AMIDINE COMPOUNDS

Abstract: A compound of the formula [I] wherein R 1 , R 2 and R 3 are the same or different and each is hydrogen atom, hydroxy, lower alkyl or aryl, R is a group of the formula or 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 and a prodrug thereof are useful as factor Xa inhibitor and blood coagulation inhibitor, and are useful for the prophylaxis and/or treatment of diseases caused by blood coagulation or thrombus.

Description: FIELD OF THE INVENTION The present invention relates to a novel amidine compound having a blood coagulation factor Xa inhibitory activity. The present invention also relates to a pharmaceutical composition, a factor Xa inhibitor and a therapeutic agent for the diseases caused by blood coagulation or thrombus, 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 promotion of blood coagulation. For the prophylaxis and treatment of thrombus, 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 thrombus. Heparin is associated with generation of an antibody against platelet factor (PF4), which promotes coagulation in some patients, and a propensity toward hemorrhage as a side effect Warfarin requires longer time for the expression of the drug effect and is not necessarily an easy and safe drug. Under the circumstances, a new anticoagulant is desired to overcome these problems. The factor X is a glycoprotein having a molecular weight of 58,000, and in an intrinsic pathway, the factor X is activated on a phospholipid membrane in the presence of a factor IXa/factor VIIIa/Ca 2+ complex and becomes factor Xa. In the coagulation system called extrinsic pathway, factor X is activated by factor VIIa in the presence of a tissue factor and becomes factor Xa. The factor Xa generated in the both pathways activates prothrombin to give thrombin. The generated thrombin further activates the upstream of this cascade to produce a large amount of thrombin. Consequently, fibrinogen becomes fibrin and coagulation of blood occurs. Inasmuch as the blood coagulation system is an amplification reaction, inhibition of generation of thrombin in the early stage is considered to be more efficient than direct inhibition of the activity of the generated thrombin. In addition, since factor Xa is the confluence of intrinsic and extrinsic coagulation pathways, inhibition of factor Xa is considered to be extremely effective. Some reports have documented that low molecular weight heparin showed a lower tendency of bleeding than heparin in clinical applications, and in a test using baboon (Thrombosis and Haemostas, 74, 464 (1995)), it was found that inhibition of factor Xa rather than thrombin showed less tendency of bleeding. Therefore, a factor Xa inhibitor has a potential of showing antithrombus effect without influencing the bleeding time observed in the use of conventional anticoagulants. As a factor Xa inhibitor, WO97/08165 discloses a compound of the formula wherein R 1 , R 2 and R 3 are each hydrogen atom, hydroxy, halogen atom, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkoxy, aralkyloxy, alkenyloxy, alkynyloxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkenyloxycarbonylalkyl or alkynyloxycarbonylalkyl, A is alkylene optionally substituted by hydroxy, carboxy, alkoxycarbonyl or halogen atom, X is a bond, alkylene or alkyleneoxy, Y is a single bond, chalcogen atom or CO, Z is a saturated or unsaturated optionally substituted hetero ring or carbon ring, optionally substituted amino, hydroxy, carboxy, alkoxycarbonyl or alkyl, n is an integer of 1 or 2, and m is an integer of 0 to 4. In addition, Japanese Patent Unexamined Publication No. 5-208946 (US Patent No. 5620991, EP No. 540051) discloses a compound of the formula wherein R 1 is hydrogen atom or lower alkoxy, R 2 is hydrogen atom, lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, R 3 is hydrogen atom, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, carboxyalkoxy or alkoxycarbonylalkoxy, R 4 is hydrogen atom, hydroxy, lower alkyl or lower alkoxy, n is an integer of 0 or 1, A is C 1 -C 4 alkylene optionally substituted by 1 or 2 substituents from hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl, X is a single bond, oxygen atom, sulfur atom or carbonyl, Y is optionally substituted saturated or unsaturated 5 or 6-membered heterocyclic group or cyclic hydrocarbon group, optionally substituted amino or optionally substituted aminoalkyl, and a group of the formula is selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl. Furthermore, WO96/16940 discloses a compound of the formula wherein R 1 is hydrogen atom or a group of the formula -A-W-R 4 wherein A is a group of the formula or -SO 2 - wherein X 2 is oxygen atom or sulfur atom, and W is a single bond or -NR 5 -, R 4 is hydroxy, lower alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, with the proviso that when W is a group of the formula -NR 5 -, R 4 may be hydrogen atom but is not hydroxy or lower alkoxy; wherein R 5 is hydrogen atom, carbamoyl, lower alkoxycarbonyl, mono- or di(lower)alkylaminocarbonyl, lower alkylsulfonyl, mono- or di(lower)alkylaminothiocarbonyl, optionally substituted lower alkyl or optionally substituted lower alkanoyl; R 2 is lower alkyl; R 3 is hydrogen atom, halogen atom, carboxy, amino, cyano, nitro, hydroxy, lower alkoxy, lower alkyl or lower alkoxycarbonyl; B is lower alkylene or carbonyl; and n is an integer of 0 or 1. DISCLOSURE OF THE INVENTION The present invention aims at providing a novel compound useful as a factor Xa inhibitor. The present invention also aims at providing a novel factor Xa inhibitor. In view of the above situation, the present inventors conducted intensive studies in an attempt to find a compound useful as a factor Xa inhibitor and found the amidine compound of the following formula [I]. They have further found that the compound can be a superior factor Xa inhibitor and completed the present invention. The compound of the present invention specifically inhibits blood coagulation factor Xa and shows strong anticoagulation action. Therefore, the compound is useful as an agent for the prophylaxis and/or treatment of various diseases caused by blood coagulation or thrombus, namely, cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (TIA), subarchnoid 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 caused by various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after recanalization such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR) and the like, thrombosis due to extracorporeal circulation and the like, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger disease, tumor thrombosis, thrombus by atrial fibrillation, and the like. As is evident from Experimental Example 2 to be mentioned later, since the compound of the present invention does not have inhibitory activity against thrombin, namely, factor IIa (FIIa), hemorrhage as a side effect is considered to be noticeably less. Experimental Examples 6 and 7 to be mentioned later reveal striking factor Xa inhibitory effect by oral administration. There is also a finding that factor Xa is involved in the growth of influenza virus (Japanese Patent Unexamined Publication No. 6-227971). Thus, the compound of the present invention is expected to be useful for the prophylaxis and/or treatment of influenza. The present invention relates to a compound of the following formula [I], which is useful as a factor Xa inhibitor. In addition, the present invention relates to a factor Xa inhibitory agent containing a compound of the following formula [I] or a salt thereof or a prodrug thereof as an active ingredient. More particularly, the present invention provides the following (1)-(19). (1) An amidine compound of the formula [I] wherein R is a group of the formula or wherein R 4 is hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group or halogen atom, R 5 is hydrogen atom, cyano group, carboxy group or C 1-6 alkoxycarbonyl group, R 6 is hydrogen atom, C 3-10 cycloalkyl group, hydroxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )oxycarbonyl group wherein said C 6-12 aralkyl(C 1-6 )oxycarbonyl group is optionally substituted by halogen atom, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group or trifluoromethyl group, nitro group, amino group, C 1-6 alkylamino group, di(C 1-6 )alkylamino group, C 6-12 aryl group, heteroaryl group selected from a 5- or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and may form a condensed ring with other ring that may be partially saturated wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl group, hydroxy group, C 1-6 alkoxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )oxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group, 5- to 7-membered saturated heterocycle having at least one nitrogen atom, wherein said saturated heterocycle is optionally substituted by C 1-6 alkyl group, acyl group, di(C 1-6 )alkylamino(C 1-6 )alkanoyl group or imidoyl group, or wherein Ak is C 1-6 alkyl group and Hal is halogen atom, X 2 is oxygen atom, sulfur atom, -SO 2 -, -SO 2 NH- or a single bond, X 3 is -(CH 2 ) m - wherein m is 0 or an integer of 1 to 3, X 4 is -CO-, -C(=NH)-, -SO 2 -, -CONH-, -CSNH-, -SO 2 NH-, -(CH 2 ) r CONH-, -(CH 2 ) r CH(OH)-, wherein r is 0 or an integer of 1 to 3, or a single bond, X 5 is alkylene group having 1 to 6 carbon atoms, alkenylene group having 2 to 6 carbon atoms, or a single bond, R 7 is hydrogen atom, C 1-6 alkyl group or wherein R 9 is oxygen atom, sulfur atom, NH, NR 11 wherein R 11 is C 1-6 alkyl group, C 6-12 aralkyl(C 1-6 )group wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group, hydroxy group, C 1-8 alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group, or hydroxy group, and R 10 is C 1-6 alkyl group, C 1-6 alkoxy group, amino group, C 1-6 alkylamino group or di(C 1-6 )alkylamino group, R 8 is hydrogen atom, C 1-6 alkyl group, C 3-10 cycloalkyl group wherein said cycloalkyl group is optionally substituted by C 1-6 alkyl group or carboxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aryl group, heteroaryl group selected from a 5- or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and may form a condensed ring with other ring that may be partially saturated wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group wherein said C 1-6 alkyl group is optionally substituted by halogen atom, hydroxy group, C 1-6 alkoxy group, carboxy group and C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )group wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group, hydroxy group, C 1-6 alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group, or 5 to 7-membered saturated heterocycle having at least one nitrogen atom, Y 1 is oxygen atom, -NH-, -CONH-, or -NR 12 - wherein R 12 is C 1-6 alkyl group or -Y 6 -R 13 wherein R 13 is hydrogen atom, C 1-6 alkyl group or C 6-12 aryl group wherein said C 1-6 alkyl group or C 6-12 aryl group is optionally substituted by carboxy group, C 1-6 alkoxycarbonyl group or C 6-12 aralkyl(C 1-6 )oxycarbonyl group, Y 6 is -CO-, -CO 2 -, -COCO 2 -, -SO 2 -, -SO 2 (CH 2 ) r - or -(CH 2 ) r - wherein r is 0 or an integer of 1 to 3, Y 2 is oxygen atom, sulfur atom or a single bond, Y 3 is wherein s and t are the same or different and each is an integer of 1 to 3, or a single bond, Y 4 is oxygen atom, -CO-, -CO 2 -, -SO 2 -, -CONH-, -CH=CH- or a single bond, Y 5 is -(CH 2 ) p -, -(CH 2 ) p' -CHAk-(CH 2 ) p'' -, -(CH 2 ) p' -CAk Ak'-(CH 2 ) p'' - or wherein Ak, Ak' are the same or different and each is C 1-6 alkyl group, p is 0 or an integer of 1 to 3, p' and p" are the same or different and each is 0 or an integer of 1 or 2, ring A is wherein R 14 is carboxy group, C 1-6 alkoxycarbonyl group or C 6-12 aralkyl(C 1-6 )oxycarbonyl group wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group or trifluoromethyl group, 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 of 1 to 3; and R 1 , R 2 and R 3 are the same or different and each is hydrogen atom, hydroxy group, C 1-6 alkyl group or C 6-12 aryl group, or a salt thereof. (2) The amidine compound of the formula [I] according to item (1), wherein R is a group of the formula or 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. (3) The amidine compound of the formula [I] according to item (2), 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. (4) The amidine compound of the formula [I] according to item (3), 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. (5) The amidine compound of the formula [I] according to item (4), wherein X 3 is -(CH 2 ) m - wherein m is as defined above and X 4 is a group of the formula and j is 1, or a salt thereof. (6) The amidine compound of the formula [I] according to item (5), wherein R 6 is hydrogen atom, X 2 is oxygen atom, and X 5 is a single bond, or a salt thereof. (7) The amidine compound of the formula [I] according to item (1), wherein R is a group of the formula wherein R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , ring A, m and n are as defined above, or a salt thereof. (8). The amidine compound of item (1), which is 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-(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-carboxamide oxime, N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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 methyl ester, 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-(pyrimidin-4-yl)piperidine-4-carboxylic acid, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide, 7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-benzylsulfonylpiperidin-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-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-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-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-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-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-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-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-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-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine, N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[1-(pyridin-4-yl)piperidin-4-yl]aminooxalic acid, 7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(2-hydroxybenzyl)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-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methy ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide, 7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide, 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-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide, N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-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-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid, 4-(2-amidino-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-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)-piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid, 7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(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-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, or a salt thereof. (9). The amidine compound of item (3), which is 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-(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-carboxamide oxime, N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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 methyl ester, 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-(pyrimidin-4-yl)piperidine-4-carboxylic acid, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide, 7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-benzylsulfonylpiperidin-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-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-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-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-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-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-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-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-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-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(2-hydroxybenzyl)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-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methy ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1 carboxamide, 7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide, 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-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide, N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-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-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid, 4-(2-amidmo-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-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid, 7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(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-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, or a salt thereof. (10). A pharmaceutical composition comprising an amidine compound of any of item (1) to item (9) or a salt thereof , and a pharmaceutically acceptable additive. (11). A blood coagulation inhibitor comprising an amidine compound of any of item (1) to item (9) or a salt thereof as an active ingredient. (12). A factor Xa inhibitor comprising an amidine compound of any of item (1) to item (9) or a salt thereof as an active ingredient. (13). An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises an amidine compound of any of item (1) to item (9) or a salt thereof as an active ingredient. (14). Use of the amidine compound of any of item (1) to item (9) or a salt thereof for the production of a blood coagulation inhibitor. (15). Use of the amidine compound of any of item (1) to item (9) or a salt thereof for the production of a factor Xa inhibitor. (16). Use of the amidine compound of any of item (1) to item (9) or a salt thereof for the production of an agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus. (17). A commercial package comprising the blood coagulation inhibitor of item (11) and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting coagulation of blood. (18). A commercial package comprising the factor Xa inhibitor of item (12) and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting factor Xa. (19). A commercial package comprising the agent for the prophylaxis or treatment of item (13) and a written matter associated therewith, the written matter stating that the agent can or should be used for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus. DETAILED DESCRIPTION OF THE INVENTION The terms used in the present specification to explain the inventive compound are defined as follows. "Lower alkyl group" is linear or branched alkyl group having 1 to 6 carbon atoms, which is exemplified by methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, tert-pentyl group, hexyl group and the like, with preference given to methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group and the like having 1 to 4 carbon atoms. Lower alkyl group at R 13 is optionally be substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group. "Cycloalkyl group" is alkyl having cyclic alkyl moiety having 3 to 10 carbon atoms. Examples thereof include cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, 3-methylcyclobutyl group, cyclopentyl group 3,4-dimethylcyclopentyl group, cyclohexyl group, 4-methylcyclohexyl group, cycloheptyl group, cyclooctyl group, norbornyl group, adamantyl group, bicyclo[3.3.0]octan-1-yl group or bicyclo[3.3.1]nonan-9-yl group and the like. Preferred are cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Cycloalkyl group at R 8 is optionally substituted by lower alkyl group or carboxy group. "Alkylene group having 1 to 6 carbon atoms" is linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group and the like, which is preferably methylene group, ethylene group, propylene group, butylene group and the like having 1 to 4 carbon atoms. "Alkenylene group having 2 to 6 carbon atoms" is linear or branched alkenylene group having 2 to 6 carbon atoms, such as ethenylene group, 1-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group, 1-pentenylene group, 2-pentenylene group, 3-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3-hexenylene group, 4-hexenylene group, 5-hexenylene group and the like. Preferred are ethenylene group, 1-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group and the like having 2 to 4 carbon atoms. "Aryl group" is phenyl group, naphthyl group or biphenyl group having 6 to 12 carbon atoms, with preference given to phenyl group. Aryl group at R 6 is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group. Aryl group at R 8 is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group. Aryl group at R 13 is optionally substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group. "Heteroaryl group" is 5 or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and may form a condensed ring with other ring that may be partially saturated. Examples thereof include imidazolyl group, pyridyl group, pyridine-1-oxide group, pyrimidyl group, thienyl group, thiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, indolyl group, quinolyl group, furyl group, benzofuryl group, 1H-benzimidazolyl group, 2-benzothiazolyl group and the like. Preferred are pyridyl group, pyridine-1-oxide group, thienyl group, thiazolyl group, isoxazolyl group, indolyl group and the like. Heteroaryl group at R 6 is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group. Heteroaryl group at R 8 is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group. The binding site of these heteroaryl groups is not limited as long as the site is chemically acceptable. "Aralkyl group" is arylalkyl group wherein aryl moiety is as exemplified for the above-mentioned "aryl group" and alkyl moiety is as exemplified for the above-mentioned ''lower alkyl group", and is exemplified by benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylhexyl group and the like. Aralkyl group may have, on the aryl group, 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, haloalkyl group, cyano group, nitro group, amino group, acyloxy group and the like. It may be substituted