MXPA00009968A - Amidine compounds - Google Patents

Abstract

Compounds represented by general formula [I]or salts thereof or prodrugs of the same [I]wherein R1, R2 and R3 are the same or different and each represents hydrogen, hydroxy, lower alkyl or aryl;and R represents formulas (a), (b) and (c) (wherein each symbol has the meaning as defined in the specification). These compounds, salts thereof or prodrugs of the same are useful as factor Xa inhibitors and anticoagulants and usable in preventing and/or treating diseases caused by blood coagulation or thrombi.

Description

COMPOSITE AMIDINE SPECIFICATION FIELD OF THE INVENTION The present invention relates to a novel amidine compound having an inhibitory activity on the coagulation factor Xa. The present invention also relates to a pharmaceutical composition, a factor Xa inhibitor and a therapeutic agent for diseases caused by blood coagulation or thrombi, which comprises this compound.

BACKGROUND OF THE INVENTION One of the etiologies of thrombosis, such as unstable angina, deep vein thrombosis and disseminated intravascular coagulation (DIC), is the promotion of blood coagulation. For the prophylaxis and treatment of thrombi, heparin and warfarin have been conventionally used. Heparin acts on antithrombin III (ATIII) to indirectly inhibit the coagulation system and, therefore, may show a weak action on arterial thrombi. Heparin is associated with the generation of an antibody against platelet factor (PF4), which causes coagulation in some patients, and a propensity towards hemorrhages as a side effect. Warfarin requires more time for the expression of the effect as a drug and is not necessarily an easy and safe drug. Under these circumstances, a new anticoagulant is desired to overcome these problems. Factor X is a glycoprotein that has a molecular weight of 58. 000 and, in an intrinsic pathway, factor X is activated on a phospholipid membrane in the presence of a factor IXa / factor Vllla / Ca2 + complex and converted to a factor Xa. In the coagulation system called the extrinsic pathway, factor X is activated by the factor Vlla in the presence of a tissue factor and becomes a Xa factor. Factor Xa generated in both pathways activates prothrombin to give thrombin. The generated thrombin in turn activates the current of this cascade to produce a large amount of thrombin. Consequently, fibrinogen is converted to fibrin and blood clotting occurs. While the blood coagulation system is an amplification reaction, the inhibition of thrombin generation in the first stage is considered more efficient than the direct inhibition of the generated thrombin activity. Furthermore, given factor Xa is the confluence of intrinsic and extrinsic coagulation pathways, the inhibition of factor Xa is considered extremely effective. Some reports have documented that low molecular weight heparin showed a lower holding bleeding than heparin in clinical applications, and in a test using a mandrel (Thrombosis and Haemostas, 74.464 (1995)), it was found that inhibition of factor Xa, unlike thrombin, showed less tendency to bleed.

Therefore a factor Xa inhibitor has a potential to show an antithromb effect without influencing the bleeding time observed in the use of conventional anticoagulants. As a factor Xa inhibitor, WO97 / 08165 describes a compound of formula; wherein R1, R2 and R3 are each a hydrogen atom, hydroxy, halogen atom, hiroxialquino, alkyl, alkenyl, alkynyl, alkoxy, aralkyloxy, alkenyloxy, alkynyloxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alqueniloxicarbonilalquilo , alquiniloxicarbonilalquilo or, A is an alkene optionally substituted by hydroxy, carboxy, alkoxycarbonyl or halogen atom, X is a bond, alkylene or alkyleneoxy, Y is a single bond, an atom chalcogen or CO, Z is a saturated hetero ring or unsaturated optionally substituted, or a carbon atom, or an amino, hydroxy, carboxy, alkoxycarbonyl or optionally substituted alkyl, n is an integer of 1 or 2 m is an integer from 0 to 4. also the Japanese patent application Unexamined , No. 5-208946 (US Patent No. 5620991, EP No. 540051) describes a compound of the formula; • * - * - - R1? _j_ HT 2 O? V? A R4 * "'0" 2 ^ wherein R 1 is a hydrogen atom or a lower alkoxy, R 2 is a hydrogen atom, lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, or alkoxycarbonylalkyl, R 3 is hydrogen atom, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, carboxyalkoxy or alkoxycarbonylcoxy, R4 is hydrogen atom, hydroxy, lower alkyl or lower alkoxy, n is an integer of 0 or 1, A is C1-C4 alkylene optionally substituted, by 1 or 2 substituents hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl X is a single bond, oxygen atom, sulfur or carbonyl atom, Y is an optionally substituted saturated or unsaturated 5- or 6-membered heterocyclic group, or a cyclic hydrocarbon group, an optionally substituted amino or an optionally substituted aminoalkyl and a group of the formula; it is selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahldronaphthyl and indanyl. In addition, WO96 / 16940 describes a compound of formula; wherein R1 is a hydrogen atom or a group of formula -A-W-R4 wherein A is a group of formula; X2 0 0 II II II - c- - C-C- or -S02- wherein X2 is an oxygen atom or a sulfur atom and W is a single bond or -NR5-, R4 is hydroxy, lower alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or heteroaryl optionally substituted with the proviso that when W is a group of formula -NR5-, R4 may be a hydrogen atom but is not hydroxy or lower alkoxy, wherein R5 is a hydrogen atom, carbamoyl, lower alkoxycarbonyl, mono or dialkylaminocarbonyl lower, lower alkylsulfonyl, mono or dialkylaminothiocarbonyl, optionally substituted lower alkyl or optionally substituted lower alkanoyl; R2 is a lower alkyl; R3 is a hydrogen atom, halogen atom, carboxy, amino, cyano, nitro, hydroxy, lower alkoxy, lower alkyl or lower alkoxycarbonyl; B is a lower alkylene or carbonyl; and n is an integer of 0 or 1.

BRIEF DESCRIPTION OF THE INVENTION The present invention seeks to provide a new compound useful as a factor Xa inhibitor. The present invention also seeks to provide a novel factor Xa inhibitor. In view of the above situation, the present inventors conducted intensive studies to try to find a compound useful as a factor Xa inhibitor and found the amidine compound of formula I. They further found that the compound can be a higher factor Xa inhibitor and completed the present invention. The compound of the present invention specifically inhibits the coagulation factor Xa and shows strong anticoagulant action. Therefore, the compound is useful as an agent for the prophylaxis and / or treatment of various diseases caused by blood coagulation or thrombi, for example cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, attack of transient ischemia ( AUNT) subarcnoid hemorrhage and the like; ischemic heart diseases such as chronic myocardial infarction, unstable angina, coronary thrombosis and the like, vascular diseases lungs such as pulmonary infarction, pulmonary embolism and the like; and diseases caused by various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after artificial blood vessel surgery or replacement of artificial valves, reocclusion or restenosis after coronary commutation, reocclusion or restenosis after recanalization such as percutaneous coronary transluminal angioplasty (PTCA), percutaneous coronary transluminal racanalization (PTCR) and the like, thrombosis due to extracorporeal circulation and the like, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger's disease, tumor thrombosis, thrombi by atrial fibrillation and the like. As is evident in the experimental example 2 mentioned below, since the compound of the present invention has no inhibitory activity against thrombin, ie the factor lia (Fila), the hemorrhage as a side effect is considered markedly inferior. Experimental examples 6 and 7 which will be mentioned below reveal a surprising effect of factor Xa inhibitor by oral administration. There is also the finding that factor Xa is involved in the growth of the influenza virus (Japanese Unexamined Patent Publication No. 6-227971). Thus, it is expected that the compound of the present invention is useful for the prophylaxis and / or treatment of influenza. The present invention relates to a compound of formula I useful as a factor Xa inhibitor. In addition, the present invention relates to factor Xa inhibiting agent that contains a compound of the formula I or a salt thereof or a prodrug that contains it as an active ingredient. More particularly, the present invention provides the following 1-23. 1) An amidine compound of formula I; .R3 XAV- (I) R¿ wherein R is a group of formula; wherein R 4 is a hydrogen atom, hydroxy, lower alkyl, lower alkoxy or halogen atom, R 5 is hydrogen atom, cyano, carboxy, or lower alkoxycarbonyl, R 6 is hydrogen atom, cycloalkyl, hydroxy, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl. Wherein said aralkyloxycarbonyl is optionally substituted by halogen atom, nitro, alkyl, alkoxy or trifluoromethyl; nitro, amino, lower alkylamino, dialkylamino, aryl, heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents selected from lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, nitro, amino, acylamino, amidino, and hydroxyamidino; a saturated 5- to 7-membered heterocycle with at least one nitrogen atom, wherein said saturated heterocycle is optionally substituted by lower alkyl, acyl, dialkylamino lower lower alkanoyl or imidoyl, or; wherein Ak is a lower alkyl and Hal is a halogen atom. X2 is an oxygen atom, sulfur atom -SO2-, SO2NH- or a single bond; X3 is - (CH2) m- where m is 0 or an integer from 1 to 3; X4 is -CO-, C = NH-, S02-, -CONH-, -CSNH-, -S02NH-, - (CH2) rCONH-, - (CH2) rCH (OH) -, where r is 0 or an integer from 1 to 3, or a single bond; X5 is an alkyiien having 1 to 6 carbon atoms, an alkylene having 2 to 6 carbon atoms or a single bond; R7 is hydrogen atom, lower alkyl or; R9 R10 wherein R9 is oxygen atom, sulfur atom, NH, NR11 wherein R11 is lower alkyl, aralkyl. Wherein said aralkyl is optionally substituted by 1 to 3 substituents selected from halogen atoms, lower alkyl, hydroxy, lower alkoxy, haloalkyl, cyano, nitro, amino and acyloxy; or hydroxy; and R10 is lower alkyl, lower alkoxy, amino, lower alkylamino or lower dialkylamino; wherein R8 is hydrogen atom, lower alkyl, cycloalkyl; wherein cycloalkyl is optionally substituted by lower alkyl or carboxy, carboxy, lower alkoxycarbonyl, aryl, heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents selected from halogen atoms, lower alkyl wherein said lower alkyl is optionally substituted by halogen atom, hydroxy, lower alkoxy, carboxy, and lower alkoxycarbonyl; aralkyl wherein the aralkyl is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl, hydroxy, lower alkoxy, haloalkyl, cyano, nitro, amino and acyloxy; or a saturated 5- to 7-membered heterocycle with at least one nitrogen atom; Y1 is an oxygen atom, -NH-, -CONH-, -NR12- wherein R12 is a lower alkyl or -Y6-R13; wherein R 13 is a hydrogen atom, lower alkyl or aryl; wherein said lower alkyl or aryl is optionally substituted by carboxy, lower alkoxycarbonyl or aralkyloxycarbonyl; Y6 is -CO-, -C02-, -COC02-, -SO2-, -S02 (CH2) r or - (CH2) r; wherein r is 0 or an integer from 1 to 3; or a simple link; Y2 is an oxygen atom, sulfur atom or a single bond; Y3 is; where s and t are the same or different and each is an integer 1 to 3, or a single link; Y4 is oxygen atom, -CO-, -C02-, -S02-, -CONH-, -CH = CH- or a single bond; Y5 is - (CH2) P-, - (CH2) p-CHAk- (CH2) p-CakAk '- (CH2) p " wherein Ak, Ak 'are the same or different and each is a lower alkyl, p is 0 or an integer from 1 to 3, p' and p "are the same or different and each is 0 or an integer from 1 to 2; or a simple link, ring A is; wherein R14 is carboxy, lower alkoxycarbonyl or aralkyloxycarbonyl wherein said aralkyloxycarbonyl is optionally substituted by halogen atom, nitro, alkyl, alkoxy or trifluoromethyl; j is l or 2, k is O or l. and m and n are the same or different and each is 0 or an integer from 1 to 3; and R1 R2 and R3 are the same or different and each is a hydrogen, hydroxy, lower alkyl or aryl atom; or a salt thereof or a prodrug thereof. (2) The amidine compound of the formula I described above in (1) wherein R is a group of the formula; wherein R 4, R 5, R 6, X 2, X 3, X 4, X 5, j and k are as defined above to a salt thereof or a prodrug thereof. (3) The amidine compound described in (2) with the formula I wherein R is a group of formula; wherein R 4, R 5, R b, X 2, X 3, X 4, X 5, j and k are as defined above, or a salt thereof or a prodrug thereof. (4) The amidine compound described in (3) with formula I wherein R is a group of formula; wherein R 4, R 5, R 6, X 2, X 3, X 4, X 5, j and k are as defined above, or a salt thereof or a prodrug thereof. (5) The amidine compound described in (4) with formula I wherein X3 is - (CH2) m- where m is as defined above and X4 is a group of formula; and j is 1; or a salt thereof or a prodrug thereof. (6) The amidine compound described in (5) with formula I wherein R6 is a hydrogen atom, X2 is an oxygen atom and X5 is a single bond; or a salt thereof or a prodrug thereof. (7) The amidine compound of the formula I described in (1) wherein R is a group of formula; wherein R7, R8, Y1, Y2, Y3, Y4, Y5, ring A, m and n are as defined above; or a salt thereof or a prodrug thereof. (8) The amidine compound described in (7) with formula I wherein ring A is a group of formula; or a salt thereof or a prodrug thereof. (9) The amidine compound of (1) selected from the group consisting of: 7- [1- (pyridin-4-yl) p -peridin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2- carboxamidine, 7- [1- (quinolin-4-yl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-methyl-7- [1- (pyridin-4-yl ) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinol Na-2-carboxamidine oxime, N-phenyl-7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, ethyl 4-carboxymethyl ester - (2-amidino-1,2,3,4-tetrahydroisoquinoline-7-yloxymethyl (1-1-pyridin-4-yl) piperidine-4-carboxylic acid 4- (2-amidino-1, 2,3,4 -tetrahydroxyquinoline-7-yloxymethyl (1-1-pyridin-4-yl) piperidine-4-carboxylic acid 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- ethyl ester (2-6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroxy-quinolin-7-yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid, methyl ester of -4- ( 2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amino-1, 2, 3,4-tetrahydroxyquinoline-7-yloxymethyl) -1- (2-methylpyridin-4-ylo) piperidine-4-carboxylic acid, 4-2 (amidino-1, 2,3,4-tetrahydroxyquinoline-7-) iloxymethyl) -1- (pyrimidin-4-yl) piperidine-4-carboxylic acid 4- (2- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxy (ethyl) -1 ethyl ester) - (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2- (2-amidino-1, 2,3,4-tetrahydroxy-quinolin-7-yloxy) ethyl) -1- (pyrimidin-4) -yl) piperidin-4-carboxylic acid, 4- (N- (5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazol-2-ylmethyl) -N- (4- (1-acetylimidopyridin-4) Lox?) Phenyl) carbamoyl) benzoic acid, 4- (N- (5-amidino-1- (4-benzylloyphenylethylcarbamoylmethyl) benzimidazol-2-methyl) -N- (4- (1-acetylimidopiperi d in-4-yloxy) phenyl) carbamoyl) benzoic acid, 2- (4- (pyrrolidin-3-yloxy) phenoxymethyl) -1- (2-methoxyethyl) benzimidazole-5-carboxamidine, 2- (4- (1-acetyl) doilpyrrolidin-3-yloxy) phenoxymethyl) -1- (2-methoxyethyl) benzimidazole-5-carboxamidine, 7- [1- (2-hiroxyethyl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline -2-carboxamidine, 7- [1- (pyridin-4-ylmethyl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (2-Hiroxyethyl-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, ethyl ester 4- (2-amidino-1,2, 3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-ylacetylglycine, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-acetic acid N-methylamide, 7- ( 1-acetylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-benzylsulfopiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (2-naphthylsulfonyl) piperidin-4-ylmethoxy) -1, 2 , 3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-fenilacetimidoilpiperidin-4-ylmethoxy) -1 , 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N- (2- (4- (2-amidin-1, 2,3,4-tetrahiroisoquinolin-7-yloxymethyl) piperidin-1-yl) pyridin-5-yl) acetamie, N- (2- (4 (2-amidin-1, 2,3,4-tetrahiroisoquinoline-7-yloxymethyl) piperidin-1-yl) pyridin-5-illo) benzamia, 3- (4- (4- (2-amidino-1, 2,3,4-tetrahiroisoquinoline-7-yloxymethyl) pyrimidin-1-yl) pyridin-3-yl ethyl ester ) -2-propenoic acid 4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-yl) pyridine-3-carboxylic acid methyl ester, 4- (4- (2-amidino-1, 2,3,4-tetrahiroisoquinoline-7-yloxymethyl) piperidin-1-yl) pyridine-3-carboxylic acid, 6- (1- (pyridin-4-yl) piperidin -4-ylmethoxy) -1, 2,3,4-tetrahiroisoquinoli-2-carboxamidine, 7- (2- (4-cyano-1- (pyridin-4-yl) piperidin-4-yl) ethoxy) - 1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4- (2-amidino-2,3,4,5-tetrahydro-1 H -benzo (c) azepine-8-yloxymethyl) -1 ethyl ester - (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-2,3,4,5-tetrahydro-1 H -benzo (c) azepine-8-yloxymethyl) -1- (pyridine -4-yl) piperidin-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2- (2-amidino-1, 2,3,4-tetrahydroquinol-7-ylthio) ethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid - (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidin-1, 2,3) , 4-tetrahydroisoquinolin-7-ylthiomethyl) -1 - (pyridin-4-yl) piperidine-4-carboxylic acid ester 4- (2-amidino-1, 2,3,4-tetrahydroisoquinol-7-ylsulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1) acid , 2,3,4-tetrahydroisoquinol-7-lysulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester of 4- (2-amidin-1, 2) , 3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid, 1- (2- (benzothiazole-2- yl) -2-oxoethyl) -2-5-carboxamidine fenoximetilbencimiazol-, trans-4- (2- (4- (1-acetimioilpiperidin-4-yloxy) phenoxymethyl) -5-amidinobencimidazol-1-ilacetilaminometil) c¡clohexanocarboxílico , trans-4- (2- (4- (1-Acetimidoylpiperidin-4-yloxy) phenoxymethyl) -5- (N-methylamidino) benzimidazol-1-ylacetylaminomethyl) cyclohexanecarboxylic acid, trans-4- (2- (4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl) -5-amino (h¡droximino) methylbenzimidazole-1-¡lacetilaminometil) cyclohexanecarboxylic, 2- (4- (piperidin-4-yloxy) phenoxymethyl) -1-fenacilbencim¡azol- 5-carboxamidine, 2- (4- (1-Acetylimdoylpiperiin-4-yloxy) phenoxymethyl) 1-phenazbenzimidazole-5-carboxamidine, 2- (2- (4-ethoxycarbonyl-1 - (pyridin-4-yl ) p¡peridin-4-yl) ethyl) -1-5-carboxamidine -ciclohexilcarbamoilmetilbenzimidazol, 4- (2- (5-amidino-1- (ciclohexilcarbamoilmetil) benzim¡dazol-2-yl) ethyl-1- (pyridin -4-yl) piperidin-4-carboxylic acid, 1-cyclohexylcarbamoylethyl-2- (N- (1- (pyridin-4-yl) piperidin-4-yl) -N-ethoxalylaminomethyl) benzimiazole-5-carboxamidine , N- (5-amidino-1-cyclohexylcarbamoylmethylvenzimidazol-2-ylmethyl) -N- (1-pyridin-4-yl) piperidin-4-yl) aminooxalic acid, 2- (N- (4- (1-acetimidoylpiperiin- 4-yloxy) phenyl) -N-ethoxycarbonylmethylaminomethyl) -1-cyclohexylcarbamoylmethylbenzimiazole-5-carboxamidine, N- (5-amidino-1-cyclohexylcarbamoylmethylbenzamidazol-2-ylmethyl) -N- (4- (1-acetimidoylpiperidin-4-yloxy) phenyl) carbamoylbenzoic acid, 2- (N- (4- (1 -aminopiperidin-4-yloxy) phenyl) -N- (4-metoxicarbon¡lbenzo¡l9aminometil- 1-ciclohexilcarbamoilmetilbenzimiazol-5-carboxamidine, N- (5-amidino-1-ciclohexilcarbamoilmetilbenzimiazol-2ylmethyl) -N- (4 - (1-amidinopiperidin-4-yloxy) phenyl) carbamoilbenzoico, N- (5-amidino-1-ciclohexilcarbamoilmetilbenz¡miazol-2ylmethyl) -N- (4- (1-am¡dinopiperidin-4-yloxy) phenyl carbamoylbenzoic, 7- (1- (pyridin-4-ylacetyl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (3-aminobenzyl) piperidine- 4-ylmethoxy) -1,2,3,4-tetrahydroquinoline-2-carboxamidine, 7- (1- (2-aminobenzyl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline- 2-carboxamidine, 7- (1- (pyridin-2-ylmethyl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 2- (4- (2-methyl) methyl ester -amidino-1, 2,3,4-tetrahydroisoquinolin-7- (loxymethyl) piperidin-1-methyl) indole-1-carboxylic acid benzyl ester (4- (2-amidino-1, 2,3,4 -tetrahydroisoquinolin-7-methoxymethyl) piperidin-1-acetic acid, N-benzyl (4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolyl-7-yloxymethyl) piperidine-1-carboxamide, 7- (1- (ndol-2-ylmethyl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-acetic acid, N-benzyl-4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-carboxamide, 4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-ylacetylaminoacetic acid, 7- (1 - (5-nitropyridin-2-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (2-nitrobenzyl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (2-nitrobenzyl) piperidin-4-methoxy) -1, 2,3,4-tetrahydroxyquinoline-2-carboxamidine, 7- (1-hexanoimidoylpiperidin-4-methoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7) -iloxymethyl) piperidin-1-sulfonamide, N-butyl-4- (2-amidino-1, 2,3,4-tetrahiroisoquinolin-7-yloxymethyl) piperidin-1-sulfonamide, N-cyclohexyl-4- (2 -amidino-1,2,3,4-tetrahydroisoquinolyl-7-yloxy) piperidin-1-sulfonamide, N- (2-nitrophenyl) -4- (2-amidino-1, 2,3,4- tetrahydroisoquinolin-7- iloxymethyl) piperidin-1-carbothioamide, 7- (1- (benzamidazol-2-yl) -piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, «_.--, -. , _. n? Ethyl 3- (4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-propionic acid ethyl ester, 3- (4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-propionic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7) -yloxymethyl) -1- (2-aminopyridin-5-ylcarbonyl) piperidin-4-carboxylic acid, 4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1 - (3-aminopropionyl) piperidin-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (imidazol-4-ylacetyl) piperidine-4-carboxylic acid , 4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) -1- (p-peridin-4-ylsulfamoyl) piperidine-4-carboxylic acid, 4- (2- amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) -1-dimethylaminoacetylpiperidine-4-carboxylic acid ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-) iloxymethyl) -1- (pyridin-3-ylcarbamoyl) piperidine-4-carboxylic acid ethyl ester of 4- (2-amidino-1) , 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-dimethylaminoacetylpiperidin-2-ylcarbonyl) piperidine-4-carboxylic acid, 4- (4- (2-amidino-1,2, 3,4-tetrahydroisoquinolin-7-yloxymethyl) -4-carboxypiperidin-1-yl) -methylpyridinium, ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinol) n-7-methoxymethyl) -4-amidinophenyljpiperidine ^ -carboxylic acid ethyl ester of 4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1 - (2,6 -dimethylpyridin-4-yl) piperidine-4-carboxylic acid, Ethyl 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-methylpyridin-4-yl) -piperidine-4-carboxylic acid ethyl ester, ethyl ester of 4- (2-amidino-1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) -1- (1-etllpiperidin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidino) -1, 2,3,4, -tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidine-4-carboxylic acid, 7- (2- (4-cyanopiperidin-4-ylethoxy) -1, 2,3,4-tetrahydroxyquinoline-2-carboxamidine, 4- (2- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl) pyridin ethyl ester -4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-6-methoxy-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1 - (pyridin-4-yl) piperidin- 4- carboxylic acid and 4- (2-amidino-6-methyl-1, 2,3,4-tetrahydroisoquinol-7-oxoxyethyl) -1- (pyridin-4-yl) piperidin- 4- carboxylic acid, or a salt thereof or a prodrug thereof. (10) The amidine compound of (3) which is selected from the group consisting of 7- [1- (pyridin-4-yl) piperidin-4-methoxy] -1, 2,3,4-tetrah Droisoquinol-2-carboxamidine, 7- [1- (quinolin-4-yl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-methyl-7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine oxime, N-phenyl-7- [1- (pyridin-4- It) piperidin-4-ylmethoxy] -1.2.3.4-tetrahydroisoquinoline-2-carboxamidine, ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl (1-pyridin-4-yl) p -peridine-4-carboxylic acid 4- (2- amidino-1, 2,3,4-tetrahydroisoquinoline-7-oxoxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester -4- (2-amidino-, 1, 2, 3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2,6-dimethyl-pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline- 7-oxoxymethyl) (2-methylpyridin-4-yl) p -peridine-4-carboxylic acid methyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) (2-methylpyridin-4-yl) piperidine-4-carboxylic acid, 4- (2- (amidinium-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2-methylpyridin-4-) ilo) piperidine-4-carboxylic acid, 4- (2- (amidinium-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, ester Ethyl 4 - (- 2 (-2 (amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid co, 4- (2 - (- 2- (amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl) -1 - (pyridin-4-yl) piperidine-4-carboxylic acid, 7- [ 1- (2-Hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-4-ylmethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (2-hydroxy-2-phenylethyl) piperidin-4 -ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-ylacetylglycine , 4- (2-amidin-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-acetic acid N-methylamide, 7- (1-acetylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamide, 7- (1-benzyl-sulfonylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (2-naphtol lsulfonyl) piperidin-4-methoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-acetimidoylpperidin-4-ylmethoxy) -1, 2,3,4- tetrahydroisoquinoline-2-carboxamidine, 7- (1-phenylacetimidoylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N- (2- (4- (2-amidino-1, 2,3 , 4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-5-yl) acetamide, N- (2- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinol ina-7-yloxymethyl) piperdin-5-yloxybenzamide, 3- (4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-yl) ethyl ester ) pyridin-3-yl) -2-propenoic, ^^^ 4- (4- (2-Amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-yl) pyridine-3-carboxylic acid methyl ester, 4- (4- (2-amido No-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidine-3-carboxylic acid, 6- (1-pyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline - 2-carboxamidine, 7- (2- (4-cyano-1- (pyridin-4-yl) piperidin-4-yl) ethoxy) -1,2,3,4-tetrahydroxyquinoline-2-carboximidine ester Ethyl 4- (2-amidino-2,3,4,5-tetrahydro-1 H -benzo (c) azepin-8-oxo-methyl) -1-pyridin-4-yl) piperidine-4-carboxylic acid; - (2-amidino-2,3,4,5-tetrahydro-1 H -benzo (c) azepin-8-yloxymethyl) -1-pyridin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidino) -1, 2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) p -peridin-4-carboxylic acid, 4- (2- (2-amidin-1, 2,3 , 4-tetrahydroquinolin-7-ylthio) -1- (piperidin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) - 1- (pyridin-4-yl) piperidine-4-carboxylic acid 4- (2- (2-aminon-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidin-1, 2) , 3,4-tetrahydroquinolin-7-ylsulfonyl-amino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester, 4- (2-amidino) -1, 2,3,4-tetrahydro-5-quinolin-7-ylsulphonylaminomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 7- (1- (pyridin-4-ylaceyl) ) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (3-aminobenzyl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2 -carboximidine, 7- (1- (2-hydroxybenzyl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-pyridin-2-ylmethyl) piperin -4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 2- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidinyl) methyl ester 1-ylmethyl) indole-1-carboxylate, benzyl ester of (4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-loxymethyl) piperidin-1-acetic acid, N-benzyl - (2-amidino-1, 2,3,4-tetrahydroisoquinolyl-7-yloxymethyl) piperidin-1-carboxamide, 7- (1-undil-2-methylmethyl) pi peridin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) pperidin-1 -acetic, N-benzyl (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1 -acetamide, 4- (2-aminon-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-ylacelacetylaminoacetic acid, 7- (1- (5-nitropyridin-2-yl) piperidine -4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1- (2-n -trobenzyl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2 -carboxamidine, 7- (1- (2-aminobenzyl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-hexanoimidoylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4- (2- amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-sulfonamide, N-butyl-4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin -1-sulfonamide, N-cyclohexyl-4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-sulfonamide, N- (2-nitrophenyl) -4- (2-amin Dn-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-carbothioamide, 7- (1- (benzimidazol-2-yl) -piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 3- (4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-loxymethyl) piperidin-1-ethyl ester propionic, 3- (4- (4- (2-amidino-1, 2,3,4-tetrahydrodichisoquinol-7-oxoethyl) piperidin-1-yl) pyridin-3-yl proponical, 4- (2-amino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-aminopyridin-5-ylcarbonyl) piperidin-4-carboxylic acid, 4- ( 2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-oxoxymethyl) -1- (3-aminopropionyl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydro) So-quinolin-7-yloxymethyl) 1- (imidazol-4-ylacetyl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydro-1,3-quinolin-7-yloxymethyl) -1 - (piperidin-4-ylsulfamoyl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1-dimethylaminoacetylpiperidine-4-carboxylic acid, ethyl 4-ethyl ester - (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-3-ylcarbamoyl) piperidin-4-carboxylic acid ester of 4- (2-amidino-1) , 2,3,4-tetrahydroisoquinolin-7-oxoxymethyl) -1- (1-dimethylaminoacetyl-pyridin-2-ylcarbonyl) piperidine-4-carboxylic acid, 4- (4- (2-amidin-1, 2, 3,4-tetrahydroisoquinolin-7-yloxymethyl) -4-carboxypiperidin-1-yl) -methylpyridinium, ethyl ester of 4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -4-amidinophenyl) piperidine-4-carboxylic acid, 4- (2-amidin-1) ethyl ester , 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester of 4- (2-amidin-1, 2,3, 4-tetrahydroisoquinolin-7-yloxymethyl) -1 - (2-methylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7) -yloxymethyl) -1 - (1-ethylpiperidin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidin-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1 - (- 1-ethylpiperidin-4-yl) piperidine-4-carboxylic acid, 7- (2- (4-c) Anopiperidin-4-yl) ethoxy) -1, 2,3,4-tetrahydroisoquinoline. -carboxamidine, 4- (2- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-ethyl) ethyl ester! loxi) ethyl) pyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridine- 4l) piperidine-4-carboxylic acid, and 4- (2-amidino-6-methyl-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) -piperidine- 4- carboxylic acid, or a salt thereof or a prodrug thereof. (11) A pharmaceutical composition comprising an amidine compound of any of the foregoing (1) to (10) or a salt thereof or a prodrug thereof and a pharmaceutically acceptable additive. (12) A blood coagulation inhibitor comprising an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as the active ingredient. (13) A factor Xa inhibitor comprising an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as the active ingredient. (14) An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombi comprising a amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as the active ingredient. (15) A method for inhibiting blood coagulation, comprising administering an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof. (16) A method for inhibiting factor Xa, which comprises administering an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof. (17) A method for the prophylaxis or treatment of diseases caused by blood coagulation or thrombi which comprises administering an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug of the same. (18) Use of amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of the blood coagulation inhibitor. (19) Use of amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of the factor Xa inhibitor. (20) Use of amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diseases caused by a coagulation of the blood or thrombi. (21) A commercial package comprising the blood coagulation inhibitor of the previous one (12) and written information related to the same, the written information indicating that the inhibitor can or should be used to inhibit the coagulation of the blood. (22) A commercial package comprising the factor Xa inhibitor of the above (13) and written information related thereto, written information indicating that the inhibitor can or should be used to inhibit factor Xa. (23) A commercial package comprising the agent for the prophylaxis or treatment of the above (14) and written information related thereto, written information indicating that the inhibitor can or should be used for the prophylaxis or treatment inhibiting of diseases caused by a blood coagulation or thrombi.

DETAILED DESCRIPTION OF THE INVENTION The terms in the present specification to explain the compound of the invention are defined as follows. A "lower alkyl" is a linear or branched alkyl with 1 to 6 carbon atoms, which can be exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like with 1 to 4 carbon atoms. A lower alkyl in R13 is optionally substituted with carboxy, lower alkoxycarbonyl or rosyloxycarbonyl.

A "cycloalkyl" is an alkyl having a cyclic alkyl unit of 3 to 10 carbon atoms. Examples thereof include cyclopropyl, 2,3-dimethylcycpropyl, cyclobutyl, 3-methylcyclobutyl, cyclopentyl, 3,4-dimethylcyclopentyl, cyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclo-acyl, norbornyl, adamantyl, bicyclo [3.3.0] octane-1- ilo or bicyclo [3.3.1] nonan-9-yl and the like. Preferred are cycloalkyls having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The cycloalkyl in R8 is optionally substituted by lower alkyl or carboxy. An "alkylene of 1 to 6 carbon atoms" is a linear or branched alkylene with 1 to 6 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like, which is preferably methylene, ethylene, propylene , butylene and the like with 1 to 4 carbon atoms.

An "alkylene with 2 to 6 carbon atoms" is a linear or branched alkylene of 2 to 6 carbon atoms, such as ethylene, 1-propenylene, 1-butenylene, 2-butenylene, 3-benthenylene, 1-pentenylene, 2 - pentylene, 3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene and the like. Ethenylene, 1-propenylene, 1-butenylene, 2-butenylene, 3-butenylene and the like having 2 to 4 carbon atoms are preferred. An "aryl" is phenyl, naphthyl or biphenyl having 6 to 12 carbon atoms, with preference given to phenyl. The aryl in Rβ is optionally substituted by 1 to 3 substituents selected from lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, nitro, amino, acylamino, amidino and hydroxyamidine. The aryl in R8 is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl, (said lower alkyl is optically substituted by halogen atom), hydroxy, lower alkoxy, carboxy and lower alkoxycarbonyl The alkyl at R13 is optionally substituted by carboxy, lower alkoxycarbonyl or aralkyloxycarbonyl A "heteroaryl" is a 5- or 6-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and may be a ring fused with another ring which may be partially saturated Examples thereof include imidazole, pindo, p? r? d? no-1 -oxido, pipmidilo, thienyl, thiazolyl, isoxazo lo, tpazohlo, indohlo, qumolilo, fuplo, benzofuplo, 1 H-benz? m? dazol ?, 2-benzot Azole and the like Pipdyl, p? r? d? no-1 -oxide, thienyl, thiazole, isoxazole, indole and the like are preferred The heteroatle in R6 is optionally substituted by 1 to 3 substituents selected from lower alkyl, hydroxy, alkoxy, lower, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, nitro, amino, acylamino, amidino and hydroxyamidino The heteroaphole in R8 is optionally substituted by 1 to 3 substituents selected from halogen atom, (said alkyl mfepor is optionally substituted by atom halogen), hydroxy, lower alkoxy, carboxy, and lower alkoxycarbonyl The linking site of these hetero groups is not limited as long as the site is chemically acceptable. "Aralkyl" is a "aplakyl" wherein the unit is exemplified by the "apl "above-mentioned and the alkyl unit is exemplified by the above-mentioned" lower alkyls ", and is exemplified by benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl and the like Aralkyl it can have, on the aryl group, from 1 to 3 substituents selected from halogen atom, lower alkyl, hydroxy, lower alkoxy, hydroxy, lower alkoxy, haloalkyl, cyano, nitro, acyloxy and the like. It can be substituted simultaneously with two or more substituents, but is preferably monosubstituted. The substitution position is not particularly limited as soon as it is chemically acceptable. A "lower alkoxy" is linear or branched with 1 to 6 carbon atoms and is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like with 1 to 4 carbon atoms are preferred. A "lower alkoxycarbonyl" is one in which the lower alkoxy unit is one of the "lower alkoxy" above exemplified. Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like, preference being given to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like. An "aralkyloxycarbonyl" is one in which the aralkyl unit is one of those exemplified above as "aralkyl". Examples thereof include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl and the like which may be substituted with halogen atom, nitro, alkyl, alkoxy, trifluoromethyl and the like. Benzyloxycarbonyl is preferred. The "acyl" is formyl; an alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, butyl, pivaloyl, and the like; or an aroyl such as benzoyl and the like wherein the aryl may have from 1 to 3 substituents. Formyl, acetyl, pivaloyl, benzoyl and the like are preferred.

An "imidoyl" is formimidoyl, acetimidoyl, propanimidoyl, butanimidoyl, pentanimidoyl or hexanimidoyl and the like with 1 to 6 carbon atoms. Acetimidoyl, propanomidoyl and the like are preferred. A "lower alkylamino" is an amino monosubstituted by those "lower alkyl" exemplified above. Examples thereof include methylamine, ethylamino, propylamino or butylamino and the like, preference being given to methylamino, ethylamino, propylamino and the like. A "(lower) dialkylamino" is an amino substituted by a lower alkyl as exemplified above, and is exemplified by dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino and the like. Dimethylamino, diethylamino and the like are preferred. A "(lower) alkanoyl (lower) dialkylamino" is an alkanoyl substituted by a "lower dialkylamino" such as those mentioned above. Examples thereof include dimentlaminoacetyl, diethylaminoacetyl, dipropylaminoacetyl, methylethylaminoacetyl, methylpropylaminoacetyl, dimethylaminopropanoyl, diethylaminopropanoyl, dipropylaminopropanoyl, and the like. Dimethylaminoacetyl, diethylaminoacetyl and the like are preferred. An "acylamino" is an amino substituted by the "acllos" exemplified above. Examples of this include formylamino; alkanoylamino with 2 to 6 carbon atoms such as acetylamino, propionylamino, butyrylamino, pivaloylamino and the like; and aroylaminos such as benzoylamino and the like, wherein the aryl may be substituted with 1 to 3 substituents. Formylamino, acetylamino, pivaloioamino, benzoylamino and the like are preferred.

A "halogen atom" is chlorine, bromine, fluorine, or iodine with preference for chlorine and bromine. A "5- to 7-membered saturated heterocycle with at least 1 nitrogen atom" is exemplified by pyrrolidine, piperidine, hexahydroazepine and oxazolidine, thiazolidine, imidazolidine, morpholine, thiomorpholine, piperazine, tetrahydrooxazepine, tetrahydrothiazepine, hexahydrodioazepine and the like having heteroatom oxygen, sulfur and / or nitrogen. A saturated 5- to 7-membered heterocycle in Rβ having at least one nitrogen atom may be substituted with lower alkyl, acyl, dialkylamino (lower) alkanoyl (lower) or midoyl. The "salt" of the compound includes, but is not limited to, addition salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate and the like; addition salts of organic acids such as acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, ascorbate and the like; addition salts with amino acids such as aspartate, glutamate and the like; salts with inorganic bases such as sodium, potassium, calcium, magnesium and the like; salts with organic bases such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, tris (hydroxymethyl) aminomethane, dicyclohexylamine, ethylenediman, quinine, guanidine, and the like; and basic salts with amino acids such as asparagine, glutamine, arginine, histidine, lysine and the like. These salts may be a compound containing water or hydrate.

The "prodrug" of a compound is a derivative of the compound of the present invention that has a chemical or metabolically degradable group and that shows pharmaceutical activity by hydrolysis, solvolysis or decomposition under physiological conditions. Several "diseases caused by blood coagulation or thrombi" include cerebrovascular diseases cerebral infarction, cerebral thrombosis, cerebral embolism, attack of transient ischemia (TIA), subarachnoid hemorrhage and the like; ischemic heart diseases such as chronic myocardial infarction, unstable angina, coronary thrombosis and the like, pulmonary vascular diseases such as pulmonary infarction, pulmonary embolism and the like; and diseases caused by various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after artificial blood vessel surgery or replacement of artificial valves, reocclusion or restenosis after coronary commutation, reocclusion or restenosis after recanalization such as percutaneous coronary transluminal angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR), thrombosis due to extracorporeal circulation and the like. The compound of the present invention is explained in detail below. Of the compounds of the invention of formula I, R is a group of formula and preferably a group of formula and particularly preferably a group of formula R1, R2 and R3 are preferably hydrogen atom. The connection mode of it is preferably as shown in the formula Preferably R4 is a lower alkoxy hydrogen atom or a halogen atom which is preferably a hydrogen atom. The R5 is . ^ m ^^^ preferably hydrogen atom, carboxy, or lower alkoxycarbonyl, preferably particularly carboxy, R6 is preferably hydrogen atom, carboxy, lower alkoxycarbonyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted by 1 to 3 substituents selected from lower alkyl, hydroxy , lower alkoxy, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, nitro, amino, acylamino, amidino and hydroxyamidine, which is particularly preferably pyridyl. X2 is preferably oxygen atom or sulfur atom, particularly preferably oxygen atom, X3 is preferably - (CH2) m- particularly preferably - (CH2) or-. X4 is preferably or a simple link particularly preferably a single link. X5 is preferably alkenylene having 2 to 6 carbon atoms or a single bond, which is particularly preferably a single bond. It is preferred that j is 1 and k is 0. R7 is preferably R9 R10 wherein R9 is preferably oxygen atom or NH, and particularly preferably NH. R 10 is preferably lower alkyl, lower alkoxy or amino and particularly preferably lower alkyl or amino. R8 is preferably hydrogen atom, aryl, heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl (said lower alkyl is optionally substituted by halogen atom), hydroxy, lower alkoxy, carboxy and lower alkoxycarbonyl, particularly preferably phenyl. Y1 is preferably oxygen atom or -NR12- wherein R12 is preferably -Y6-R13 wherein R13 is preferably phenyl optionally substituted by carboxy or lower alkoxycarbonyl, Y6 is preferably -CO- particularly preferably -N-Y6-R13. Y2 is preferably an oxygen atom. Y3 is preferably wherein s and t are each preferably 2. Y 4 is preferably -CONH-. Y5 is preferably - (CH2) p -, - (CH2) p., - CHAk- (CH2) p "-, - (CH2) P-Cak Ak '- (CH2) P- wherein p is preferably 1 or 2 , p 'is preferably 1 and p "is preferably 0, which is particularly preferably - (CH_) p-CHAk- (CH2) P-. Ring A is preferably a group of the formula The compound of formula I of the present invention includes stereoisomer tautomers, optical isomers and geometric isomers. The present invention comprises all of them.

The production method of the compound of the present invention is explained below, to which the production method of the compound of the invention is not limited.

Production method 1 portion [i] portion [i¡] portion [ü¡] portion [iv] portion [v] The production method shown here is suitable for producing the compounds of the formula I, the compound of the formula I ' In this case, the connection between the units i, i, ii, iv and v can be started from any position. The construction or conversion of each unit can be carried out independently or it can be done after connecting some units. When a reactive functional group is present, it can be introduced or removed to a protecting group as appropriate. 11 Connection of unit i and unit ii A compound of unit ii of formula 2 where _. { . { means connection to another unit or linkage of a convertible group such as a hydrogen atom, protecting group or leaving group and the like (hereinafter the same in the following formulas) and R4, X2, j and k are each as defined above, are it reacts with the compound of unit i of formula 3 wherein R1 ', R2' and R3 'are the same or different and each is a hydrogen atom, hydroxy, lower alkyl, aryl or a nitrogen atom protecting group or a salt thereof in the presence of a base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and the like to give a compound of formula 4 wherein R1 ', R2', R3 ', R4, X2, j and k are each as defined above. Where any of R1 ', R2' and R3 'is a protecting group, this protecting group can be removed by a conventional method. Alternatively, ammonium thiocyanate and benzoyl chloride are reacted in advance under heating and a compound of formula 2 reacts to give a thiomide compound. Then, after dealing with an acid such as hydrochloric acid, hydrogen bromide and the like the compound is reacted with methyl iodide under heating preferably at 50 ° C-70 ° C. The compound can be reacted with an amine having the desired substituent. Alternatively, the compound of formula 2 and the compound of formula R1-NCS (5) wherein R1 is as defined above, is reacted with methyl iodide to give the thiomethyl compound followed by reaction with ammonium acetate or an amine having the desired substituent. When a compound of unit ii wherein j is 2 is desired, a compound of formula 6 wherein Rh is a protective group such as methyl and the like and R, X and k are as defined above, reacted with sodium azide and subjected to rearrangement reaction to give a azepinone compound. This compound is reduced from aluminum and lithium to give a compound of formula 7 where R4, X2, Rh and k are as defined above. 2] Connection or construction of unit ii and unit iii A compound of unit ii of formula 8 wherein R, X and j and k are as defined above and a compound of unit ii of formula 9 -X3A ^ (9) wherein L1 is a leaving group such as halogen atom and the like or hydroxy and X3 is as defined above, are reacted to give a compound of the formula where R4, X2, X3 j and k are as defined above. Where L1 is a leaving group it is subjected to alkylation using a base such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like, and when L1 is hydroxy is subjected to the Mitsunobu reaction using triphenylphosphine and diisopropyl azodicarboxylate. When a compound wherein X2 is -S02 is desired, a compound of the formula wherein X2 is sulfur is oxidized using a peracid such as m-chloroperbenzoic acid or peracetic acid and the like to give a compound of formula where R4, X3, j and k are as defined above. When a compound wherein X2 is -S02NH- is the desired one, a compound of formula 12 ^^^ wherein R4 j and k are as defined above, and a compound of formula 13 H2N-X3-% (13) wherein X3 is as defined above, undergo a typical amidation under basic conditions to give a compound of formula 14 where R4, X3, j and k are as defined above. When a compound is desired wherein k is 1 and X2 is oxygen atom, a compound of formula wherein R 4, Ak and j are as defined above is reduced using a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride and the like to give a compound of formula where R4 and j are as defined above. The resulting compound is condensed with a compound of formula 9 by the method shown in the method of producing a compound of formula 10 to give a compound of formula 17 where R4, X3 and j are as defined above. 31 Connection or construction of unit ii and unit iv. When a compound wherein R5 is a hydrogen atom and X3 is -CH2-, - (CH2) 2- or - (CH2) 3-, the formula wherein m 'is 0 or an integer from 1 to 2 and Ak is as defined above, is reduced using a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like to give a compound of formula 19 where m "is an integer from 1 to 3.

Alternatively, a compound of formula 20 H02C- (CH2) m, (NAS (20) wherein m 'is as defined above, it is reduced using a reducing agent such as borane and the like to give a compound of formula 19. This compound corresponds to a compound of formula 9 wherein X3 is - (CH2) m "- and L 1 is hydroxy When a compound wherein R 5 is cyano, lower alkoxycarbonyl or carboxy and X 3 is -CH 2 -, - (CH 2) 2, or - (CH 2) 3 is the desired, a compound of formula wherein R5 'is cyano, lower alkoxycarbonyl or carboxy, reacts with a compound of formula 22. L2- (CH2) m-CH = CH2 wherein L2 is a leaving group such as halogen atom and the like and m' is as above defined in the presence of a base such as lithium diisopropylamide and the like at -80 ° C-0 ° C to give a compound of formula 23 where R5 'and m' are as defined above. The obtained compound is reacted with an oxidizing agent such as osmium tetroxide and similar to give a diol compound where the double bond was oxidized. This diol compound is subjected to oxidation with periodate to allow the adjacent diol to be oxidatively broken to yield an aldehyde compound. This is reduced with a reducing reagent such as sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like for a compound of formula 24 wherein R5 'and m "are as defined above This compound corresponds to a compound of formula 9 wherein X3 is (CH2) m" - and L1 is hydroxy. Alternatively, a compound of formula 23 is subjected to oxidation with periodate to give a carboxylic acid which is reduced with a reducing agent such as borane and the like to give a compound of formula 24. Alternatively, a compound of formula 21 and a compound of formula 25 wherein L2 and m are as defined above, they can react in the presence of a base such as lithium diisopropylamide and the like at -80 ° C-0 ° C. _i __? __,. -, ..___ .__..-.

