triethylamine (5.41 mL, 39 mmol), and hydrogen sulfide in accordance with described in example 1/4. Purification by flash chromatography on silica gel was carried out with dichloromethane / methanol 19: 0.15 to provide 138 mg (27%) of the desired product. 3) l- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid 3-amidino-c-l amyl acid hydrochloride 3-benzyloxy-1- (3- 3-thiocarbamoyl-benzylamide was dissolved thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid (138 mg, 0.24 mmol) in 5 ml of acetone in a bottle, the bottle was sealed and methyl iodide (0.4 ml, 26 equivalents) was added through a syringe . The reaction mixture was stirred at room temperature. 4 days later, the yellow precipitate was collected by filtration and washed with diethyl ether. The precipitate (188 mm, 0.22 mmol), acetic acid (0.15 ml, 12 equivalents), ammonium acetate (307 mg 18 equivalents) and methanol (6 ml) were treated in accordance with that described in example 1/5. The crude material was purified by flash chromatography on a RP? 8 material with ethanol / water / trifluoroacetic acid 1: 1: 0.1 to provide 157 mg of the desired compound (90%) after lyophilization. Melting point 138 ° C. (decomposition). MS: 531.3 (M + H +). Example 60: [4- ( { [1- (3-amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] amino] -methyl) -phenyl] -benzyl chloride hydrochloride di ethyl ammonium 1. benzyl- [4- ( { [1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) -phenyl] -dimethyl-ammonium bromide This compound was prepared from 1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzylamide (840 mg, 1.97 mmol, example 30/3), benzyl bromide (237 μl, 1 equivalent), and acetone (8 ml) analogously to example 20/1, but the temperature of the reaction was maintained at 50 ° C. The precipitate was removed by filtration to provide 1.02 g of the desired product (87%). 2) [4- ( { [1- (3-amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -benzyl-dimethyl chloride hydrochloride ammonium This compound was prepared from benzyl- [4- ( { [1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl bromide. ) -phenyl] -dimethyl-ammonium (200 mg, 0.335 mmol), ethanol, hydrogen chloride, and liquid ammonia in a manner analogous to Example 19/3. Purification by reverse phase chromatography on material R is (water / ethanol / acetic acid 7: 3: 01) followed by lyophilization yielded 156 mg of the desired product (77%). Melting point 136 ° C. MS: 534.4 (4%, M +). Example 61: Acetic acid salt of allyl- [4- ( { [1- (3-amidino-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) -phenyl] -dimethyl-ammonium 1) allyl- [4- ( { [1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -dimethyl- bromide ammonium This compound was prepared from 1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzylamide (200 mg, 0.47 mmol, example 30/3) , allyl bromide (81 μl, 2 equivalents), and acetone (3.5 ml). The members of the reaction were mixed, the bottle was closed and heated to a temperature of 55 ° C. After 6 hours, heating was stopped. Four weeks later an additional 1.06 ml of allyl bromide was added, the bottle was closed, and it was heated to a temperature of 55 ° C again. After three weeks a white precipitate was removed by filtration, washed with diethyl ether and dried in vacuo to provide 222 mg of the desired product (86%). Melting point 163-164 ° C. 3) Acetic acid salt of allyl- [4- ( { [1- (3-amidino-benoyl) -5-fluoro-lH-indole-2-carbonyl] -amino} -methyl) - phenyl] -dimethyl-ammonium This compound was prepared from allyl- [4- ( { [1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -a- bromide. .) - methyl) -phenyl] -dimethyl-ammonium (222 mg, 0.406 mmol), ethanol (12 ml), hydrogen chloride, and liquid ammonia in a manner analogous to example 19/3. The crude product was purified by chromatography on silica gel with dichloromethane / methanol / acetic acid 3: 2: 0.05 to 1: 4: 0.05. Lyophilization gave 131 mg of the desired product (56%). Melting point 133 ° C (decomposition). MS: 484.3 (M +). Example 62: Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -5-fluor-lH-indole-2-carbonyl] -amino} -methyl) -phenyl acetate ] - dimethyl-2-propynyl ammonium 1) [4- ( { [1- (3-Cyano-benzyl) -5-fluoro-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -dimethyl-2-bromide propynylammonium This compound was prepared from 1- (3-cyano-benzyl) -5-fluoro-lH-indole-2-carboxylic acid (4-dimethylamino) -benzylamide] (200 mg, 0.47 mmol, example 30/3), propargyl bromide (140 mg, 2 equivalents, 80% in toluene), acetone (5 ml). The elements of the reaction were mixed, the bottle was closed and heated to 50 ° C. After 5 hours the heating was suspended. After 2 days, the mixture was concentrated in vacuo and the desired product was precipitated with diethylether to give 220 mg of a white solid (86%). 2) Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -5-fluor-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -dimethyl-2-propynyl ammonium This compound was prepared from bromide of - [4- ( { [l- (3-cyano-benzyl) -5-fluor-lH-indol-2-carbonyl] -amino .} .methyl) -phenyl] -dimethyl-2-propynylammonium (220 mg, 0.406 mmol), ethanol (12 ml), hydrogen chloride, and liquid ammonia in a manner analogous to example 19/3. The crude product was purified by chromatography on silica gel with dichloromethane / methanol / acetic acid 3: 2: 0.05 to 1: 4: 0.05. Lyophilization gave 131 mg of the desired product (56%).

Melting point 109 ° C (decomposition). MS: 482.3 (M +). Example 63: Acetic acid salt of 1- (3-amidino-benzyl) -4-methyl-1H-indole-2-carboxylic acid 3-amidino-benzyl ester The fraction obtained in the chromatography of Example 42/3 consisted of three compounds that were separated by preparative HPLC to provide 2.5 mg of the lyophilization title compound. Performance: 7%. Melting point 52 ° C (decomposed): MS: 440.3 (M + H *). Example 64: Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -4-methyl-lH-indole-2-carbonyl] -amino} -methyl) -phenyl acetate ] -trimethyl-ammonium g of AG-1-X8 ion exchange resin (Bio-Rad) was filled into a column, rinsed first with water, and then with a solution of sodium acetate IN, and again with water. A trifluoroacetic acid salt of [4- (. {[1- (3-amidino-benzyl) -4-methyl-lH-indole-2-carbonyl] -amino] -methyl) -phenyl trifluoroacetate was dissolved. ] -dimethyl-ammonium (example 35) in water and passed through the ion exchange column. After rinsing with 150 ml of water, the solution was concentrated in vacuo to 25 ml which were lyophilized to provide 39 mg of the desired product (100%). Melting point 89 ° C (decomposition). MS: 454.3 (M +). Example 65: 1- (3-Amino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid 4-hydroxy-benzyl-amide hydrochloride 1) 1- (3-cyano-benzyl) -4-methoxy-lH-indole-2-carboxylic acid 4-hydroxy-benzylamide The title compound was prepared using l- (3-cyano-benzyl) -4- methoxy-lH-indole-2-carboxylic acid (400 mg, 1.31 mmol, example 24/2), diphenylphosphoryl azide (365 μl, 1.3 equivalents), N, -diisopropylethylamine (850 μl, 3.75 equivalents), and 4-aminomethyl- phenol (560 mg, 2.1 equivalents) in N, -dimethylformamide (10 ml) according to that described in example 3/1. 2) l- (3-amidino-benzyl) -4-, ethoxy-lH-indole-2-carboxylic acid 4-hydroxy-benzylamide hydrochloride This compound was prepared from 4-hydroxy-benzyl amide of acid 1- (3-Cyano-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (200 mg, 0.49 mmol), hydrogen chloride, and liquid ammonia in a manner analogous to Example 19/3. Purification by reverse phase chromatography on RPis material with water / ethanol / acetic acid 7: 3: 0.1 and lyophilization gave 179 mg of the desired product (79%). Melting point 202 ° C (decomposition). MS: 429.2 (100%; M + H *). Example 66: Acetic acid salt of l- (3-amidino-benzyl) -4-methoxy-lH-indole-2-carboxylic acid 4-amidino-benzylamide 1) 1- (3-cyano-benzyl) -4-methoxy-l-indole-2-carboxylic acid 4-cyano-benzylamide The title compound was prepared using l- (3-cyano-benzyl) -4- methoxy-lH-indole-2-carboxylic acid (400 mg, 1.31 mmol, example 24/2), diphenylphosphoryl azide (365 μl, 1.3 equivalents), N, N-diisopropylethylamine (850 μl, 3.75 equivalents), and 4-aminomethyl -benzonitrile (585 mg, 2.1 equivalents) in N, N-dimethylformamide (10 ml) in accordance with that described in example 3/1. 