simultaneously with two or more substituents, but preferably mono-substituted. The position of substitution is not particularly limited as long as it is chemically acceptable. "Lower alkoxy group" is linear or branched alkoxy group having 1 to 6 carbon atoms and is exemplified by methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group, hexyloxy group and the like. Preferred are methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group and the like having 1 to 4 carbon atoms. "Lower alkoxycarbonyl group" is that wherein the lower alkoxy moiety is those exemplified for the above-mentioned "lower alkoxy group". Examples thereof include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like, with preference given to methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group and the like. "Aralkyloxycarbonyl group" is that wherein the aralkyl moiety is those exemplified for the above-mentioned "aralkyl group". Examples thereof include benzyloxycarbonyl group, 2-phenylethoxycarbonyl group, 3-phenylpropoxycarbonyl group and the like, which may be substituted by halogen atom, nitro group, alkyl group, alkoxy group, trifluoromethyl group and the like. Preferred is benzyloxycarbonyl group. "Acyl group" is formyl group; alkanoyl group having 2 to 6 carbon atoms such as acetyl group, propionyl group, butyryl group, pivaloyl group and the like; or aroyl group such as benzoyl group and the like wherein aryl group may have 1 to 3 substituents. Preferred are formyl group, acetyl group, pivaloyl group, benzoyl group and the like. "Imidoyl group" is formimidoyl group, acetimidoyl group, propanimidoyl group, butanimidoyl group, pentanimidoyl group or hexanimidoyl group and the like having 1 to 6 carbon atoms. Preferred are acetimidoyl group, propanimidoyl group and the like. "Lower alkylamino group" is amino group monosubstituted by those exemplified to the above-mentioned "lower alkyl group". Examples thereof include methylamino group, ethylamino group, propylamino group or butylamino group and the like, with preference given to methylamino group, ethylamino group, propylamino group and the like. "Di(lower)alkylamino group" is amino group disubstituted by those exemplified for the above-mentioned "lower alkyl group", and is exemplified by dimethylamino group, diethylamino group, dipropylamino group, methylethylamino group, methylpropylamino group and the like. Preferred are dimethylamino group, diethylamino group and the like. "Di(lower)alkylamino(lower)alkanoyl group" is alkanoyl group substituted by those exemplified for the above-mentioned "di(lower)alkylamino group". Examples thereof include dimethylaminoacetyl group, diethylaminoacetyl group, dipropylaminoacetyl group, methylethylaminoacetyl group, methylpropylaminoacetyl group, dimethylaminopropanoyl group, diethylaminopropanoyl group, dipropylaminopropanoyl group and the like. Preferred are dimethylaminoacetyl group, diethylaminoacetyl group and the like. "Acylamino group" is amino group substituted by those exemplified for the above-mentioned "acyl group". Examples thereof include formylamino group; alkanoylamino group having 2 to 6 carbon atoms such as acetylamino group, propionylamino group, butyrylamino group, pivaloylamino group and the like; and aroylamino group such as benzoylamino group and the like, wherein aryl group may be substituted by 1 to 3 substituents. Preferred are formylamino group, acetylamino group, pivaloylamino group, benzoylamino group and the like. "Halogen atom" is chlorine, bromine, fluorine or iodine, with preference given to chlorine or bromine. "Saturated 5- to 7-membered heterocycle having at least one nitrogen atom" is exemplified by pyrrolidine, piperidine, hexahydroazepine, and oxazolidine, thiazolidine, imidazolidine, morpholine, thiomorpholine, piperazine, tetrahydrooxazepine, tetrahydrothiazepine, hexahyorodiazepine and the like having, as hetero atom, oxygen, sulfur and/or nitrogen atom. Saturated 5- to 7-membered heterocycle having at least one nitrogen atom at R 6 may be substituted by lower alkyl group, acyl group, di(lower)alkylamino(lower)alkanoyl group or imidoyl group. "The salt" of the compound includes, but not limited to, inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate and the like ; organic acid addition salt such as acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, ascorbate and the like ; addition salt with amino acid such as aspartate, glutamate and the like ; salt with inorganic base such as sodium, potassium, calcium, magnesium and the like ; salt with organic base such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, trishydroxymethylaminomethane, dicyclohexylamine, ethylenedimane, quinine, guanidine and the like ; and base salt with amino acid such as asparagine, glutamine, arginine, histidine, lysine and the like. The salt may be water containing compound or hydrate. "The prodrug" of a compound is a derivative of the compound of the present invention, which has a chemically or metabolically degradable group and which shows pharmaceutical activity upon hydrolysis, solvolysis, or decomposition under physiolocial conditions. "Various diseases caused by blood coagulation or thrombus" include cerebrovascular deseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (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, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR), thrombosis due to extracorporeal circulation, and the like. The compound of the present invention is explained in detail in the following. Of the inventive compounds of the formula [I], R is a group of the formula or and preferably a group of the formula or and particularly preferably a group of the formula R 1 , R 2 and R 3 are preferably hydrogen atom. The mode of connection of and is preferably as shown by the formula or Preferable R 4 is hydrogen atom, lower alkoxy group or halogen atom, which is particularly preferably hydrogen atom. Preferable R 5 is hydrogen atom, carboxy group or lower alkoxycarbonyl group, particularly preferably carboxy group. Preferable R 6 is hydrogen atom, carboxy group, lower alkoxycarbonyl group, aryl group or heteroaryl group wherein aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group, which is particularly preferably pyridyl group. Preferable X 2 is oxygen atom or sulfur atom, which is particularly preferably oxygen atom. X 3 is preferably -(CH 2 ) m -, particularly preferably -(CH 2 ) 0 -, X 4 is preferably or a single bond, particularly preferably a single bond. X 5 is preferably alkenylene group having 2 to 6 carbon atoms or a single bond, which is particularly preferably a single bond. Preferred j is 1, and k is preferably 0. R 7 is preferably wherein R 9 is preferably oxygen atom or NH, and particularly preferably NH. R 10 is preferably lower alkyl group, lower alkoxy group or amino group, and particularly preferably lower alkyl group or amino group. R 8 is preferably hydrogen atom, aryl group, heteroaryl group wherein aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group, particularly preferably phenyl group. Y 1 is preferably oxygen atom or -NR 12 - wherein R 12 is preferably -Y 6 -R 13 wherein R 13 is preferably phenyl group optionally substituted by carboxy group or lower alkoxycarbonyl group, Y 6 is preferably -CO-, particularly preferably -N-Y 6 -R 13 . Y 2 is preferably oxygen atom. Y 3 is preferably wherein s and t are each preferably 2. Y 4 is preferably -CONH-. Y 5 is preferably -(CH 2 ) p -, -(CH 2 ) p' -CHAk-(CH 2 ) p "-, -(CH 2 ) p' -CAk Ak'-(CH 2 ) p" - wherein p is preferably 1 or 2, p' is preferably 1 and p" is preferably 0, which is particularly preferably -(CH 2 ) p' -CHAk-(CH 2 ) p" -. The compound of the formula [I] of the present invention includes tautomer, stereoisomer, optical isomer and geometrical isomer. The present invention encompasses all of them. The production method of the compound of the present invention is explained in the following, to which the production method of the inventive compound is not limited. Production Method 1 The production method shown here is suitable for producing, of the compounds of the formula [I], compound of the formula [I'] In this case, connection between moieties [i], [ii], [iii], [iv] and [v] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate. [1] Connection of moiety [i] and moiety [ii] A compound at the moiety [ii] of the formula (2) wherein means connection with other moiety or binding of a convertible group such as hydrogen atom, protecting group or leaving group and the like (hereinafter the same in the following formulas), and R 4 , X 2 , j and k are each as defined above, is reacted with the compound of the moiety [i] of the formula (3) wherein R 1' , R 2' and R 3' are the same or different and each is hydrogen atom, hydroxy group, lower alkyl group, aryl group or a protecting group of nitrogen atom, 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 the formula (4) wherein R 1' , R 2' , R 3' , R 4 , X 2 , j and k are each as defined above. When any of R 1' , R 2' and R 3' 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 the formula (2) is reacted to give a thioamide compound. Then, after treating with an acid such as hydrogen chloride, hydrogen bromide and the like, the compound is reacted with methyl iodide under heating, preferably at 50°C - 70°C. The compound may be reacted with amine having the desired substituent Alternatively, the compound of the formula (2) and the compound of the formula (5) R 1 -N C S wherein R 1 is as defined above, are reacted and then with methyl iodide to give thiomethyl compound, followed by reaction with ammonium acetate or amine having the desired substituent. When a compound of moiety [ii] wherein j is 2 is desired, a compound of the formula (6) wherein Rh is a protecting group such as methyl group and the like, and R 4 , X 2 and k are as defined above, is reacted with sodium azide and subjected to rearrangement reaction to give an azepinone compound. This compound is reduced with lithium aluminum hydride to give a compound of the formula (7) wherein R 4 , X 2 , Rh and k are as defined above. [2] Connection or construction of moiety [ii] and moiety [iii] A compound at the moiety [ii] of the formula (8) wherein R 4 , X 2 , j and k are as defined above, and a compound at the moiety [iii] of the formula (9) wherein L 1 is leaving group such as halogen atom and the like or hydroxy and X 3 is as defined above, are reacted to give a compound of the formula (10) wherein R 4 , X 2 , X 3 , j and k are as defined above. When L 1 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 L 1 is hydroxy, it is subjected to Mitsunobu reaction using triphenylphosphine and diisopropyl azodicarboxylate. When a compound wherein X 2 is -SO 2 - is desired, a compound of the formula (10) wherein X 2 is sulfur atom is oxidized using a peracid such as m-chloroperbenzoic acid or peracetic acid and the like to give a compound of the formula (11) wherein R 4 , X 3 , j and k are as defined above. When a compound wherein X 2 is -SO 2 NH- is desired, a compound of the formula (12) wherein R 4 , j and k are as defined above, and a compound of the formula (13) wherein X 3 is as defined above, are subjected to typical amidation under basic conditions to give a compound of the formula (14) wherein R 4 , X 3 , j and k are as defined above. When a compound wherein k is 1 and X 2 is oxygen atom is desired, a compound of the formula (15) wherein R 4 , Ak and j are as defined above is reduced using a reducing reagent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride and the like to give a compound of the formula (16). wherein R 4 and j are as defined above. The resultant compound is condensed with a compound of the formula (9) by the method shown in the production method of a compound of the formula (10) to give a compound of the formula (17) wherein R 4 , X 3 and j are as defined above. [3] Connection or construction of moiety [iii] and moiety [iv] When a compound wherein R 5 is hydrogen atom and X 3 is -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 - is desired, the formula (18) wherein m' is 0 or an integer of 1 or 2 and Ak is as defined above, is reduced using a reducing reagent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like to give a compound of the formula (19) wherein m" is an integer of 1 to 3. Alternatively, a compound of the formula (20) wherein m' is as defined above, is reduced using a reducing reagent such as borane and the like to give a compound of the formula (19). This compound corresponds to a compound of the formula (9) wherein X 3 is -(CH 2 ) m" - and L 1 is hydroxy group. When a compound wherein R 5 is cyano group, lower alkoxycarbonyl group or carboxy group and X 3 is -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 - is desired, a compound of the formula (21) wherein R 5' is cyano group, lower alkoxycarbonyl group or carboxy group, is reacted with a compound of the formula (22) L 2 -(CH 2 ) m' -CH=CH 2 wherein L 2 is a leaving group such as halogen atom and the like and m' is as defined above, in the presence of a base such as lithium diisopropylamide and the like at -80°C to 0°C to give a compound of the formula (23) wherein R 5' and m' are as defined above. The obtained compound is reacted with an oxidizing reagent such as osmium tetroxide and the like to give a diol compound wherein the double bond was oxidized. This diol compound is subjected to periodate oxidation to allow adjacent diol to be oxidatively cleaved to give an aldehyde compound. This is reduced using a reducing reagent such as sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like to give a compound of the formula (24) wherein R 5' and m" are as defined above. This compound corresponds to a compound of the formula (9) wherein X 3 is -(CH 2 ) m" - and L 1 is hydroxy group. Alternatively, a compound of the formula (23) is subjected to periodate oxidation to give a carboxylic acid, which is reduced with a reducing reagent such as borane and the like to give a compound of the formula (24). Alternatively, a compound of the formula (21) and a compound of the formula (25) wherein L 2 and m are as defined above, may be reacted in the presence of a base such as lithium diisopropylamide and the like at -80°C to 0°C. When a compound wherein R 5 is cyano group is desired, a compound of the formula (26) is amidated and reacted using a dehydrating reagent such as triphenylphosphine and the like to give a compound of the formula (27) Then, this compound may be bonded with a compound of moiety [iii] by a method similar to the production method of a compound of the formula (23) or a known method. The leaving group L 2 can be introduced into a compound of the formula (25) by, for example, a compound of the formula (28) wherein m is as defined above is reacted with a halogenation reagent such as sulfuryl chloride and the like to give a compound of the formula (25). The compound of the formula (25) may be converted to a compound with a leaving group having higher reactivity by the use of alkai metal halide. When a compound wherein X 2 is -SO 2 NH- and X 3 is -(CH 2 ) m - is desired, a compound of the formula (29) wherein R 5 and m are as defined above, is subjected to Curtius rearrangement, Hofmann rearrangement and the like to give a carbamate compound, which is subjected to typical removing reaction of amino group to give a compound of the formula (30) wherein R 5 and m are as defined above. This compound corresponds to a compound of the formula (13) wherein X 3 is -(CH 2 ) m -. Alternatively, a compound of the formula (31) is subjected to Strecker reaction by reacting hydrogen cyanide in the presence of ammonia to give a compound of the formula (32) , This compound corresponds to a compound of the formula (30) wherein R 5 is cyano group and m is 0. Subsequent alcoholysis gives a compound of the formula (33) wherein R 5 of the formula (30) is lower alkoxycarbonyl wherein Ak is as defined above, and hydrolysis of the resultant compound gives a compound of the formula (34) wherein R 5 of the formula (30) is carboxy group [4] Connection or construction of moiety [iv] and moiety [v] A compound at the moiety [iv] of the formula (35) wherein R 5 is as defined above, is reacted with a compound at the moiety [v] of the formula (36) L 2 -X 4 -X 5 -R 6 wherein R 6 , X 4 , X 5 and L 2 are as defined above, in the presence of a base such a sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like or reacted using a base such as triethylamine, N,N-diisopropylethylamine and the like at 120 - 160°C to give a compound of the formula (37) wherein R 5 , R 6 , X 4 and X 5 are as defined above. When a compound wherein R 6 is aryl group or heteroaryl group and the aryl group or heteroaryl group is substituted by amino group or acylamino group is desired, a compound having nitro group as a substituent at aryl group or heteroaryl group is reduced to give a compound having amino as a substituent. Further, an acylation reagent such as acyl halide, acid anhydride and the like is reacted to give a compound having of acylamino group as a substituent When a compound wherein X 5 is -CH=CH- is desired, a compound of the formula (38) wherein X 4 is as defined above, is reacted with a compound of the formula (39) wherein R 6 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 the formula (40) wherein R 6 and X 4 are as defined above. Production Method 2 moiety [i] moiety [vi] moiety [iii] moiety [iv] moiety [v] The production method shown here is suitable for producing, of the compounds of the formula [I], a compound of the formula [I"] In this case, connection between moieties [i], [iii], [iv], [v] and [vi] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate. [5] Connection and construction of moiety [i] and moiety [vi] A compound at the moiety [vi] of the formula (41) wherein R 4 , X 2 and k are as defined above, is reacted with a sulfonylation reagent such as trifluoromethanesulfonic anhydride and the like to convert hydroxy group thereof to a leaving group and reacted with 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 resultant compound is reacted with hydrogen sulfide under basic conditions to give a thioamide compound, which is further S-alkylated with methyl iodide and the like and reacted with ammonium acetate or amine having a desired substituent to give a compound of the formula (42) wherein R 1 , R 2 , R 3 , R 4 , X 2 and k are as defined above. When a compound of the formula (43) having halogen atom at the 8-position at R 4 wherein Hal is halogen atom, and X 2 and k are as defined above, is desired, a compound of the formula (44) wherein X 2 and k are as defined above is halogenized with a halogenizing reagent such as tert-butyl hypochlorite and the like. Connection of moiety [vi] and moiety [iii], and moiety [iii] - moiety [v] can be carried out in the same manner as in the connection of moiety [ii] - moiety [v] shown in Production Method 1. Production Method 3 The production method shown here is suitable for producing, of the compounds of the formula [I], a compound of the formula [I"'] In this case, connection between moieties [i], [vii], [viii], [ix], [x] and [xi] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate. [6] Connection and construction of moiety [i] and moiety [vii] Using a compound of the formula (45) and connection or construction of moiety [i] and moiety [vi] as shown in Production Method 2 is carried out to give a compound of the formula (46) wherein R 1 , R 2 , R 3 are each as defined above. [7] Connection and construction of moiety [vii] and moiety [viii], moiety [xi] A compound of the formula (47) wherein L 2 is as defined above, is reacted with a compound at the moiety [xi] of the formula (48) H 2 N-(CH 2 ) n -Y 4 -Y 5 -R 8 wherein R 8 , Y 4 , Y 5 and n are each as defined above, or a salt thereof, in the presence of a base such as triethylamine, N,N-diisoropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate and the like to give a compound of the formula (49) wherein R 8 , Y 4 , Y 5 and n are as defined above. The compound of the formula (48) itself may be used as a base. The nitro group of a compound of the formula (49) is reduced by a known method to give a compound of the formula (50) wherein R 8 , Y 4 , Y 5 and n are each as defined above, and reacted with a compound of moiety [viii] of the formula (51) wherein m is as defined above, to give a compound of the formula (52) wherein R 8 , Y 4 , Y 5 , m and n are as defined above. Alternatively, a compound of the formula (53) and a compound of the formula (51) are reacted to give a compound of the formula (54) wherein m is as defined above. This reaction can be a typical amidation reaction. For example, a condensing reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), diphenylphosphorylazide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and the like is used, or mixed acid anhydride method using alkylhalocarbonate and the like, or after conversion of carboxylic acid to acid halide using thionyl chloride, oxalyl chloride and the like, reaction under basic conditions, or other method may be used. A compound of the formula (55) wherein Rh' is a protecting group such as methyl group, ethyl group and the like and m is as defined above, is deprotected by a conventional method to give a compound of the formula (51). Alternatively, a compound of the formula (56) wherein m is as defined above, is oxidized by a typical method to give a compound of the formula (51). A compound of the formula (52) and a compound of the formula (54) are subjected to ring-closing reaction under acidic conditions using acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like to give a compound of the formula (57) wherein R 8 , Y 4 , Y 5 , m and n are as defined above, or a compound of the formula (58) wherein m is as defined above, respectively. Alternatively, a compound of the formula (59) is converted to imidate using an alkoxide, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and reacted with a compound of the formula (50) or a compound of the formula (53) under acidic conditions to give a compound of the formula (57) or a compound of the formula (58), respectively. When a compound wherein Y 4 is -CONH- is desired, a compound of the formula (60) wherein n is as defined above, and a compound of the formula (61) H 2 N-Y 5 -R 8 wherein R 8 and Y 5 are as defined above, are reacted in the same manner as shown in the production method of a compound of the formula (52) or a compound of the formula (54), to give a compound of the formula (62) wherein R 8 ,Y 5 and n are as defined above. When a compound wherein Y 4 is oxygen atom, Y 5 is a single bond and R 8 is lower alkyl group is desired, a compound of the formula (63) wherein n is as defined above, and a compound of the formula (64) L 1 -R 8' wherein R 8' is lower alkyl group and L 1 is as defined above, are reacted in the same manner as shown in the production method of a compound of the formula (37) to give a compound of the formula (65) wherein R 8' and n are as defined above. When a compound wherein Y 4 is -CO-, Y 5 is a single bond and R 8 is heteroaryl group is desired, a compound of the formula (60) is reacted with N,O-dimethylhydroxylamine in the same manner as shown in the production method of a compound of the formula (52) or a compound of the formula (54) to give a compound of the formula (66) wherein n is as defined above. Separately, a compound of the formula (67) H-R 8" wherein R 8" is heteroaryl group is activated with a base such as butyl lithium and the like and reacted with the above-mentioned compound (66) to give a compound of the formula (68) wherein R 8" and n are as defined above. [8] Connection and construction of moiety [viii] and moiety [ix] A compound at the moiety [viii] of the formula (69) wherein L 2 and m are as defined above, is reacted with a compound of the formula (70) wherein Y 1 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 hydrogencarbonate, potassium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like to give a compound of the formula (71) wherein Y 1 , ring A and m are each as defined above. When a compound wherein Y 1 is NH is desired, the compound is protected with a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl and the like and subjected to the reaction and deprotected to give a compound of the formula (72) wherein ring A and m are as defined above. In addition, when a compound wherein Y 1 is -NR 12 - is desired, a compound of the formula (72) is reacted with a compound of the formula (73) L 2 -R 12 wherein R 12 and L 2 are as defined above, in the same manner as in the production method of a compound of the formula (49) to give a compound of the formula (74) wherein R 12 and m are as defined above. When a compound wherein R 12 is -Y 6 -R 13 , Y 6 is -CO-, -CO 2 -, -COCO 2 - or -SO 2 - is desired, a compound of the formula (72) is reacted with a compound of the formula (75) HO-Y 6' -R 13 wherein Y 6' is -CO-, -CO 2 -, -COCO 2 - or -SO 2 - and R 13 is as defined above, in the same manner as in the production method of a compound of the formula (52) or the formula (54) to give a compound of the formula (76) wherein R 13 , Y 6' , ring A and m are as defined above. When a compound wherein Y 1 is a single bond and the ring A is a group of the formula is desired, a compound of the formula (77) wherein R 14 is as defined above, and a compound of the formula (69) are reacted in the same manner as in the production method of a compound of the formula (23) to give a compound of the formula (78) wherein R 14 and m are as defined above. When a compound wherein Y 1 is oxygen atom is desired, a compound of the formula (79) wherein ring A is as defined above, is oxidized with peracid such as m-chloroperbenzoic acid, peracetic acid and the like to give a compound of the formula (80) wherein ring A is as defined above. This compound corresponds to a compound of the formula (70) wherein Y 1 is oxygen atom. [9] Connection and construction of moiety [ix] and moiety [x] A compound at the moiety [ix] of the formula (81) wherein Y 1 , L 1 and ring A are as defined above, is reacted with a compound of the formula (82) H-Y 2 -Y 3 -R 7 wherein R 7 ,Y 2 and Y 3 are as defined above, in the same manner as in the production method of a compound of the formula (10) to give a compound of the formula (83) wherein R 7 , Y 1 , Y 2 , Y 3 and ring A are as defined above. When a compound wherein ring A has the following formula and Y 2 is a single bond, is desired, a compound of the formula (84) wherein Y 1 is as defined above, or a compound of the formula (85) wherein R 14 and Y 1 are as defined above, is reacted with a compound of the formula (86) L 2 -Y 3 -R 7 wherein R 7 , Y 3 and L 2 are as defined above, in the same manner as in the production method of a compound of the formula (37) to give a compound of the formula (87) wherein R 7 , Y 1 and Y 3 are as defined above, or a compound of the formula (88) wherein R 7 , R 14 , Y 1 and Y 3 are as defined above. When a compound wherein Y 3 is a group of the formula and R 7 is lower alkyl group or is desired, a compound of the formula (89) wherein Y 2 , s and t are as defined above, is reacted with a compound of the formula (90) L 3 -R 7' wherein L 3 is a leaving group such as ethoxy group, 1-pyrazolyl group, halogen atom and the like and R 7' is lower alkyl group or a group of the formula wherein R 9 and R 10 are as defined above, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride and the like to give a compound of the formula (91) wherein R 7' , Y 2 , s and t are as defined above. The compound of the formula [I] of the present invention thus obtained has a factor Xa inhibitory action. When the inventive compound is used as a factor Xa inhibitor or anti-blood coagulation agent, it is generally administered orally or parenterally and systemically or locally. While the dose varies depending on the age, body weight, symptom, therapeutic effect, administration route, treatment time and the like, it is generally from 0.01 mg to 1 g for an adult, which is orally or parenterally administered once to several doses per day. When the compound of the present invention is formulated into solid compositions for oral administration, it can be prepared into a dosage form such as tablet, pill, powder, granule and the like. In such solid compositions, one or more active substances are admixed with at least one inert diluent, dispersing agent or absorbent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystralline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate and anhydrous silicate powder. Moreover, the composition may comprise additives other than the diluent according to a conventional method. When the compound is formulated into tablet or pill, gastric coating or enteric coating of, for example, sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate may be applied, or two more layers may be formed. Moreover, a capsule made from a substance such as gelatin and ethylcellulose may be used. When a liquid composition for oral administration is desired, the compound can be formulated into a dosage form such as pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like. Examples of diluent to be used include purified water, ethanol, vegetable oil and emulsifier. This composition may also comprise, besides the diluent, auxiliary agents such as wetting agent, suspending agent, sweetener, flavor, aromatic and preservative. When the compound is prepared into an injection for parenteral administration, a sterile aqueous or nonaqueous solution, solubilizer, suspending agent or emulsifier is used. Examples of the 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 inorganic alkaline solution. When the compound is prepared into an aqueous solution, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and the like may be used. As the solubilizer, for example, polyoxyethylene hydrogenated castor oil, surfactants such as sucrose fatty acid ester (forming mixed micelle), lecithin and hydrogenated lecithin (forming liposome) may be used. In addition, an emulsion preparation comprising a nonaqueous solvent such as vegetable oil, and lecithin, polyoxyethylene hydrogenated castor oil, or polyoxyethylene polyoxypropylene glycol may be produced. As other composition for parenteral administration, an external liquid, liniment such as ointment, suppository or pessary comprising one or more active ingredients, which can be formulated by a method known in this field of the art, may be employed. Examples The compound of the formula [I] of the present invention and production method thereof are explained in detail by way of the Examples below. It is needless to say that the present invetnion is not to be limited to these Examples. Example 1 Synthesis of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (370 mg) was dissolved in 1N aqueous sodium hydroxide solution (4 ml) and 1,4-dioxane (8 ml) and di-tert-butyl dicarbonate (386 mg) was added, which was followed by stirring at room temperature overnight. The reaction mixture was extracted with,ethyl acetate and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (385 mg). Step 2 4-Hydroxymethyl-1-(pyridin-4-yl)piperidine Under an argon atmosphere, to a solution of 1-(pyridin-4-yl)piperidine-4-carboxylic acid ( Tetrahedron , vol. 44, No. 23, page 7095 (1988)) (500 mg) in tetrahydrofuran (5 ml) was added 1M borane-tetrahydrofuran solution (14.5 ml). with ice-cooling, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction 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. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate and 4N aqueous sodium hydroxide solution, and extracted 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(δ ppm,CDCl 3 ) 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=5.1Hz,2H), 8.22(d,J=5.1Hz,2H) Step 3 7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a mixture of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (389 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (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 reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2 - 1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (500 mg). 1 H-NMR(δ ppm,CDCl 3 ) 1.36-1.50(m,11H), 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(1H), 8.25(2H) Step 4 7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (500 mg) in chloroform (5 ml) was added trifluoroacetic acid (2.5 ml) 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 hydrogencarbonat 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). 1 H-NMR(δ ppm,CDCl 3 ) 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(1H), 6.66-6.72(m,3H), 6.99(1H), 8.25(2H) Step 5 7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-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 1H-pyrazole-1-carboxamidine hydrochloride (23 mg), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, diethyl ether was added and insoluble material was collected by filtration. The obtained solid was washed with diethyl ether. A part (45 mg) of the obtained solid was treated with hydrogen chloride-methanol and dried under reduced pressure to give the title compound (44 mg). 1 H-NMR(δ ppm,DMSO-d 6 ) 1.20-1.45(m,2H), 1.88-1.93(m,2H), 2.17(m,1H), 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,1H), 6.82(dd,J=2.7, 8.4Hz,1H), 7.13(d,J=8.4Hz,1H), 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]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 1-(Quinolin-4-yl)piperidine-4-carboxylic acid ethyl ester A solution of 4-chloroquinoline (2 g), isonipecotinic acid ethyl ester (2.8 ml) and triethylamine (3.4 ml) in ethanol (7.5 ml) was stirred in a sealed tube at 150°C for 5 days. After completion of the reaction, 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 silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (3.2 g). Step 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 ml) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, aqueous sodium sulfate was added with ice-cooling and the mixture was filtered through celite. The solvent was evaporated and the obtained solid was washed with diisopropyl ether and dried under reduced pressure to give the title compound (750 mg). 1 H-NMR(δ ppm,CDCl 3 ) 1.57-1.90(m,3H), 1.93-2.05(m,2H), 2.85(m,2H), 3.64-3.68(m,4H), 6.84(d,J=4.8Hz,1H), 7.47(m,1H), 7.65(m,1H), 8.01(m,2H), 8.67(d,J=4.8Hz,1H) Step 3 7-[1-(Quinolin-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 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (206 mg), 4-hydroxymethyl-1-(quinolin-4-yl)piperidine (200 mg), triphenylphosphine (238 mg) and diisopropyl azodicarboxylate (0.18 ml). Step 4 7-[1-(Quinolin-4-yl)piperidin-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-[1-(quinolin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (275 mg). Step 5 7-[1-(Quinolin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine 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 1H-pyrazole-1-carboxamidine hydrochloride (28 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.55-1.66(m,2H), 1.96-2.02(m,2H), 2.22(m,1H), 2.82(tr,J=6.0Hz,2H), 3.49(m,2H), 3.58(tr,J=6.0Hz,2H), 3.92(m,2H), 4.17-4.23(m,2H), 4.56(s,2H), 6.73(d,J=2.4Hz,1H), 6.85(dd,J=2.4, 8.1Hz,1H), 7.15(d,J=8.4Hz,1H), 7.20(1H), 7.64(brs,4H), 7.69(1H), 7.96(1H), 8.12(m,2H), 8.63(1H) Example 3 Synthesis of N-methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 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 dropwise added benzoyl chloride (0.32 ml) at room temperature, and the mixture was stirred at 75°C for 10 min. Then, a mixture of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (850 mg) in acetone (4.5 ml) and methylene chloride (4.5 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, 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 was added conc. hydrochloric acid (10 ml), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, water was added and the mixture was washed successively with ethyl acetate and chloroform. The aqueous layer was concentrated and the resultant residue was dissolved in water and ethanol, and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 - 20:1) and dried under reduced pressure to give the title compound (450 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.22-1.35(m,2H), 1.76-1.88(m,2H); 2.01(m,1H), 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(1H), 7.44(brs,2H), 8.11(2H) Step 2 7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester 7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrogen chloride - ethanol solution. To a suspension of the obtained residue in methanol (6 ml) was added methyl iodide (0.1 ml), 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 and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated and dried under reduced pressure to give the title compound (200 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.20-1.40(m,2H), 1.80-1.90(m,2H), 2.03(m,1H), 2.47(s,3H), 2.79(tr,J=6.0Hz,2H), 2.89(m,2H), 3.72(tr,J=6.0Hz,2H), 3.82(d,2H), 3.96-4.02(m,2H), 4.67(s,2H), 6.77-6.86(m,4H), 7.08(1H), 8.12(2H) Step 3 N-Methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride To an ethanol solution (2 ml) of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (100 mg) were added methylamine hydrochloride (20 mg) and sodium acetate (25 mg), and the mixture was stirred at 80°C for 3 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added aqueous sodium hydrogencarbonate solution and the mixture was washed with chloroform. To the aqueous layer was added 4N aqueous sodium hydroxide solution and the mixture was extracted 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 obtained residue was treated with hydrogen chloride - ethanol solution and dried under reduced pressure to give the title compound (80 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.19-1.38(m,2H), 1.87-1.94(m,2H), 2.17(m,1H), 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(1H), 6.81(1H), 7.12(1H), 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-tetrahydroisoquinoline-2-carboxamide oxime dihydrochloride To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (135 mg) in ethanol (3 ml) were added hydroxyamine hydrochloride (47 mg) and sodium acetate (56 mg), and the mixture was stirred at 40°C for 2 hours. After completion of the reaction; water was added and the mixture was washed with chloroform. Thereto was added 4N aqueous sodium hydroxide solution, 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 obtained solid was treated with hydrogen chloride ― ethanol solution and dried under reduced pressure to give the title compound (82 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.25-1.38(m,2H), 1.88-1.95(m,2H), 2.17(m,1H), 2.81(tr,J=5.7Hz,2H), 3.05-3.25(m,2H), 3.56(tr,J=5.7Hz,2H), 3.84(m,2H), 4.22-4.29(m,2H), 4.52(s,2H), 6.70(d,J=2.4Hz,1H), 6.82(dd,J=2.4, 8.0Hz,1H), 7.12(d,J=8.0Hz,1H), 7.19(d,J=7.5Hz,2H), 8.08(brs,2H), 8.19(d,J=7.5Hz,2H), 10.06(s,1H), 10.85(brs,1H), 13.71(brs,1H) Example 5 Synthesis of N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 N-Phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (30 mg) in methylene chloride (0.5 ml) was added phenyl isothiocyanate (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% triethylamine) and dried under reduced pressure to give the title compound (40 mg). 1 H-NMR (δ 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(1H), 7.09-7.38(m,6H), 8.24(2H) Step 2 N-Phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride N-Phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (35 mg) was treated with hydrogen chloride - ethanol solution. To a suspension of the obtained residue 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 obtained residue was dissolved in water and ethanol and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated. To the obtained residue were added ethanol (1 ml) and ammonium acetate (24 mg) , and the mixture was stirred under reflux for 12 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added aqueous sodium hydrogencarbonate solution 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 obtained residue was purified by reverse phase preparative TLC (50% acetonitrile-water, 1.5% trifluoroacetic acid). The obtained residue was treated with hydrogen chloride - ethanol solution and dried under reduced pressure to give the title compound (12 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.21-1.37(m,2H), 1.88-1.93(m,2H), 2.17(m,1H), 2.89(m,2H), 3.69(m,2H), 3.85(m,2H), 4.23-4.28(m,2H), 4.64(s,2H), 6.74(1H), 6.84(1H), 7.15-7.28(m,6H), 7.43(2H), 7.96(2H), 8.20(2H), 9.66(brs,1H), 13.38(brs,1H) Example 6 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 1 7-Methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (13 g) in dimethylformamide (100 ml) was added 60% sodium hydride (2.5 g) under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, chloromethyl methyl sulfide (5.2 ml) was dropwise added with ice-cooling, and the mixture was stirred at room temperature overnight. 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 silica gel column chromatography (hexane:acetone=20:1 - 10: 1) and dried under reduced pressure to give the title compound (9.6 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.49(s,9H), 2.25(s,3H), 2.77(tr,J=5.7Hz,2H), 3.62(tr,J=5.7Hz,2H), 4.54(s,2H), 5.13(s,2H), 6.70(1H), 6.78(1H), 7.06(1H) Step 2 7-Chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a solution of 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (9.6 g) in methylene chloride (100 ml) was added a solution of sulfuryl chloride (2.75 ml) in methylene chloride (30 ml) under an argon atmosphere and with ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated and toluene was added to the obtained residue to filter off insoluble material. The solvent was evaporated and dried under reduced pressure to give the title compound (7.4 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.49(s,9H), 2.79(tr,J=6.3Hz,2H), 3.64(tr,J=6.3Hz,2H), 4.57(s,2H), 5.88(s,2H), 6.85(1H), 6.91(1H), 7.11(1H) Step 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 1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester ( Tetrahedron , voL 44, No. 23, p. 7095 (1988)) (13.4 g) in tetrahydrofuran (300 ml) was dropwise added a 2M-lithium diisopropylamide-tetrahydrofuran solution (31 ml) at -70°C under an argon atmosphere, and the mixture was stirred at the same temperature for 45 min. To this solution was dropwise added a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (7.4 g) in tetrahydrofuran (80 ml) at the same temperature, and the mixture was allowed to warm to room temperature in 5.5 hours in 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 obtained residue was dissolved in methanol (150 ml). Thereto was dropwise added 1N aqueous sodium hydroxide solution (50 ml) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the obtained residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1 - 10:1) and dried under reduced pressure to give the title compound (10.87 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.26(tr,J=7Hz,3H), 1.49(s,9H), 1.68-1.80(m,2H), 2.30-2.40(m,2H), 2.75(m,2H), 3.10-3.20(m,2H), 3.61(brtr,2H), 3.68-3.76(m,2H), 3.97(s,2H), 4.22(q,J=7Hz,2H), 4.52(s,2H), 6.61(1H), 6.65-6.71(m,3H), 7.02(1H), 8.25(2H) Step 4 1-(Pyridin-4 yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester To a solution of 7-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (10.87 g) in chloroform (50 ml) was dropwise added trifluoroacetic acid (30 ml) with ice-cooling, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated and to the obtained residue was added aqueous sodium hydrogencarbonate solution, 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 reduced pressure to give the title compound (8.29 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.25(tr,J=7Hz,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=7Hz,2H), 6.52(1H), 6.65-6.67(m,3H), 6.98(1H), 8.25(2H) Step 5 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride To a solution of 1-(pyridin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (8.29 g) in dimethylformamide (50 ml) were added diisopropylethylamine (4.4 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (3.69 g), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether (350 ml) and the supernatant was removed. The obtained oil was dissolved in methanol (20 ml) and thereto was dropwise added diethyl ether (700 ml) with stirring. The supernatant was removed and dried under reduced pressure. Fifty (50) mg from the obtained 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (10.0 g) was dissolved in ethanol and dil. hydrochloric acid was added. The mixture was concentrated and dried under reduced pressure to give the title compound (55 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.15(tr,3H), 1.65-1.80(m,2H), 2.15-2.22(m,2H), 2.81(tr,J=6.0Hz,2H), 3.30-3.50(m,2H), 3.56(tr,J=6.0Hz,2H), 3.95-4.18(m,6H), 4.53(s,2H), 6.68(d,J=2.1Hz,1H), 6.81(dd,J=2.1, 8.4Hz,1H), 7.14(d,J=8.4Hz,1H), 7.19(d,J=7.5Hz,2H), 7.58(brs,4H), 8.22(d,J=7.5Hz,2H) Example 7 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (9 g) was dissolved in conc. hydrochloric acid (50 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insoluble material was filtered off and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (9.0 g). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.65-1.75(m,2H), 2.14-2.20(m,2H), 2.81(tr,J=5.7Hz,2H), 3.57(tr,J=5.7Hz,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,1H) Example 8 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride (11 g) was dissolved in water (100 ml) and filtrated. 4N Aqueous sodium hydroxide solution (20 ml) was added dropwise at 50°C, and the mixture was stirred at the same temperature for 30 min. After completion of the reaction, the resultant solid was collected by filtration, washed successively with water and ethanol, and dried under reduced pressure to give the title compound (7.7 g). 1 H-NMR (δ 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,1H), 6.83(d,J=8.3Hz,1H), 7.09(d,J=7.2Hz,2H), 7.17(d,J=8.3Hz,1H), 8.13(d,J=7.2Hz,2H) Example 9 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid hydrochloride 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-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 thereto was successively added dropwise 1N aqueous sodium hydroxide solution (2.9 ml) and 1N hydrochloric acid (1 ml). The mixture was stood at room temperature for 12 hours and the resultant crystals were collected by filtration, washed with water and dried to give the title compound (4.7 g). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.59-1.70(m,2H), 2.05-2.16(m,2H), 2.82(tr,J=5.7Hz,2H), 3.15(m,2H), 3.57(tr,J=5.7Hz,2H), 3.65-3.80(m,2H), 4.03(m,2H), 4.52(s,2H), 6.70(1H), 6.79-6.86(m,3H), 7.13(1H), 7.61(brs,4H), 8.14(2H) Example 10 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 1 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (3 g) was dissolved in 1N aqueous sodium hydroxide solution (46 ml) and tetrahydrofuran (10 ml) and benzyl chlorocarbonate (2.45 g) was added. The mixture was stirred at room temperature for 30 min. 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). Step 2 7-Methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (2.5 g) in dimethylformamide (25 ml) was added 60% sodium hydride (390 mg) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 30 min. Then, chloromethyl methyl sulfide (0.96 ml) was added, 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 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 silica gel column chromatograph (hexane:ethyl acetate=8:1) and dried under reduced pressure to give the title compound (2.7 g). 1 H-NMR (δ ppm,CDCl 3 ) 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(1H), 6.79(1H), 7.06(1H), 7.26-7.38(m,5H) Step 3 7-Chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (200 mg) in methylene chloride (4 ml) was dropwise added sulfuryl chloride (0.052 ml) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated azeotropically with toluene and the residue was dried under reduced pressure to give the title compound (213 mg). 1 H-NMR(δ ppm,CDCl 3 ) 2.82(brtr,2H), 3.72(brtr,2H), 4.65(s,2H), 5.18(s,2H), 5.87(s,2H), 6.84(1H), 6.91(1H), 7.11(1H), 7.26-7.39(m,5H) Step 4 1-tert-Butoacycarbonylpiperidine-4-carboxylic acid ethyl ester 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). Step 5 7-(1-tert-Butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester (300 mg) in tetrahydrofuran (3 ml) was dropwise added a 1.5M lithium diisopropylamide-tetrahydrofuran solution (0.97 ml) at -70°C, and the mixture was stirred at the same temperature for 50 min. Then, a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (213 mg) in tetrahydrofuran (3 ml) was dropwise added at the same temperature, and the mixture was allowed to warm to room temperature in 2 hours in stirring. After completion of the reaction, aqueous ammonium chloride solution and water were added with ice-cooling. 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=7:1) and dried under reduced pressure to give the title compound (170 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.23(tr,J=7.2Hz,3H), 1.46(s,9H), 1.52-1.62(m,2H), 2.16-2.21(m,2H), 2.77(m,2H), 3.04(m,2H), 3.69(m,2H), 3.80-4.00(m,4H), 4.19(q,J=7.2Hz,2H), 4.60(s,2H), 5.17(s,2H), 6.60(1H), 6.69(1H), 7.02(1H), 7.32-7.38(m,5H) Step 6 7-(4-Ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-(1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-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 aqueous sodium hydrogencarbonate solution was added to the obtained residue. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (135 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.23(tr,J=7.5Hz,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=7.5Hz,2H), 4.60(s,2H), 5.17(s,2H), 6.60(1H), 6.69(1H), 7.02(1H), 7.26-7.38(m,5H) Step 7 7-[1-(2,6-Dimethylpyridin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) were 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 in a sealed tube. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (160 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.26(tr,J=6.6Hz,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=6.6Hz,2H), 4.60(s,2H), 5.17(s,2H), 6.41(s,2H), 6.60(1H), 6.69(1H), 7.04(1H), 7.34-7.38(m,5H) Step 8 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride To 7-[1-(2,6-dimethylpyridin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (155 mg) was added 25% hydrogen bromide-acetic acid solution (3 ml), and the mixture was stirred for 10 min. After completion of the reaction, diisopropyl ether was added and the resultant solid was collected by filtration. To the obtained solid were added dimethylformamide (1 ml), diisopropylethylamine (0.25 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (80 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the obtained residue was washed with tetrahydrofuran and separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=4:1 - 2:3). The obtained residue was treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (120 mg). Example 11 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride To 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (85 mg) was added 6N hydrochloric acid, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. The obtained residue was washed with diethyl ether and dried under reduced pressure to give the title compound (76 mg). 1 H-NMR (δ 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(1H), 6.82(1H), 6.99(s,2H), 7.15(1H), 7.72(brs,4H), 13.69(brs,1H) Example 12 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid methyl ester dihydrochloride Step 1 4-Chloro-2-methylpyridine hydrochloride According to the method of Journal of Heterocyclic Chemistry , vol. 27, p. 1841 (1990), the title compound (743 mg) was obtained from 2-methylpyridine N-oxide (5.1 g). 1 H-NMR(δ ppm,CDCl 3 ) 2.99(s,3H), 7.70(s,1H), 7.77(d,J=6.3Hz,1H), 8.01(d,J=6.3Hz,1H) Step 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 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (100 mg), 4-chloro-2-methylpyridine hydrochloride (40 mg) and triethylamine (0.07 ml). Step 3 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-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 7-[4-ethoxycarbonyl-1-(2-methylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (100 mg), 25% hydrogen bromide-acetic acid solution (2 ml), diisopropylethylamine (0.16 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (55 mg). Example 13 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-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 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (63 mg). 1 H-NMR (δ 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(1H), 6.83(1H), 7.07-7.16(m,3H), 7.63(brs,4H), 8.12(1H), 13.74(brs,1H) Example 14 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrimidin-4-yl)piperidine-4-carboxylic acid dihydrochloride Step 1 7-[1-(2-Chloropyrimidin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (295 mg) in ethanol (5 ml) were added triethylamine (0.15 ml) and 2,4-dichloropyrimidine (150 mg), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) and dried under reduced pressure to give the title compound (263 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.25(tr,J=6.9Hz,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=6.1Hz,1H), 6.60(1H), 6.69(1H), 7.03(1H), 7.26-7.38(m,5H), 8.03(d,J=6.1Hz,1H) Step 2 1-(Pyrimidin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester To a solution of 7-[1-(2-chloropyrimidin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (263 mg) in ethanol(5 ml) were added 7.5% palladium carbon (120 mg) and ammonium formate (200 mg) with ice-cooling, and the mixture was stirred under reflux for 30 min. After completion of the reaction, 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 sodium hydrogencarbonate solution 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). Step 3 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrimidin-4-yl)piperidine-4-carboxylic acid dihydrochloride To a solution of 1-(pyrimidin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (260 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.24 ml) and 1H-pyrazole-1-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 obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=6:4 - 2:8). The obtained residue was refluxed with conc. 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 (δ 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=2.4Hz,1H), 6.81(dd,J=2.4, 8.4Hz,1H), 7.13(d,J=8.4Hz,1H), 7.23(d,J=7.8Hz,1H), 7.66(brs,4H), 8.32(d,J=7.8Hz,1H), 8.81(s,1H) Example 15 Synthesis of 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 1 7-(2-Iodoethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester 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 40% diethyl azodicarboxylate-toluene solution (33.6 ml), and the mixture was stirred at room temperature for hour. After completion of the reaction, the solvent was evaporated and to the obtained residue were added dimethylformamide (30 ml) and sodium iodide (9.6 g). The mixture was stirred at 90°C for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and dried under reduced pressure to give the title compound (1.19 g). 1 H-NMR (δ ppm,CDCl 3 ) 2.79(m,2H), 3.40(tr,J=6.9Hz,2H), 3.70(m,2H), 4.21(tr,J=6.9Hz,2H), 4.61(s,2H), 5.18(s,2H), 6.63(1H), 6.74(1H), 7.05(1H), 7.26-7.38(m,5H) Step 2 7-[2-(1-tert-Butoxycarbonyl-4-ethoxycarbonylpiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, Step 5, the title compound (935 mg) was obtained from 7-(2-iodoethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.4 g), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester (1.81 g) and 2M-lithium diisopropylamide-tetrahydrofuran solution (0.82 ml). 1 H-NMR (δ ppm,CDCl 3 ) 1.25(tr,J=6.9Hz,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=6.9Hz,2H), 4.60(s,2H), 5.18(s,2H), 6.56(1H), 6.67(1H), 7.01(1H), 7.31-7.38(m,5H) Step 3 7-[2-[4-Ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, Step 6, 7-[2-(4-ethoxycarbonylpiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester 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 trifluoroacetic 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. Step 4 4-[2-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in Example 10, Step 8, the title compound (208 mg) was obtained from 7-[2-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (397 mg), 25% hydrogen bromide-acetic acid solution (3 ml), diisopropylethylamine (0.64 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (214 mg). Example 16 Synthesis of 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 11, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (200 mg) was reacted. The obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=1:1) and the obtained residue was treated with dil. hydrochloric acid to give the title compound (29 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 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(1H), 6.78(1H), 7.14(1H), 7.19(d,J=7.4Hz,2H), 7.61(brs,4H), 8.21(d,J=7.4Hz,2H) Example 17 Synthesis of 7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 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) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration. The obtained solid was dissolved in dimethylformamide (5 ml) and thereto was added 1H-pyrazole-1-(N, N'-bis-tert-butoxycarbonyl)carboxamidine ( Synthesis , p. 579 (1994)) (742 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (700 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.50(s,18H), 2.87(m,2H), 3.73(m,2H), 4.62(brs,2H), 6.53(d,J=2.5Hz,1H), 6.66(dd,J=2.5, 8.2Hz,1H), 6.97(d,J=8.2Hz,1H) Step 2 4-Hydroxymethylpiperidine-1-carboxylic acid benzyl ester 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 obtained compound in tetrahydrofuran (100 ml) were added dropwise at -15°C triethylamine (5.56 ml) and isobutyl chlorocarbonate (5.2 ml) under an argon atmosphere, and the mixture was stirred at the same temperature for 20 min. After completion of the reaction, the reaction mixture was filtrated, and the filtrate was dropwise added to aqueous sodium borohydride (4.3 g) solution with ice-cooling. The mixture was stirred at the same temperature for 15 min and then at room temperature for 2 hours. After completion of the reaction, water was added and insoluble material was removed. The solvent was partially evaporated and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide, 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 (δ 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) Step 3 4-Bromomethylpiperidine-1-carboxylic acid benzyl ester To a solution of 4-hydroxymethylpiperidine-1-carboxylic acid benzyl ester (1.11 g), carbon tetrabromide (1.77 g) in methylene chloride (11 ml) was added triphenylphosphine (1.4 g) with ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=10:1) and dried under reduced pressure to give the title compound (1.25 g). 1 H-NMR (δ 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) Step 4 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-carboxylic acid benzyl ester To a solution of N,N'-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (50 mg) and 4-bromomethylpiperidine-1-carboxylic acid benzyl ester (120 mg) in dimethyl sulfoxide (1 ml) was added 4N aqueous sodium hydroxide solution (0.13 ml), and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (55 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.20-1.35(m,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(1H), 6.71(1H), 7.03(1H), 7.30-7.40(5H) Step 5 N,N'-Di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-carboxylic acid benzyl ester (500 mg) was hydrogenated using 7.5% palladium carbon (150 mg) in a mixture of tetrahydrofuran (5 ml) and ethanol (100 ml) at 3 atm over 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 (δ 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(1H), 6.72(1H), 7.03(1H) Step 6 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid ethyl ester 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 9.1N aqueous sodium hydroxide solution (0.027 ml) and ethyl bromoacetate (0.027 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (100 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.28(tr,J=5.2Hz,3H), 1.51(s,18H), 1.60-1.85(m,5H), 2.17-2.23(m,2H), 2.85-3.05(m,4H), 3.22(s,2H), 3.55-3.95(m,4H), 4.19(q,J=5.2Hz,2H), 4.86(brs,2H), 6.61(1H), 6.71(1H), 7.03(1H), 10.22(brs,1H) Step 7 N,N'-Di-tert-butoxycarbonyl-7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of 4-[2-(N,N'-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-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 at room temperature for 3 hours. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (65 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.30-1.55(m,20H), 1.70-1.90(m,3H), 2.11(brtr,2H), 2.54(tr,J=5.4Hz,2H), 2.85-3.00(m,4H), 3.61(tr,J=5.4Hz,2H), 3.65-3.85(m,4H), 4.67(s,2H), 6.63(1H), 6.72(1H), 7.03(1H), 10.21(brs,1H) Step 8 7-[1-(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)solution was added trifluoroacetic acid (0.3 ml), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue was added a hydrogen chloride - ethanol solution and insoluble material was removed. The resultant mixture was concentrated and dried under reduced pressure to give the title compound (40 mg). 1 H-NMR (δ 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(1H), 6.83(1H), 7.14(1H), 7.59(4H), 10.08(1H) Example 18 Synthesis of 7-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine trihydrochloride Step 1 N,N'-Di-tert-butoxycarbonyl-7-[1-(pyridin-4-ylmethyl)piperidin-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-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) were added 9.1N sodium hydroxide (0.068 ml) and 4-picolyl chloride hydrochloride (51 mg), and the mixture was stirred at 50°C for 5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and was 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 preparative thin layer chromatography (chloroform:methanol=20:1) and dried under reduced pressure to give the title compound (93 mg). Step 2 7-[1-(Pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine trihydrochloride 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 (δ ppm,DMSO-d 6 ) 1.70-2.00(m,5H), 2.81(m,2H), 3.00(m,2H), 3.38(m,2H), 3.57(m,2H), 3.81(m,2H), 4.48-4.54(m,4H), 6.71(1H), 6.82(1H), 7.13(1H), 7.60(4H), 8.19(d,J=6.0Hz,2H), 8.88(d,J=6.0Hz,2H), 11.63(1H) Example 19 Synthesis of 7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 N,N'-Di-tert-butoxycarbonyl-7-(1-phenacylpiperidin-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-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (200 mg), phenacyl bromide (90 mg) and 9.1N sodium hydroxide (0.054 ml). Step 2 N,N'-Di-tert-butoxycarbonyl-7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine To a solution of N,N'-di-tert-butoxycarbonyl-7-(1-phenacylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (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 at room temperature for 2 hours. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1, 1% triethylamine) and dried under reduced pressure to give the title compound (90 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.39-1.55(m,20H), 1.75-1.95(m,3H), 2.08(m,1H), 2.36(m,1H), 2.46-2.56(m,2H), 2.85-2.95(m,3H), 3.15-3.25(m,1H), 3.65-3.85(m,4H), 4.60-4.77(m,3H), 6.64(1H), 6.73(1H), 7.04(1H), 7.26-7.40(m,5H) Step 3 7-[1-(2-Hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-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)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (85 mg). 1 H-NMR (δ 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,1H), 6.73(1H), 6.84(1H), 7.15(1H), 7.25-7.50(m,5H), 7.60(brs,4H), 9.98(brs,1H) Example 20 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester dihydrochloride Step 1 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid benzyl ester 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-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (1 g), benzyl chloroacetate (0.34 ml) and 9.1N sodium hydroxide (0.025 ml). Step 2 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid benzyl ester (735 mg) was hydrogenated using 7.5% palladium carbon (220 mg) in a mixture of tetrahydrofuran (7 ml) and methanol (14 ml) at atmospheric pressure over 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 (600 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.34-1.56(m,20H), 1.80-2.10(m,5H), 2.77(brtr,2H), 2.89(brtr,2H), 3.49(s,2H), 3.55-3.90(m,4H), 4.66(s,2H), 6.60(1H), 6.70(1H), 7.03(1H) Step 3 4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidin-1-ylacetylglycine ethyl ester To a solution of 4-[2-(N,N'-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid (120 mg) and glycine ethyl ester hydrochloride in methylene chloride (1.5 ml) were added triethylamine (0.031 ml), 4-dimethylaminopyridine (27 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg), 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 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 (hexane:acetone=5:2) and dried under reduced pressure to give the title compound (100 mg). 1 H-NMR (δ 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=7.2Hz,2H), 4.67(brs,2H), 6.63(1H), 6.73(1H), 7.04(1H), 7.70(brtr,1H), 10.20(brs,1H) Step 4 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester dihydrochloride In the same manner as in Example 21, Step 8, the title compound (75 mg) was obtained from 4-[2-(N,N'-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidin-1-ylacetylglycine ethyl ester (100 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.20(tr,J=7.0Hz,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=7.0Hz), 4.56(s,2H), 6.72(d,J=2.1Hz,1H), 6.83(dd,J=2.1, 8.3Hz,1H), 7.15(d,J=8.3Hz,1H), 7.68(brs,4H), 9.24(brtr,1H), 10.07(brs,1H) Example 21 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-acetic acid N-methylamide dihydrochloride Step 1 4-[2-(N',N"-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid N-methylamide In the same manner as in Example 24, Step 3, the title compound (25 mg) was obtained from 4-[2-(N,N'-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid (120 mg), methylamine hydrochloride (148 mg), triethylamine (0.6 ml), 4-dimethylaminopyridine (27 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg) and N-methylmorpholine (0.24 ml). Step 2 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide dihydrochloride In the same manner as in Example 21, Step 8, the title compound (15 mg) was obtained from 4-[2-(N',N"-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid N-methylamide (20 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.60-1.78(m,2H), 1.88-2.08(m,2H), 2.67(s,3H), 2.83(tr,J=4.4Hz,2H), 3.00-3.15(m,2H), 3.45-3.55(m,2H), 3.58(tr,J=4.4Hz,2H), 3.82-3.92(m,4H), 4.62(s,2H), 6.72(1H), 6.85(1H), 7.15(1H), 7.63(brs,4H), 8.67(brs,1H), 9.93(brs,1H) Example 22 Synthesis of 7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride Step 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-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.021 ml) and pyridine (0.025 ml), and the mixture was stirred at room temperature for 2 hours. 