When a compound wherein R 5 is cyano is a desired compound of formula 26 H02CA NAS (26) is amidated and reacted using a dehydrating reagent such as triphenylphosphine and the like to give a compound of formula 27 CA N-SS (27) Then, that compound can be condensed with a compound of unit ii by a method similar to the method of producing a compound of formula 23 or a known method. The leaving group L2 can be introduced into a compound of formula 25 by, for example, a compound of formula SS- (CH ^ SMe (28) wherein m is as defined above and reacts with a halogenation reagent such as sulfuryl chloride and the like to give a compound of formula 25. The compound of formula 25 can be converted to a compound with a leaving group having greater reactivity for the use of a halide of an alkali metal. When a compound is desired wherein X2 is -S02NH- and X3 is - (CH2) m-, a compound of formula 29 (29) wherein R5 and m are as defined above, Curtius is subjected to the Hofmann rearrangement and the like to give a carbamate compound, which is subjected to a typical removal reaction of the amino group to give a compound of formula where R5 and m are as defined above. This compound corresponds to a compound of the formula 13 wherein X3 is - (CH2) m- Alternatively, a compound of the formula it is subjected to the Strecker reaction by reacting hydrogen cyanide in the presence of ammonia to give a compound of the formula 32.

H2N-NAS (32) CN This compound corresponds to a compound of formula 30 wherein R5 is cyano and m is 0. Subsequent alcoholysis gives a compound of formula 33 wherein R5 of formula 30 is a lower alkoxycarbonyl _ ^^ ¡^^ £ ¿_ wherein Ak is as defined above, and hydrolysis of the resulting compound gives a compound of formula 34 wherein R 5 of formula 30 is carboxy 41 Connection or construction of unit iv and unit v A compound in unit iv of formula 35 wherein R5 is as defined above, reacts with a compound in unit v of formula 36 L2-X -X5-R6 (36) wherein R6, X4, X5 and L2 are as defined above in the presence of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropylamine, pyridine and similar or reacts using a base such as triethylamine, NN-diisopropylethylamine and the like at 120 ° C-160 ° C to give a compound of formula 37 where R5, R6, X4, and X5 are as defined above. When a compound wherein R6 is aryl or heteroaryl and the aryl or heteroaryl is substituted by amino or acylamino is the desired one, a compound having nitro as a substituent on the aryl or heteroaryl is reduced to give a compound having amino as a substituent. In addition, an acylating reagent such as acyl halide, acid anhydride and the like reacts to give a compound having acylamino as a substituent. When a compound is desired wherein X5 is -CH = CH-, a compound of formula 38 SVX4- CHO (38) where X4 is as defined above, reacts with a compound of formula 39 O II (AkO) 2P-CH2-R6 (39) wherein R6 and Ak are as defined above, in the presence of a base such as sodium hydride, potassium hydride and the like to give a compound of formula VX4-CH = CH-F- (40) where R6 and X4 are as defined above.

Production method 2 portion [i] portion [vi] portion [iii] portion pv] portion [v] The production method shown here is suitable for producing, of the compounds of formula I, a compound of formula I " _p In this case, the connection between units i, iii, iv, v and vi can be started from any position. The construction or conversion of any unit can be carried out independently or it can be done after connecting some units. When a reactive functional group is present, a protecting group may be introduced or removed as appropriate. 51 Connection and construction of unit i and unit vi. A compound of unit vi of formula 41 ? j ~ (cH2) "? 2 ~ $ (4 where R4, X2 and k are as defined above, react with a sulfonylating reagent such as trifluoromethanesulfonic anhydride and the like to convert the hydroxy to a leaving group and react with a cyanation reagent such as zinc cyanide and the like in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium and the like to give a cyano compound The resulting compound reacts with hydrogen sulfide under basic conditions to give a thioamide compound, which is subsequently S-alkylated with methyl iodide and the like and reacted with ammonium acetate or an amine having a desired substituent to give a compound of formula 42. wherein R1, R2, R3, R4, X2 and k are as defined above. When a compound of formula 43 with halogen atom in the 8-position in R4 wherein Hal is halogen atom and X2 and k are as defined above, is the desired, a compound of formula 44 wherein X2 and k are as defined above are halogenated with a halogenating reagent such as tert-butyl hypochlorite and the like. The connection of the unit vi and the unit iii, and of the unit iii-unit v can be carried out in the same way as the connection of the unit ii-unit v shown in the production method 1.

Production method 3 A + "(CH2) m • + -YM-A -Y3- R7 portion [i] portion [vii] portion [viii] portion [ix] portion [x] (Cpy.-Y4- Y5- 8 The production method shown here is suitable for producing, of the compounds of the formula I, a compound of the formula I " [1 '"] In this case, the connection between the units i, vii, viii, ix, x, and xi can be started from any position.The construction or conversion of each unit can be carried out independently or performed after connecting some Units When a reactive functional group is present, a protecting group may be introduced or removed as appropriate. 6] Connection and construction of unit i and unit vii. Using a compound of formula 45 and the connection and construction of unit i and unit vi as shown in production method 2, is carried out to give a compound of formula 46 wherein R, R2, R3 are each as defined above. 71 Connection and construction of unit vii and unit viii, unit xi A compound of formula 47 X ^^ N02 TA where L2 is as defined above, reacts with a compound as in unit xi of formula 48 H2N- ( CH2) n-Y4-Y5-R8 (48) wherein R8, Y4, Y5 and n are each as defined above, or a salt thereof, in the presence of a base such as triethanolamine, N, N-diisopropylethylamine , sodium bicarbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate and the like to give a compound of formula 49 where R8, Y4, Y5 and n are as defined above. The compound of formula 48 itself that can be used as a base.

The nitro of a compound of formula 49 is reduced by a known method to give a compound of formula 50 wherein R8, Y4, Y5 and n are each as defined above, and are reacted with a compound of unit viii of formula 51 where m is as defined above, to give a compound of formula 52 where R, Y, Y, m and n are as defined above. Alternatively, a compound of formula 53 and a compound of formula 51 react to give a compound of formula 54 where m is as defined above. This reaction can be a typical amidation reaction. For example, a condensation reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HC1), diphenylphosphoryl azide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and the like is either the mixed method of acid anhydride using alkylhalocarbonate and the like or after the conversation of the carboxylic acid to an acid halide using thionyl chloride, oxalyl chloride and the like, reaction under basic conditions, or other method that can also be used. A compound of formula 55 wherein Rh 'is a protecting group such as methyl, ethyl and the like and m is as defined above, is deprotected by a conventional method to give a compound of formula 51. Alternatively, a compound of formula 56 OHC- (CH2) m- SS (56) wherein m is as defined above, is oxidation by a method to give a compound of formula 51. A compound of formula 52 and a compound of formula 54 are subjected to ring closure reaction under acidic conditions using acetic acid, methanesulfonic acid , p-toluenesulfonic acid and the like to give a compound of formula 57 SS- TXA (CHo) - (CH2, m? S (57) Y4- Y5- R8 wherein R8, Y4, Y5, m and n are as defined above or a compound of formula 58 H where m is as defined above, respectively. Alternatively, a compound of formula 59 NC- (CH2) m-SS (59) is converted to an imidate using an alkoxide such as sodium methoxide, sodium heptoxide, potassium tert-butoxide and the like and reacts with a compound of formula 50 or a compound of formula 53 under acidic conditions to give a compound of formula 57 or a compound of formula 58, respectively. When a compound wherein Y4 is -CONH- is the desired, a compound of formula 60 wherein n is as defined above and a compound of formula 61 H2N-Y5-R8 (61) wherein R8 and Y5 are as defined above, they react in the same manner as shown in the production method of a compound of formula 52 or a compound of formula 54 to give a compound of formula 62? (CH 2 -CONH-Y 5 -R 8 (62) wherein R 8, Y 5 and n are as defined above When a compound wherein Y 4 is an oxygen atom, Y 5 is a single bond and R 3 is a lower alkyl is the desired one, a compound of formula 63 f (63) (CH 2) n-OH wherein n is as defined above, and a compound of formula 64 L -R8, (64) wherein R8 'is lower alkyl and L1 is as defined above, they react in the same manner as shown in the method of producing a compound of formula 37 to give a compound of formula 65", (65) (CH2) -C-R8 where R8 'and n are as defined above. When a compound wherein Y4 is -CO-, Y5 is a single bond and R8 is a heteroaryl is desired, a compound of formula 60 reacts with N.O-dimethylhydroxylamine in the same manner as shown in - * - -_ »" - the method of producing a compound of formula 52 or a compound of formula 54 to give a compound of formula where n is as defined above. Separately, a compound of formula 67 H-R3"(67) wherein R8"is heteroaryl is activated with a base such as butyl lithium and the like and reacts with the aforementioned compound 66 to give a compound of formula I o .. (68) (CH2) n- CO-R8 'where R8"and n are as defined above. 8] Connection and construction of unit viii and unit ix A compound of unit VIII of formula 69 SS- (CH2) m-L2 (69) where L2 and m are as defined above react with a compound of formula 70 ^ '(70) wherein Y1 and ring A are as defined above in the presence of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate , potassium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, pyridine and the like to give a compound of formula where Y1 the ring A and m are as defined above. When a compound in which Y1 is NH is the desired one, the compound is protected with a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl and the like and is subjected to the reaction and deprotected to give a compound of formula where ring A and m are as defined above. Further, when a compound wherein Y1 is -NR12- is the desired one, a compound of formula 72 is reacted with a compound of formula 73 L2-R12 (73) wherein R12 and L2 are as defined above, of the same formula as in the production method of a compound of formula 49 to give a compound of formula 74 where R12 and m are as defined above. When a compound is desired wherein R12 is Y6-R13, Y6 is -CO-, -C02-, COC02- or -S02-, a compound of formula 72 reacts with a compound of formula HO-Y6'-R13 (75) wherein Y6"is -CO-, -C02-, -COC02- or -S02- and R13 is as defined above, in the same manner as in the production method of a compound of formula 52 or of formula 54 to give a compound of formula 76 wherein R13, Y6 ', ring A and m are as defined above. When a compound where Y1 is a single bond and ring A is a group of the formula is the desired one, a compound of formula 77 __My _________ «______________ ^ lii wherein R14 is as defined above, and a compound of formula 69 reacts in the same manner as the method of producing a compound of formula 23 to give a compound of formula 78 where R14 and m are as defined above. When a compound in which Y1 is an oxygen atom is the desired one, a compound of formula 79 OHCV A A-% (79) wherein ring A is as defined above, is oxidized with a peracid such as m-chloroperbenzoic acid, peracetic acid and the like to give a compound of the formula 80H? A -H (80) where ring A is as defined above. This compound corresponds to a compound of formula 70 wherein Y 1 is an oxygen atom. 91 Connection and construction of unit ix and unit x A compound of unit ix of formula 81 SS-Y! -0- 1 (81) wherein Y1, L1 and ring A are as defined above, react with a compound of formula 82 H-Y2-Y3-R7 (82) wherein R7, Y2 and Y3 are each as defined above, in the same manner as in the method of producing a compound of formula 10 to give a compound of formula 83 SS-Y- Y2- Y3- R7 (83) wherein R7, Y1, Y2, Y3 and ring A are as defined above. When a compound where ring A has the following formula and Y2 is a single bond, is the desired one, a compound of formula 84 wherein Y1 is as defined above, or a compound of formula 85 wherein R14 and Y1 are as defined above, reacts with a compound of formula 86 L2-Y3-R7 (86) wherein R7, Y3 and L2 are as defined, in the same manner as in the production method of a compound of formula 37 to give a compound of formula 87 _-v- ^ N- Y3-R7 (87) wherein R7, Y1 and Y3 are as defined, or a compound of formula 88 wherein R7, R14, Y1 and Y3 are as defined above. When a compound where Y3 is a group of formula and R7 is lower alkyl or is the desired, a compound of formula 89 wherein Y2, s and t are as defined above, is reacted with a compound of formula 90 L3-R7, (90) wherein L3 is a leaving group such as ethoxy, 1-pyrazolyl, halogen atom and the like and R7 'is lower alkyl or a group of formula wherein R9 and R10 are as defined above, in the presence of a base such as triethylamine, NN-d sopropoxylamine, sodium bicarbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium hydroxide, lithium, sodium hydride, potassium hydride and the like to give a compound of formula 91 where R7 ', Y2, s and t are as defined above. The compound of formula I of the present invention thus obtained has an action of factor Xa inhibitor. When the compound of The invention is used as a factor Xa inhibitor or as a blood anticoagulation agent, it is generally administered orally or parenterally and systemically or locally. While the dose varies depending on age, body weight, symptoms, therapeutic effect, route of administration, treatment time and the like, it generally ranges from 0.01 mg to 1 g to give an adult, which are administered orally and parenterally from a at several doses per day.

When the compound of the present invention is formulated into solid compositions for oral administration, it can be prepared in a dosage form such as tablets, pills, powders, granules and the like. In such solid compositions, one or more active substances are mixed with at least one diluent, dispersant or inert absorbent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate and anhydrous silicate powder. further, the composition may comprise additives other than the diluent according to a conventional method. When the compound is formulated into tablets or pills, a gastric or enteric coating, for example sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose, may be applied, or two or more layers may be formed. In addition, a capsule made of a substance such as gelatin and ethylcellulose can be used. When a liquid composition for oral administration is desired, the compound can be formulated in a dosage form such as an emulsion, solution, suspension, syrup, elixir and the like pharmaceutically. acceptable Examples of usable diluents include water, ethanol, vegetable oil and purified emulsifiers. This composition may also comprise, in addition to a diluent, auxiliary agents such as humectants, suspending agents, sweeteners, flavors, flavorings and preservatives. When the compound is prepared in the form of injection for parenteral administration, aqueous or non-aqueous solution, solubilizers, sterile suspending or emulsifying agents are used. Examples of aqueous solution, solubilizer and suspending agent include distilled water for injection, physiological saline, cyclodextrin and its derivatives, organic amines such as triethanolamine, diethanolamine, monoethanolamine, triethylamine and an inorganic alkaline solution. When the compound is prepared in aqueous solution, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and the like can be used. As a solubilizer for example, polyoxyethylene, hydrogenated castor oil, surfactants such as fatty acid ester of sucrose (forming a mixed mycelium), lecithin, and hydrogenated lecithin (forming a liposome) can be used. In addition, an emulsion preparation containing a non-aqueous solvent such as vegetable oil, lecithin, hydrogenated polyoxyethylene castor oil, or a polyoxyethylene polyoxypropylene glycol can be produced. It can be used as another composition for parenteral administration, an external liquid, a liniment such as ointment, suppository, pessary, comprising one or more active ingredients, which can be formulated by a method known in this field of the art.

EXAMPLES It is explained in detail in the following examples to the compound of formula [I] of the present invention and its production method. It is unnecessary to say that the present invention is not limited to these examples.

EXAMPLE 1 Synthesis of 7-ri - (pyridin-4-yl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamide dihydrochloride Stage 1 7-Hydroxy-1,2,3,4-tetrahydroisoauinoline-2-carboxylic acid tert-butyl ester Dissolve hydrobromide of 7-hydroxy-1, 2,3,4, tetrahydroisoquinoline (370 mg) in 1 N aqueous sodium hydroxide solution (4 ml) and add 1,4-dioxane (8 ml) and di-ter. -butyl dicarbonate (386 mg), which was followed by stirring at room temperature overnight. At the conclusion of the reaction, the reaction mixture was extracted with ethyl acetate and washed to the organic layer with saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to the solvent under reduced pressure to give the title compound (385 mg).

Stage 2 4-hydroxymethyl-1-1- (pyridin-4-? Lo) piperidine Under an argon atmosphere, to a solution of 1- (pyridin-4-yl) piperidine-4-carboxylic acid (Tetrahedron, vol.44, No. 23, p.7095 (1998)) (500 mg) in tetrahydrofuran (5). ml) was added boranotetrahydrofuran 1 (14.5 ml) solution with ice cooling and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in 12% hydrochloric acid and stirred at 50 ° C for 1 hour. After neutralizing the reaction mixture with aqueous sodium bicarbonate and 4N aqueous solution of sodium hydroxide, and extracting with ethyl acetate. The organic layer was washed with Saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound (400 mg). 1 H-NMR (d ppm, CDC13) 1.24-1.38 (m, 2H), 1.70-1.90 (m, 3H), 2.86 (m, 2H), 3.53 (d, 2H), 3.92 (m, 2H), 6.66 ( d, J = 5.1 Hz, 2H), 8.22 (d, J = 5.1 Hz, 2H) Stage 3 Ter-butyl ester of 7-f1- (pyridin-4-yl) piperidin-4-ylmethoxy1-1, 2,3,4-tetrahydro-soauinolinoline carboxylic acid To a mixture of 7-hydroxy-1, 2,3,4-tetrahydro-sucquinyl-2-carboxylic acid tert-butyl ester (389 mg) and 4-hydroxymethyl-1- (pyridin-4-yl) pyridine (300 mg) in tetrahydrofuran (15 ml) and methylene chloride (5 ml) were added triphenylphosphine (450 mg) and diisopropyl azodicarboxylate (0.34 ml) and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel (hexane: acetone = 3: 2-1: 1.1% triethylamine) and dried under reduced pressure to give the title compound (500 mg). 1 H-NMR (d ppm, CDC 13) 1.36-1.50 (m, 11 H), 1.92-2.15 (m, 3H), 2. 76 (brtr, 2H), 2.90 (brtr, 2H), 3.62 (brtr, 2H), 3.80 (d, 2H), 3.90-3.96 (m, 2H), 4.53 (s, 2H), 6.62-6.74 (m, 4H), 7.04 (1 H), 8.25 (2H) Stage 4 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoauinoline To a solution ter-butyl ester of 7- (1-pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquipoline-2-carboxylic acid ester (500 mg) in chloroform (5 ml) trifluoroacetic acid (2.5 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and dried under reduced pressure to give the title compound (350 mg). H-NMR (d ppm, CDC13) 1.30-1.49 (m, 2H), 1.91-2.15 (m, 3H), 2. 72 (tr, J = 6.0Hz, 2H), 2.90 (m, 2H), 3.11 (tr, J = 6.0Hz, 2H), 3.79 (d, 2H), 3.90-3.98 (m, 4H), 6.54 (1 H), 6.66-6.72 (m, 3H), 6.99 (1 H), 8.25 (2H) Stage 5 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoauimolin-2-carboxamidine dihydrochloride To a solution of 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline (50 mg) in dimethylformamide (0.5 ml) were added diisopropylethylamine (0.027 ml) and 1 H-pyrazole carboxamidine hydrochloride (23 mg) and the mixture was stirred at room temperature for 12 hours. After finishing the reaction diethyl ether was added and the insoluble material was collected by filtration. A part of the solid obtained (45 mg) was treated with hydrochloric acid-methanol and dried over anhydrous sodium sulfate to give the title compound (44 mg). - you »- - '• _ - • 1 H-NMR (d ppm, DMSO-dβ) 1.20-1.45 (m.2H), 1.88-1.93 (m, 2H), 2. 17 (m, 1 H), 2.81 (tr, J = 6.0Hz, 2H), 3.20 (m, 2H), 3.57 (tr, J = 6.0Hz, 2H), 3. 85 (m, 2H), 4.23-4.28 (m, 2H), 4.54 (s, 2H), 6.70 (d, J = 2.7Hz, 1 H), 6.82 (dd, J = 2.7, 8. 4Hz, 1 H), 7.13 (d, J = 8.4Hz, 1 H), 7.19 (d, J = 7.8Hz, 2H), 7.64 (brs, 4H), 8.19 (d, J = 7.8Hz, 2H), 13.68 (brs, 1H).

EXAMPLE 2 Synthesis of 7- (1- (quinolin-4-yl.piperidin-4-ylmethoxy) -1,2,4,4-tetrahydroisoauolin-2-carboxamidine dihydrochloride Stage 1 Ethyl ester of 1- (quinolin-4-yl. Piperidine-4-carboxylic acid) To a solution of ethyl 4-chloro quinoline acid (2 g), isonepecotinate (2.8 ml) and triethyl amine (3.4 ml) in ethanol (7.5 ml) was stirred in a sealed tube at 150 ° C for 5 days. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography on silica gel (hexane: acetone = 3: 1) and dried under reduced pressure to give the title compound (3.2 g).

Stage 2 4-Hydroxymethyl-1- (quinolin-4-yl. Piperidine To a solution of lithium aluminum hydride (267 mg) in tetrahydrofuran (10 ml) was added dropwise 1- (quinolin-4-yl) piperidine-4-carboxylic acid ethyl ester (1 g) in tetrahydrofuran (10 g). ml) under nitrogen atmosphere and with ice cooling and the mixture was stirred at the same temperature for 2 hours. After the reaction was complete, sodium sulfate was added with ice and the mixture was filtered through celite. The solvent was evaporated and the solid obtained was washed with diisopropyl ether and dried over anhydrous sodium sulfate to give the title compound (750 mg). 1 H-NMR (d ppm, CDC 13) 1.57-1.90 (m, 3 H), 1.93-2.05 (m, 2 H), 2.85 (m, 2 H), 3.64-3.68 (m, 4 H), 6.84 (d, J = 4.8 Hz, 1 H), 7.47 (m, 1 H), 7.65 (m, 1 H), 8.01 (m, 2 H), 8.67 (d, J = 4.8 Hz, 1 H).

- * "'» »'" «- *» •• Stage 3 7- (1- (Olinolin-4-yl. Piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester In the same manner as in Example 1 step 3, the title compound (280 mg) was obtained from the tert-butyl ester of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid ( 206 mg), 4-hydroxymethyl-1- (quinolin-4-yl) piperidine (200 mg), triphenyl phosphine (238 mg) and dusopropyl azodicarboxylate (0.18 ml).

Stage 4 7-p-.quinolin-4-yl.piper? Din-4-ylmethoxy.-1, 2,3,4-tetrahydroisoquinoline In the same manner as in Example 1, step 4, the title compound (200 mg) was obtained from 7-l- (quinolin-4-yl) piperidin-4-ylmethoxy-tert-butyl ester. -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (275 mg). 'Stage 5 7- (1-.quinolin-4-yl) pyridin-4-ylmethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxymethine dihydrochloride In the same manner as in Example 1, step 5, the title compound (75 mg) was obtained from 7- (1- (quinolin-4-yl) piperidin-4-ylmethoxy) -1, 2,3 , 4-tetrahydroisoquinoline (70 mg), diisopropylethylamine (0.033 ml) and 1 H-pyrazole-1-carboximidine hydrochloride (28 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.55-1.66 (m, 2H), 1.96-2.02 (m, 2H), 2.22 (m, 1 H), 2.82 (tr, J = 6.0 Hz, 2H), 3.49 (m, 2H), 3.58 (tr, J = 6.0 Hz, 2H), 3.92 (m, 2H), 4.17-4.23 (m, 2H), 4.56 (s, 2H), 6.73 (d, J = 2.4 Hz, 1 H), 6.85 (dd, J = 2 4, 8.1 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.20 (1 H), 7.64 (brs, 4 H), 7.69 (1 H) ), 7.96 (1 H), 8.12 (m, 2H), 8.63 (1 H).

EXAMPLE 3 Synthesis of N-methyl 7- (1- (pyridip-4-yl) piperdin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamide dihydrochloride Stage 1 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carbothioamide To a solution of ammonium isothiocyanate (220 mg) in acetone (4.5 ml) was added dropwise benzoyl chloride at room temperature and the mixture was stirred at 75 ° C for 10 minutes. Then, a mixture of 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline (850 mg) in acetone (4.5 ml) was added dropwise. and methylene chloride (4.5 ml) and the mixture was stirred at the same room temperature for 1 hour. After the reaction was complete, the solvent was evaporated and water was added. The mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated. To the obtained residue, concentrated hydrochloric acid was added and the mixture was stirred under reflux for 1 hour. After After the reaction was complete, water was added and the mixture was washed successively with ethyl acetate and chloroform. The aqueous layer was concentrated and the resulting residue was dissolved in water and ethanol, and neutralized with ion exchange resin (IRA-410). It was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (chloroform: methanol = 100: 1-20: 1) and drying under reduced pressure to give the title compound (450 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.22-1.35 (m, 2H), 1.76-1.88 (m, 2H), 2.01 (m, 1 H), 2.74 (m, 2H), 2.84 (m, 2H) , 3.81-4.00 (m, 6H), 4.85 (s, 2H), 6.70-6.82 (m, 4H), 7.08 (1 H), 7.44 (brs, 2H), 8.11 (2H).

Stage 2 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroquinoline-methyl-carbothioimidic acid methyl ester 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrochloric acid-ethanol solution. To a suspension of the residue obtained in methanol, methyl iodide was added and The mixture was stirred at 60 ° C for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in water and ethanol was neutralized with ion exchange resin (IRA 410). This was filtered and the filtrate was concentrated under reduced pressure to give the title compound (200 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.20-1.40 (m, 2H), 1.80-1.90 (m, 2H), 2.03 (m, 1 H), 2.47 (s, 3H), 2.79 (tr, J = 6.0 Hz, 2H), 2.89 (m, 2H), 3.72 (tr, J = 6.0 Hz, 2H), 3.82 (d, 2H), 3.96-4.02 (m, 2H), 4.67 (s, 2H), 6.77- 6.86 (m, 4H), 7.08 (1 H), 8.12 (2H).

Stage 3 N-methyl 7- (1-fpyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoouynoline-2-carboxamidine dihydrochloride To an ethanol solution of 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroquinoline-2-carbothioimidic acid methyl ester was added methylamine hydrochloride. and sodium acetate and the mixture was stirred at 80 ° C for 3 hours. After the reaction was completed, water was added and the mixture was washed with chloroform, aqueous sodium bicarbonate solution was added thereto and the mixture was washed with chloroform. The extract was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the residue obtained was treated with a solution of hydrochloric acid-ethanol and dried under reduced pressure to give the title compound (80 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.19-1.38 (m, 2H), 1.87-1.94 (m, 2H), 2.17 (m, 1 H), 2.80 (m, 5H), 3.20 (m, 2H) , 3.59 (m, 2H), 3.84 (m, 2H), 4.20-4.29 (m, 2H), 4.56 (s, 2H), 6.70 (1 H), 6.81 (1 H), 7.12 (1 H), 7.19 (2H), 7.75 (2H), 8.03 (1H), 8.20 (2H), 13.74 (1H).

EXAMPLE 4 Synthesis of 7- (1 - (pyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine oxime dihydrochloride To a solution of 7- (1- (pyridin-4-yl) pyridin-4-ylmethoxy) -1,2,4,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester in ethanol (3 ml) were added Hydroxyamine hydrochloride and sodium acetate and the mixture was stirred at 40 ° C for 2 hours. After the reaction is completed, water was added and the mixture was washed with chloroform. 4N aqueous sodium hydroxide solution was added and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the solid obtained was treated with hydrochloric acid-ethanol solution and dried under reduced pressure to give the title compound (82 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.25-1.38 (m, 2H), 1.88-1.95 (m, 2H), 2.17 (m, 1 H), 2.81 (tr, J = 5.7 Hz, 2H), 3.05 -3.25 (m, 2H), 3.56 (tr, J = 5.7 Hz, 2H), 3.84 (m, 2H), 4.22-4.29 (m, 2H), 4.52 (s, 2H), 6.70 (d, J = 2.4 Hz, 1 H), 6.82 (dd, J = 2.4, 8.0 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 2H), 8.08 (brs, 2H), 8.19 (d, J = 7.5 Hz, 2H), 10.06 (s, 1 H), 10.86 (brs, 1 H), 13.71 (brs, 1 H).

EXAMPLE 5 Synthesis of N-phenyl (1 -.pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Stage 1 N-Phenyl (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxyamide To a solution of 7- (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline (30 mg) in methylene chloride was added phenyl isothiacyanate (0.012 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1.1% triethylamino) and dried under reduced pressure to give the title compound (40%). mg). 1 H-NMR (d ppm, CDCl 3) 1.36-1.49 (m, 2H), 1.90-2.15 (m, 3H), 2.85-2.95 (m, 4H), 3.79 (d, 2H), 3.84-4.00 (m, 4H ), 4.92 (s, 2H), 6.66-6.68 (m, 3H), 6.76 (1 H), 7.09-7.38 (m, 6H), 8.24 (2H).

Stage 2 N-phenyl (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride N-Phenyl (1- (pyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carbothiamide dihydrochloride (35 ml) was treated with a solution of hydrochloric acid-ethanol . To a suspension of the residue obtained in methanol (1 ml) was added methyl iodide (0.014 ml), and the mixture was stirred at 60 ° C for 1.5 hours. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and ethanol and neutralized with ion exchange resin (IRA 410). This was filtered and the filtrate was concentrated. To the obtained residue was added ethanol (1 ml) and ammonium acetate (24 mg), and the mixture was stirred under reflux for 12 hours. After the reaction was completed, water was added and the mixture was washed with chloroform. Aqueous sodium bicarbonate solution was added and extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by reverse phase preparative CCD (50% acetonitrile-water, 1.5% trifluoroacetic acid). The residue obtained was treated with hydrochloric acid-ethanol solution and dried under reduced pressure to give the title compound (12 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.21-1.37 (m, 2H), 1.88-1.93 (m, 2H), 2.17 (m, 1 H), 2.89 (m, 2H), 3.69 (m, 2H) , 3.85 (m, 2H), 4.23-4.28 (m, 2H), 4.64 (s, 2H), 6.74 (1 H), 6.84 (1 H), 7.15-7.28 (m, 6H), 7.43 (2H), 7.96 (2H), 8.20 (2H), 9.66 (brs, 1 H), 13.38 (brs, 1 H).

EXAMPLE 6 Synthesis of 4- (2-amido-1,2,3,4-tetrahydroisoquinoline-7-oxoxymethyl) -1- (pyridin-4-yl) p -peridin-4-carboxylic acid ethyl ester dihydrochloride Stage 1 7-methyl-thiomethoxy-1, 2,3,4-tetrahydroisoouinoline-2-carboxylic acid tert-butyl ester To a solution of tert-butyl ester of 7-methyl-thiomethoxy-1,2,4,4-tetrahydroisoquinoline-2-carboxylic acid (13 g) in dimethyl formamide was added (2.5 g) of 60% sodium hydride under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, chloromethyl methyl sulfide (2.5 ml) was added dropwise with ice and stirred at room temperature.

Room temperature during the night. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was purified by column chromatography on silica gel (hexane: acetone = 20; 1-10: 1) and dried under reduced pressure to give the composed of the title (9.6g). 1 H-NMR (d ppm, CDC13) 1.49 (s, 9H), 2.25 (s, 3H), 2.77 (tr, J = 5.7 Hz, 2H), 3.62 (tr, J = 5.7 Hz, 2H), 4.54 (s) , 2H), 5.13 (s, 2H), 6.70 (1 H), 6.78 (1 H), 7.06 (1 H).

Stage 2 7-Chloromethoxy-1,2,3,4-tetrahydro-soquinoline-2-carboxylic acid tert-butyl ester To a solution of tert-butyl ester of 7-methylthiomethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid in methylene chloride (100 ml) was added a solution of sulfuryl chloride (2.75 ml) in methylene chloride (30 ml) under an argon with ice atmosphere and the sample was stirred at the same temperature for 1 hour. The solvent was evaporated and toluene was added to the residue obtained to eliminate the insoluble material by filtration. The solvent was evaporated and dried under reduced pressure to give the title compound (7.4 g). 1 H-NMR (d ppm, CDC13) 1.49 (s, 9H), 2.79 (tr, J = 6.3 Hz, 2H), 3.64 (tr, J = 6.3 Hz, 2H), 4.57 (s, 2H), 5.88 (s) , 2H), 6.85 (1 H), 6.91 (1 H), 7.11 (1 H).

Stage 3 7- (4-Ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a solution of ethyl ester of 1- (pyridin-4-yl) piperidine-4-carboxylic acid ester (Tetrahedron, vol 44, No. 23, p.7095 (1988)) in tetrahydrofuran (300 ml) was added dropwise drop a solution of 2M lithium-tetrahydrofuran diisopropylamide at -70 ° C under an argon atmosphere, and the mixture was stirred at the same temperature for 45 minutes. A solution of 7-chloromethoxy-1,2,4,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (7.4 g) in tetrahydrofuran (80 ml) was added dropwise to the same temperature, and the mixture was allowed to warm to room temperature for 5.5 hours under stirring. After completion of the reaction, aqueous ammonium chloride solution (50 ml) and water (50 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the residue dissolved in methanol (150 ml). 1N aqueous sodium hydroxide solution (50 ml) was added dropwise on ice and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue obtained was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (chloroform: methanol: 20: 1-10: 1) and dried under reduced pressure to give the title compound (10.87 g). 1 H-NMR (d ppm, CDC 13) 1.26 (tr, J = 7 Hz, 3 H), 1.49 (s, 9 H), 1.68-1.80 (m, 2 H), 2.30-2.40 (m, 2 H), 2.75 (m, 2 H) ), 3.10-3.20 (m, 2H), 3.61 (brtr, 2H), 3.68-3.76 (m, 2H), 3.97 (s, 2H), 4.22 (q, J = 7 Hz, 2H), 4.52 (s, 2H), 6.61 (1 H), 6.65-6.71 (m, 3H), 7.02 (1 H), 8.25 (2H).

^ ¡¡¡^ Stage 4 Ethyl ester of 1- (pyridin-4-yl) -4-1, 2,3,4-tetrahydroisoouinoline-7-yloxymethyl-piperidine-4-carboxylic acid To a solution of 7- [4-ethoxy carbonyl-1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-tert-butyl ester. carboxylic acid (10.87 g) in chloroform (50 ml) was added dropwise trifluoroacetic acid (30 ml) on ice, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and an aqueous solution of sodium bicarbonate was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under pressure to give the title compound (8.29 g). 1 H-NMR (d ppm, CDC13) 1.25 (tr, J = 7 Hz, 3H), 1.65-1.95 (m, 2H), 2.30-2.36 (m, 2H), 2.72 (brtr, 2H), 3.05-3.18 ( m, 4H), 3.69-3.76 (m, 2H), 3.96 (s, 4H), 4.21 (q, J = 7 Hz, 2H), 6.52 (1 H), 6.65-6.67 (m, 3H), 6.98 ( 1 H), 8.25 (2H).

Stage 5 4-.2-amidine-1,2,3,4-tetrahydroisoquinoline-7-yloxymethyl) 1- (pyridin-4-ylpperidine-4-carboxyl) ethyl ester dihydrochloride To a solution of 1- (pyridin-4-yl) -4- (1, 2,3,4-tetrahydroxyquinoline-7-oxoxyethyl) piperidine-4-carboxylic acid ethyl ester in dimethyl formamide (50%). ml) were added diisopripylethylamine (4.4 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (3.69 g), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue obtained was mixed with diethyl ether (350 ml) and the supernatant was removed. The oil obtained was dissolved in methanol (20 ml) and diethyl ether (700 ml) was added dropwise with stirring. The supernatant was removed and dried under reduced pressure. Fifty (50) mg of the 4- (2-amidine-1, 2,3,4-terahydro-1,3-quinoline-7-oxo-methyl) -1- (pyridin-4-yl) ethyl ester The obtained piperidine-4-carboxylic acid was dissolved (10.0 g) in ethanol and dilute hydrochloric acid was added. The mixture was concentrated and dried under reduced pressure to give the title compound (55 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.15 (tr, 3H), 1.65-1.80 (m, 2H), 2.15-2.22 (m, 2H), 2.81 (tr, J = 6.0 Hz, 2H), 3.30- 3.50 (m, 2H), 3.56 (tr, J = 6.0 Hz, 2H), 3.95-4.18 (m, 6H), 4.53 (s, 2H), 6.68 (d, J = 2.1 Hz, 1 H), 6.81 (dd, J = 2.1, 8.4 Hz, 1 H), 7.14 (d , J = 8.4 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 2H), 7.58 (brs, 4H), 8.22 (d, J = 7.5 Hz, 2H).

EXAMPLE 7 Synthesis of 4- (2-amidine-1,2,3,4-tetrahydroisoquinoline-7-oxo-methyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Ethyl 4- (2-amidine-1, 2,3,4-tetrahydroisoquinol-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride was dissolved (9 g) in concentrated hydrochloric acid (50 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the insoluble material was filtered and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (9.0 g). 1 H-NMR (d ppm, DMSO-d 6) 1.65-1.75 (m, 2H), 2.14-2.20 (m, 2H), 2.81 (tr, J = 5.7 Hz, 2H), 3.57 (tr, J = 5.7 Hz, 2H), 4.00-4.15 (m, 4H), 4.54 (s, 2H), 6.70 (1H), 6.81 (1H), 7.15 (m, 3H), 7.63 (brs, 4H), 8.22 (2H), 13.71 (brs, 1 H).

EXAMPLE 8 Synthesis of 4- (2-amidine-1,2,3,4-tetrahydroisoquinoline-7-yloxymethiD-1- (pyridin-4-yl) piperidin-4-carboxylic acid Ethyl ester dihydrochloride of 4- (2-amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (pyridin-4?) Piperidine-4-carboxylic acid (11 g) was dissolved in water (100 ml) and filtered. A 4N aqueous sodium hydroxide solution (20 ml) was added dropwise at 50 ° C, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the resulting solid was collected by filtration, washed successively with water and ethanol and dried under reduced pressure to give the title compound (7.7 9). 1 H-NMR (d ppm, DMSO-d 6) 1.66-1.73 (m, 2H), 2.18-2.23 (m, 2H), 2.84 (m, 2H), 3.39 (m, 2H), 3.56 (m, 2H), 3.92-3.97 (m, 2H), 4.50 (s, 2H), 6.78 (s, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 7.09 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1 H), 8.13 (d, J = 7.12 Hz, 2H).

EXAMPLE 9 Synthesis of 4- (2-amidine-1.2.3.4-tetrahydroisoquinoline-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid hydrochloride 4- (2-Amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid (7.55 g) was suspended in water (135 ml) and 1N hydrochloric acid (20 ml) was added. The mixture was heated to 60 ° C and an aqueous solution of sodium hydroxide (2.9 ml) and 1N hydrochloric acid (1 ml) was added dropwise. The mixture was allowed to stand at room temperature for 12 hours and the resulting crystals were collected by filtration, washed with water and dried to give the title compound (4.7 g). 1 H-NMR (d ppm, DMSO-d 6) 1.59-1.70 (m, 2H), 2.05-2.16 (m, 2H), 2.82 (tr, J = 5.7 Hz, 2H), 3.15 (m, 2H), 3.57 ( tr, J = 5.7 Hz, 2H), 3.65-3.80 (m, 2H), 4.03 (m, 2H), 4.52 (s, 2H), 6.70 (1 H), 6.79-6.86 (m, 3H), 7.13 ( 1 H), 7.61 (brs, 4H), 8.14 (2H).

EXAMPLE 10 Synthesis of 4- (2-amidin-1, 2,3,4-tetrahydroisoquinoline-7-oxo-methyl) -,2.6-d-methyl-pyridin-4-ylpiperidine-4-carboxylic acid ethyl ester dihydrochloride Stage 1 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester The hydrobromide of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline (3 g) was dissolved in 1 N aqueous sodium hydroxide solution (46 ml) and tetrahydrofuran (10 ml) and benzyl chlorocarbonate (2.45 g) were added. ). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (3.3 g).

Stage 2 Benzyl ester of 7-methylthiomethoxy-1, 2,3,4-tetrahydroisoouinoline-2-carboxylic acid To a solution of benzyl ester of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (2.5 g) in dimethyl formamide (25 ml) was added 60% sodium hydride on ice and under an atmosphere of argon and the mixture was stirred at the same room temperature for 30 minutes. Then, chloromethylmethyl sulfide (0 96 ml) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained oil was purified by column chromatography on silica gel (hexane: ethyl acetate = 8: 1) and dried under reduced pressure to give the title compound (2.7 g). 1 H-NMR (d ppm, CDC13) 2.24 (s, 3H), 2.79 (brs, 2H), 3.71 (brtr, 2H), 4.62 (s, 2H), 5.11 (s, 2H), 5.18 (s, 2H) , 6.69 (1 H), 6.79 (1 H), 7.06 (1 H), 7.26-7.38 (m, 5H).

Stage 3 Benzyl ester of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid To a solution of benzyl ester of 7-methylthiomethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (200 mg) in methylene chloride (4 ml) was added sulfuryl chloride (0.052 ml) dropwise. with ice and under an argon atmosphere and the mixture was stirred at the same temperature for 1 hour. The solvent was azeotropically evaporated with toluene and the residue was dried under reduced pressure to give the title compound (213 mg). 1 H-NMR (d ppm, CDC 13) 2.82 (brtr, 2 H), 3.72 (brtr, 2 H), 4.65 (s, 2 H), 5.18 (s, 2 H), 5.87 (s, 2 H), 6.84 (1 H), 6.91 (1 H), 7.11 (1 H), 7.26-7.39 (m, 5H).

Stage 4 Ethyl ester of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid In the same manner as in example 1, step 1, the title compound (41.4 g) was obtained from ethyl isonipecotinate (25.5 g) and di-tert-butyl dicarbonate (36.5 g).

Stage 5 Benzyl Ester of 7- (1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidine-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid To a solution of ethyl ester of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (300 mg) in tetrahydrofuran (3 ml) was added dropwise a solution of lithium-tetrahydrofuran-1-propylamide 1.5M (0.97 ml) at - 70 ° C, and the mixture was stirred at the same temperature for 50 minutes. Then, a solution of benzyl ester of 7-chloromethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (213 mg) was added dropwise at the same temperature in tetrahydrofuran (3 ml) and the mixture was added. let warm at room temperature for 2 hours with shaking. After completion of the reaction, an aqueous solution of ammonium chloride and water was added and cooled with ice. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the The residue obtained was purified by column chromatography on silica gel (hexane: acetone = 7.1) and dried under reduced pressure to give the title compound (170 mg). 1 H-NMR (d ppm, CDC 13) 1.23 (tr, J = 7.2 Hz, 3 H), 1.46 (s, 9 H), 1.52-1.62 (m, 2 H), 2.16-2.21 (m, 2 H), 2.77 (m, 2H), 3.04 (m, 2H), 3.69 (m, 2H), 3.80-4.00 (m, 4H), 4.19 (q, J = 7.2 Hz, 2H), 4.60 (s, 2H), 5.17 (, 2H) , 6.60 (1 H). 6.69 (1 H), 7.02 (1 H), 7.32-7.38 (m, 5H).

Stage 6 Benzyl Ester of 7-.4-ethoxycarbonylpiperidine-4-ylmethoxy) -1.2.3.4-tetrahydroisoouinoline-2-carboxylic acid To a solution of 7- (1-tert-butoxycarbonyl-4-ethoxy-caryl-piperidine-4-ylmethoxy) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid benzyl ester (165 mg) in chloroform (1.5 ml) was added dropwise trifluoroacetic acid (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and an aqueous solution of sodium bicarbonate was added to the obtained residue. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate. anhydrous. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (135 mg). H-NMR (d ppm, CDC13) 1.23 (tr, J = 7.5 Hz, 3H), 1.50-1.65 (m, 2H), 2.15-2.25 (m, 2H), 2.65-2.90 (m, 4H), 2.95- 3.05 (m, 2H), 3.69 (m, 2H), 3.93 (s, 2H), 4.19 (q, J = 7.5 Hz, 2H), 4.60 (s, 2H), 5.17 (s, 2H), 6.60 (1 H), 6.69 (1 H), 7.02 (1 H), 7.26-7.38 (m, 5H).

Stage 7 Benzyl ester of 7- (1-.2,6-dimethyl-pyridin-4-yl) -ethoxycarbonylpiperidine-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid To a solution of 7 - (4-ethoxycarbonylperidin-4-ylmethoxy) -1,2,4,4-tertrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) was added triethylamine (0.05 ml) and 4-chloro-2,6-dimethylpyridine (Journal of Heterocyclic Chemistry, vol.27, p.1841 (1990)) (45 mg) and the mixture was stirred at 150 ° C for 25 hours is a sealed tube. After completion of the reaction, the solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 4: 1) and dried under reduced pressure to give the title compound (160 mg). 1 H-NMR (d ppm, CDC13) 1.26 (tr, J = 6.6 Hz, 3H), 1.70-1.85 (m, 2H), 2.35-2.45 (m, 2H), 2.66 (s, 6H), 2.78 (m, 2H), 3.28-3.37 (m, 2H), 3.70 (m, 2H), 3.80-3.90 (m, 2H), 3.97 (s, 2H), 4.24 (q, J = 6.6 Hz, 2H), 4.60 (s) , 2H), 5.17 (s, 2H), 6.41 (s, 2H), 6.60 (1 H), 6.69 (1 H), 7.04 (1 H), 7.34-7.38 (m, 5H).

Stage 8 4- (2-Amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) - (2,6-d? Methylpyridin-4-y? Piperidine-4-carboxylic acid ethyl ester dihydrochloride To the 7- (1- (2,6-dimethylpyridin-4-yl) -ethoxycarbonylpiper? Dna-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester ( 155 mg) was added a solution of 25% hydrogen bromide-acetic acid (3 ml), and the mixture was stirred for 10 minutes. After completed ~ ¡^^ After the reaction, düsopropyl ether was added and the resulting solid was collected by filtration. To the obtained solid was added dimethyl formamide (1 ml), diisolpropylethethylamine (0.25 ml) and 1 H -pral-1-carboxamidine hydrochloride (80 mg) and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue obtained was washed with tetrahydrofuran and separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 4: 1-2: 3). The obtained residue was treated with dilute hydrochloric acid and dried under reduced pressure to give the title compound (120 mg).

EXAMPLE 11 Synthesis of 4- (2-amidiin-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride To the ethyl ester dihydrochloride of 4- (2-amidine-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) pperidin-4- carboxylic acid (85 mg) was added 6N hydrochloric acid, and the mixture was stirred under reflux for 3 hours. After the reaction was completed, the insoluble material was removed and the solvent evaporated. The residue obtained was washed with diethyl ether and dried under reduced pressure to give the title compound (76 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.60-1.75 (m, 2H), 2 05-2.20 (m, 2H), 2.46 (s, 6H), 2.83 (m, 2H), 3.59 (m, 2H) , 3.80-4.15 (m, 4H), 4.57 (s, 2H), 6.72 5 (1 H), 6.82 (1 H), 6.99 (s, 2H), 7.15 (1 H), 7.72 (brs, 4H), 13.69 (brs, 1 H).

EXAMPLE 12 Synthesis of 4- (2-amidine-1,2,3,4-tetrahydroisoquinolipa-7-chloro-methyl-1-methyl-4-yl) piperidin-4-10-carboxylic acid methyl ester dihydrochloride Stage 1 According to the method of the Journal of Heterocyclic Chemistry, vol. 20 27, p. 1841 (1990) the title compound (743 mg) was obtained from the 2-methylpyridine N-oxide (5.1 g). 1 H-NMR (d ppm, CDC 13) 2.99 (s, 3 H), 7.70 (s, 1 H), 7.77 (d, J = 6.3 Hz, 1 H), 8.01 (d, J = 6.3 Hz, 1 H).

Stage 2 7- (4-Ethoxycarbonyl-1- (2-methylpyridin-4-yl) piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, step 7, the title compound (105 mg) was obtained from the benzyl ester of 7- (4-ethoxycarbonyl piperidin-4-ylmethoxy) -1, 2, 3,4-tetrahydroisoquinoline-2-carboxylic acid, (100 mg), with 4-chloro-2-methylpyridine hydrochloride and triethylamine (0.07 ml).