2) Acetic acid salt of 1- (3-amidino-benzyl) -4-methoxy-lH-indole-2-carboxylic acid 4-amidino-benzyl amide This compound was prepared from 4-cyano-benzyl-amide of 1- (3-amidino-benzyl) -4-methoxy-1H-indole-2-carboxylic acid (200 mg, 0.48 mmol), hydrogen chloride and liquid ammonia in a manner analogous to Example 19/3. Purification by reverse phase chromatography on RPis material with water / ethanol / acetic acid 1: 1: 0.1 followed by lyophilization gave 68 mg of the desired product (25%). Melting point 186 ° C (decomposition). MS: 228.1 ((M + 2H +) / 2). Example 67: Acetic acid salt of 1- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid 3-amidino-benzyl ester 1) 3-benzyloxy-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 3-cyano-benzyl ester 5-benzyloxy-l- (3-cyano-benzyl) -lH- acid was dissolved indole-2-carboxylic acid (500 mg, 1.31 mmol, example 21/2) in N, N-dimethylformamide (20 ml) and heated to 60 ° C. Potassium carbonate (282 mg, 1.44 mmol) was added and the solution was stirred at 60 ° C. One hour later, 3-cyano-benzyl bromide (282 mg, 1.44 mmol) was added and the reaction mixture was stirred for a further 5 hours at a temperature of 60 ° C. The next day it was partitioned between water and methyl tert-butyl ether, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with dichloromethane / heptane 4: 1 to provide 524 mg of the desired product (80%). Melting point: 125-128 ° C. 2) 3-benzyloxy-l- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid 3-thiocarbamoyl-benzyl ester Hydrogen sulphide was introduced for 15 minutes in a solution cooled with ice water of 520 mg of the 3- cyano-benzyl ester of 5-benzyloxy-1- (3-cyano-benzyl) -1H-indole-2-carboxylic acid in 7.7 ml of pyridine and 6.2 ml of triethylamine. The mixture was stirred at room temperature for 18 hours in a sealed flask and then divided between toluene and a 10% aqueous sodium carbonate solution. The organic layer was dried and evaporated and the residue was purified by flash chromatography on silica gel with dichloromethane / methanol 19: 0.2 to provide 487 mg of the desired product (82%). Melting point: 177-180 ° C. 3) Acetic acid salt of 1- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid 3-amidino-benzyl ester 3-benzyloxy-3-benzoyl-3-thiocarbamoyl ester was dissolved 1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid (487 g, 0.86 mmol) in 15 ml of acetone in a flask. The vial was sealed and methyl iodide was added through a syringe. The reaction mixture was stirred at room temperature. Four days later the yellow precipitate was collected by filtration and washed with diethyl ether. The precipitate (597 mg, 0.7 mmol), acetic acid (0.48 ml, 12 equivalents), ammonium acetate (957 mh, 18 equivalents), and methanol (10 ml) was treated in accordance with that described in example 1/5 . The crude material was purified by flash chromatography on RPIS material with ethanol / water / trifluoroacetic acid to provide 460 mg of the trifluoroacetic acid salt of the desired compound. To obtain the acetic acid salt of the product, it was passed in a column with 46 g of ion exchange resin analogously to Example 64. The resulting solution was concentrated to 100 ml and lyophilized to provide 311 mg of the desired product (68). %). Melting point: 147 ° c (decomposition). MS: 532.3 (M + H +). Example 68: iodide hydroiodide of [4- ( { [1- (3-amidino-benzyl) -4-benzyloxy-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethylammonium 1) ethyl ester of 4-benzyloxy-l- (3-cyano-benzyl) -1H-indole-2-carboxylic acid This compound was prepared from 4-benzyloxy-1H-indole-2-carboxylic acid ethyl ester ( 3 g, 10 mmol), sodium hydride (294 mg, 12 mmol), 3-cyano-benzyl bromide (2.4 g, 12 mmol), and N, N-dimethylformamide (20 ml) analogously to example 21 / 1. The reaction mixture was neutralized with 2N hydrochloric acid and partitioned between water and methyl tert-butyl ether. The organic layer was dried, concentrated in vacuo and purified by flash chromatography with dichloromethane / heptane 7: 3 to provide 2.914 g (71%) of the desired product. 2) 4-benzyloxy-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 4-benzyloxy-l- (3-cyano-benzyl) -lH ethyl ester -indole-2-carboxylic (2.914 g, 7.1 mmol), sodium hydroxide (2.13 g, 53 mmol), methanol (175 ml), and water (8.95, 1) analogously to example 1/2. The reaction mixture was neutralized with 4N hydrochloric acid. The white precipitate was collected by filtration, washed with water, and purified by flash chromatography on silica gel with dichloromethane / methanol 19: 1 to provide 2.147 g (79%) of the desired product. 3) 4-benzyloxy-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 4- (dimethylamino) -benzylamide This compound was prepared from 4-benzyloxy-l- (3-cyano) -benzyl) -lH-indole-2-carboxylic acid (400 mg, 1.05 mmol), diphenylphosphoryl azide (290 μL, 1.36 mmol), N, N-diisopropylethylamine (360 μl, 2.1 mmol), and 4- (dimethylamino) dihydrochloride -benzylamine (261 mg, 1.12 mmol) in N, N-dimethylformamide (10 ml) in accordance with that described in example 3/1. Purification flash chromatography on silica gel was carried out with dichloromethane / methanol 20: 0.05 to provide 347 mg (64%) of the desired product. 4) 4- (dimethylamino) -benzylamide of 1-benzyloxy-1- (3-thiocarbamoyl-benzyl) -1H-indo-1-carboxylic acid This compound was prepared from 4- (dimethylamino) -benzylamide 4- benzyloxy-1- (3-cyano-benzyl) -IH-indole-2-carboxylic acid (347 mg, 0.67 mmol), and hydrogen sulfide according to that described in example 1/4. Purification by flash chromatography on silica gel was carried out with dichloromethane / methanol 19: 1 to provide 342 mg (92%) of the desired product. 5) [4- ( { [1- (3-amidino-benzyl) -4-benzyloxy-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethylammonium iodide This compound was prepared from 4-benzyloxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid 4- (dimethylamino) -benzylamide (342 mg, 0.62 mmol), acetone (15 ml), iodide methyl (0.98 ml, 15 mmol), acetic acid (0.4 m, 0.7 mmol), ammonium acetate (809 mg, 10 mmol), and methanol (1 ml), in accordance with that described in example 1/5, but the solvent for methylation - it was pure acetone. The crude material was purified by flash chromatography on RPis material with ethanol / water / acetic acid 1: 1: 0.1 to provide 374 mg of the desired compound (80%). Melting point: 158 ° C (decomposition). MS: 546.2 (M +). Example 69: Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -5-hydroxy-1H-indole-2-carboxylic acid 3-amidino-benzylamide Dihydroiodide of 1-amidino-benzylamide acid was dissolved 1- (3-amidino-benzyl) -5-benzyloxy-1H-indole-2-carboxylic acid (74 g, 0.09 mmol, example 59) in ethanol (9 ml). Hydrogen chloride gas was bubbled through the solution for 5 hours. After standing for about 3 days, the mixture was evaporated and purified by flash chromatography in RPIS material with ethanol / water / trifluoroacetic acid 1: 1: 0.1 to provide 51 mg of the desired product containing an unknown impurity. HPLC. of 44 mg preparation of this mixture gave 6.7 of the pure desired compound (10%). Melting point: 125 ° C (decomposition). MS: 441.3 (M + H *). Example 70: Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -4-bromo-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethylammonium 1) ethyl ester of 4-bromo-l- (3-cyano-benzyl) -1H-indole-2-carboxylic acid The compound was prepared from 4-bromo-lH-indole-2-carboxylic acid ethyl ester (5 g, 19 mmol), sodium hydride (537 mg, 22 mmol), 3-cyano-benzyl bromide (4.39 g, 22 mmol), and N, N-dimethylformamide (50 mL) analogously to Example 21 /1. The crude material was purified by crystallization from methanol to provide 6.093 g (84%) of the desired product. Melting point: 163-165 C (decomposition) 2) 4-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 4-bromo-l- (3-cyano-benzyl) -lH ethyl ester -indole-2-carboxylic (6.093 g, 16 mmol), sodium hydroxide (477 g, 120 mmol), methanol (800 ml), and water (20.2 ml) analogously to example 1/2. The precipitated product was washed and dried. Yield: 5,562 g (98%). Melting point: 236-238 ° C. 3)) 4-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 4-dimethylamino-benzylamide This compound was prepared from 4-bromo-l- (3-cyano- benzyl) -lH-indole-2-carboxylic acid (1 g, 2.8 mmol), diphenylphosphoryl azide (790 μL, 3.66 mmol), N, N-diisopropylethylamine (960 μL, 5.6 mmol), and 4- (dimethylamino) dihydrochloride -benzylamide (703 mg, 3.1 mmol) in N, N-dimethylformamide (40 ml) in accordance with that described in example 3/1. Purification by flash chromatography on silica gel was carried out with dichloromethane / methanol 20: 0.05 to provide 818 mg (60%) of the desired product. Melting point: 110-112 ° C. 4) iodide [4- ( { [4-bromo-l- (3-cyano-benzyl) -lH-indole-2-carbonyl] -amino.