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 (δ ppm,CDCl 3 ) 1.20-1.40(m,2H), 1.45-1.65(m,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(1H), 6.72(1H), 7.04(1H) Step 2 7-(1-Acetylpiperidin-4-ylmethoxy)-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-tetrahydroisoquinoline-2-carboxamidine (94 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.00-1.30(m,2H), 1.70-1.85(m,2H), 1.98(m,4H), 2.52(m,1H), 2.81(tr,J=6.0Hz,2H), 3.02(m,1H), 3.57(tr,J=6.0Hz,2H), 3.75-3.90(m,3H), 4.53(s,2H), 6.69(d,J=2.4Hz,1H), 6.82(dd,J=2.4, 8.4Hz,1H), 7.13(d,J=8.4Hz,1H), 7.57(brs,4H) Example 23 Synthesis of 7-(1-benzylsulfonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride Step 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-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added pyridine (0.02 ml), 4-dimethylaminopyridine (12 mg) and α-toluenesulfonyl chloride (43 mg), and the mixture was stirred at room temperature for 12 hours and then at 50°C for 6 hours. 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (48 mg). 1 H-NMR (δ 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(1H), 6.68(1H), 7.03(1H), 7.36-7.40(5H) Step 2 7-(1-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 (δ ppm,DMSO-d 6 ) 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=2.7Hz,1H), 6.82(dd,J=2.7, 8.3Hz,1H), 7.13(d,J=8.3Hz,1H), 7.35-7.40(m,5H), 7.53(s,4H) Example 24 Synthesis of 7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride Step 1 N,N'-Di-tert-butoxycarbonyl-7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine In the same manner as in Example 27, Step 1, the title compound (75 mg) was obtained from N,N'-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg), 2-naphthalenesulfonyl chloride (51 mg) and pyridine (0.02 ml). Step 2 7-[1-(2-Naphthylsulfonyl)piperidin-4-ylmethoxy]-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)-piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (70 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.22-1.40(m,2H), 1.60-1.84(m,3H), 2.32(m,2H), 2.78(tr,J=5.7Hz,2H), 3.54(tr,J=5.7Hz,2H), 3.72-3.80(m,4H), 4.49(s,2H), 6.62(d,J=2.3Hz,1H), 6.74(dd,J=2.3, 8.4Hz,1H), 7.08(d,J=8.4Hz,1H), 7.50(brs,4H), 7.66-7.77(m,3H), 8.07-8.20(m,3H), 8.43(s,1H) Example 25 Synthesis of 7-(1-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 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-(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) were added triethylamine (0.086 ml) and ethylacetoimidate hydrochloride (38 mg), and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, ethyl acetate and diethyl ether were added and insoluble material was removed. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (120 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.43-1.54(m,20H), 2.00-2.20(m,3H), 2.46(s,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,1H), 6.60(1H), 6.70(1H), 7.04(1H) Step 2 7-(1-Acetimidoylpiperidin-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-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.28-1.48(m,2H), 1.86-1.90(m,2H), 2.12(m,1H), 2.29(s,3H), 2.83(tr,J=4.4Hz,2H), 3.00-3.29(m,2H), 3.59(tr,J=4.4Hz,2H), 3.85(m,2H), 3.92-4.20(m,2H), 4.56(s,2H), 6.72(d,J=1.7Hz,1H), 6.84(dd,J=1.7, 6.3Hz,1H), 7.15(d,J=6.3Hz,1H), 7.65(brs,4H), 8.77(brs,1H), 9.33(brs,1H) Example 26 Synthesis of 7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 Ethyl phenylacetoimidate hydrochloride Hydrogen chloride was blown into a solution of benzyl cyanide (5.8 ml) in diethyl ether (10 ml) with ice-cooling, and the mixture was stood at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated. The obtained solid was washed with diethyl ether, collected by filtration and dried under reduced pressure to give the title compound (9.43 g). Step 2 N,N'-Di-tert-butoxycarbonyl-7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-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-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (105 mg) and ethyl phenyl acetoimidate hydrochloride (64 mg). Step 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-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 0.80-1.00(m,1H), 1.20-1.40(m,1H), 1.60-1.65(m,1H), 1.80-1.95(m,1H), 2.05(m,1H), 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(1H), 6.77(1H), 7.12(1H), 7.25-7.42(m,5H), 7.62(brs,4H), 9.13(brs,1H), 9.75(brs,1H) Example 27 Synthesis of N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridin-5-yl]acetamide dihydrochloride Step 1 N,N'-Di-tert-butoxycarbonyl-7-[1-(5-nitropyridin-2-yl)piperidin-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-tetrahydroisoquinoline-2-carboxamidine (120 mg) in a mixture of tetrahydrofuran (1.2 ml) and dimethylformamide (1.2 ml) were added triethylamine (0.068 ml) and 2-chloro-5-nitropyridine (58 mg), and the mixture was stirred at room temperature for 2 hours. 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (120 mg). 1 H-NMR (δ 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(1H), 7.04(1H), 8.19(1H), 9.03(1H), 10.19(brs,1H) Step 2 N,N'-Di-tert-butoxycarbonyl-7-[1-(5-aminopyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-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 using 7.5% palladium carbon (30 mg) in a mixture of tetrahydrofuran (1 ml) and methanol (2 ml) at 2.5 atm over 4 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. The obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) and dried under reduced pressure to give the title compound (90 mg). Step 3 N-[2-[4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-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 (1.5 ml) were added acetic anhydride (0.017 ml) arid pyridine (0.017 ml), and the mixture was stirred at room temperature for 2 hours. 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 obtained residue was purified by silica gel column chromatography (hexane:acetone=2:1). The obtained residue was dissolved in methanol and treated with active charcoal, and dried under reduced pressure to give the title compound (75 mg). 1 H-NMR (δ 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) Step 4 N-[2-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide dihydrochloride In the same manner as in Example 21, Step 8, the title compound (50 mg) was obtained from N-[2-[4-[2-(N,N'-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidin-1-yl]pyridin-5-yl]acetamide (70 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.25-1.45(m,2H), 1.88-1.95(m,2H), 2.00-2.20(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(1H), 6.83(1H), 7.13(1H), 7.39(1H), 7.57(brs,4H), 8.00(1H), 8.46(1H), 10.49(1H) Example 28 Synthesis of N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridin-5-yl]benzamide dihydrochloride Step 1 N-[2-[4-[2-(N,N'-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidin-1-yl]pyridin-5-yl]benzamide 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)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg), benzoyl chloride (0.021 ml) and pyridine (0.017 ml). Step 2 N-[2-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)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-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidin-1-yl]pyridin-5-yl]benzamide (84 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.30-1.48(m,2H), 1.87-1.93(m,2H), 2.12(m,1H), 2.82(tr,J=5.8Hz,2H), 3.19(m,2H), 3.57(tr,J=5.8Hz,2H), 3.86(m,2H), 4.29-4.36(m,2H), 4.54(s,2H), 6.71(d,J=2.7Hz,1H), 6.84(dd,J=2.7, 8.4Hz,1H), 7.14(d,J=8.4Hz,1H), 7.43(1H), 7.51-7.64(7H), 8.02(2H), 8.30(1H), 8.63(1H), 10.65(1H) Example 29 Synthesis of 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester dihydrochloride Step 1 4-(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxylic acid benzyl ester To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (1.2 g), 4-hydroxymethylpiperidine-1-carboxylic acid benzyl ester (2.39 g) in tetrahydrofuran (30 ml) were added triphenylphosphine (2.52 g) and diisopropyl azodicarboxylate (1.90 ml), and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=6:1) and dried under reduced pressure to give the title compound (1.82 g). 1 H-NMR (δ 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,1H), 6.71(dd,J=2.5, 8.3Hz,1H), 7.29(d,J=8.3Hz,1H), 7.26-7.38(m,5H) Step 2 7-(Piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester 4-(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carboxylic acid benzyl ester (1.3 g) was hydrogenated using 7.5% palladium carbon (300 mg) in a mixture of tetrahydrofuran (10 ml) and methanol (20 ml) at 3 atm over 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 (δ 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(1H), 6.71(1H), 7.03(1H) Step 3 7-[1-(3-Formylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a solution of 7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (442 mg) in ethanol (3 ml) were 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 insoluble material was removed. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) and dried under reduced pressure to give the title compound (430 mg). 1 H-NMR (δ 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(1H), 6.73(1H), 6.84(d,J=6.0Hz,1H), 7.05(1H), 8.42(d,J=6.0Hz,1H), 8.74(s,1H), 10.02(s,1H) Step 4 3-[4-[4-(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester 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)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (95 mg) in tetrahydrofuran (1 ml) was added dropwise and the mixture was stirred for 2 hours. After completion of the reaction, 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 title compound (100 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.35(tr,J=6.4Hz,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=6.4Hz,2H), 4.54(s,2H), 6.45(d,J=15.9Hz,1H), 6.65(1H), 6.74(1H), 6.83(d,J=6.0Hz,1H), 7.05(1H), 7.76(d,J=15.9Hz,1H), 8.38(d,J=6.0Hz,1H), 8.55(s,1H) Step 5 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 at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate solution 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 dried under reduced pressure to give the title compound (70 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.35(tr,J=7.1Hz,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=7.1Hz,2H), 6.45(d,J=16.2Hz,1H), 6.55(d,J=2.3Hz,1H), 6.72(dd,J=2.3, 8.2Hz,1H), 6.83(d,J=6.0Hz,1H), 7.01(d,J=8.2Hz,1H), 7.76(d,J=16.2Hz,1H), 8.37(d,J=6.0Hz,1H), 8.55(s,1H) Step 6 3-[4-[4-(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-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (70 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.032 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (27 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether and the supernatant was removed. This procedure was repeated twice and hydrogen chloride-ethanol solution was added to the obtained residue and insoluble material was removed. The solution was concentrated and dried under reduced pressure to give the title compound (50 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.25(tr,J=7.3Hz,3H), 1.40-1.55(m,2H), 1.82-2.05(m,3H), 2.76-2.96(m,4H), 3.42(m,2H), 3.57(m,2H), 3.90(m,2H), 4.18(q,J=7.3Hz,2H), 4.53(s,2H), 6.63(d,J=16.1Hz,1H), 6.73(1H), 6.85(1H), 7.04(1H), 7.14(1H), 7.51(brs,4H); 7.60(d,J=16.1Hz,1H), 8.35(1H), 8.64(s,1H) Example 30 Synthesis of 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridine-3-carboxylic acid methyl ester dihydrochloride Step 1 7-[1-(3-Methoxycarbonylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a soution of 7-[1-(3-formylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (50 mg) in a mixture of chloroform (0.5 ml) and methanol (0.2 ml) were added sodium cyanide (8 mg), manganese dioxide (250 mg) and acetic acid (0.003 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=15:1) and dried under reduced pressure to give the title compound (50 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.49-1.70(m,11H), 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(1H), 6.72(1H), 6.78(d,J=6.0Hz,1H), 7.04(1H), 8.35(d,J=6.0Hz,1H), 8.73(s,1H) Step 2 4-[4-(1,2,3,4-Tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester To a solution of 7-[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (37 mg) in chloroform (0.5 ml) was added trifluoroacetic acid (0.15 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate 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 dried under reduced pressure to give the title compound (30 mg). Step 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-yl]pyridine-3-carboxylic acid methyl ester (30 mg). 1 H-NMR (δ 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=7.2Hz,1H), 7.59(brs,4H), 8.30(d,J=7.2Hz,1H), 8.58(s,1H) Example 31 Synthesis of 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidin-1-yl]pyridine-3-carboxylic acid dihydrochloride To a solution of 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester dihydrochloride (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 reaction mixture was neutralized with 1N-hydrochloric acid and the solvent was evaporated. The obtained residue was purified by reverse phase preparative thin layer chromatography (40% aqueous acetonitrile, 1% trifluoroacetic acid) and the obtained residue was treated with hydrogen chloride-ethanol solution and dried under reduced pressure to give the title compound (15 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 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(1H), 6.82(1H), 7.14(1H), 7.34(d,J=7.4Hz,1H), 7.44(brs,4H), 8.27(d,J=7.4Hz,1H), 8.59(s,1H) Example 32 Synthesis of 6-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide 6-Methoxy-1,2,3,4-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 to the obtained residue were added ethanol and diethyl ether. The mixture was filtrated and dried under reduced pressure to give the title compound (3.93 g). 1 H-NMR (δ ppm,DMSO-d 6 ) 2.90(tr,J=6.3Hz,2H), 3.35(m,2H), 4.13(brs,2H), 6.59(d,J=2.4Hz,1H), 6.65(dd,J=2.4, 8.4Hz,1H), 7.00(d,J=8.4Hz,1H), 8.91(brs,2H), 9.43(brs,1H) Step 2 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 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-tetrahydroisoquinoline hydrobromide (350 mg) and di-tert-butyl dicarbonate (365 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.49(s,9H), 2.76(tr,J=6.0Hz,2H), 3.61(tr,J=6.0Hz,2H), 4.49(s,2H), 5.33(s,1H), 6.63(1H), 6.67(1H), 6.95(1H) Step 3 6-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-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) were successively added triphenylphosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2 - 1:1, 1%triethylamine) and dried under reduced pressure to give the title compound (400 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.35-1.54(m,11H), 1.90-2.15(m,2H), 2.79(tr,J=6.0Hz,2H), 2.90(m,2H), 3.62(tr,J=6.0Hz,2H), 3.81(d,2H), 3.90-3.96(m,2H), 4.50(s,2H), 6.66-6.68(m,3H), 6.73(1H), 7.01(1H), 8.25(2H) Step 4 6-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline In the same manner as in Example 33, Step 5, the title compound (265 mg) was obtained from 6-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (400 mg) and trifluoroacetic acid (1.5 ml). 1 H-NMR (δ ppm,CDCl 3 ) 1.36-1.50(m,2H), 1.90-2.15(m,3H), 2.80(tr,J=6.0Hz,2H), 2.93(m,2H), 3.15(tr,J=6.0Hz,2H), 3.80(d,2H), 3.92-3.99(m,4H), 6.62(1H), 6.67-6.70(m,3H), 6.93(1H), 8.24(2H) Step 5 6-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-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), 1H-pyrazole-1 carboxamidine hydrochloride (35 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.20-1.45(m,2H), 1.84-2.00(m,2H), 2.17(m,1H), 2.86(tr,J=5.8Hz,2H), 3.20(m,2H), 3.56(tr,J=5.8Hz,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(1H) Example 33 Synthesis of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 4-Carbamoylpiperidine-1-carboxylic acid benzyl ester To a solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.5 g) in tetrahydrofuran (100 ml) were dropwise added N-methylmorpholine (4.6 ml) and isobutyl chlorocarbonate (5.4 ml) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 10 min. Then, 28% aqueous ammonia (100 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 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 hydrogencarbonate solution, 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 (δ ppm,CDCl 3 ) 1.58-1.75(m,2H), 1.80-1.95(m,2H), 2.25-2.40(m,1H), 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) Step 2 4-Carbamoylpiperidine-1-carboxylic acid tert-butyl ester 4-Carbamoylpiperidine-1-carboxylic acid benzyl ester (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 atm over 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 at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and water was added. 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 filtrated and dried under reduced pressure to give the title compound (5.6 g). 1 H-NMR(δ ppm,CDCl 3 ) 1.46(s,9H), 1.57-1.70(m,2H), 1.78-1.90(m,2H), 2.26-2.38(m,1H), 2.65-2.88(m,2H), 4.00-4.25(m,2H), 5.30-5.80(m,2H) Step 3 4-Cyanopiperidine-1-carboxylic acid tert-butyl ester To a solution of 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester (5.6 g) in a mixture of tetrahydrofuran (110 ml) and carbon tetrachloride (90 ml) was added triphenylphosphine (24.4 g), and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (3.5 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.46(s,9H), 1.70-1.95(m,4H), 2.75-2.85(m,1H), 3.30-3.38(m,2H), 3.62-3.70(m,2H) Step 4 4-Allyl-4-cyanopiperidine-1-carboxylic acid tert-butyl ester To a solution of 2M lithium diisopropylamide-tetrahydrofuran solution (9.96 ml) in tetrahydrofuran (20 ml) was dropwise added a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.5 g) in tetrahydrofuran (15 ml) at -78°C and under argon atmosphere, and the mixture was stirred at room temperature for 30 min. Then, allyl bromide (2.15 ml) was added at -78°C, and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) and dried under reduced pressure to give the title compound (3.5 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.37-1.55(m,11H), 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,2H), 5.81-5.95(m,1H) Step 5 4-Cyano-4-(2,3-dihydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-allyl-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.5 g) in a mixture of acetone (160 ml) and water (20 ml) were added N-methylmorpholine N-oxide (2.5 g) and osmium tetroxide (5% tert-butanol solution, 8 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, aqueous sodium thiosulfate was added and the mixture was filtrated. The solvent was evaporated and water was added to the obtained 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 obtained residue was purified by silica gel column chromatography (ethyl acetate) and dried under reduced pressure to give the title compound (3.65 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.40-1.81(m,13H), 1.90-1.96(m,1H), 2.00(brs,1H), 2.15-2.21(m,1H), 2.50(brs,1H), 2.95-3.20(m,2H), 3.49(brtr,1H), 3.65-3.72(brd,1H), 4.00-4.20(m,3H), Step 6 4-Cyano-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-cyano-4-(2,3-dihydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (3.65 g) in tetrahydrofuran (100 ml) was added 10% aqueous sodium periodate solution (100 ml), and the mixture was stirred at room temperature for 40 min. After completion of the reaction, 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 obtained residue (3.3 g) was dissolved in tetrahydrofuran (100 ml) and sodium borohydride (360 mg) and methanol (20 ml) were added with ice-cooling, and the mixture was stirred at room temperature for 30 min. 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 obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) and dried under reduced-pressure to give the title compound (3.13 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.49-1.55(m,11H), 1.86(m,2H), 1.96-2.00(m,2H), 3.00-3.09(m,2H), 3.93(m,2H), 4.05-4.20(m,2H) Step 7 7-[2-(1-tert-Butoxycarbonyl-4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.1 g), 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g) and triphenylphosphine (1.22 g) in tetrahydrofuran (40 ml) was added diethyl azodicarboxylate (2 g) with ice-cooling, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3: 1) and dried under reduced pressure to give the title compound (1.6 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.46-1.55(m,11H), 1.96-2.10(m,4H), 2.78(m,2H), 3.00-3.14(m,2H), 3.71(m,2H), 4.05-4.25(m,4H), 4.61(s,2H), 5.18(s,2H), 6.60-6.80(m,2H), 7.04(1H), 7.26-7.40(m,5H) Step 8 7-[2-(4-Cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, Step 6, the title compound (1 g) was obtained from 7-[2-(1-tert-butoxycarbonyl-4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.2 g) and trifluoroacetic acid (10 ml). 1 H-NMR (δ 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(brtr,2H), 4.18(tr,J=6.3Hz,2H), 4.61(s,2H), 5.18(s,2H), 6.63-6.75(m,2H), 7.04(1H), 7.26-7.38(m,5H) Step 9 7-[2-[4-Cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester In the same manner as in Example 10, Step 7, the title compound (590 mg) was obtained from 7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (850 mg), 4-chloropyridine hydrochloride (300 mg) and triethylamine (0.84 ml). 