Stage 3 4- (2-Amidine-1,2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in Example 10, step 8, the title compound (83 mg) was obtained from the benzyl ester of 7- (4-ethoxycarbonyl-1- (2-methylpyridin-4-yl) benzyl ester. ) pperiodin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (100 mg), a solution of hydrogen bromide-25% acetic acid (2 ml), diisopropylethylamine (0.16 ml) and 1 H-pyrazole-1 -carboxamidine hydrochloride (55 mg).

EXAMPLE 13 Synthesis of 4- (2-amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (2-methylpyridin-4-yl. Piperidine-4-carboxylic acid dihydrochloride.

In the same manner as in Example 11, the title compound (53 mg) was obtained from the ethyl ester dihydrochloride of 4- (2-amidine-1, 2,3,4-tetrahydroisoquinoline-7-) iloxymethyl) -1- (2-methylpyridin-4-yl) piperidine-4-carboxylic acid (63 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.63-1.75 (m, 2H), 2.05-2.25 (m, 2H), 2.47 (s, 3H), 2.83 (m, 2H), 3.30-3.70 (m, 4H ), 3.95-4.10 (m, 4H), 4.55 (s, 2H), 6. 71 (1 H), 6.83 (1 H), 7.07-7.16 (m, 3H), 7.63 (brs, 4H), 8.12 (1 H), 13.74 (brs, 1 H).

EXAMPLE 14 Synthesis of 4- (2-amidine-1.2.3.4-tetrahydroisoquinoline-7-yloxymethyl) -1. Pyrimidin-4-yl) piperidine-4-carboxylic acid dihydrochloride Stage 1 Benzyl Ester of 7- (1- (2-chloro-pyrimidin-4-yl-ethoxycarbonylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid To a solution of 7- (4-ethoxycarbonylpiperidine-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (295 mg) in ethanol (5 ml) was added triethylamine (0.15). ml), and 2,4-dichloropyrimidine (150 mg), and the mixture was stirred under reflux for 1 hour. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by chromatography of column on silica gel (hexane: ethyl acetate = 1: 2) and dried under reduced pressure to give the title compound (263 mg). 1 H-NMR (d ppm, CDCl 3) 1.25 (tr, J = 6.9 Hz, 3H), 1.50-1.70 (m, 2H), 2.25-2.40 (m, 2H), 2.78 (m, 2H), 3.18-3.30 (m, 2H), 3.70 (m, 2H), 3.95 (s, 2H), 4.09-4.26 (m, 4H), 4.60 (s, 2H), 5.17 (s, 2H), 6.40 (d, J = 6.1 Hz, 1 H), 6.60 (1 H), 6.69 (1 H), 7.03 (1 H), 7.26-7.38 (m, 5H), 8.03 (d, J = 6.1 Hz, 1 H).

Stage 2 Ethyl ester of 1- (pyrimidin-4-yl) -4- (1, 2,3,4, -tetrahydroisoauinoline-7-yloxymethyl) piperidine-4-carboxylic acid To a solution of benzyl ester of 7- (1- (2-chloropyrimidin-4-yl) -ethoxycarbonylpiperidine-4-methoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ester ( 263 mg) in ethanol (5 ml) was added palladium on carbon (120 mg) at 7.5% and ammonium formate (200 mg) on ice, and the mixture was stirred under reflux for 30 minutes. After the reaction was completed, the solvent was evaporated and water was added to the obtained residue. The mixture was extracted with chloroform and the organic layer was washed with aqueous bicarbonate solution of sodium and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (270 mg).

Stage 3 4- (2-amidine-1, 3,4-tetrahydroisoquinoline-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride To a solution of 1- (pyrimidin-4-yl) -4- (1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidine-4-carboxylic acid ethyl ester (260 mg) in dimethyl formamide (1 ml) was added diisopropylethylamine (0.24) and 1 H-pyrazole carboxamidine hydrochloride (200 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the residue obtained was separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 6: 4-2: 8). The obtained residue was refluxed with concentrated hydrochloric acid for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was washed with diethyl ether and dried under reduced pressure to give the title compound (51 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.60-1.80 (m, 2H), 2.10-2.25 (m, 2H), 2.81 (m, 2H), 3.40-3.60 (m, 4H), 4.05 (s, 2H) ), 4.05-4.80 (2H), 4.54 (s, 2H), 6.69 (d, J = 2.4 Hz, 1 H), 6.81 (dd, J = 2.4, 8.4 Hz, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.66 (brs, 4 H), 8.32 (d, J = 7.8 Hz, 1 H), 8.81 (s, 1 H).

EXAMPLE 15 Synthesis of 4- (2- (2-amidine-1, 2.3.4-tetrahydroisoquinoline-7-yloxy) ethyl) -1- (pyridin-4-ylpperidine-4-carboxylic acid ethyl ester dihydrochloride Stage 1 Benzyl ester of 7- (2-vodoethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid BnO CN X XV XX To a solution of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.21 g), 2-bromoethanol (5.46 ml) and triphenylphosphine (20.11 g) in tetrahydrofuran (30 ml) was added a solution of diethylazodicarboxylate-toluene (33.6 ml) at 40%, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and dimethyl formamide (30 ml) and sodium iodide (9.6 g) were added to the obtained residue. The mixture was stirred at 90 ° C for 15 hours.

After completion of the reaction, the solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 4: 1) and dried under reduced pressure to give the title compound (1.19 g ). 1 H-NMR (d ppm, CDCl 3) 2.79 (m, 2 H), 3.40 (tr, J = 6.9 Hz, 2 H), 3.70 (m, 2 H), 4.21 (tr, J = 6.9 Hz, 2 H), 4.61 (s) , 2H), 5.18 (s, 2H), 6.63 (1H), 6.74 (1H), 7.05 (1H), 7.26-7.38 (m, 5H).

Stage 2 Benzyl Ester of 7- (2- (1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-yl) ethoxy) -1,2,4,4-tetrahydroisoouinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, step 5, the title compound (935 mg) was obtained from the benzyl ester of 7- (2-iodoethoxy) -1,2,3,4-tetrahydroisoquinolin-2-benzyl ester carboxylic acid (1.4 g), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester (1.81 g) and 2M lithium-tetrahydrofuran diisopropylamide solution (0.82 ml). 1 H-NMR (d ppm, CDCl 3) 1.25 (tr, J = 6.9 Hz, 3H), 1.60-1.65 (m, 2H), 2.01-2.04 (m, 2H), 2.13-2.19 (m, 2H), 2.77 ( m, 2H), 2.94 (m, 2H), 3.70 (m, 2H), 3.80-4.00 (m, 4H), 4.18 (q, J = 6.9 Hz, 2H), 4.60 (s, 2H), 5.18 (s, 2H), 6.56 (1 H), 6.67 (1 H), 7.01 (1 H), 7.31-7.38 (m, 5H).

Stage 3 Benzyl ester of 7-.2-.4-ethoxycarbonyl-1- (pyridin-4-ylpiperidin-4-yl) ethoxy.-1, 2,3,4-tetrahydroisoouinoline-2-carboxylic acid In the same manner as in Example 10, step 6, the benzyl ester of 7- (2- (4-ethoxycarbonylpiperidin-4-yl) ethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid was obtained from 7- (2- (1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-yl) ethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (935 mg) and trieloxacidic acid (5 ml). In the same manner as in Example 10, step 7, the title compound (680 mg) was obtained from this compound, 4-chloropyridine hydrochloride (248 mg) and triethylamine (1.38 ml). The reaction was carried out for 2 days.

Stage 4 Ethyl 4- (2- (2-amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxy) ethyl) -1- (pyridin-4-yl) piperidin-4-ethyl ester dihydrochloride carboxylic In the same manner as in example 10, step 8, the title compound (208 mg) was obtained from the benzyl ester of 7- (2- (4-ethoxycarbonyl-1- (pyridin-4-yl) piperidiphenyl) 4-yl) ethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid, a solution of hydrogen bromide-acetic acid (3 ml) at 25%, diisopropylethylamine (0.64 ml) and 1 H-pyrazole hydrochloride -1-carboxamidine (214 mg).

EXAMPLE 16 Synthesis of 4- (2- (2-amidine-1,2,3,4-tetrahydroisoquinoline-7-yloxy.ethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 11, the 4- (2- (2-amidine-1, 2,3,4-tetrahydroisoquinoline-7-yloxy) ethyl) -1- ethyl ester dihydrochloride was reacted ( pyridin-4-yl) piperidine-4-carboxylic acid (200 mg). The residue obtained was separated by HPLC (aqueous trifluoroacetic acid, 0.05%: methanol = 1: 1) and the residue obtained was treated with dilute hydrochloric acid to give the title compound (29 mg). 1 H-NMR (d ppm, DMSO-de) 1.54-1.68 (m, 2H), 1.95-2.22 (m, 4H), 2.82 (m, 2H), 3.58 (m, 2H), 3.92-4.12 (m, 4H ), 4.55 (s, 2H), 6.67 (1 H), 6.78 (1 H), 7.14 (1 H), 7.19 (d, J = 7.4 Hz, 2H), 7.61 (brs, 4H), 8.21 (d, J = 7.4 Hz, 2H).

EXAMPLE 17 Synthesis of the acid dihydrochloride (S.-4-rN-.5-amidino-1- (1-phenylethylcarbamoylmethi-benzimidazol-2-ylmethyl-1-N-r4- (1-azetimidoylpiperidin-4-yloxy) phenyl-1-carbomoyl) benzoic acid Stage 1 4-.4-Nitrophenoxy) piperidin-1-carboxylic acid t-butyl ester To a solution of 4-hydroxypiperidine-1-carboxylic acid t-butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under nitrogen atmosphere on ice and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (52.384 g). 1 H-NMR (d ppm, CDCl 3) 1.48 (s, 9 H), 1.80 (m, 2 H), 1.96 (m, 2 H), 3.39 (m, 2 H), 3.70 (m, 2 H), 4.61 (m, 1 H ), 6.96 (d, J = 9.3 Hz, 2H), 8.20 (d, J = 9.3 Hz, 2H).

Stage 2 4- (4-aminophenoxy) piperidin-1-carboxylic acid t-butyl ester The 4- (4-nitrophenoxy) p-peridin-1-carboxylic acid t-butyl ester (53.687 g) was hydrogenated using 7.5% palladium on charcoal in a mixture of tetrahydrofuran (215 ml) and ethanol (215 ml) at three atmospheres for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. It was added hexane to the obtained residue and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound (42157 g). 1 H-NMR (d ppm, CDCl 3) 1.46 (s, 9 H), 1.71 (m, 2 H), 1.86 (m, 2 H), 3.27 (, 2 H), 3.71 (m, 2 H), 4.26 (m, 1 H) , 6.63 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H).

Stage 3 T-butyl ester of] 4- (4-benzyloxycarbonylammonophenoxy) piperidine-1-carboxylic acid To a solution of the 4- (4-aminophenoxy) piperidin-1-carboxylic acid t-butyl ester (6.63 g) and sodium bicarbonate (2.1 g) in a mixture of tetrahydrofuran (100 ml) and water (100 ml) was added dropwise benzyl chlorocarbonate (3.24 ml) and the mixture was stirred at room temperature for one hour. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (7.189 g). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9 H), 1.74 (m, 2 H), 1.88 (m, 2 H), 3.69 (m, 2 H), 4.39 (m, 1 H), 5.19 (s, 2 H) ), 6.54 (brs, 1 H), 6.86 (2H), 7.26-7.42 (m, 7H) Stage 4 4-f4- (N-benzyloxycarbonyl-N-ethoxycarbonylmethylamino) phenoxypiperidine-1-carboxylic acid t-butyl ester To a solution of 4- (4-aminophenoxy) piperidin-1-carboxylic acid t-butyl ester (42.28 g) in dimethyl formamide (254 ml) was added 60% sodium hydride (3.97 g) and the mixture was stirred at room temperature for 20 minutes. Then ethyl bromoacetate (12.1 ml) was added on ice and the mixture was stirred at room temperature for 15 hours. After this, 60% sodium hydride (3.97 g) and ethyl bromoacetate (12.1 ml) were added and the mixture was stirred at room temperature for 4 hours. In addition, 60% sodium hydride (1.19 g) and ethyl bromoacetate (3.3 ml) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer is dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by column chromatography with silica gel (hexane: ethyl acetate = 7: 3) to give the title compound (49.916 g). 1 H-NMR (d ppm, CDCl 3) 1.28 (3 H), 1.47 (s, 9 H), 1.75 (m, 2 H), 1.89 (m, 2 H), 3.34 (m, 2 H), 3.68 (m, 2 H), 4.19 (2H), 4.30 (brs, 2H), 4.43 (m, 1 H), 5.19, 5.17 (2H), 6.86 (2H), 7.13-7.35 (m, 7H) Stage 5 N-4 - (1-tert-butoxycarbonylpiperidin-4-yloxy) -phenira-N-benzyloxycarbonyl-aminoacetic acid To a solution of t-butyl ester 4- [4- (N-benzyloxycarbonyl-N-ethoxycarbonylmethylamino) phenoxy] piperidine-1 -carboxylic acid (49.916 g) in ethanol (102 ml) aqueous solution of sodium hydroxide was added 1 N (102 ml) and tetrahydrofuran (102 ml) and the mixture was stirred at room temperature for 10 minutes and at 50 ° C for 1 hour. After completion of the reaction, the solvent was evaporated. The residue obtained was extracted with ethyl acetate and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate. _________________ The solvent was evaporated and dried under reduced pressure to give the title compound (47.18 mg). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9 H), 1.76 (m, 2 H), 1.89 (m, 2 H), 3.34 (m, 2 H), 3.68 (m, 2 H), 4.35 (s, 2 H) , 4.44 (m, 1 H), 5.16 (brs, 2H), 6.86 (2H), 7.15-7.45 (m, 7H).

Stage 6 T-butyl ester of N-.4-cyano-2-nitrophenyl) qlicine To a solution of 4-chloro-3-nitrobenzonitrile (33.87 g) and tert-butyl ester glycine hydrochloride (55.98 g) in ethanol (400 ml) was added triethyl amine (77.6 ml) and the mixture was stirred at room temperature for 15 hours and then at 50 ° C for 3 hours. After completion of the reaction, the solvent was evaporated and the residue obtained was extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether and collected by filtration to give the title compound (38.419 mg) 1 H-NMR (d ppm, CDCl 3) 1.53 (s, 9 H), 4.03 (d, J = 5.0 Hz, 2 H), 6.75 (d, J = 8.9 Hz, 1 H), 7.64 (dd, J = 2.0, 8.9 Hz, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.81 (brs, 1 H).

Stage 7 T-butyl ester of N-.2-amino-4-cyanophenyl) qlicine The N- (4-cyano-2-nitrophenol) glycine t-butyl ester (17,337 g) was hydrogenated using 7.5% palladium on charcoal (1.73 g) in tetrahydrofuran (173 ml) at atmospheric pressure for 2 hours and adding palladium on charcoal to 7.5% (3.84 g) for one more hour. After completion of the reaction, the mixture was filtered through celite and the solvent was evaporated. The obtained residue was washed with diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (8.324 g). 1 H-NMR (d ppm, CDCl 3) 1.51 (s, 9 H), 3.84 (s, 2 H), 6.45 (1 H), 7.15 (1 H).

*** "**" - Stage 8 4-f4- [N-benzyloxycarbonyl-N- (2-tert-butoxycarbonylmethylamino-5-cyanophenyl) carbamoylmethylamino-phenoxypiperidine-1-carboxylic acid t-butyl ester To a solution of the N- (2-amino-4-cyanophenyl) glycine t-butyl ester (21.53 g) and N- [4 - (- tert -butoxycarbonylpiperidin-4-yloxy) phenyl] -N-benzyloxycarbonyl acid -amino-acetic acid (42.18 g) in chloroform (300 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (23.68 g), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give the title compound (44,479 g) 1 H-NMR ( d ppm, CDCl 3) 1.47 (s, 9H), 1.76 (m, 2H), 1.90 (m, 2H), 3.34 (m, 2H), 3.67 (m, 2H), 3.78 (brd, 2H), 4.36 (s , 2H), 4.45 (m, 1 H), 5.10-5.25 (m, 1 H), 5.20 (s, 2H), 6.53 (1 H), 6.89 (2H), 7.20-7.31 (m, 7H), 7.40 (2H), 7.96 (brs, 1 H) Stage 9 2-fN-Benzylcarbonyl-N-4 (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl-1-aminomethyl-5-cyanobenzimidazole-1-acetic acid A solution of 4- [4- [N-benzyloxycarbonyl-N- (2-tert-butoxycarbonylmethylamino-5-cyanophenyl) carbamoylmethylamino] phenoxy] piperidine-1-carboxylic acid t-butyl ester (44,479 g) in acetic acid (600 ml) was stirred at 90 ° C for 4 days. After completion of the reaction, the solvent was evaporated and the obtained residue was reacted with sodium carbonate (19.8 g) and di-tert-butyl dicarbonate (13.6 g) by a conventional method. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) and dried under reduced pressure to give the title compound (23.545 g) 1 H-NMR (d ppm, CDCl 3) 1.46 (s) , 9H), 1.67 (m, 2H), 1.81 (m, 2H), 3.27 (m, 2H), 3.63 (m, 2H), 4.35 (m, 1 H), 5.05 (brs, 6H), 6.75 (2H) ), 7.02-7.27 (m, 7H), 7.30 (d, J = 8.4Hz, 1H), 7.50 (d, J = 1.1, 8.4Hz, 1H), 7.99 (d, J = 1.1Hz, 1 H) Stage 10 (S) -2- (N - (- benzyloxycarbonyl-N-f4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenin-aminomethyl-1-5-cyano-1- (1-phenylethylcarbamoylmethyl) benzimidazole To a solution of 2- [N-benzyloxycarbonyl-N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid (583) mg) and 1-hydroxybenzotriazole hydrate (135 mg) in dimethyl formamide (5 ml) was added (S) -phenethylamine (0.118 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (193 mg) and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water, aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. Diisopropyl ether was added to the residue and the resulting solid was collected by filtration to give the title compound (623 mg). 1 H-NMR (d ppm, CDCl 3) 1.46 (s, 12H), 1.70 (m, 2H), 1.86 (m, 2H), 3.30 (m, 2H), 7.30 (m, 12H), 7.48 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 8.6 (s, 1 H) Stage 11 (SV2-fN-β4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl-1-N-4-methoxycarbonylbenzoipaminomethyl-1-5-cyano-1- (1-phenylethylcarbamoylmethyl) -benzimidazole Hydrogenated (S) -2- [N-benzyloxycarbonyl-N- [4- (1-tert-butoxycarbonylpiperidip-4-yloxy) phenyl] aminomethyl] -5-cyano-1- (1-phenylethylcarbamoylmethyl) benzamidazole (623 mg) in tetrahydrofuran (6 ml) using 7.5% palladium on charcoal (310 mg) at 3 atmospheres for 7 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The obtained residue was dissolved in chloroform (6 ml) and thereafter triethylamine (0.176 ml), methyl 4-chloroformibenzoate (167 mg) and 4-dimethylaminopyridine (10 mg) were added and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by column chromatography with silica gel (hexane: ethyl acetate = 3: 7) and dried under reduced pressure to give the title compound (284 mg). 1? -NMR (d ppm, CDCl 3) 1.36 (d, 3 H), 1.46 (s, 9 H), 1.70 (m, 2 H), 1. 86 (m, 2H), 3.30 (m, 2H), 3.69 (m, 2H), 3.87 (s, 3H), 4.36 (m, 1 H), 5.02-5.09 (m, 3H), 5.15-5.28 (s) , 2H), 5.21 (m, 2H), 6.73 (d, J = 9Hz, 2H), 7.11 (d, J = 9Hz, 2H), 7. 15-7.23 (m, 6H), 7.30 (d, J = 8.4Hz, 2H), 7.40 (1H), 7.51 (1H), 7.82 (d, J = 8.4Hz, 2H), 8.04 (1 H).

* 'M ^ Stage 12 (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenin-N-4-methoxycarbonylbenzoyl) aminomethyl1-1- (1-phenylethylcarbamoylmethyl) benzimidazole-5-carboxamidine Hydrogen sulphide was bubbled through a solution of (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) -aminomethyl] - 5-cyano-1- (1-phenylethylcarbamoylmethyl)) benzimidazole (284 mg) in a mixture of pyridine-triethylamine (5: 1) on ice and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the residue was treated with hydrogen chloride-ethanol. After this, acetone (6 ml), methanol (6 ml) and methyl iodide (0.229 ml) were added and the mixture was stirred at reflux for 2 hours. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in ethanol (12 ml). Ammonium acetate (43 mg) was added and the mixture was stirred at 75 ° C. * • * for 2 hours. After completion of the reaction, the solvent was evaporated and the residue obtained was purified by silica gel column chromatography (chloroform: methanol = 95: 5-90: 10) and dried under reduced pressure to give the title compound (113 mg) 1 H-NMR (d ppm, DMSO-d 3) 1.30-1.45 (m, 14H), 1.76 (m, 2H), 3.07 (m, 2H), 3.57 (m, 2H), 3.80 (s, 3H ), 4.40 (m, 1 H), 4.92 (m, 1 H), 5.21-5.38 (m, 4H), 6.75 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H) , 7.21-7.33 (m, 7H), 7.63-7.70 (m, 2H), 7.75 (2H), 8.14 (s, 1 H), 8.96 (brd, 1 H) Stage 13 (S) -4-IN-r5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazol-2-ylmethyl-1-N-f4- (1-acetimidoylpiperidin-4-yloxOfeni Hcarbamoylbenzoic acid) hydrochloride To a solution of (S) -2- [N- (4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (1-phenylethylcarbamoyl) benzimidazole-5 -carboxamidine (113 mg) in chloroform (2 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 5 minutes.The solvent was evaporated and 4N sodium hydroxide aqueous solution (1.1 ml) was added to the obtained residue. and the mixture was stirred for 5 hours.After completion of the reaction, dilute hydrochloric acid was added and the solvent was evaporated.The residue was dried under reduced pressure to give a residue.The residue obtained was dissolved in methanol (2 ml) and triethylamine (0.2 ml) and ethyl acetoimidate hydrochloride (89 mg) were added.The mixture was stirred at room temperature for 18 hours.After completion of the reaction, the insoluble material was removed and the solvent was evaporated. obtained was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). added dilute hydrochloric acid to the obtained residue and the solvent was evaporated and dried under reduced pressure to give the title compound (78 mg). 1 H-NMR (d ppm, DMSO-d 3) 1.37 (d, J = 7.2 Hz, 3 H), 1.63 (m, 2 H), 1.94 (m, 2 H), 2.25 (s, 3 H), 3.43 (m, 2 H) , 4.56 (m, 1 H), 4.9 (quint, J = 7.2 Hz, 1 H), 5.23-5.39 (m, 4H), 6.80 (2H), 7.16-7.37 (m, 9H), 7.72-7.74 (m , 4H), 8.17 (s, 1 H), 8.73 (brs, 1 H), 9.09 (brs, 2H), 9.20 (d, J = 7.2 Hz, 1 H), 9.31 (brs, 3H) EXAMPLE 18 Synthesis of 4-rN- [5-amidino-1- (4-benzyloxyphenylcarbarnoylmethyl) benzimidazol-2-ylmethyl-1-N-r4- (1-acetimidoylpiperidin-4-yloxy) phenyl-1-carbamoyl-1-benzoic acid hydrochloride Stage 1 2- [N- [4- (1-tert-Butoxycarbonylpiperidin-4-yloxy) phenyl-1-aminomethin-5-cyanobenzimidazole-1-acetic acid 2- [N-Benzyloxycarbonyl] N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylaminomethyl] -5-cyanobenzimidazole-1-acetic acid (7.037 g) was hydrogenated using palladium on charcoal. 7.5% (3.52 g) in ethanol (70 ml) at 3 atmospheres for 3 hours. After the reaction was complete, the mixture was filtered through cellta and the solvent evaporated. The obtained residue was washed with diisopropyl ether, filtered and dried under reduced pressure to give the title compound (4.189 g) 1 H-NMR (d ppm, CD 3 OD) 1.44 (s, 9 H), 1.58 (m, 2 H), 1.84 (m, 2H), 3.25 (m, 2H), 3.66 (m, 2H), 4.29 (m, 1H), 4.60 (s, 2H), 5.23 (s, 2H), 6.67 (d, J = 6.6 Hz, 2H), 6.77 (d, J = 6.6 Hz, 2H), 7.59 (d, J = 6.6 Hz, 1 H), 7.63 (d, J = 6.6 Hz, 1 H), 8.02 (s, 1 H) Stage 2 2- [N- [4- (1-tert-Butoxycarbonylpiperidin-4-yloxy) phenyl-1-N- (4-methoxycarbonylbenzoyl) aminomethyl-5-cyanobenzimidazole-1-acetic acid To a solution of 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid (3.36 g) and sodium bicarbonate (1.67 g) in a mixture of water (34 ml) and tetrahydrofuran (34 ml) was added methyl 4-chloroformylbenzoate (1.32 g), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water, 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by column chromatography with silica gel (ethyl acetate) to give the title compound (2,907 g) 1 H NMR (d ppm, CDCl 3) 1.45 (s, 9 H), 1.63 (m, 2 H), 1.80 (m, 2 H), 3.25 (m, 2 H), 3.63 (m, 2 H), 3.83 (s, 3 H) ), 4.31 (m, 1 H), 5.28 (s, 2H), 5.32 (s, 2H), 6.65 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 7.23 ( d, J = 8.4 Hz, 2H), 7.37 (1 H), 7.55 (1 H), 7.64 (d, J = 8.4 Hz, 2H), 7.99 (1 H) Stage 3 2- [N-R4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl1-N- (4-methoxycarbonylbenzoyl) aminomethy1-15-cyano-1- (4-benzyloxyphenylcarbamoylmethyl-V-benzimidazole 2- [N- [4- (1-tert-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -5-cyanobenzimidazole-1-acetic acid (632 mg), hydrate, was treated of 1-hydroxybenzotriazole (128 mg), 4-benzyloxyaniline hydrochloride (223 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (182 mg) and N-methylmorpholine (0.104 ml) in the same manner as in Example 17, step 10. The solvent was evaporated and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 7-2: 8) to give the title compound (605 mg). 1 H-NMR (d ppm, CDCl 3) 1.46 (s, 9 H), 1.85 (m, 2 H), 3.29 (m, 2 H), 3. 66 (m, 2H), 3.84 (s, 3H), 4.35 (m, 1 H), 4.98 (s, 2H), 5.23 (s, 2H), 5.31 (s, 2H), 6.72 (d, J = 9.0 Hz, 2H), 6.80 (d, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.30-7.41 (m, 7H), 7.56 (s, 2H), 7.73 (d, J = 8.4, 2H), 8.06 (s, 1H), 8.72 (brs, 1 H) Stage 4 2-fN-r4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenin-N- (4-methoxycarbonylbenzoyamomethyl) -1- (4-benzyloxyphenylcarbamoylmethyl) benzylnidazole-5-carboxamidine Hydrogen sulfide was bubbled through a solution of 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4- methoxycarbonylbenzoyl) aminomethyl] -5-cyano-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole (605 mg) in a mixed solution (15 ml) of pyridine-triethylamine (5: 1) on ice and the mixture was stirred at room temperature for 15 hours. After the reaction was complete, the solvent was evaporated and the residue obtained was collected by filtration and washed with toluene. To the obtained solid was added acetone (15 ml) and methyl iodide (0.443 ml) and the mixture was stirred under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and dried under reduced pressure to give a crude product (804 mg). From the crude product obtained, 434 mg was dissolved in ethanol (10 ml) and then ammonium acetate (44 mg) was added at room temperature. The mixture was stirred at 75 ° C for 3.5 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by column chromatography with silica gel (chloroform: methanol = 95: 5-90: 10) and dried under reduced pressure to give the title compound ( 141 mg). 1 H NMR (d ppm, DMSO-d 3) 1.38 (s, 9 H), 1.75 (m, 2 H), 3.05 (m, 2 H), 3.60 (m, 2 H), 3.79 (s, 3 H), 4.40 (m , 1 H), 5.06 (s, 2H), 5.35 (brs, 4H), 6.77 (2H), 6.97 (2H), 7.25-7.50 (10H), 7.65-7.76 (4H), 8.13 (1 H) Stage 5 Synthesis of 4- [N- [5-amidino-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazol-2-ylmethyl1-N- (4- (1-acetimidoylpiperidin-4-ylox) phenyl-1-carbamoyl-1-benzoic acid dihydrochloride] In the same manner as in example 17, step 13, the title compound (59 mg) was obtained from 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenol. ] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole-5-carboxamidine (141 mg), trifluoroacetic acid (1 ml), 4N sodium hydroxide solution (0.973 ml), triethylamine (0.226 ml) and ethyl acetoimidate hydrochloride (100 mg). 1 H-NMR (d ppm, DMSO-d 3) 1.63 (m, 2 H), 1.95 (m, 2 H), 2.27 (s, 3 H), 3.45 (m, 2 H), 4.57 (m, 1 H), 5.06 (s) , 2H), 5.39 (brs, 2H), 5.45 (brs, 2H), 6.82 (d, 2H), 6.97 (d, 2H), 7.18 (d, 2H), 7.27-7.45 (m, 8H), 7.53 ( d, 2H), 7.65 (d, 2H), 7.75 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 8.19 (s, 1 H), 8.74 (brs, 1H), 9.09 (brs, 2H), 9.30-9.33 (m, 3H) EXAMPLE 19 Synthesis of 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl-benzimidazole-5-carboxamidine dihydrochloride Stage 1 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) benzaldehyde To a solution of 3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (3.07 g), 4-hydroxybenzaldehyde (2 g) and triphenyl phosphine (4.51 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (2.7 ml). ) and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane: acetone = 5: 1) and dried under reduced pressure to give the title compound (3.2 g). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9 H), 2.19 (m, 2 H), 3.59 (m, 4 H), 4.99 (m, 1 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.85 (d, J = 9.0 Hz, 2H), 9.89 (s, 1 H) Stage 2 4- (1-tert-butoxycarbomlpyrrolidin-3-yloxy) phenol To a solution of 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) benzaldehyde (500 mg) in methylene chloride (10 ml) was added 70% 3-chloroperbenzoic acid on ice and the mixture was stirred at room temperature during 4.5 hours After completion of the reaction, aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution were added and the mixture was extracted with methylene chloride and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was dissolved in methanol (3.4 ml) and after that 1N sodium hydroxide aqueous solution (1.7 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 10% aqueous citric acid solution was added and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The solid obtained was washed with diethyl ether and dried under reduced pressure to give the title compound (350 mg). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9 H), 2.09 (m, 2 H), 3.54 (m, 4 H), 4.75 (m, 1 H), 6.71-6.79 (m, 4 H) Stage 3 Ethyl 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxophenoxyacetic acid) ethyl ester To a solution of 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenol (2.14 g) in tetrahydrofuran (43 ml) were added ethyl bromoacetate (1.1 ml) and 60% sodium hydride (368 mg) on ice and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, ice water was added and the mixture was extracted with ethyl acetate and washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography with silica gel (hexane: ethyl acetate = 7: 3) and dried under reduced pressure to give the title compound (2605 g). 1 H-NMR (d ppm, CDCl 3) 1.30 (tr, J = 7.02 Hz, 3H), 1.46 (s, 9H), 2.13 (m, 2H), 3.54 (m, 4H), 4.27 (q, J = 7.2 Hz , 2H), 4.57 (s, 2H), 4.79 (brs, 1 H), 6.78-6.87 (m, 4H) Stage 4 4- (1-tert-Butoxycarbonylpyrrolidin-3-yloxy. Phenoxyacetic acid.

To a solution of the 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxyacetic acid ethyl ester (2.5 g) in a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was added an aqueous solution of sodium hydroxide. 1 N lithium (7.5 ml) on ice and the mixture was stirred at room temperature for 30 minutes. After the reaction is completed, the solvent was evaporated and to the obtained residue was added ice water and 10% aqueous citric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (2.30 g). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9H), 2.14 (m, 2H), 3.54 (m, 4H), '4.61 (brs, 2H), 4.79 (m, 1H), 6.80-6.89 (m , 4H) riftttMii ^^^^ MMta Stage 5 4- (2-H? Droxyethylamino) -3-nitrobenzonitriio H A solution of 4-chloro-3-nitrobenzonitrile (10.13 g) and ethanolamine (3.52 ml) was stirred in a mixture of ethanol (150 ml) and tetrahydrofuran (50 ml) at room temperature for 2 hours. Ethanolamine (3.35 ml) was added and the mixture was stirred at 50 ° C for 1 hour. Then, ethanolamine (3.35 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained solid was washed with isopropanol and collected by filtration and dried under reduced pressure to give the title compound (7.25 g). 1 H-NMR (d ppm, DMSO-d 3) 3.48 (m, 2 H), 3.63 (m, 2 H), 5.00 (brs, 1 H), 7.22 (d, J = 9.0 Hz, 1 H), 7.81 (dd) , J = 1.8 Hz, 9 Hz, 1 H)), 8.50 (d, J = 1.8 HZ, 1 H), 8.62 (brtr, 1 H) Stage 6 3-amino-4-.2-hydroxyethylamino) benzonitrile H A solution of 4- (2-Hydroxyethylamino) -3-nitrobenzonitrile (3.11 g) and tin chloride dihydrate (16.94 g) in ethanol (50 ml) was stirred at 70 ° C for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained residue was mixed with tetrahydrofuran and aqueous 15% sodium hydroxide solution. The mixture was stirred and the insoluble material and the aqueous layer were removed. The organic layer obtained was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained solid was washed with chloroform, filtered and dried under reduced pressure to give the title compound (2.08 g) 1 H-NMR (d ppm, DMSO-d 3) 3.17 (q, J = 5.6 Hz, 2 H), 3.58 ( q, J = 5.6 Hz, 2H), 4.74 (tr, J = 5.6 Hz, 1 H), 4.93 (brs, 2H), 5.34 (tr, J = 5.6 Hz, 2H), 6.49 (1 H), 6.77 ( 1 H), 6.91 (1 H) Stage 7 3- (4- (5-Cyano-2- (2-hydroxyethylamino) phenylcarbamoylmethoxy) -phenoxy) pyrrolidin-1-carboxylic acid tert-butyl ester To a solution of 3-amino-4- (2-hydroxyethylamino) benzonitrile (1.21 g) and 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxyacetic acid (2.30 g) in chloroform (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (2.19 g) and the mixture was stirred for 15 hours at room temperature. After completion of the reaction the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give the title compound (2.56 g) 1 H-NMR (d ppm , CDCI3) 1.46 (s, 9H), 2.13 (m, 2H), 3.31 (m, 2H), 3.55 (m, 4H), 3.73 (m, 2H), 4.64 (s, 2H), 4.82 (m, 1 H), 6.73 (1 H), 6.85-6.94 (m, 4H) 7.41-7.50 (2H), 7.99 (1 H), 8.10 (1 H).

Jgjj ^ j ^^^^ gfiá ^^ Stage 8 2-r4- (1-tert-Butoxycarbonyl-pyrrolidin-3-yloxyphenoxymethyl-1-5-cyano-1- (2-hydroxyethyl) benzimidazole To a solution of 3- [4- [5-cyano-2- (2-hydroxyethylamino) phenylcarbamoylmethoxy] phenoxy] pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g) in acetic acid (15.4 ml) were added. stirred at 65 ° C for 4 hours. After completion of the reaction the solvent was evaporated and the residue was extracted with ethyl acetate, and washed with aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: ethyl acetate = 1: 4-ethyl acetate) to give the title compound (1356 g). 1 H-NMR (d ppm, CDCl 3) 1.44 (s, 9 H), 2.11 (m, 2 H), 3.44-3.54 (m, 4 H), 3.75 (brs, 1 H), 4.06 (m, 2 H), 4.46 (m , 2H), 4.77 (m, 1 H), 5.32 (s, 2H), 6.77 (2H), 6.93 (2H), 7.49 (2H), 7.79 (1 H).

Stage 9 2-r4- (1-tert-Butoxycarbonylpyrrolidin-3-yloxy) phenoxymethin-5-cyano-1- (2-methoxyethyl) benzimidazole To a solution of 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -5-cyano-1- (2-hydroxyethyl) benzimidazole (270 mg) in tetrahydrofuran (5 ml) was added sodium hydride to 60% (271 mg) at room temperature and the mixture was stirred for 30 minutes. Methyl iodide (0.105 ml) was added and the mixture was stirred for 24 hours. After completion of the reaction, 10% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane-acetone = 4: 1) and dried under reduced pressure to give the title compound (199 mg) 1 H-NMR (d ppm, CDCl 3) 1.46 (s, 9H ), 2.10 (m, 2H), 3.27 (s, 3H), 3.55 (m, 4H), 3.72 (tr, 2H), 4.52 (tr, 2H), 4.79 (m, 1 H), 5.39 (s, 2H) ), 6.79 (2H), 6.90 (2H), 7.50 (1H), 7.55 (1H), 8.10 (1H).

Stage 10 2-r4- (1-tert-butoxycarbonylpyrrolidin-3-yloxflfenoxymethip-1- (2-methoxyethyl) benzimidazole-5-carboxamidine In the same manner as in example 18 step 4 the title compound (119 mg) was obtained from 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -5-cyano-1- (2 -methoxyethyl) benzamidazole, (195 mg) methyl iodide (1 ml) and ammonium acetate (37 mg). 1 H-NMR (d ppm, CDCl 3) 1.45 (s, 9 H), 2.10 (m, 2 H), 3.24 (s, 3 H), 3. 54 (m, 4H), 3.69 (brtr, 2H), 4.47 (brtr, 2H), 4.76 (m, 1 H), 5.32 (s, 2H); 6.79 (2H), 6.94 (2H), 7.48 (1H), 7.66 (1H), 8.08 (1H).

Stage 11 2-f4- (pyrrolidin-3-yloxy) phenoxymethyl1-1- (2-methoxyethyl-benzimidazole-5-carboxamidine dihydrochloride To a solution of 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxamidine (115 mg) in chloroform (3 ml) was added acid trifluoroacetic acid (3ml) and the mixture was stirred for 5 minutes. The solvent was evaporated and the residue was mixed with 1 N-diethyl ether hydrogen chloride (2 ml). The solvent was evaporated and the residue was washed with tetrahydrofuran and dried under reduced pressure to give the title compound (97 mg). 1 H-NMR (d ppm, DMSO-dβ) 2.10 (m, 2H), 3.18 (s, 3H), 3.28-3.42 (m, 4H), 3.69 (brtr, 2H), 4.59 (brtr, 2H), 5.02 ( m, 1 H), 5.43 (s, 2H), 6.94 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1 H), 8.23 (s, 1 H), 9.08 (brs, 2H), 9.34 (brs, 2H).

EXAMPLE 20 Synthesis of 2-Í4-Í1-acetirnidoylpyrrolidin-3-yloxy-phenoxymethyl-1 - (2-methoxyethyl-benzimidazole-5-carboxamidine dihydrochloride To a solution of 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxamidine dihydrochloride (44 ml) in a mixture of tetrahydrofuran (2 ml) and water ( 0.6 ml) was added sodium bicarbonate (38 mg) and ethyl acetoimidate hydrochloride (33 mg), and the mixture was stirred for 16 hours at room temperature. After completion of the reaction the insoluble material was removed and the solvent evaporated. The residue was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). The residue was mixed with dilute hydrogen chloride and the solvent was evaporated and dried over anhydrous sodium sulfate under reduced pressure to give the title compound (40 mg). 1 H-NMR (d ppm, DMSO-d 6) 2.12-2.28 (m, 5H), 3.18 (s, 3H), 3.35-3.95 (m, 6H), 4.59 (brs, 2H), 5.06-5.13 (m, 1 H), 5.43 (s, 2H), 6.94 (dd, J = 2.9, 9.0 Hz, 2H), 7.07 (dd, J = 2.9, 9.0 Hz, 2H), 7.77 (1 H), 7.88 (1H), 8.24 (1 H), 8.47-8.54 (1 H), 9.13 (2H), 9.27-9.31 (1 H), 9.36 (2H).

EXAMPLE 21 Synthesis of 7-f1- (2-hydroxyethyl) piperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Stage 1 N, N'-di-tert-butoxycarbonyl-7-hydroxy 1,2,3,4-tetrahydroisoquinoline-2-carboxamidine To a suspension of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline hydrobromide (500 mg) in acetonitrile (5 ml) was added triethylamine (0.3 ml) on ice and the mixture was stirred for one hour at room temperature. The solid precipitate was collected by filtration. The solid obtained was dissolved in dimethyl formamide (5 ml) and 1 H-pyrazole-1- (N, N'-bis-tert-butoxycarbonyl) carboxamidine was added (Synthesis, p.579 (1994)) (742 mg) and the mixture was stirred for 2 hours at room temperature. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: ethyl acetate = 3: 1) and dried under reduced pressure to give the title compound (700 mg). riÉtÉfaáM ___ 1 H-NMR (d ppm, CDCl 3) 1.50 (s, 18 H), 2.87 (m, 2 H), 3.73 (m, 2 H), 4.62 (brs, 2 H), 6.53 (d, J = 2.5 Hz, 1 H), 6.66 (dd, J = 2.5, 8.2 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H).

Stage 2 Benzyl ester of 4-hydroxymethylpiperidine-1-carboxylate In the same manner as in Example 10, step 1, 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10 g) was obtained from isonipecotic acid (15.5 g). To a solution of this compound obtained in tetrahydrofuran (100 ml) was added dropwise at -15 ° C triethylamine (5.56 ml) and so-butylchlorocarbonate (5.2 ml) under an argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. After completion of the reaction the reaction mixture was filtered and the filtrate was added dropwise aqueous solution of sodium borohydride (4.3 g) under ice. The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 2 hours. After the reaction was completed, water was added and the insoluble material was removed. The solvent was partially removed and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 N aqueous sodium hydroxide solution, water and Saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (7.2 g). 1 H-NMR (d ppm, CDCl 3) 1.05-1.30 (m, 2H), 1.55-1.80 (m, 3H), 2.70-2.85 (m, 2H), 3.50 (d, 2H), 4.10-4.30 (m, 2H ), 5.13 (s, 2H), 7.26-7.40 (m, 5H).

Stage 3 4-Bromomethylpiperidine-1-carboxylic acid benzyl ester To a solution of 4-hydromethylpiperidine-1-carboxylic acid benzyl ester (1.11 g), carbon tetrabromide (1.77 g) in methylene chloride (11 ml) was added triphenylphosphine (1.4 g) on ice, and the mixture was stirred for 5 hours at room temperature. After completion of the reaction the solvent was evaporated and the residue was purified by column chromatography with silica gel (hexane: acetone = 10: 1) and dried under reduced pressure to give the title compound (1.25 g). 1 H-NMR (d ppm, CDCl 3) 1.05-1.30 (m, 2H), 1.70-1.90 (m, 3H), 2.78 (m, 2H), 3.29 (d, 2H), 4.10-4.30 (m, 2H), 5.13 (s, 2H), 7.26-7.38 (m, 5H).

Stage 4 Benzyl Ester of 4-r2- (N.N'-di-tert.butoxycarbonylamidoino-1,2,3,4-tetrahydroisoquinoline-7-yloxymethylpiperidine-1-carboxylic acid To a solution of N, N'-di-tert-butoxycarbonyl-7-hydroxy-1, 2,3,4-tetrahydroisoquinol-na-2-carboxamidine (50 mg) and benzylester of 4-bromomethylpiperidin-1 acid carboxylic acid (120 mg) in dimethylsulfoxide (1 ml) was added 4N aqueous sodium hydroxide solution (0.13 ml) and the mixture was stirred for 17 hours at room temperature. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: acetone = 5: 1) and dried under reduced pressure to give the title compound (55 mg). 1 H-NMR (d ppm, CDCl 3) 1.20-1.35 (, 2H), 1.51 (s, 18H), 1.75-2.05 (m, 3H), 2.70-2.95 (m, 4H), 3.65-3.80 (m, 4H) , 4.15-4.35 (m, 2H), 4.67 (brs, 2H), 5.14 (s, 2H), 6.61 (1 H), 6.71 (1 H), 7.03 (1 H), 7.30-7.40 (5H).

Stage 5 N, N'-Di-tert-butoxycarbonyl-7- (p -peridin-4-ylmethoxy-1,2,3,4-tetrahydroisoquinoline-carboxamidine) Benzyl ester of 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1, 2,3,4-tetrahydroisoquinol-7-yloxymethyl] piperidin-1-carboxylic acid (500 mg) was hydrogenated using 7.5% palladium-carotene (150 mg) in a mixture of tetrahydrofuran (5 ml) and ethanol (100 ml) at 3 atmospheres for 3 hours. After completion of the reaction the mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg). 1 H-NMR (d ppm, CDCl 3) 1.20-1.40 (m, 2H), 1.56 (s, 18H), 1.75-2.00 (m, 3H), 2.67 (brtr, 2H), 2.89 (brtr, 2H), 3.10- 3.20 (m, 2H), 3.65-3.85 (m, 4H), 4.67 (s, 2H), 6.62 (1 H), 6.72 (1 H), 7.03 (1 H).

Stage 6 Ethyl ester of 4-r2- (N, N-di-tert-butoxycarbonylamine) -. 1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl-1-piperidin-1-acetic acid To a solution of N, N'-di-tert-butoxycarbonyl-7- (piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) were added aqueous solution of sodium hydroxide 9.1 N (0.027 ml) and ethyl bromoacetate (0.027 ml) and the mixture was stirred for 1 hour at room temperature. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: acetone = 4: 1) and dried under reduced pressure to give the title compound (100 mg). 1 H-NMR (d ppm, CDCl 3) 1.28 (tr, J = 5.2 Hz, 3 H), 1.51 (s, 18 H), 1. 60-1.85 (m, 5H), 2.17-2.23 (m, 2H9, 2.85-3.05 (m, 4H), 3.22 (s, 2H), 3.55-3.95 (m, 4H), 4.19 (q, J = 5.2 Hz , 2H), 4.86 (brs, 2H), 6.61 (1 H), 6.71 (1 H), 7.03(1 H), 10.22 (brs, 1 H).

Stage 7 N, N'-di-tert-butoxycarbonyl-7-f1- (2-hydroxyethyl) piperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1, 2,3,4-tetrahydroisoquinoline-7-ylmethyl] -piperidin-1-acetic acid ethyl ester (155 mg) in a mixture of tetrahydrofuran (2 ml) and methanol (0.008 ml) was added lithium borohydride (11 mg) and the mixture was stirred for 3 hours at room temperature. After the reaction was completed, water was added and the reaction mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: acetone = 3: 1) and dried under reduced pressure to give the title compound (65 mg). 1 H NMR (d ppm, CDCl 3) 1.30-1.55 (m, 20H9, 1.70-1.90 (m, 3H), 2. 11 (brtr, 2H), 2.54 (tr, J = 5.4 Hz, 2H), 2.85-3.00 (m, 4H), 3.61 (tr, J = 5.4 Hz, 2H), 3.65-3.85 (m, 4H), 4.67 (s, 2H), 6.63 (1 H), 6.72 (1 H), 7.03 (1 H), 10.21 (brs, 1 H).