}. -methyl) -phenyl] -trimethyl-ammonium This compound was prepared from 4-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 4-dimethylamino-benzylamide (818 mg, 1.68 mmol), methyl iodide (2.27 ml, 44 mmol) ), and acetone (8 ml), analogously to example 20/1. Yield: 927 mg (88%). Melting point: 219-220 ° C. 5) Acetic acid salt of acetate [4- ( { [1- (3-amidino-benzyl) -4-bromo-lH-indole-2-carbonyl] -amino.} - methyl) -phenyl] - trimethyl ammonium This compound was prepared from [4- ( { [4-bromo-1- (3-cyano-benzyl) -1H-indo1-2-carbonyl] -amino] -methyl iodide. phenyl] -trimethylammonium (200 mg, 0.32 mmol), ethanol (13 ml), hydrogen chloride, and liquid ammonia analogously to example 19/3. Purification by reverse phase chromatography in RPis material with water / ethanol / trifluoroacetic acid 1: 1: 0.1 gave 249 mg of the desired product as the trifluoroacetic acid salt. This compound was converted to the acetic acid salt by ion exchange chromatography in a manner analogous to Example 64. Yield: 150 mg (74%). Melting point: 145 ° C (decomposition). MS: 518.2 (M +; 79Br). Example 71: Acetic acid salt of [4- ( { [1- (3-amidino-benzyl) -5-bromo-lH-indole-2-carbonyl] -amino] -methyl) -phenyl] -trimethylammonium 1) 5-bromo-l- (3-cyano-benzyl) -1H-indole-2-carboxylic acid ethyl ester This compound was prepared from 5-bromo-lH-indole-2-carboxylic acid ethyl ester ( 6 g, 22 mmol), sodium hydride (645 mg, 27 mmol), 3-cyano-benzyl bromide (5.26 g, 27 mmol), and N, N-dimethylformamide (50 mL) in a manner analogous to Example 21 / 1. The crude material was purified by crystallization from methanol to provide 8.07 g (96%) of the desired product. Melting point: 124-128 ° C (decomposition). 2) 5-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid This compound was prepared from 5-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester (8.07 g, 21 mmol), sodium hydroxide (6.32 mg, 160 mmol) , methanol (360 ml), and water (26.8 ml) analogously to example 1/2. The precipitate was washed and dried. It was used in the next step without further purification. Yield: 6.63 g (89%). Melting point: 230-233 ° C. 3) 5-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 4-dimethylamino-benzylamide This compound was prepared from 5-bromo-l- (3-cyano-benzyl) ) -lH-indole-2-carboxylic acid (1 g2.8 mmol), diphenylphosphoryl azide (790 μL, 3.66 mmol), N, N-diisopropylethylamine (960 μL, 5.6 mmol), and 4- (dimethylamino) -benzylamide dihydrochloride (703 mg, 3.1 mmol) in N, N - dimethylformamide (40 ml) according to that described in example 3/1. Purification by flash chromatography on silica gel was carried out with dichloromethane / methanol 20: 0.5 to provide 949 mg (69%) of the desired product. Melting point: 145-146 ° C. 4) iodide [4- ( { [5-bromo-l- (3-cyano-benzyl) -lH-indole-2-carbonyl] -amino.} - methyl) -phenyl] -trimethyl-ammonium This compound was prepared from 5-bromo-l- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 4-dimethylamino-benzylamide (890 mg, 1.83 mmol), methyl iodide (2.95 mL, 47 mmol) ), and acetone (8 ml), analogously to example 20/1. Yield: 1,289 g. Melting point: 145-148 ° C. The compound was used for the following steps without further purification. 5) acetate acetic acid salt [4- ( { [1- (3-amidino-benzyl) -5-bromo-lH-indole-2-carbonyl] -amino} .methyl) -phenyl] - trimethyl ammonium This compound was prepared from [4- (. {[[5- bromo-1- (3-cyano-benzyl) -lH-indole-2-carbonyl] -amino] -methyl. phenyl] -trimethylammonium (200 mg, 0.32 mmol), ethanol, hydrogen chloride, and liquid ammonia in a manner analogous to Example 19/3. Purification by reverse phase chromatography on RPIA material with water / ethanol / trifluoroacetic acid 1: 1: 0.1 gave 199 mg of the desired product as a trifluoroacetic acid salt. This compound was converted to the acetic acid salt by ion exchange chromatography in a manner analogous to Example 64. Yield: 130 mg (64%). Melting point: 86 ° C (decomposition). MS: 520.2 (M +; 81Br). Example 72: Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -lH-indole-3-carboxylic acid 3-amidino-benzylamide 1) 1- (3-cyano-benzyl) -lH-indol-3-carboxylic acid 3-cyano-benzylamide This compound was prepared from l- (3-cyanobenzyl) -lH-indole-3-acid carboxylic acid (1 g, 3.62 mmol, example 19/1), diphenylphosphoryl azide (1.29 g, 4.60 mmol), N, N-diisopropylethylamine (1.82 ml), and 3-cyanobenzylamine hydrobromide (1.16 g, 3.3 mmol) in N, -dimethylformamide (50 ml) according to that described in example 3/1. Purification by flash chromatography on silica gel was carried out with toluene / ethyl acetate first 19: 0.25, then 19: 0.5 to provide 289 mg (20%) of the desired product. MS: 391.2 (M + H +). 2) Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -lH-indole-3-carboxylic acid 3-amidino-benzylamide this compound was prepared from 3-cyano-benzylamide of 1- (3-cyano) acid -benzyl) -lH-indole-3-carboxylic acid (280 mg, 0.72 mmol) ethanol, hydrogen chloride, and liquid ammonia in a manner analogous to example 19/3. MPLC purification in RP? 8 material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 gave 110 mg of the desired product. Melting point: 146-148 ° C. MS: 425.2 (M + H +). Example 73: 1- (3-pyridyl) -methyl-lH-indole-2-carboxylic acid 4-dimethylamino-benzylamide 1) 1- (3-pyridyl) -methyl-lH-indole-2-carboxylic acid ethyl ester This compound was prepared from lH-indole-2-carboxylic acid ethyl ether (lg, 5.28 mmol), hydride sodium (139.5 mg, 5.8 mmol), 3-chloromethyl-pyridine (2.05 g, 15.8 mmol), dimethyl sulfoxide (10 ml), N, N-dimethylformamide (60 ml) analogously to example 21/2. The precipitate was partitioned between ethyl acetate and hydrochloric acid, 162 mg and the organic layer was dried and evaporated to give 437.1 mg (45%) of the desired product. Melting point: 92-93 ° C. MS: 281.4 (M + H +). 2) 1- (3-pyridyl-methyl) -lH-indole-2-carboxylic acid This compound was prepared from 1- (3-pyridyl-methyl) -lH-indole-2-carboxylic acid ethyl ester (313 mg, 1.1 mmol), a solution of IN sodium hydroxide in water (5.58 ml), and ethanol (25 ml). The ester was dissolved in ethanol, the sodium hydroxide solution was added and the mixture was heated to 40 ° C. After 2.5 hours, the heating was removed and the reaction mixture was neutralized with IN hydrochloric acid (5.58 ml). The solution was partitioned between water and ethyl acetate and the organic layer was dried and evaporated to provide 251 mg of the desired product (89%). MS: 253.1 (M + H +). 3) 1- (3-pyridyl-methyl) -1H-indole-2-carboxylic acid 4-dimethylamino-benzylamide this compound was prepared from 1- (3-pyridyl-ethyl) -lH-indole-2- carboxylic (200 mg, 0.79 mmol), diphenylphosphoryl azide (222.7 μl, 1.03 mmol), N, N-diisopropylethylamine (364 μl), and 4-dimethylamino-benzylamine dihydrochloride (632.3 mg, 2.84 mmol) in N, N-dimethylformamide (10 ml) in accordance with that described in example 3/1. Purification by flash chromatography on silica gel was carried out with toluene / lime acetate first 6: 1, and then to pure ethyl acetate in two steps: 228.7 mg (76%) of the desired product were obtained. Melting point: 108-110 ° C. MS: 385.3 (M + H +). Examples 74-78 were synthesized in solid phase using a polystyrene resin (PS) with a 2-chlorotryl chloride (L) linker (substitution: 1.05 mmol / g and 0.67 mmol / g, respectively; Novabiochem).

Linker L The general procedures applied in examples 74 to 78 are as follows. Link: The indole derivatives were dissolved in dichloromethane or mixtures of dichloromethane and tetrahydrofuran. N, N-diisopropylethylamine was added and the mixture was sucked into a syringe equipped with a polyethylene sheet and containing the resin. After stirring for 2 hours at room temperature, the mixture was removed and the resin was washed with dichloromethane. A mixture of methanol, N, N-diisopropylethylamine, and dichloromethane was added, and the syringe was stirred at room temperature. After 1.5 hours, the mixture was removed and the resin was washed with N, N-dimethylformamide (1 time), dichloromethane (3 times), and methanol (3 times). Dissociation: The compounds were dissociated from the resin by treating the resin with a mixture of dichloromethane, acid-trifluoroacetic acid, and water (60: 40: 0.1).

