JP3283485B2 - Amidine compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel amidine compound having a blood coagulation factor Xa inhibitory activity. The present invention also relates to pharmaceutical compositions containing these compounds, factor Xa inhibitors, and agents for treating diseases caused by blood coagulation or thrombus.

[0002]

2. Description of the Related Art Thrombosis such as unstable angina, deep vein thrombosis, and general intravascular coagulation (DIC) is caused by enhanced blood coagulation ability. Conventionally, heparin and warfarin have been used as agents for preventing and treating thrombus formation. Antithrombin II for heparin
Since it acts on I (ATIII) and indirectly suppresses the coagulation system, it may have a weak effect on arterial thrombus. In addition, some patients generate an antibody against platelet factor (PF4) to enhance the coagulation system, and may also have a tendency to bleed as a side effect. Warfarin is not always a safe and easy-to-use drug because it takes time to develop the action of the drug. Therefore, development of an anticoagulant is required to solve these problems.

Factor X is a glycoprotein having a molecular weight of 58,000. In the endogenous system, factor X is factor IXa, factor VIIIa, or Ca.
^In the presence of the ²⁺ complex, it is activated on the phospholipid membrane to become factor Xa. On the other hand, in a coagulation system called an extrinsic system, it is activated by factor VIIa in the presence of tissue factor to become factor Xa. Factor Xa produced in both systems activates prothrombin to thrombin. The generated thrombin activates further upstream of this cascade, producing large amounts of thrombin. As a result, fibrinogen becomes fibrin and blood coagulation occurs.

[0004] Since the blood coagulation system is an amplification reaction, it is considered that it is more efficient to suppress the production at a previous stage than to directly inhibit the activity of the generated thrombin. In addition, since factor Xa is a junction of intrinsic and extrinsic coagulation systems, inhibiting factor Xa is considered to be extremely effective. Also, in clinical practice, low molecular weight heparin has less bleeding tendency than heparin, and experiments using baboons [thrombosis and hemostas, 74
Vol.464, 1995 [Thronbosis and Haemostas,
74 , 464 (1995)]] that there is less bleeding tendency when factor Xa is suppressed than when thrombin is suppressed. Therefore, factor Xa inhibitors have the potential to exhibit antithrombotic effects without affecting the bleeding time seen with conventional anticoagulants.

[0005] As a factor Xa inhibitor, International Publication WO 9
In the specification of 07/08165, the general formula

Embedded image (Wherein R ¹ , R ² , and R ³ represent a hydrogen atom, a hydroxyl group, a halogen atom, a hydroxyalkyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aralkyloxy group, an alkenyloxy group, an alkynyloxy group, and a carboxy group. Group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an alkenyloxycarbonylalkyl group or an alkynyloxycarbonylalkyl group, A represents a hydroxyl group, a carboxy group, an alkoxy group as a substituent X represents an alkylene group which may be substituted with a carbonyl group or a halogen atom, X represents a bond, an alkylene group or an alkyleneoxy group, Y represents a single bond, a chalcogen atom or a CO group, and Z represents a saturated or unsaturated substituent. Sa It represents good heterocyclic or carbon ring, which may, optionally substituted amino group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group or an alkyl group, n 1 or 2
And m represents an integer of 0 to 4. ) Are described. Also, Japanese Patent Laid-Open No. 5-208946.
In general, US Pat. No. 5,620,991 and European Patent No. 540051 describe general formulas.

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkoxy group;
R ² is a hydrogen atom, a lower alkyl group, a lower alkoxy group,
Represents a carboxy group, an alkoxycarbonyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group,
R ³ represents a hydrogen atom, a carboxy group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group, and R ⁴ represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group. , N is 0-1
A is an integer of 1 to 2 hydroxyalkyl groups,
A carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkylene group having 1 to 4 carbon atoms which may be substituted by an alkoxycarbonylalkyl group; X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group; Is a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, an amino group which may have a substituent, or an aminoalkyl which may have a substituent Represents a group,

Embedded image Represents a group selected from an indolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a naphthyl group, a tetrahydronaphthyl group and an indanyl group. ) Are described. In addition, in the specification of International Publication WO96 / 16940, a general formula

Embedded image (Wherein, R ¹ represents a hydrogen atom or a formula —AWR ⁴ ,
A is the formula

Embedded image Or -SO ₂ - represents, X ² represents an oxygen atom or a sulfur atom, W is a single bond or -NR ⁵ - represents, R ⁴ is a hydroxyl group, a lower alkoxy group, optionally substituted lower alkyl group, a substituted Represents an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. However, when W is a group represented by the formula —NR ⁵ —, R ⁴ may be a hydrogen atom, but is not a hydroxyl group or lower alkoxy. R ⁵ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may be substituted or an optionally substituted lower alkanoyl group, R ²
Represents a lower alkyl group, R ³ represents a hydrogen atom, a halogen atom, a carboxy group, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower alkyl group or a lower alkoxycarbonyl group, and B represents a lower alkylene group Or n represents a carbonyl group, and n represents an integer of 0 or 1. ) Are described.

[0006]

An object of the present invention is to provide a novel compound useful as a factor Xa inhibitor. Another object of the present invention is to provide a novel factor Xa inhibitor.

[0007]

Means for Solving the Problems In view of the above-mentioned problems, the present inventors have conducted intensive studies in search of compounds useful as factor Xa inhibitors. Compound was found. The present inventors have also found that these compounds are excellent factor Xa inhibitors and completed the present invention.

The compound of the present invention specifically inhibits blood coagulation factor Xa and has a strong anticoagulant effect. Therefore, various diseases caused by blood coagulation and thrombus, such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TI
A), diseases in cerebrovascular disorders such as subarachnoid hemorrhage, ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral Arterial embolism, deep vein thrombosis, generalized intravascular coagulation, thrombosis after vascular prosthesis or valve replacement, reocclusion or restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty Diseases in various vascular disorders such as reocclusion or restenosis after revascularization therapy such as PTCA or coronary thrombolytic therapy (PTCR), thrombosis during extracorporeal circulation, glomerulonephritis, nephrotic syndrome, diabetic It is useful as a prophylactic and / or therapeutic agent for retinopathy, arteriosclerosis obliterans, Buerger's disease, tumor thrombosis, thrombus associated with atrial fibrillation, and the like.

Further, as is apparent from Test Example 2 described below,
Since the compound of the present invention has no inhibitory activity on thrombin, that is, factor IIa (FIIa), it is considered that bleeding as a side effect is extremely small. Furthermore, as is clear from Test Examples 6 and 7 described below, the agent exerts an excellent Xa factor inhibitory effect even in oral administration.

[0010] In addition, for influenza virus propagation,
Finding that factor Xa is involved (JP-A-6-227)
No. 971), and the compound of the present invention is considered to be useful for prevention and / or treatment of influenza.

The present invention relates to a compound represented by the following general formula [I], which is useful as a factor Xa inhibitor. The present invention also provides a compound represented by the following general formula [I] or a salt thereof or a prodrug thereof as an active ingredient.
It relates to factor a inhibitors. More specifically, the following (1) to (2)
As shown in 3).

(1) General formula [I]

Embedded image [Where R is

Embedded image [Where R ⁴ is a hydrogen atom, a hydroxyl group, a lower alkyl group,
Represents a lower alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom, a cyano group, a carboxy group or a lower alkoxycarbonyl group, R ⁶ represents a hydrogen atom, a cycloalkyl group,
Hydroxyl group, carboxy group, lower alkoxycarbonyl group,
An aralkyloxycarbonyl group (the aralkyloxycarbonyl group is a halogen atom, a nitro group, an alkyl group,
Optionally substituted with an alkoxy group or a trifluoromethyl group), a nitro group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an aryl group, a heteroaryl group (the aryl or heteroaryl group is Alkyl group, hydroxyl group, lower alkoxy group, carboxy group,
A lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a nitro group, an amino group, an acylamino group, an amidino group or a substituent selected from a hydroxyamidino group;
Or 3 may be substituted. ) A 5- to 7-membered saturated heterocyclic ring containing at least one nitrogen atom (the saturated heterocyclic ring may be substituted by a lower alkyl group, an acyl group, a di-lower alkylamino lower alkanoyl group or an imidoyl group) .) Or

Embedded image (Where Ak represents a lower alkyl group, Hal represents a halogen atom), and X ² represents an oxygen atom, a sulfur atom,-
SO ₂ -, -SO ₂ NH- or a single bond, X ³
It is _{- (CH 2) m - (} . Here, m represents an integer of 0 or 1 to 3) represent, X ⁴ is -CO-, -C (= N
_{H) -, -SO 2 -,} -CONH-, -CS
_{NH-, -SO 2 NH-, - (} CH 2) r CONH-
_{, - (CH 2) r CH} (OH) -,

Embedded image (Where r represents 0 or an integer of 1 to 3) or a single bond; X ⁵ represents an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or a single bond; ⁷
Is a hydrogen atom, a lower alkyl group or