Stage 8 7-ri-.2-Hydroxyethyl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine-dihydrochloride To a solution of N, N'-di-tert-butoxycarbonyl) -7- [1- (2-hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (60 mg) in chloroform (0.6 ml) trifluoroacetic acid (0.3 ml) was added and the mixture was stirred for 5 hours at room temperature. After completion of the reaction the solvent was evaporated and the residue was mixed with hydrogen-ethanol solution and the insoluble material was removed. The resulting mixture was concentrated and dried under reduced pressure to give the title compound (40 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.58-1.80 (m, 2H), 1.85-2.10 (m, 3H), 2.82 (m, 2H), 2.90-3.15 (m, 5H), 3.55-3.60 (m , 2H), 3.75-3.83 (m, 6H), 4.54 (s, 2H), 6.71 (1 H), 6.83 (1 H), 7.14 (1 H), 7.54 (4H), 10.08 (1 H).

EXAMPLE 22 Synthesis of 7-Í1 - (pyridin-4-ylmethylpiperidin-4-ylmethoxyl-1, 2.3.4-tetrahydroisoquinoline-2-carboxamidine-trichlorhydrate Stage 1 N, N'-di-tert-butoxycarbonyl-7-y1- (pyridin-4-ylmethyl-piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoouinoline-2-carboxamidine To a solution of N, N'-di-tert-butoxycarbonyl-7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) was added aqueous solution of sodium hydroxide 9.1 N (0.68 ml) and hydrochloride of 4-picolyl chloride (51 mg) and the mixture was stirred for 5 hours at 50 ° C. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by preparative thin layer chromatography (chloroform: methanol = 20: 1) and dried under reduced pressure to give the title compound (93 mg). ldliaÉbMÉ_tt ________________ ÉM__? Stage 2 7- [1- (pyridin-4-ylmethyl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroiso-Quinolin.-Carboxamidine trihydrochlorhydrate In the same manner as in Example 21 step 8 the title compound (65 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- [1- (pyridin-4-ylmethyl ) -piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (88 mg) and trifluoroacetic acid (0.45 ml). 1 H-NMR (d ppm, DMSO-d 6) 1.70 -2.00 (m, 5H), 2.81 (m, 2H), 3.00 (m, 2H), 3.88 (m, 2H), 3.57 (m, 2H), 3.81 ( m, 2H), 4.48-4.54 (m, 4H), 6.71 (1 H), 6.82 (1 H), 7.13 (1 H), 7.60 (4H), 8.19 (d, J = 6.0 Hz, 2H), 8.88 (d, J = 6.0 Hz, 2H), 11.63 (1 H).

- "» "- • - - -" • EXAMPLE 23 Synthesis of 7-ri- (2-hydroxy-2-phenylethihpiperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Stage 1 N, N'-Di-tert-butoxycarbonyl-7- (1-phenacylpiper? Din-4-ylmethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine In the same manner as in example 21 step 6, the title compound (125 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (piperidin-4-methylmethoxy-1,2). , 3,4-tetrahydroisoquinoline-2-carboxamidine (200 mg), phenacyl bromide (90 mg) and sodium hydroxide 9.1 N (0.054 ml).

Stage 2 N. N'-di-butoxycarbonyl ^ -ri-.S-hydroxy-phenylethiOpiperidin-1-methylmethoxy-1'-S-tetrahydroisoquinoline-carboxamidine To a solution of N, N, -di-tert-butoxycarbonyl-7- (1-phenacylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamide (120 mg) in a mixture of tetrahydrofuran (1 ml) and methanol (0.2 ml) was added sodium borohydride (11 mg), and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by chromatography on silica gel (hexane: acetone = 5: 1, 1% triethylamine) and dried under reduced pressure to give the title compound (90 mg). 1 H-NMR (d ppm, CDCl 3) 1.39-1.55 (m, 20H), 1.75-1.95 (m, 3H), 2. 08 (m, 1H), 2.36 (m, 1 H), 2.46-2.56 (m, 2H), 2.85-2.95 (m, 3H), 3.15-3.25 (m, 1 H), 3.65-3.85 (m, 4H) ), 4.60-4.67 (m, 3H), 6.64 (1 H), 6.73 (1 H), 7.04 (1 H), 7.26-7.40 (m, 5H).

Stage 3 7-p- (2-Hydroxy-2-phenylethyl) piperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinoline -2-carboxamidine dihydrochloride In the same manner as in example 21 step 8 the title compound (55 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- [1- (2-hydroxy-2-phenylethyl) piperidine -4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (85 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.60-2.10 (m, 5H), 2.82 (m, 2H), 2.95-3.25 (m, 3H), 3.58 (m, 2H), 3.84 (d, 2H), 4.55 (s, 2H), 5.17 (m, 1 H), 6.73 (1 H), 6.84 (1 H), 7.15 (1 H), 7.25-7.50 (m, 5H), 7.60 (brs, 4H), 9.98 (brs, 1 H).

EXAMPLE 24 Synthesis of 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl-piperidin-1-ylacetyl-quinoline ethyl ester dihydrochloride Stage 1 Benzyl ester of 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1, 2,3,4-tetrahydroisoquinolin-7-yloxymethylpiperidine-1-acetic acid In the same manner as in example 21 step 6, the title compound (810 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7-piperidin-4-methoxy) -1, 2, 3,4-tetrahydroisoquinoline-2-carboxamidine (1 g), benzyl chloroacetate (0.34 ml) and sodium hydroxide 9.1 N (0.025 ml).

Stage 2 4- [2- (N, N'-di-tert-butoxycarbonylamido-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethylpiperidin-1-acetic acid Benzyl ester of 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidin-1-acetic acid (735 mg) was hydrogenated using palladium carbon 7.5% (220 mg) in a mixture of tetrahydrofuran (7 ml) and methanol (14 ml) at atmospheric pressure for 3 hours. After completion of the reaction the mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (600 mg). 1 H-NMR (d ppm, CDCl 3) 1.34-1.56 (m, 20H), 1.80-2.10 (m, 5H9, 2.77 (brtr, 2H), 2.89 (brtr, 2H), 33.49 (s, 2H), 3.55-3.90 (m, 4H), 4.66 (s, 2H), 6.60 (1 H), 6.70 (1 H), 7.03 (1 H).

Stage 3 Ethyl ester of 4-f2- (N, N'-di-tert-butoxycarbonylamino) -1, 2,3,4-tetrahydroisoquinoline-7-yloxymethylpiperidin-1-ylacetylcholine To a solution of 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1,2,4,4-tetrahydroisoquinoline-7-yloxymethyl] piperidine-1-acetic acid (120 mg) and glycine ethyl ester hydrochloride in methylene chloride (1.5 ml) was added triethylamine (0.031 ml), 4-dimethylaminopyridine (27 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (42 mg) and the The mixture was stirred for 12 hours at room temperature. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography with silica gel (hexane: acetone = 5: 2) and dried under reduced pressure to give the title compound (100 mg) 1 H-NMR (d ppm, CDCl 3) 1.29 (tr, J = 7.2Hz, 3H), 1.45-1.65 (m, 2H), 1.70-1.90 (m, 3H), 2.21 (brtr, 2H), 2.87-3.00 (m, 4H), 3.05 (s, 2H), 3.70- 3. 85 (m, 4H), 4.07 (d, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.67 (brs, 2H), 6.63 (1 H), 6.73 (1 H), 7.04 (1 H) , 7.70 (brtr, 1 H), 10.20 (brs, 1 H).

Stage 4 Ethyl ester dihydrochloride of 4- (2-amidino-1,2,3,4-tetrahydroisoouinoline-7-yloxymethyl) piperidin-1-ylacetylcholine H In the same manner as in example 21 step 8 the title compound (75 mg) was obtained from ethyl ester of 4- [2- (N, N'-di-tert-butoxycarbonylamino) -1, 2,3,4-tetrahydroisoquinolyl-7-yloxymethyl] pyridin-1-ylacetylglycine (100 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.20 (tr, J = 7.0 Hz, 3H), 1.58-2.1 (m, 5H), 2.82 (m, 2H), 3.00-3.20 (m, 2H), 3.51 (m, 2H), 3.82 (m, 2H), 3.9-3.98 (m, 4H), 4.11 (q, J = 7.0 Hz), 4.56 (s, 2H), 6.72 (d, J = 2.1 Hz, 1 H), 69.83 (dd, J = 2.1, 8. 3 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.68 (brs, 4 H), 9.24 (brtr, 1 H), 10.07 (brs, 1 H).

EXAMPLE 25 Synthesis of 4- (2-amidino-, 2,3,4-t-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-acetic acid N-methylamide dihydrochloride Stage 1 N-methylamide of 4- [2- (N ', N "-di-tert-butoxycarbonylamido-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethylpiperidin-1-acetic acid In the same way as in example 24 step 3 the title compound (25 mg) was obtained from 4- [2- (N, N'-di-tert-butoxycarbonylamido) -1, 2,3,4 -tetrahydroisoquinolin-7-yloxymethyl] piperidin-1-acetic acid (120 mg), methylamine hydrochloride (148 mg), triethylamine (0.6 ml), 4-dimethylaminopyridine (27 mg), 1- (3-dimethylaminopripyl) hydrochloride -3-ethylcarbodumide (42 mg) and N-methylmorpholine (0.24 ml) Stage 2 N-methylamide dihydrochloride of 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-acetic acid In the same manner as in Example 21 step 8 the title compound (15 mg) was obtained from 4- [2- (N ', N "-d'-tert-butoxycarbonylamido) -N-methylamide. 2,3,4-tetrahydroisoquinoline-7-yloxymethyl] p-peridin-1-acetic acid H-NMR (d ppm, DMSO-D6) 1.60-1.78 (m, 2H), 1.88-2.08 (m, 2H ), 2.67 (s, 3H), 2.83 (tr, J = 4.4 Hz, 2H), 3.00-3.15 (m, 2H), 3.45-3.55 (m, 2H), 3.58 (tr, J = 4.4 Hz, 2H) , 3.82-3.92 (m, 4H), 4.62 (s, 2H), 6.72 (1H), 6.85 (1 H), 7.15 (1 H), 7.63 (brs, 4H), 8.67 (brs, 1 H), 9.93 (brs, 1 H). , d _______________ EXAMPLE 26 Synthesis of 7- (1-acetylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride Stage 1 N, N'-Di-tert-butoxycarbonyl-7- (1-acetylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of N, N'-di-tert-butoxycarbonyl-7- (piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroxyquinoline-2-carboxamidine (100 mg) in tetrahydrofuran ( 1.5 ml) was added acetic anhydride (0.21 ml) pyridine (0.025 ml) and the mixture was stirred for 2 hours at room temperature. After completion of the reaction the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (100 mg). 1 H-NMR (d ppm, CDCl 3) 1.20-1.40 (m, 2H), 1.45-1.65 (, 20H), 1.80-2.10 (m, 6H), 2.59 (m, 1H), 2.90 (brtr, 2H), 3.08 (m, 2H), 3.85-3.90 (m, 4H), 4.67 (brs, 2H), 6.62 (1 H), 6.72 (1 H), 7.04 (1 H). __j _? _ i_____i__________ ...._ Éa ___ Stage 2 7- (1-Acetylpididin-4-ylmethoxy1-1.2.3.4-tetrahydroisoquinoline-2-carboxamidine hydrochloride In the same manner as in Example 21 step 8 the title compound (60 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1-acetylpiperidin-4-ylmethoxy). ) -1, 2, 3,4-tetrahydroquinoline-carboxamidine (94 mg). 1 H-NMR (d ppm, DMSO-de) 1.00-1.30 (m, 2H), 1.70-1.85 (m, 2H), 1.98 (m, 4H), 2.52 (m, 1 H), 2.81 (tr, J = 6.0 Hz, 2H), 3.02 (m, 1 H), 3.57 (tr, J = 6.0 Hz, 2H), 3.75-3.90 (m, 3H), 4.53 (s, 2H), 6.69 (d, J = 2.4 Hz , 1 H), 6.82 (dd, J = 2.4, 8.4 Hz, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.57 (brs, 4H).

EXAMPLE 27 Synthesis of 7- (1-benzylsulfonylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine hydrochloride Stage 1 N, N'-Di-tert-butoxycarbonyl-7- (1-benzylsulfonylpiperidin-4-ylmethoxy) -1.2.3.4-tetrahydroisoquinoline-2-carboxamidine To a solution of N, N'-di-tert-butoxycarbonyl-7- (1-piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) pyridine (0.02 ml), 4-dimethylaminopyridine (2 mg) and alpha-toluenesulfonyl chloride (43 mg) were added and the mixture was stirred for 12 hours at room temperature and then for 6 hours at 50 ° C. After completion of the reaction the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography on silica gel (hexane: acetone = 3: 1) and dried under reduced pressure to give the title compound (48 mg). 1 H-NMR (d ppm, CDCl 3) 1.20-1.40 (m, 2H), 1.45-1.60 (m, 20H), 1.70-1.90 (m, 3H), 2.60 (m, 2H), 2.89 (m, 2H), 3.65-3.80 (m, 4H), 4.22 (s, 2H), 4.66 (brs, 2H), 6.59 (1 H), 6.68 (1H), 7.03 (1 H), 7.36-7.40 (5H).

Stage 2 7-f1-benzylsulfonylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride In the same manner as in example 21 step 8 the title compound (30 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1-benzylsulfonylpiperidin-4-ylmethoxy) -1, 2 , 3,4-tetrahydroisoquinoline-2-carboxamidine (43 mg). 1 H-NMR (d ppm, DMSO-de) 1.14-1.30 (m, 2H), 1.70-1.88 (m, 3H), 2.68-2.83 (m, 4H), 3.56 (m, 4H), 3.80 (m, 2H) ), 4.38 (s, 2H), 4.52 (s, 2H), 6.69 (d, J = 2.7 Hz, 1 H), 8.82 (dd, J = 2.7, 8.3 Hz, 1 H), 7.13 (d, J = 8.3 Hz, 1 H), 7.35-7.40 (m, 5H), 7.53 (s, 4H).

EXAMPLE 28 Synthesis of 7-.1- (2-naphthysulfonyl) piperidin-4-methylmethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride .carboxamidine Stage 1 N, N'-Di-tert-butoxycarbonyl-7-H-.2-naphthylsulfonyl) piperidin-4-ylmethoxy-1, 2, 3, 4-tetrahydroisoouine-2-carboxamidine In the same manner as in example 27 stage 1 the title compound (75 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (piperidn-4-ylmethoxy) - 1, 2,3,4-tetrahydroisoquinolin. -carboxamidine (100 mg), 2-naphthalenesulfonyl chloride (51 mg) and pyridine (0.02 ml).

Stage 2 7- [1-.2-naphthylsulfonyl) piperidin-4-ylmethoxy1-1.2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride In the same manner as in example 21 step 8 the title compound (55 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- [1- (2-naphthylsulfonyl) piperdin-4 -ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (70 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.22-1.40 (m, 2H), 1.60-1.84 (m, 3H), 2. 32 (m, 2Hg, 2.78 (tr, J = 5.7 Hz, 2H), 3.54 (tr, J = 5.7 Hz, 2H), 3.72-3.80 (m, 4H), 4.49 (s, 2H), 6.62 (d, J = 2.3 Hz, 1 H), 6.74 (dd, J = 2.3, 8.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.50 (brs, 4H), 7.66-7.77 (m, 3H), 8.07-8.20 (m, 3H), 8.43 (s, 1 HOUR).

EXAMPLE 29 Synthesis of dihydrochloride 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline -2 -carboxamidine Stage 1 N-N, di-tert-butoxycarbonyl-7- (1-acetimidoylpiperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of N-, N'-di-tert-butoxycarbonyl-7- (1-piperidin-4-ylmethoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1.5 ml) and ethanol (1.5 ml) was added triethylamine (0.086 ml) and ethylacetoimidate hydrochloride (38 mg) and the mixture was stirred for 18 hours at room temperature. After the reaction was completed, ethyl acetate and diethyl ether were added and the insoluble material was removed. The solvent was evaporated and the residue was dried under reduced pressure to give the compound the title (120 mg). 1 H-NMR (d ppm, CDCl 3) 1.43-1.54 (m, 20H), 2.00-2.20 (m, 3H), 2.43 (m, 3H), 2.90 (m, 2H), 3.05-3.15 (m, 2H), 3.70-3.95 (m, 5H), 4.67 (brs, 2H), 4.80-4.90 (m, 1 H), 6.60 (1 H), 6.70 (1 H), 7.04 (1 H).

Stage 2 7- (1-Acetylimidopiperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride In the same manner as in Example 21 step 8, the title compound (80 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1-acetylimidopidyl) L-methoxy) -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.28-1.48 (m, 2H), 1.86-1.90 (m, 2H), 2. 12 (, 1 H), 2.29 (s, 3H), 2 83 (tr, J = 4.4 Hz, 2H), 3.00-3.29 (m, 2H), 3.59 (tr, J = 4.4 Hz, 2H), 3.85 (m, 2H), 3.92-4.20 (m, 2H), 4.56 (s, 2H), 6.72 (d, J = 1.7 Hz, 1 H), 6.84 (dd, J = 1.7, 6.3 Hz, 1 H), 7.15 (d, J = 6.3 Hz, 1 H), 7.65 (brs, 4 H), 8.67 (brs, 1 H), 9.33 (brs, 1 H).

EXAMPLE 30 Synthesis of 7- (1-phenylacetimidoylpperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Stage 1 Ethylphenylacetoimidate hydrochloride Hydrogen chloride was bubbled into a solution of benzyl cyanide (5.8 ml) in diethyl ether (10 ml) on ice and the mixture was allowed to stand at room temperature for 12 hours. After completion of the reaction the solvent was evaporated. The solid obtained was washed with diethyl ether, collected by filtration and dried under reduced pressure to give the title compound (9.43 g).

Stage 2 N.N'-Di-tert-butoxycarbonyl-7- (1-phenylacetylimidopiperidin-4-ylmethoxy) -1,2,3-tetrahydroisoquinoline-2-carboxamidine In the same manner as in example 29, step 1, the title compound (105 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1-piperidin-4-ylmethoxy) -1.2 , 3,4-tetrahydroxysoquinoline-2-carboxamidine, and ethyl phenylacetoimidate hydrochloride (64 mg) Stage 3 7- (1-Phenylacetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride In the same manner as in example 21 step 8, the title compound (70 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1-phenylacetimido-piperidin-4-ylmethoxy) -1, 2 , 3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) 1 H NMR (d ppm, DMSO-d 6) 0.80-1.00 (m, 1 H), 1.20-1.40 (m, 1 H), 1.60-1.65 (m, 1 H), 1.80-1.95 (m, 1 H), 2.05 (m, 1 H), 2.80 (m, 2H), 3.05-3.25 (m, 2H), 3.56 (m, 2H), 3.74 (m, 2H) ), 3.93-4.26 (m, 2H), 4.07 (s, 2H), 4.53 (s, 2H), 6.66 (1 H), 6.77 (1 H), 7.12 (1 H), 7 25-7.42 (m, 5H), 7.62 (brs, 4H), 9.13 (brs, 1 H), 9.75 (brs, 1 H). ^ fl__ EXAMPLE 31 Synthesis of N-.2- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethoxy) piperidin-1-yl) pyridin-5-yl dihydrochloride) acetamide Stage 1 N, N'-di-tert-butoxycarbonyl-7- (1- (5-nitroDÍridin-2-yl) piperidin-4-ylmethoxy) 1,2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of N, N'-di-tert-butoxycarbonyl-7- (1-pyridin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg) in a mixture of tetrahydrofuran and dimethylformamide (1.2 ml) was added triethylamine (0.068 ml) and 2-chloro-5-nitropyridine (58 mg) and the mixture was stirred for two hours at room temperature. After completion of the reaction the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography on silica gel (hexane: acetone = 4: 1) and dried under reduced pressure to give the title compound (120 mg). 1 H NMR (d ppm, CDCl 3) 1.30-1.50 (m, 20H), 1.90-2.20 (m, 3H), 2.90 (brtr, 2H), 3.06 (m, 2H), 3.65-3.82 (m, 4H), 4.50. -4.70 (m, 4H), 6.57-6.63 (2H), 6.72 (1 H), 7.04 (1 H), 8.19 (1 H), 9.03 (1 H), 10.19 (brs, 1 H).

Stage 2 N, N'-di-tert-butoxycarbonyl-7- (1- (5-aminopyridin-2-yl) piperidin-4-ylmethoxy) 1, 2,3,4-tetrahydroaisoinoline-2-carboxamidine N, N'-di-tert-butoxycarbonyl-7- (1- (5-nitropyridin-2-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) was hydrogenated with palladium carbon (30mg) at 7.5% in a mixture of tetrahydrofuran (1 ml) and methanol (2ml) at 2.5 atmospheres for 4 hours. After completion of the reaction the mixture was filtered through celite and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 10: 1) and dried under reduced pressure to give the title compound (90 mg). _áttß & __________ Stage 3 N- (2- (4- (2-N, N'-di-tert-butoxycarbonylamino, -1, 2,3,4-tetrahydroisoauinoline-7-yloxymethyl) piperidin-1-yl) pyridin-5-yl) acetamide To a solution of N, N'-di-tert-butoxycarbonyl-7- (1- (5-aminopyridin-2-yl) piperidin-4-ylmethoxy) 1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran, acetic anhydride (0.017ml) and pyridine (0.017ml) were added and the mixture was stirred for two hours at room temperature. After completion of the reaction the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: acetone = 2: 1). The residue was dissolved in methanol and treated with activated carbon and dried under reduced pressure to give the title compound (75 mg). 1 H NMR (d ppm, CDCl 3) 1.30-1.55 (m, 20H), 1.85-2.10 (m, 3H), 2.17 (s, 3H), 2.80-2.90 (m, 2H), 3.65-3.85 (m, 4H) , 4.20-4.30 (m, 2H), 4.67 (s, 2H), 6.60-6.76 (m, 3H), 7.04 (1H), 7.11 (1H), 7.82 (1H), 8.09 (1H).

Stage 4 N- (2- (4- (2-amino-1, 2,3,4-tetrahydroisoquinoline-7-yloxymethyl) piperidin-1-yl) pyridin-5-yl acetamide dihydrochloride In the same manner as in example 21 step 8 of the title compound (50 mg) was obtained from N- (2- (4- (2-N, N'-di-tert-butoxycarbonyllamine) -1 , 2,3,4-tetrahydroisoquinoline-7-methoxymethyl) piperidin-1-yl) pyridin-5-yl) acetamide (70 mg). 1 H NMR (d ppm, DMSO-d 6) 1.25-1.45 (m, 2H), 1.88-1.95 (m, 2H), 2.00-2.2 (m, 4H), 2.81 (m, 2H), 3.16 (m, 2H) , 3.57 (m, 2H), 3.85 (m, 2H), 4.24-4.30 (m, 2H), 4.53 (s, 2H), 6.71 (1 H), 6.83 (1 H), 7.13 (1 H), 7.39 (1 H), 7.57 (brs, 4H), 8.00 (1 H), 8.46 (1 H), 10.49 (1 H).

EXAMPLE 32 Synthesis of N-α2-f4-, 2-amino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl.pipTridin-1-yl. Pyridin-5-yl. Benzamide dihydrochloride Stage 1 N- (2-.4- (2-N, N'-di-tert-butoxycarbonylamino-1, 2,3,4-tetrahydroisoouinolin-7-yloxymethyl) piperidin-1-yl) pyridin-5-ylbenzamide In the same manner as in Example 31 step 3 the title compound (90 mg) was obtained from N, N'-di-tert-butoxycarbonyl-7- (1- (5-aminopyridin-2-yl) p Peridin-4-ylmethoxy) 1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg), benzoyl chloride (0.021 ml) and pyridine (0.017 ml).

Stage 2 N- (2- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxirnethyl) piperidin-1-yl) pyridin-5-yl) benzamide dihydrochloride In the same manner as in example 21 step 8 the title compound (70 mg) was obtained from N- (2- (4- (2-N-N'-di-tert-butoxycarbonylamine) -1, 2,3 , 4-tetrahydro-1,3-quinolin-7-yloxymethyl) piperidin-1-yl) pyridin-5-yl) benzamide (84 mg). 1 H NMR (d ppm, DMSO-d 6) 1.30-1.48 (m, 2H), 1.87-1.93 (m, 2H), 2.12 (m, 1 H), 2.82 (tr, J = 5.8Hz, 2H), 3.19 ( m, 2H), 3.57 (tr, J = 5.8Hz, 2H), 3.86 (, 2H), 4.29-4.36 (m, 2H), 4.54 (s, 2H), 6.71 (d, J = 2.7Hz, 1 H ), 6.84 (dd, J = 2.7, 8.4Hz, 1 H), 7.14 (d, J = 8.4Hz, 1 H), 7.43 (1 H), 7.51-7.64 (7H), 8.02 (2H), 8.30 ( 1 H), 8.63 (1 H), 10.65 (1 H). _ ^ g ^ EXAMPLE 33 Synthesis of 3- (4- (4- (2-amidino-1, 2,3,4-t-tetrahydroisoquinolin-7-yloxymethyl) pyridin-1-yl) pyridinium ethyl ester dihydrochloride -3-yl-2- propenoic Stage 1 4- (2-tert.-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-carboxylic acid benzyl ester To a solution of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid terbutyl ester (2.39 g) in tetrahydrofuran (30 ml) was added triphenylphosphine (2.52 g) and diisopropylazodicarboxylate (1.90 ml) and the mixture it was stirred for 20 hours at room temperature. After completion of the reaction the solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane: acetone = 6: 1) and dried under reduced pressure to give the title compound (1.82 g) 1 H NMR (d. ppm, CDCl 3) 1.20-1.35 (m, 2H), 1.48 (s, 9H), 1.75-2.05 (m, 3H), 2.70-2.90 (m, 4H), 3.62 (m, 2H), 3.77 (d, 2H ), 4.10-4.35 (m, 2H), 4. 53 (s, 2H), 5.14 (s, 2H), 6.67 (d, J = 2.5Hz, 1 H), 6.71 (d, J = 2.5, 8.3Hz, 1 H), 7.29 (d, J = 8.3Hz , 1 H), 7.26-7.38 (m, 5H).

Stage 2 } 7- (Piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid terbutyl ester Benzyl ester of 4- (2-tert-butoxycarbonyl-1, 2,3,4-tetrahydroquinolin-7-yloxymethyl) piperidine-1-carboxylic acid (1.3 g) was hydrogenated using 7.5% palladium char (300 mg) in a mixture of tetrahydrofuran (10 ml) and methanol (20 ml) at 3 atmospheres for 3 hours. After completion of the reaction the reaction mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg) 1 H NMR (d ppm, CDCl 3) 1.20-1.35 (m, 2H), 1.49 (s, 9H), 1.75-2.00 (m, 4H), 2.62-2.76 (m, 4H), 3.10-3.20 (m, 2H), 3.62 (m, 2H), 3.76 (d, 2H), 4.53 (s, 2H), 6.63 (1 H), 6.71 (1 H) 7.03 (1 H).

Stage 3 7- (1- (3-formylpyridin-4-yl. Piperidin-4-ylmethoxyl, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid, terbutyl ester To a solution of 7- (piperidin-4-lmetoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ester (442 mg) in ethanol (3 ml) was added triethylamine (0.3 ml) and 4-chloro-3-formylpyridine (Journal of Heterocyclic Chemistry, vol.25, p 81 (1988)) (150 mg) and the mixture was stirred under reflux for 27 hours. After completion of the reaction, tetrahydrofuran and diethyl ether were added and the insoluble material was removed. The solvent was evaporated and the residue was purified by column chromatography on silica gel (chloroform: methanol = 100: 1) and dried under reduced pressure to give the title compound (430 mg) 1 H-NMR (d ppm, CDCl 3) 1.49 (s, 9H), 1.60-1.70 (m, 2H), 1.95-2.15 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H), 3.60-3.65 (m, 4H), 3.86 ( d, 2H), 4.54 (s, 2H), 6.65 (1 H), 6.73 (1 H), 6.84 (d, J = 6.0 Hz, 1 H), 7.05 (1 H), 8.42 (d, J = 6.0 Hz, 1 H), 8.74 (s, 1 H), 10.02 (s, 1 H) Stage 4 Ethyl ester of 3-f4-β4- (2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl.pyridin-1-yl) pyridin-3-yl.-2-propenoic acid To a solution of triethyl phosphonoacetate (0.05 ml) in tetrahydrofuran (1 ml) was added sodium hydride (12 mg) with ice cooling, and the mixture was stirred at the same temperature for 1 hour. A solution of 7- [1- (3-formylpyridin-4-yl) piperdin-4-ylmethoxy] -1,2,3,4-tetrahydroquinoline-2-carboxylic acid tert-butyl ester was added dropwise. 95mg) in tetrahydrofuran (1 ml) and the mixture was stirred for 2 hours. After completion of the reaction, an aqueous ammonium chloride solution was added with ice cooling, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1-10: 1) and dried under reduced pressure to give the compound (100mg). 1 H-NMR (d ppm, CDCl 3) 1.35 (tr, J = 6.4 Hz, 3H), 1.49 (s, 9H), 1. 50-1.80 (m, 2H), 1.95-2.10 (m, 3H), 2.75-2.95 (m, 4H), 3.40-3.50 (m, 2H), 3. 63 (m, 2H), 3.86 (d, 2H), 4.27 (q, J = 6.4 Hz, 2H), 4.54 (s, 2H), 6.45 (d, J = 15.9 Hz, 1 H), 6.65 (1 H), 6.74 (1 H), 6.83 (d, J = 6.0 Hz, 1 H), 7.05 (1 H), 7.76 (d, J = 15.9 Hz, 1 H), 8.38 (d, J = 6.0 Hz, 1 H), 8.55 (s, 1 H) Step 5 Ethyl 3- [4- [4- (1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl-] pyridin-3-yl] -2-propenoic acid ethyl ester To a solution of 3- [4- [4- (2-tert.-butoxycarbonyl-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl) pyridin-3-yl) -2-propenoic acid ethyl ester ( 100 mg) in chloroform (1.5 ml) was added trifluoroacetic acid (0.45 ml) and the mixture was stirred for one hour at room temperature. After completion of the reaction the solvent was evaporated. To the obtained residue, aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was dried under reduced pressure to give the title compound (70 mg) 1 H-NMR (d ppm, CDCl 3) 1.35 (tr, J = 7.1 Hz, 3H), 1.50-1.65 (m, 2H), 1.90-2.10 (m, 3H), 2.70-2.90 (m, 4H), 3.13 (m, 2H), 3.40-3.50 (m, 2H), 3.84 (d, 2H), 3.99 (s, 2H) , 4.28 (q, J = 7.1 Hz, 2H), 6.45 (d, J = 16.2 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 6.72 (dd, J = 2.3, 8.2 Hz, 1 H), 6.83 (d, J = 6.0 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 16.2 Hz, 1H), 8.37 (d, J = 6.0 Hz. 1H), 8.55 (s, 1H) Stage 6 3- [4-l4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl-piperidin-1-yl) pyridin-3-yl) -2-propenoic acid ethyl ester dihydrochloride.

To a solution of 3- [4- [4- (1, 2,3,4-tetrahydroisoquinolyl-7-yloxymethyl) piperidin-1-yl) pyridin-3-yl) -2-propenoic acid ethyl ester ( 70 mg) in dimethyl formamide (1 ml) was added diisopropylethylamine (0.032 ml) and 1 H-pyrazole-1-carboxamide hydrochloride (27 mg) and the mixture was stirred for 12 hours at room temperature. The solvent was evaporated and diethyl ether was added to the obtained residue and the supernatant was removed. The procedure was repeated 2 times and hydrogen chloride-ethanol solution was added to the obtained residue and the insoluble material was removed. The solution was concentrated and dried under pressure to give the title compound (50 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.25 (tr, J = 7.3 Hz, 3H), 1.40-1.55 (m, 2H), 1.82-2.05 (m, 3H), 2.76-2.96 (, 4H), 3.42 (m, 2H), 3.57 (m, 2H), 3.90 (m, 2H), 4.18 (q, J = 7.3 Hz, 2H), 4.53 (s, 2H), 6.63 (d, J = 16.1 Hz, 1 H), 6.73 (1 H), 6. 85 (1 H), 7.04 (1 H), 7.14 (1 H), 7.51 (brs, 4 H), 7.60 (d, J = 16.1 Hz, 1 H), 8.35 (1 H), 8.64 (s, 1H) EXAMPLE 34 Synthesis of 4- [4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-pyridin-3-carboxylic acid methyl ester dihydrochloride Stage 1 Ter-butyl ester of 7- (1- (3-methoxycarbonylpyridin-4-yl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydrois-quinoline-2-carboxylic acid To a solution of 7- (1- (3-formylpyridin-4-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid terbutyl ester (50 mg) in a mixture of chloroform and methanol (0.2 ml) was added sodium cyanide (8 mg), manganese dioxide (250 mg) and acetic acid (0.003 ml) and the mixture was stirred for 12 hours at room temperature. After completion of the reaction the reaction mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (chloroform: methanol = 15: 1) and dried under reduced pressure to give the title compound (50 mg). 1 H-NMR (d ppm, CDCl 3) 1.49-1.70 (m, 11 H), 1.90-2.10 (m, 3H), 2. 76 (m, 2H), 2.97 (m, 2H), 3.50-3.68 (m, 4H), 3.83 (d, 2H), 3.91 (s, 3H), 4.54 (s, 2H), 6.64 (1 H), 6.72 (1 H), 6.78 (d, J = 6.0 Hz, 1 H), 7.04 (1 H), 8.35 (d, J = 6.0 Hz, 1 H), 8.73 (s, 1 H) Stage 2 Methyl ester of 4- [4- (1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl.piperidin-1-y. Pyridin-3-carboxylic acid) A solution of 7 - [(1- (3-methoxycarbonylpyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroquinoline-2-carboxylic acid terbutyl ester (37 mg) in chloroform ( 0.5 ml) was added trifluoroacetic acid (0.15 ml) and the mixture was stirred for one hour at room temperature After the completion of the reaction the solvent was evaporated.to the residue was added aqueous sodium bicarbonate solution and the mixture was extracted with acetate The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate The solvent was evaporated and dried under reduced pressure to give the title compound (30 mg) Stage 3 (4- (4- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl. Pyridine-3-carboxylic acid methyl ester dihydrochloride In the same manner as in Example 33 step 6 the title compound (15 mg) was obtained from 4- [4- (1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-methyl ester. -yl) pyridine-3-carboxylic acid (30 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.34-1.54 (m, 2H), 1.87-1.93 (m, 2H), 2.15 (m, 1H), 2.82 (m, 2H), 3.29 (m, 2H), 3.57 (m, 2H), 3.76-3.87 (m, 7H), 4.54 (s, 2H), 6.71 (1H), 6.82 (1H), 7.14 (1H), 7.40 (d, J = 7.2 Hz, 1H ), 7.59 (brs, 4H), 8.30 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H) EXAMPLE 35 Synthesis of 4- (4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethylpiperidin-1-pyridin-3-carboxylic acid dihydrochloride.

To a solution of synthesis of 4- [4- (2-amidino-1, 2,3,4-tetrahydro-5-quinolin-7-yloxymethyl) pyridin-1-yl) pyridinyl methyl ester dihydrochloride. 3-carboxylic acid (43 mg) in methanol (0.2 ml) was added 1N aqueous sodium hydroxide solution (0.1 ml) and the mixture was stirred under reflux for 3 hours. After completion of the reaction the mixture was neutralized with 1N hydrogen chloride and the solvent was evaporated. The residue was purified by preparative thin layer reverse phase chromatography (40% aqueous acetonitrile, trifluoroacetic acid 1%) and the residue was treated with hydrogen chloride-ethanol solution and dried under reduced pressure to give the title compound mg). 1 H-NMR (d ppm, DMSO-de) 1.38-1.58 (m, 2H), 1.85-1.95 (m, 2H), 2.15 (m, 1H), 2.82 (m, 2H), 3.56 (m, 2H), 3.80-3.95 (m, 4H), 4.51 (s, 2H), 6.70 (1 H), 6.82 (1 H), 7.14 (1 H), 7.34 (d, J = 7.4 Hz, 1 H), 7.44 (brs) , 4H), 8.27 (d, J = 7.4 Hz, 1 H), 8.59 (s, 1H) EXAMPLE 36 Synthesis of 6- [1-piperidin-4-yl] pipßridin-4-ylmetoxfl-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Stage 1 6-Hydroxy-1, 2,3,4-tetrahydroisoquinoline Bromohydrate 6-Methoxy-1,2,4,4-tetrahydroisoquinoline (2.89 g) was dissolved in 48% aqueous hydrogen bromide solution (70 ml) and the mixture was refluxed for 2 hours. The solvent was evaporated and ethanol and diethyl ether were added to the residue. The mixture was filtered and dried under reduced pressure to give the title compound (3.93 g). 1 H-NMR (d ppm, DMSO-de) 2.90 (tr, J = 6.3 Hz, 2H), 3.35 (m, 2H), 4.13 (brs, 2H), 6.59 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 2.4, 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1 H), 8.91 (brs, 2H), 9.43 (brs, 1 H) Stage 2 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic tert-butyl ester In the same manner as in Example 1 step 1 the title compound (325 mg) was obtained from 6-hydroxy-1, 2,3,4-tetraisoquinoline Bromohydrate (350 mg) and di-tert-butyldicarbonate ( 365 mg). 1 H-NMR (d ppm, CDCl 3) 1.49 (s, 9H), 2.76 (tr, J = 6.0 Hz, 2H), 3.61 (tr, J = 6.0 Hz, 2H), 4.49 (s, 2H), 5.33 (s) , 1 H), 6.63 (1H), 6.67 (1 H), 6.95 (1H) Stage 3 6- [1-pyridin-4-ii) pyrimidin-4-ylmethoxy-1, 2,3,4-tetraisoquinoline-2-carboxylic acid tert-butyl ester To a solution of 6-hydroxy-1, 2,3,4-tetraisoquinoline-2-carboxylic acid tert-butyl ester (320 mg) and 4-hydroxymethyl-1- (pyridin-4-yl) piperidine (247 mg) in a mixture of tetrahydrofuran (15 ml) and methylene chloride (5 ml) was added successively triphenyl phosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml) and the mixture was stirred for 12 hours at room temperature. After completion of the reaction the solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane: acetone = 3: 2-1: 1, 1% triethylamine) and dried under reduced pressure to give the title compound (400 mg). H-NMR (d ppm, CDCl 3) 1.49 (s, 9H), 2.76 (tr, J = 6.0 Hz, 2H), 3. 61 (tr, J = 6.0 Hz, 2H), 4.49 (s, 2H), 5.33 (s, 1H), 6.63 (1H), 6.67 (1H), 6.95 (1H) Stage 4 6-f1-pyridin-4-yl) piperidin-4-ylmethoxyl-1,2,3,4-tetrahydroisoquinoline In the same manner as in example 33 step 5 the title compound (265 mg) was obtained from the ter-butyl ester of 6- [1-] acid pyridin-4-yl) p -peridin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (400 mg) and trifluoroacetic acid (1.5 ml) 1 H-NMR (d ppm, CDCl 3) 1.36- 1.50 (m, 2H), 1.90-2.15 (m, 3H), 2.80 (tr, J = 6.0 Hz, 2H), 2.93 (m, 2H), 3.15 (tr, J = 6.0 Hz, 2H), 3.80 (d , 2H), 3.92-3.99 (m, 4H), 6.62 (1 H), 6.67-6.70 (m, 3H), 6.93 (1 H), 8.24 (2H) Stage 5 6-f1-pyridin-4-yl) piperidin-4-ylmethoxy1-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride In the same manner as in example 33 step 6 the title compound (60 mg) was obtained from 6- [1-pyridin-4-yl) piperidin-4-ylmethoxy] -1, 2,3,4 -tetrahydroisoquinoline (70 mg), diisopropylethylamine (0.042 ml), 1 H-pyrazole-1 -carboxamidine hydrochloride (35 mg) 1 H-NMR (d ppm, DMSO-de) 1.20-1.45 (m, 2H), 1.84-2.00 (m, 2H), 2.17 (, 1 H), 2.86 (tr, J = 5.8 Hz, 2H), 3.20 (m, 2H), 3.56 (tr, J = 5.8 Hz, 2H), 3. 85 (m, 2H), 4.23-4.28 (m, 2H), 4.48 (s, 2H), 6.80 (2H), 7.05 (1H), 7.19 (2H), 7.60 (4H), 8.19 (2H), 13.65 (1 HOUR) EXAMPLE 37 Synthesis of 7-.2-r4-cyano-1- (pyridin-4-yl) p -peridin-4-yllethoxy dihydrochloride. _.2,3,4-tetrahyd.oisoquinoline-2-carboxamidine Stage 1 4-Carbamoylpiperidin-1-carboxylic acid benzyl ester To a solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.5 g) in tetrahydrofuran (100 ml) was added dropwise N-methylmorphine (4.6 ml) and isobutylchlorocarbonate (5.4 ml) on ice under Argon atmosphere and the mixture was stirred for 10 minutes at the same temperature. Then 28% aqueous ammonia (100 ml) was added dropwise and the mixture was stirred for one hour at room temperature. After completion of the reaction the solvent was evaporated and water was added. The mixture was extracted with ethyl acetate and washed successively with aqueous sodium bicarbonate solution and 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and dried under reduced pressure to give the title compound (8.3 g). 1 H-NMR (d ppm, CDCl 3) 1.58-1.75 (m, 2H), 1.80-1.95 (m, 2H), 2.25-2.40 (m, 1 H), 2.75-2.95 (m, 2H), 4.05-4.30 ( m, 2H), 5.13 (s, 2H), 5.30-5.90 (brd, 2H), 7.26-7.62 (m, 5H) Stage 2 4-carbamoylpiperidin-1-carboxylic acid tert-butyl ester Benzyl ester of 4-carbamoylpiperidin-1-carboxylic acid (8.3 g) was hydrogenated using 7.5% palladium carbon (2 g) in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) at 3 atmospheres for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite and to the obtained solution was added di-tert-butyl dicarbonate (7.6 g). The mixture was stirred for one hour at room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and hexane was added. The mixture was filtered and dried under reduced pressure to give the title compound. (5.6 g) 1 H-NMR (d ppm, CDCl 3) 1.46 (s, 9 H), 1.57-1.70 (m, 2 H), 1.78-1.90 (m, 2 H), 2.26-2.38 (m, 1 H), 2.65- 2.88 (m, 2H), 4.00-4.25 (m, 2H), 5.30-5.80 (m, 2H) Stage 3 4-Cyanopiperidin-1-carboxylic acid tert-butyl ester To a solution of tert-butyl ester of 4-carbamoylpiperidin-1-carboxylic acid (5.6 g) in a mixture of tetrahydrofuran (110 ml) and carbon tetrachloride (90 ml), triphenyl phosphine (24.4 g) was added and the mixture was stirred. stirred under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1) and dried under reduced pressure to give the title compound (3.5 g) 1 H-NMR (d ppm, CDCl 3) 1.46 ( s, 9H), 1.70-1.95 (m, 4H), 2.75-2.85 (m, 1 H), 3.30-3.38 (m, 2H), 3.62-3.70 (m, 2H) < Stage 4 4-allyl-4-cyanopiperidin-1-carboxylic acid tert-butyl ester To a solution in tetrahydrofuran of lithium diisopropylamide 2M- (9.96 ml) in tetrahydrofuran (20 ml) was added dropwise a solution of tert-butyl ester of 4-cyanopiperidin-1-carboxylic acid in tetrahydrofuran (15 ml). -78 ° C and under argon atmosphere and the mixture was stirred for 30 minutes at room temperature. Allyl bromide (2.15 ml) was then added at -78 ° C and the mixture was stirred for 30 minutes at the same room temperature for one hour. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate = 5: 1) and dried under reduced pressure to give the title compound (3.5 g) 1 H-NMR (d ppm, CDCI3) 1.37-1.55 (m, 11 H), 1.85-1.95 (m, 2H), 2.33 (d, 2H), 2.98-3.10 (m, 2H), 4.00-4.25 (m, 2H), 5.17-5.23 (m m, 2H), 5.81-5.95 (m, 1 H) Stage 5 4-cyano-4- (2,3-dohydroxylpropyl) piperidin-1-carboxylic acid t-butyl ester To a solution of 4-ailyl-4-cyanopiperidin-1-carboxylic acid t-butyl ester (3.5 g) in a mixture of acetone (160 ml) and water (20 ml) was added N-methyl morpholine N-oxide (2.5 g) and osmium tetroxide (5% solution in tert-butanol, (8 ml) and the mixture was stirred for one hour at room temperature After the reaction was complete, aqueous sodium thiosulfate was added and the mixture was filtered The solvent was evaporated and water was added to the residue The mixture was extracted with ethyl acetate and washed with saturated brine The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated The residue obtained was purified by chromatography of column on silica gel (ethyl acetate) and dried under reduced pressure to give the title compound (3.65 g). 1 H-NMR (d ppm, CDCl 3) 1.40-1.81 (m, 13H), 1.90-1.96 ( m, 1H), 2.00 (brs, 1 H), 2.15-2.21 (m, 1 H), 2.50 (brs, 1 H), 2.95-3.20 (m, 2H), 3.49 (brtr, 1 H), 3.65- 3.72 (brd, 1 H), 4.00-4.20 (m, 3 H), Stage 6 4-cyano-4- (2-hydroxyethyl) piperidine-1-carboxylic acid t-butyl ester To a solution of 4-cyano-4- (2,3-dihydroxylpropyl) piperidin-1-carboxylic acid t-butyl ester (3.65 g) in tetrahydrofuran (100 ml), an aqueous solution of sodium periodate (100 g) was added. ml) and the mixture was stirred for 40 minutes at room temperature. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue (3.3 g) was dissolved in tetrahydrofuran (100 ml) and sodium borohydride (360 mg) and metapol (20 ml) were added on ice and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography on silica gel (chloroform: methanol = 95: 5) and dried under reduced pressure to give the title compound (3.13 g) 1 H-NMR (d ppm, CDCl 3) 1.49-1.55 ( m, 11 H), 1.86 (m, 2H), 1.96-2.00 (, 2H), 3.00-3.09 (m, 2H), 3.93 (m, 2H), 4.05-4.20 (m, 2H) Stage 7 Benzyl ester of 7- [2- (1-tert-butoxycarbonyl-4-cyanopiperidin-4-yl-ethoxyl-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of benzyl ester of 7-hydroxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxylic acid (1.1 g), t-butyl ester of 4-cyano-4- (2-hydroxyethyl) piperidine-1-carboxylic acid (1 g) and triphenylphosphine (1.22 g) in tetrahydrofuran (40 ml) were added diethyl azodicarboxylate (2 g) with ice cooling and the mixture was stirred at room temperature for 16 hours. After completing the reaction, the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1) and dried under reduced pressure to give the title compound (1.6 g). 1 H-NMR (d ppm, CDCl 3) 1.46-1.55 (m, 1 H), 1.96-2.10 (m, 4 H), 2.78 (m, 2 H), 3.00-3.14 (, 2 H), 3.71 (, 2 H), 4.05 -4.25 (m, 4H), 4.61 (s, 2H), 5.18 (s, 2H), 6.60-6.80 (m, 2H), 7.04 (1 H), 7.26-7.40 (, 5H) Stage 8 Benzyl Ester of 7-f2- (4-cyanopperidin-4-yl) ethoxyl-1.2.3.4-tetrahydroisoquinoline-2-carboxylic acid In the same manner as in example 10, step 6, the title compound (1 g) was obtained from 7- [2- (1-terbutoxycarbopyl-4-cyanopiperidin-4-yl) benzyl ester) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid (1.2 g) and trifluoroacetic acid (10 ml). 1 H-NMR (d ppm, CDCl 3) 1.53-1.64 (m, 2H), 1.99-2.05 (m, 2H), 2.07 (tr, J = 6.3Hz, 2H), 2.78 (brs, 2H), 2.92-3.12 ( m, 4H), 3.70 (btr, 2H), 4.18 (tr, J = 6.3Hz, 2H), 4.61 (s, 2H), 5.18 (s, 2H), 6.63-6.75 (m, 2H), 7.26-7.38 (m, 5H) Stage 9 Benzyl ester of 7-f2-f4-cyano-1- (pyridin-4-yl) piperidin-4-ipetoxy1-1.2.3.4-tetrahydroisoouine-2-carboxylic acid In the same manner as in Example 10, step 7, the title compound (590 mg) was obtained from benzyl ester of 7- [2- (4-cyanopiperidin-4-yl) ethoxy] -1, 2-benzyl ester. , 3,4-tetrahydroisoquinolyl-2-carboxylic acid (850 mg), 4-chloropyridine hydrochloride (300 mg) and triethylamine (0.84 ml). 1 H-NMR (d ppm, CDCl 3) 1.68-1.78 (m, 2H), 2.08-2.16 (m, 4H), 2.79 (brs, 2H), 3.17-3.24 (m, 2H), 3.71 (brtr, 2H), 3.84-3.91 (m, 2H), 4.21 (m, 2H), 4.62 (S, 2H), 5.18 (s, 2H), 6.63 (1H), 6.68 (dd, J = 1.0, 3.9 Hz, 2H), 6.74 (1 H), 7.05 (1 H), 7.32-7.40 (m, 5H), 8.29 (dd, J = 1.0, 3.9 Hz, 2H).