After 15 minutes, the dissociation mixture was transferred into a flask and the resin was washed with methanol (3 times) . The methanol washes were added to the dissociation mixture and the resulting solution was evaporated in vacuo. The residue was dissolved in an appropriate acetonitrile-water mixture and characterized by HPLC and MS (HPLC Beckman used with the following columns: A: YMC ODS-AM 4. 6 mm x250 mm; B: VYDAC RPis, 90 A, 4.6 mm x 250 mm; C: Basic YMC, 4.6 mm x 250 mm; Thermo Separation Products HPLC used with column D: Macherey-Nagel ET 250/8/4 Nucleosil / Cis). Purification: The final products were purified by preparative HPLC using the following conditions: System 1 used for Examples 74-78: Beckman HPLC, column: VYDAC Protein & Peptide, C? 8, 10 μm, 22 x 250 mm; flow 8 ml / min, acetonitrile / water gradient, wavelength 324 nm, or System 2 used for all other compounds synthesized in solid phase: Thermo Separation Products HPLC, column: Macherey-Nagel 100 7 Cis, 20 mm x 250 mm; flow 5-6 ml / min, appropriate mixtures of water (70-60%) and acetonitrile (30-40%), wavelength 236-242 nm. Example 74: Trifluoroacetic acid salt of 4 - (((1- (3-amidino-benzyl) -5-amino-1H-indole-2-carbonyl) -amino) -methyl) -1-ethyl-pyridinium trifluoroacetate 1) Trifluoroacetic acid salt of 5- amino-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid ethyl ester 5-amino-1H-indole-2-carboxylic acid ethyl ester ( 343 mg, 1.68 mmol) was added to the resin (529 mg, 0.56 mmol) in accordance with that described above. The resin coupled with dry indole was stirred in dry N, N-dimethylformamide for 5 minutes. After the removal of the N, N-dimethylformamide, a mixture of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,3-diazaphosphorine (405 μl, 1.4 mmol) and N was added. N-dimethylformamide (5 ml) through a solution of 3-cyano-benzyl bromide (220 mg, 1.12 mmol) in N, N-dimethylformamide after 1 hour. 3 hours later the mixture was removed, the resin was washed with N, N-dimethylformamide (5 times) and methanol (5 times) and dried in vacuo. A sample was taken and dissociated in accordance with what was described above. The obtained compound was characterized by HPLC and MS. HPLC: column B, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 16.88 min. MS: 320.1 (M + H +). 2) Trifluoroacetic acid salt of 5-amino-1- (3-cyanobenzyl) -lH-indole-2-carboxylic acid The resin from step 1 (331 mg) was stirred for 5 minutes with N, N-dimethylformamide ( 8 ml). After the removal of the N, N-dimethylformamide, a mixture of benzyltrimethylammonium hydroxide (40% in methanol, 2.8 mmol, 1.27 ml) and N, N-dimethylformamide (10 ml) was sucked off and stirred for 4 hours 40 minutes. After the mixture was removed, the resin was washed with N, N-dimethylformamide (5 times) and dichloromethane (3 times) and dried in vacuo. A sample was taken and dissociated. HPLC: column B, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 11.72 minutes. MS: 292.1 (M + H +). 3) salt of trifluoroacetic acid (4-pyridylmethyl) -amide of 5-amino-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid The resin from step 2 (105 mg) was stirred for 5 minutes with N, N-dimethylformamide, before the addition of the reagent mixture consisting of 4- (aminomethyl) pyridine (34 μl, 0.33 mmol), N, N'-diisopropylcarbodiimide (49 mg, 0.39 mmol), and hydrate 1-hydroxybenzotriazole (53 mg, 0.39 mmol) in N, N-dimethylformamide (4 ml). After 22 hours, the reaction mixture was removed and the resin was washed with N, N-dimethylformamide, methanol and dichloromethane and dried in vacuo. A sample was taken, which was dissociated. HPLC: column B, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 9.73 minutes. MS: 382.1 (M + H +). 4) salt of trifluoroacetic acid (4-pyridyl-methyl) -amide of 5-amino-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid The resin from step 3 (45 mg) was stirred in 2 ml of pyridine / triethylamine (2: 1) for 15 minutes. The solution was removed, a saturated solution of hydrogen sulphide in pyridine / triethylamine (2: 1) (1 ml) was added and the mixture was stirred overnight. The next day, the hydrogen sulphide solution was removed. The resin was washed with acetone and dried in vacuum. A sample was taken that was dissociated. HPLC: column C, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 14.30 minutes. MS: 416.0 (M + H +). ) trifluoroacetic acid salt of 4- (((1- (3-amidino-benzyl) -5-amino-1H-indole-2-carbonyl) -amino) -methyl) -methyl-pyridinium trifluoroacetate acid) to 10 mg of the resin from step 4, a solution of methyl iodide (100 μl) in acetone (0.4 ml) was added. After stirring overnight, the reaction mixture was removed and the resin was washed with acetone (7 times) and methanol. A solution of ammonium acetate (31 mg), acetic acid (15 μl), and methanol (300 μl) was added.The syringe was closed and heated in a water bath at a temperature of 50 ° C for 3 hours. After this conversion, the solution was removed and the resin was washed with methanol, N, N-dimethylformamide and dichloromethane, 5.2) to 10 mg of the resin from step 4, a solution of N, N-dimethylformamide (0.4 ml) was added. ) and methyl iodide (100 μl).

After stirring overnight, the reaction mixture was removed and the resin was washed with acetone (7 times) and methanol. A solution of ammonium acetate (31 mg), acetic acid (15 μl), and methanol (300 μl) was added. The syringe was closed and encouraged in a water bath at a temperature of 50 ° C for 3 hours. After this conversion, the solution was removed and the resin was washed with methanol, N, N-dimethylformamide, and dichloromethane. 5.3) the resin from step 4 (25 mg) was stirred with acetone for 5 minutes. The acetone was replaced by a solution of methyl iodide (0.3 ml) in acetone (1.2 ml) and the syringe was stirred overnight. The next day, the methyl iodide solution was removed and the resin was washed with acetone and methanol. A solution of ammonium acetate (92 mg), acetic acid (45 μl), and methanol (300 μl) was added and the syringe was heated at 50 ° C for 3 hours.

The solution was removed and the resin was washed with methanol, N, N-dimethylformamide, and dichloromethane. The resins obtained in steps 5.1 - 5.3 were combined. The combined material was dissociated and then purified by preparative HPLC. After lyophilization, 8 mg of a solid material was obtained.

Melting point: 115 ° C. HPLC: column C, 0-40% acetonitrile in water, 20 minutes, 230 nm, retention time: 11.05 minutes. MS: 413.0 (M ").

Examples 75 and 76: Trifluoroacetic acid salt of 1- (3-amidino-benzyl) -5-amino-1H-indole-2-carboxylic acid 4-amidino-benzylamide (example 75) 3-amidino-benzylamide acid trifluoroacetic acid salt of 1- (3-amidino-benzyl) -5-amino-1H-indole-2-carboxylic acid (Example 76) 1) Salt of trifluoroacetic acid 4-cyano-benzylamide of 5-amino-1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid and trifluoroacetic acid salt of 3-cyano-benzylamide of 5- amino acid 1- (3-cyano-benzyl) -lH-indole-2-carboxylic acid 1. 1) The resin of example 74, step 2 (130 mg, 0.11 mmol) was stirred with N, N-dimethylformamide for 5 minutes. After the removal of N, N-dimethylformamide, a solution of diphenylphosphoryl azide (36 μL, 0.165 mmol), N, N-diisopropylethylamine (172 μL, 0.99 mmol), and 4-aminomethyl-benzonitrile hydrobromide was added. (70 mg, 0.33 mmol) in N, N-dimethylformamide (4 ml), and the syringe was stirred overnight. After 16 hours, the reaction mixture was removed, the resin was washed with N, N-dimethylformamide, methanol and dichloromethane and dried. After drying, a sample was taken that was dissociated. HPLC analysis showed a 50% conversion. 1.2) The resin from step 1.1 was stirred with N, N-di-ethylformamide for 5 minutes. The removal of N, N-dimethylformamide was followed by the addition of the reagent mixture consisting of 3-aminomethyl-benzonitrile (22 mg, 0.165 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), N, N 'diisopropylcarbodiimide (24 mg, 0.193 mmol), and N, N-dimethylformamide (2 ml). After stirring for 16 hours, the reaction mixture was removed, the resin was washed with N, N-dimethylformamide, methanol, and dichloromethane and dried. A sample was taken which was dissociated. HPLC: column C, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 23.70 minutes (peak showed one shoulder). 2) 5-amino-1- (3-thiocarbamoyl-benzyl) -1H-indole-2-carboxylic acid trifluoroacetic acid salt of 4-thiocarbamoyl-benzylamide -amino-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid trifluoroacetic acid 3-thiocarbamoyl-benzylamide salt.