Embedded image ｛Where R ⁹ is an oxygen atom, a sulfur atom, an NH group, NR
¹¹ [where R ¹¹ is a lower alkyl group, an aralkyl group (the aralkyl group is a halogen atom, a lower alkyl group,
A hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, an acyloxy group, which may be substituted by 1 to 3) or a hydroxyl group. R ¹⁰ represents a lower alkyl group, a lower alkoxy group, an amino group, a lower alkylamino group or a di-lower alkylamino group. ). Represents}, R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group (the cycloalkyl group may be substituted with a lower alkyl group or a carboxy group), a carboxy group, lower alkoxycarbonyl group, an aryl group, a heteroaryl Group—The aryl group or heteroaryl group is selected from a halogen atom, a lower alkyl group (the lower alkyl group may be substituted with a halogen atom), a hydroxyl group, a lower alkoxy group, a carboxy group or a lower alkoxycarbonyl group. It may be mono- to tri-substituted with a substituent. An aralkyl group (the aralkyl group is selected from a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, and an acyloxy group. 1 to 3
May be substituted), or at least nitrogen atoms consists of 5 to 7-membered represents a heterocycle of the one comprising at saturation, Y ¹
Is an oxygen atom, -NH-, -CONH-, -NR
¹² - <where, R ¹² is a lower alkyl group or -Y ⁶ -R
¹³ Ｒwherein, R ¹³ represents a hydrogen atom, a lower alkyl group or an aryl group (the lower alkyl group or the aryl group may be substituted with a carboxy group, a lower alkoxycarbonyl group, or an aralkyloxycarbonyl group); ⁶ is _{-CO-, -CO 2 -, -COCO 2} -, -
SO ₂ −, −SO ₂ (CH ₂ ) _r − or − (CH ₂ ) _r −
(Where r represents 0 or an integer of 1 to 3). Represents｝. Or represents a single bond, Y ² is an oxygen atom,
Represents a sulfur atom or a single bond, and Y ³ is

Embedded image (Where s and t are the same or different and are 1 to 3
Represents an integer. ) Or a single bond, wherein Y ⁴ is an oxygen atom,
_{-CO-, -CO 2 -, -SO 2} -, -CO
NH-, represents -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 "-,

Embedded image (Where Ak and Ak ′ are the same or different and each represent a lower alkyl group, p represents 0 or an integer of 1 to 3,
p ′ and p ″ are the same or different and are 0 or 1 to 2
Represents an integer. ) Or a single bond, and ring A is

Embedded image Wherein R ¹⁴ is a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group (the aralkyloxycarbonyl group may be substituted with a halogen atom, a nitro group, an alkyl group, an alkoxy group or a trifluoromethyl group) J is 1 or 2, k is 0 or 1, m and n are the same or different and each represents 0 or an integer of 1 to 3. ], R ¹ ,
R ² and R ³ are the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkyl group or an aryl group. Or a salt thereof or a prodrug thereof.

(2) In the general formula [I], R is

Embedded image (R ⁴ , R ⁵ , R ⁶ , X ² , X ³ , X ⁴ , X ⁵ , j, and k each have the same meaning as described above), or the amidine compound or a salt thereof according to the above (1). Or its prodrug.

(3) In the general formula [I], R is

Embedded image (R ⁴ , R ⁵ , R ⁶ , X ² , X ³ , X ⁴ , X ⁵ , j, and k each have the same meaning as described above), or the amidine compound or a salt thereof according to the above (2). Or its prodrug.

(4) In the general formula [I], R is

Embedded image (R ⁴ , R ⁵ , R ⁶ , X ² , X ³ , X ⁴ , X ⁵ , j, and k each have the same meaning as described above), or the amidine compound according to the above (3) or a salt thereof. Or its prodrug.

(5) In the general formula [I], X ³ is
— (CH ₂ ) _m − (m represents the same meaning as described above),
X ⁴

Embedded image , J is 1, the compound according to the above (4), a salt thereof, or a prodrug thereof.

(6) In the general formula (I), R ⁶ is a hydrogen atom, X ² is an oxygen atom, and X ⁵ is a single bond.
Or the salt thereof or a prodrug thereof.

(7) In the general formula [I], R is

Embedded image (R ⁷ , R ⁸ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , ring A,
m and n each have the same meaning as described above. The amidine compound according to the above (1), or a salt thereof or a prodrug thereof.

(8) In the general formula [I], ring A is

Embedded image The amidine compound according to the above (7), or a salt thereof or a prodrug thereof.

(9) 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4
-Tetrahydroisoquinoline-2-carboxamidine, 7- [1- (quinolin-4-yl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, N-methyl-7-
[1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (pyridin-4)
-Yl) piperidin-4-ylmethoxy] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxamide oxime, N-phenyl-7- [1- (pyridine-
4-yl) piperidin-4-ylmethoxy] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxyamidine, 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-dimethylpyridine-
4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-
7-yloxymethyl) -1- (2-methylpyridine-
4-yl) piperidine-4-carboxylic acid methyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-
Methylpyridin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyrimidin-4-yl) piperidin- 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, 4- [N- [5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazole-2-
Ilmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl] benzoic acid, 4- [N- [5-amidino-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole] -2-ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl] benzoic acid, 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2 -Methoxyethyl) benzimidazole-5-carboxyamidine, 2
-[4- (1-acetimidoylpyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine, 7
-[1- (2-hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinolin-2-carboxyamidine, 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-tetrahydroisoquinolin-2-carboxyamidine, 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-phenylacetimidoylpiperidine -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] pyridine-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) piperidine-1
-Yl] pyridine-3-carboxylic acid, 6- [1- (pyridin-4-yl) piperidin-4-ylmethoxy]-
1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [2- [4-cyano-1- (pyridin-4-yl) piperidin-4-yl] ethoxy]-
1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 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) piperidin-4-carboxylic acid, 4-
(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridine-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-tetrahydroisoquinoline-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 -Tetrahydroisoquinoline-
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- [2- (benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5-carboxyamidine, trans-4- [2- [4
-(1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-amidinobenzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, trans-4- [2- [4- (1-acetimidoyl) Piperidin-4-yloxy) phenoxymethyl] -5- (N-methylamidino) benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, trans-4- [2- [4- (1-acetimidoylpiperidine- 4-yloxy) phenoxymethyl] -5- [amino (hydroxyimino) methyl] benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, 2- [4- (piperidin-4-
Yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine, 2- [4-
(1-acetimidoylpiperidin-4-yloxy)
Phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine, 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -1- (cyclohexylcarbamoyl Methyl) benzimidazole-5-carboxyamidine, 4- [2- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-yl] ethyl] -1- (pyridin-4-yl) piperidin-4- Carboxylic acid, 1- (cyclohexylcarbamoylmethyl) -2- [N- [1- (pyridin-4-yl) piperidin-4-yl] -N-ethoxalylaminomethyl] benzimidazole-5-carboxyamidine, N
-[5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N-
[1- (pyridin-4-yl) piperidin-4-yl]
Aminooxalic acid, 2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5
-Carboxyamidine, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid, 2 -[N- [4- (1-amidinopiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5
-Carboxyamidine, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N- [4- (1-amidinopiperidin-4-yloxy) phenyl] carbamoylbenzoic acid, N- [ 5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl]
-N- [4- (1-acetimidoylpiperidine-4-
Yloxy) phenyl] sulfamoylacetic acid, 7- [1
-(Pyridin-4-ylacetyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 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-
Ilmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-
7-yloxymethyl) piperidin-1-ylmethyl]
Indole-1-carboxylic acid methyl 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-tetrahydro Isoquinoline-7-
Yloxymethyl) piperidine-1-carboxamide,
7- [1- (Indol-2-ylmethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 4- (2-amidino-1,2,3,4- Tetrahydroisoquinoline-
7-yloxymethyl) piperidine-1-acetic acid, N-benzyl-4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-acetamide, 4- (2 -Amidino-1,2,2
3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-ylacetylaminoacetic acid, 7-
[1- (5-nitropyridin-2-yl) piperidine-
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
-Carboxyamidine, N-benzyl-4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-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- (benzimidazole-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-tetrahydroisoquinoline-7-
Yloxymethyl) piperidin-1-yl] pyridine-
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 -Tetrahydroisoquinoline-7
-Yloxymethyl) -1- (3-aminopropionyl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (imidazole -4-ylacetyl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-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,
-(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-tetrahydroisoquinoline-7-
Yloxymethyl) -1- (2-methylpyridine-4-
Il) piperidine-4-carboxylic acid ethyl ester,
4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid ethyl ester, 4- (2 -Amidino-1,2,3
4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-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) piperidin-
4-carboxylic acid and 4- (2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid Or a salt thereof or a prodrug thereof according to the above (1), which is selected from the group consisting of:

(10) 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4
-Tetrahydroisoquinoline-2-carboxamidine, 7- [1- (quinolin-4-yl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, N-methyl-7-
[1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (pyridin-4)
-Yl) piperidin-4-ylmethoxy] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxamide oxime, N-phenyl-7- [1- (pyridine-
4-yl) piperidin-4-ylmethoxy] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxyamidine, 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-dimethylpyridine-
4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-
7-yloxymethyl) -1- (2-methylpyridine-
4-yl) piperidine-4-carboxylic acid methyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-
Methylpyridin-4-yl) piperidin-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyrimidin-4-yl) piperidin- 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) piperidin-4-carboxylic acid, 7- [1- (2-hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine , 7- [1-
(Pyridin-4-ylmethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (2-hydroxy-2-phenylethyl) piperidin-4-ylmethoxy ] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxamidine, 4- (2-amidino-1,2,2,
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-carboxyamidine, 7- [1- (2-naphthylsulfonyl) piperidin-4-ylmethoxy] -1,
2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-acetimidoylpiperidine-
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] pyridine-5
-Yl] benzamide, 3- [4- [4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-7-
Yloxymethyl) piperidin-1-yl] pyridine-
3-yl] -2-propenoic acid ethyl ester, 4-
[4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-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
-Carboxyamidine, 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] azepine-
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) piperidin-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridin-4-yl) piperidin-4 -Carboxylic acid, 4- [2
-(2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridine-
4-yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-
7-ylsulfonylmethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid, 4- [2- (2-amidino-1,2,3,4-tetrahydroisoquinoline-
7-ylsulfonyl) ethyl] -1- (pyridine-4-
Yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-7-
Ylsulfonylamino) -1- (pyridin-4-yl)
Piperidine-4-carboxylic acid methyl ester, 4- (2
-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1- (pyridine-4
-Yl) piperidine-4-carboxylic acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-7
-Ylsulfonylaminomethyl) -1- (pyridine-4
-Yl) piperidine-4-carboxylic acid ethyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-
1- (pyridin-4-yl) piperidin-4-carboxylic acid, 7- [1- (pyridin-4-ylacetyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine , 7- [1
-(3-Aminobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxyamidine, 7- [1- (2-hydroxybenzyl) piperidin-4-ylmethoxy] -1,2,2.
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) piperidine-1
-Ylmethyl] indole-1-carboxylic acid methyl 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-carboxyamidine, 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) piperidine-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 -Tetrahydroisoquinoline-7-
Yloxymethyl) piperidine-1-sulfonamide,
N-cyclohexyl-4- (2-amidino-1,2,2,
3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-sulfonamide, N- (2-nitrophenyl) -4- (2-amidino-1,2,3,4
-Tetrahydroisoquinolin-7-yloxymethyl)
Piperidin-1-carbothioamide, 7- [1- (benzimidazol-2-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-
2-carboxyamidine, 3- [4- [4- (2-amidino-1,2,3,4-tetrahydroisoquinoline-7
-Yloxymethyl) piperidin-1-yl] pyridin-3-yl] propionic acid ethyl ester, 3- [4
-[4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-
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-tetrahydro Isoquinolin-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-dimethylaminoacetylpiperidine-
2-ylcarbonyl) piperidine-4-carboxylic acid ethyl ester, 4- [4- (2-amidino-1,2,2
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- Tetrahydroisoquinoline-7
-Yloxymethyl) -1- (2,6-dimethylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yl Oxymethyl) -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) piperidin-4-carboxylic acid, 7
-[2- (4-cyanopiperidin-4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxyamidine, 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) piperidin-4-carboxylic acid, and 4-
(2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1-
The compound according to the above (3), selected from (pyridin-4-yl) piperidine-4-carboxylic acid, or a salt thereof or a prodrug thereof.

(11) A pharmaceutical composition comprising the amidine compound or a salt thereof or a prodrug thereof according to any one of the above (1) to (10), and a pharmaceutically acceptable additive.

(12) A blood coagulation inhibitor comprising, as an active ingredient, the amidine compound or a salt thereof or a prodrug thereof according to any one of the above (1) to (10).

(13) A factor Xa inhibitor comprising as an active ingredient the amidine compound or a salt thereof or a prodrug thereof according to any one of the above (1) to (10).

(14) Prevention of a disease caused by blood coagulation or thrombus, comprising as an active ingredient the amidine compound or a salt thereof or a prodrug thereof according to any one of the above (1) to (10). Therapeutic agent.

The terms used in the present specification for describing the compound of the present invention are defined as follows. The term "lower alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
a t-butyl group, a pentyl group, a tert-pentyl group or a hexyl group, preferably a methyl group having 1 to 4 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group. And so on.
The lower alkyl group for R ¹³ may be substituted with a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group.

The term "cycloalkyl group" refers to an alkyl group having a cyclic alkyl moiety having 3 to 10 carbon atoms.
For example, a cyclopropyl group, a 2,3-dimethylcyclopropyl group, a cyclobutyl group, a 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] nonane-9-
Il group and the like. Preferably, it is a C3-C7 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The cycloalkyl group of R ⁸ may be substituted with a lower alkyl group or a carboxy group.

The "alkylene group having 1 to 6 carbon atoms"
Represents a linear or branched alkylene group having 1 to 6 carbon atoms, such as a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or a hexylene group, and preferably a methylene group having 1 to 4 carbon atoms. Group, ethylene group,
And a propylene group or a butylene group.

The "alkenylene group having 2 to 6 carbon atoms" means a linear or branched alkenylene group having 2 to 6 carbon atoms, for example, an ethenylene group, a 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 or 5-
And a hexenylene group. Preferred are an ethenylene group having 2 to 4 carbon atoms, a 1-propenylene group, a 1-butenylene group, a 2-butenylene group and a 3-butenylene group.

The "aryl group" represents a phenyl group having 6 to 12 carbon atoms, a naphthyl group or a biphenyl group, and is preferably a phenyl group. The aryl group for R ⁶ is a substituent selected from a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a nitro group, an amino group, an acylamino group, an amidino group and a hydroxyamidino group. May be substituted by 1 to 3. The aryl group for R ⁸ is a substituent selected from a halogen atom, a lower alkyl group (the lower alkyl group may be substituted with a halogen atom), a hydroxyl group, a lower alkoxy group, a carboxy group or a lower alkoxycarbonyl group. Or may be tri-substituted. The aryl group of R ¹³ may be substituted with a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group.

The term "heteroaryl group" refers to a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in the ring, and is partially saturated. A condensed ring may be formed with another ring that may be used. For example, imidazolyl, pyridyl, pyridine-1-oxide, pyrimidyl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, triazolyl, indolyl, quinolyl, furyl, benzofuryl, 1H-benzimidazolyl or And a 2-benzothiazolyl group. Preferred are a pyridyl group, a pyridine-1-oxide group, a thienyl group, a thiazolyl group, an isoxazolyl group, an indolyl group and the like. The heteroaryl group for R ⁶ is a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group,
Aralkyloxycarbonyl group, nitro group, amino group,
It may be substituted with 1 to 3 substituent (s) selected from an acylamino group, an amidino group or a hydroxyamidino group. The heteroaryl group for R ⁸ is a substituent selected from a halogen atom, a lower alkyl group (the lower alkyl group may be substituted with a halogen atom), a hydroxyl group, a lower alkoxy group, a carboxy group or a lower alkoxycarbonyl group. It may be mono- to tri-substituted. The bonding positions of these heteroaryl groups are not specified as long as they are chemically permissible.

The "aralkyl group" is an arylalkyl group in which the aryl part is represented by the above "aryl group" and the alkyl part is represented by the above "lower alkyl group". A phenethyl group, a phenylpropyl group, a phenylbutyl group or a phenylhexyl group; and the like on the aryl group, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, an acyloxy group. It may have 1 to 3 substituents selected from groups and the like.
Further, two or more substituents may be substituted at the same time, but it is preferably mono-substitution, and the substitution position is not particularly limited as long as it is chemically permissible.

The term "lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy. , A pentyloxy group, a tert-pentyloxy group or a hexyloxy group, preferably a methoxy group having 1 to 4 carbon atoms, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group. .

The term "lower alkoxycarbonyl group" refers to the lower alkoxy moiety represented by the above "lower alkoxy group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl. , An isobutoxycarbonyl group or a tert-butoxycarbonyl group. Preferred are a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.

The “aralkyloxycarbonyl group” is
The aralkyl moiety represents the one represented by the above “aralkyl group”, such as a benzyloxycarbonyl group, a 2-phenylethoxycarbonyl group or a 3-phenylpropoxycarbonyl group, and a halogen atom, a nitro group, an alkyl group, or an alkoxy group as a substituent. Or a trifluoromethyl group or the like. Preferably, it is a benzyloxycarbonyl group.

The term "acyl group" means a formyl group; an alkanoyl group having 2 to 6 carbon atoms such as an acetyl group, a propionyl group, a butyryl group or a pivaloyl group; or an aryl group having 1 to 3 substituents. And an aroyl group such as a benzoyl group. Preferred are a formyl group, an acetyl group, a pivaloyl group and a benzoyl group.