Stage 10 7-f2-id4-cyano-1- (pyridin-4-inpiperidin-4-ylletol-1,2,3,4-tetrahydroisoquinoline) To a solution of benzyl ester 7- [2- [4-cyano-1- (pyridin-4-yl) piperidin-4-yl] ethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxy (585 mg) in ethanol (5 ml) were added 7.5% palladium carbon (220 mg) and ammonium formate (220 mg), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated. To the obtained residue was added aqueous sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (385 mg). 1 H-NMR (d ppm, CDC 13) 1.62-1.84 (m, 2 H), 2.02-2.21 (m, 4 H), 2.73 (m, 2 H), 3.12 (m, 2 H), 3.17-3.24 (m, 2 H), 3.84-3.95 (m, 2H), 3.98 (s, 2H), 4.21 (m, 2H), 6.55 (1 H), 6.67-6.71 (3H), 7.00 / 1 H), 8.29 (2H).

Stage 11 7-r2-f4-cyano-1- (pyridin-4-yl) piperidin-4-inetoxil-1, 2,3,4-tetrahydro-soothinoline-2-carboxamidine dihydrochloride To a solution of 7- [2- [4-cyano-1- (pyridin-4-yl) piperidin-4-yl] ethoxy] -1, 2,3,4-tetrahydroisocyanol -2-carboxamidine (70 mg) in dimethylformamide solution (5 ml) were added diisopropylethylamine (0.1 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (85 mg) and the mixture was stirred at room temperature for 15 hours. After completing the reaction, the solvent was evaporated and the residue obtained was purified by HPLC (0.05% acid aqueous tpfluoroacetic: methanol = 1: 1). The obtained residue was treated with dilute hydrochloric acid and dried under reduced pressure to give the title compound (67 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.65-1.80 (m, 2H), 2.05-2.20 (m, 4H), 2.82 (tr, J = 6. = Hz, 2H), 3.29 (m, 2H), 3.58 (m, 2H), 4.17 (tr, J = 6.0Hz, 2H) 4.27-4.34 (m, 2H), 4.56 (s, 2H), 6.74 (d, J = 2.4 Hz, 1 H), 6.85 (dd) , J = 2.4, 8.4 Hz, 1 H), 7. 16 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 7.5 Hz, 1 H), 7.61 (brs, 4H), 8.26 (d, J = 7.5 Hz, 1 H), 13.80 (brs, 1 H).

EXAMPLE 38 Synthesis of 4-.2-amidino-8-chloronaphthalen-7-yloxymethyl-1-pyridin-4-inpipßridine-4-carboxylic acid ethyl ester dihydrochloride Stage 1 7-Methoxy-2-trifluoromethanesulfonyloxynaphthalene To a solution of 2-hydroxy-7-methoxynaphthalene (12.34 g) and triethylamine (9.87 ml) in chloroform (185 ml) was added trifluoromethanesulfonic anhydride (20 g) with ice-cooling and the mixture was stirred at the same temperature for 30 minutes. min. After completing the __ _.

After the reaction, aqueous sodium bicarbonate was added and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 9: 1) and dried under reduced pressure to give the title compound (15.36 g). 1 H-NMR (d ppm.CDC 13) 3.96 (s, 3 H), 7.14 (d, J = 2.4 Hz, 1 H), 7.21 (d, J = 2.4, 8.9 Hz, 2 H), 7.64 (d, J = 2.4 Hz , 1H), 7.77 (dd, J = 8.9 Hz, 1H), 7.83 (d, J = 8.9Hz, 1 H) Stage 2 7-Methoxy? Naphthalene-2-carbon? To a solution of 7-methoxy-2-trifluoromethanesulfonyloxynaphthalene (2.23g) in dimethylformamide (8.9 ml) were added zinc cyanide (598 mg) and tetrakis palladium (triphenylphosphine) (337 mg) at room temperature, and the mixture was stirred at 80 ° C for 1 hour. After completing the reaction, water and ethyl acetate were added and the insoluble material was removed. The organic layer was separated and concentrated, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) and drying under reduced pressure to give the title compound (965 mg). 1 H-NMR (d ppm.CDC13) 3.95 (s, 3H), 7.15 (d, J = 2.5 Hz, H), 7.29 (dd, J = 2.5, 9.0 Hz, 1H), 7.47 (1 H), 7.78 ( d, J = 9.0 Hz, H), 7.83 (1 H), 8.11 (1 H).

Stage 3 7-Hydroxynaphthalene-2-carbonitrile NC? AXAVx0H To a solution of 7-methoxynaphthalene-2-carbonitrile (6 g) in chlorobenzene (60 ml) was added aluminum chloride (15.3 g) at room temperature and the mixture was heated under reflux for 30 minutes. After completion of the reaction, the reaction mixture was cooled by ice and ice, ethyl acetate and concentrated hydrochloric acid were added and the mixture was then stirred. The organic layer was separated and concentrated. To the obtained residue, hexane was added and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (5.21 g). H-NMR (d ppm.CDC13) 5.42 (1H), 7.20 (1H), 7.25-7.28 (1 H), 7.79-7.85 (2H), 8.07 (1 H) Stage 4 8-Chloro-7-hydroxynaphthalene-2-carbonitrile To a solution of 7-hydroxynaphthalene-2-carbonitrile (2.23 g) in chloroform (120 ml) was added dropwise tert-butyl hypochlorite (1.64 ml) with ice-cooling, and the mixture was stirred at room temperature for 15 minutes. minutes After completion of the reaction, the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (1.88 g). 1 H-NMR (d ppm.CDC1β) 7.49 (d, J = 9.0 Hz, 1 H), 7.68 (1 H), 7.94 (d, J = 9.0 Hz, 1H), 8.19 (1 H), 8.46 (1 H) ) Stage 5 8-Chloro-7-methylthiomethoxynaphthalene-2-carbonitrile In the same manner as in example 10, step 2, the title compound (1.31 mg) was obtained from 8-chloro-hydroxynaphthalene-2-carbonitrile (1.88 g). 1 H-NMR (d ppm.CDC 13) 2.32 (s, 3 H), 5.40 (s, 2 H), 7.48 (d, J = 9.0 Hz, 1 H), 7.57 (dd, J = 1.5, 8.4 Hz, 1 H) , 7.82 (d, J = 9.0 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 1 H) 8.63 (d, J = 1.5 Hz, 1 H) Stage 6 8-Chloro-7-chloromethoxynaphthalene-2-carbonitrile In the same manner as in example 10, step 3, the title compound (939 mg) was obtained from 8-chloro-7-methylthiomethoxynaphthalene -2-carbonitrile (1.28 g) 1 H-NMR (d ppm.CDC13) 6.04 (s, 2H), 7.61-7.67 (2H), 7.88 (1 H), 7.94 (1 H), 8.65 (1 H) Stage 7 Ethyl ester of 4- (8-chloro-2-cyanonaphthalen-7-yloxymethyl) -1- In the same manner as in example 10, step 5, the title compound (128 mg) was obtained from 8-chloro-7-chloromethoxy-naphthalene-2-carbonitrile (295 mg) and ethyl ester of 1- (pyridine) -4-yl) piperidine-4-carboxylic acid (603 mg). 1 H-NMR (d ppm.CDC13) 1.28 (tr, J = 7 Hz 3H), 1.78-1.88 (m, 2H), 2.41-2.48 (m, 2H), 3.16-3.25 (m, 2H), 3.75-3.85 (m, 2H), 4.22 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 6.69 (dd, J = 1.4 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1 H), 7.55 (1H), 7.81 (d, J = 9.0 Hz, 1 H), 7.88 (1 H), 8.27 (dd, J = 1.4, 5.1 Hz, 2H), 8.61 (1 H).

Stage 8 4-.2-amidin-8-chloronaphthalen-7-yloxymethyl-1- (pyridin-4-yl. Piperidine-4-carboxylic acid ethyl ester dihydrochloride.

Hydrogen sulfide was bubbled into a solution of 4- (8-chloro-2-cyanonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (124 mg ) in a mixture of pyridine (2.5 ml) and triethylamine (0.5 ml) with ice cooling, and the mixture was stirred at room temperature for 12 hours. After completing the reaction, the solvent was evaporated and the residue was treated with hydrogen chloride-ethanol. To the residue were added acetone (2 ml), methanol (2 ml) and methyl iodide (0.172 ml), and the mixture was stirred under reflux for 2 hours. After completing the reaction, the solvent was evaporated and the residue obtained was dissolved in ethanol (4 ml). Ammonium acetate (106 mg) was added and the mixture was stirred at 75 ° C for 2 hours. After completing the reaction, the solvent was evaporated and the obtained residue was purified by column chromatography on silica gel (chloroform: methanol: ammonia). The obtained residue was treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (92 mg).

EXAMPLE 39 Synthesis of 4- (2-amidino-8-chloronaphthalene-7-yloxymethyl) -1- (pyridin-4-yl. Piperidine-4-carboxylic acid dihydrochloride A solution of 4- (2-amidino-8-chloronaphthalen-7-yloxymethyl) -1 - (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride (78 mg) in concentrated hydrochloric acid was stirred between 50 ° C - 100 ° C for 3 hours. After completing the reaction, the solvent was evaporated and the residue obtained was separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 1: 1). The residue obtained was treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (49 mg). 1 H-NMR (d ppm.DMSOde) 1.75-1.94 (m, 2H), 2.19-2.31 (m, 2H), 3.49 (m, 2H), 4.07 (m, 2H), 4.41 (s, 2H), 7.22 (m, 2H), 2H), 7.78 (2H), 8.12 (1H), 8.18-8.25 (m, 3H), 8.56 (s, 1 H), 9.34 (brs, 2H), 9.62 (brs, 2H), 12.98 (brs, 1 H) ), 13.65 (brs, 1 H) EXAMPLE 40 Synthesis of 4-.2-amidinonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester dihydrochloride Stage 1 7-Methylthiomethoxynaphthalene-2-carbonitrile In the same manner as in example 10, step 2, the title compound (907 mg) was obtained from 7-hydroxynaphthalene-2-carbonitrile (1.12 g).

Stage 2 7-Chloroethoxynaphthalene-2-carbonitrile In the same manner as in example 10, step 3, the title compound (567 mg) was obtained from 7-methylthiomethoxynaphthalene-2-carbonitrile (647 mg).

Stage 3 Ethyl ester of 4- (2-cyanonaphthalen-7-yloxymethyl-1- (pyridine-4-) In the same manner as example 10, step 5, the title compound (430 mg) was obtained from 7-chloromethoxynaphthalene-2-carbonltrile (314 mg), ethyl ester of 1- (pyridin-4-) il) piperidin-4-carboxylic acid (743 mg) and a solution of 2M-lithium-diisopropylamide-tetrahydrofuran (1.73 ml).

Stage 4 4- (2-Amidinonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl. Piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in example 38, step 8, the title compound (36 mg) was obtained from 4-ethyl acetate. (2-cyanonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid (51 mg) and methyl iodide (0.6 ml). 1 H-NMR (d ppm.CDC1β) 1.14 (tr, J = 7 Hz, 3H), 1.75-1.88 (m, 2H), 2. 19-2.31 (m, 2H), 3.44 (m, 2H), 4.00-4.20 (m, 4H) 4.27 (s, 2H), 7.21 (d, J = 7.0Hz, 2H), 7.34 (d, J = 8.9 Hz, 1 H), 7.48 (s, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7. 98 (d, J = 8.9 Hz, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 8.24 (d, J = 7 Hz, 2 H), 8.32 (s, 1 H), 9. 19 (brs, 1H), 9.45 (brs, 2H), 13.53 (brs, 1H).

EXAMPLE 41 Synthesis of 4- (2-amidin-2, 3,4,5-t-tetrahydro-1H-benfclazepin-8-yloxymethyl-1- (pyridin-4-illpiperidine-4-carboxylic acid ethyl ester dihydrochloride.

Stage 1 8-Methoxy-2,3,4,5-tetrahydrobenfc1azepin-1-one To a solution of 7-methoxy-1, 2,3,4-tetrahydronaphthalen-1-one (5.21 g) in concentrated hydrochloric acid (26 ml) was added sodium azide (1.98 g) in portions with ice-cooling and the mixture was stirred to the same temperature for 2 hours, and then at room temperature for 2 hours. After completing the reaction, the reaction mixture was poured into ice water and aqueous potassium carbonate was added thereto. The mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate) and dried under reduced pressure to give the title compound (470 mg). 1 H-NMR (d ppm.CDC13) 1.98 (quint, J = 6.9 Hz, 2H), 2.80 (tr, J = 6.9 Hz, 2H), 3.13 (q, J = 6.9 Hz, 2H), 3.83 (s, 3H) ), 6.96 (1 H), 7.09 (1H), 7.26 (1 H).

Stage 2 8-Methoxy-2.3.4.5-tetrahydro-1 H-benfclazepine To a solution of lithium aluminum hydride (3.07 g) in tetrahydrofuran (60 ml) was added dropwise a solution of 8-methoxy-2,3,4,5-tetrahydrobenz [c] azepin-1-one (4.42). g) in 1,4-dioxane (30 ml) with ice cooling and the mixture was refluxed for 20 hours. After completion of the reaction, an aqueous sodium hydroxide solution was added dropwise with ice cooling and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (4.05 g). 1 H-NMR (d ppm.CDC13) 1.68 (m, 2H), 2.82-2.90 (m, 2H), 3.10-3.25 (m, 2H), 3.77 (s, 3H), 6.60-6.70 (2H), 7.05 ( 1 HOUR) Stage 3 Hydrobromide of 8-hydroxy -2,3,4,5-tetrahydro-1 H-benzfc1azepine 8- Methoxy-2,3,4,5-tetrahydro-1 H-benz [c] azepine (3.65 g) was dissolved in aqueous hydrogen bromide solution (48%) (36 ml) and the mixture was refluxed for 2 hours. The solvent was evaporated and ethanol and diethyl ether were added to the obtained residue. The mixture was filtered and dried under reduced pressure to give the title compound (4.56 g). 1 H-NMR (d ppm, DMSO-d 6) 1.80-1.83 (m, 2H), 2.85 -2.88 (m, 2H), 3.22 (m, 2H), 4.20-4.22 (m, 1 H), 6.69 (dd, J = 2.5, 8.1 Hz, 1 H), 6.82 (d, J = 2.5 Hz, 1 H), 7.05 (d, J = 8.1 Hz, 1 H), 8.80 (brs, 2H), 9.42 (brs, 1 H) ) Stage 4 Tbutilic ester of 8-hydroxy acid -2.3.4,5-tetrahydro-1 H-benzfclazepin-2-carboxylic acid In the same manner as in Example 1, step 1, the title compound (2.64 g) was obtained from hydrobromide of 8-hydroxy-2,3,4,5, -tetrahydro-1 H-benz [c] azepine (3 g) 2N aqueous sodium hydroxide solution (30 ml) and di-tert-butyl dicarbonate (3.2 g). 1 H-NMR (d ppm.CDC13) 1.40 (s, 9H), 1.68-1.80 (m, 2H), 2.84-2.88 (m, 2H), 3.66 (m, 2H), 4.28-4.37 (m, 2H), 5.19-5.91 (1 H), 6.63 (1 H), 6.70-6.85 (1 H), 6.98 (1 H).

Stage 5 T-butyl ester of 8-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzfclazepi n-2-caboxylic acid In the same manner as in Example 6, step 1, the title of the compound (1.07 g) was obtained from the terbutyl ester of 8-hydroxy-2,3,4,5-tetrahydro-1 H-benz [c ] azepine-2-carboxylic acid (1.06 g), 60% sodium hydride (195 mg) and chloromethyl methiisulfide (0.41 ml). H-NMR (d ppm.CDC13) 1.40 (s, 9H), 1.75 (m, 2H), 2.24 (s, 3H), 2.87 (m, 2H), 3.68 (m, 2H), 4.30-4.45 (m, 2H), 5.13 (s, 2H), 6.74 (1 H), 6.81-6.92 (1 H), 6.81-6.92 (1 H), 7.06 (1 H).

Stage 6 Terbutilic ester of 8-f4-ethoxycarbonyl-1- (pyridin-4-y? Piperidin-4-ylmethoxy? 1,2,3,4,5-tetrahydro-1H-benzfclazepin-2-carboxylic acid In the same manner as in example 6, step 2, there was obtained terbutyl ester of 8-chloromethoxy-2,3,4,5-tetrahydro-1 H-benz [c] azepine-2-carboxylic acid (850 mg) a from tert-butyl ester of 8-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benz [c] azepine-2-carboxylic acid (530 mg) and sulfuryl chloride (0.145 ml) under an argon atmosphere. After, the same so that in Example 6, step 3, the title compound (755 mg) was obtained. 1 H-NMR (d ppm.CDC13) 1.27 (tr, J = 6.9 Hz, 3H), 1.39 (s, 9H), 1.64-1.78 (m, 4H), 2.30-2.36 (m, 2H), 2.85-2.88 ( m, 2H), 3.01-3.18 (m, 2H), 3.62-3.75 (m, 4H), 3.98 (s, 2H), 4.21 (q, J = 6.9 Hz, 2H), 4.30-4.38 (m, 2H) , 6.62-6.67 (m, 3H), 6.72-6.84 (1 H), 7.02 (1 H), 8.25 I2H).

Stage 7 Ethyl ester of 1- (pyridin-4-yl) -4- (2,3,4,5-tetrahydro-1 H-benzFlazepin-8-yloxymethyl-piperidine-4-carboxylic acid) In the same manner as in example 6, step 4, the title compound (600 mg) was obtained from the terbutyl ester of 8- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-acid. ylmetoxy] -2,3,4,5-tetrahydro-1 H-benz [c] azepine-2-carboxylic acid (750 mg) and trifluoroacetic acid (2.5 ml).

Stage 8 4- (2-amidino-2,3,4,5-tetrahydro-1 H-benzfc1azepin-8-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in example 6, step 5, the title compound (200 mg) was obtained from ethyl ester of 1- (pyridin-4-yl) -4- (2,3,4,5) -tetrahydro-1 H-benz [c] azepin-8-yloxymethyl) piperidin-4-carboxylic acid (200 mg), dlsopropylethylamine (0.105 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (90 mg). 1 H-NMR (d ppm DMSO-dβ) 1.16 (tr, J = 7.2 Hz, 3H), 1.75 (m, 4H), 2. 20 (m, 2H), 2.89 (m, 2H), 3.41 (m, 2H), 4.04 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.58 (s, 2H), 4.58 (s) , 2H), 6.76 (1 H), 7.11-7.22 (m, 4H), 7.47 (brs, 4H), 8.24 (1 H), 13.60 (brs, 1 H).

EXAMPLE 42 Synthesis of 4-.2-amidino-2.3.4.5-tet.hydro-1H-benzylclazepin-8-yloxymethyl-1-pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Ethyl 4- (2-amidino-2,3,4,5-tetrahydro-1 H-benz [c] azepin-8-yloxymethyl) -1- (pyridin-4-yl) ethyl ester dihydrochloride ) piperidine-4-carboxylic acid (150 mg) was dissolved in 6N hydrochloric acid (2 ml) and the mixture was stirred under reflux for 3 hours. After completing the reaction, the insoluble material was removed and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (140 mg). 1 H-NMR (d ppm.CDC1β) 1.56-1.81 (m, 4H), 2.12-2.25 (m, 2H), 2. 88-3.00 (m, 2H), 3.42 (m, 2H), 4.00-4.13 (m, 4H), 4.59 (s, 2H), 6.76 (1 H), 7.12 (1 H), 7.19-7.23 (m, 3H), 7.54 (brs, 4H), 8.23 (2H), 8.23 (2H), 13.70 (brs, 1 H).

EXAMPLE 43 Synthesis of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid dihydrochloride Stage 1 4-Ethoxycarbonyl-4-vodomethylpiperidine-1-carboxylic acid tert-butyl ester To a solution of ethyl ester of 1-tert-butoxycarbonylisonipecotinic acid (7.14 g) in tetrahydrofuran (140 ml) was added dropwise a solution of 2M lithium diisopropylamide-tetrahydrofuran (16.6 ml) and diiodomethane (2.7 ml) at 78 °. C, and the mixture was stirred for 15 hours. After completion of the reaction, an aqueous solution of 10% citric acid was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1) and dried under reduced pressure to give the title compound (8.68 g).

H-NMR (d ppm.CDC.) 1.27-1.33 (m, 3H), 1.38-1.45 (m, 10H), 1.59-1.64 (m, 1 H), 2.10-2.22 (m, 2H), 2.90-3.10 (m, 2H), 3.29 (s, 2H), 3.65-3.95 (m, 2H), 4.18-4.26 (m, 2H).

Stage 2 4- (2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -4-ethoxycarbonylpiperidin-1-carboxylic acid tert-butyl ester Crude crystals of 2-acetyl-1, 2,3,4-tetrahydroisoquinoline-7-t-ol were obtained from 2-acetyl-7-chlorosulfonyl-1, 2,3,4-tetrahydroisoquinoline (U.S. 3725388) (7-98 g) and tin chloride dihydrate (25.3 g) according to the method described in Journal of Medicinal Chemistry, vol. 23, No. 8, p. 837 (1980) and the obtained crystals were dissolved in dimethylformamide (120 ml). To these were added potassium carbonate (4.27 g) and tert-butyl ester of 4-ethoxycarbonyl-4-iodomethyl-pyridin-1-carboxylic acid (3.71 g) and the mixture was stirred at 100 ° C for 1 hour. After completing the reaction, the reaction mixture was filtered and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate). ethyl = 2.8-ethyl acetate) and dried under reduced pressure to give the title compound (3.92 g). 1H-NMR (d ppm.CDC) 1.18-1.24 (3H), 1.44-1.51 (11H), 2.12-2.18 (5H), 2.80-3.05 (4H), 3.12 (2H), 3.66 (1H), 3.72 -3.95 (3H), 4.01-4.11 (2H), 4.57-4.69 (2H), 7.03-7.22 (3H).

Stage 3 Ethyl 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester To a solution of 4- (2-acetyl-1,2,4,4-tetrahydroisoquinolin-7-ylthiomethyl-4-ethoxycarbonylpiperidin-1-carboxylic acid tert-butyl ester (221 mg) in chloroform (0.5 ml) was added Trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 10 minutes After completing the reaction, the solvent was evaporated and ethanol (3 ml), triethylamine (0.39 ml) and hydrochloride 4- were added to the obtained residue. Chloropyridine (70 mg) The mixture was stirred in a se tube at 150 ° C for two days After completing the reaction, the solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (methanol-chloroform 5%) and dried under reduced pressure to yield the title compound (63 mg). 1 H-NMR (d ppm, CDCl 3) 1.21-1.26 (3H), 1.58-170 (2H), 2.17 (3H), 2.25-240 (2H), 2.78 -2.90 (2H), 3.05-3.22 (4H), 3.64. -3.85 (4H), 4.07-4.15 (2H), 4.57-4.69 (2H), 6.69 (2H), 7.04-7.20 (3H), 8.25 (2H).

Stage 4 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl-1 - (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride To 4- (2-acetyl-1, 2,3,4-tetrahydroisoquinolyl-7-ylthiomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (63 mg) hydrochloric acid conc. (2 ml) and the mixture was stirred at 90 ° C for 21 hours. After completing the reaction, the solvent was evaporated and a solution of 1 N aqueous sodium hydroxide (0.7 ml), acetone (2 ml) and 1 H-pyrazole-1-carboxyamidine hydrochloride (61 mg) were added to the obtained residue. and the mixture was stirred for 12 hours. Then the reaction was completed, acid was added diluted hydrochloric acid to make the solution and the solvent was evaporated. Methanol was added to the obtained residue and the mixture was filtered. The solvent was evaporated and the residue obtained was separated by HPLC (25% -40% methanol-water, 0.05% trifluoroacetic acid) and treated with dilute hydrochloric acid, which was dried under reduced pressure to give the title compound (47 mg). 1 H-NMR (d ppm, DMSO-dβ) 1.57-1.70 (m, 2H), 2.08 -2.20 (m, 2H), 2.84-2.92 (m, 2H), 3.20-3.40 (m, 4H), 3.60 (m , 2H), 3.95-4.10 (m, 2H), 4.57 (s, 2H), 7.14-7.20 (m, 5H), 7.66 (brs, 4H), 8.22 (2H).

EXAMPLE 44 Synthesis of 4-f2 (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylthioletip-1-y-pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Stage 1 4-Allyl-4-ethoxycarbonylpperidine-1-carboxylic acid tert-butyl ester To a solution of ethyl ester of 1-tert-butoxycarbonylisonipecotinic acid (6 g) in tetrahydrofuran (120 ml) were added dropwise a solution of 2M-diisopropylamide lithium-tetrahydrofuran (14 ml) and allyl bromide (2.42 ml) at -78 ° C and the mixture was stirred for 3 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was purified by chromatography on silica gel (hexane: ethyl acetate = 4: 1) and dried under reduced pressure to give the title compound (5.07 g).

Stage 2 1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylacetic acid To a solution of sodium periodate (14.69 g) in a mixture of water (90 ml), carbon tetrachloride (50 ml) and acetonitrile (50 ml) was added ruthenium chloride (111 mg) and a ternary ester solution. 4-allyl-4-ethoxycarbonylpiperidin-1-carboxylic acid butyl ester (5.07 g) in a mixture of carbon tetrachloride (10 ml) and acetonitrile (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After completing the reaction, the reaction mixture was filtered and the residue was washed with ethyl acetate. The aqueous layer of the obtained filtrate was removed and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the The residue obtained was purified by column chromatography on silica gel (ethyl acetate) and dried under reduced pressure to give the title compound (4.23 g). 1 H-NMR (d ppm, CDCl 3) 1, 26 (tr, J = 7.0 Hz, 3 H), 1.48-1.57 (m, 11 H), 2.05-2.18 (m, 2 H), 2.65 (s, 2 H), 3.21 (m, 2H), 3.65-3.75 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H).

Stage 3 4-Ethoxycarbonyl-4- (2-hydroxyethyl) piperidin-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonyl-4-ethoxycarbonyl-piperidin-4-ylacetic acid (2.34 g) in tetrahydrofuran (60 ml) was added a solution of 1 M borane tetrahydrofuran (7.42 ml) at -78 ° C, and The mixture was allowed to warm to room temperature for 15 hours under stirring. After completing the reaction, water and potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was washed with hexane. The layer was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate Anhydrous magnesium and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (1.92 g). 1 H-NMR (d ppm, CDCl 3) 1.28 (tr, J = 7.1 Hz, 3H), 1.35-1.75 (m, 11 H), 1.82 (tr, J = 6.7 Hz, 2H), 2.10-2.20 (m, 2H ), 2.91 (m, 2H), 3.68 (tr, J = 6.7 Hz, 2H), 3.75-4.00 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H).

Stage 4 Ter-butyl ester of 4-ethoxycarbonyl-4- (2-methanesulfonylaxyethyl) piperidin-1-carboxylic acid To a solution of 4-ethoxycarbonyl-4- (2-hydroxyethyl) p -peridin-1-carboxylic acid tert-butyl ester (1.92 g) in a mixture of triethylamine (1.15 ml) and methylene chloride (40 ml) were added. added methanesulfonyl chloride (0.592 ml) at -78 ° C, and the mixture was stirred for 1 hour. After completion of the reaction, aqueous sodium hydrogen carbonate was added and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) and dried under reduced pressure to give the title compound (2.38 g). 1 H-NMR (d ppm, CDCl 3) 1.29 (tr, 3H), 1.36-1.52 (m, 11 H, 2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.291 (m, 2H), 2.99 ( s, 3H), 3.80-4.00 (m, 2H), 4.17-4.34 (m, 4H).

Stage 5 Ester-butyl ester of 4-ethoxycarbonyl-4- (2-vodoethyl-piperidin-1-carboxylic acid) To a solution of tert-butyl ester of 4-ethoxycarbonyl-4- (2-iodoethyl) piperidin-1-carboxylic acid (2.38 g) in dimethylformamide (24 ml) was added sodium iodide (4.77 g) and the mixture it was stirred at 70 ° C for 7 hours. After completing the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) and dried under reduced pressure to give the title compound (1.03 g) 1 H-NMR (d ppm, CDCl 3) 1.28 (tr, J = 7.1 Hz, 3H), 1.26-1.45 (m, 11H), 2.5-2.20 (m, 4H), 2.87 (m, 2H), 3.01-3.07 (m, 2H), 3.75-4.00 (m , 2H), 4.20 (q, J = 7.1 Hz, 2).

Stage 6 Ter-butyl ester of 4-22- (2-acetyl-1, 2,3,4-tetrahydroisoquinolin-7-ylthio) -ethyl-4-ethoxycarbonylpyridin-1-carboxylic acid Crude crystals (1.26 g) of 2-acetyl-1, 2,3,4-tetrahydroisoquinoline-7-thiol were dissolved in dimethylformamide (15 ml) and 60% sodium hydride (243 mg) and ternary ester were added thereto. butylated 4-ethoxycarbonyl-4- (2-iodoethyl) piperidine-1-carboxylic acid (1 g), and the mixture was stirred at 70 ° C for 1 hour. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 7) and dried under reduced pressure to give the title compound (535 mg). 1 H-NMR (d ppm, CDCl 3), 1.26 (3 H), 1.30-1.44 (11 H), 1.75-1.85 (2 H), 2.5-2.20 (5 H), 2.75-300 (6 H), 3.67 (1 H), 3.79 -3.95 (3H), 4.19 (2H), 4.57-4.69 (2H), 7.05-7.15 (3H).

Stage 7 Ethyl ester of 4-l2-.2-acetyl-1, 2,3,4-tetrahydroisoouinolin-7-ylthio) ethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid In the same manner as in example 43, step 3, the title compound (98 mg) was obtained from 4- [2- (2-acetyl-1, 2,3,4-tetrahydic acid) butyl ester. droisoquinolin-7-ylthio) ethyl] -4-ethoxycarbonyl-pperidyl-1-carboxylic acid (233 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (72 mg) and triethylamine (0.4 ml).

Stage 8 4-f2- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylthio.ethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid dichlorohydrate In the same manner as in example 43, step 4, the title compound (53 mg) was obtained from ethyl ester of 4-4- [2- (2-acetyl-1, 2,3,4- tetrahydro? soqu? nol? n-7-? lt? o) et? l] -1- (p? r? d? n-4-? l) p? pepd? n-4-carboxyl (94 mg ), concentrated hydrochloric acid (2 ml), aqueous sodium hydroxide solution 1 N (1 ml) and hydrochloride of 1 Hp? razol-1-carboxam? d? na (88 mg) 1 H-NMR (d ppm, DMSO -d6) 1 48-1 60 (, 2H), 1 75-1 90 (m, 2H), 2 5-2 20 (m, 2H), 2 80-2 98 (m, 4H), 3 17-3 34 (m, 2H), 3 60 (m, 2H), 4 04 (m, 2H), 4 57 (s, 2), 7 07-7 18 (m, 5H), 7 63 (brs, 4H), 8 21 (2H), 12 93 (brs, 1 H), 13 62 (brs, 1) EXAMPLE 45 Synthesis of 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -1- (pyryridin-4 .l.piperidine-4-carboxylic acid dihydrochloride Stage 1 Ester ter-buti co of acid 4-.2-acet? L-1.2.3.4-tetrahydro? Soou? Nol? P-7-? Lsulfon? Lmet? L.-4-ethoxy? Carbon? Lp? Per? d? n-1-carbox? l? co To a solution of 4- (2-acetyl-1,2,4,4-tetrahydroisoquinolin-7-ylthiomethyl) -4-ethoxycarbonylpiperidin-1-carboxylic acid tert-butyl ester (252 mg) in methylene chloride (5 ml) ) 70% 3-chloroperbenzoic acid was added (260 mg) at room temperature, and the mixture was stirred for 12 hours. After completing the reaction, an aqueous solution of sodium acid carbonate and aqueous solution of sodium thiosulfate was added, and the mixture was stirred for 30 minutes, after extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography on silica gel (ethyl acetate) and dried under reduced pressure to give the title compound (203 mg). 1 H-NMR (d ppm, CDCl 3) 1.32 (3H), 1.45 (9H), 1.66 (2H), 2.10-2.30 (5H), 2.88-3.04 (2H), 3.23 (2H), 3.43 (2H), 3.65- 3.78 (3H), 3.85 (1 H), 4. 16-4.25 (2H), 4.69, 4.81 (2H), 7.32-7.75 (3H).

Stage 2 Ethyl 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl-1- (pyridin-4-yl .pyridin-4-carboxylic acid ethyl ester In the same manner as in example 43, step 3, the title compound (120 mg) was obtained from 4- (2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-tert-butyl ester). l-sulfonylmethyl) -4-ethoxycarbonylpiperidine-1-carboxylic acid (203 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (72 mg) and triethylamine (0.33 ml).

Stage 3 4- (2-Aminidin-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl-1- (pyridin-4-yl) -peridin-4-carboxylic acid dihydrochloride In the same manner as in example 43, step 4, the title compound (120 mg) was obtained from ethyl 4- (2-acetyl-1,2,3,4-tetrahydroquinoline-7-ylsulphonylmethyl) ethyl ester. ) -1- (pyridin-4-yl) piperidine-4-carboxylic acid (200 mg), concentrated hydrochloric acid (10 ml), 1N aqueous sodium hydroxide solution (2.06 ml) and 1 H-pyrazole-1 hydrochloride -carboxamidine (181 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.78-1.90 (m, 2H), 2.08-2.20 (m, 2H), 3.03 (m, 2H), 3.51 (m, 2H), 3.67 (m, 2H), 3.77 (s, 2H), 3.92 (m, 2H), 4.72 (s, 2H), 7.19 (d, J = 7.5 Hz, 2H), 7.54 (1 H), 7.65 (1 H), 7.72-7.76 (m, 5H), 8.23 (d, J = 7.5 Hz, 2H).

EXAMPLE 46 Synthesis of 4-f2-.2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfoni-oetill-1- (pyridin-4-yl) piperidin-4-carboxylic acid dihydrochloride Stage 1 Ter-butyl ester of 4-f2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-isulfonylletyl-4-ethoxycarbonylpiperidin-1-carboxylic acid) In the same manner as in example 45, step 1, the title compound (173 mg) was obtained from 4- [2- (2-acetyl-1, 2,3,4-tetrahydroisoquinyl) -butyl ester. nolin-7-isulfonyl) etl] -4-ethoxycarbonylpiperidine-1-carboxylic acid (295 mg) and 70% 3-chloroperbenxoic acid (297 mg).

Stage 2 Ethyl ester of 4-22- (2-acetyl-1, 2,3,4-tetrahydroisoquinolin-7-isulfonyl) ethyll-1- (pyrifin-4-illpiperidine-4-carboxylic acid) In the same manner as in example 43, step 3, the title compound (97 mg) was obtained from 4- [2- (2-acetyl-1, 2,3,4-tetrahydroisoquinol) tert-butyl ester. n-7-isulfonyl) ethyl] -4-ethoxycarbonylpperidyl-1-carboxylic acid (173 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (60 mg) and triethylamine (0.28 ml).

Stage 3 4-f2- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-isulfonyl) ethyl1-1- (pyridin-4-ylpylfidin-4-carboxylic acid, hydrochloride In the same manner as in example 43, step 4, the title compound (57 mg) was obtained from ethyl 4- [2- (2-acetyl-1, 2,3,4-tetrahydroisoquinolin-7-ethyl ester. isulfonyl) ethyl] -1- (pyrifin-4-yl) piperidine-4-carboxylic acid (97 mg), concentrated hydrochloric acid (2 ml), 1 N sodium hydroxide aqueous solution (0.97 ml) and 1 H- hydrochloride pyrazole-1-carboxamidine (86 mg). 1 H-NMR (d ppm, DMSO-de) 1.42-1.56 (m, 2H), 1.78-1.90 (m, 2H), 1.96-2.12 8m, 2H), 3.03 (m, 2H), 3.17-3.30 (m, 4H), 3.66 (m, 2H), 3.95-4.10 (m, 2H), 4.71 (s, 2H), 7.17 (2H), 7.53 (1H), 7.67-7.82 (m, 6H), 8.20 (2H) .

EXAMPLE 47 Synthesis of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulphonylaminol-1-pyridin-4-iQ-piperidine-4-carboxylic acid methyl ester dihydrochloride.

Stage 1 1 - . 1 - (Pyridin-4-yl-ylperidin-4-one) * -C. A solution of 4-chloropyridine hydrochloride (10 g), 1,4-dioxo-8-azaspiro [4,4] decane (10 g) and triethylamine (29 ml) in a mixture of ethanol (10 g). ml) and water (30 ml) was stirred at 150 ° C for 22 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and a solution of 5N aqueous sodium hydroxide (25 ml) was added. The mixture was extracted with a mixed solvent of chloroform-methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. To the obtained residue was added dropwise concentrated hydrochloric acid (30 ml) with ice cooling, and the mixture was stirred at the same temperature for 10 minutes. After completing the reaction, sodium hydroxide (15 g) was added. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 9: 1, 1% aqueous ammonia) and dried under reduced pressure to give the title compound 86.1 g). 1 H-NMR (d ppm, CDCl 3) 2.75 (tr, J = 6.2 Hz, 4H), 3.74 (tr, J = 6.2 Hz, 4H), 6.7 (dd, J = 1.5, 4.4 Jz, 2H), 8.33 (dd) , J = 1.54.5 Hz, 2H).

Stage 2 Methyl ester of 4-amino-1- (pyrirdin-4-yltoiperidine-4-carboxylic acid Ammonium acetate (880 mg), aqueous sodium cyanide solution (560 mg.sup.5) were added to a solution of 1- (pyridin-4-? L) piperidin-4-one (1 g) in methanol solution. ml), aqueous ammonia (5 ml) and acetic acid (2 ml) and the mixture was stirred at room temperature for 12 hours. After completing the reaction, the solvent was evaporated and the aqueous ammonia (3 ml) was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a residue. Hydrochloric acid was bubbled into a solution of the residue in 10% hydrochloric acid-methanol (25 ml) with ice-cooling and the solution was allowed to stand at room temperature for 12 hours. After completing the reaction, the solvent was evaporated and 2N-hydrogen chloride (25 ml) was added to the obtained residue. After stirring for 2 hours, the mixture was neutralized with sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (760 mg). H-NMR (d ppm, CDCl 3) 1.55-1.65 (, 2H), 2.08-2.17 (m, 2H), 3.46-3.50 / (m, 4H), 3.74 (s, 3H), 6.66 (dd, J = 1.5 , 4.5 Hz 2H), 8.25 (dd, J = 1.5, 4.5 Hz, 2H).

Stage 3 Methyl ester of 1- (pyridin-4-yl) -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-? Sulphonylamino.piperidine-4-carboxylic acid) To a solution of 4-amino-1- (pyryridin-4-yl) piperidine-4-carboxylic acid methyl ester (330 mg) in chloroform (5 ml) were added 7-chlorosulfonyl-2-trifluoroacetyl-1, 2,3,4-tetrahydroisoquinoline (Journal of Medicinal Chemistry, vol.23, No. 8, p.837 (1980) (500 mg) and pyridine (0.23 ml) and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added and the mixture was extracted with chloroform and washed successively with water and saturated brine.The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated.The residue was dried under reduced pressure to give the title compound (627 mg). 1 H-NMR (d ppm, CDCl 3) 2.202-2.16 (2H), 2.22-2.35 (2H), 2.94-3.08 (2H), 3.39, 3.46 (3H), 3.42-3.58 ( 2H), 3.62-3.76 (2), 3.80-3.96 (2H), 4.77-4.82 (2H), 6.80 (2H), 7.16-7.32 (1H), 7.68-7.82 (1H), 8.20 (2H).

Stage 4 4- (2-amidino-1,2,3,4-tetrahydro-xuanquinolin-7-ylsulphonylamino) -1- (pyridin-4-yl. Piperidine-4-carboxylic acid methyl ester dihydrochloride To a solution of 1- (priridin-4-yl) -4- (2-trifluoroacetyl-1, 2,3,4-tetrahydroisoquinolyl-7-ylsulfonylamino) piperidine-4-carboxylic acid methyl ester (627 mg) a 2N sodium hydroxide aqueous solution (1.1 ml) was added to a mixture of chloroform (5 ml) and methanol (1 ml) and the mixture was stirred at room temperature for 2 hours. After completing the reaction, 2N hydrochloric acid (1.1 ml) was added and the mixture was concentrated. To the obtained residue, dimethylformamide (3 ml), diisopropylethylamine (0.91 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (305 mg) were added in succession and the mixture was stirred at room temperature for 12 hours. After completing the reaction, the reaction mixture was filtered, and the filtrate was added dropwise to diethyl ether. The resulting solid was separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 4: 1-3: 2) and treated with dilute hydrochloric acid and dried under reduced pressure to give the title compound (480 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.86-2.16 (m, 4H), 3.00 (m, 2), 3.35-3.42 (m, 5H), 3.67 (m, 2H), 3.84 (m, 2H), 4.74 (s, 2H), 7.17 (d, J = 7.1 Hz 2H), 7.47 (1H), 7.56 (1H), 7.62 (1H), 7.82 (brs, 4H), 8.22 (d, J = 7.1 Hz, 2H ), 8.56 (s, 1 H), 13.89 (brs, 1 H).

EXAMPLE 48 Synthesis of 4-.2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulphonylamino-1- (pyridin-4-yl. Piperidine-4-carboxylic acid dihydrochloride.

To 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1 - (pyridin-4-yl) piperidine-4-carboxylic acid methyl ester dihydrochloride (415 mg) 6N hydrochloric acid (2 ml) was added and the mixture was stirred under reflux for 4 hours. After completing the reaction, the insoluble material was removed and the solvent was evaporated. Diethyl ether was added and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (363 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.85-2.10 (m, 4H), 2.99 (m, 2H), 3.30 (m, 2H), 3.67 (m, 2H), 3.80-3-95 (m, 2H ), 4.7 (s, 2H), 7.16 (d, J = 7.3 Hz 2H), 7. 44 (1 H), 7.56 (1 H), 7.67 (1 H), 7.80 (brs, 4H), 8.20 (d, J = 7.3 Hz, 2H), 8.356 (s, 1 H).

EXAMPLE 49 Synthesis of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-ylsulphonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride Stage 1 4-benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonyl-4-ethoxycarbonyl-piperidin-4-yl-acetic acid (1.6 g) and triethylamine (0.71 ml) in dimethylformamide (20 ml) was added diphenylphosphoryl azide (1.1 ml) at room temperature, and the mixture was stirred at 70 ° C for 30 minutes and then at 90 ° C for 10 minutes. Benzyl alcohol (0.58 ml) was added at the same temperature, and the mixture was stirred for 20 hours. After completing the reaction, water was added and the mixture was extracted with ethyl acetate and washed with a 1 N aqueous sodium hydroxide solution. The organic cova was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel and dried under reduced pressure to give the title compound (1.35 g). 1 H-NMR (d ppm, CDCl 3) 1.26 (tr, J = 7.0 Hz, 3 H), 1.36-1.50 (m, 11 H), 1.96-2.10 (m, 2 H), 3.12 (m, 2 H), 3.37 (m , 2H), 3.70 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 5.01 (brtr, 1 H), 5.09 (3.2), 7.26-74.40 (m, 5).

Stage 2 Ethyl ester of 4-benzyloxycarbonylaminomethyl-1- (pyridin-4-yl. Piperidine-4-carboxylic acid ethyl ester To a solution of 4-benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidin-1-carboxylic acid tert-butyl ester (851 mg) in chloroform (5 ml) was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature. environment for 30 minutes. After completing the reaction, the solvent was evaporated and ethanol (5 ml) 4-chloropyridine hydrochloride (304 mg) and triethylamine (1.69 ml) were added to the obtained residue. The mixture was stirred at 150 ° C for 2 days in a sealed tube. After completing the reaction, the solvent was evaporated. To the obtained residue was added a 2N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 93: 7) and dried under reduced pressure to give the title compound (738 mg). 1 H-NMR (d ppm, CDCl 3) 1.27 (tr, J = 7.0 Hz, 3), 1.50-1.70 (m, 2H), 2. 5-2.22 (m, 2H), 3.10-3.22 (m, 2), 3.35-3.45 (m, 2), 3.52-3.68 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 5.05 ( brtr, 1 H), 5.09 (s, 2H), 6.63 (d, J = 6.4 z, 2H), 7.26-7.38 (m, 5H), 8.25 (d, J = 6.4 z 2) Stage 3 4-aminomethyl-1-pyryridin-4-iQpiperidine-4-carboxylic acid ethyl ester dihydrobromide To a solution of 4-benzyloxycarbonylaminomethyl-1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester (331 mg) in chloroform (0.5 ml) was added 20% hydrogen bromide- acetic acid (2 ml) and the mixture was stirred at room temperature for 10 minutes. After completing the reaction, hexane, diisopropyl ether and diethyl ether were added, and the supernatant was removed. Then dimethylformamide (1 ml) was added and the The resulting solid was collected by filtration and washing with diethyl ether and drying under reduced pressure to give the title compound (423 mg).

Stage 4 Ethyl ester of 1- (pyridin-4-yl-4-.2-trifluoroacetyl-1, 2,3,4-tetrahydroisoquinolin-7-ylsaphonylaminomethyl) -piperidine-4-carboxylic acid 4-amin 4-yl) piperidine-4-carboxylic acid ethyl ester dibromhydrate (423 mg) were added pyridine (2 ml) and 7-chlorosulfonyl-2-trifluoroacetyl-1,2,4,4-tetrahydroisoquinoline (273 mg), and the mixture was stirred at room temperature for 2 hours. After completing the reaction, the solvent was evaporated and water was added. The mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 4: 1) and dried under reduced pressure to give the title compound (222 mg). 1 H-NMR (d ppm, CDCl 3) 1.20 -1.35 (3H), 1.75-1.85 (2H), 2.15-2.30 (2H), 2.88-3.15 (4H), 3.30-3.45 (2H), 3.75-3.95 (4H) , 4.15-4.25 (2H), 4.65-4.85 (2H), 6.82-6.88 (2H), 7.12-7.36 (1H), 7.65-7.80 (2H), 8.15-8.25 (2H) . «__._ x.