The resin obtained in step 1.2 was treated with hydrogen sulfide, pyridine, and triethylamine in accordance with that described in Example 74/4. Due to the fact that there was still some initial material present, it was treated once more with hydrogen sulfide, pyridine, and triethylamine to obtain a complete conversion. After the dissociation of a small sample, the obtained compounds were characterized by HPLC analysis. HPLC: column C, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 20.17 minutes (53%), 20.52 minutes (32%). 3) Salt of trifluoroacetic acid 4-amidino-benzylamide of 1- (3-amidino-benzyl) -5-amino-1H-indole-2-carboxylic acid and salt of trifluoroacetic acid 3-amidino-benzylamide of acid 1- (3 -amidino-benzyl) -5-amino-lH-indole-2-carboxylic acid The resin from step 2 was treated with methyl iodide (250 μl, 4 mmol), acetone (12 ml), ammonium acetate (210 mg, 2.7 mmol), acetic acid (100 μl), and methanol (2 ml) analogously to the example (74 / 5.3). The compounds were dissociated from the resin. After evaporation, the residue was dissolved in acetonitrile / water 15:85 (400 μl). HPLC preparation of the residue resulted in two main fractions. Fraction I contained meta-para-amidine with a bis-meta-amidine impurity, Fraction II contained bis-amylamine with a meta-para-amidine impurity. A second HPLC preparation of fraction I provided . 2 mg of the meta-para-amidine (example 75) in the form of a white solid. Melting point: 146 ° C (decomposition). HPLC: column C, 0-40% acetonitrile in water, 20 minutes, 230 nm, retention time: 12.45 minutes. MS: 439.9 (M + H +).

A second HPLC for preparation of fraction II provided 12.5 mg of the bis-meta-amidine (example 76). Melting point: 125 ° C (decomposition). HPLC: column C, 0-40% acetonitrile in water, 20 minutes, 230 nm, retention time: 12.57 minutes. MS: 440.0 (M + H +).

Example 77: Acid trifluoroacetic acid 3-amidino-benzylamide salt 1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid 1) 1- (3-cyano-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid ethyl ester. 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (345 mg, 1.69 mmol) was coupled. ) to the resin (535 mg, 0.56 mmol). The resin was then stirred in dry N, N-dimethylformamide for 5 minutes, washed with N, -dimethylformamide and a mixture of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3 was added to the resin. , 2-diazaphosphorine (405 μl, 1.4 mmol) and N, N-dimethylformamide (5 ml). After stirring for 1 hour, 3-cyano-benzyl bromide (220 mg, 1.12 mmol) was added. 3 hours later the mixture was stirred. The resin was washed with N, N-dimethylformamide (5 times) and methanol (5 times) and dried in vacuo. After dissociation of a small sample, the product was characterized by HPLC. HPLC: column B, 0-80% acetonitrile in water, 40 minutes, 324 nm, retention time: 25.53 minutes. 2) 1- (3-Cyano-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid The resin obtained in step 1 was treated with benzyltrimethylammonium hydroxide (40% in methanol, 2.5 ml, 5.6 mmol) in N, N-dimethylformamide (15 ml) analogously to the resin in example 74/2. A sample was taken which was dissociated. HPLC: column B, 0-60% acetonitrile in water, 30 minutes, 324 nm, retention time: 20.98 minutes. 3) 1- (3-Cyano-benzyl-4-hydroxy-1H-indole-2-carboxylic acid 3-cyano-benzylamide The resin obtained in step 2 (98 mg, 0.1 mmol) was reacted with a hydrobromide-3 mixture. -aminomethyl-benzonitrile (64 mg, 0.3 mmol), N, N-diisopropylethylamine (70 μL, 0.4 mmol), 1-hydroxybenzotriazole (54 mg, 0.4 mmol), and N, N'-diisopropylcarbodiimide (44 mg, 0.35 mmol) in a manner analogous to examples 75 and 76, steps 1.2.4) 3-thiocarbamoyl-benzylamide of 4-hydroxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid The resin obtained in step 3 was treated with hydrogen sulfide, pyridine, and thiatrylamine in accordance with that described in Example 74.4. 5) Salt of trifluoroacetic acid 3-amidino-benzylamide of 1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid The resin obtained in step 4 was treated with methyl iodide (250 μl, 4 mmol), acetone (2 ml), ammonium acetate (210 mg, 2.7 mmol), acetic acid (100 μl), and methanol (2 ml). ) in a manner analogous to example 74, step 5.3. HPLV preparation after dissociation: the residue was dissolved in water and acetonitrile to provide 900 μl of volume. This solution was divided into two parts and each part was separated by HPLC to provide a total amount of 11 mg of a white solid. Melting point: 128-131 ° C. HPLC: column B, 0-40% acetonitrile in water, 20 minutes, 230 nm, retention time: 11.97 minutes. MS: 441.0 (M + H +). Example 78: Salt of trifluoroacetic acid 4-amidino-benzylamide of 1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid 1) 1- (3-cyano-benzyl) -4-hydroxy-l-indole-2-carboxylic acid 4-cyano-benzylamide 50 mg (0.05 mmol) of the resin obtained in example 77/2 reacted with a mixture of 4-aminomethyl-benzonitrile hydrobromide (32 mg, 0.15 mmol), N, N-diisopropylethylamine (35 μL, 0.2 mmol), 1-hydroxybenzotriazole (27 mg, 0.2 mmol), and N, N '-diisopropylcarbodiimide (22 mg , 0.175 mmol), analogously to example 74/3. 2)) 4-thiocarbamoyl-benzylamide of 4-hydroxy-1- (3-thiocarbamoyl-benzyl) -lH-indole-2-carboxylic acid The resin obtained in step 4 was treated with hydrogen sulphide, pyridine, and triethylamine. in accordance with what is described in example 74/4. 3) Salt of trifluoroacetic acid 4-amidino-benzylamide of 1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid The resin obtained in step 2 was treated with methyl iodide (125 μl , 2 mmol), acetone (1 ml), ammonium acetate (105 mg, 1.35 mmol), acetic acid (50 μl), and methanol (1 ml) analogously to example 75 / 5.3. HPLC preparation after dissociation: the residue was dissolved in water and acetonitrile and purified to provide 7 mg of a white solid. Melting point: 155- 157 ° C HPLC: column B, 0-40% acetonitrile in water, 20 minutes, 324 nm, retention time: 11.77 minutes. MS: 441.0 (M + H +). Example 79: trifluoroacetic acid salt [1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid (2- (2,4-dichloro-phenyl) -ethyl] -amide 1) [1- (3-cyano-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid (2-4,2-dichloro-phenyl) -ethyl] -amide This compound was synthesized using a substituted resin as the resin described in example 77/2 but with a minor substitution (the 2-chlorotryl chloride resin used in the binding step had only a substitution of 0.67 mmol / g). This resin (300 mg, 0.201 mmol) carrying 1- (3-cyano-benzyl) -4-hydroxy-1H-indole-2-carboxylic acid was treated with N, N-dimethylformamide for 5 minutes. After the removal of N, N-dimethylformamide, a mixture of 2- (2,4-dichlorophenyl) -ethylamine (0.51 mL, 3.35 mmol), N, N-diisopropylethylamine (0.57 mL, 3.35 mmol), diphenylphosphoryl (0.72 ml, 3.35 mmol), and N, N-dimethylformamide (6 ml). After stirring overnight, the reaction mixture was removed and the resin was washed with N, N-dimethylformamide (5 times) and methanol (5 times). After drying the vacuum, a sample was taken and dissociated. HPLC: column D; water / acetonitrile 90:10 at 10:90, 30 minutes, 324 nm, retention time: 23.10 minutes. 2) [2 (2,4-dichloro-phenyl) -ethyl] -amide of 4-hydroxy-1- (3-thiocarbamoyl-benzyl) -1H-indole-2-carboxylic acid The resin of Example 79/1 was treated similarly to that described in example 74/4. HPLC: column D; water / acetonitrile 90:10 at 10:90, 30 minutes, 324 nm, retention time: 20.74 minutes. 3) trifluoroacetic acid salt [1- (3-amidino-benzyl) -4-hydroxy-lH-indole-2-carboxylic acid [2- (2,4-dichloro-phenyl) -ethyl] -amide] The resin of Example 79 / 2 was treated in a manner similar to that described in example 74 / 5.3. HPLC preparation after dissociation gave 20 mg of a white solid. Melting point: 144 ° C. HPLC: column D; water / acetonitrile 45:55, 30 minutes, 236 nm, retention time: 9.43 minutes. MS: 481.2 (M + H +; 2x35Cl).