The "imidoyl group" is a formimidoyl group having 1 to 6 carbon atoms, an acetimidoyl group, a propanimidoyl group, a butanimidoyl group, a pentanimidoyl group or a hexaneimidoyl group. Preferred are an acetimidoyl group and a propanimidoyl group.

The term "lower alkylamino group" refers to an amino group monosubstituted by the above-mentioned "lower alkyl group". is there. Preferred are a methylamino group, an ethylamino group and a propylamino group.

The "di-lower alkylamino group" refers to an amino group disubstituted by the above-mentioned "lower alkyl group", such as a dimethylamino group, a diethylamino group, a dipropylamino group, a methylethylamino group. Or a methylpropylamino group. Preferably, it is a dimethylamino group or a diethylamino group.

The "di-lower alkylamino lower alkanoyl group" refers to an alkanoyl group substituted by the above-mentioned "di-lower alkylamino group", for example, dimethylaminoacetyl, diethylaminoacetyl, dipropylaminoacetyl. Group, methylethylaminoacetyl group, methylpropylaminoacetyl group, dimethylaminopropanoyl group, diethylaminopropanoyl group, dipropylaminopropanoyl group and the like. Preferred are a dimethylaminoacetyl group and a diethylaminoacetyl group.

The term "acylamino group" refers to an amino group substituted by the above-mentioned "acyl group", for example, a formylamino group; 2 to 6 alkanoylamino groups; or
An aroylamino group such as a benzoylamino group which may have one to three substituents on the aryl group. Preferred are a formylamino group, an acetylamino group, a pivaloylamino group and a benzoylamino group.

The "halogen atom" is chlorine, bromine, fluorine or iodine, preferably chlorine or bromine.

"5 to 7 members and at least nitrogen atom
A saturated heterocyclic ring comprising one
With peridine, hexahydroazepine and even heteroatoms
Having an oxygen, sulfur and / or nitrogen atom
Gin, thiazolidine, imidazolidine, morpholine, thi
Omorpholine group, piperazine, tetrahydrooxazepi
, Tetrahydrothiazepine or hexahydrodiazepine
And the like. R ⁶Of 5 to 7 members
Saturated heterocycles containing one nitrogen atom
Kill group, acyl group, di-lower alkylamino lower alkano
It may be substituted with an yl group or an imidoyl group.

The "salt" of a compound includes an inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, glycolate,
Organic acids such as lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate Addition salts; amino acid addition salts such as aspartate or glutamate; inorganic base salts with sodium, potassium, calcium or magnesium; methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, trishydroxymethylaminomethane , Dicyclohexylamine, ethylenediamine, quinine, guanidine and the like; organic base salts with amino acids such as asparagine, glutamine, arginine, histidine or lysine, but are not limited thereto. In some cases, it may be a hydrate or a hydrate.

A "prodrug" of a compound has a group that can be chemically or metabolically degraded and exhibits pharmaceutically activity by hydrolysis or solvolysis, or by degradation under physiological conditions. It is a derivative of the compound of the present invention.

"Various diseases caused by blood coagulation and thrombus" include diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), and subarachnoid hemorrhage, acute or Ischemic heart disease such as chronic myocardial infarction, unstable angina, coronary artery thrombosis, disease in pulmonary vascular disorders such as pulmonary infarction, pulmonary embolism, peripheral arterial embolism, deep vein thrombosis,
Generalized intravascular coagulation syndrome, thrombosis after vascular prosthesis or valve replacement, reocclusion or restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty (PTCA), or coronary thrombolysis Diseases in various vascular disorders such as reocclusion or restenosis after (PTCR) and thrombosis during extracorporeal circulation.

[0047]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound of the present invention will be described in more detail. In the compound of the present invention represented by the general formula [I], R is

Embedded image And preferably

Embedded image And particularly preferably

Embedded image It is. R ¹ , R ² and R ³ are preferably hydrogen atoms.

Also,

Embedded image When

Embedded image The connection form of

Embedded image Is preferred.

R ⁴ is preferably a hydrogen atom, a lower alkoxy group or a halogen atom, and particularly preferably a hydrogen atom. R ⁵ is preferably a hydrogen atom, a carboxy group or a lower alkoxycarbonyl group, and particularly preferably a carboxy group. R ⁶ is preferably a hydrogen atom, a carboxy group, a lower alkoxycarbonyl group, an aryl group or a heteroaryl group (the aryl group or heteroaryl group is preferably a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an aralkyl group). Oxycarbonyl group, nitro group, amino group, acylamino group, amidino group or hydroxyamidino group, which may be mono- to tri-substituted), and particularly preferably a pyridyl group.

X ² is preferably an oxygen atom or a sulfur atom, particularly preferably an oxygen atom. X ³ is preferably — (CH ₂ ) _m −, and particularly preferably —.
(CH ₂ ) ₀ −. Preferably X ⁴

Embedded image Alternatively, it is a single bond, particularly preferably a single bond. X ⁵
Is preferably an alkenylene group having 2 to 6 carbon atoms or a single bond, and particularly preferably a single bond. j is preferably 1 and k is preferably 0.

Preferably, R ⁷ is

Embedded image(Where R⁹Is preferably an oxygen atom or an NH group
And particularly preferably an NH group. R^TenPreferred as
Or a lower alkyl group, a lower alkoxy group or an amino group
And particularly preferably a lower alkyl group or an amino group.
You. ). R ⁸Preferably a hydrogen atom, aryl
Group, heteroaryl group ｛the aryl group or heteroaryl
A halogen group, a lower alkyl group (the lower alkyl
The radical may be substituted by a halogen atom. ), Hydroxyl,
Lower alkoxy group, carboxy group or lower alkoxy group
Mono- to tri-substituted by a substituent selected from a rubonyl group
Good. ｝, And particularly preferably a phenyl group. Y
¹Is preferably an oxygen atom or -NR¹²− ｛Here
And R¹²Is preferably -Y⁶-R¹³ (Where R
¹³Is preferably a carboxy group or lower alkoxyca
A phenyl group which may be substituted with a rubonyl group;⁶
Is preferably -CO-. )
And particularly preferably -NY.⁶-R¹³ It is. Y^Twoage
And preferably an oxygen atom. Y^ThreePreferably as

Embedded image (Here, each of s and t is preferably 2.) Y ⁴ is preferably -CONH-. The preferred _{^{Y 5 - (CH 2) p}} -, - (CH
_{2) p '-CHAk- (CH 2} ) p "-, - (CH 2) p' -CAk A
_{k '- "- (. (} CH 2) p , where preferably the p is 1 or 2, p' is preferably a is 1, p" is preferably a 0), and particularly preferably -
(CH ₂ ) _{p ′} -CHAk- (CH ₂ ) _{p ″} −. Ring A is preferably

Embedded image It is.

The compounds represented by the general formula [I] of the present invention include tautomers, stereoisomers, optical isomers and geometric isomers, and the present invention includes all of them.

Next, a method for producing the compound of the present invention will be described, but it goes without saying that the method for producing the compound of the present invention is not limited to these. Manufacturing method 1

Embedded image

The production method described here is based on the compound represented by the general formula [I '] among the compounds represented by the general formula [I].

Embedded image It is suitable for producing a compound represented by the formula: In this case, the formation of the bond between the sites [i], [ii], [iii], [iv] and [v] may be started from any position. Furthermore, construction or conversion of each site may be performed independently, or may be performed after formation of an appropriate bond. At this time, if there is a reactive functional group, a protecting group may be appropriately introduced and removed.

[1] Bonding between site [i] and site [ii] General formula (2)

Embedded image (here,

Embedded image Represents that another site is bonded or a convertible group such as a hydrogen atom, a protecting group or a leaving group is bonded.
Hereinafter, this symbol described in each general formula represents this meaning.
R ⁴ , X ² , j and k each have the same meaning as described above. ) In the presence of a base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in the presence of a compound of formula (3)

Embedded image Wherein R ¹ ′, R ² ′ and R ³ ′ are the same or different and each represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aryl group or a protecting group for a nitrogen atom. When reacted with the salt, general formula (4)

Embedded image (Wherein R ¹ ′, R ² ′, R ³ ′, R ⁴ , X ² , j, and k each have the same meaning as described above). When any of R ¹ ′, R ² ′, and R ³ ′ is a protecting group, a method generally used for deprotecting the protecting group may be used.

Alternatively, ammonium thiocyanate and benzoyl chloride are reacted in advance under heating, and the compound represented by the general formula (2) is reacted to obtain a thioamide compound. Next, after treatment with an acid such as hydrogen chloride or hydrogen bromide, the resultant is reacted with methyl iodide under heating, preferably at 50 to 70 ° C. And you may make it react with the amine which has a desired substituent.

Alternatively, a compound represented by the general formula (2) is reacted with a compound represented by the general formula (5), R ¹ -NCS (R ¹ has the same meaning as described above). After reacting with methyl to form a thiomethyl compound, it may be reacted with ammonium acetate or an amine having a desired substituent.