Stage 5 4- (2-Amidino-1, 2,3,4-tetrahydro-5-trinol-7-ylsulphonylaminomethyl) -1- (pyridin-4-yl) -piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in example 47, step 4, the title compound 875 mg) was obtained from ethyl ester of 1- (pyridin-4-yl) -4- (2-trifuloroacetyl-1, ethyl ester, 2,3,4-tetrahydroisoquinolin-7-lysulfonylamnomethyl) piperidin-4-carboxylic acid (222 mg), diisopropylethylamine (0.28 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (117 mg). 1 H-NMR (or ppm, DMSO-d 6) 1.21 (tr, J = 7.1 Hz, 3H), 1.50-1.65 (m, 2H), 2.00-2.15 (m, 2H), 2.89-3.15 (m, 3.15 (m , H), 3.28 (m, 2H), 3.64 (m, 2H), 3.95-4.18 (m, 4H), 4.67 (s, 2H), 7.18 (2H), 7.46 (1 H), 7.57 (1 H) , 7.60-7.70 (m, 5H), 7.94 (brtr, 1 H), 8.22 (2H).

EXAMPLE 50 Synthesis of 4-.2-amidino-1,2,3,4-tetrahydroisoquinolin-7-sulfosilamomethyl-1-pyridin-4-yl) piperidin-4-carboxylic acid dihydrochloride In the same manner as in Example 48, the title compound (52 mg) was obtained from 4- (2-am? Dino-1, 2,3,4-tetrahydroisoquinolin-7-) ethyl ester dihydrochloride. ilsulfonylaminomethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid (59 mg). 1 H-NMR (d ppm, DMSO-de) 1.50-1.65 (m, 2H), 1.96-2.10 (m, 2H), 2.86-3.05 (m, 4H), 3.28 (m, 2H), 3.64 (m, 2H) ), 4.04 (m, 2H), 4.67 (s, 2H), 7.19 (d, J = 7.3 Hz, 2H), 7.45 (1H), 7.58 (1H), 7.60-7.70 (m, 5H), 7.90 (brtr, 1 H), 8.21 (d, J = 7.3 Hz, 2), 12.88 (brs, 1 H), 13.57 (brs, 1 H) EXAMPLE 52 Synthesis of 1-β2-hydrochloride (benzothiazol-2-ill-2-oxoetill-2-phenoxymethylbenzimidazole-5-carboxamidine Stage 1 N- (4-cyano-2-phenoxyacetamidophenyl) glycine tert-butyl ester In the same manner as in example 17, step 8, the title compound (6.66 g) was obtained from N- (2-amino-4-cyanophenyl) glycine tert-butyl ester (5.97 g), phenyloxyacetic acid (3.44 g) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (6.15 g). 1 H-NMR (d ppm, CDCl 3) 1.49 (s, 9 H), 3.81 (d, J = 4.8 Hz, 2 H), 4.72 (s, 2 H), 4.95 (brtr, 1 H) 6.58 (d, J = 8.7 Hz , 1 H), 7.02 (d, J = 7.5 Hz, 2H), 7.08 (tr, = 7.5 Hz, 1 H), 7.36 (d, J = 7.5, 1 Hz, 1 H), 7.39 (D, J = 7.5 Hz, 1H), 7.44 (dd, J = 1.5, 8.7 Hz 1H), 7.57 (d, J = 1.5 Hz, 1H), 8.06 (brs, 1H).

Stage 2 -Cyano-2-phenoxymethylbenzimidazole-1-acetic acid A solution of tert-butyl ester of N- (4-cyano-2-phenoxyacetamidophenyl) glycine (6.61 g) in acetic acid (250 ml) was stirred at 80 ° C. for 12 hours After completing the reaction, the solvent was evaporated and trifluoroacetic acid (60 ml) was added to the obtained residue and the mixture was stirred at 50 ° C for 30 minutes.After completing the reaction, the solvent was evaporated.To the obtained residue chloroform and acetone were added the resulting solid was collected by filtration and drying under reduced pressure to give the title compound (5.0 g). 1 H-NMR (d ppm, CDCl 3) 5.25 (s, 2 H), 5.43 (s, 2 H), 6.97 (1 H), 7.5 (2 H) , 7.27-7.33 (2H), 7.68 (dd, J = 1.3, 8.4, 1 H), 7.82 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1 H).

Stage 3 N-methoxy-N-methyl- (5-c-ano-2-phenoxymethylbenzimidazole) -1-acetamide In the same manner as in example 17, step 10, the title compound (1.83 g) was obtained as a white solid from 5-cyano-2-phenoxymethylbenzimidazole-1-acetic acid (2.14 g), N-hydrochloride. , 0-dimethylhydroxylamine (815 mg), N-methylmorpholine (0.919 ml), hydrated 1-hydroxybenzotriazole (1.13 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.6 g). 1 H-NMR (d ppm, CDCl 3) 3.22 (s, 3 H), 5.27 (s, 2 H), 5.41 (s, 2 H), 6.98-7.03 (3 H), 7.26-7.36 (3 H), 7.54 (1 H), 8.11 (1 H) Stage 4 N-Methoxy-N-methyl-f5- (N'.N "-di-tert-butoxycarbonylamino) -2-phenoxymethylbenzimidazole-1 -acetamide In the same manner as in example 17, step 12, N-methoxy-N-methyl-5-amidino-2-phenoxymethylbenzimidazole-1 -acetamide was obtained from N-methoxy-N-methyl- (5-cyano-2-phenoxymethylbenzamidazole) -1 -acetamide (893 g), methyl iodide (1.3 ml) and ammonium acetate (295 mg). In the same manner as in Example 1, step 1, the title compound (144 mg) was obtained from this compound and di-tert-butyl dicarbonate (1.11 g). The solvent used was tetrahydrofuran (10 ml) and a saturated aqueous solution of sodium hydrogen carbonate (10 ml) was used instead of the aqueous solution of 1 H sodium hydroxide. 1 H-NMR (d ppm, CDCl 3) 1.57 (s) , 9H), 3.22 (s, 3H), 3.70-3.80 (m, 3H), 5.25 (S, 2), 5.40 (s, 2H), 6.90-7.05 (, 3H), 7.25-7.35 (m, 3H) 7.94-8.19 (m, 2H) Stage 5 N, N'-Di-tert-butoxycarbonyl-1 f2- (benzothiazol-2-yl) -2-oxoetyl-2-phenoxymethylbenzimidazole-5-carboxamidine To a solution of benzothiazole (42 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of 1.66 M n-butyl lithium-hexane (0.204 ml) at -78 ° C, and the mixture was stirred thereto. temperature for 10 minutes. Then, a solution of N-methoxy-N-methyl-5 - [(N ', N "-d'-tert-butoxycarbonylamino) -2-phenoxymethylbenzimidazole] -1-acetamide (144 mg) in tetrahydrofuran ( 1 ml) was added dropwise, and the mixture was stirred at the same temperature for 3 hours.After completing the reaction, an aqueous solution of ammonium chloride and water was added, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 2: 3) and dried under reduced pressure to give the title compound (25 mg). 1 H-NMR (d ppm, CDCl 3) 1.57 (s, 9H), 5.45 (s, 2H), 6.07 (s, 2H), 6.898-6.95 (3H), 7.17-7.22 (2H), 7.34 (1H ), 7.63 (2H), 7.97 (1 H), 8.22-8.25 (2H).

Stage 6 1-f2- (benzothiazol-2-yl) -2-oxoetyl-2-phenoxymethylbenzimidazole-5-carboximidine hydrochloride In the same manner as in example 9, step 11, the title compound (18 mg) was obtained from N, N'-di-tert-butoxycarbonyl-1 [2- (benzothiazol-2-yl) -2 -oxyethyl] -2-phenoxymethylbenzimidazole-5-carboxamidine (25 mg) and trifluoroacetic acid (1 ml). 1 H NMR (d ppm, DS0-d6) 5.52 (s, 2H), 6.32 (s, 2H), 6.84-6.88 (m, 3H), 7.13-7.18 (m, 2H), 7.69-7.76 (m, 3H), 7.93 (d, 1H), 8.28-8.34 (m, 3H), 9.01 (brs, 2H), 9.32 (brs, 2H).

EXAMPLE 53 Synthesis of trans-4-f2-r4-.l-acetimidoylpiperidin-4-yloxy-1-phenoxymethyl-1-5-amidinobenzimidazol-1-yl-acetylaminomethyl-cyclohexanecarboxylic acid dihydrochloride Stage 1 Ethyl 4-benzyloxyphenoxyacetate To a solution of 4-benzyloxyphenol (18.34 g) in tetrahydrofuran (150 ml) was added 60% sodium hydride (4.76 g) with ice-cooling and the mixture was stirred at the same temperature for 15 minutes. Ethyl bromoacetate (14.2 ml) was added dropwise and the mixture was stirred at room temperature for 16 hours. After completing the reaction, 5% hydrochloric acid was added and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained solid was filtered with hexane and dried under reduced pressure to give the title compound (21.78 g) as a white solid. 1 H-NMR (d ppm, CDCl 3) 1.29 (tr, J = 7.2Hz, 3H), 4.26 (q, J = 7.2Hz, 2H), 4.56 (s, 2H), 5.01 (s, 2H), 6.84- 6.92 (m, 4H), 7.26-7.43 (m, 5H) Stage 2 Ethyl 4-hydroxyphenoxyacetate Ethyl 4-benzyloxyphenoxyacetate (21.78 g) was hydrogenated using 7.5% palladium carbon (3.2 g) in tetrahydrofuran (220 ml) at 3 atmospheres for 7 hours. After completing the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The solid obtained was filtered with disopropyl ether and dried under reduced pressure to give the title compound (13.88 g) as a white solid. 1 H-NMR (d ppm, DMSO-dβ) 1.19 (tr, J = 7.2Hz, 2H), 4.61 (s, 2H), 6.63-6.76 (m, 4H), 8.95 (s, 1 H) Stage 3 4- (ethyl 1-tert-butoxycarbonylpiperidin-4-yloxy enoxyacetate) In the same manner as Example 37, Step 7, the title compound (23.71 g) was obtained from 4- tert-butyl ester hydroxypiperidinecarboxylic acid (35.59 g) ethyl 4-hydroxyphenoxyacetate (5 g), triphenylphosphine (46.4 g) and diethyl azodicarboxylate (27.8 ml). 1 H-NMR (d ppm, CDCl 3) 1.30 (tr, J = 7.2Hz, 3H), 1.47 (s, 9H), 1.73 (m, 2H), 1.88 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2H), 4.27 (q, J = 7.2Hz, 2H), 4.33 (m, 1 H), 4.56 (s, 2H), 6.85 (s, 4H) Stage 4 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetic acid To a solution of ethyl -4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetate (23.71 g) in a mixture of tetrahydrofuran (34 ml) and ethanol (34 ml) was added an aqueous hydroxide solution dropwise. 1 N lithium (68.7 ml) with ice cooling, and the mixture was stirred at room temperature for 20 minutes. After completing the reaction, the solvent was evaporated and an aqueous solution of 10% citric acid was added to the obtained residue. The mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The solid obtained was filtered with hexane and dried under reduced pressure to give the title compound (19.09 g). 1 H-NMR (d ppm, DMSO-d 6) 1.40 (s, 9 H), 1.49 (m, 2 H), 1.83 (m, 2 H), 3.15 (m, 2 H), 3.63 (m, 2 H), 4.40 (m, 1 H), 4.58 (s, 2H), 6.83 (d, J = 9 2Hz, 2H), 6.91 (d, J = 9.2Hz, 2H) Stage 5 Ter-butyl ester of N-f4-cyano-2-f4- (1-tert-butoxycarbonylpperidin-4-yloxy) phenoxyacetamidolfenyl-1-glycine In the same manner as in example 17, step 8, the title compound (17.11 g) was obtained as a white solid from the N- (2-amino-4-cyanophenyl) glycine terbutyl ester (9.11 g) and 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetic acid (12.94 g). 1 H-NMR (d ppm, CDCl 3) 1.47 (s, 9 H), 1.50 (s, 9 H), 1.71 (m, 2 H), 1.88 (m, 2 H), 3.31 (m, 2 H), 3.71 (m, 2 H) , 3.82 (brd, 2H), 4.37 (m, 1 H), 4.66 (s, 2H), 4.99 (brtr, 1H), 6.58 (d, J = 8.7Hz, 1 H), 6.89-6.97 (m , 4H), 7.45 (d, J = 8.7Hz, 1 H), 7.57 (s, 1 H), 8.07 (brs, 1 H) _______V -_, Stage 6 -Cyano-2-f4- (1-tert-butoxycarbonylpiperidin-4-yloxy-phenoxymethyl-benzimidazole-1-acetic acid A solution of N- [4-cyano-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetamido] phenyl] glycine ester (16.91 g) in acetic acid (500 ml) ) was stirred at 75 ° C for 12 hours. The solvent was evaporated and trifluoroacetic acid (100 ml) was added to the obtained residue and the mixture was stirred at room temperature for 30 minutes. After completing the reaction, the solvent was evaporated. To the obtained residue was added ice and then aqueous sodium hydroxide solution and the resulting solid was collected by filtration and washed successively with water and ethyl acetate to give N- [4-cyano-2- [4- (piperidin-4 -iloxy) phenoxyacetamido] phenyl] glycine (8.642 g). In the same manner as in example 1, step 1, the title compound (9506 g) was obtained from this compound, di-tert-butyl dicarbonate (6.96 g) and aqueous solution of 1 N sodium hydroxide ( 23.4 ml). 1 H-NMR (d ppm, CDCl 3) 1, 46 (s, 9H), 1.64 (m, 2H), 1.79 (m, 2H), 3.25 (m, 2H), 3.63 (m, 2H), 4.28 (m, 1 H), 5.12 (s, 2H), 5.12 (s, 2H9, 5.33 (3.2H), 6. 77 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 7.43 (d, J = 8.4Hz, 1 H), 7.59 (dd, J = 12, 8.4 Hz, 1 H ), 8.10 (d, J = 1.2Hz, 1 H) Stage 7 Trans-4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride The title compound (8.8 g) was obtained from trans-4-aminomethylcyclohexanecarboxylic acid (7 g) and thionyl chloride (11.6 ml) by a conventional method. 1 H-NMR (d ppm, DMSO-d 6) 0.98 (m, 2H), 1.29 (m, 2H), 1.55 (m, 1 H), 1.82 (m, 2H), 1.91 (m, 2H9, 2.25 ( m, 1 H), 2.26 (m, 2H), 3.59 (s, 3H), 8.07 (brs, 3H) Stage 8 2-f4- (1-tert-Butoxycarbonylpiperidin-4-yloxy) phenoxymethyl-5-cyano-1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethylbenzimidazole In the same manner as in example 17, step 10, the title compound (1.37 g) was obtained from 5-cyano-2- [4- (1-tert-butoxycarbonyl-1-piperidin-4-ylsi) Phenoxymethyl] benzimidazole-1-acetic acid (1.1 g), trans-4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride (452 mg), N-methylmorpholine (0.263 ml), hydrated 1-hydroxybenzotriazole (293 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (437 mg). 1 H NMR (d ppm, CDCl 3) 0.79 (m, 2 H), 1.27 (m, 3 H), 1.46 (s, 9 H), 1. 55 (m, 2H), 1.72 (m, 2H), 1.85 (m, 4H), 2.09 (m, 1 H), 3.02 (tr, 2H), 3.30 (m, 2H9, 3.64 (s, 3H), 3.67. (m, 2H), 4.35 (m, 1H9, 4.97 (s, 2H9, 5.37 (s, 2H), 5.66 (brtr, 1H), 6. 87 (d, J = 9.0Hz, 2H), 6.95 (d, J = 9.0Hz, 2H), 7.48 (1H), 7.61 (1H), 8.14 (1H) Stage 9 2-r4- (1-tert-Butoxycarbonylpperidin-4-yloxy) phenoxymethin-1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethylbenzimidazole-5-carboxamidine Hydrogen sulfide was blown into a solution of 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole (1.1 g) in a mixture (30 g. ml) of pyridine-triethylamine (5: 1) with ice cooling and to the mixture was stirred at room temperature for 12 hours. After completing the reaction, the solvent was evaporated and the residue obtained was collected by filtration with toluene. To the obtained solid were added acetone (30 ml) and methyl iodide (1.3 ml) and the mixture was stirred under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and the residue was dried under reduced pressure to give 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-) methyl ester. methoxycarbonylcyclohexylmethylcarbamoylmethyl) -benzimidazole-5-carbothioimide (1.819 g). One part (606 mg) of it was dissolved in ethanol (10 ml) and ammonium acetate (80 mg) was added thereto at room temperature. it was stirred at 75 ° C for 3 hours. After completing the reaction, the solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 95: 5-93: 7) and dried under reduced pressure to give the title compound (341). mg). 1 H-NMR (d ppm, DMSO-d 6) 0.91 (m, 2H), 1.20-1.55 (m, 4H), 1.70 (m, 2H), 1.86 (m, 4H), 2.18 (m, 1H9, 2.94 (brtr , 2H), 3.15 (m, 3H), 3.58 (s, 3H), 3.62 (m, 2H), 4.40 (m, 1 H), 5.10 (s, 2H), 5.30 (s, 2H), 6.91 (d , J = 9.0hz, 2h), 6.99 (d, J = 9.0Hz, 2H), 7.70 (1 H), 7.78 (1 H), 7.78 (1 H), 8.21 (1 H), 8.35 (brtr, 1 H), 8.79 (brtr, 1 H), 9.26 (brtr, 1 H) Stage 10 Trans-4-y2-f4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl-5-amidinonobenzimidazol-1-ylacetylaminomethyl-cyclohexane-carboxylic acid dihydrochloride In the same manner as in example 19, step 11, 2- [4- (pperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethyl- carbamoylmethyl) benzimidazole-5-carboxamidine (299 mg) was obtained from 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxamidine ( 341 mg) and trifluoroacetic acid (5 ml). To a solution of this compound (205 mg) in methanol (1 ml) was added an aqueous solution of 1N sodium hydroxide (1.57 ml) at room temperature, and the mixture was stirred for 15 hours. After completing the reaction, 1 N hydrochloric acid (0.944 ml) was added and the solvent was evaporated and the residue was dried under reduced pressure. To the obtained residue were added methanol (5 ml), triethylamine (0.439 ml) and ethyl acetimidate hydrochloride (195 mg) and the mixture was stirred at room temperature for 15 hours. After completing the reaction, the solvent was evaporated and the residue obtained was separated by means of HPLC (40% methanol-water, 0.05% trifluoroacetic acid). Dilute hydrochloric acid was added to it, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (78 mg).

EXAMPLE 54 Synthesis of trans-4-f2-r4- (1-acetylimidoylpiperidin-4-yloxy) phenoxymethyl-5- (N-methylamidino) benzimidazol-1-ylacetylaminomethyl-cyclohexanecarboxylic acid dihydrochloride Stage 1 N-Methyl-2-f4-p-tert-butoxycarbonylpiperidin-4-yloxy-phenoxymethyri-1- (trans-4-methoxycarbonyl-cyclohexylmethylcarbamoylmethylbenzimidazole-5-carboxamidine In the same manner as in example 53, step 9, the title compound (447 mg) was obtained from acid methyl ester 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethyl-carbamoylmethyl) benzimidazole-5-carbothioimide (606 mg), methylamine hydrochloride (70 mg) and Sodium acetate (85 mg). 1 H-NMR (d ppm, DMSO-de) 0.91 (m, 2H), 1.16-1.55 (m, 14H), 1.70 (m, 2H9, 1.85 (m, 4H), 2.18 (m, 1H), 2.94 (brtr, 2H9, 3.03 (s, 3H9, 3.16 (m, 2H), 3. 58 (s, 3H), 3.61 (m, 2H), 4.42 (m, 1H), 5.10 (s, 2H), 5.30 (s, 2H), 6. 91 (d, J = 9.0Hz, 2H), 6.99 (d, J = 9.0Hz, 2H), 7.64 (d, J = 1.5, 8.5 Hz, 1 H), 7.77 (d, J = 7.77Hz, 1 H ), 8.11 (d, J = 1.5 Hz, 1 H), 8.34 (brtr, 1 H).

Stage 2 Trans-4-22 - [- 4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl-5- (N-methylamidino) benzimidazol-1-ylacetylaminomethyl-cyclohexane-carboxylic acid dichlorohydrate In the same manner as in example 53, step 10, the title compound (149 mg) was obtained from N-methyl-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1 - (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxamide (447 mg), trifluoroacetic acid (5 ml), 1 N sodium hydroxide aqueous solution (2.15 ml), triethyl amine (0.599 ml) and ethyl acetimidate hydrochloride ( 265 mg). 1 H-NMR (d ppm, DMSO-dβ) 0.8-1.0 (m, 2H), 1.12 -1.42 (m, 3H), 1.71 (m, 4H), 1.86 (m, 2H9, 192-2.18 (m, 3H ), 2.30 (s, 3H), 2.95 (m, 2H), 3.05 (d, 3H), 3. 42-3.88 (m, 4H9, 4.58 (m, 1 H), 5.19 (s, 2H), 5.37 (s, 2H), 6.96 (d, J = 9.3Hz, 2H), 7 04 (d, J = 9.3 Hz, 2H), 7.74 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 1 H), 8.18 (s, 1 H), 8.63 (brtr, 1 H), 8.87 (brs, 1 H), 9.01 (brs, 1 H), 9.43 (brs, 1 H), 9 53 (brs, 1 H), 9 94 (brs, 1 H), EXAMPLE 55 Synthesis of trans-4-.2-r4- (1-acetimidoylpiperidin-4-loxy) phenoxymethyl-5-amino (hydroxyimino) methylbenzimidazol-1-ylacetylaminomethylcyclohexanecarboxylic acid dihydrochloride Stage 1 2-t4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl-1 - (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxamide oxime In the same manner as in example 53, step 9, the title compound (181 mg) was obtained from 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1 methyl ester. - (trans-4- methoxycarbonylcyclohexylmethyl-carbamoylmethyl) benzimidazole-5-carbothioimide (606 mg), hydroxyamine hydrochloride (72 mg) and sodium acetate (85 mg). 1 H-NMR (d ppm, DMSO-dβ) 0.90 (m, 2 H), 1.15-1.55 (m, 14 H), 1.70 m (m, 2 H), 1.86 (m, 4 H), 2.29 (m, 1 H), 2.94 (tr, 2H), 3.16 (m, 2H), 3.58 (s, 3H9, 3.65 (m, 2H), 4.40 (m, 1 H), 5.00 (s, 2H), 5.26 (s, 2H), 5.92 (brs, 1 H9, 6.91 (d, J = 9.0Hz, 2H), 7.00 (d, J = 9.0Hz, 2H9, 7.49 (1H), 7.63 (1H), 7.95 (1H), 8.27 (brtr , 1 H9, 9.59 (brs, 1 H).

Stage 2 Trans-4- [2-44- (1-acetimidoylpiperidin-4-ylxylphenoxymethyl-5-amino (hydroxyimino) methylbenzimidazol-1-ylacetylaminomethyl-1-cyclohexanecarboxylic acid dihydrochloride] In the same manner as in example 53, step 10, the title compound (22 mg) was obtained from 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- oxime ( trans-4-methoxycarbonylcyclohexylmethyl-carbamoylmethyl) benzimidazole-5-carboxamide (181 mg), trifluoroacetic acid (5 ml), aqueous 1 N hydroxide solution (0.669 ml) triethylamine (0.187 ml) and ethyl acetimidate hydrochloride (83 mg). 1 H-NMR (d ppm, DMSO-de) 0.8-1.0 (m, 2H), 1.12-1.42 (m, 3H), 1.71 (m, 4H), 1.86 (m, 2H), 2.04 (m, 3H ), 2.29 (s, 3H), 2.94 (m, 2H), 3.45-3.60 (m, 2H), 4.58 (m, 1H), 5.14 (s, 2H), 5.34 (s, 2H), 6.95 / d, J = 9.0Hz, 2H), 7.02 (d, J = 9.0Hz, 2H), 7.64 (d, J = 8.7Hz, 1H), 7.81 (d, = 8.7 Hz, 1 H), 8.10 (s, 1 H), 8.49 (brtr, 1 H), 8.74 (brs, 1 H), 8.98 (brs, 1 H), 9.29 (brs, 2H), 11.29 (brs, 1 H), 12.86 (brs, 1 H).

EXAMPLE 56 2-r4- (pipetidin-4-yloxy) phenoxymethyl-1-phenacylbenzimidazole-5-carboxamidine dihydrochloride Stage 1 3,4-Diaminobenzonitrile 2-Nitro-4-cyanoaniline (2.1 g) was hydrogenated using 7.5% palladium on carbon (320 mg) in ethanol (44 ml) at atmospheric pressure for 2 hours. After completing the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The residue obtained was added Chloroform and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (474 mg). 1 H-NMR (d ppm, DMSO-de) 4.82-4.85 (2H), 5.41-5.43 (2H), 6.54 (d, J = 8.1 Hz, 1 H), 6.75 (d, J = 2.1 Hz, 1 H) , 6.79 (dd, J = 2.1, 8.1 Hz, 1 H).

Stage 2 Ter-butyl ester of 4-r4- (2-amino-5-cyanophenylcarbamoylmethoxy) phenyloxypiperidin-1-carboxylic acid To a solution of 3,4-diaminobenzonitrile (474 mg), 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetic acid (1.25 g) in tetrahydrofuran (50 ml) was added 1-ethoxycarbonyl-2-ethoxy -1,2-dichloroquinoline (1.06 g) with ice cooling and the mixture was stirred at room temperature for 16 hours. After completing the reaction, the solvent was evaporated and chloroform and hexane were added to the obtained residue. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (1.55 g). H-NMR (d ppm, CDCl 3) 1.47 (s, 9H), 1.74 (m, 2H), 1.90 (m, 2H), 3.32 (m, 2H), 3.70 (m, 2H), 4.28 (brs, 2H) , 4.38 (m, 1H), 4.64 (s, 2H), 6.80 - - - (d, J = 8.4Hz, 1 H), 6.92 (s, 4H), 7.37 (dd, J = 1.8, 8.4 Hz, 1H), 7.56 (d, J = 1.8Hz, 1 H), 8.10 (brs, 1 HOUR).

Stage 3 2-F4- (1-tert-Butoxycarbonylpiperidin-4-yloxyWenoxylmetill-5-cyanobenzimidazole) H In the same manner as in example 19, step 8, the title compound (1.04 mg) was obtained from 4- [4- (2-amino-5-cyanophenylcarbamoylmethoxy) phen-tert-butyl ester. Loxi] piperidin-1-carboxylic acid (1.52 g). 1 H NMR (d ppm, CDCl 3) 1.47 (s 9 H), 1.73 (m, 2 H), 1.88 (m, 2 H), 3.30 (m, 2 H), 3.69 (m, 2 H), 4.35 (m, 1 H), 5.36 (s, 2H), 6.86-6.96 (m, 4H), 7.54 (s, 1 H).

Stage 4 2-f4- (1-tert-Butoxycarbonylpiperidin-4-yloxy) phenoxymethyl-5-cyano-1-phenacylbenzimidazole To a solution of 2- [4- (1-tert-butoxycarbonylpperidin-4-yloxy) phenoxymethyl] -5-cyanobenzimidazole (915 mg) in dimethylformamide (15 ml) was added 60% sodium hydride (90 mg) with ice cooling and the mixture was stirred at the same temperature for 20 minutes. Phenacyl bromide (426 mg) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was purified by HPLC (hexane: ethyl acetate = 2: 3) to give the title compound (385 mg). 1 H NMR (d ppm, CDCl 3) 1.46 (s, 9 H), 1.68 (m, 2 H), 1.83 (m, 2 H), 3.27 (m, 2 H), 3.66 (m, 2 H), 4.29 (m, 1 H), 5.34 (s, 2H), 5.79 (s, 2H), 6.75-6.82 (m, 4H), 7.27 (1 H), 7.54 (1 H), 7.59 (2H), 7.72 (tr, 1 H) , 8.02 (2H), 8.15 (1H).

Stage 5 2- [4- (piperidin-4-isoxy-phenoxymethip-1-phenacylbenzimidazole-5-carboxamide dihydrochloride In the same manner as in example 53, step 9, 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carbothioimidic acid methyl ester (127 mg) was obtained from from 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyano-1-phenacylbenzimidazole (182 mg), hydrogen sulfide, methyl iodide (0.204 ml) and ammonium acetate (38 mg). To a solution of this compound in chloroform (1 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 5 minutes. The solvent was evaporated and the residue obtained was dissolved in methanol. Thereto was added 10% hydrochloric acid-methanol (0.5 ml) and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (109 mg). 1 H-NMR (d ppm, DMSO-de) 1.77 (m, 2 H), 2.00 (m, 2 H), 3.01 (m, 2 H), 3.15 (m, 2 H), 4.45 (m, 1 H), 5.37 (s) , 2H), 6.18 (s, 2H), 6.78-6.86 (m, 4), 7.59-7.84 (m, 5H), 8.09 (d, 2H), 8.26 (s, 1 H), 8.80-9.10 (m, 4H), 9.33 (brs-2H).

EXAMPLE 57 Synthesis of 2-l4- (1-acetimidoylpiperidin-4-ylxylphenoxymethyl-1-phenazylbenzimidazole-5-carboxamidine dihydrochloride In the same manner as in Example 29, step 1, 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxamide was obtained from 2- [4-dihydrochloride] - (piperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxamidine (85 mg), triethylamine (0.128 ml) and ethyl acetimidate hydrochloride (57 mg). Isopropanol was added to this compound and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (17 mg). 1 H-NMR (d ppm, DMSO-d 6) 1.69 (m.2H), 1.95 (m, 2H), 2.27 (s, 3H), 3.50 (m, 2H), 3.71 (m, 2H), 4.52 (m, 1 H), 5.37 (s, 2H), 6.19 (s, 2H), 6. 80 (d, J = 9.0Hz, 2H), 6.86 (d, J = 9.0Hz2H), 7.63 (tr, 2H), 7.71-7.79 (m, 2H), 7.83 (1H), 8.10 (2H) ,. 826 (s, 1 H), 8.60, 8.95, 9.20, 9.31 (6H).

EXAMPLE 58 Synthesis of 2-r2-f4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl-ethyl-1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxamide dihydrochloride Stage 1 Ter-butyl ester of 4-ethoxycarbonyl-4-f2- (1,3-dioxolan-2-yl-ethylpiperidin-1-carboxylic acid) In the same manner as in example 10, step 5, the title compound (520 mg) was obtained from ethyl ester of 1-tert-butoxycarbonylisonipecotinic acid (500 mg), a solution of lithium diisopropylamide-tetrahydrofuran 1.5M (1.6 ml) and 2- (2-bromoethyl) -1, 3-dioxolane (0.27 ml). 1 H-NMR (d ppm, CDCl 3) 1.26 (tr, J = 7.2Hz, 2H), 1.35 (m, 2H), 1.44 (s, 9H), 1.62 (m, 4H), 2.07-2.11 (m, 2H) , 2.88 (m, 2H), 3.81 -3.97 (m, 6H), 4.17 (q, J = 7.2Hz, 2H), 4.81 (tr, 1 H).

Stage 2 Benzyl ester of 4-ethoxycarbonyl-4-f2- (1,3-dioxolan-2-yl) et? 1-piper? Din-1-carboxylic acid To a solution of 4-ethoxycarbonyl-4- [2- (1, 3-dioxolan-2-yl) ethyl] piperidine-1-carboxylic acid tert-butyl ester (450 mg) in chloroform (2 ml) was added acid trifluoroacetic acid (2 ml) and the mixture was stirred for several minutes. After completing the reaction, the solvent was evaporated and the obtained residue was added an aqueous solution of sodium acid carbonate. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was extracted over anhydrous sodium sulfate and the solvent was evaporated to give 4- [2- (1, 3-dioxolan-2-yl) ethyl] piperidin-4-carboxylic acid ethyl ester. Then, in the same manner as in example 10, step 1, the title compound (460 mg) was obtained from sodium hydrogen carbonate (127 mg) and benzyloxycarbonyl chloride (0.22 ml).

Stage 3 4-Ethoxycarbonyl-4-f2-formilethylpiperidine-1-carboxylic acid benzyl ester Benzyl ester of 4-ethoxycarbonyl-4- [2- (1, 3-dioxolan-2-yl) ethyl) piperidine-1-carboxylic acid (460 mg) was dissolved in tetrahydrofuran (5 ml) and added thereto. drip form concentrated hydrochloric acid (5 ml) with ice cooling, and the mixture was stirred at room temperature for one hour. After completing the reaction, the reaction mixture was poured into aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (hexane: acetone = 5: 1) to give the title compound (300 mg). 1 H-NMR (d ppm, CDCl 3) 1.27 (tr, J = 7.2Hz, 3H), 1.36 (m, 2H), 1.85 (tr, J = 8.0Hz, 2H), 2.10 (m, 2H), 2.43 ( tr, j = 8.0Hz, 2H), 2.94 (m, 2H), 3.98 (m, 2H), 4.18 (q, J = 7.2Hz, 2H), 5.12 (s, 2H), 7.28-7.38 (m, 5H) ), 9.74 (s, 1 H).

Stage 4 Benzyl ester of cyclohexylcarbamoylmethylcarbamic acid To a solution of N- (benzyloxycarbonyl) glycine (13.21 g), 1-hydroxybenzotriazole hydrate (9.39 g) in dimethylformamide (92 ml) were added cyclohexylamine (7.95 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. (13.32 g), and the mixture was stirred at room temperature for 7 hours. After completing the reactionThe reaction mixture was extracted with ethyl acetate and washed successively with water, aqueous sodium hydrogen carbonate solution, 10% hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was recrystallized from ethyl acetate and hexane to give the title compound (16,799 g) f-NMR (d ppm, CDCl 3) 1.13 (m, 3H), 1.35 (m, 2H), 1.67 (m, 3H), 1.86 (m, 2H), 3.76 (m, 1H), 3.82 (d, J = 5.7Hz, 2H), 5.13 (s, 2H), 5.41 (brs, 1 H), 5.81 (brs, 1 H) ), 7.32-7.37 (m, 5H).

Stage 5 4- (Cyclohexylcarbamoylmethylamino.-3-nitrobenzonitrile Benzyl ester of cyclohexylcarbamoylmethylcarbamic acid (16,359 g) was hydrogenated using 7.5% palladium carbon solution (3.24 g) in ethanol (164 ml) at atmospheric pressure for 8 hours. After completing the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. The obtained residue was dissolved in a mixture of ethanol (50 ml) and isopropanol (50 ml). Thereto were added 4-chloro-3-nitrobenzonitrile (8.23 g) and triethylamine (7.1 ml), and the mixture was stirred under reflux for 6 hours. After completing the reaction, water was added under reflux and the mixture was cooled by ice. The resulting solid was collected by filtration and washed successively with water and dilsopropyl ether to give the title compound (10.211 g). 1 H-NMR (d ppm, CDCl 3) 1.13 (m, 3 H), 1.38 (m, 2 H), 1.70 (m 3 H)), 1.91 (m, 2 H), 3.84 (m, 1 H), (4.01 (d, J = 5.4Hz, 2H), 5.76 (brd, 1 H), 6.81 (d, J = 8.7Hx, 1 H), 7.65 (d, J = 2.1, 8.7Hz, 1 H), 8.54 (d, J = 5Hz , 1 H), 8.81 (brtr, 1 H).

Stage 6 3-Amino-4-.cyclohexylcarbamoylmethylaminobenzonitrile 4- (Cyclohexylcarbamoylmethylamino) -3-nitrobenzonitrile (3.64 g) was hydrogenated using 7.5% palladium carbon (1.1 g) in tetrahydrofuran (100 ml) at atmospheric pressure for 40 minutes. After completing the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (3.274 g). H-NMR (d ppm, DMSO-de) 1.21 (m, 5H), 1.52-1.72 (m, 5H), 3.57 (m, 1 H), 3.70 (d, J = 5.72Hz, 2H), 4.97 (brs) , 2H), 5.74 (d, J = 5.7Hz, 1H), 6.30 (d, J = 8.4Hz, 1H), 6.82 (d, J = 1.8Hz, 1H), 6.92 (dd, J = 1.8, 8.4 Hz, 1H), 7.80 (brd, 1 H) Stage 7 Benzyl ester of 4-f2- (5-cyano-2- (cyclohexylcarbamoylmethylaminolyphenylcarbamoilletin-4-ethoxycarbonylpiperidine-1-carboxylic acid To a solution of 4-ethoxycarbonyl-4- (2-formyl) piperidin-1-carboxylic acid benzyl ester (50 mg) in tert-butanol (1 ml) was added an aqueous solution of sodium acid diphosphate (25 mg / ml). 0.5 ml), amylene (0.06 ml) and aqueous sodium chloride solution (40 mg / 0.5 ml), and the mixture was stirred at room temperature for 1 hour. After completing the reaction, hydrochloric acid and a 5% sodium thiosulfate aqueous solution were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was dissolved in dimethylformamide (1 ml). Thereto was added 3-amino-4-cyclohexylcarbamoylmethylamidobenzonitrile (39 mg), 1-hydroxybenzotriazole hydrate (21 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. (30 mg), and the mixture was stirred at room temperature for 12 hours. After completing the reaction, an aqueous sodium hydrogen carbonate solution was added and the reaction mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue obtained was recrystallized from ethyl acetate and dried under reduced pressure to give the title compound (51 mg). 1 H-NMR (d ppm, CDCl 3) 1.29 (tr, J = 7.2 Hz, 3H), 0.95-1.76 (m, 12H), 1.99 (m, 2H), 2.18 (m, 2H), 2.44 (tr, 2H) ), 2.96 (m, 2H), 3.74 (m, 1 H), 3.90 (d, J = 6.3Hz, 2H), 4.00 (m, 2H), 4.17 (q, J = 7.2Hz, 2H), 5.12 ( 3, 2H), 5.22 (tr, J = 6.3Hz, 1H), 6.49 (1H), 6.82 (1H), 7.31-7.44 (m, 8H).

Stage 8 2-f2- (1-Benzyloxycarbonyl-4-ethoxycarbonylpiperidinyl-4-yl ethyl-5-cyano-1-cyclohexylcarbamoylmethyl) benzimidazole A solution of benzyl ester of 4- [2- (5-cyano-2-cyclohexylcarbamoylmethylaminophenylcarbamoyl) etl] -4-ethoxycarbonylpiperidin-1- carboxylic acid (300 mg) in acetic acid (10 ml) was stirred at 100 ° C for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) and dried under reduced pressure to give the title compound (200 mg). 1 H-NMR (d ppm, CDCl 3) 0.8-1.75 (m, 13H), 1.80 (m, 2H), 2.22 (m, 4h), 2.84 (tr, 2H), 3.01 (m, 2H), 3.77 (m, 1H), 3.85-4.05 (m, 4H), 4.72 (s, 2H), 5.13 (s, 2H), 5.91 (d, 1 H), 7.26-7.45 (M, 6H), 7.5481 H), 8.01 (1 H) Stage 9 2-f2- (4-ethoxycarbonylpiperidin-4-yl) et.p.-5-cyano-1-cyclohexylcarbamoylmethylbenzimidazole In the same manner as in example 14, step 2, the title compound (150 mg) was obtained from 2- [2- (1-benzyloxycarbonyl-4-ethoxycarbonylpiperidin-4-yl) etl. ] -5-c¡ano-1- cyclohexylcarbamoylmethylbenzimidazole (200 mg), 7.5% palladium-carbon (100 mg) and ammonium formate (105 mg), 1 h-NMR (or ppm, CDCl 3) 0.9-1.85 (m, 12 H), 1.26 (tr, J = 7.2 Hz, 3H), 2.15-2.25 (m, 4H), 2.68 (m, 2H), 2.85 (tr, 2H), 2.90-3.00 (m, 2H), 3.79 (m, 1 H), 3.98 (q, J = 7.2JHz, 2H), 4.73 (s, 2H), 6.04 (d, 1 H), 7.53 (1 H), 8.01 (1 H) Stage 10 2-f2-f4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl-ethyl-5-cyano-1-cyclohexylcarbamoylmethyl. benzimidazole In the same manner as in example 10, step 7, the title compound (110 mg) was obtained from 2- [2- [1- (4-ethoxycarbonylpyridin-4-yl) pperidin-4-) il] etl] -5-cyano-1-cyclohexylcarbamoylmethylbenzimidazole (150 mg), 4-chloropyridine hydrochloride (48 mg) and triethylamine (0.14 ml). 1 H-NMR (d ppm, CDCl 3) 0.95-1.40 (m, 6H), 1.28 (tr, J = 7.2Hz, 3H), 1.82 (m, 2H), 2.25 (tr, J = 7.6Hz, 2H), 2.32 (m, 2H), 2.87 (tr, J = 7.6Hz, 2H), 3.02 (m, 2H), 3.69 (m, 2H), 3.80 (m, 1 H), 4.03 (q, J = 7.2Hz, 2H), 4.73 (s, 2H), 5.97 (d, 1 H), 6.65 (d, J) = 6.6 Hz, 2H), 7.35 (1 H), 8.01 (1 H), 8.26 (d, J = 6.6Hz, 2H) Stage 11 2-f-2f4-Ethoxycarboryl-1- (pyridin-4-yl) piperidin-a-yl) ethyl 1-1- (cyclohexylcarbamoylmethylbenzimidazole-5-carboxamide dihydrochloride Of the same as in example 38, step 8, the title compound (60 mg) was obtained from 2- [2- [4-ethoxycarbonyl-1- (pyridin) -4-yl) piperidin-4-yl. ] ethyl-5-cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole (100 mg), methyl iodide (1 ml), ammonium acetate (22 mg) and sodium acetate (23 mg). 1 H-NMR (d ppm, DMSO-dβ) 1.10-1.38 (m, 8H), 1.50-1.70 (m, 7H), 2.10 (m, 2H), 2.22 (m, .2H), 3.26 (m, 2H) , 3.51 (m, 1 H), 4.92 (s, 2H), 7.20 (d, J = 7.0Hz, 2H), 7.66 (s, 2H), 8.08 (s, 1H), 8.22 (d, J = 7.0Hz , 2H), 8.37 (d, 1 H), 8.94 (s, 2H), 9.20 (s, 2H), 1.34 (brs, 1H) EXAMPLE 59 Synthesis of 4-f2-5-amidino-1- (cyclohexylcarabamoylmethyl-benzimidazol-yl) ethyl-1-pyridin-4-yl) piperidin-4-carboxylic acid dichlorohydrate In the same manner as in example 7, the title compound (20 mg) was obtained from 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole dihydrochloride. 5-carboxamidine (50 mg) and concentrated hydrochloric acid (1.5 ml). The compound was purified by preparative HPLC (30-50% methanol-water). 1 H-NMR (d ppm, DMSO-de) 1.19 (m, 5H), 1.65 (m, 7H), 2.17 (m, 4H), 2.87 (m, 2H), 3.29 (m, 2H), 4.08 (m, 2H), 5.01 (s, 2H), 7.19 (2H), 7.72 (d, J = 8.7Hz, 1 H), 7.77 (d, J = 8.7Hz, 1 H), 8.14 (s, 1 H), 8.21 (2H), 8.56 (d, 1 H), 9.07 (brs, 2H), 9.34 (brs, 2H), 13.56 (brs, 1 H) EXAMPLE 60 Synthesis of 1- (cyclohexylcarbamoylmethyl) -2-fN-f1- (pyridin-4-yl. Piperidip-4-ip-N-ethoxyallylaminomethylbenzimidazole-5-carboxamide dihydrochloride Stage 1 Benzyl ester of 1- (pyridin-4-yl_iperidin-4-carbamic acid To a suspension of 1- (pyridin-4-yl) p -peridin-4-carboxylic acid (11.18 g) and triethylamine (11.3 ml) in dimethylformamide (110 ml) was added diphenylphosphoryl azide 812.9 ml) at room temperature. environment, the mixture was stirred at 80 ° C for 30 minutes. Benzyl alcohol (6.17 ml) was added at the same temperature, the mixture was stirred for 12 hours. After completing the reaction, the solvent was evaporated and the residue was purified by column chromatography on silica gel (chloroform: methanol = 99.1-95.5) and dried under reduced pressure to give the title compound (9.46 g). 1 H-NMR (d ppm, CDCl 3) 1.45 (m, 2 H), 2.05 (m, 2 H), 2.98 (m, 2 H), 3.79 (m, 3 H), 4.82 (brd, 1 H), 5.10 (s, 2 H) , 6.64 (dd, J = 1.2, 5.1 Hz, 2H), 7.29-7.41 (m, 5H), 8.25 (dd, J = 1.2, 5.1 Hz, 2H) Stage 2 4-Amino-1 - (pyridin-4-ippiperidin Benzyl ester of 1- (pyridin-4-yl) piperidine-4-carbamic acid (9.46 g) was hydrogenated using a solution of 7.5% carbon palladium (3.57 g) in ethanol (95 ml) at 3 atmospheres per hour. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (5.38 g). 1 H-NMR (d ppm, DMSO-d 6) 1.22 (m, 2 H), 1.73 (m, 2 H), 2.87 (m, 3 H), 3.82 (m, 2 H), 6.78 (d, J = 6.5 Hz, 2 H) , 8.11 (d, J = 6.5Hz, 2H) Stage 3 2-Chloromethyl-1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole To a solution of chloroacetonitrile 83.9 ml) in methanol (166 ml) was added sodium methoxide (3.29 g) and the mixture was stirred at room temperature for 40 minutes under a nitrogen atmosphere. Methanesulfonic acid (7.91 ml) and 3-amino-4- (cyclohexylcarbamoylmethylammon) -benzonitrile (8.3 g) were added and the mixture stirred for 3 hours. After completing the reaction, water (166 ml) was added and the precipitated solid was collected by filtration and washed with a small amount of water. The solid obtained was stirred in a mixture of hexane and tatrahydrofuran, collected by filtration and dried under reduced pressure to give the title compound (9.30 g). t1H-NMR (d ppm, DSO-dβ) 1.22 (m, 5H), 1.57 (m, 1 H), 1.74 (m, 4H), 3.55 (m, 1 H), 5.02-5.03 (m, 4H), 7.69 (s, 2H), 8.21 (s, 1 H), 8.34 (brd, 1H) Stage 4 1- (Cilcohexilcarbamoilmetiiy5-cyano-2-f1- (pyridin-4-iDpiperidin-4-ylaminomethyl-tabeimidazole A solution of 4-amino-1- (pyridin-4-yl) piperidine (191 g), 2-chloromethyl-1- (cylcohexylcarbamoylmethyl) -5-cyanobenzimidazole (3.25 g) and triethylamine (2.74 ml) in dimethylformamide ( 15 ml) was stirred at room temperature for 1 day. After completing the reaction, the solvent was evaporated. The residue obtained was extracted into chloroform and washed with water, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by column chromatography on silica gel (chloroform: methanol = 9: 1, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (1464 g). 1 H-NMR (d ppm, CDCl 3) 0.84-1.08 (m, 3H), 1.26 (m, 2H), 1.43 (m, 2H), 1.50 (m, 3H), 2.06 (m, 2H), 2.84-3.00 (m, 3H), 3.68 (m, 1 H), 3.89 (m, 2H), 4.17 (s, 2H), 4.87 ( s, 2H), 6.62-6.67 (m, 3H), 7.49 (1 H), 7.56 (1 H), 8.04 (1 H), 8.24 (2H) Stage 5 1- (Cylclohexylcarbamoylmethyl) -5-cyano-2-fN-f1-pyridin-4-yl) piperidin-4-ill-N-ethoxyallylaminomethylbenzimidazole To a solution of 1- (cyclohexylcarbamoylmethyl) -5-cyano -2- [1- (pyridin-4-yl) piperidin-4-ylaminomethyl] benzimidazole (203 mg) and triethylamine (0.18 ml) in chloroform (5 ml) ) ethyl chloroaxalate (0.119 ml) was added and the mixture was stirred at room temperature for 2 hours. After completing the reaction, water was added and the mixture was extracted with chloroform and washed with an aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (chloroform: methanol = 95.5, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (205 mg). 1 H-NMR (d ppm, CDCl 3) 1.04-1.36 (m, 6H), 1.39 (tr, J = 7.2Hz, 3H), 1.83 (m, 3H), 1.94-2.15 (m, 4H), 2.86 (m, 2H), 3.65-.390 (m, 2H), 4.01 (m, 2H), 4. 40 (q, J = 7.2Hz, 2H), 4.73IS, 2H), 6.27 (1H), 6.65 (d, J = 6.3Hz, 2H), 7.4 (1H), 7.54 (1H), 8.00 ( 1 H), 8.27 (d, J = 6.3HZ, 2H) Stage 6 1-f-Cyclohexylcarbamoyl-phenyl-2-yN-f1- (pyridin-4-yl. Piperidin-4-ip-N-ethoxalylaminomethyl-1-benzimidazole-5-carboxamidine dihydrochloride.