Example 80: Salt of trifluoroacetic acid 1- (2- (4-aminophenyl) -ethyl) -1H-indole-2-carboni1-L-arginylamide 1) 1- (2- (4-nitrophenyl) -ethyl) -lH-indole-2-carboxylic acid 1H-indole-2-carboxylic acid ethyl ester (1.027 g, 5.4 mmol) was dissolved in 15 ml of dry dimethylformamide and stirred under a nitrogen atmosphere in an ice bath. Sodium hydride (60% in paraffin oil, 174 mg, 6.85 mmol) was added and the solution was stirred for 1.5 hours at room temperature. To the reaction mixture was added 2- (4-nitrophenyl) -ethyl bromide (1.29 g, 5.6 mmol) and the solution was stirred overnight. The reaction mixture was heated for 4 hours at a temperature of 60 ° C. After the reaction was finished (thin layer chromatography, chloroform / methanol / acetic acid 90: 9.1), 20 ml of 2N hydrochloric acid were added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, and evaporated to give an orange-red oil. The oily product was taken up in methanol / water (15 ml), and 1.2 g of potassium hydroxide was added. The reaction mixture was stirred overnight to complete the hydrolysis. The treatment was achieved by the addition of 2N hydrochloric acid, and extraction with ethyl acetate. Washing of the ethyl acetate layer with water, drying with magnesium sulfate and evaporation in vacuo afforded 1- (2- (4-nitrophenyl) -ethyl) -2H-indole-2-carboxylic acid. MS: 310.2. 2) 1- (2- (4-aminophenyl) -ethyl-1H-indole-2-carbonyl-arginylamide trifluoroacetic acid salt. 1- (2- (4-Nitrophenyl) -ethyl) -lH-indole-2 acid was coupled carboxylic acid (250 mg, 0.8 mmol) to 0.54 g of Rink-L-arginyl resin (sub.0.52 mmol / g) in the presence of N, N-diisopropylcarbodiimide / 1-hydroxybenzotriazole in dimethylformamide After completion of the coupling, the resin was washed with dimethylformamide / dichloromethane and dissociated with 95% trifluoroacetic acid for 3 hours After the evaporation of trifluoroacetic acid and lyophilization, 1- (2- (4-nitrophenyl) -ethyl) -lH-indole 2- Crude carboxylic-L-arginylamide was dissolved in methanol / water (60 ml) and hydrogenated in the presence of Raney nickel catalyst at 30 psi (2. 07 hPa) for 3 hours Catalyst filtration, evaporation of the solvent and lyophilization of the residue gave the crude title compound which was purified by HPLC on a Cie column (Vydac) MS: 435.2 Example 81: Salt of trifluoroacetic acid 1- (4-amidinobenzyl) -lH-indole-2-carbonyl-L-argini lamide 1) 1- (4-amidinobenzyl) -lH-indole-2-carboxylic acid hydroiodide. LH-Indole-2-carboxylic acid ethyl ester (266 ml, 1.4 mmol) and lithium hydroxide (177 mg) were dissolved in water. ml of dry dimethyl sulfoxide. The solution was sonicated for 5 minutes and then 4-cyanobenzyl bromide (266 mg, 1.37 mmol) in 1.5 ml of dimethyl sulfoxide was slowly added. The reaction mixture was stirred overnight at room temperature. The treatment was achieved by adding 10 ml of a 1: 1 mixture of methanol and water and stirring the reaction mixture at room temperature for 6 hours. The reaction mixture was then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with water, dried with magnesium sulfate, and evaporated to dryness to provide a residual solid. The product was purified by chromatography on silica gel with ethyl acetate / hexane 5: 1 and crystallized from methanol / water to provide 202 mg of a white solid I having NMR spectra in line with the l- (4- cyano-benzyl) -lH-indole-2-carboxylic acid expected. Hydrogen sulfide gas was bubbled through a solution of 1- (4-cyano-benzyl) -lH-indole-2-carboxylic acid (202 mg) in 25 ml of pyridine / triethylamine 4: 1. After exhausting the green solution for 16 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 2N hydrochloric acid. The layers were separated and the ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude thioamide. The thioamide was dissolved in acetone (25 ml). 1.5 ml of methyl iodide was added and the reaction mixture was stirred for 8 hours. The reaction mixture was then concentrated in vacuo to dryness, the residue was dissolved in 30 ml of methane and 2.9 g of ammonium acetate were added. The reaction mixture was sonicated and heated to a temperature of 60 ° C for 15 minutes followed by stirring at room temperature for 12 hours. The precipitated solid was filtered, washed with ether and dried in vacuo. The hydroiodide of crude 1- (4-amidino-benzyl) -lH-indole-2-carboxylic acid was identified by mass spectrometry and its purity was checked by HPLC. It was used in the next step without further purification. 2) trifluoroacetic acid salt 1- (4-amidino-benzyl) -1H-indole-2-carbonyl-L-arginylamide 1- (4-amidino-benzyl) -lH-indole-2-carboxylic acid hydroiodide was coupled ( 182 mg, 0.6 mmol) was added to 0.5 g of a Rink-L-arginyl resin (sub 0.52 mmol / g) in the presence of N, N 'diisopropylcarbodiimide / 1-hydroxybenzotriazole in dimethylformamide for 8 hours. After carrying out the coupling, the resin was washed with dimethylformamide / dichloromethane and dissociated with 95% trifluoroacetic acid for 3 hours. The evaporation of trifluoroacetic acid and lyophilization-from the residue afforded the title compound. The crude product was purified by HPLC on a C? 8 column (Vydac). MS: 448.2. Example 82: 1 (N- (4-amidino-phenyl) -carba oi-methyl) -lH-indole-2-carboxylic acid ethyl ester hydroiodide 1) ethyl ester of 1- (tert-butoxycarbonyl-methyl) -1H-indo1-2-carboxylic acid this compound was synthesized from lH-indole-2-carboxylic ethyl ester and tert-butyl bromoacetate using potassium tert-butoxide in dimethylformamide with a technique similar to that described in example 79. The intermediate product was characterized by NMR spectroscopy. 2) 1- (chlorocarbonyl-methyl) -lH-indole-2-carboxylic acid ethyl ester 1- (tert-butoxycarbonyl-methyl) -1H-indole-2-carboxylic acid ethyl ester was treated with trifluoroacetic acid in dichloromethane to provide 1- (carboxymethyl) -lH-indole-2-carboxylic acid ethyl ester. Reaction of the latter intermediate with oxalyl chloride in dichloromethane afforded the title compound. 3) 1- (N- (4-cyano-phenyl) -carbamoyl-methyl) -lH-indole-2-carboxylic acid ethyl ester 1- (chlorocarbonyl-methyl) -lH-indole-2-carboxylic acid ethyl ester reacted with 4-cyano-aniline in dichloromethane in the presence of N, N-diisopropylethylamine. Treatment of the reaction mixture afforded the title compound. 4) 1- (N- (4-amidino-phenyl) -carbamoyl-methyl) -lH-indole-2-carboxylic acid ethyl ester 1- (N- (4-cyano-phenyl) -carbamoyl- ethyl ester methyl) -lH-indole-2-carboxylic acid was converted to amidine using hydrogen sulfide, methyl iodide, and ammonium acetate (without acetic acid) analogously to 1/4 and 1/5 (Example 80). The title compound was characterized by mass spectrometry and purified by HPLC. MS: 364.2. Example 83: Trifluoroacetic acid salt N- (3-amidino-benzyl) -2- [1- (3-amidino-benzyl) -lH-indol-3-yl] -acetamide 1) N- (3-cyano-benzyl) -2- (lH-indol-3-yl) -acetamide To a solution of 4 g (22.8 mmol) of (lH-indol-3-yl) -acetic acid in 90 ml of dimethylformamide was added a solution of 3.85 g (22.8 mmol) of 3-aminomethyl-benzonitrile and 3.88 ml (22.8 mmol) of ethyl-diisopropylamine in 10 ml of dimethylformamide and 3.5 g (22.8 mmol) of 1-hydroxy-benzotriazole hydrate, at a temperature of 0 ° C. After stirring for 30 minutes, 5.17 g (25.1 mmol) of dicyclohexylcarbodiimide were added. After 1 hour, the mixture was warmed to room temperature and stirred for 36 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a sodium bicarbonate solution, brine and waterdried, and evaporated.The crude product was purified by flash chromatography on silica gel by first using dichloromethane / ethyl acetate (9: 1, then 7: 3) and second dichloromethane / methanol 9: 1 to provide the product. desired with a 71% yield in the form of an oil MS: 290.2 (M + H *) 2) Trifluoroacetic acid salt N- (3-amidino-benzyl) -2- [1- (3-amidino-benzyl) ) -lH-indol-3-yl) -acetamide The title compound was prepared from N- (3-cyanobenzyl) -2- (lH-indol-3-yl) -acetamide, 3-cyanobromide- benzyl, and 2.2 equivalents of sodium hydride analogously to example 21/1 and example 1/4 and 1/5.The crude product was purified by flash chromatography on RPis material with water / ethanol / trifluoroacetic acid 7: 3: 0.1 to give the title compound in a yield of 22% Melting point: 196 ° C (decomposition) MS: 439.3 (M *) Example 84: Salt of trifluoroacetic acid 2- (4-amidino-benzoyl) -9 - (3-amidino-benzyl) -1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indole F-T ^? H 1) 2- (4-cyano-benzoyl) -1,2,3,4-tetrahydro-9H-pyrido [3,4- b] indole A mixture of 175 mg of 1, 2, 3, 4-tetrahydro-9H -pyrid [3, 4-b] indole, 5 ml of dimethylformamide, 0.2 g of 4-cyanobenzoic acid, 0.35 g of diphenylphosphoryl azide and 0.4 ml of diisopropylethylamine was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and a 10% aqueous sodium carbonate solution. The organic phase was washed with IN hydrochloric acid, dried over magnesium sulfate, and evaporated. Crystallization of the residue from methylene chloride / ether gave 245 mg of 2- (4-cyano-benzoyl) -1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indole with fusion 228-232 ° C. 2) 2- (4-cyano-benzoyl) -9- (3-cyano-benzyl) -1,2,4,4-tetrahydro-9H-pyrido [3,4-b] indole 150 mg (0.4 mmol) was dissolved ) of 2- (4-cyano-benzoyl) -1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indole in __ 5 ml of dimethylformamide. 