When a compound in which j is 2 among the compounds at the site [ii] is desired, the compound represented by the general formula (6)

Embedded image (Rh represents a protecting group such as a methyl group, and R ⁴ , X ² , and k each have the same meaning as described above.) After reacting sodium azide with the compound represented by To obtain an azepinone compound, which is subjected to a reduction reaction using lithium aluminum hydride to obtain a compound represented by the general formula (7):

Embedded image (R ⁴ , X ² , Rh, and k each have the same meaning as described above.)

[2] Bonding or Construction of Site [ii] and Site [iii] General Formula (8)

Embedded image (Wherein R ⁴ , X ² , j, and k represent the same meanings as described above), and a compound represented by the general formula (9):

Embedded image (L ¹ represents a leaving group or a hydroxyl group such as a halogen atom, X ³
Represents the same meaning as described above. ) [Iii]
Is reacted with the compound of the general formula (10)

Embedded image (R ⁴ , X ² , X ³ , j, and k each have the same meaning as described above). When L ¹ is a leaving group, an alkylation reaction using a base such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine is performed, and L ¹ is In the case of a hydroxyl group, a Mitsunobu reaction using triphenylphosphine and diisopropyl azodicarboxylate may be performed.

When a compound in which X ² is —SO ₂ — is desired, a compound represented by the general formula (10) in which X ² is a sulfur atom is converted to a peracid such as m-chloroperbenzoic acid or peracetic acid. The oxidation reaction is carried out by using the general formula (11)

Embedded image (R ⁴ , X ³ , j, and k each have the same meaning as described above.)

When a compound in which X ² is —SO ₂ NH— is desired, the compound represented by the general formula (12)

Embedded image (R ⁴ , j and k each have the same meaning as described above.)
And a compound represented by the general formula (13)

Embedded image (X ³ represents the same meaning as described above), and the compound represented by the general formula (14) is subjected to an amidation reaction usually performed under basic conditions.

Embedded image (R ⁴ , X ³ , j, and k each have the same meaning as described above.)

When a compound in which k is 1 and X ² is an oxygen atom is desired, the compound represented by the general formula (15)

Embedded image (R ⁴ , Ak, and j each have the same meaning as described above.)
Is reduced with a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride or sodium cyanoborohydride to give a compound represented by the general formula (16):

Embedded image (R ⁴ and j each have the same meaning as described above.) Next, the compound represented by the general formula (17) is condensed with the compound represented by the general formula (9) by the method described in the method for producing the compound represented by the general formula (10).

Embedded image (R ⁴ , X ³ , and j each have the same meaning as described above.)
The compound represented by

[3] Bonding or Construction of Site [iii] and Site [iv] R ⁵ is a hydrogen atom, and X ³ is —CH ₂ —, — (CH ₂ ) ₂ —
Or - (CH _{2) 3} - in which case the desired compound of the general formula (18)

Embedded image (M ′ represents 0 or an integer of 1 to 2, and Ak represents the same meaning as described above) by using lithium aluminum hydride, sodium borohydride, lithium borohydride, cyano hydride, When a reduction reaction is performed with a reducing agent such as sodium borohydride, the general formula (19)

Embedded image (M ″ represents an integer of 1 to 3). Or the general formula (20)

Embedded image (M ′ has the same meaning as described above), and the compound represented by the general formula (19) can be obtained by performing a reduction reaction with a reducing agent such as borane. This means that among the compounds represented by the general formula (9), X ³ is-(CH ₂ ) _{m ″}
And corresponds to a compound in which L ¹ is a hydroxyl group.

R ⁵ is a cyano group, lower alkoxycarbonyl group or carboxy group, and X ³ is —CH ₂ —, — (C
If a compound of the formula H ₂ ) _2- and-(CH ₂ ) _3- is desired, the compound represented by the general formula (21)

Embedded image (R ⁵ ′ represents a cyano group, a lower alkoxycarbonyl group or a carboxy group) in the presence of a base such as lithium diisopropylamide at −80 ° C. to 0 ° C.
℃ by formula ^{(22) L 2 - (CH} 2) m '-CH = CH 2 (L 2 represents a leaving group such as a halogen atom, m' have the same meanings as defined above.)
And reacting with a compound represented by the general formula (23)

Embedded image (R ⁵ 'and m' each have the same meaning as described above.)
After reacting with an oxidizing agent such as osmium tetroxide, a diol compound having a double bond oxidized is obtained. Periodic acid oxidation of this diol compound causes adjacent diols to undergo oxidative cleavage, yielding an aldehyde compound. This is sodium borohydride,
When a reduction reaction is performed using a reducing agent such as lithium borohydride or sodium cyanoborohydride, the general formula (24)

Embedded image (Wherein R ⁵ ′ and m ″ each have the same meaning as described above). This is because, among the compounds represented by the general formula (9), X ³ is-(CH ₂ ) _{m ″}
And corresponds to a compound in which L ¹ is a hydroxyl group.

Alternatively, a carboxylic acid compound obtained by periodate oxidation of a compound represented by the general formula (23) is reduced with a reducing agent such as borane to obtain a compound represented by the general formula (24). Good.

Alternatively, the compound represented by the general formula (21) and the compound represented by the general formula (25)

Embedded image (L ² and m each have the same meaning as described above.) May be reacted at −80 ° C. to 0 ° C. in the presence of a base such as lithium diisopropylamide.

When a compound in which R ⁵ is a cyano group is desired, the compound represented by the general formula (26)

Embedded image Is amidated and reacted with a dehydrating agent such as triphenylphosphine to obtain a compound represented by the general formula (27)

Embedded image The compound represented by is obtained. Then, the general formula (23)
May be combined with the compound at the site [iii] by a method similar to the method for producing the compound represented by the formula or by other known methods.

The introduction of the leaving group L ² of the compound represented by the general formula (25)

Embedded image (M represents the same meaning as described above) is reacted with a halogenating agent such as sulfuryl chloride to obtain a compound represented by the general formula (25). The compound represented by the general formula (25) may be converted to a more reactive leaving group using an alkali metal halide.

X ² is —SO ₂ NH— and X ³ is — (CH
₂ ) When a compound having _m − is desired, the compound represented by the general formula (29)

Embedded image (R ⁵ and m each have the same meaning as described above.) The compound represented by the formula (1) is subjected to Curtius rearrangement, Hoffman rearrangement and the like to give a carbamate compound. Equation (30)

Embedded image (R ⁵ and m each have the same meaning as described above.) This corresponds to a compound in which X ³ is — (CH ₂ ) _m − among the compounds represented by the general formula (13).

Alternatively, the general formula (31)

Embedded image Is reacted with hydrogen cyanide in the presence of ammonia to give a compound represented by the general formula (3)
2)

Embedded image The compound represented by This is the general formula (30)
Among a compound represented by at R ⁵ is a cyano group, and corresponds to a compound wherein m is 0, then by performing the alcoholysis, the general formula R ⁵ in the general formula (30) is a lower alkoxycarbonyl group (33)

Embedded image (Ak has the same meaning as described above) is obtained, and further hydrolyzed, the compound represented by the general formula (34) wherein R ⁵ in the general formula (30) is a carboxy group

Embedded image The compound represented by is obtained.

[4] Bonding or Construction of Site [iv] and Site [v] General Formula (35)

Embedded image (R ⁵ has the same meaning as described above), and a compound represented by the formula [36]: L ² -X ⁴ -X ⁵ -R ⁶ (R ⁶ , X ⁴ , X ⁵⁾ , L ² have the same meanings as described above, respectively.) The compound at the site [v] represented by the formula (I) is converted into sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, carbonate The reaction is carried out in the presence of a base such as potassium, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, pyridine or the like, or triethylamine at a temperature of 120 to 160 ° C.
When the reaction is carried out using a base such as N, N-diisopropylethylamine, the compound represented by the general formula (37)

Embedded image (Wherein R ⁵ , R ⁶ , X ⁴ , and X ⁵ each have the same meaning as described above).

When R ⁶ is an aryl group or a heteroaryl group and a compound having an amino group or an acylamino group as a substituent on the aryl group or the heteroaryl group is desired, a substituent may be added on the aryl group or the heteroaryl group. When a compound having a nitro group is reduced, a compound having an amino group as a substituent is obtained, and further reacted with an acylating agent such as an acyl halide or an acid anhydride to obtain a compound having an acylamino group as a substituent. Is also good.

When a compound in which X ⁵ is —CH ＝ CH— is desired, the compound represented by the general formula (38)

Embedded image (X ⁴ has the same meaning as described above), and the compound represented by the general formula (39) in the presence of a base such as sodium hydride and potassium hydride.

Embedded image (R ⁶ and Ak each have the same meaning as described above), and reacted with a compound represented by the general formula (40).

Embedded image (R ⁶ and X ⁴ each have the same meaning as described above.)