In the same manner as in example 38, step 8, the title compound / 87 mg) was obtained from 1- (cyclohexylcarbamoylmethyl) -5-cyano-2- [N- [1- (pyridine-4 -yl) piperidin-4-yl] -N-ethoxyallylaminomethybenzimidazole (205 mg), hydrogen sulphide, methyl iodide (5 ml), ammonium acetate (138 mg) and sodium acetate (59 mg). 1 H-NMR (d ppm, DMS0-dβ) 1.10-1.288m, 5H), 1.32 (tr, J = 2Hz, 3H), 1.45-2.03 (m, 9h), 3.15-3.30 (m, 2H), 3.56 (m, 1 H), 4.25-4.42 (m, 2H), 4.38 (q, J = 7.2Hz, 2H), 4.76 (s, 1 H), 4.90-5.10 (m, 3H), 7.15-7.75 (m, 2H). 7.76- 7. 75 (m, 2H), 8.15-8.25 (m, 3H), 8.40-8.52 (m, 1 H), 8.90-9.00 (brs, 2H), 9.20-9.30 (m, 2H), 13.42 (brs, 1 H) ) EXAMPLE 61 Synthesis of N-_5-amidino-1-cyclohexylcarbamoylbenzimidazole-2-ylmethyl-N-.1-.pyridin-4 .l.piperidin-4-aminoaminoic acid dichlorohydrate To a solution of 1- (cyclohexylcarbamoylmethyl) -2- [N- [1- (pyridin-4-yl) piperidin-4-yl] N-ethoxalylaminomethylbenzimidazole-5-carboxamidine dihydrochloride (50 mg) in methanol (1 ml) an aqueous solution of 2N sodium hydroxide (0.107 ml) was added, and the mixture was stirred for 10 minutes. After completing the reaction, dilute hydrochloric acid was added. The solvent was evaporated and the residue obtained was separated by means of HPLC (50% methanol-water, 0.05% trifluoroacetic acid). The obtained residue was treated with hydrogen chloride and dried under reduced pressure to give the title compound (20 mg) 1 H-NMR (d ppm, DMSO, d 6) 1.10-1.28 (m, 5H), 1.45-2.03 (m, 9H), 3.10-3.30 (m, 2H), 4.01 (m, 1 H), 4.20-4.40 ( m, 2H), 4.74 (s, 1 H), 4.95-5.10 (m, 3H), 7.16-7.19 (m, 2H), 7.70-7.80 (m, 2H), 8.13-8.30 (m, 3H), 8.47 -8.65 (m, 1 H), 8.95-9.10 (brs, 2H), 9.23-9.30 (m, 2H), 13.57 (brs, 1 H), EXAMPLE 62 Synthesis of 2-fN-f4-d-acetimidoylpiperidin-4-yloxy) phenyl-1-N-ethoxycarbonylmethylaminomethyl-1-cyclohexylcarbamoylmethylbenzimidazole-5-caboxamidine dihydrochloride Stage 1 2-f4- (1-tert-butoxycarbonylpiperidin-4-yloxyphenylaminomethyl-1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole A solution of ter-buti 4- (4-aminophenoxy) plperidin-1-carboxylate 88. 21 g), 2-chloromethyl-1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole 89.29 g) and diisopropylethylamine (9.8 ml) in dimethylformamide (93 ml) was stirred at 60 ° C for 14 hours. After completing the reaction, the solvent was evaporated and the The residue obtained was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. To the obtained residue, ethyl acetate and hexane were added and the precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (15.726 g). 1 H-NMR (d ppm, CDCl 3) 0.75 (m, 2 H), 0.97 (m, 1 H), 1.23 (m, 2 H), 1.46-1.73 (m, 16 H), 1.85 (m, 2 H), 3.27 (m , 2H), 3.65 (m, 3H), 4.28 (m, 1 H), 4.61 (s, 2H), 5.63 (d, 1 H), 6.74 (d, J = 8.7Hz, 2H), 7.44 (d, J = 8.4Hz, 1 H), 7.57 (dd, J = 1.2, 8.4Hz, 1 H), 8.10 (d, J = 1.2Hz, 1 H) Stage 2 2- [N-f4- (1-tert-butoxycarbonylpiperidin-4-yloxy) fepine-N-ethoxycarbonylmethylaminomethyl-1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole To a solution of 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylaminomethyl] -1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole (247 mg) in dimethylformamide (2.5 ml) was added potassium carbonate ( 175 mg) and ethyl bromoacetate (0.07 ml) and the mixture was stirred at room temperature for 24 hours. To this was added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml) and the mixture was stirred at room temperature for 24 hours. Then ethyl bromoacetate (0.07 ml) was added and the mixture was stirred at room temperature for 24 hours. After completing the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) to give the title compound (124 mg). 1 H-NMR (d ppm, CDCl 3) 0.88-1.35 (m, 10H), 1.46 (s, 9H), 1.67 (m, 5H), 1.86 (m, 2H), 3.29 (m, 2H), 3.67 (m, 3H), 4.01-4.07 (m, 1 H), 4.69 (s, 2H), 4.93 (s, 2H), 6.50 (d, 1 H), 6.81 (d, J = 9.1 Hz, 2H), 6.88 (d) , J = 9.1 Hz, 2H), 7.54 (1 H), 8.03 (1 H) Stage 3 2-.N-4- (1-Acetimidoylpiperidin-4-yloxy) feniir-N-ethoxycarbonylmethylaminomethyl-1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxamidine dihydrochloride In the same manner as in example 38, step 8, 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1-c-clohexylcarbamoylmethylbenzimidazole-5 -carboxamidine (47 mg) was obtained from 2 - [- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethyl-amiamomethyl] -1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole (247 mg), hydrogen sulfide, methyl iodide (1 ml) and ammonium acetate 821 mg), then in the same manner as in example 53, Step 10, the title compound (28 mg) was obtained. 1 H-NMR (d ppm, DMSO-d 6) 1.17 (tr, J = 7.2Hz, 3H), 1.10-1.35 (m, 5H), 1.50-1.80 (m, 7H), 1.99 (m, 2H), 2.28 ( s, 3H), 3.40-3.60 (m, 3H), 4.108q, J = 7.2Hz, 2H), 4.18 (m, 2H), 4.46 (m, 1 H), 4.86 (m, 2H), 5.07 (s) , 2H), 6.74 (d, - ~ a * s "j -1- J = 9.0Hz, 2H), 6.85 (d, J = 9.0Hz, 2H), 7.73 (1H), 7.80 (1H), 8.15 (1H), 8.47 (1H), 8.70 (1H), 9.04 (2H), 9.25 (1 H), 9.3 (2H) EXAMPLE 63 Synthesis of N-.5-amidino-l (cyclohexylcarbamoylmethyl) benzyl-2-ylmethyl) -N-r4-M-acetylimidoylpiperidin-4-yloxycarbamoylbenzoic acid Stage 1 2- [N-R4- (1-tert-butoxycarbonylpiperidin-4-yloxyphenyi-N- (4-methoxycarbonylbenzoyl) aminomethyl) -1- (cyclohexylcarbamoylmethyl) -5- To a solution of 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) fenlaminomethyl] -1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (331 mg) and triethylamine (0.118 ml) in chloroform (10 ml) were added benzoate methyl-4-chloroformyl benzoate (112 ml) and 4-dimethylaminopyridine (15 mg) and the mixture was stirred at room temperature for 13 hours. After completing the reaction, the solvent was evaporated and the residue obtained was extracted with ethyl acetate and washed successively with an aqueous solution of 10% citric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was washed with chloroform-diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (333 mg). 1 H-NMR (d ppm, CDCl 3) 1.09-1.23 (m, 7H), 1.46 (s, 9H), 1.50- 1.94 (m, 7H), 3.29 (m, 2H), 3.69 (m, 3H), 4.36 ( m, 1 h), 5.07 (s, 2H), 5.25 (s, 1 H), 6. 38 (d, 1 H), 6.72 (d, J = 8.9Hz, 2H), 7.08 (d, J = 8.9Hz, 2H), 7.34 (d, J = 8.4Hz, 2H), 7. 48 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 1.2, 8.6 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 2 H), 8.06 (d, J = 1.2 Hz, 1 H) Stage 2 2-rN-r4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl-N- (4-methoxycarbonylbenzoyl) aminomethyl-1-cyclohexylcarbamoyl-methylbenzamidazole-5-carboxamidine In the same manner as in example 17, step 12, the title compound (201 mg) was obtained from 2- [N - [- (1-tert-butoxycarbonyl-pyrpridin-4-yloxy) phenyl] -N-methoxycarbonylbenzoyl ) ammonomethyl] -1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole (333 mg), hydrogen sulfide, methyl iodide (0.277 ml) and ammonium acetate (51 mg). 1 H-NMR (d ppm, CDCl 3) 1.08 (m, 3 H), 1.23 (m, 2 H), 1.46 (s, 9 H), 1. 52-1.80 (m, 7H), 1.86 (m, 2H), 3.29 (m, 2h9, 3.29 (m, 2H), 3.67 (m, 3H), 3.87 (s, 3H), 4.36 (m, 1 h), 5.07 (s, 2H), 5.25 (s, 2H), 6.41 (d, 1 H), 6.72 (d, J = 8.9Hz, 2H), 7. 08 (d, J = 8.9Hz, 2H), 7.34 (d, 8.3Hz, 2H), 7.47 (1H), 7.56 (1H), 7.84 (d, J = 8.3Hz, 2H), 8.05 (1H) ) Stage 3 2-fN-r4- (piepridin-4-yloxy) phenyl-N- (4-methoxycarbonylbenzoyl) aminomethyl-1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxamidine dichlorohydrate To a solution of 2-N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl-benzimidazole-5-carboxamidine ( 201 mg) in chloroform (1 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 5 minutes After completing the reaction, the solvent was evaporated and a solution of 1 N chloride was added to the obtained residue. of hydrogen-diethyl ether The solid obtained was collected by filtration and dried under reduced pressure to give the title compound (175 mg). 1 H-NMR (d ppm, DMSO-de) 1.21 (m, 5H), 1.50-1 , 84 (m, 7H), 2.00 (m, 2H), 2.99 (m, 2H), 3.14 (m, 2H), 3.53 (m, 1 H), 3.81 (s, 3H), 4.52 (m, 1 H) ), . 18 (s, 2H), 5.35 (s, 2h), 6.28 (d, J = 9.0Hz, 2H), 7.21 (d, J = 9.0Hz, 1H), 7.75 (s, 2H), 7.79 (d, J = 8.4Hz, 2H), 8.19 (s, 1 H), 8.57 (d, 1 H), 9.05 (brs, 2H), 9.33 (brs, -H) Stage 4 N- (5-amidino-1 -.cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl) -N-F4-ri-acetimidoylpiperidin-4-yloxy) phenyl-1-carbamoylbenzoic acid To a solution of 2- [N- [4- (piperidin-4-yloxy) phenyl] -N-4-methoxycarbonylbenzoyl) aminomethyl] -1-cyclohexylcarbamoylmethyl-benzimidazole-5-carboxamidine dichlorohydrate (93 mg) in methanol (1 ml) was added a 1 N sodium hydroxide aqueous solution (0.629 ml), and the mixture was stirred at room temperature for 15 hours. After supplementing the reaction, 1 N hydrogen chloride (0.377 ml) was added and the solvent was evaporated and dried under reduced pressure. The residue obtained was dissolved in methanol (2 ml) and treated in the same manner as in example 29, step 1, using triethylamine (0.175 ml) and ethyl acetimidate hydrochloride (78 mg) to give the title compound (28 mg) as a white solid. 1 H-NMR (d ppm, DMSO-de) 1.20 (m, 5H9, 1.46-1.60 (m, 7H), 1.96 (m, 2H), 2.27 (s, 3H), 3.35 -3.60 (m, 3H), 4.57 (m, 1 H), 5.17 (s, 2H), 6.82 (d, J = 5.6Hz, 2H), 7.20 (d, J = 5.6Hz, 2H), 7.3782H), 7.70-7.80 (m, 4H) , 8.19 (s, 1 H), 8.56 (1 H), 8.75 (brs, 1 H), 9.11 (brs, 2H9, 9.33 (brs, 3H) EXAMPLE 64 Synthesis of 2-FN-F4- (1-amidinopiperidin-4-yloxy) phenin-N- (4-methoxycarbonyl-benzoyl) aminomethyl-1- (cyclohexylcarbamoylmethyl) benzamidozol-5-carboxamidine dihydrochloride 2- [N- [4- (piperidin-4-yloxy) phenyl] -N- (4-methoxycarbonyl-benzoyl) -aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxamidine dihydrochloride (220 mg ) was dissolved in 10% methanol (2 ml) and neutralized with ion exchange resin (IRA-410). The mixture was filtered, and the filtrate was concentrated. To a solution of the residue obtained in dimethylformamide (2 ml) were added disopropylethylamine (0.053 ml) and 1 H-pyrazole-1-carboxamidine hydrochloride (44 mg) at room temperature and the mixture was stirred for 20 hours. After completing the reaction, the solvent was evaporated and the residue obtained was separated with HPLC (50% methanol-water, 0.05% trifluoroacetic acid) and diluted hydrogen chloride was added thereto. The solvent was evaporated and dried under reduced pressure to give the title compound (155 mg). 1 H-NMR (d ppm, DMSO, dβ) 1.20 (m, 5H), 1.45-1.75 (m, 7H), 1. 87 (m, 2H), 3.27 (m, 2H), 3.45-3.65 (m, 3H), 3.80 (s, 3H), 5.16 (s, 2H), 5.33 (s, 2H), 6.80 (d, J = 9.0Hz, 2H), 7.19 (d, J = 9.0Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7. 52 (brs, 4H), 7.74 (s, 2H), 7.78 (d, J = 8.1 Hz, 2H), 8.18 (s, 1 H), 8.56 (d, 1 H), 9.11 (brs, 2H), 9.32 (brs, 2H) EXAMPLE 65 Synthesis of N-F5-amidino-1-cyclohexyl-cranbamoylmethylbenzimidazole-2-methyl-1-cyclohexyl-4-yl) -NÍ4. 1 -amidinopiperidin-4-yloxy) phenyl-carbamoyl-benzoic acid dihydrochloride To a solution of 2- [N- [4- (1-amidinopypridin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) -benzimidazole-5-dihydrochloride carboxamidine (130 mg) in methanol (2 ml) was added an aqueous solution of 1 N sodium hydroxide (0.7 ml) and the mixture was stirred at room temperature for 6 hours. After completing the reaction, the solvent was evaporated and the residue obtained was separated by means of HPLC (50% methanol-water, 0.05% trifluoroacetic acid) and acid was added thereto. diluted water The solvent was evaporated and dried under reduced pressure to give the title compound (100 mg). 1 H-NMR (d ppm, DMSO-de) 1.19 (m, 5H), 1.45-1.75 (m, 7H), 1.90 (m, 2H), 3.27 (m, 2H), 4.51 (m, 1 H), 5.17 (s, 2H9, 5.33 (s, 2H), 6.80 (d, J = 5.7Hz, 2H), 7.18 (d, J = 5.7Hz, 2H), 7.36 (2H), 7.52 (s, 4H), 7.74- 7.77 (m, 4H), 8.18 (s, 1 H), 8.55 (1 H), 9.10 (brs, 2H), 9.32 (brs, 2H) EXAMPLE 66 Synthesis of N-.5-amidino-1- (cyclohexylcarbamoylmethylbenzimidazol-2-ylmethyl-N-F4- (1-acT-thimidoylpiperidin-4-yloxy) phenyl-sulphamoyl acetic acid dihydrochloride Stage 1 2-f4-.N- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylH-N-ethoxycarbonylmethylsulfonylaminomethyl-1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole To a solution of chlorosulfonylacetyl chloride (2 g) in chloroform (40 ml) was added ethanol (0.696 ml) at -78 ° C and the mixture was stirred at room temperature for 30 minutes. After completing the reaction, the solvent was evaporated. A solution of the residue obtained in chloroform (10 ml) was added dropwise to a solution of 2- [4 - [- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylamomethyl] 1- (cyclohexylcarbamoylmethyl) 1) -5-Cyanobenzimidazole (5.1 g) and pyridine (2.1 ml) in chloroform (88 ml) with ice-cooling. The mixture was stirred at the same temperature for 1 hour. After completing the reaction, water was added and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue obtained was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 7-2: 8) and dried under reduced pressure to give the title compound (4.25 g). 1 H-NMR (d ppm, CDCl 3) 1.14-1.44 (m, 5H), 1.37 (tr, J = 7.2Hz, 3H), 1. 46 (s, 9H), 1.55-1.78 (m, 5H), 1.80-200 (m, 4H), 3.32 (m, 2H), 3.65 (m, 2H), 3.77 (m, 1 H), 4.10 (s) , 2H), 4.34 (q, J = 7.2Hz, 2H), 4.39 (m, 1 H), 4.99 (s, 2H), 5.21 (s, 2H), 6.04 (d, 1 H), 6.84 (d, J = 8.9Hz, 2H), 7.32 (d, J = 8.9Hz, 2H), 7.53 (s, 2H), 7.94 (s, 1 H) Stage 2 N- (5-amidino-1-cyclohexylcarbamoylmethyl-benzimidazol-2-ylmethyl) -N-4 (1-acetylimidopiperidin-4-yloxy) phenyl-sulphamoyl acetic acid dihydrochloride Hydrogen chloride was bubbled into a solution of 2-. { 4- [N- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonyl-methyl-sulfonyl-aminomethyl] -1-cyclohexylcarbamoylmethyl-5-cyanobenzimidazole (3.34 g) in ethanol (33 ml) with ice-cooling and The mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the obtained residue was dissolved in methanol (30 ml) and ethanol (33 ml). Ammonium acetate (3.49 g) was added and the mixture was stirred at room temperature for 15 hours. After the reaction was complete, a solution of 4N hydrogen chloride-dioxane (7.9 ml) was added and the resulting insoluble material was removed. The solvent was evaporated and the residue dried under reduced pressure. The residue was dissolved in methanol (33 ml) and reacted in the same manner as in example 29, step 1 with triethylamine (8.1 ml) and ethyl acetimidate hydrochloride (4.48 g). After Complete the reaction, the insoluble material was removed and the solvent was evaporated. To the obtained residue 2 N hydrochloric acid (50 ml) was added, and the mixture was stirred under reflux for 2 hours. After completing the reaction, the solvent was evaporated and the residue obtained was separated by HPLC (37-35% methanol-water, 0.05% trifluoroacetic acid) and dilute hydrogen chloride was added. The solvent was evaporated and dried under reduced pressure to give the title compound (1.76 g). 1 H-NMR (d ppm, DMSO-de) 1 -23 (m, 5H), 1.50-1.85 (m, 7H), 2.00 (m, 2H), 2.29 (s, 3H), 3.52 (m, 3H), 3.75 (m, 2H), 4.37 (s, 2H), 4.66 (m, 1 H), 5.10 (s, 2H), 5.22 (s, 2H), 6.97 (d, J = 8.9 Hz, 2H), 7.42 ( d, J = 8.9 Hz, 2H), 7.72 (s, 2H), 8.13 (s, 1H), 8.57 (d, 1 H), 8.82 (br, 1H), 9.15-9.50 (5H) EXAMPLE 67 Synthesis of 4- (2-amidino-1,2,3,4-tetrahydroquinolquin-7-yloxymethyl) -1- (pyridin-4 .l.piperidin-4-carboxylic acid metasulphonate 4- (2-Amidino-1, 2,3,4-tetrahydroisoquinilin-7-yloxymethyl) -1- (pyridin-4-yl) p-peridin-4-carboxylic acid (10 g) was suspended in water (50 ml ) and methanesulfonic acid (1.6 ml) was added. The mixture was heated at 50 ° C to Dissolve it Then acetone (150 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was allowed to cool to room temperature. The precipitated crystals were collected by filtration to give the title compound (11.56 g). 1 H-NMR (d ppm, D 20) 1.60 (m, 2 H), 2.19 (m, 2 H), 2.72 (tr, J = 5.8 Hz, 2H), 3.34 (m, 2H), 3.45 (tr, J = 5.8 Hz, 2H), 3.84-3.92 (m, 4H), 4.38 (s, 2H), 6.72 (s, 1 H), 6.79 ( d, J = 8.4 Hz, 1 H), 6.92 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 2H) Of the same so that in Examples 1 to 67, the compounds of Example 68 to 115 were obtained. The compounds obtained are illustrated in Table 1 to 8.

EXAMPLE 68 7-1 - (Pyridin-4-ylacetyl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-D.) 1.20 (m, 2 H), 1.80 (m, 2 H), 2.65 (m, 1 H), 2.81 (m, 2 H), 3.11 (m, 1 H), 3.82. (d, 2H), 3.95 (m, 1 H), 4.13 (s, 2H), 4.40 (m, 1 H), 4.54 (s, 2H), 6.71 (s, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.61 (brs, 4H), 7.90 (d, J = 6.6 Hz, 2H) EXAMPLE 69 7-M- (3-aminobenzyl) pyridin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.67 (m, 2 H), 1.95 (m, 3 H), 2.81 (m, 2H), 2.96 (m, 2H), 3.34 (m, 2H), 3.56 (m, 2H), 3.86 (m, 2H), 6.70 (1 H), 6.81 (1 H), 7.07-7.37 (m, 5H) ), 7.56 (brs, 4H), 10.52 (brs, 1 H) EXAMPLE 70 7-l-1,2-Hydroxybenzylpyridin-4-ylmethoxy-1-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.64 (m, 2 H), 1.94 (m, 3 H), 2.81 (m, 2 H), 3.00 (m, 2 H), 3.38 (, 2 H), 3.79 (m, 2 H) ), 4.17 (m, 2H), 4.53 (m, 2H), 6.69 (1 H), 6.79-6.88 (m, 2H), 6.97 (1 H), 7.13 (1 H), 7.26 (t, 1 H) , 7.46 (1 H), 7.56 (brs, 4H), 9.94 (brs, 1 H), 10.25 (brs, 1 H) EXAMPLE 71 7-H - (pyridin-2-ylmethyl) piperidin-4-ylmethoxyl-1.2.3.4-tetrahydroisoquinolin-2-carboxamidine triclohydrate 1 H-NMR (d ppm, DMSO-d 6) 1.75 (m, 2 H), 2.00 (m, 2 H), 2.10 (m, 1 H), 2.88 (m, 2 H), 3.16 (m, 2 H), 3.49 (m , 2H), 3.63 (m, 2H), 3.91 (m, 2H), 4.51 _ »! ___, • * _ ,. (s, 2H), 4.60 (s, 2H), 6.77 (d, J = 2.3 Hz, 1H), 6.89 (d, J = 2.3, 8.4 Hz, 1H), 7.21 (d, 8.4 Hz, 1 H), 7.55 (1 H), 7.63 (brs, 4H), 7.69 (1 H), 8.74 (1 H), 10.35 (brs, 1 H) EXAMPLE 72 2-f4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethipiperidin-1-lrnethyl) -carboxylic acid methyl ester dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.54 (m, 2H), 1.86 (m, 3H), 2.68 (m, 2H), 3.03 (m, 2H), 3.43 (m, 2H), 3.94 (m, 2H), 4.40 (s, 2H), 4.54 (m, 2H), 6.57 (1 H), 6.68 (1 H) ), 6.99-702 (m, 2H), 7.18 (tr, J = 7.8 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.44 (brs, 4H), 7.56 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 9.20 (brs, 1 HOUR) EXAMPLE 73 4-.2-amidine-1,2,3,4-tetrahydroisoquinolin-7-yloxymethi-piperidin-1-acetic acid benzyl ester hydrochloride 1 H NMR (d ppm, DMSO-d 6) 1.67 (m, 2 H), 1.97 (m, 3 H), 2,838 m, 2 H), 3.09 (m, 2 H), 3.58 (m, 4 H), 3.83 (m, 2H), 4.36 (2H), 4.55 (s, 2H), 5.27 (s, 2H), 6.72 (1H), 6.84 (1H), 7.16 (1H), 7.36-7.44 (m, 5H), 7.58 (brs, 4H), 10.36 (brs, 1 H) EXAMPLE 74 N-Benzyl 4-.2-amidine-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl-Piperidin-1-carboxamidine hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.17 (m, 2 H), 1.70 (m, 2 H), 1.94 (m, 1 H), 2.70 (m, 2H), 2.82 (m, 2H), 3.60 (m, 2H), 3.81 (m, 2H), 4.23 (s, 2H), 4.54 (s, 2H), 6.70 (d, J = 1.4 Hz, 1 H), 6.82 (dd, J = 1.4-6.4 Hz, 1 H), 7.13 (d, J = 6.4 Hz, 1 H), 7.00-7.31 (m, 6H), 7.61 (brs, 4H) EXAMPLE 75 7-f 1 - (Indole-2-ylmethyl-piperidin-4-ylmethoxy-1-2,3,3-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.67 (m, 2 H), 1.97 (m, 2 H), 2.81 (m, 2 H), 2.98 (m, 2 H), 3.58 (m, 2 H), 3 81 (d , 2H), 4.44 (d, 2H), 4.56 (2H), 6.69 (2H), 6.82 (1H), 7.03 (1H), 7.13 (2H), 7.41 (1H), 7.56-7.65 (m, 5H), 11.05 (brs, 1 H), 11.50 (s, 1 H) EXAMPLE 76 4-r2-aminidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-acetic acid dichlorhydrate 1 H-NMR (d ppm, DMSO-d 6) 1.70 (m, 2 H), 1.97 (m, 3 H), 3.12 (m, 2H), 3.84 (m, 2H), 4.11 (brs, 2H), 4.57 (s, 2H9, 6.72 (s, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.69 (brs, 4H), 10.18 (brs, 1 H) EXAMPLE 77 N-Benzyl-4-r2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1 -acetamide dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.68 (m, 2 H), 2.82 (m, 2 H), 3.12 (m, 2 H), 3.45-3.60 (m, 4 H), 3.83 (m, 2 H), 3.99 ( m, 2H), 4.36 (d, J = 5.8 Hz, 2H), 4.56 (s, 2H), 6.72 (1H), 6.8 (1H), 7.15 (1H), 7.24-7.34 (, 5H), 7.67 ( brs, 5H), 9.26 (tr, J = 5.8 Hz, 1 H), 9.97 (brs, 1 H) EXAMPLE 78 4-r2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethi-diperidin-1-ylacetylaminoacetic acid dichlorhydrate 1 H NMR (d ppm, DMSO-dβ) 1.67 (m, 2H), 1.96 (m, 3H), 2.83 (tr, J = 4.3 Hz, 2H), 3.11 (m, 2H), 3.51 (m, 2H) ), 3.59 (tr, J = 4.3 Hz, 2H), 3.83 (, 2H), 3.87 (2H), 3.96 (s, 1H), 4.56 (s, 1H), 6.72 (1H), 6.83 (1H), 7.15 (1H), 7.66 (brs, 4H), 9.06 (m, 1H) , 10.00 (brs, 1H) EXAMPLE 79 7- [1-5-nitropyridin-2-yl) piperidin-4-ylmethoxyl-l, 2,3,4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1-26 (m, 2H), 1.88 (m, 2H), 2.12 (m, 1H), 2.81 (tr, J = 6.0 Hz, 2H), 3.08 (m, 2H), 3.57 (tr, J = 6.0 Hz, 2H), 3.83 (d, 2H), 4.53-5.49 (m, 4H), 6.70 (tr, J = 2.4 Hz, 1H), 6.82 (dd, J = 2.4, 8.1 Hz, 1H), 6.95 (d, J = 9.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.60 (brs, 4H), 8.18 (dd, J = 3.0, 9.6 Hz, 1H), 8.94 (d, J = 3.0 Hz, 1H) EXAMPLE 80 7-H - (2-Nitrobenzyl) piperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.60-2.158m, 5H), 2.81 (m, 2H), 3.61 (m, 2H), 3.57 (m, 2H), 4.54-4.60 (m, 4H), 6.71 (1H), 6.82 (1H), 7.13 (1H), 7.62 (brs, 4H), 7.76 (tr, J = 7.9 Hz, 1H), 7.87 (tr, J = 7.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 10.27 (brs, 1H) EXAMPLE 81 7-f1- (2-amidinobenzyl) piperidin-4-ylmethoxyl-1, 2,3,4-tetrahydroisoquinoline -carboxamidine trichlorohydrate 1 H-NMR (d ppm, DMSO-de) 1.71 (m, 2H), 1.97 (m, 3H), 2.81 (m, 2H), 3.12 (m, 2H), 3.57 (m, 2H), 3.83 (m, 2H), 4.38 (m, 2H), 4.54 (s, 2H), 6.71 (1H), 6.83 (1H), 7.02 ( 1H), 7.13 (12H), 7.34 (1H9, 7.51) (1H), 7.61 (4H) EXAMPLE 82 7- (1-Hexanimidodopiperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 0.87 (tr, 3H), 1.31 (m, 6H), 1.52 (m, 2H), 1.90 (m, 2H), 2.12 (m, 1 H), 2.56 (m, 2H), 2.81 (m, 2H), 3.12 (m, 1 H), 3.26 (m, 1 H), 3.57 ( , 2H), 3.84 (m, 2H), 3.97 (m, 1 H), 4.16 (m, 1 H), 4.55 (s, 2H), 6. 70 (d, J = 2.4 Hz, 1 H), 6.82 (dd, J = 2.4, 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7. 64 (brs, 4H), 8.79 (1H), 9.25 (1H) EXAMPLE 83 N-Benzyl-4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-sulfonamide hydrochloride 1 H NMR (d ppm, DMSO-d 6) 1.19 (m, 2 H), 1.76 (m, 3 H), 2.61 (m, 2H), 2.81 (m, 2H), 3.55 (m, 4H), 3.77 (d, 2H), 4.08 (d, J = 6 Hz, 2H), 4.53 (s, 2H), 6.69 (d, J = 2.7 Hz, 1H), 6.81 (dd, J = 2.7, 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1 H), 7.22-7.34 (m, 5H), 7.53 (brs, 4H), 7.72 ( tr, J = 6 Hz, 1 H) EXAMPLE 84 N-Butyl-4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethylpiperidin-1-sulfanamide hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 0.85 (tr, 3H), 1.06-1.46 (m, 6H), 1.84 (m, 2H), 2.64 (m, 2H), 2.84 (m, 4H), 3.56 ( m, 4H), 3.81 (m, 2H), 4.53 (s, 2H), 6.69 (1H), 6.81 (m, 2H), 7.10-7.14 (m, 2H), 7.55 (brs, 4H) EXAMPLE 85 N-Cyclohexyl-4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethylpiperidin-1-sulfonamide hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.05-1.83 (m, 15H), 2.59 (m, 2H), 2. 81 (m, 2H), 2.95 (m, 1 H), 3.56 (m, 4H), 3.81 (m, 2H), 4.53 (s, 2H), 6.70 (1 H), 7.13 (m, 2H), 7.54 (brs, 4H) EXAMPLE 86 N- (2-nitropheni0-4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-carbothiamide hydrochloride 1 H-NMR (d ppm, DMSO-de) 1 -35 (m, 2 H), 1.85 (m, 2 H), 2.11 (m, 1 H), 2.82 (m, 2 H), 3.18 (m, 2 H), 3.57 (m, 2H), 4.54 (s, 2H), 4.73 (m, 2H), 6.73 (1H9), 6.84 (1H), 7.14 (1H), 7.34-7.42 (m, 2H), 7.55 (brs, 4H9), 7.66 (1 H), 7.94 (1 H), 9.62 (s, 1 H) EXAMPLE 87 7-f1- (Benzimidazol-2-yl) piperidin-4-ylmethoxy1-1, 2,3,4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.45 (m, 2 H), 1.93 (m, 3 H), 2 82 (m, 2 H), 3.57 (m, 2 H), 3.87 (m, 2 H), 4.23 (m , 2H), 4.54 (s, 2H), 6.72 (s, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.22-7.25 (m, 2H9), 7.39-7.42 (8m, 2H) 7.59 (brs, 4H), 13.46 (s) , 2H) EXAMPLE 88 3-f4-R4- (2-amidino-1.2.3.4-tetrahydroisoquinolin-7-yloxymethylpiperidin-1-yl) pyridin-3-yl-1-propionic acid ethyl ester dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.14 (tr, J = 7.2 Hz, 3 H), 1.44 (m, 2 H), 1.91 (m, 2 H), 2.09 (m, 1 H), 2.72-2.74 (m , 4H), 2.95 (m, 2H), 3.15 (m, 2H), 3.57 (m, 2H), 3.76 (m, 2H), 3.88 (m, 2H), 4.04 (q, J = 7.2 Hz, 2H9) , 4.54 (s, 2H9m), 6.72 (1H9, 6.8381 H), 7.14 (1H), 7.26 (1H), 7.60 (brs, 4H), 8.33 (m, 2H) EXAMPLE 89 3-R 4 -4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl dichloride. propionic 1 H-NMR (d ppm, DMSO-de) 1-46 (m, 2H), 1.90 (m, 3H), 2.59-2.87 (m, 8H), 3.57 (m, 2H), 3.88 (m, 2H), 4.53 (s, 2H), 4.53 (s, 2H), 6.72 (s, 2H), 6.84 (1H), 6.97 (1m9, 7.141H), 7.51 (brs, 4H), 8.25 (m, 2H) EXAMPLE 90 4- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl-1-f2-aminopyridin-5-ylcarbonylpiperidin-4-carboxylic acid hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.59 (m, 2 H), 2.07 (m, 2 H), 2.82 (m, 2H), 3.20 (, 2H), 3.59 (m, 2H), 4.01 (s, 2H), 4.51 (s, 2H), 6.69 (s, 1 H), 6.82 (d, J = 8.6 Hz, 1 H) , 6.91 (d, J = 9.2 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 7.48 (brs, 4H), 7.84 (dd, J = 2.1, 9.2 Hz, 1 H), 8.07 (d, J = 2.1 Hz, 1 H) EXAMPLE 91 4- (2-Amidino-1,2,3,4-tetrahydroisoouinolin-7-yloxymethyl-1- (3-aminopropionyl) piperidin-4-carboxylic acid dichloride. 1 H-NMR (d ppm, DMSO-d 6) 1.49 (m, 1 H), 1.59 (m, 1 H), 2.05 (m, 2 H), 2.71 (m, 2 H), 2.71 (m, 2 H), 2.81 ( m, 2H), 2.97 (m, 3H), 3.65 (m, 1H), 4.00 (m, 3H), 4.54 (s, 2H), 6.68 (s, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.66 (brs, 4 H), 7.98 (brs, 1 H) EXAMPLE 92 4-22-amidino-1,2,3,4-tetrahydroxyquinolin-7-yloxymethyl) -1- (irnidazol-4-ylacetylpiperidine-4-carboxylic acid dihydrochloride. 1 H-NMR (d ppm, DMSO-d 6) 1.51 (m, 1 H), 1.64 (m, 1 H), 2.06 (m, 2 H), 2.81 (m, 2 H), 3.01 (m, 1 H), 3.20 ( m, 1 H), 3.57 (m, 2H), 3.78 (m, 2H), 3.91 (s, 2H), 4.02 (s, 2H), 4.54 (s, 2H), 6.70 (s, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 4H), 7.43 (s, 4H), 7.55 (s, 1 H), 7.62 (brs, 4H), 9.01 (s, 1H) 14.36 (brs, 1H) EXAMPLE 93 4- (2-Amino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (piperidin-4-ylsulfamoyl-piperidin-4-carboxylic acid hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.62 (m, 4 H), 1.93 (m, 2 H), 2.11 (m, 2H), 2.78-3.00 (m, 6H), 3.17 (m, 2H), 3.36 (m, 3H), 3.57 (m, 2H), 3.99 (m, 2H), 4.53 (s, 2H), 6.69 (1H) ), 6.80 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.52 (d, 1H), 7.60 (brs, 4H), 8.85 (brs, 1H), 9.02 (brs) , 1 HOUR) EXAMPLE 94 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolip-7-yloxymethiO-l-dimethylaminoacetylpiperidin-4-carboxylic acid hydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.53-1.64 (m, 2H), 2.06 (m, 2H), 2.80 (m, 8H), 3.06 (m, 1H), 3.21 (m, 1 H), 3.50-3.59 (m, 3H), 4.29 (m, 2H), 4.55 (m, 2H), 6.70 (1 H), 6.81 (1 H), 7.14 (1 H), 7.65 (brs, 4H), 9.68 (brs, 1 H) EXAMPLE 95 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl-1- (pipidin-3-ylcarbamoyl) piperidin-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.16 (tr, J = 6.9 Hz, 3 H), 1.63 (m, 2 H), 2.10 (m, 8 H), 2.81 (tr, J = 5.7 Hz, 2 H), 3.17 (m, 2H), 3.57 (tr, J = 5.7 Hz, 2H), 3.99-4.05 (m, 4H), 4.14 (q, J = 6.9 Hz, 2H), 4.53 (s, 2H), 6.69 (d, J = 2.4 Hz, 1 H), 6.80 (dd, J = 2.4, 8.4Hz, 1 H), 7.13 (d, J = 8.4 Hz, 4H), 7.58 (brs, 4H), 7.91 (dd, J = 5.3 , 9.1 Hz, 1 H), 7.13 (brs, 4H), 7.91 (dd, J = 5.3, 9.1 Hz, 1 H), 8.46 (d, J = 5.3 Hz, 1H), 8.64 (d, J = 9.1 Hz , 1H), 9.15 (s, 1H), 9.93 (s, 1H).

EXAMPLE 96 Ethyl 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-carboxymethyl-1-dimethylaminoacetylpiperidin-2-lcarbonylpiperidine-4-carboxylic acid ethyl ester dihydrochloride. 1 H-NMR (d ppm, DMSO-d 6) 1.39 (tr, 3H), 1.40-2.09 (m, 10H), 2.79 (m, 10H), 3.49 (m, 2H), 3.56 (m, 2H), 3.65- 4.45 (m, 8H), 4.53 (s, 2H), 5.28 (m, 1 H), 6.68 (1 H), 6.79 (1 H), 7.14 (1 H), 7.58 (brs, 4H), 9.65 (brs) , 1 HOUR) EXAMPLE 97 4-f4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxirnethyl-4-carboxypiperidin-1-yl-1-methylpyridinium chloride hydrochloride 1 H-NMR (d ppm, DMSO-de) 1.15 (tr, J = 7.2 Hz, 3H), 1.72 (m, 2H), 2.17 (m, 2H), 2.81 (m, 2H), 3.40 (m, 2H) , 3.57 (m, 2H), 3.89 (s, 3H), 4.00-4.07 (m, 4H), 4.14 (q, J = 7.2 Hz, 2H), 4.53 (s, 1 H), 6.68 (1 H), 6.80 (1 H), 7.13 (1 H), 7.24 (d, J = 7.8 Hz, 2H), 7.64 (brs, 4H), 8.25 (d, J = 7.8 Hz, 2H) EXAMPLE 98 4- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (4-amidinophenyl) piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR (d ppm, DMS0-dβ) 1.14 (tr, J = 6.9 Hz, 3H), 1.69 (m, 2H), .14 (m, 2H), 2.81 (, 2H), 3.14 (m, 2H) , 3.56 (m, 3H), 3.82 (m, 2H), 4.05 (s, H), 4.13 (q, J = 6.9 Hz, 2H), 4.52 (s, 2H), 6.69 (1 H), 6.81 (1H) ), 7.07 (d, J = 9 Hz, H), 7.13 (1 H), 7.56 (brs, 4H), 7.75 (d, J = 9 Hz, 2H), 8.71 (brs, 2H), 8.97 (brs, H) EXAMPLE 99 4- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.16 (tr, J = 7.0 Hz, 3H), 1.71 (m, 2H), .17 (m, 2H), 2.44 (m, 6H), 2.82 (m , 2H), 3.56 (m, 2H), 3.99 (m, 2H), 4.09 (s, H), 4.16 (q, J = 7.0 Hz, 2H), 4.54 (s, 2H), 6.70 (1 H), 6.82 (d, J = 8.3 Hz, 1H), .98 (s, 2H), 7.15 (d, J = 8.3 Hz, 1 H), 7.59 (brs, 4H), 13.41 (brs, 1 H) EXAMPLE 100 4-.2-amidino-l, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1-.2-methylpyridin-4-ylpperidin-4-carboxylic acid ethyl ester hydrochloride. 1 H-NMR (d ppm, DMSO-de) 1.17 (tr, J = 7.0 Hz, 3 H), 1.73 (m, 2 H), (m, 2 H), 2.47 (s, 3 H), 2.83 (m, 2 H), 3.37-3.57 (m, 4H), 4.00-4.08 (m, 4H), (q, J = 7.0 Hz, 2H), 4.54 (s, 2H), 6.70 (1H), 6.82 (1H), 7.70-7.16 (m, 3H), (brs, 4H), 8.13 (1 H), 13.64 (brs, 1 H) EXAMPLE 101 4- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymetip-1- (1-ethylpperiod-4-yl. Piperidine-4-carboxylic acid ethyl trichlorohydrate. 1 H-NMR (d ppm, DMSO-de) 1.26-1.42 (m, 6H), 2.07-2.40 (m, 8H), -3.07 (, 7H), 3.50-3.70 (m, 5H), 3.96 (s, 2H ), 4.16 (q, 2H), 4.53 (s, 2H), (1H), 6.82 (1H), 7.57 (brs, 4H) EXAMPLE 102 4- (2-Amidino-, 2,3,4-tetrahydro-diazolinolin-7-yloxy-methyl-1- (1-ethyl-piperidin-4-yl) -piperidine-4-carboxylic acid trichlorohydrate. 1 H-NMR (d ppm, DMSO-de) 1 -25 (tr, 3H), 2.00--2.45 (m, 10H), 2. 80-33.30 (m, 10H), 3.97 (s, 2H), 4.56 (s, 2H), 6.74 (1H), 6.84 (1H), 7.16 (1H), 7.64 (brs, 4H), 10.76 (brs) , 1H), 11.34 (brs, 1 H) EXAMPLE 103 7-r2-r4-cyanopiperidin-4-yl) ethoxy1-1.2.3.4-tetrahydroisoquinolin-2-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-d 6) 1.92 (m, 2 H), 2.11 (m, 2 H), 2.19 (m, 2 H), 2.82 (m, 2 H), 2.93 (m, 2 H), 3.58 (m, 2H), 4.54 (m, 2H), 5.11 (s, 2H), 6.78 (s, 1 H), 6.85 (d, J = 6.3 Hz, 1 H), 7.16 (d, J = 6.3 Hz, 1 H) , 7.59 (brs, 4H), 9.26 (brs, 2H) EXAMPLE 104 4- [2- (2-Amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ether dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.19 (tr, J = 7.1 Hz, 3 H), 1.62 (m, 2 H), 2.05 (m, 2 H), 2.20 (m, 2 H), 2.82 (m, 2 H) , 3.27 (m, 2H), 3.58 (m, 2H), 3.58 (m, 2H), 3.97 (m, 2H), 4.06 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.55 (s, 2H), 6.65 (1H), 6.76 (1H), 7.14 (1H) ), 7.19 (d, J = 7.6 Hz, 2H), 7.60 (brs, 4H), 8.22 (d, J = 7.6 Hz, 2H) EXAMPLE 105 4- (2-Amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperdin-4-carboxylic acid dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.74 (m, 2 H), 2.18 (m, 2 H), 2.82 (m, 2 H), 3.44 (m, 2 H), 3.59 (m, 2 H), 3.72 (s, 3H), 4.404 (m, 2H), 4.49 (s, 2H), 6.69 (s, 1 H), 6.99 (s, 1 H), 7.21 (2H), 7.71 (brs, 4H), 8.23 (2H) EXAMPLE 106 4- (2-Amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dichloride. 1 H-NMR (d ppm, DMSO-de) 1.73 (m, 2H), 2.08 (s, 3H), 2.22 (m, 2H), 2.78 (m, 2H), 3.42 (m, 2H), 3.58 (m, 2H), 4.05 (m, 2H), 4.53 (s, 2H), 6.69 (s, 1H), 6.69 (s, 1H), 7.21 (2H), 7.71 (brs, 4H), 8.23 (2H) EXAMPLE 107 2-R4- (1-Acetimido-piperidin-4-ylxylphenoxymethi 11-1-benzylbenzimidazole-5-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.70 (m, 2H), 2.00 (m, 2H), 2.29 (s, 3H), 3.52 (m, 2H), 3.73 (m, 2H), 4.56 (m, 1 H), 5.42 (s, 2H), 5.69 (s, 2H), 6.93 (s, 4H), 7.17 (d, 2H), 7.28-7.33 (m, 3H), 7.71 (s, 2H), 8.23 (s, 1H), 8.77 (brs, 1 H), 9.12 (brs, 2H), 9.31-9.32 (m, 3H) EXAMPLE 108 2-R4- (1-Acetimidoylpiperidin-4-yloxy) phenoxymethyl-1-oxo-3-piperidinopropylbenzimidazole-5-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.30 (m, 4H), 1.49 (m, 2H), 1.70 (m, 2H), 1.99 (m, 2H), 2.27 (s, 3H), 2.90 (br, 2H), 3.21 (br, 2H), 3.34 (m, 2H), 3.53 (m, 2H), 4.60 (m, 3H), 5.47 (s, 2H), 6.96 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 8.23 (s, 1 H), 9.01 (brs, 2H), 9.25 (brs, 1 H), 9.30 (brs, 2H) EXAMPLE 109 N- [5-amidino-1- (3-phenyl-2-propenyl) benzimidazole-2-ylmethyl-N- [4- (1-acetimidoylpiperidin-4-yloxy) phenylcarbamoylbenzoic acid dihydrochloride] 1 H-NMR (d ppm, DMSO-de) 1.61 (m, 2H), 1.92 (m, 2H), 2.25 (s, 3H), 3.35-3.50 (m, 2H), 3.60-3.83 (m, 2H), 5.24 (s, 2H), 5.41 (s, 2H), 6.40-6.60 (m, 2H), 6.82 (2), 7.20 -7.38 (m, 9H), 7.73-7.76 (m, 3H), 7.87 (1 H), 8.24 (s, 1H), 8.74 (brs, 1 H), 9.10 (brs, 2H), 9.29 (brs, 3H) ) EXAMPLE 110 N-.5-amidinno-1- (cyclohexylcarbamoylmethylbenzimidazole-2-alkyl-N-4-r-famino (benzylimino) metillpiperidin-4-yloxy) phenylcarbamoylbenzoic acid dichlorhydrate. 1 H-NMR (d ppm, DMSO-de) 1.19 (m, 5H), 1.43-1.75 (m, 7H), 1.89 (m, 2H), 3.32 (m, 2H), 4.45 (d, 2H), 4.52 (m, 1 H), 5.16 (s, 2H), 5.32 (s, 2H), 6.80 (d, J = 5.7 Hz , 2H), 7.18 (d, J = 5.7 Hz, 2H), 7.25-7.38 (m, 7H), 7.707.78 (m, 6H), 8.18 (s, 1 H), 8.41 (m, 1 H), 8.56 (d, 1 H), 9.11 (brs, 2H), 9.32 (brs, 2H) EXAMPLE 111 N-.5-amidino-1- (cyclohexylcarbamoylrnethyl) benzimidazol-2-ylmethyl-N-.4- (1-acetylimidoylpperidin-4-yloxy) phenylcarbamoylbenzoic acid dihydrochloride 1 H-NMR (or ppm, DMSO-de) 1.21 (m, 5H), 1.45-1.80 (m, 5H), 5.18 (s, 2H), 5.40 (s, 2H), 6.98 (m, 4H), 7.35- 7.42 (m, 4H), 7.75 (s, 2H), 7.82 (m, 4H), 5.20 (s, 2H), 8.61 (brs, 1 H), 9.13 (m, 4H), 9.32 (brs, 4H) EXAMPLE 12 N-r5-amidino-1- (cyclohexylcarbamoylmethiobenzimidazol-2-ylmethyl-N-f4-ri- (N-ethylaminidino-piperidin-4-yloxyphenylcarbazylbenzoic acid) hydrochloride 1 H-NMR (or ppm, DMSO-d 6) 1.07-1.20 (m, 8H), 1.42-1.75 (m, 7H), 1. 87 (m, 2H), 3.15-3.35 (m, 4H), 4.50 (m, 1 H), 5.20 (s, 2H), 5.36 (s, 2H), 6.80 (2H), 7.18 (2H), 7.39 ( 2H), 7.62-7.85 (m, 7H), 8.18, 8.20 (1 H), 8.55 (1 H), 9.09, 9.19, 9.32, 9.38 (4H) EXAMPLE 113 1-Cyclohexylcarbamoylmethyl) -2-l4-methoxycarbonyl-1 - (pyridin-4-yl. Piperidin-4-ylaminomethyl-benzimidazole-5-carboxamidine dihydrochloride 1 H-NMR (d ppm, DMSO-de) 1.13-1.25 (, 5H), 1.53 (, 1 H), 1.64-4.72 (m, 4H), 1.82 (m, 2H), 2.01 (m, 2H), 3.49 (m, 1 H), 3.59-3.65 (, 5H), 3.75 (m, 2H), 3.99 (s, 2H), 5.06 (s, 2H), 7.18 (d, J = 5.5 Hz, 2H), 7.66- 7.72 (m, 2H), 8.15 (s, 1 H), 8.21 (d, J = 5.5 Hz, 2H), 8.30 (1 H), 9.02 (brs, 2H), 13.38 (brs, 1 H) EXAMPLE 114 1 -.Cyclohexylcarbamoylmethyl-2-r4-methoxycarbonyl-1- (pyridin-4-piperidin-1-capybamoipbenzimidazole-5-carboxarnidine dihydrochloride. 1 H-NMR (d ppm, DMSO-de) 1.06-1.30 (m, 5H), 1.54 (m, 1H), 1.70 (m, 4H), 2.11 (m, 2H), 2.25-2.33 (m, 2H), 3.41-3.62 (, 6H), 3.95 (m, 2H), 5.32 (s, 2H), 7.23 (2H), 7.80 (1 H), 7.89 (1 H), 8.20-8.26 (m, 4H), 9.18 (brs, 2H), 9.34 (brs, 2H), 9.55 (br, 1 H), 13.46 (brs, 1 H) EXAMPLE 115 (S) -N-.5-amidino-1 -. (1- phenylethylcarbamoylmethylbenzimidazole-1-yltrnetyl-N-r4- (1-acetylimidoylpiperidin-4-yloxy) phenylsulfamoylacetic acid dihydrochloride. 1 H-NMR (d ppm, DMSO-d 6) 1.41 (d, 3 H), 1.70 (m, 2 H), 2.00 (m, 2 H), 2.28 (s, 2 H), 3.50 (m, 2 H), 3.72 (m, 2H), 4.37 (s, 2H), 4.66 (m, 1 H), 4.90 (m, 1 H), 5.19 (brs, 4H), 6.95 (2H), 7.18-7.42 (m, 7H), 7.71 (s) , 2H), 8.12 (s, 1 H), 8.78 (brs, 1 H), 9.09 (brs, 2H), 9.30-9.33 (3H) TABLE 1 TABLE 1 (Continued) TABLE 3 TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLE 8 EXPERIMENTAL EXAMPLES The biological activity of the compound of the present invention was tested. The compound of the present invention was compared to a control compound, (25) -2- (4 - ((35) -1-acetimidoylpyrrolidin-3-yloxy) phenyl) .3. (7-amidinonaphthalen-2-yl) propionic acid hydrochloride pentahydrate of the following formula as a comparative example 1. Enzymatic inhibition test using synthetic substrate (experimental examples 1-2) EXPERIMENTAL EXAMPLE 1 Determination of anti-factor Xa activity (FXA) The human Fxa enzyme (Enzyme research Laboratories (EUA)) (40 μl, 0.16 U / ml) and the test compounds (40 μl) adjusted to various concentrations were incubated in a 0.1 M tris (tris-hydroxymethyl-aminomethane) regulator ( pH 8.4) containing 0.2 M sodium chloride (hereinafter referred to as tris buffer 0.1 M-NaCl 0.2 M (40 μL) at 37 ° C for 10 minutes.) A synthetic substrate S-2222 (Daiichi Pure Chemical (Tokyo, Japan) , _to____________ 40 μl) adjusted to 0.8 mM was added and the mixture was incubated at 37 ° C for 10 minutes. The reaction was determined by the addition of 60% acetic acid (40 μl) and the absorbance at 405 nm was measured with model 3550 (BIORAD) for control solvent was used instead of test compound. The control value was taken as 100% and the drug concentration with 50% absorbance of the control was taken as IC50. The results are shown in table 9.