60 mg of potassium tert-butoxide was added and the mixture was stirred for 5 minutes, treated with 100 mg of 3-cyano-benzyl bromide and heated slowly to a temperature of 80 ° C. The mixture was acidified by the addition of acetic acid and evaporated under reduced pressure. The residue was partitioned between methylene chloride and an aqueous 10% sodium carbonate solution, dried and evaporated. Chromatography of the residue in 12 g of silica using 10% (volume / volume) of ethyl acetate in methylene chloride and crystallization from ethyl acetate / hexane gave 132 mg of 2- (4-cyano-benzoyl) -9 - (3- cyano-benzyl) -1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indole with a melting point of 178-180 ° C. 3) Trifluoroacetic acid salt 2- (4-amidino-benzoyl) -9- (3-amidino-benzyl) -1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole A solution of 120 mg of 2- (4-cyano-benzoyl) -9- (3-cyano-benzyl) -1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole in 5 ml of pyridine and 2.5 ml of thiatrylamine was saturated with hydrogen sulphide and stirred in a sealed flask at room temperature overnight. The solvents were evaporated and finally co-evaporated azeotropically with toluene. The residue was stirred and the solids were collected and dried. The obtained bis-thioa ida was combined with 10 ml of acetone and 0.4 ml of methyl iodide. The mixture was stirred overnight in a sealed flask and then diluted with ether. The precipitated solids were separated, dried and dissolved in 15 ml of methanol. After the addition of 0.5 g of ammonium acetate and 0.25 ml of acetic acid, the mixture was stirred at a temperature of 55 ° C for 3 hours. The solvent was evaporated and the residue was lyophilized from acetonitrile / water containing 0.1% trifluoroacetic acid. Purification by HPLC gave the title compound with a retention time of 18.2 minutes and the correct molecular weight of 450.2 (MS). Exemplary compounds of the formula Ib listed in table 2 were prepared analogously to the compounds described above, Unless otherwise indicated in table 2, the compounds of examples 85 to 165 were obtained as trifluoroacetic acid salts .

Table 2: Example compounds of formula Ib Example No-R > 1 1 «to -RO" 18 »--PR2 * -R3 -R P.f. (a) (° C) 86 -. 86 -H -H -H 'CH, nd 95 -. 95 -H -OH -H -COOH twenty-one - . 21 -OH -H -H 184 s tt "& - < *» ^ T " 143 -. 143 -OH -H -H 210 s ^ > "H 150 -. 150 -CH3 -H (•) -H at 103 CN nd = not determined (a) form of preparation: c = classical synthesis, s = solid phase chemistry (b) obtained as acetic acid salt instead of trifluoroacetic acid salt (c) not obtained as trifluoroacetic acid salt but as the free compound (which, in the case of Example 135, is a betaine) (d) obtained as a hydrochloride instead of a trifluoroacetic acid salt analogously to the compounds described above, the compound of Example 166 was also prepared. Example 166: Salt of trifluoroacetic acid of 1-. { 3- [4- (amidino) phenyl] -2-propynyl} -N- [(4-pyridyl) methyl]. lH.indol-2-carboxamide The disclosure of all publications mentioned above is expressly incorporated herein by reference in its entirety in the same manner as if each publication were incorporated individually by reference.

Claims (16)

1. 25Q * - CLAIMS. Compounds of the formula I, where two of the radicals Rla, Rlb, Rlc and Rld independently of each other are hydrogen, F, Cl, Br, I, alkyl (C? -C), CF3, phenyl, phenylalkyl (C? -C4), alkoxy (C) C4), phenyloxy, phenylalkoxy (C? -C "), OH, N02, -NR5aR5, -NR5b-S02-R6a, -S-R6b, -SOn-R6c where n is 1 or 2, -S02- NR5aR5b, -CN or -CO-R7, and are identical or different, and the other two of the radicals Rla, Rlb, Rlc and Rld are hydrogen; R5a is hydrogen, (C1-C4) alkyl, phenyl, phenylalkyl (Ci-C4), formyl, (C 1 -C 4) alkylcarbonyl-, phenylcarbonyl-, phenyl- (C 1 -C 4) alkylcarbonyl- or phenyl (alkoxy (Ci-C)) carbonyl-; R5b is hydrogen, alkyl (C? -C4), phenyl or phenylalkyl (C? -C4); R6a is alkyl (C? ~ C4), phenyl, phenylalkyl (C? -C4) - or phenyl-NH-; R6b is (C1-C4) alkyl, phenyl or phenylalkyl (C? -C4); 6c is hydroxy, (C 1 -C 4) alkyl, phenyl or phenylalkyl (Cr C4); R7 is hydroxy, (C1-C4) alkoxy, phenylalkoxy (C? -C) or -NR5aR5b; where all radicals R5a, R5b, R6a, R615, R6c and R7 if present more than once in the molecule, are independent of each other and can be identical or different; and wherein the phenyl present in the radicals Rla, Rlb, Rlc, Rld, R5a, R5b, R6a, R60, R6c and R7 represents an unsubstituted phenyl radical or a phenyl radical substituted by one or two identical or different substituents selected from the series which consists of (C 1 -C 4) alkyl, F, Cl, Br, CF 3, (C 1 -C 4) alkoxy, N 2, OH, NH 2 and CN; one of the radicals R2 and R3 is - (CH2) p-CO-R8 and the other is hydrogen, F, Cl, Br, (C1-C4) alkyl or - (CH2) P) -CO-R8, or R2 and R3 together form a group of the formula -CH2-CH2-N (-CO-R20) -CH2- where R20 is phenyl, phenyl (C1-C4) alkyl, pyridyl or pyridylalkyl (C1-C4) and where each residue of phenyl is unsubstituted or substituted by R15a and each pyridyl residue is unsubstituted or substituted at the nitrogen atom by R14; p is 0, 1 or 2; is -NR 9'R-aAl -OR 10 or -S- (C1-C4) alkyl, where radicals R8 if present more than once in the molecule, are independent of each other and may be identical or different; R9 is hydrogen, alkyl (C? -C4) -, hydroxycarbonylalkyl (C? -C4) -, (C1-C4) alkoxycarbonyl-(C1-C4) alkyl or aminocarbonylalkyl (C? -C) -; R10 is hydrogen, (C1-C10) alkyl-, phenyl, naphthyl, phenylalkyl (C? -C4), naphthylalkyl (C1-C4), pyridyl or the radical Het, where the alkyl radical (C1-C10) and each phenyl radical and naphthyl is unsubstituted or substituted by one, two or three identical or different radicals R11, and wherein the pyridyl radical is unsubstituted or substituted at the nitrogen atom by R14, and where Het is unsubstituted or substituted by R15a; or R9 and R10 together with the nitrogen atom where they are attached form a 5 or 6 membered saturated heterocyclic ring which may contain an additional nitrogen atom in the ring and which is unsubstituted or substituted by R15a or -CO-R7; Het is the radical of a 5 or 6 membered saturated heterocyclic ring containing 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; R11 is -N (R12) 2, -OR12, -C0-N (R13) 2, -CO-R7, R15b, alkyl (C? -C? 4), phenyl unsubstituted or substituted by one, two or three radicals R > 15b identical or different, naphthyl unsubstituted or substituted by one, two or three identical or different R15b radicals, quinolinyl unsubstituted or substituted by one, two or three identical or different radicals, R15b and / or substituted at the nitrogen atom by R14, isoquinolinyl unsubstituted or substituted by one, two or three R15b radicals identical or different and / or substituted on the nitrogen atom by R14, unsubstituted pyridyl or substituted at the nitrogen atom by R14, or Het unsubstituted or substituted by R15a, where radicals R11 if present more than once in the molecule, are independent of each other and can be identical or different; each radical R12 independently of the denotation of another radical R12 is hydrogen, (C? -C4) alkyl, phenyl, phenylalkyl (C? ~ C4), naphthyl, naphthylalkyl (C? -C4) -, pyrrolidinyl, piperidinyl, pyrrolidinylalkyl (C ? -C) - or piperidinylalkyl (C? ~ C4) -, wherein each pyrrolidinyl radical and each piperidinyl radical is unsubstituted or substituted at the nitrogen atom by phenylalkyl (Ci-C) or R15a; each radical R13 independently of the denotation of another radical R13 is hydrogen, alkyl (C? -C), phenyl, phenylalkyl (C? -C4), naphthyl or naphthylalkyl (C1-C4), or the two radicals R13 together with the The nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclic ring which may contain an additional nitrogen atom or an additional oxygen atom in the ring where the additional nitrogen atom in the ring is unsubstituted or