Manufacturing method 2

Embedded image

The production method described here is based on the compound represented by the general formula [I ″] among the compounds represented by the general formula [I].

Embedded image It is suitable for producing a compound represented by the formula: In this case, the formation of the bond between the sites [i], [iii], [iv], [v] and [vi] may be started from any position. Furthermore, construction or conversion of each site may be performed independently, or may be performed after formation of an appropriate bond. At this time, if there is a reactive functional group, a protecting group may be appropriately introduced and removed.

[5] Bonding or construction of site [i] and site [vi] General formula (41)

Embedded image (R ⁴ , X ² and k each have the same meaning as described above.)
A hydroxyl group of the compound at the site [vi] represented by is converted to a leaving group using a sulfonylating agent such as trifluoromethanesulfonic anhydride, and is reacted with zinc cyanide or the like in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium. A cyano compound is formed using a cyanating agent. Then, under basic conditions, hydrogen sulfide is reacted to form a thioamide compound, which is further S-alkylated with methyl iodide or the like, and then reacted with ammonium acetate or an amine having a desired substituent to obtain a compound represented by the general formula (42).

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ , X ² , and k have the same meanings as described above).

Formula (43) having a halogen atom at the 8-position as R ⁴

Embedded image (Where Hal represents a halogen atom and X ² and k each have the same meaning as described above).
General formula (44)

Embedded image (X ² and k each have the same meaning as described above.) May be halogenated with a halogenating agent such as tert-butyl hypochlorite.

The bond between the site [vi] and the site [iii], and the site [iii] to the site [v] can be formed by the site [ii] shown in the production method 1.
To the site [v].

Manufacturing method 3

Embedded image

The production method shown here is based on the compound represented by the general formula [I ′ ″] of the compound represented by the general formula [I].

Embedded image It is suitable for producing a compound represented by the formula: In this case, the formation of the bond between each of the sites [i], [vii], [viii], [ix], [x] and [xi] may be started from any position. Furthermore, construction or conversion of each site may be performed independently, or may be performed after formation of an appropriate bond. that time,
When there is a reactive functional group, a protecting group may be appropriately introduced and removed.

[6] Binding or Construction of Site [i] and Site [vii] General Formula (45)

Embedded image When a method similar to the method for forming or constructing the bond between the site [i] and the site [vi] in Production Method 2 is carried out using the compound represented by the general formula (46),

Embedded image (Wherein R ¹ , R ² , and R ³ each have the same meaning as described above).

[7] Bonding or construction of site [vii] with site [viii] and site [xi] General formula (47)

Embedded image (L ² has the same meaning as described above), and a compound represented by the general formula (I) is used in the presence of a base such as triethylamine, N, N-diisopropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, or potassium carbonate. equation _{(48) H 2 N- (CH} 2) n -Y 4 -Y 5 -R 8 (R 8, Y 4, Y 5,
n represents the same meaning as above. By reacting with the compound at the site [xi] or a salt thereof,
General formula (49)

Embedded image (R ⁸ , Y ⁴ , Y ⁵ , and n each have the same meaning as described above). In some cases,
The compound represented by the general formula (48) itself may be used as a base.

The nitro group of the compound represented by the general formula (49) is reduced by a conventional method to give a compound of the general formula (50)

Embedded image (R ⁸ , Y ⁴ , Y ⁵ , and n each have the same meaning as described above), and represented by the general formula (51)

Embedded image (M represents the same meaning as described above) [vi
When reacted with the compound of ii], the compound represented by the general formula (52)

Embedded image (R ⁸ , Y ⁴ , Y ⁵ , m, and n each have the same meaning as described above). Or the general formula (53)

Embedded image When the compound represented by the general formula (51) is reacted with the compound represented by the general formula (51),

Embedded image (M represents the same meaning as described above). This reaction may be carried out by an ordinary amidation reaction, for example, dicyclohexylcarbodiimide (DC
C), diisopropylcarbodiimide, 1-ethyl-3
A method using a condensing agent such as-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), diphenylphosphoryl azide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ);
A mixed acid anhydride method using an alkyl halocarbonate or the like,
A method in which a carboxylic acid is converted into an acid halide using thionyl chloride, oxalyl chloride, or the like, and then reacted under basic conditions, may be mentioned.

General formula (55)

Embedded image (Rh ′ represents a protecting group such as a methyl group and an ethyl group, and m represents the same meaning as described above.) By deprotecting the protecting group of the compound represented by the general formula, the general formula ( The compound represented by 51) may be used. Also, the general formula (56)

Embedded image (M represents the same meaning as described above.) The compound represented by the general formula (51) may be oxidized by an ordinary method to give a compound represented by the general formula (51).

When the compound represented by the general formula (52) or the compound represented by the general formula (54) is subjected to a ring-closing reaction under acidic conditions using acetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc., Equation (57)

Embedded image (R ⁸ , Y ⁴ , Y ⁵ , m and n each have the same meaning as described above) or a compound represented by the general formula (58)

Embedded image (M represents the same meaning as described above).

Alternatively, the general formula (59)

Embedded image Is converted to an imidate using an alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and a compound represented by the general formula (50) or a compound represented by the general formula (53). Even when reacted under the conditions, a compound represented by the general formula (57) or a compound represented by the general formula (58) is obtained.

When a compound in which Y ⁴ is —CONH— is desired, the compound represented by the general formula (60)

Embedded image (N is the same in meaning.) (Representing R ^8, Y ⁵ is the same meaning, respectively.) A compound represented by general formula _{(61) H 2 N-Y} 5 -R 8 with The compound represented by the general formula (62) is reacted with the compound represented by the general formula (52) or the compound represented by the general formula (54) in the same manner as in the method for producing the compound.

Embedded image (R ⁸ , Y ⁵ , and n each have the same meaning as described above.)
The compound represented by

When a compound in which Y ⁴ is an oxygen atom, Y ⁵ is a single bond and R ⁸ is a lower alkyl group is desired, a compound represented by the general formula (63)

Embedded image (N represents the same meaning as described above) and a compound represented by the general formula (64): L ¹ -R ⁸ ′ (R ⁸ ′ represents a lower alkyl group, and L ¹ represents the same meaning as described above.) The compound represented by the general formula (65) is reacted by a method similar to the method for producing the compound represented by the general formula (37).

Embedded image (R ⁸ ′ and n each have the same meaning as described above.)

When a compound in which Y ⁴ is —CO—, Y ⁵ is a single bond and R ⁸ is a heteroaryl group is desired, a compound represented by the general formula (6)
The compound represented by formula (0) is reacted with N, O-dimethylhydroxylamine in the same manner as in the method for producing the compound represented by formula (52) or the compound represented by formula (54). General formula (66)

Embedded image (N represents the same meaning as described above), and then the compound represented by the general formula (67) HR ⁸ ″ (R ⁸ ″ represents a heteroaryl group) is converted to butyl. After activation with a base such as lithium, the reaction is carried out to obtain a compound represented by the general formula (6)
8)

Embedded image (R ⁸ ″ and n each have the same meaning as described above.)

[8] Bonding or Construction of Site [viii] and Site [ix] General Formula (69)

Embedded image (L ² and m each have the same meaning as described above.) The compound at the site [viii] represented by sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, Potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine,
Formula (70) in the presence of a base such as N, N-diisopropylethylamine and pyridine

Embedded image (Y ¹ and ring A have the same meanings as described above), respectively, to form a compound represented by the general formula (7)
1)

Embedded image (Y ¹ , ring A and m each have the same meaning as described above).

When a compound in which Y ¹ is an NH group is desired,
After performing a reaction using a compound protected with a protecting group such as a benzyloxycarbonyl group or a tert-butoxycarbonyl group, the protecting group is removed to obtain a compound of the general formula (72)

Embedded image (Rings A and m each have the same meaning as described above.) Moreover, Y ¹ is -NR ¹² - If the compound represented by the desired, a compound represented by the general formula (72), the general formula ^{(73) L 2 -R 12 (} R 12, L 2 is the respective The compound represented by the general formula (74) is reacted in the same manner as in the method for producing the compound represented by the general formula (49).

Embedded image (R ¹² and m each have the same meaning as described above.)

In addition, R¹²Is -Y⁶-R¹³ And Y⁶But
-CO-, -CO_Two−, −COCO_Two− Or
-SO_TwoIf desired, a compound of the general formula (7)
The compound represented by the formula (2) is represented by the general formula (75): HO-Y⁶'-R¹³ (Y⁶’Is -CO-, -CO_Two
−, −COCO_Two-Or -SO_Two−
R ¹³Represents the same meaning as described above. Compound represented by)
Is a compound represented by the general formula (52) or a compound represented by the general formula (5)
The compound is reacted in the same manner as in the method for producing the compound represented by 4).
And the general formula (76)

Embedded image (R ¹³ , Y ⁶ ′, ring A and m each have the same meaning as described above.)