1 H-NMR (δ 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, 3.9Hz,2H), 6.74(1H), 7.05(1H), 7.32-7.40(m,5H), 8.29(dd,J=1.0, 3.9Hz,2H) Step 10 7-[2-[4-Cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (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 filtrated and the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate 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 (δ ppm,CDCl 3 ) 1.68-1.84(m,2H), 2.02-2.21(m,4H), 2.73(m,2H), 3.12(m,2H), 3.17-3.24(m,2H), 3.84-3.95(m,2H), 3.98(s,2H), 4.21(m,2H), 6.55(1H), 6.67-6.71(3H), 7.00(1H), 8.29(2H) Step 11 7-[2-[4-Cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline (70 mg) in dimethylformamide (5 ml)solution were added diisopropylethylamine (0.1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (85 mg), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by HPLC (0.05% aquesous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (67 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.65-1.80(m,2H), 2.05-2.20(m,4H), 2.82(tr,J=6.0Hz,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=2.4Hz,1H), 6.85(dd,J=2.4,8.4Hz,1H), 7.16(d,J=8.4Hz,1H), 7.25(d,J=7.5Hz,1H), 7.61(brs,4H), 8.26(d,J=7.5Hz,1H), 13.80(brs,1H) Example 34 Synthesis of 4-(2-amidino-8-chloronaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 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 min. After completion of the reaction, aqueous sodium hydrogencarbonate 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 (δ ppm,CDCl 3 ) 3.96(s,3H), 7.14(d,J=2.4Hz,1H), 7.21(dd,J=2.4, 8.9Hz,2H), 7.64(d,J=2.4Hz,1H), 7.77(d,J=8.9Hz,1H), 7.83(d,J=8.9Hz,1H) Step 2 7-Methoxynaphthalene-2-carbonitrile To a solution of 7-methoxy-2-trifluoromethanesulfonyloxynaphthalene (2.23 g) in dimethylformamide (8.9 ml) were added zinc cyanide (598 mg) and tetrakis(triphenylphosphine) palladium (337 mg) at room temperature, and the mixture was stirred at 80°C for 1 hour. After completion of the reaction, water and ethyl acetate were added and insoluble material was removed. The organic layer was separated and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) and dried under reduced pressure to give the title compound (965 mg). 1 H-NMR (δ ppm,CDCl 3 ) 3.95(s,3H), 7.15(d,J=2.5Hz,H), 7.29(dd,J=2.5, 9.0Hz,1H), 7.47(1H), 7.78(d,J=9.0Hz,H), 7.83(1H), 8.11(1H), Step 3 7-Hydroxynaphthalene-2-carbonitrile 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 refluxing for 30 min. After completion of the reaction, the reaction mixture was ice-cooled and ice, ethyl acetate and conc. hydrochloric acid were added, and the mixture was stirred. The organic layer was separated and concentrated. To the obtained residue was added hexane and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (5.21 g). 1 H-NMR (δ ppm,CDCl 3 ) 5.42(1H), 7,20(1H), 7.25-7.28(1H), 7.46(1H), 7.79-7.85(2H), 8.07(1H) Step 4 8-Chloro-7-hydroxynaphthalene-2-carbonitrile To a solution of 7-hydroxynaphthalene-2-carbonitrile (2.23 g) in chloroform (120 ml) was dropwise added tert-butyl hypochlorite (1.64 ml) with ice-cooling, and the mixture was stirred at room temperature for 15 min. After completion of the reaction, the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (1.88 g). 1 H-NMR (δ ppm,DMSO-d 6 ) 7.49(d,J=9.0Hz,1H), 7.68(1H), 7.94(d,J=9.0Hz,1H), 8.19(1H), 8.46(1H) Step 5 8-Chloro-7-methylthiomethoxynaphthalene-2-carbonitrile In the same manner as in Example 10, Step 2, the title compound (1.31 g) was obtained from 8-chloro-7-hydroxynaphthalene-2-carbonitrile (1.88 g). 1 H-NMR (δ ppm,CDCl 3 ) 2.32(s,3H), 5.40(s,2H), 7.48(d,J=9.0Hz,1H), 7.57(dd,J=1.5, 8.4Hz,1H), 7.82(d,J=9.0Hz,1H), 7.90(d,J=8.4Hz,1H), 8.63(d,J=1.5Hz,1H) Step 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 (δ ppm,CDCl 3 ) 6.04(s,2H), 7.61-7.67(2H), 7.88(1H), 7.94(1H), 8.65(1H) Step 7 4-(8-Chloro-2-cyanonaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester In the same manner as in Example 10, Step 5, the title compound (128 mg) was obtained from 8-chloro-7-chloromethoxynaphthalene-2-carbonitrile (295 mg) and 1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (603 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.28(tr,J=7.1Hz,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=7.1Hz,2H), 6.69(dd,J=1.4, 5.1Hz,2H), 7.38(d,J=9.0Hz,1H), 7.55(1H), 7.81(d,J=9.0Hz,1H), 7.88(1H), 8.27(dd,J= 1.4, 5.1Hz,2H), 8.61(1H), Step 8 4-(2-Amidino-8-chloronaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Hydrogen sulfide was blown 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 completion of 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 completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in ethanol (4 ml). Ammonium acetate (106 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 obtained residue was purified by silica gel column chromatography (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 35 Synthesis of 4-(2-amidino-8-chloronaphthalen-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 conc. hydrochloric acid was stirred at 50°C - 100°C for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (49 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 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(2H), 7.78(2H), 8.12(1H), 8.18-8.25(m,3H), 8.56(s,1H), 9.34(brs,2H), 9.62(brs,2H), 12.98(brs,1H), 13.65(brs,1H) Example 36 Synthesis of 4-(2-amidinonaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 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). Step 2 7-Chloromethoxynaphthalene-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). Step 3 4-(2-Cyanonaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester In the same manner as in Example 10, Step 5, the title compound (430 mg) was obtained from 7-chloromethoxynaphthalene-2-carbonitrile (314 mg), 1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (743 mg) and a 2M-lithium diisopropylamide-tetrahydrofuran solution (1.73 ml). Step 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-(2-cyanonaphthalen-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (51 mg) and methyl iodide (0.6 ml). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.14(tr,J=7.1Hz,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=8.9Hz,1H), 7.48(s,1H), 7.66(d,J=8.9Hz,1H), 7.98(d,J=8.9Hz,1H), 8.07(d,J=8.9Hz,1H), 8.24(d,J=7Hz,2H), 8.32(s,1H), 9.19(brs,2H), 9.45(brs,2H), 13.53(brs,1H) Example 37 Synthesis of 4-(2-amidino-2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4- carboxylic acid ethyl ester dihydrochloride Step 1 8-Methoxy-2,3,4,5-tetrahydrobenz[c]azepin-1-one To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one (5.21 g) in conc. hydrochloric acid (26 ml) was added sodium azide (1.98 g) by portions with ice-cooling, and the mixture was stirred at the same temperature for 2 hours, and then at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and aqueous potassium carbonate was added. 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 silica gel column chromatography (ethyl acetate) and dried under reduced pressure to give the title compound (470 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.98(quint,J=6.9Hz,2H), 2.80(tr,J=6.9Hz,2H), 3.13(q,J=6.9Hz,2H), 3.83(s,3H), 6.96(1H), 7.09(1H), 7.26(1H) Step 2 8-Methoxy-2,3,4,5-tetrahydro-1H-benz[c]azepine To a solution of lithium aluminum hydride (3.07 g) in tetrahydrofuran (60 ml) was dropwise added 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, 20% 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 filtrated, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (4.05 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.68(m,2H), 2.82-2.90(m,2H), 3.10-3.25(m,2H), 3.77(s,3H), 3.88(s,2H), 6.60-6.70(2H), 7.05(1H) Step 3 8-Hydroxy-2,3,4,5-tetrahydro-1H-benz[c]azepine hydrobromide 8-Methoxy-2,3,4,5-tetrahydro-1H-benz[c]azepine (3.65 g) was dissolved in 48% aqueous hydrogen bromide solution (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 filtrated and dried under reduced pressure to give the title compound (4.56 g). 1 H-NMR (δ 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,2H), 6.69(dd,J=2.5, 8.1Hz,1H), 6.82(d,J=2.5Hz,1H), 7.05(d,J=8.1Hz,1H), 8.80(brs,2H), 9.42(brs,1H) Step 4 8-Hydroxy-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester In the same manner as in Example 1, Step 1, the title compound (2.64 g) was obtained from 8-hydroxy-2,3,4,5-tetrahydro-1H-benz[c]azepine hydrobromide (3 g), 2N aqueous sodium hydroxide solution (30 ml) and di-tert-butyl dicarbonate (3.2 g). 1 H-NMR (δ ppm,CDCl 3 ) 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(1H), 6.63(1H), 6.70,6.85(1H), 6.98(1H) Step 5 8-Methylthiomethoxy-2,3,4,5-tetxahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester In the same manner as in Example 6, Step 1, the title compound (1.07 g) was obtained from 8-hydroxy-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester (1.06 g), 60% sodium hydride (195 mg) and chloromethyl methyl sulfide (0.41 ml). 1 H-NMR (δ ppm,CDCl 3 ) 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(1H), 6.81,6.92(1H), 7.06(1H) Step 6 8-[4-Ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester In the same manner as in Example 6, Step 2, 8-chloromethoxy-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester (850 mg) was obtained from 8-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester (530 mg) and sulfuryl chloride (0.145 ml) under an argon atmosphere. Then, in the same manner as in Example 6, Step 3, the title compound (755 mg) was obtained. 1 H-NMR (δ ppm,CDCl 3 ) 1.27(tr,J=6.9Hz,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=6.9Hz,2H), 4.30-4.38(m,2H), 6.62-6.67(m,3H), 6.72,6.84(1H), 7.02(1H), 8.25(2H) Step 7 1-(Pyridin-4-yl)-4-(2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)piperidine-4-carboxylic acid ethyl ester In the same manner as in Example 6, Step 4, the title compound (600 mg) was obtained from 8-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-2,3,4,5-tetrahydro-1H-benz[c]azepine-2-carboxylic acid tert-butyl ester (750 mg) and trifluoroacetic acid (2.5 ml). Step 8 4-(2-Amidino-2,3,4,5-tetrahydro-1H-benz[c]azepin-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 1-(pyridin-4-yl)-4-(2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (200 mg), diisopropylethylamine (0.105 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (90 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.16(tr,J=7.2Hz,3H), 1.75(m,4H), 2.20(m,2H), 2.89(m,2H), 3.41(m,2H), 4.04(m,4H), 4.16(q,J=7.2Hz,2H), 4.58(s,2H), 4.58(s,2H), 6.76(1H), 7.11-7.22(m,4H), 7.47(brs,4H), 8.24(1H), 13.60(brs,1H) Example 38 Synthesis of 4-(2-amidino-2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride 4-(2-Amidino-2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (150 mg) was dissolved in 6N-hydrochloric acid (2 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, 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 (δ ppm,DMSO-d 6 ) 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(1H), 7.12(1H), 7.19-7.23(m,3H), 7.54(brs,4H), 8.23(2H), 13.70(brs,1H) Example 39 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride Step 1 4-Ethoxycarbonyl-4-iodomethylpipenidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonylisonipecotinic acid ethyl ester (7.14 g) in tetrahydrofuran (140 ml) were dropwise added a 2M -lithium diisopropylamide-tetrahydrofuran solution (16.6 ml) and diiodomethane (2.7 ml) at -78°C, and the mixture was stirred for 15 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and dried under reduced pressure to give the title compound (8.68 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.27-1.33(m,3H), 1.38-1.45(m,10H), 1.59-1.64(m,1H), 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) Step 2 4-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester Crude crystals of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol were obtained from 2-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline (US Patent No. 3725388)(7.68 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). Thereto were added potassium carbonate (4.27 g) and 4-ethoxycarbonyl-4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (3.71 g), and the mixture was stirred at 100°C for 1 hour. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:8 - ethyl acetate) and dried under reduced pressure to give the title compound (3.92 g). 1 H-NMR (δ ppm,CDCl 3 ) 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) Step 3 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-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-4-ethoxycarbonylpiperidine-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 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ethanol (3 ml), triethylamine (0.39 ml) and 4-chloropyridine hydrochloride (70 mg). The mixture was stirred in a sealed tube at 150°C for 2 days. After completion of the reaction, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (5% methanol-chloroform) and dried under reduced pressure to give the title compound (63 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.21-1.26(3H), 1.58-1.70(2H), 2.17(3H), 2.25-2.40(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) Step 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-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (63 mg) was added conc. hydrochloric acid (2 ml), and the mixture was stirred at 90°C for 21 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue were added 1N aqueous sodium hydroxide solution (0.7 ml), acetone (2 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (61 mg), and the mixture was stirred for 12 hours. After completion of the reaction, dil. hydrochloric acid was added to make the solution acidic and the solvent was evaporated. To the obtained residue was added methanol and the mixture was filtrated. The solvent was evaporated and the obtained residue was separated by HPLC (25% - 40% methanol-water, 0.05% trifluoroacetic acid) and treated with dil. hydrochloric acid, which was dried under reduced pressure to give the title compound (47 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 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 40 Synthesis of 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride Step 1 4-Allyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonylisonipecotinic acid ethyl ester (6 g) in tetrahydrofuran (120 ml) were dropwise added a 2M -lithium diisopropylamide-tetrahydrofuran solution (14 ml) and allyl bromide (2.42 ml) at 78°C, and the mixture was stirred for 3 hours. After completion of 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4: 1) and dried under reduced pressure to give the title compound (5.07 g). Step 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 solution of 4-allyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-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 completion of the reaction, the reaction mixture was filtrated 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 obtained residue was purified by silica gel column chromatography (ethyl acetate) and dried under reduced pressure to give the title compound (4.23 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.26(tr,J=7.0Hz,3H), 1.48-1.57(m,11H), 2.05-2.18(m,2H), 2.65(s,2H), 3.21(m,2H), 3.65-3.75(m,2H), 4.19(q,J=7.0Hz,2H) Step 3 4-Ethoxycarbonyl-4-(2-hydroxyethyl)piperidine-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 1M borane tetrahydrofuran solution (7.42 ml) at -78°C, and the mixture was allowed to warm to room temperature in 15 hours in stirring. After completion of 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 aqueous layer 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 dried under reduced pressure to give the title compound (1.92 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.28(tr,J=7.1Hz,3H), 1.35-1.75(m,11H), 1.82(tr,J=6.7Hz,2H), 2.10-2.20(m,2H), 2.91(m,2H), 3.68(tr,J=6.7Hz,2H), 3.75-4.00(m,2H), 4.18(q,J=7. 1Hz,2H). Step 4 4-Ethoxycarbonyl-4-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-ethoxycarbonyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.92 g) in a mixture of triethylamine (1.15 ml) and methylene chloride (40 ml) was added methanesulfonyl chloride (0.592 ml) at -78°C, and the mixture was stirred for 1 hour. After completion of the reaction, aqueous sodium hydrogencarbonate was added and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (2.38 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.29(tr,3H), 1.36-1.52(m,11H), 2.00(m,2H), 2.10-2.20(m,2H), 2.91(m,2H), 2.99(s,3H), 3.80-4.00(m,2H), 4.17-4.34(m,4H) Step 5 4-Ethoxycarbonyl-4-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-ethoxycarbonyl-4-(2-methanesulfonyloxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (2.38 g) in dimethylformamide (24 ml) was added sodium iodide (4.77 g), and the mixture was stirred at 70°C for 7 hours. After completion of 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (1.03 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.28(tr,J=7.1Hz,3H), 1.26-1.45(m,11H), 2.05-2.20(m,4H), 2.87(m,2H), 3.01-3.07(m,2H), 3.75-4.00(m,2H), 4.20(q,J=7.1Hz,2H) Step 6 4-[2-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester Crude crystals (1.26 g) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol were dissolved in dimethylformamide (15 ml) and thereto were added 60% sodium hydride (243 mg) and 4-ethoxycarbonyl-4-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g), and the mixture was stirred at 70°C for 1 hour. After completion of the reaction, 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and dried under reduced pressure to give the title compound (535 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.26(3H), 1.30-1.44(11H), 1.75-1.85(2H), 2.05-2.20(5H), 2.75-3.00(6H), 3.67(1H), 3.79-3.95(3H), 4.19(2H), 4.57,4.69(2H), 7.05-7.15(3H) Step 7 4-[2-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester 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-tetrahydroisoquinolin-7-ylthio)ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (233 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (72 mg) and triethylamine (0.4 ml). Step 8 4-[2-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 43, Step 4, the title compound (53 mg) was obtained from 4-[2-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (94 mg), conc. hydrochloric acid (2 ml), 1N aqueous sodium hydroxide solution (1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (88 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.48-1.60(m,2H), 1.75-1.90(m,2H), 2.05-2.20(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,2H), 7.07-7.18(m,5H), 7.63(brs,4H), 8.21(2H), 12.93(brs,1H), 13.62(brs,1H) Example 41 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride Step 1 4-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester To a solution of 4-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (252 mg) in methylene chloride (5 ml) was added 70% 3-chloroperbenzoic acid (260 mg) at room temperature, and the mixture was stirred for 12 hours. After completion of the reaction, aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added, and the mixture was stirred for 30 min, followed by 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 silica gel column chromatography (ethyl acetate) and dried under reduced pressure to give the title compound (203 mg). 1 H-NMR (δ 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(1H), 4.16-4.25(2H), 4.69,4.81(2H), 7.32-7.75(3H) Step 2 4-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-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-tetrahydroisoquinolin-7-ylsulfonylmethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (203 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (72 mg) and triethylamine (0.33 ml). Step 3 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 43, Step 4, the title compound (120 mg) was obtained from 4-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (200 mg), conc. hydrochloric acid (10 ml) ,1N aqueous sodium hydroxide solution (2.06 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (181 mg). 1 H-NMR (δ 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=7.5Hz,2H), 7.54(1H), 7.65(1H), 7.72-7.76(m,5H), 8.23(d,J=7.5Hz,2H) Example 42 Synthesis of 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride Step 1 4-[2-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester 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-tetrahydroisoquinolin-7-ylthio)ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (295 mg) and 70% 3-chloroperbenzoic acid (297 mg). Step 2 4-[2-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester 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-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (173 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (60 mg) and triethylamine (0.28 ml). Step 3 4-[2-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 43, Step 4, the title compound (57 mg) was obtained from 4-[2-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (97 mg), conc. hydrochloric acid (2 ml), 1N aqueous sodium hydroxide solution (0.97 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (86 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.42-1.56(m,2H), 1.78-1.90(m,2H), 1.96-2.12(m,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 43 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester dihydrochloride Step 1 1-(Pyridin-4-yl)piperidin-4-one A solution of 4-chloropyridine hydrochloride (10 g), 1,4-dioxo-8-azaspiro[4,5]decane (10 g) and triethylamine (29 ml) in a mixture of ethanol (10 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 5N aqueous sodium hydroxide solution (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 dropwise added conc. hydrochloric acid (30 ml) with ice-cooling, and the mixture was stirred at the same temperature for 10 min. After completion of 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 obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (6.1 g). 1 H-NMR (δ ppm,CDCl 3 ) 2.57(tr,J=6.2Hz,4H), 3.74(tr,J=6.2Hz,4H), 6.71(dd,J=1.5, 4.5Hz,2H), 8.33(dd,J=1.5,4.5Hz,2H) Step 2 4-Amino-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester To a solution of 1-(pyridin-4-yl)piperidin-4-one (1 g) in methanol solution were added ammonium acetate (880 mg), aqueous sodium cyanide solution (560 mg/5 ml), aqeuous ammonia (5 ml) and acetic acid (2 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and 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. Hydrogen chloride was blown into a solution of the residue in 10% hydrogen chloride-methanol (25 ml) with ice-cooling and the solution was stood at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue was added 2N-hydrochloric acid (25 ml). After stirring for 2 hr, 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). 