substituted by alkyl ( C? -C4), or phenylalkyl (C1-C4); R14 is alkyl (C? -C6), alkenyl (C? -C6), alkynyl (Ci-Ce), phenylalkyl (Ci-Ce) - or (C? -C6 alkoxy) carbonylalkyl (C? -C6), where the phenyl present in R14 refers to an unsubstituted phenyl radical, the substitution by these radicals in the nitrogen atom of the heterocyclic radical causes a positively charged group having X "as counter ion, or R14 is oxide, this substitution in the nitrogen atom of the heterocyclic radical causing an N-oxide, and where the radicals R14 if present more than once in the molecule, are independent of each other and can be identical or different; R15a is alkyl (Cx) -C6), (alkyl (C? -C6) -C (= NH) -, - (CH2) tN (R16) 2, - (CH2) t-N + (R15a) 2 (-0-), - (CH2 ) t-N + (R16a) 3XJ - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t ~ CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or well - (CH2) t-NH-C (= NR17) -NHR17, where (alkyl (C? -C6) -C (= NH) - is attached to a ring nitrogen atom, and where the radicals R15a, if they are present more than once in the molecule, they are independent among them and can be identical or different; R 15b is alkyl (C? -C6), hydroxy, (C1-C4) alkoxy, F, Cl, Br, I, N02, - (CH2) tN (R, 1i6D) 2, - (CH2) t-N + (R16a) 2 (-0"), - (CH2) t- N + (R16a) 3X ~, - (CH2) t-NHR17, - (CH2) t-CO-OR18, - (CH2) t-CO-N (R18) 2, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where alkyl may be substituted 1, 2, 3, 4, 5, 6 or 7 times by fluoro , and where the radicals R15b, if present more than once in the molecule, are independent of each other and can be identical or different, t is 0, 1, 2 or 3, where the numbers t, if present, are more than once in the molecule, they are independent of each other and can be identical or different, each radical R16 independently of the denotations of another radical R16 is hydrogen, alkyl (Ci-Cß), alkenyl (Ci-Cß), alkynyl (Ci-Cß), phenylalkyl (Ci-Cß), or (C 1 -C 6 alkoxy) carbonylalkyl (C 1 -C 6) wherein the phenyl present in R 16 represents an unsubstituted phenyl radical, and where groups containing R 16 radicals if present more than once in the molecule, are independent of each other and they can be identical or different; each radical R16a, independently of the denotations of another radical R16a is alkyl (Ci-Cß), alkenyl (Ci-Cß), alkynyl (C? -C6), phenylalkyl (Ci-Cß), or (alkoxy (Ci- Ce )) carbonylalkyl (Ci-Cß), where the phenyl present in > 16a refers to an unsubstituted phenyl radical, and where groups containing R, 16a radicals, if present more than once in the molecule, are independent of each other and can be identical or different; each radical R17 independent of the denotation of another radical R17 is hydrogen, alkyl (C? -C6), alkylcarbonyl (Ci-Cß) -, alkoxycarbonyl (Ci-Cß) -, alkylcarbonyloxy (Cx-C6) -, alkoxycarbonyl (Ci-) Cß) -, phenylcarbonyl-, phenoxycarbonyl-, phenylalkoxycarbonyl (C? -C6), hydroxy, alkoxy (Ci-Ce), phenylalkoxy (Ci-Cß) - or amino, and also in the groups - (CH2) tC (= NR17 ) -NHR17 and - (CH2) t-NH-C (= NR17) -NHR17 the two radicals R17 together with the group C (= N) -NH to which they are attached, can form a 5- or 6-membered heterocyclic ring and wherein the phenyl present in R17 refers to an unsubstituted phenyl radical, and wherein groups containing R17 radicals if present more than once in the molecule, are independent of each other and may be identical or different; each radical R18 independent of the denotation of another radical R18 is hydrogen or (C1-C4) alkyl; A is a direct bond, a radical-saturated (C1-C4) alkyl-divalent or containing a double bond or a triple bond, -CO-, -Sor-, where r is 1 or 2, -CO-alkyl ( C? -C4) -, -alkyl (C? -C) -CO- or -alkyl (C? ~ C4) -CO-NH- -where nitrogen is bound to R4; R 4 is phenyl substituted by a radical R 15c and which may additionally be substituted by one or two substituents of the series consisting of (C 1 -C 4) alkyl, F, Cl and Br, or R 4 is unsubstituted or substituted pyridyl at the atom of nitrogen by R14, or R4 is the radical Het substituted by R1 d; R15c is - (CH2) tN (R16) 2, - (CH2) t -N + (R16a) 2 (-0 ~), - (CH2) t- N + (R16a) 3X ", - (CH2) t-NHR17, - (CH2) t ~ CN, - (CH2) t ~ CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17; R15d is ((C? -C6) alkyl) -C (= NH) -, - (CH2) tN (R16) 2, - (CH2) t- N + (R16a) 2 (-0 '), - (CH2 ) t-N + (R16a) 3XJ - (CH2) t-NHR17, - (CH2) t-CN, - (CH2) t-CS-N (R18) 2, - (CH2) tC (= NR17) -NHR17 or - (CH2) t-NH-C (= NR17) -NHR17, where (alkyl (C? C6)) -C (= NH) - is attached on a ring nitrogen atom; X "is a physiologically acceptable anion, in all its stereoisomeric forms and mixtures thereof in any proportion, and its physiologically acceptable salts 2. Compounds of the formula I according to claim 1, wherein A is a -alkyl radical ( C? -C4) - divalent, in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically acceptable salts 3. Compounds of the formula I according to claim 1 and / or according to claim 2 wherein R 4 is phenyl substituted by a radical R 15c, in all its stereoisomeric forms and mixtures thereof in any proportion, and physiologically acceptable salts thereof. Compounds of the formula I according to one or more of claims 1 to 3, wherein R15c is - (CH2) tC (= NR17) -NHR17, in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically acceptable salts. These of the formula I according to one or more of claims 1 to 4, wherein A is the methylene radical -CH2- and R4 is phenyl substituted by -C (= NR17) -NHR17 in the meta position, in all its forms stereoisomers and mixtures thereof in any proportion, and their physiologically acceptable salts. Compounds of the formula I according to one or more of claims 1 to 5, wherein R3 is -CO-R8, in all its stereoisomeric forms and mixtures thereof in any proportion, and their physiologically acceptable salts. Compounds of the formula I according to one or more of claims 1 to 6, wherein R 2 is hydrogen, Cl or Br, in all their stereoisomeric forms and mixtures thereof in any proportion, and their physiologically acceptable salts. Compounds of the formula I according to one or more of claims 1 to 7, wherein the radicals Rlc and Rld are hydrogen, in all their stereoisomeric forms and mixtures thereof in any proportion and their physiologically acceptable salts. 9. Compounds of formula I according to one or more of claims 1 to 8, wherein one of the radicals Rla and Rlb is hydrogen and the other is selected from the series consisting of hydrogen, methyl, F, Cl, Br, I, hydroxy, alkoxy (C? -C), phenylalkoxy (C? ~ C) - and -NHR5a, in all their stereoisomeric forms and mixtures thereof in any proportion, and their physiologically acceptable salts. 10. A process for the preparation of a compound of the formula I according to one or more of claims 1 to 9, comprising the condensation of a compound of the formula VII with a compound of the formula HR8 to provide a compound of the formula VIII, and the optional conversion of the compound of the formula VIII into a compound of the formula I, Vile Vile! where the radicals R8, identical or different, may have the denotations of R8 indicated in claims 1 to 9, but where in R8 functional groups may also be present in the form of groups subsequently transformed into the final functional groups present in R8, and where the radical R40 can mean the group -A-R4 or can mean a group subsequently transformed into the group -A-R4, and where the groups -COR41, identical or different, can be carboxylic acid groups or derivatives thereof, and wherein the groups Rla, Rlb, Rlc and Rld are defined according to claims 1 to 9 or functional groups may also be present therein in protected form or in the form of precursor groups. 11. A pharmaceutical composition comprising one or more compounds of the formula I according to one or more of claims 1 to 9 and / or their physiologically acceptable salts together with a pharmaceutically acceptable carrier. 12. A compound of formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts, for use as a pharmaceutical agent. 13. A compound of the formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts, for use as a factor Xa inhibitor. A compound of the formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts, for use as an inhibitor of blood coagulation. 15. A compound of the formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts, for use in the treatment or prophylaxis of cardiovascular disorders or thromboembolic conditions. 16. A compound of formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts for use in the treatment or prophylaxis of thrombosis, cardiac infarction, angina pectoris, restenosis or reocclusion.