Y ¹ is a single bond and ring A is

Embedded image If desired, a compound of general formula (77)

Embedded image (R ¹⁴ represents the same meaning as described above) and a compound represented by the general formula (69),
The compound represented by the general formula (78) is reacted by a method similar to the method for producing the compound represented by 3).

Embedded image (R ¹⁴ and m each have the same meaning as described above.)

When a compound in which Y ¹ is an oxygen atom is desired, the compound represented by the general formula (79)

Embedded image (Ring A represents the same meaning as described above.) The compound represented by the general formula (80) is oxidized with a peracid such as m-chloroperbenzoic acid or peracetic acid.

Embedded image (Ring A has the same meaning as described above.) This corresponds to the compound represented by the general formula (70) in which Y ¹ is an oxygen atom.

[9] Bonding or Construction of Site [ix] and Site [x] General Formula (81)

Embedded image (Y ¹ , L ¹ , and ring A each have the same meaning as described above), and a compound represented by the general formula (8)
2) A compound at the site [x] represented by H—Y ² —Y ³ —R ⁷ (R ⁷ , Y ² and Y ³ each have the same meaning as described above) is represented by the general formula (10). When reacted in the same manner as in the method for producing the compound represented by the general formula (83),

Embedded image (R ⁷ , Y ¹ , Y ² , Y ³ , and ring A each have the same meaning as described above).

Ring A is

Embedded image In the case where a compound in which Y ² is a single bond is desired, the compound represented by the general formula (84)

Embedded image (Y ¹ represents the same meaning as described above) or a compound represented by the general formula (85)

Embedded image (R ¹⁴ and Y ¹ each have the same meaning as described above) and a compound represented by the general formula (86): L ² -Y ³ -R ⁷ (R ⁷ , Y ³ and L ² each represent The compound represented by the general formula (37):
By reacting in the same manner as in the method for producing the compound represented by the general formula (87)

Embedded image (R ⁷ , Y ¹ and Y ³ each have the same meaning as described above) or a compound represented by the general formula (88)

Embedded image (R ⁷ , R ¹⁴ , Y ¹ , and Y ³ each have the same meaning as described above.)

Y ³ is

Embedded image Wherein R ⁷ is a lower alkyl group or

Embedded image If desired, a compound of the general formula (89)

Embedded image (Y ² , s, and t each have the same meaning as described above.)
Is converted to triethylamine, N, N-diisopropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, etc. In the presence of a base of the formula (9)
0) L ³ -R ⁷ 'where L ³ is an ethoxy group, a 1-pyrazolyl group,
Represents a leaving group such as a halogen atom, and R ⁷ ′ is a lower alkyl group or

Embedded image (R ⁹ and R ¹⁰ each have the same meaning as described above). And a compound represented by the general formula (9)
1)

Embedded image (R ⁷ ′, Y ² , s, and t each have the same meaning as described above).

The compound of the present invention represented by the general formula [I] thus obtained has a factor Xa inhibitory action. When the compound of the present invention is used as a factor Xa inhibitor or an anticoagulant, it is usually administered systemically or locally, orally or parenterally.

The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like, but is usually in the range of 0.01 mg to 1 g per adult, once or several times a day orally or parenterally. Is done.

When the compound of the present invention is made into a solid composition for oral administration, it can be in the form of tablets, pills, powders, granules and the like. In such a solid composition, the one or more active substances include at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol,
It is mixed with glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate or anhydrous silica powder.
Further, the composition may be mixed with additives other than the diluent according to a conventional method.

When preparing tablets or pills, they may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or with two or more layers. May be. In addition, the capsule may be made of a substance such as gelatin or ethyl cellulose.

In the case of liquid compositions for oral administration, dosage forms such as pharmaceutically acceptable emulsions, solubilizers, suspensions, syrups and elixirs are possible. The diluent used includes, for example, purified water, ethanol, vegetable oil and emulsifier. In addition, the composition may contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances, preservatives and the like in addition to the diluent.

When preparing a parenteral injection,
Sterile aqueous or non-aqueous solutions, solubilisers, suspending agents or emulsifiers are used. Aqueous solutions, solubilizing agents, and suspending agents include, for example, distilled water for injection, physiological saline, cyclodextrin and its derivatives, triethanolamine,
Examples thereof include organic amines such as diethanolamine, monoethanolamine, and triethylamine, and inorganic alkali solutions.

In the case of preparing a water-soluble solution, for example, 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, a surfactant such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester (mixed micelle formation), or lecithin or hydrogenated lecithin (liposome formation) is also used. or,
An emulsion formulation comprising a water-insoluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol can also be used.

Other compositions for parenteral administration include topical solutions, ointments and other suppositories, suppositories or pessaries containing one or more active substances and formulated in a manner known per se. And so on.

[0106]

EXAMPLES The compounds represented by the general formula [I] according to the present invention and the method for producing the same will be specifically described by the following examples. However, it goes without saying that the present invention is not limited to these embodiments.

Example 1 Synthesis of 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride Step 1 7-hydroxy -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester

Embedded image 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (370 mg) was dissolved in a 1N aqueous solution of sodium hydroxide (4 ml) and 1,4-dioxane (8 ml), and di-tert-butyl was dissolved. Dicarbonate (386 mg) was added and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (385 mg).

Step 2 4-Hydroxymethyl-1- (pyridin-4-yl) piperidine

Embedded image Under an argon atmosphere, 1- (pyridin-4-yl) piperidine-4-carboxylic acid (tetrahedron, vol.
No. 3, p. 7095, 1988) (500 mg) in tetrahydrofuran (5 ml) was added with a 1M borane-tetrahydrofuran solution (14.5 ml) under ice-cooling, and the solution was added at room temperature.
Stir for 2 hours. After completion of the reaction, the reaction mixture was opened in ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 12% hydrochloric acid, and the mixture was stirred at 50 ° C for 1 hour. The reaction solution was neutralized with aqueous sodium hydrogen carbonate and 4N-aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and dried under reduced pressure to give the title compound (4
00 mg). ¹ H-NMR (δ ppm, CDCl ₃ ) 1.24-1.38 (m, 2H), 1.70-1.90 (m, 3
H), 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

Embedded image 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (389 mg), 4-hydroxymethyl-1- (pyridin-4-yl) piperidine (300 mg) in tetrahydrofuran (15 ml) And a mixed solution of methylene chloride (5 ml) and 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 solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: acetone = 3: 2-1: 1, 1% triethylamine), dried under reduced pressure, and dried under reduced pressure to give the title compound (50
0 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

Embedded image 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (5
To a solution of (00 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 solution was concentrated under reduced pressure, an aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. Organic layer with water,
The extract was washed successively with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off and dried under reduced pressure to give the title compound (350
mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.30-1.49 (m, 2H), 1.91-2.15 (m, 3
H), 2.72 (tr, J = 6.0Hz, 2H), 2.90 (m, 2H), 3.11 (tr, J = 6.0
Hz, 2H), 3.79 (d, 2H), 3.90-3.98 (m, 4H), 6.54 (1H), 6.6
6-6.72 (m, 3H), 6.99 (1H), 8.25 (2H)

Step 5 7- [1- (Pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride

Embedded image 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline (50 mg) in dimethylformamide (0.5 m
l) Diisopropylethylamine (0.027m
l) 1H-Pyrazole-1-carboxamidine hydrochloride (23 mg) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, diethyl ether was added, and insolubles were collected by filtration.
The obtained solid was washed with diethyl ether. The obtained solid (45 mg) was treated with a methanol solution of hydrogen chloride and dried under reduced pressure to give the title compound (44 mg). ¹ H-NMR (δppm, 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, 2
H), 3.57 (tr, J = 6.0Hz, 2H), 3.85 (m, 2H), 4.23-4.28 (m, 2
H), 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, 2
H), 7.64 (brs, 4H), 8.19 (d, J = 7.8Hz, 2H), 13.68 (brs, 1H
H)

Example 2 Synthesis of 7- [1- (quinolin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinolin-2-carboxyamidine dihydrochloride Step 11 1- ( Quinolin-4-yl) piperidine-4-carboxylic acid ethyl ester

Embedded image 4-chloroquinoline (2 g), ethyl isonipecotate (2.8 ml), triethylamine (3.4 m)
The ethanol (7.5 ml) solution of 1) was stirred at 150 ° C. for 5 days using a pressure-resistant reaction vessel. 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 saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 3: 1), and dried under reduced pressure to obtain the title compound (3.2 g).

Step 2 4-Hydroxymethyl-1- (quinolin-4-yl) piperidine

Embedded image Under a nitrogen atmosphere, lithium aluminum hydride (267m
g) in tetrahydrofuran (10 ml) was added to 1- (quinolin-4-yl) piperidine-4-carboxylic acid ethyl ester (1 g) in tetrahydrofuran (1 g) under ice cooling.
0 ml) solution was added dropwise and stirred at the same temperature for 2 hours. After completion of the reaction, aqueous sodium sulfate was added under ice cooling, and the mixture was filtered through celite. The solid obtained by distilling off the solvent was washed with diisopropyl ether and dried under reduced pressure to give the title compound (750 mg).
I got ¹ H-NMR (δppm, CDCl ₃ ) 1.57-1.90 (m, 3H), 1.93-2.05 (m, 2
H), 2.85 (m, 2H), 3.64-3.68 (m, 4H), 6.84 (d, J = 4.8Hz, 1
H), 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

Embedded image 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) to give the title compound (280 mg) in the same manner as in Step 3 of Example 1.