1 H-NMR (δ ppm,CDCl 3 ) 1.55-1.65(m,2H), 2.08-2.17(m,2H), 3.46-3.50(m,4H), 3.74(s,3H), 6.66(dd,J=1.5,4.5Hz,2H), 8.25(dd,J=1.5, 4.5Hz,2H) Step 3 1-(Pyridin-4-yl)-4-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)piperidine-4-carboxylic acid methyl ester To a solution of 4-amino-1-(pyridin-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 (δ ppm,CDCl 3 ) 2.02-2.16(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(2H), 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) Step 4 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester dihydrochloride To a solution of 1-(pyridin-4-yl)-4-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)piperidine-4-carboxylic acid methy ester (627 mg) in a mixture of chloroform (5 ml) and methanol (1 ml) was added a 2N aqueous sodium hydroxide solution (1.1 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2N-hydrochloric acid (1.1 ml) was added and the mixture was concentrated. To the obtained residue were successively added dimethylformamide (3 ml), diisopropylethylamine (0.91 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (305 mg), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtrated, and the filtrate was dropwise added to diethyl ether. The resultant solid was separated by HPLC (0.05% aqueous trifluoroacetic add:methanol=4:1 - 3:2) and treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (480 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.86-2.16(m,4H), 3.00(m,2H), 3.35-3.42(m,5H), 3.67(m,2H), 3.84(m,2H), 4.74(s,2H), 7.17(d,J=7.1Hz,2H), 7.47(1H), 7.56(1H), 7.62(1H), 7.82(brs,4H), 8.22(d,J=7.1Hz,2H), 8.56(s,1H), 13.89(brs,1H) Example 44 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-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) was added 6N hydrochloric acid (2 ml), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. Diethyl ether was added and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (363 mg). 1 H-NMR (δ 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), 4.71(s,2H), 7.16(d,J=7.3Hz,2H), 7.44(1H), 7.56(1H), 7.67(1H), 7.80(brs,4H), 8.20(d,J=7.3Hz,2H), 8.35(s,1H) Example 45 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 1 4-Benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylacetic 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 min and then at 90°C for 10 min. Benzyl alcohol (0.58 ml) was added at the same temperature, and the mixture was stirred for 20 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography and dried under reduced pressure to give the title compound (1.35 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.26(tr,J=7.0Hz,3H), 1.36-1.50(m,11H), 1.96-2.10(m,2H), 3.12(m,2H), 3.37(m,2H), 3.70(m,2H), 4.14(q,J=7.0Hz,2H), 5.01(brtr,1H), 5.09(s,2H), 7.26-7.40(m,5H) Step 2 4-Benzyloxycarbonylaminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester To a solution of 4-benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidine-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 for 30 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ethanol (5 ml), 4-chloropyridine hydrochloride (304 mg) and triethylamine (1.69 ml). The mixture was stirred at 150°C for 2 days in a sealed tube. After completion of the reaction, the solvent was evaporated. To the obtained residue was added 2N aqeuous sodium hydroxide solution, and the mixture was extracted chloroform. 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=93:7) and dried under reduced pressure to give the title compound (738 mg). 1 H-NMR (δ ppm,CDCl 3 ) 1.27(tr,J=7.0Hz,3H), 1.50-1.70(m,2H), 2.05-2.22(m,2H), 3.10-3.22(m,2H), 3.35-3.45(m,2H), 3.52-3.68(m,2H), 4.19(q,J=7.0Hz,2H), 5.05(brtr,1H), 5.09(s,2H), 6.63(d,J=6.4Hz,2H), 7.26-7.38(m,5H), 8.25(d,J=6.4Hz,2H) Step 3 4-Aminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrobromide To a solution of 4-benzyloxycarbonylaminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (331 mg) in chloroform (0.5 ml) was added 25% hydrogen bromide-acetic acid (2 ml), and the mixture was stirred at room temperature for 10 min. After completion of the reaction, hexane, diisopropyl ether and diethyl ether were added and the supernatant was removed. Then, dimethylformamide (1 ml) was added and the resultant solid was collected by filtration, and washed with diethyl ether and dried under reduced pressure to give the title compound (423 mg). Step 4 1-(Pyridin-4-yl)-4-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)piperidine-4-carboxylic acid ethyl ester To 4-aminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrobromide (423 mg) were added pyridine (2 ml) and 7-chlorosulfonyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (273 mg), and the mixture was stirred.at room temperature for 2 hours. After completion of 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 obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (222 mg). 1 H-NMR (δ 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), 6.80-6.88(2H), 7.12-7.36(1H), 7.65-7.80(2H), 8.15-8.25(2H) Step 5 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride In the same manner as in Example 47, Step 4, the title compound (75 mg) was obtained from 1-(pyridin-4-yl)-4-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfbnylaminomethyl)piperidine-4-carboxylic acid ethyl ester (222 mg), diisopropylethylamine (0.28 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (117 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.21(tr,J=7.1Hz,3H), 1.50-1.65(m,2H), 2.00-2.15(m,2H), 2.89-3.15(m,4H), 3.28(m,2H), 3.64(m,2H), 3.95-4.18(m,4H), 4.67(s,2H), 7.18(2H), 7.46(1H), 7.57(1H), 7.60-7.70(m,5H), 7.94(brtr,1H), 8.22(2H) Example 46 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride In the same manner as in Example 48, the title compound (52 mg) was obtained from 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (59 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 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=7.3Hz,2H), 7.45(1H), 7.58(1H), 7.60-7.70(m,5H), 7.90(brtr,1H), 8.21(d,J=7.3Hz,2H), 12.88(brs,1H), 13.57(brs,1H) Example 47 Synthesis of 1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine dihydrochloride Step 1 1-(Pyridin-4-yl)piperidine-4-carbamic acid benzyl ester To a suspension of 1-(pyridin-4-yl)piperidine-4-carboxylic acid (11.18 g) and triethylamine (11.3 ml) in dimethylformamide (110 ml) was added diphenylphosphoryl azide (12.9 ml) at room temperature, and the mixture was stirred at 80°C for 30 min. Benzyl alcohol (6.17 ml) was added at the same temperature, and the mixture was stirred for 12 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1 - 95:5) and dried under reduced pressure to give the title compound (9.46 g). 1 H-NMR (δ ppm,CDCl 3 ) 1.45(m,2H), 2.05(m,2H), 2.98(m,2H), 3.79(m,3H), 4.82(brd,1H), 5.10(s,2H), 6.64(dd,J=1.2, 5.1Hz,2H), 7.29-7.41(m,5H), 8.25(dd,J=1.2,5.1Hz,2H) Step 2 4-Amino-1-(pyridin-4-yl)piperidine 1-(Pyridin-4-yl)piperidine-4-carbamic acid benzyl ester (9.46 g) was hydrogenated using 7.5% palladium carbon (3.57 g) in ethanol (95 ml) solution at 3 atm over 3 hours. 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 (δ ppm,DMSO-d 6 ) 1.22(m,2H), 1.73(m,2H), 2.87(m,3H), 3.82(m,2H), 6.78(d,J=6.5Hz,2H), 8.11(d,J=6.5Hz,2H) Step 3 2-Chloromethyl-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole To a solution of chloroacetonitrile (3.9 ml) in methanol (166 ml) was added sodium methoxide (3.29 g), and the mixture was stirred at room temperature for 40 min under a nitrogen atmosphere. Methanesulfonic acid (7.91 ml) and 3-amino-4-(cyclohexylcarbamoylmethylamino)benzonitrile (8.3 g) were added, and the mixture was stirred for 3 hours. After completion of the reaction, water (166 ml) was added and the precipitated solid was collected by filtration, and washed with a small amount of water. The obtained solid was stirred in a mixture of hexane and tetrahydrofuran, collected by filtration and dried under reduced pressure to give the title compound (9.30 g). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.22(m,5H), 1.57(m,1H), 1.74(m,4H), 3.55(m,1H), 5.02-5.03(m,4H), 7.69(s,2H), 8.21(s,1H), 8.34(brd,1H) Step 4 1-(Cyclohexylcarbamoylmethyl)-5-cyano-2-[1-(pyridin-4-yl)piperidin-4-ylaminomethyl]benzimidazole A solution of 4-amino-1-(pyridin-4-yl)piperidine (1.91 g), 2-chloromethyl-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (3.25 g) and triethylamine (2.74 ml) in dimethylformamide (15 ml) was stirred at room temperature for 1 day. After completion of the reaction, the solvent was evaporated. The obtained residue was extracted with 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 silica gel column chromatography (chloroform:methanol=9:1, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (1.464 g). 1 H-NMR (δ 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,1H), 3.89(m,2H), 4.17(s,2H), 4.87(s,2H), 6.62-6.67(m,3H), 7.49(1H), 7.56(1H), 8.04(1H), 8.24(2H) Step 5 1-(Cyclohexylcarbamoylmethyl)-5-cyano-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole 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) was added ethyl chlorooxalate (0.119 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added, and the mixture was extracted with chloroform and washed with aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (205 mg). 1 H-NMR (δ 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), 3.65-3.90(m,2H), 4.01(m,2H), 4.40(q,J=7.2Hz,2H), 4.73(s,2H), 4.90(s,2H), 6.27(1H), 6.65(d,J=6.3Hz,2H), 7.43(1H), 7.54(1H), 8.00(1H), 8.27(d,J=6.3Hz,2H) Step 6 1-(Cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]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-(pyridin-4-yl)piperidin-4-yl)-N-ethoxalylaminomethyl]benzimidazole (205 mg), hydrogen sulfide, methyl iodide (5 ml), ammonium acetate (138 mg) and sodium acetate (59 mg). 1 H-NMR (δ ppm,DMSO-d 6 ) 1.10-1.28(m,5H), 1.32(tr,J=7.2Hz,3H), 1.45-2.03(m,9H), 3.15-3.30(m,2H), 3.56(m,1H), 4.25-4.42(m,2H), 4.38(q,J=7.2Hz,2H), 4.76(s,1H), 4.90-5.10(m,3H), 7.15-7.19(m,2H), 7.76-7.75(m,2H), 8.15-8.25(m,3H), 8.40-8.52(m,1H), 8.90-9.00(brs,2H), 9.20-9.30(m,2H), 13.42(brs,1H) Example 48 Synthesis of N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[1-(pyridin-4-yl)piperidin-4-yl]aminooxalic acid dihydrochloride To a solution of 1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine dihydrochloride (50 mg) in methanol (1 ml) was added 2N aqueous sodium hydroxide solution (0.107 ml), and the mixture was stirred for 10 min. After completion of the reaction, dil. hydrochloric acid was added. The solvent was evaporated and the obtained residue was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). The obtained residue is treated with hydrogen chloride-ethanol and dried under reduced pressure to give the title compound (20 mg). 1 H-NMR(δ 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,1H), 4.20-4.40(m,2H), 4.74(s,1H), 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,1H), 8.95-9.10(brs,2H), 9.23-9.30(m,2H), 13.57(brs,1H) Example 49 Synthesis of 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methanesulfonate 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid (10 g) was suspended in water (50 ml) and methanesulfonic acid (1.6 ml) was added. The mixture was heated to 50°C for dissolution. 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(δ ppm,D 2 O) 1.60(m,2H), 2.19(m,2H), 2.72(s,3H), 2.77(tr,J=5.8Hz,2H), 3.34(m,2H), 3.45(tr,J=5.8Hz,2H), 3.84-3.92(m,4H), 4.38(s,2H), 6.72(s,1H), 6.79(d,J=8.4Hz,1H), 6.92(d,J=7.8Hz,2H), 7.09(d,J=8.4Hz,1H), 7.89(d,J=7.8Hz,2H) In the same manner as in Example 1 to Example 67, the compounds of Example 68 to Example 115 were obtained. The obtained compounds are shown in Table 1 to Table 8. Example 50 7-[1-(Pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.20(m,2H), 1.80(m,2H), 2.02(m,1H), 2.65(m,1H), 2.81(m,2H), 3.11(m,1H), 3.82(d,2H), 3.95(m,1H), 4.13(s,2H), 4.40(m,1H), 4.54(s,2H), 6.71(s,1H), 6.82(d,J=8.4Hz,1H), 7.14(d,J=8.4Hz,1H), 7.61(brs,4H), 7.90(d,J=6.6Hz,2H), 8.83(d,J=6.6Hz,2H) Example 51 7-[1-(3-Aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.67(m,2H), 1.95(m,3H), 2.81(m,2H), 2.96(m,2H), 3.34(m,2H), 3.56(m,2H), 3.86(m,2H), 6.70(1H), 6.81(1H), 7.07-7.37(m,5H), 7.56(brs,4H), 10.52(brs,1H) Example 52 7-[1-(2-Hydroxybenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.64(m,2H), 1.94(m,3H), 2.81(m,2H), 3.00(m,2H), 3.38(m,2H), 3.79(m,2H), 4.17(m,2H), 4.53(m,2H), 6.69(1H), 6.79-6.88(m,2H), 6.97(1H), 7.13(1H), 7.26(t,1H), 7.46(1H), 7.56(brs,4H), 9.94(brs,1H), 10.25(brs,1H) Example 53 7-[1-(Pyridin-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine trihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.75(m,2H), 2.00(m,2H), 2.10(m,1H), 2.88(m,2H), 3.16(m,2H), 3.49(m,2H), 3.63(m,2H), 3.91(m,2H), 4.51(s,2H), 4.60(s,2H), 6.77(d,J=2.3Hz,1H), 6.89(dd,J=2.3, 8.4Hz,1H), 7.21(d,J=8.4Hz,1H), 7.55(1H), 7.63(brs,4H), 7.69(1H), 7.99(1H), 8.74(1H), 10.35(brs,1H) Example 54 2-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methy ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.54(m,2H), 1.86(m,3H), 2.68(m,2H), 3.03(m,2H), 3.43(m,2H), 3.94(s,3H), 4.40(s,2H), 4.54(m,2H), 6.57(1H), 6.68(1H), 6.99-7.02(m,2H), 7.18(tr,J=7.8Hz,1H), 7.30(tr,J=7.8Hz,1H), 7.44(brs,4H), 7.56(d,J=7.8Hz,1H), 8.00(d,J=7.8Hz,1H), 9.20(brs,1H) Example 55 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.67(m,2H), 1.97(m,3H), 2.83(m,2H), 3.09(m,2H), 3.58(m,4H), 3.83(m,2H), 4.36(s,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,1H) Example 56 N-Benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.17(m,2H), 1.70(m,2H), 1.94(m,1H), 2.70(m,2H), 2.82(m,2H), 3.60(m,2H), 3.81(m,2H), 4.04(m,2H), 4.23(s,2H), 4.54(s,2H), 6.70(d,J=1.4Hz,1H), 6.82(dd,J=1.4, 6.4Hz,1H), 7.13(d,J=6.4Hz,1H), 7.00-7.31(m,6H), 7.61(brs,4H) Example 57 7-[1-(Indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.67(m,2H), 1.97(m,3H), 2.81(m,2H), 2.98(m,2H), 3.58(m,2H), 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,1H), 11.50(s,1H) Example 58 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.70(m,2H), 1.97(m,3H), 2.83(m,2H), 3.12(m,2H), 3.84(m,2H), 4.11(brs,2H), 4.57(s,2H), 6.72(s,1H), 6.83(d,J=8.3Hz,1H), 7.15(d,J=8.3Hz,1H), 7.69(brs,4H), 10.18(brs,1H) Example 59 N-Benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.68(m,2H), 1.97(m,3H), 2.82(m,2H), 3.12(m,2H), 3.45-3.60(m,4H), 3.83(m,2H), 3.99(m,2H), 4.36(d,J=5.8Hz,2H), 4.56(s,2H), 6.72(1H), 6.83(1H), 7.15(1H), 7.24-7.34(m,5H), 7.67(brs,4H), 9.26(tr,J=5.8Hz,1H), 9.97(brs,1H) Example 60 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylaminoacetic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.67(m,2H), 1.96(m,3H), 2.83(tr,J=4.3Hz,2H), 3.11(m,2H), 3.51(m,2H), 3.59(tr,J=4.3Hz,2H), 3.83(m,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 61 7-[1-(5-Nitropyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.26(m,2H), 1.88(m,2H), 2.12(m,1H), 2.81(tr,J=6.0Hz,2H), 3.08(m,2H), 3.57(tr,J=6.0Hz,2H), 3.83(d,2H), 4.53-4.59(m,4H), 6.70(d,J=2.4Hz,1H), 6.82(dd,J=2.4, 8.1Hz,1H), 6.95(d,J=9.6Hz,1H), 7.12(d,J=8.4Hz,1H), 7.60(brs,4H), 8.18(dd,J=3.0, 9.6Hz,1H), 8.94(d,J=3.0Hz,1H) Example 62 7-[1-(2-Nitrobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.60-2.15(m,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=7.9Hz,1H), 7.87(tr,J=7.9Hz,1H), 8.06(d,J=7.9Hz,1H), 8.22(d,J=7.9Hz,1H), 10.27(brs,1H) Example 63 7-[1-(2-Aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine trihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 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(s,2H), 4.54(s,2H), 6.71(1H), 6.83(1H), 7.02(1H), 7.13(2H), 7.34(1H), 7.51(1H), 7.61(4H) Example 64 7-(1-Hexanimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 0.87(tr,3H), 1.31(m,6H), 1.52(m,2H), 1.90(m,2H), 2.12(m,1H), 2.56(m,2H), 2.81(m,2H), 3.12(m,1H), 3.26(m,1H), 3.57(m,2H), 3.84(m,2H), 3.97(m,1H), 4.16(m,1H), 4.55(s,2H), 6.70(d,J=2.4Hz,1H), 6.82(dd,J=2,4, 8.4Hz,1H,), 7.14(d,J=8.4Hz,1H), 7.64(brs,4H), 8.79(1H), 9.25(1H) Example 65 N-Benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.19(m,2H), 1.76(m,3H), 2.61(m,2H), 2.81(m,2H), 3.55(m,4H), 3.77(d,2H), 4.08(d,J=6Hz,2H), 4.53(s,2H), 6.69(d,J=2.7Hz,1H), 6.81(dd,J=2.7, 8.4Hz,1H), 7.13(d,J=8.4Hz,1H), 7.22-7.34(m,5H), 7.53(brs,4H), 7.72(tr,J=6Hz,1H) Example 66 N-Butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide hydrochloride 1 H-NMR(δ 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 67 N-Cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.05-1.83(m,15H), 2.59(m,2H), 2.81(m,2H), 2.95(m,1H), 3.56(m,4H), 3.81(m,2H), 4.53(s,2H), 6.70(1H), 6.81(1H), 7.13(m,2H), 7.54(brs,4H) Example 68 N-(2-Nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carbothioamide hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.35(m,2H), 1.85(m,2H), 2.11(m,1H), 2.82(m,2H), 3.18(m,2H), 3.57(m,2H), 4.54(s,2H), 4.73(m,2H), 6.73(1H), 6.84(1H), 7.14(1H), 7.34-7.42(m,2H), 7.55(brs,4H), 7.66(1H), 7.94(1H), 9.62(s,1H) Example 69 7-[1-(Benzimidazol-2-yl)piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.45(m,2H), 1.93(m,2H), 2.12(m,1H), 2.82(m,2H), 3.57(m,2H), 3.87(m,2H), 4.23(m,2H), 4.54(s,2H), 6.72(s,1H), 6.83(d,J=8.4Hz,1H), 7.14(d,J=8.4Hz,1H), 7.22-7.25(m,2H), 7.39-7.42(m,2H), 7.59(brs,4H), 13.46(s,2H) Example 70 3-[4-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.14(tr,J=7.2Hz,3H), 1.44(m,2H), 1.91(m,2H), 2.09(m,1H), 2.72-2.84(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=7.2Hz,2H), 4.54(s,2H), 6.72(1H), 6.83(1H), 7.14(1H), 7.26(1H), 7.60(brs,4H), 8.33(m,2H) Example 71 3-[4-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 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), 6.72(1H), 6.84(1H), 6.97(1H), 7.14(1H), 7.51(brs,4H), 8.25(m,2H) Example 72 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.59(m,2H), 2.07(m,2H), 2.82(m,2H), 3.20(m,2H), 3.59(m,2H), 4.01(s,2H), 4.51(s,2H), 6.69(s,1H), 6.82(d,J=8.6Hz,1H), 6.91(d,J=9.2Hz,1H), 7.13(d,J=8.6Hz,1H), 7.48(brs,4H), 7.84(dd,J=2.1, 9.2Hz,1H), 8.07(d,J=2.1Hz,1H) Example 73 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(3-aminopropionyl)-piperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.49(m,1H), 1.59(m,1H), 2.05(m,2H), 2.71(m,2H), 2.71(m,2H), 2.81(m,2H), 2.97(m,3H), 3.57(m,2H), 3.65(m,1H), 4.00(m,3H), 4.54(s,2H), 6.68(s,1H), 6.81(d,J=8.4Hz,1H), 7.13(d,J=8.4Hz,1H), 7.66(brs,4H), 7.98(brs,3H) Example 74 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.51(m,1H), 1.64(m,1H), 2.06(m,2H), 2.81(m,2H), 3.01(m,1H), 3.20(m,1H), 3.57(m,2H), 3.78(m,2H), 3.91(s,2H), 4.02(s,2H), 4.54(s,2H), 6.70(s,1H), 6.81(d,J=8.6Hz,1H), 7.14(d,J=8.6Hz,1H), 7.43(s,4H), 7.55(s,1H), 7.62(brs,4H), 9.01(s,1H), 14.36(brs,1H) Example 75 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(piperidin-4-ylsulfamoyl)piperidine-4-carboxylic acid hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.62(m,4H), 1.93(m,2H), 2.11(m,2H), 2.78-3.00(m,6H), 3.17(m,2H), 3.36(m,3H), 3.57(m,2H), 3.99(s,2H), 4.53(s,2H), 6.69(1H), 6.80(d,J=8.4Hz,1H), 7.14(d,J=8.4Hz,1H), 7.52(d,1H), 7.60(brs,4H), 8.85(brs,1H), 9.02(brs,1H) Example 76 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-dimethylaminoacetylpiperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ 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,1H), 3.50-3.59(m,3H), 4.29(m,2H), 4.55(s,2H), 6.70(1H), 6.81(1H), 7.14(1H), 7.65(brs,4H), 9.68(brs,1H) Example 77 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.16(tr,J=6.9Hz,3H), 1.63(m,2H), 2.10(m,8H), 2.81(tr,J=5.7Hz,2H), 3.17(m,2H), 3.57(tr,J=5.7Hz,2H), 3.99-4.05(m,4H), 4.14(q,J=6.9Hz,2H), 4.53(s,2H), 6.69(d,J=2.4Hz,1H), 6.80(dd,J=2.4, 8.4Hz,1H), 7.13(d,J=8.4Hz,4H), 7.58(brs,4H), 7.91(dd,J=5.3,9.1Hz,1H), 8.46(d,J=5.3Hz,1H), 8.64(d,J=9.1Hz,1H), 9.15(s,1H), 9.93(s,1H) Example 78 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR(δ 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,1H), 6.68(1H), 6.79(1H), 7.14(1H), 7.58(brs,4H), 9.65(brs,1H) Example 79 4-[4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride hydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.15(tr,J=7.2Hz,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=7.2Hz,2H), 4.53(s,1H), 6.68(1H), 6.80(1H), 7.13(1H), 7.24(d,J=7.8Hz,2H), 7.64(brs,4H), 8.25(d,J=7.8Hz,2H) Example 80 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)-piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.14(tr,J=6.9Hz,3H), 1.69(m,2H), 2.14(m,2H), 2.81(m,2H), 3.14(m,2H), 3.56(m,2H), 3.82(m,2H), 4.05(s,2H), 4.13(q,J=6.9Hz,2H), 4.52(s,2H), 6.69(1H), 6.81(1H), 7.07(d,J=9Hz,2H), 7.13(1H), 7.56(brs,4H), 7.75(d,J=9Hz,2H), 8.71(brs,2H), 8.97(brs,2H) Example 81 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(δ ppm,DMSO-d 6 ) 1.16(tr,J=7.0Hz,3H), 1.71(m,2H), 2.17(m,2H), 2.44(m,6H), 2.82(m,2H), 3.56(m,2H), 3.99(m;2H), 4.09(s,2H), 4.16(q,J=7.0Hz,2H), 4.54(s,2H), 6.70(1H), 6.82(d,J=8.3Hz,1H), 6.98(s,2H), 7.15(d,J=8.3Hz,1H), 7.59(brs,4H), 13.41(brs,1H) Example 82 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.17(tr,J=7.0Hz,3H), 1.73(m,2H), 2.18(m,2H), 2.47(s,3H), 2.83(m,2H), 3.37-3.57(m,4H), 4.00-4.08(m,4H), 4.16(q,J=7.0Hz,2H), 4.54(s,2H), 6.70(1H), 6.82(1H), 7.07-7.16(m,3H), 7.58(brs,4H), 8.13(1H), 13.64(brs,1H) Example 83 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester trihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.26-1.42 (m,6H), 2.07-2.40(m,8H), 2.82-3.07(m,7H), 3.50-3.70(m,5H), 3.96(s,2H), 4.16(q,2H), 4.53(s,2H), 6.71(1H), 6.82(1H), 7.14(1H), 7.57(brs,4H) Example 84 4-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid trihydrochloride 1 H-NMR( δ ppm,DMSO-d 6 ) 1.25(tr,3H), 2.00-2.45(m,10H), 2.80-3.30(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,1H) Example 85 7-[2-(4-Cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetehydroisoquinoline-2-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.92(m,2H), 2.11(m,2H), 2.19(m,2H), 2.82(m,2H), 2.93(m,2H), 3.58(m,2H), 4.54(m,2H), 5.11(s,2H), 6.78(s,1H), 6.85(d,J=6.3Hz,1H), 7.16(d,J=6.3Hz,1H), 7.59(brs,4H), 9.26(brs,2H) Example 86 4-[2-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.19(tr,J=7.1Hz,3H), 1.62(m,2H), 2.05(m,2H), 2.20(m,2H), 2.82(m,2H), 3.27(m,2H), 3.58(m,2H), 3.97(m,2H), 4.06(m,2H), 4.15(q,J=7.1Hz,2H), 4.55(s,2H), 6.65(1H), 6.76(1H), 7.14(1H), 7.19(d,J=7.6Hz,2H), 7.60(brs,4H), 8.22(d,J=7.6Hz,2H) Example 87 4-(2-Amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.74(m,2H), 2.18(m,2H), 2.82(m,2H), 3.44(m,2H), 3.59(m,2H), 3.72(s,3H), 4.04(m,2H), 4.49(s,2H), 6.69(s,1H), 6.99(s,1H), 7.21(2H), 7.71(brs,4H), 8.23(2H) Example 88 4-(2-Amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 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), 6.99(s,1H), 7.21(2H), 7.71(brs,4H), 8.23(2H) Example 89 1-(Cyclohexylcarbamoylmethyl)-2-[4-methoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylaminomethyl]benzimidazole-5-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 1.13-1.25(m,5H), 1.53(m,1H), 1.64-1.72(m,4H), 1.82(m,2H), 2.01(m,2H), 3.49(m,1H), 