EXPERIMENTAL EXAMPLE 2 Determination of anti-factor activity Ha (Row) The human Enzyme Fila (sigma) (40 μl, 3. U / ml) and the 40 μl test compounds adjusted to various concentrations were incubated in a 0.2 M tris buffer (pH 8.4, 4.40 μl) at 37 ° C for 10 minutes . A synthetic substrate S-2238 (Daiichi Puré Chemical) (Tokyo, Japan), 40 μl adjusted to 0.8 mM was added and the mixture was incubated at 37 ° C for 20 minutes. The reaction was determined by the addition of 60% acetic acid (40 μl) and the absorbance at 405 nm was measured with the model 3550 (BIORAD). For control, solvent was used instead of test compound. The control value was taken as 100% and the drug concentration, 50% absorbance of the control was taken as IC50 (Um). The results are shown in table 9.

TABLE 9 EXPERIMENTAL EXAMPLE 3 Determination of prothrombin time (PT) Blood was taken from mouse, rat, crab-eating monkey and healthy human volunteers and citric acid was added. The blood was centrifuged at 4 ° C and 2000 G for 15 minutes to obtain normal plasma from the various animals. Purified water (5 μl) containing various concentrations of the test compound was added to the plasma (45 μl) and the resulting mixtures were used as samples. The thrombin reagent (Baxter) was prepared and heated at 37 ° C for 5 minutes, and a sample was mixed (50 μl) * g ^^ with the thrombin reagent (100 μl). The time (PT) until the fibrin precipitation was measured. The concentration of drug that doubled the PT hours of the group not treated with drug was calculated and taken as CT2. The results are shown in table 10.

TABLE 10 INTRAVENOUS ADMINISTRATION TESTS (EXPERIMENTAL EXAMPLES 4-5) EXPERIMENTAL EXAMPLE 4 Tests for intravenous administration in mice A test test compound dissolved in physiological saline was intravenously administered to ICR mice (body weight 20-30 g, 4-6 weeks of age) and the activity of the test compound was evaluated based on the human Fxa inhibitory activity in the serum as an indicator.

At 10, 30, 60, 120 minutes of intravenous administration, blood was taken from the lacrimal using a hematocrit tube. The blood was centrifuged at 9000 G for 5 minutes and the serum obtained was used for the determination. The inhibitory activity of human Fxa was measured as follows.

The human enzyme Fxa (Enzyme Research Laboratories EUA) (40 μl, 0.5 U / ml) and a sample of plasma diluted 4 times (40 μl), was incubated in 0.2 M tris-NaCl 0.2 M buffer (pH 8.4, 40 μl) at 37 | C for 10 minutes. A synthetic substrate S-2222 (Daiichi Puré Chemical Tokyo, Japan, 40 μl) adjusted to 0.8 mm was added and the mixture was incubated at 37 ° C for 5 minutes. The reaction was stopped by reaction of 60% acetic acid (40 μl) and the absorbance at 405 Nm was measured with a model 3550 (Biorad). For control, serum or plasma obtained before blood sampling was used for measurement. The inhibitory activity of human Fxa was calculated as percentage of inhibition (%) against the control. The results are shown in table 11.

TABLE 11 EXPERIMENTAL EXAMPLE 5 Tests of intravenous administration in monkeys A test compound dissolved in physiological saline solution was administered intravenously to monkeys (crab-eating monkeys, body weight 3.5-4.5 kg) and the activity of the test compound was evaluated based on the human Fxa inhibitory activity in the plasma as indicator . At 10, 30, 60, 120 minutes of intravenous administration, blood was taken from the saphenous vein over time and the blood was centrifuged at 2 G for 10 minutes the plasma in citric acid obtained was used for the determination. The inhibitory activity of the Fxa was determined in the same way that using test mice the results are shown in Table 12.

TABLE 12 EVIDENCE OF ORAL ADMINISTRATION (EXPERIMENTAL EXAMPLES) EXPERIMENTAL EXAMPLE 6 Oral administration test in mice A test compound dissolved in distilled water was administered orally to ICR mice (body weight 20-30 g, 4-6 weeks of age) and the activity of the test compound was evaluated based on the inhibitory activity of human Fxa in serum as indicator . At 30, 60, 120, 180 minutes of oral administration, blood was taken from the lacrimal gland using a hematocrit tube. The blood was centrifuged at 9000 G for 5 minutes and the serum obtained for the determination was used. The inhibitory activity of human Fxa was determined in the same way as in the intravenous administration test. The results are shown in table 13.

TABLE 13 EXPERIMENTAL EXAMPLE 7 Tests of oral administration in monkeys A test compound dissolved in distilled water was administered to monkeys (crab-eating monkeys), body weight 3.5-4.5 kg) and the activity of the test compound was evaluated based on the human FXa inhibitory activity with plasma as an indicator. At 30, 60, 120, 240, 480 minutes of the oral administrat blood was taken from the saphenous vein with the passage of time and the blood was centrifuged at 2000 G for 10 minutes. The plasma obtained in citric acid was used for the determinat The inhibitory activity of human FXa was determined in the same way as in the test by administrat The results are shown in table 14.

TABLE 14 EXPERIMENTAL EXAMPLE 8 Blood coagulation model in rats Intravenous administration of thromboplastin (sigma) in rats promotes the coagulation system, which in turn decreases platelets and increases the fibrin degradation product (FDP), thus the test compound was administered intravenously 10 minutes before the administration of thromboplastin and the effects of the test compound on platelet depletion and the formation of FDP by thromboplastin were studied. The thromboplastin administered had sufficient concentration to form clots at 20 seconds after the addition of a dose of 1 ml / kg. The platelets (VALOR PLT) were counted 10 minutes later in a Sysmex f-800 blood cell counter (Dade International Inc. (E.UA)), and the FDP was measured 30 minutes later using FDP latex reagent for the soil ( Teikoku Hormone Mfg. Co., Ltd. (Tokyo, Japan)). The results are shown in table 15. In each example the PLT value of the PDF for this group was 0 ± 0 μg / ml.

TABLE 15 (mean ± D.E.) INDUSTRIAL APPLICABILITY The compound of the formula I of the present invention has a factor Xa inhibitor with superior blood coagulation activity, as is evident in the preceding experimental examples. Therefore, the compound is useful as an agent for the prophylaxis and / or treatment of various diseases caused by blood coagulation or thrombi, for example, cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, transient attack of ischemia (TIA). , subarachnoid hemorrhage and the like; ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis and the like; pulmonary vascular diseases such as pulmonary infarction, pulmonary embolism and the like; and diseases associated with various vascular disorders such as peripheral arterial embolism, post-thrombosis ______! ___________ artificial blood spleens surgery or replacement of artificial valves, reocclusion or restenosis after coronary commutation, reocclusion or restenosis after coronary commutation, reocclusion or restenosis after recanalization such as percutaneous coronary transluminal angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR) ) and similar, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger's disease, thrombosis thrombi by atrial fibrillation and the like. It is expected, therefore, that the compound of the present invention will become an extremely useful therapeutic agent for these diseases. This request is based on applications Nos. 116233/1998 and 237869/1998 filed in Japan, the contents of which are incorporated herein by reference.

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1. - An amidine compound of the formula I where R is a group of formula wherein R 4 is a hydrogen atom, hydroxy, lower alkyl, lower alkoxy or halogen atom, R 5 is hydrogen atom, cyano, carboxy or lower alkoxycarbonyl, R 6 is a hydrogen atom, cycloalkyl, hydroxy, ^ Ütt __________? carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl; wherein said aralkyloxycarbonyl is optionally substituted by halogen atom, nitro, alkyl, alkoxy or trifluoromethyl, nitro, amino, lower alkylamino, dialkylamino, aryl, heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents selected from alkyl lower, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, aralkyloxycarbonyl, nitro, amino, acylamino, amidino and hydroxyamidino; a saturated 5- to 7-membered heterocycle with at least one nitrogen atom, wherein said saturated heterocycle is optionally substituted by lower alkyl, acyl, dialkylamino lower alkanoyl or imidoyl; or wherein Ak is a lower alkyl and Hal is a halogen atom; X2 is an oxygen atom, sulfur atom, -S02-, SO2NH- or a single bond; X3 is - (CH2) -m- where m is 0 or an integer from 1 to 3; X4 is -CO-, C = NH-, -SO2-, -CONH-, -CSNH-, -SO2NH-, - (CH2) RCONH-, - (CH2) rCH (OH) -; where r is 0 or an integer from 1 to 3, or a single bond; X5 is an alkylene having 1 to 6 carbon atoms, an alkylene having 2 to 6 carbon atoms or a single bond; R7 is hydrogen atom, lower alkyl or ________________ wherein R9 is oxygen atom, sulfur atom, NH, NR11; wherein R 11 is lower alkyl, aralkyl; wherein said aralkyl is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl, hydroxy, lower alkoxy, haloalkyl, cyano, nitro, amino and acyloxy; or hydroxy; and R10 is lower alkyl, lower alkoxy, amino, lower alkylamino or lower dialkylamino; wherein R8 is hydrogen atom, lower alkyl, cycloalkyl; wherein cycloalkyl is optionally substituted by lower alkyl or carboxy; carboxy, lower alkoxycarbonyl, aryl, heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl wherein said lower alkyl is optionally substituted by halogen atom, hydroxy, lower alkoxy, carboxy, and lower alkoxycarbonyl; aralkyl wherein the aralkyl is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl, hydroxy, lower alkoxy, haloalkyl, cyano, nitro, amino and acyloxy; 0 a saturated 5- to 7-membered heterocycle with at least one nitrogen atom; Y1 is an oxygen atom, -NH-, -CONH-, -NR12-; wherein R12 is a lower alkyl 0 -Y6-R13; wherein R 13 is a hydrogen atom, lower alkyl or aryl; wherein said lower alkyl or aryl is optionally substituted by carboxy, lower alkoxycarbonyl or aralkyloxycarbonyl; Y6 is -CO-, -C02-, -COC02-, -S02-, -S02 (CH2) r or - (CH2) r-; in where r is 0 or an integer from 1 to 3; Or a simple link; And it is an oxygen atom, sulfur atom or a single bond; Y3 is: where s and t are the same or different and each is an integer from 1 to 3, or a single link; Y4 is oxygen atom, -CO-, CO2-, -S02-, -CONH-, -CH = CH- or a single bond; Y5 is - (CH2) P-, - (CH2) p-CHAk- (CH2) p-, - (CH2) P-CakAK- (CH2) p "-, wherein Ak, Ak 'are identical or different and each is a lower alkyl, p is 0 or an integer from 1 to 3, p' and p "are the same or different and each is 0 or an integer from 1 to 2 Or a simple link, ring A is: wherein R is carboxy, lower alkoxycarbonyl or aralkyloxycarbonyl wherein said aralkyloxycarbonyl is optionally substituted by halogen atom, nitro, alkyl, alkoxy, or trifluoromethyl; J is 1 or 2, k is 0 or 1 and M and n are the same or different and each is 0 or an integer from 1 to 3; and R1, R2 and R3 are the same or different and each is a hydrogen, hydroxy, lower alkyl or aryl atom; or a salt thereof or a prodrug thereof.
2. 2. The amidine compound of the formula I described in claim 1 wherein R is a group of the formula: wherein R 4, R 5, R 6, X 2, X 3, X 4, X 5, j and k are as defined above or a salt thereof or a prodrug thereof.
3. 3. The amidine compound described in claim 2 with the formula I wherein R is a group of the formula: wherein R 4, R 5, R 6, X 2, X 3, X 4, X 5, j and k are as defined above, or a salt thereof or a prodrug thereof. _________________ 4. - The amidine compound described in claim 3 with formula I wherein R is a group of the formula: wherein R 4, R 5, R 6, X 2, X 3, X 4, X 5, J and K are as defined above, or a salt thereof or a prodrug thereof. 5. The amidine compound described in claim 4 with formula I wherein X3 is - (CH2) - wherein m is as defined above and X4 is a group of the formula: and j is 1, or a salt thereof or a prodrug thereof. 6. The amidine compound described in claim 5 with formula I wherein R6 is a hydrogen atom, X2 is an oxygen atom and X5 is a single bond, or a salt thereof or a prodrug thereof. 7. The amidine compound of the formula I described in claim 1 wherein R is a group of the formula: . __. .__, wherein R7, R8, Y1, Y2, Y3, Y4, Y5, ring A, m and n are as defined above, or a salt thereof or a prodrug thereof. 8. The amidine compound described in claim 7 with formula I wherein ring A is a group of formula: or a salt thereof or a prodrug thereof. 9. The amidine compound of claim 1 selected from the group consisting of: 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (quinolin-4-yl) piperidin-4-ylmethoxy-1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-methyl-7- [1- (pyridine-4- ilo) p? peridin-4-ylmethoxy] -1, 2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-4-ylo) piperidin-4-ylmethoxy] -1, 2 , 3,4-tetrahydroisoquinoline-2-carboxamidine oxime, N-phenyl-7- [1- (pyridn-4-ylo) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline- 2-carboxamidine, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl (1-1-pyridin-4-yl) pipepdin-4-carboxylic acid ethyl ester 4- (2- amidipo-1, 2,3,4-tetrahydroxyquinolin-7-yloxymethyl (1-1-pyridin-4-yl) piperidin-4-carboxylic acid, ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinol) Nolin-7-yloxymethyl) -1- (2-6-d? Methylpyridin-4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroxy-quinolin-7-ylox) imethyl) -1- (2,6-dimethylpyridin-4-yl) piperidin-4-carboxylic acid methyl ester of 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) ) -1- (2-methylpyridin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroxyquinoline-7-) . * __,. -, * __ > -__ ? lox? met?) -1- (2-met? lp? pd? n-4-? lo) p? per? d? n-4-carboxylic acid, 4-2 (am? d? no-1 , 2,3,4-tetrahydro? Xoqu? Nol? N-7-? Lox? Met?) -1- (p? R? M? D? N-4-? Lo) p? Pepd? N -4-carboxylic acid ethyl ester 4- (2- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? (Et? L ) -1- (p? R? D? N-4-? Lo) p? Pepd? N-4-carboxyl? Co, 4- (2- (2-am? D? No-1, 2.3) , 4-tetrah? Dro? Xoqu? Nol? N-7-? Lox?) Et? L) -1- (p? R? M? D? N-4-? Lo) p? Per? D? N- 4- carboxylic acid 4- (N- (5-am? D? No-1- (1-phen? Let? Lcarbamo? Lmet? L) benz? M? Dazol-2-? Lmet? L) -N- (4- (1-acet? M? D? Lp? Per? D? N? 4-? Lox?) Fen? L) carbamo? L) benzo? Co, acid 4- (N- (5-am? D) ? no-1- (4-benz? lox? phen? let? lcarbamo? lmet? l) benz? m? dazol-2-? lmet? l) -N- (4- (1-acet? m? do? lp? per? d? n-4-? lox?) fen? l) carbamo? l) benzo? co, 2- (4- (p? rrol? d? n -3? lox?) fenox? met? l) -1- (2-methox? et? l) benz? m? dazol-5-carboxam? d? na, 2- (4- (1-acet? m? do? lp? rrol? d? n- 3-? Lox?) Fenox? Met? L) -1- (2-methox? Et? L) benz? M? Dazol-5-carboxamidine, 7- [1- (2-h? Rox? Et? L) p? per? d? n-4-? lmethox? j-1, 2,3,4-tetrahydro? so? nol? n-2-carboxam? d? na, 7- [1- (p? r ? d? n-4-? lmet? l) p? per? d? n-4-? lmethox?] - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, 7- [1- (2-h? rox? et ? l-2-fen? let? l) p? pepd? n-4-? lmetox?] - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, ethyl ester 4- (2-am? D? No-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-ylacetylglycine, 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-acetic acid N-methylamide, 7- (1-acet? lp? pepd? n-4-? lmetox?) - 1 , 2,3,4-tetrahydro? Soqu? Nohn-2-carboxamidine, 7- (1-benz? Lsulfop? Per? D? N-4-? Lmethox?) - 1, 2,3,4-tetrah Soil? socol? n-2-carboxam? d? na, 7- (1- (2-paft? lsulfon? l) p? per? d? n-4-? lmethox?) - 1, 2, 3,4-tetrahydro-so-quinol-2-carboxamide, 7- (1-acet? M? Do? Lp? Pepd? N-4-? Lmethox?) - 1, 2, 3,4-tetrahydroquinolone-2-carboxamide, 7- (1-fen? Lacet? M? Do? Lp? Pepd? N-4-? Lmethox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? P-2- carboxamidine, N- (2- (4- (2-am? d? no-1, 2,3,4-tetrah? ro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1 -? l) p? pd? p-5-? lo) acetam? a, N- (2- (4 (2-am? d? no-1, 2,3,4-tetrah? ro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-? l) p? pd? n-5-? llo) benzam? a, acid ethyl ester 3? - (4- (4- (2-am? D? No-1, 2,3,4-tetrah? Ro? Soqu? Nol? N-7-? Lox? Met? L) p? Pepd? P-1 -? l) p? pd? n-3-? lo) -2-propene? co, methyl ester of acid 4- (4- (2-am? d? no-1, 2,3,4-tetrah? dro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-? l) p? r? d? n-3-carboxylic acid, 4- (4- (2-am ? d? no-1, 2,3,4-tetrah? ro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-? l) p? pd? n-3 - carboxy, 6- (1- (p? pd? n-4-? l) p? per? d? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol ? -2-carboxam? D? Na, 7- (2- (4-c? Ano-1- (p? R? D? N-4-? L) p? Per? D? N-4-? ) ethoxy?) -1, 2,3,4-tetrahydro-so-quinol-2-carboxamide, ethyl ester of 4- (2-am? d? no-2,3, 4,5-tetrahydro-1 H-benzo (c) azep? Na-8-? Lox? Met? L) -1- (p? Pd? N-4-? L) p? Per? D? N -4-carboxylic acid, 4- (2-am? D? No-2, 3,4,5-tetrahydro-1 H-benzo (c) azep? Na-8-? Lox? Met ? l) -1- (p? pd? n-4-? l) p? pepd? n-4-carboxy co, 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7? lt? omet? l) -1- (p? r? d? n-4-? l) p? pepd? n-4-carboxylic acid, 4- (2- (2-am? d? no-1, 2,3,4, -tetrahydro? soqu? nol? n -7-? Lt? O) et? L) -1- (p? Pd? N-4-? L) p? Per? D? N-4-carboxylic acid, 4- (2-am? D? No) -1, 2,3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lt? Omet? L) -1- (p? Pd? N-4-? L) p? Per? D? n-4-carboxy, 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lt? omet? l) -1- (p? pd? n-4-? l) p? pepd? n-4-carboxylic acid methyl ester 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu ? nol? -7-? lsulfon? lam? no) -1- (p? pd? n-4-? l) p? pepd? n-4-carboxylic acid, 4- (2-am? d? no- 1, 2,3,4-tetrahydro? Soqu? Nol? -7-? Lsulfon? Lam? No) -1 - (p? Pd? N-4-? L) p? Pepd? N-4-carboxyhc , ethyl ester of 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7? lsulfon? lam? nomet) -1- (p. ? pd? n-4-? l) p? pepd? n-4-carboxylic acid, 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n- 7- ? lsulfon? lam? nomet? l) -1- (p? pd? n-4-? l) p? pepd? n-4-carboxylic, 1- (2- (benzot? azol-2-? l) - 2-ox? Et? L) -2-phenox? Met? Lbenc? M? Azol-5-carboxam? D? Na, trans-4- (2- (4- (1 -acet? M? O? Lp ? pepd? n-4-? lox?) fenox? met? l) -5-arn? d? nobenc? m? dazol-1-? lacet? lam? nomet?) c) clohexanecarboxylic acid, 4- (2- (4- (1 -acet? M? Do? Lp? Pepd? N-4-? Lox?) Fenox? Met? L) -5- (N-met? Lam? D? No) benc ? m? dazol-1-? lacet? lam? nomet) l? clohexanecarboxylate, trans-4- (2- (4- (1 -acet? m? do? lp? pepd? n-4- lox?) fenox? met? l) -5-am? no (hydrox? no?) met? lbenc? m? dazol-1-? lacet? lam? nomet?) c? clohexanecarboxylic, 2- (4- (p? Pepd? N-4-? Lox?) Phenox? Met? L) -1-phenane? -benzene? -olol-5-carboxam? D? Na, 2- (4- (1 -acet? m? do? lp? per? n-4-? lox?) fenox? met? l) 1-phenacenyl? -benz? dazole-5-carboxam? d? na, 2- (2- ( 4-ethoxycarbon? L-1- (p? R? D? N-4-? L) p? Pepd? N-4-? L) et? L) -1.? Clohex? Lcarbamo? Lmet? Lbenz m? dazol-5-carboxamidma, 4- (2- (5-am? d? no-1- (c? clohex? lcarbamo? lmet? l) benz? m? dazol-2-? l) et? l-1- (p? pd? n-4-? l) p? pepd? n-4-carboxy co, 1 -c? clohex? lcarbamo? let? l-2- (N- (1 - (p? pd? n- 4-? L) p? Pepd? N-4-? L) -N-ethoxal? Lam? Nomet) benz? M? Azol-5-carboxam? D? Na, N- (5-am? D) acid ? no-1-c? clohex? lcarbamo? lmet? lvenz? m? dazol-2-? lmet? l) -N- (1-p? pd? n-4-? l) p? pepd? n-4 -? l) aminooxa co, 2- (N- (4- (1 -acet? m? do? lp? pep? n-4-? lox?) phen? l) -N-ethoxy? carbon? lmet? lam ? nomet) -1-c? clohex? lcarbamo? lmet? lbenz? m? azol-5-carboxamidine, N- (5-am? d? no-1-c? clohex? lcarbamo? lmet? lbenz? m? dazol-2-? lmet? l) -N- (4- (1-acet? m? do? lp? per? d? n-4-? lox?) fep? l) carbamoylbenzoic, 2- (N - (4- (1-am? Nop? Per? D? N-4-? Lox?) Phen? L) -N- (4-methox? Carbon? Lbenzo? L9am? Nomet? L-1-c? Clohex lcarbamo? lmet? lbenz? m? azol-5-carboxam? d? na, N- (5-amin? d? no-1-c? clohex? lcarbamo? lmet? lbenz? m? azol-2? lmet? l) -N- (4- (1-am? d? nop? pepd? n-4-? lox?) fen? l) carbamoylbenzoic acid, N- (5-am? d? no-1-) cyclohexylcarbamoylmethylbenzimiazole _-? lmet? l) -N- (4- (1-am? d? nop? pepd? n-4-? lox?) fen? l) carbamoylbenzoic acid, 7- (1- (p? r? d ? n-4-? lacet? l) p? pepd? n-4-? lmethox?) -1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, 7 - (1- (3-am? Nobenz? L) p? Pepd? N-4-? Lmetox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? na, 7- (1- (2-am? nobenz? l) p? pepd? n-4-? lmetox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxamidma , 7- (1- (p? Pd? N-2-? Lmet? L) p? Per? D? N-4-? Lmethox?) - 1, 2,3,4-tetrahydro? Soqu? Nol ? n-2-carboxam? d? na, methyl ester of acid 2- (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-? lmet? l)? ndol-1-carbox? l? co, acid benzyl ester (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-acet? co, N-benz? l (4- (2-am? d? no-1, 2.3, 4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-carboxam? Da, 7- (1 - (? Ndol-2-? Lmet? l) p? pepd? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, 4- (2-am? d) acid ? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) p? per? d? n? 1-acetic, N-benc? l-4 - (2-am? D? No-1, 2,3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met?) P? Per? D? N-1-carboxam? da, acid 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1- ilacetylammoacetic, 7- (1- (5-n? trop? r? d? n-2-? l) p? per? d? n-4-? lmethox?) - 1,2,3,4-tetrah? dro? soqu? nol? n-2-carboxamidina, 7- (1- (2-n? trobenz? l) p? per? d? n-4-? lmetox?) - 1, 2,3,4-tetrah Soil? Socol? n-2-carboxam? d? na, 7- (1- (2-n? trobenz? l) p? pepd? n-4-? lmethox?) - 1, 2,3, 4-tetrahydroquinolone-2-carboxamide, 7- (1-hexane? M? Do? Lp? Per? D? N-4-? Lme tox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, N-benzyl-4- (2-am? d? no-1, 2 , 3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-sulfonam? Da, N-but? L-4- (2-am) ? d? no-1, 2,3,4-tetrah? ro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-sulfonam? da, N-cx? clohex? l-4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox?) p? pepd? n-1- sulfonamide, N- (2-n? trofen? l) -4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-carbot? oam? da, 7- (1- (benz? m? dazol -2-? l) -p? pepd? n-4-? lmetox?) - 1 , 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, ethyl ester of 3- (4- (4- (2-am? D? No-1, 2, 3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-propionic, ethyl ester of acid 3- (4- (4- (2 -am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-prop? on? co , acid 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met?) -1- (2-am? nop) ? r? d? n-5? lcarbon? l) p? per? d? n-4-carboxylic, acid 4- (2-am? d? no-1, 2,3,4, -tetrah? dro Soqu? nol? n-7-? lox? met? l) -1- (3-am? noprop? on? l) p? pepd? n-4-carboxy, acid 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met?) -1 - (? m? dazol-4-? lacet? l) p? per? d? n-4-carboxylic acid, 4- (2-am? d? no-1, 2,3,4, -tetrahydro? soqu? nol? n-7-? lox? met?) -1 - (p? per? d? n-4-? lsulfamo? l) p? pepd? n-4-carboxylic acid, 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) -1-d? met? lam? noacet? lp? pepd? n 4-carboxy, ethyl ester of 4- (2-am? D? No-1, 2,3,4, -tetrahydro? So? Nol? N-7-? Lox? Met? L) - 1- (p? R? D? N -3? Lcarbamo?) P? Per? D? N-4-carboxy, ethyl ester of 4- (2-am? D? No-1, 2, 3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met? L) -1- (1-d? Met? L? Noace? Lp? Per? D? N-2-? Lcarbon ? l) p? pepd? n-4-carboxyl? co, 4- (4- (2-am? d? no-1, 2,3,4, -tetrahydro? soqu? nol? n- chloride) 7-? Lox? Met?) -4-carbox? P? Pepd? N-1-? L) -met? Lp? Pd? N? O, ethyl ester of 4- (2-am? D? No) -1, 2,3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met?) -4-am? D? Nofen? L) p? Per? D? N-4- carboxylic acid ethyl ester 4- (2-am? d? no-1, 2,3,4, -tetrahydro? soqu? nol? n-7-? lox? met? l) - 1- (2,6-d? Met? Lp? R? D? N-4-? L) p? Per? D? N-4-carboxyl? Co, ethyl ester of 4- (2-am? D) acid ? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) -1- (2-met? lp? r? d? n-4-? l) -p? pend? n-4-carboxylic acid ethyl ester of 4- (2-am? d? no-1, 2,3,4, -tetrahydro? soqu? nol? n-7- ? lox? met?) -1- (1-et? lp? pepd? n-4-? l) p? pepd? n-4-carbox? l? co, acid 4- (2-am? d? no-1, 2,3,4, -tetrah? dro? soqu? nol? n-7-? lox? met? l) -1- (1-et? lp? pepd? n-4-? l) p ? pepd? n-4-carboxylic, 7- (2- (4-c? anop? per? d? n-4-? letox?) - 1, 2,3,4, -tetrahydro? soqu? nol n-2-carboxamidine, ethyl 4- (2- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox) ethyl ester) et? l) p? r? d? n-4-? l) p? per? d? n-4-carboxyl? co, 4- (2-am? d? no-6-methox? -1, 2,3,4, -tetrah? Dro? Soqu? Nol? N-7-? Lox? Met? L) -1- (p? Pd? N-4? L) p? Per? D? N-4- carboxylic acid and 4- (2-am? d? no-6-met? l-1, 2,3,4, -tetrahydro? soqu? nol? n-7-? lox? met?) -1 - (p? r? d? n-4? l) p? per? d? n-4-carboxylic acid, or a salt thereof or a prodrug thereof 10 - The amidine compound of claim 3 which is select from the group consisting of 7- [1- (p? r? d? n-4-? lo) p? per? d? n-4-? lmethox?] - 1, 2,3,4-tetrahydro Soco-nol? -2-carboxam? d? na, 7- [1- (qu? nol? n-4-? lo) p? per? d? n-4-? lmetox?] - 1, 2 , 3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, N-met? L-7- [1- (p? R? D? N-4-? Lo) p? pepd? n-4-? lmetox?] - 1 , 2,3,4-tetrahydroisoquinoline -2-carboxamide, 7- [1- (p? Pd? N-4-? Lo) p? Per? D? N-4-? Lmethox?] - 1 , 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na oxime, N-phen? L-7- [1- (p? R? D? N-4-? Lo ) p? pepd? n-4-? lmetox?] - 1 2 3 4-tetrahydro? soqu? nol? n-2-carboxam? d? na, ethyl ester of acid -4- (2-am? d) ? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l (1-p? pd? n-4-? lo) p? per? d? n -4-carboxyl? Co 4- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) -1- (p. ? r? d? n-4-? lo) p? pepd? n-4- carboxy, ethyl ester of acid 4- (2-am? d? no-, 1, 2,3,4-tetrah? dro? soqu? nol? n-7-? lox? met? l) -1- (2,6-d? met? lp? pd? n-4-? lo) p? per? d? n-4- carboxylic acid, 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met?) (2-met? lp? r? d? n-4-? lo) p? per? d? n-4-carboxylic acid methyl ester -4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu nol? n-7-? lox? met? l) (2-met? lp? pd? n-4-? lo) p? pepd? n-4- carboxylic acid, 4- (2- (am? d? n? o-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) -1- (2- met? lp? r? d? n-4-? lo) p? pepd? n-4- carboxihco, acid 4- (2- (am? d? n? o-1, 2,3,4-tetrah? dro? soqu? nol? n-7-? lox? met? l) -1- (p? r? d? n-4-? lo) p? per? d? n-4-carboxylic acid ethyl ester 4 - (- 2 (-2 (am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox?) Et? L) -1- (p? R ? d? n-4-? l) p? pepd? n-4-carbox? l? co, acid 4- (2 - (- 2- (am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox?) et? l) -1- ( p? r? d? n-4-? l) p? per? d? n-4-carboxylic, 7- [1- (2-h? drox? et? l) p? per? d? n-4 -? lmetox?] - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, 7- [1- (p? pd? n-4-? lmet? l ) p? per? d? n-4-? lmethox?] - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxamidine, 7- [1- (2-h? drox? -2-fen? Let? L) p? Pepd? N-4-? Lmetox?] - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, ethyl ester of 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-? lacet? lgl? c? na, acid 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? pepd N-1-acetic acid N-methylamide, 7- (1-acetyl-p-pepd? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2- carboxam? da, 7- (1-benz? lsulfon? lp? pepd? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n -2-carboxamidine, 7- (1- (2-naphth-lsulfon? L) p? Pepd? N-4-? Lmethox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na , 7- (1-acet? M? Do? Lp? Pepd? N-4-? Lmetox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na , 7- (1-fen? Lacet? M? Do? Lp? Pepd? N-4-? Lmethox?) - 1, 2,3,4-tetrah? D ro? soqu? nol? n-2-carboxam? d? na, N- (2- (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n -7-? Lox? Met? L) p? Per? D? N? 5-? It) acetam? Da, N- (2- (4- (2-am? D? No-1, 2,3, 4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N? 5-? Lo) benzam? Da, ethyl ester of acid 3- (4- (4- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-? L) p ? pd? n-3-? lo) -2-propene? co, 4- (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol) methyl ester ? n-7-? lox? met? l) p? per? d? n-1-? l) p? pd? n-3-carboxylic acid, 4- (4- (2-am? d? no- 1, 2,3,4-tetrahydro? Soqu? Nol? N-7- ? lox? met?) p? pepd? n -3-carboxy co, 6- (1-p? r? d? n-4-? l) p? per? dm-4-? lmetox?) - 1 , 2,3,4-tetrahydro? Soqu? Nol? N-2carboxam? D? Na, 7- (2- (4-c? Ano-1- (p? R? D? N-4-? ) p? per? d? n-4-? l) ethoxy?) - 1, 2,3,4 tetrahydro? soqu? nol? n-2-carbox? m? d? na, ethyl ester of acid 4- (2-am? D? No-2,3,4,5-tetrahydro-1 H-benzo (c) azep? N-8-? Lox? Met? L) -1p? R? D? N- 4-? L) p? Pepd? N-4 -carboxylic acid, 4- (2-am? D? No -2,3,4,5-tetrahydro-1 H-benzo (c) azep? N- 8-? Lox? Met?) -1 p? Pd? N-4-? L) p? Pepd? N-4-carboxylic acid, 4- (2-am? D? No-1, 2,3, 4-tetrahydro? Soqu? Nol? N-7-? L? Omet? L) -1- (p? Pd? N-4-? L) p? Pepd? N-4-carboxyl, acid 4- ( 2- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lt? O) -1- (p? Per? D? N-4- ? l) p? per? d? n-4-carboxylic acid, 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7? lsulfon? lmet? l) -1- (p? r? d? n-4-? l) p? per? d? n-4-carboxylic acid, 4- (2- (2-am? d? no-1, 2,3,4-tetrahydro-soqu? Nol? N-7-? Sulfon? L) et? L) -1- (p? Pd? N-4-? L) p? Pepd? N-4- carboxylic acid ethyl ester 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? sulfon? lam?) -1- (p? r ? d? n-4-? l) p? per? d ? n-4-carboxylic acid, 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? sulfon? lam? no) -1- (p? R? D? N-4-? L) p? Per? D? N-4- carboxylic acid ethyl ester 4- (2-am? D? No-1, 2.3, 4-tetrahydro? Socolol? N-7-? Sulfon? Lam? Nomet? L) -1- (p? Pd? N-4-? L) p? Pepd? N-4-carboxy co, acid 4- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Sulfon? La? Nomet?) -1- (p? R? D? n-4-? l) p? pepd? n-4-carboxylic, 7- (1- (p? r? d? n-4-? lacet? l) p? pepd? n-4-? lmetox?) -1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, 7- (1- (3-am? Nobenc? L) p? Pepd? N-4-? lmetox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboximidine, 7- (1- (2-hydrox? benc? l) p? per? d? n- 4-? Lmethox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? D? Na, 7- (1-p? Pd? N-2-? Lmet? L ) p? pepd? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, methyl ester of acid 2- (4- ( 2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Pepd? N-1- ? lmet? l)? ndol-1-carboxylate, benzyl ester of acid (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n- 7-? Lox? Met? L) p? Per? D? N-1-acet? Co, N-benz? L (4- (2-am? D? No-1, 2,3,4-tetrah? dro? soqu? nol? n-7-? lox? met? l) p? pend? n-1-carboxam? da, 7- (1-? nd? l-2-? lmet? l) p? pepd? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxam? d? na, 4- (2-am? d? no-1, 2 , 3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Pepd? N-1-acetic, N-benzyl (4- (2-am? D? No -1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-acetam? Da, acid 4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1- ilacetilammoacetico, 7- (1- (5-n ? trop? r? d? n-2-? l) p? per? d? n-4-? lmethox?) -1, 2,3,4-tetrahydro? soqu? nol? n-2-carboxamidine , 7- (1- (2-n? Trobenc? L) p? Pepd? N-4-? Lmetox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2-carboxam? d? na, 7- (1- (2-am? nobenc? l) p? per? d? n-4-? lmethox?) - 1, 2,3,4-tetrahydro? soqu? nol? n -2-carboxam? D? Na, 7- (1-hexane? M? Do? Lp? Per? D? N-4-? Lmethoxy?) - 1,2,4-tetrahydro? Soqu? Nol? n-2-carboxamidine, N-benzyl-4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n- 7-? Lox? Met? L) p? Pepd? N-1-sulfonamide, N-but? L-4- (2-am? D? No-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? pepd? n-1-sulfonamide, N? clohex? l-4- (2-am? d? no-1, 2.3, 4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-sulfonam? Da, N- (2-n? Trofen? L) -4- ( 2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met? L) p? Per? D? N-1-carbothioamide, 7- ( 1- (benz? M? Dazol-2-? L) -p? Per? D? N-4-? Lmethox?) - 1, 2,3,4-tetrahydro? Soqu? Nol? N-2- carboxam? d? na, ethyl ester of acid 3- (4- (4- (2-am? d? no-1, 2,3,4-tetrahydro? soqu? nol? n-7-? lox? met? l) p? per? d? n-1-prop? on? co, acid 3- (4- (4- (2-am? d? no-1, 2,3,4-tetrahydro? so? nol? n-7-? lox? met? l) p? per? d? n-1-? l) p? r? d? n-3-?) prop? on? co, acid 4- (2-am? D? No-1, 2,3,4-tetrahydro? Soqu? Nol? N-7-? Lox? Met?) -1- (2 am? Nop? Pd? N -5- ? lcarbon? l) p? per? d? n-4- carboxylic acid, 4- (2-am? d? no-1, 2,3,4- tetrahydroisoquinolin-7-yloxymethyl) -1- (3-aminopropionyl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) 1- (imidazole-4 -acetyl) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolyl-7-yloxymethyl) -1- (piperidin-4-ylsulfamoyl) piperidine-4-carboxylic acid, acid 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1-dimethylaminoacetylpiperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-3-ylcarbamoyl) piperidine-4-carboxylic acid ethyl ester, 4- (2-ethyl) ethyl ester -amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-dimethylaminoacetylpiperidin-2-ylcarbonyl) piperidin-4-carboxylic acid, 4- (4- (2-amidino-1 , 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -4-carboxypiper-din-1-yl) -methylpyridino, ethyl ester of 4- (2-amidino-1, 2,3,4-tetrahyl) droisoquinolin-7-yloxymethyl) -4-amidinophenyl) piperidine-4-carboxylic acid 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2, 6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- ( 2-methylpyridin-4-yl) piperidine-4-carboxylic acid 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) ethyl ester ) piperidine-4-carboxylic acid, 4- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxim) ethyl) -1 - (- 1-ethylpiperidin-4-yl) piperidine-4-carboxylic acid, 7- (2- (4-cyanopiperidin-4-yl) ethoxy) -1,2, 2,3,4-tetrahydroisoquinoline-2-carboxamidine , ethyl 4- (2- (2-amidino-1, 2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl) pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester, 4- (2- amidino-6-methoxy-1, 2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, and 4- (2-amidino-6-methyl-1) , 2,3,4- tetrahydroisoquinolin-7-oxoxymethyl) -1- (pyridin-4-yl) -piperidine-4-carboxylic acid, or a salt thereof or a prodrug thereof. 11. A pharmaceutical composition comprising an amidine compound of any of claims 1 to 10 or a salt thereof or a prodrug thereof and a pharmaceutically acceptable additive. 12. A blood coagulation inhibitor comprising an amidine compound of any one of claims 1 to 10 or a salt thereof or a prodrug thereof as an active ingredient. 13. A factor Xa inhibitor comprising an amidine compound of any of claims 1 to 10 or a salt thereof or a prodrug thereof as an active ingredient. 14. An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombi comprising an amidine compound of any of claims 1 to 10 or a salt thereof or a prodrug thereof as an active ingredient. 15. The use of an amidine compound as claimed in any of claims 1 to 10 or a salt thereof or a prodrug thereof for the production of a blood coagulation inhibitor. 16. The use of an amidine compound as claimed in any of claims 1 to 10 or a salt thereof or a prodrug thereof for the production of a factor Xa inhibitor. 17. The use of an amidine compound as claimed in any of claims 1 to 10 or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombi. 18. A commercial package comprising the blood coagulation inhibitor according to claim 12 and written information related thereto, written information indicating that the inhibitor can or should be used to inhibit blood coagulation. 19.- A commercial package that includes the factor inhibitor Xa according to claim 13 and written information related thereto, written information indicating that the inhibitor can or should be used to inhibit factor Xa. 20. A commercial package comprising the agent for the prophylaxis or treatment according to claim 14 and written information related thereto, the written information indicating that the agent can or should be used for the prophylaxis or treatment of diseases caused by coagulation of blood or thrombi. SUMMARY OF THE INVENTION A compound of the formula I wherein R1, R2 and R3 are the same or different and each is a hydrogen atom, hydroxy, lower alkyl or aplo, R is a group of the formula wherein each symbol is as defined in the specification, a salt thereof or a prodrug thereof; the compound of the present invention, a salt thereof or a prodrug thereof are useful as an inhibitor of Factor Xa and blood coagulation inhibitor, and are useful for the prophylaxis and / or treatment of diseases caused by blood coagulation or thrombi. TAKASHIMA / TE All * P00 / 1382F __________i