3.59-3.65(m,5H), 3.75(m,2H), 3.99(s,2H), 5.06(s,2H), 7.18(d,J=5.5Hz,2H), 7.66-7.72(m,2H), 8.15(s,1H), 8.21(d,J=5.5Hz,2H), 8.30(1H), 9.02(brs,2H), 9.23(brs,2H), 13.38(brs,1H) Example 90 1-(Cyclohexylcarbamoylmethyl)-2-[4-methoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylcarbamoyl]benzimidazole-5-carboxamidine dihydrochloride 1 H-NMR(δ ppm,DMSO-d 6 ) 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(m,6H), 3.95(m,2H), 5.32(s,2H), 7.23(2H), 7.80(1H), 7.89(1H), 8.20-8.26(m,4H), 9.18(brs,2H), 9.34(brs,2H), 9.55(brs,1H), 13.46(brs,1H) [Experimental Examples] The biological activity of the compound of the present invention was tested. The compound of the present invention was compared with a control compound, (2S)-2-[4-[(3S)-1-acetimidoylpyrrolidin-3-yloxy]phenyl]-3-[7-amidinonaphthalen-2-yl]propionic acid hydrochloride pentahydrate of the following formula: as Comparative Example 1. Test of enzyme inhibition using synthetic substrate (Experimental Examples 1-2) Experimental Example 1 Determination of anti-factor Xa (FXa) activity Human FXa [Enzyme research Laboratories (USA)] enzyme (40 µl, 0.16U/ml) and test compounds (40 µl) adjusted to various concentrations were incubated in 0.1M Tris (Tris-hydroxymethyl-aminomethane) buffer (pH 8.4) containing 0.2M sodium chloride (herein to be referred to as 0.1M tris-0.2M NaCl buffer) (40 µl) at 37°C for 10 min. A synthetic substrate S-2222 (Daiichi Pure Chemical (Tokyo, Japan), 40 µl) adjusted to 0.8 mM was added and the mixture was incubated at 37°C for 10 min. The reaction was stopped by addition of 60% acetic acid (40 µl) and absorbance at 405 nm was measured by Model 3550 (BIO-RAD). For the control, the solvent was used instead of the test compound. The value of control was taken as 100% and the drug concentration showing 50% absorbance of control was taken as IC 50 . The results are shown in Table 9. Experimental Example 2 Determination of anti-factor IIa (FIIa) activity Human FIIa (Sigma) enzyme (40 µl, 3.2 U/ml) and test compounds (40 µl) adjusted to various concentrations were incubated in 0.1M tris-0.2M NaCl buffer (pH 8.4) (40 µl) at 37°C for 10 min. A synthetic substrate S-2238 (Daiichi Pure Chemical (Tokyo, Japan), 40 µl) adjusted to 0.8 mM was added and the mixture was incubated at 37°C for 20 min. The reaction was stopped by addition of 60% acetic acid (40 µl) and absorbance at 405 nm was measured by Model 3550 (BIO-RAD). For the control, the solvent was used instead of the test compound. The value of control was taken as 100% and the drug concentration showing 50% absorbance of control was taken as IC 50 (µM). The results are shown in Table 9. test compound Experimental Example 1 (µM) Experimental Example 2 (µM) test compound Experimental Example 1 (µM) Experimental Example 2 (µM) Example 1 0.06 >10 Example 36 0.5 >10 Example 2 0.4 >10 Example 39 0.4 >10 Example 4 0.6 >10 Example 40 0.7 >10 Example 6 0.08 >10 Example 47 0.9 >10 Example 7 0.03 >10 Example 48 0.3 >10 Example 10 0.7 >10 Example 49 >10 Example 11 0.3 >10 Example 65 0.7 >10 Example 12 0.6 >10 Example 70 0.2 >10 Example 13 0.2 >10 Example 71 0.2 >10 Example 14 0.1 >10 Example 80 0.4 >10 Example 15 0.2 >10 Example 81 0.7 >10 Example 16 0.2 >10 Example 82 0.6 >10 Example 17 0.7 >10 Example 18 0.8 >10 Example 25 0.5 >10 Example 26 0.4 >10 Example 28 0.4 >10 Example 29 0.3 >10 Example 30 0.2 >10 Example 33 0.04 >10 Example 35 0.5 >10 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 min to obtain normal plasma of various animals. Purified water (5 µl) containing various concentrations of test compound was added to plasma (45 µl) and the resultant mixtures were used as samples. Thrombin reagent (Baxter) was prepared and heated at 37°C for 5 min, and a sample (50 µl) was admixed with the thrombin reagent (100 µl). The time (PT) until precipitation of fibrin was measured. The drug concentration that doubled the PT hours of the drug untreated group was calculated and taken as CT 2 . The results are shown in Table 10. CT 2 (µM) test compound mouse rat crab-eating monkey human Example 7 10 30 0.5 Example 49 5 Comparative Example 1 10 10 4 2 Intravenous administration tests (Experimental Examples 4-5) Experimental Example 4 Intravenous administration tests in mouse A test compound dissolved in physiological saline was intravenously administered to ICR mice (body weight 20 - 30 g, 4-6 weeks old) and the activity of the test compound was evaluated based on the human FXa inhibitory activity in serum as an indicator. At 10, 30, 60, 120 min from the intravenous administration, blood was taken from the eye ground using a hematocrit tube. The blood was centrifuged at 9000 G for 5 min and the obtained serum was used for the determination. Human FXa inhibitory activity was measured as follows. Human FXa [Enzyme research Laboratories (USA)] enzyme (40 µl, 0.5 U/ml) and a 4-fold diluted plasma sample (40 µl) were incubated in 0.1M Tris-0.2M NaCl buffer (pH 8.4) (40 µl) at 37°C for 10 min. A synthetic substrate S-2222 (Daiichi Pure Chemical (Tokyo, Japan), 40 µl) adjusted to 0.8 mM was added and the mixture was incubated at 37°C for 5 min. The reaction was stopped by addition of 60% acetic acid (40 µl) and absorbance at 405 nm was measured by Model 3550 (BIO-RAD). For the control, serum or plasma obtained prior to blood sampling was used for measurement Human FXa inhibitory activity was calculated as inhibition percentage (%) against control. The results are shown in Table 11. inhibition (%) (mean±S.D.; n=3) test compound dose (mg/kg) 10 minutes 30 minutes 60 minutes 120 minutes Example 7 1 64±2 54±1 46±4 30±5 3 82±1 78±1 72±2 59±5 Comparative Example 1 1 43±3 14±2 0±1 1±2 Experimental Example 5 Intravenous administration tests in monkey A test compound dissolved in physiological saline was intravenously administered to monkey (crab-eating monkey, body weight 3.5 - 4.5 kg) and the activity of the test compound was evaluated based on the human FXa inhibitory activity in plasma as an indicator. At 10, 30, 60, 120, 180 min from the intravenous administration, blood was taken from the saphenous vein with the passage of time and the blood was centrifuged at 2000 G for 10 min. The obtained citric acid plasma was used for the determination. Human FXa inhibitory activity was determined in the same manner as in the test using mouse. The results are shown in Table 12. Inhibition (%) (mean±S.D. ; n=3) test compound dose (mg/kg) 10 minutes 30 minutes 60 minutes 120 minutes 180 minutes Example 9 1 82±1 72±2 58±4 41±3 29±2 Oral administration tests (Experimental Examples 6-7) Experimental Example 6 Oral administration tests in mouse A test compound dissolved in distilled water was orally administered to ICR mice (body weight 20 - 30 g, 4-6 weeks old) and the activity of the test compound was evaluated based on the human FXa inhibitory activity in serum as an indicator. At 30, 60, 120, 180 min from the oral administration, blood was taken from the eye ground using a hematocrit tube. The blood was centrifuged at 9000 G for 5 min and the obtained serum was used for the determination. Human FXa inhibitory activity was determined in the same manner as in the test by intravenous administration. The results are shown in Table 13. Inhibition (%) (mean±S.D.; n=3) test compound dose (mg/kg) 30 minutes 60 minutes 120 minutes 180 minutes Example 7 10 48±7 40±9 26±7 18±9 Comparative Example 1 10 11±4 6±4 6±4 6±4 Experimental Example 7 Oral administration tests in monkey A test compound dissolved in distilled water was orally administered to monkey (carb-eating monkey, body weight 3.5 - 4.5 kg) and the activity of the test compound was evaluated based on the human FXa inhibitory activity in plasma as an indicator. At 30, 60, 120, 240, 480 min from the oral administration, blood was taken from the saphenous vein with the passage of time and the blood was centrifuged at 2000 G for 10 min. The obtained citric acid plasma was used for the determination. Human FXa inhibitory activity was determined in the same manner as in the test by intravenous administration. The results are shown in Table 14. Inhibition (%) (mean±S.D. ; n=3) test compound dose (mg/kg) 30 minutes 60 minutes 120 minutes 240 minutes 480 minutes Example 9 10 28±33 37±27 46±20 49±9 23±11 Experimental Example 8 Blood coagulation model in rat Intravenous administration of thromboplastin (Sigma) to rat promotes coagulation system, which in turn decreases platelets and increases fibrin degradation product (FDP). Thus, the test compound was intravenously administered 10 min before thromboplastin administration and the inhibitory effects of the test compound on the decrease of platelets and the formation of FDP by thromboplastin were studied. The thromboplastin administered had such concentration as to form clots within 20 seconds from the addition of one plasma dose to two thromboplastin doses and was administered in 1 ml/kg dose. Platelets were counted (PLT value) 10 min later on a blood cell counter sysmex F-800 [Dade International Inc. (USA)], and FDP was measured 30 min later using FDP latex reagent for serum [Teikoku Hormone Mfg. Co., Ltd. (Tokyo, Japan)]. The results are shown in Table 15. In every Example, the PLT value of the thromboplastin untreated group was (106±13)× 10 4 and the FDP value of this group was 0±0 µg/ml. (n=3) test compound dose (mg/kg) PLT value (x 10 4 blood platelet/µl) FDP value (µg/ml) Example 7 1 96±18 0±0 0.3 72±10 4±1 0.1 66±21 7±3 Vehicle 49±11 8±3 Comparative Example 1 0.3 100±5 1±1 0.1 67±16 3±2 0.03 41±9 9±2 Vehicle 42±18 8±3 (mean±S.D) INDUSTRIAL APPLICABILITY The compound of the formula [I] of the present invention has superior blood coagulation factor Xa inhibitory activity, as is evident from the foregoing Experimental Examples. Therefore, the compound is useful as an agent for the prophylaxis and/or treatment of various diseases caused by blood coagulation or thrombus, namely, cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (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, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after recanalization such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR) and the like, thrombosis due to extracorporeal circulation and the like, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger disease, tumor thrombosis, thrombus by atrial fibrillation, and the like. It is expected, therefore, that the compound of the present invention will make an extremely useful therapeutic agent of these diseases.

Claims: An amidine compound of the formula [I] wherein R is a group of the formula or wherein R 4 is hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group or halogen atom, R 5 is hydrogen atom, cyano group, carboxy group or C 1-6 alkoxycarbonyl group, R 6 is hydrogen atom, C 3-10 cycloalkyl group, hydroxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )oxycarbonyl group wherein said C 6-12 aralkyl(C 1-6 )oxycarbonyl group is optionally substituted by halogen atom, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group or trifluoromethyl group, nitro group, amino group, C 1-8 alkylamino group, di(C 1-6 )alkylamino group, C 6-12 aryl group, heteroaryl group selected from a 5- or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and may form a condensed ring with other ring that may be partially saturated wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl group, hydroxy group, C 1-6 alkoxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )oxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group, 5- to 7-membered saturated heterocycle having at least one nitrogen atom, wherein said saturated heterocycle is optionally substituted by C 1-6 alkyl group, acyl group, di(C 1-6 )alkylamino(C 1-6 )alkanoyl group or imidoyl group, or wherein Ak is C 1-6 alkyl group and Hal is halogen atom, X 2 is oxygen atom, sulfur atom, -SO 2 -, -SO 2 NH- or a single bond, X 3 is -(CH 2 ) m - wherein m is 0 or an integer of 1 to 3, X 4 is -CO-, -C(=NH)-, -SO 2 -, -CONH-, -CSNH-, -SO 2 NH-, -(CH 2 ) r CONH-, -(CH 2 ) r CH(OH)-, wherein r is. 0 or an integer of 1 to 3, or a single bond, X 5 is alkylene group having 1 to 6 carbon atoms, alkenylene group having 2 to 6 carbon atoms, or a single bond, R 7 is hydrogen atom, C 1-6 alkyl group or wherein R 9 is oxygen atom, sulfur atom, NH, NR 11 wherein R 11 is C 1-6 alkyl group, C 6-12 aralkyl(C 1-6 )group wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group, hydroxy group, C 1-6 alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group, or hydroxy group, and R 10 is C 1-6 alkyl group, C 1-6 alkoxy group, amino group, C 1-6 alkylamino group or di(C 1-6 )alkylamino group, R 8 is hydrogen atom, C 1-6 alkyl group, C 3-10 cycloalkyl group wherein said cycloalkyl group is optionally substituted by C 1-6 alkyl group or carboxy group, carboxy group, C 1-6 alkoxycarbonyl group, C 6-12 aryl group, heteroaryl group selected from a 5- or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and may form a condensed ring with other ring that may be partially saturated wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group wherein said C 1-6 alkyl group is optionally substituted by halogen atom, hydroxy group, C 1-6 alkoxy group, carboxy group and C 1-6 alkoxycarbonyl group, C 6-12 aralkyl(C 1-6 )group wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, C 1-6 alkyl group, hydroxy group, C 1-6 alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group, or 5 to 7-membered saturated heterocycle having at least one nitrogen atom, Y 1 is oxygen atom, -NH-, -CONH-, or -NR 12 - wherein R 12 is C 1-6 alkyl group or -Y 6 -R 13 wherein R 13 is hydrogen atom, C 1-6 alkyl group or C 6-12 aryl group wherein said C 1-6 alkyl group or C 6-12 aryl group is optionally substituted by carboxy group, C 1-6 alkoxycarbonyl group or C 6-12 aralkyl(C 1-6 )oxycarbonyl group, Y 6 is -CO-, -CO 2 -, -COCO 2 -, -SO 2 -, -SO 2 (CH 2 ) r - or -(CH 2 ) r - wherein r is 0 or an integer of 1 to 3, Y 2 is oxygen atom, sulfur atom or a single bond, Y 3 is wherein s and t are the same or different and each is an integer of 1 to 3, or a single bond, Y 4 is oxygen atom, -CO-, -CO 2 -, -SO 2 -, -CONH-, -CH=CH- or a single bond, Y 5 is -(CH 2 ) p -, -(CH 2 ) p' -CHAk-(CH 2 ) p" -, -(CH 2 ) p' -CAk Ak'-(CH 2 ) p" - or wherein Ak, Ak' are the same or different and each is C 1-6 alkyl group, p is 0 or an integer of 1 to 3, p' and p" are the same or different and each is 0 or an integer of 1 or 2, ring A is wherein R 14 is carboxy group, C 1-6 alkoxycarbonyl group or C 6-12 aralkyl(C 1-6 )oxycarbonyl group wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group or trifluoromethyl group, 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 of 1 to 3; and R 1 , R 2 and R 3 are the same or different and each is hydrogen atom, hydroxy group C 1-6 alkyl group or C 6-12 aryl group, or a salt thereof. The amidine compound of the formula [I] according to claim 1, wherein R is a group of the formula or 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. The amidine compound of the formula [I] according to claim 2, 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. The amidine compound of the formula [I] according to claim 3, 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. The amidine compound of the formula [I] according to claim 4, wherein X 3 is -(CH 2 ) m - wherein m is as defined above and X 4 is a group of the formula and j is 1, or a salt thereof. The amidine compound of the formula [I] according to claim 5, wherein R 6 is hydrogen atom, X 2 is oxygen atom, and X 5 is a single bond, or a salt thereof. The amidine compound of the formula [I] according to claim 1, wherein R is a group of the formula wherein R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , ring A, m and n are as defined above, or a salt thereof. The amidine compound of claim 1, which is 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-(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-carboxamide oxime, N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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 methyl ester, 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-(pyrimidin-4-yl)piperidine-4-carboxylic acid, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide, 7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-benzylsulfonylpiperidin-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-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-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-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-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-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-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-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-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-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine, N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[1-(pyridin-4-yl)piperidin-4-yl]aminooxalic acid, 7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(2-hydroxybenzyl)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-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methy ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide, 7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide, 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-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide, N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-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-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid, 4-(2-amidino-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-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)-piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid, 7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(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-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, or a salt thereof. The amidine compound of claim 3, which is 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-(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-carboxamide oxime, N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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 methyl ester, 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-(pyrimidin-4-yl)piperidine-4-carboxylic acid, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 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, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide, 7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-benzylsulfonylpiperidin-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-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide, N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)pipezidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-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-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-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-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-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-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-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-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, 7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-[1-(2-hydroxybenzyl)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-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methy ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide, 7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide, 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-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide, N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide, N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-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-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester, 3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid, 4-(2-amidino-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-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pipenidin-4-ylsulfamoyl)piperidine-4-carboxylic 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-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester, 4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester, 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid, 7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(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-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, or a salt thereof. A pharmaceutical composition comprising an amidine compound of any of claim 1 to claim 9 or a salt thereof, and a pharmaceutically acceptable additive. A blood coagulation inhibitor comprising an amidine compound of any of claim 1 to claim 9 or a salt thereof as an active ingredient. A factor Xa inhibitor comprising an amidine compound of any of claim 1 to claim 9 or a salt thereof as an active ingredient An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises an amidine compound of any of claim 1 to claim 9 or a salt thereof as an active ingredient. Use of the amidine compound of any of claim 1 to claim 9 or a salt thereof for the production of a blood coagulation inhibitor. Use of the amidine compound of any of claim 1 to claim 9 or a salt thereof for the production of a factor Xa inhibitor. Use of the amidine compound of any of claim 1 to claim 9 or a salt thereof for the production of an agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus. A commercial package comprising the blood coagulation inhibitor of claim 11 and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting coagulation of blood. A commercial package comprising the factor Xa inhibitor of claim 12 and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting factor Xa. A commercial package comprising the agent for the prophylaxis or treatment of claim 13 and a written matter associated therewith, the written matter stating that the agent can or should be used for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus.

Inventors: HAYASHI MIKIO, KATOH SUSUMU, YOKOTA KATSUYUKI, HAYASHI, MIKIO, KATOH, SUSUMU, YOKOTA, KATSUYUKI, HAYASHI, MIKIO,, YOKOTA, KATSUYUKI,
Applicants: JAPAN TOBACCO INC, JAPAN TOBACCO INC.
Application year: 1999
Main classification: C07D401
IPC codes: C07D417, A61K31, C07D401, A61P7, C07D403