Step 4 7- [1- (Quinolin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline

Embedded image 7- [1- (quinolin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (2
75 mg) to give the title compound (200 mg) in the same manner as in Step 4 of Example 1.

Step 5 7- [1- (Quinolin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinolin-2-carboxyamidine dihydrochloride

Embedded image 7- [1- (Quinolin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline (70 mg), diisopropylethylamine (0.
033 ml) and the title compound (75 mg) was obtained from 1H-pyrazole-1-carboxamidine hydrochloride (28 mg) in the same manner as in Step 5 of Example 1. ¹ H-NMR (δppm, 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, 2
H), 3.58 (tr, J = 6.0Hz, 2H), 3.92 (m, 2H), 4.17-4.23 (m, 2
H), 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 (br
s, 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-carboxyamidine dihydrochloride 17- [1- (Pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide

Embedded image Benzoyl chloride (0.32m) was added to a solution of ammonium isothiocyanate (220mg) in acetone (4.5ml).
l) was added dropwise at room temperature, and the mixture was stirred at 75 ° C for 10 minutes.
A mixed solution of-[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) is added dropwise. Then, the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was distilled off, water was added, and the mixture was extracted with chloroform. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Concentrated hydrochloric acid (10 ml) was added to the obtained residue, and the mixture was stirred under reflux for 1 hour. After completion of the reaction, water was added and ethyl acetate was added.
The residue obtained by successively washing with chloroform and concentrating the aqueous layer was dissolved in water and ethanol, and the residue was ion-exchanged with an ion exchange resin (IR
A-410). This was filtered, and the residue obtained by concentrating the filtrate was subjected to silica gel column chromatography (chloroform: methanol = 100: 1 to 20: 1).
And dried under reduced pressure to give the title compound (450 mg). ¹ H-NMR (δppm, 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

Embedded image 7- [1- (Pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with a hydrogen chloride ethanol solution to obtain a residue. Methyl iodide (0.1 ml) was added to a methanol (6 ml) suspension, and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, the residue obtained by evaporating the solvent was dissolved in water and ethanol, and neutralized with an ion exchange resin (IRA-410). This was filtered, the filtrate was concentrated and dried under reduced pressure to give the title compound (200 m
g) was obtained. ¹ H-NMR (δppm, 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, 2
H), 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

Embedded image 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (10
To a solution of 0 mg) in ethanol (2 ml) 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. An aqueous sodium hydrogen carbonate solution was added, and the mixture was washed with chloroform. A 4N aqueous solution of sodium hydroxide was added to the aqueous layer, extracted with chloroform, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was treated with a hydrogen chloride ethanol solution and dried under reduced pressure to give the title compound (80 m
g) was obtained. ¹ H-NMR (δppm, 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

Embedded image 7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (13
5 mg) in an ethanol solution (3 ml), hydroxyamine hydrochloride (47 mg), sodium acetate (56 mg)
Was added and stirred at 40 ° C. for 2 hours. After completion of the reaction, water was added and the mixture was washed with chloroform, and a 4N aqueous solution of sodium hydroxide was added thereto, followed by extraction with chloroform. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent was treated with a hydrogen chloride ethanol solution and dried under reduced pressure to obtain the title compound (82 mg). ^{1 H-NMR (δppm, 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, 1
H), 10.86 (brs, 1H), 13.71 (brs, 1H)

Example 5 Synthesis process of N-phenyl-7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride 1 N-phenyl-7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide

Embedded image 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 phenylisothiocyanate (0.012 ml). Was added and stirred at room temperature for 1 hour. After completion of the reaction, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 100: 1, 1% triethylamine), dried under reduced pressure and dried to give the title compound (40
mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.36-1.49 (m, 2H), 1.90-2.15 (m, 3
H), 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

Embedded image N-phenyl-7- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (35 m
g) was treated with a solution of hydrogen chloride in ethanol, and a suspension of the obtained residue in methanol (1 ml) was added to methyl iodide (0.0%).
14 ml) and stirred at 60 ° C. for 1.5 hours. After completion of the reaction, the residue obtained by evaporating the solvent was dissolved in water and ethanol, and neutralized with an ion exchange resin (IRA-410). This was filtered, and the residue obtained by concentrating the filtrate was added to ethanol (1 ml) and ammonium acetate (24 m
g)) and stirred under reflux for 12 hours. After completion of the reaction, water was added, and the mixture was washed with chloroform. An aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is subjected to reverse layer preparative TL
Purified with C (50% acetonitrile-water, 1.5% trifluoroacetic acid). The obtained residue was treated with a hydrogen chloride ethanol solution and dried under reduced pressure to obtain the title compound (12 mg). ^{1 H-NMR (δppm, 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 (2
H), 9.66 (brs, 1H), 13.38 (brs, 1H)

Example 6 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride Synthesis of salt Step 1 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester

Embedded image Under an argon atmosphere, 7-hydroxy-1,2,3,4-
Tetrahydroisoquinoline-2-carboxylic acid tert
To a solution of -butyl ester (13 g) in dimethylformamide (100 ml) was added 60% sodium hydride (2.
After stirring at room temperature for 30 minutes, chloromethyl methyl sulfide (5.2 ml) was added dropwise under 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 sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 20: 1 to 10: 1), and dried under reduced pressure to give the title compound (9 0.6 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.49 (s, 9H), 2.25 (s, 3H), 2.77 (t
r, 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

Embedded image Under an argon atmosphere, 7-methylthiomethoxy-1,2,2
3,4-tetrahydroisoquinoline-2-carboxylic acid
Sulfuryl chloride (2.7) was added to a solution of tert-butyl ester (9.6 g) in methylene chloride (100 ml) under ice cooling.
(5 ml) in methylene chloride (30 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Toluene was added to the residue obtained by evaporating the solvent, and the insolubles were separated by filtration. The solvent was distilled off and dried under reduced pressure to obtain the title compound (7.4 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.49 (s, 9H), 2.79 (tr, J = 6.3 Hz, 2
H), 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- (pyridine-4-
Yl) piperidin-4-ylmethoxy] -1,2,3
4-tetrahydroisoquinoline-2-carboxylic acid te
rt-butyl ester

Embedded image Under an argon atmosphere, 1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (tetrahedron, Vol. 44, No. 23, p. 7095, 1988) (1)
To a solution of 3.4 g) in tetrahydrofuran (300 ml) was added dropwise a 2M lithium diisopropylamide-tetrahydrofuran solution (31 ml) at -70 ° C.
Stir for 5 minutes. To this solution was added 7-chloromethoxy-
4. A solution of 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (7.4 g) in tetrahydrofuran (80 ml) was added dropwise at the same temperature.
The temperature was raised to room temperature while stirring for 5 hours. After completion of the reaction, an 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 distilled off. The obtained residue was dissolved in methanol (150 ml), a 1N aqueous sodium hydroxide solution (50 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (chloroform: methanol = 20: 1 to 10: 1).
And dried under reduced pressure to give the title compound (10.87 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.26 (tr, J = 7 Hz, 3H), 1.49 (s, 9H),
1.68-1.80 (m, 2H), 2.30-2.40 (m, 2H), 2.75 (m, 2H), 3.1
0-3.20 (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

Embedded image 7- [4-ethoxycarbonyl-1- (pyridine-4-
Yl) piperidin-4-ylmethoxy] -1,2,3
4-tetrahydroisoquinoline-2-carboxylic acid te
To a solution of rt-butyl ester (10.87 g) in chloroform (50 ml) was added trifluoroacetic acid (30 m
l) was added dropwise and stirred at room temperature for 30 minutes. An aqueous solution of sodium hydrogen carbonate was added to the residue obtained by evaporating the solvent, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and then dried under reduced pressure to obtain the title compound (8.29 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.25 (tr, J = 7 Hz, 3H), 1.65-1.95
(m, 2H), 2.30-2.36 (m, 2H), 2.72 (brtr, 2H), 3.05-3.18
(m, 4H), 3.69-3.76 (m, 2H), 3.96 (s, 4H), 4.21 (q, J = 7Hz,
2H), 6.52 (1H), 6.65-6.67 (m, 3H), 6.98 (1H), 8.25 (2H) Process 5

4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1
-(Pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride

Embedded image 1- (pyridin-4-yl) -4- (1,2,3,4-
Tetrahydroisoquinolin-7-yloxymethyl) piperidine-4-carboxylic acid ethyl ester (8.29
To a solution of g) in dimethylformamide (50 ml), diisopropylethylamine (4.4 ml) and 1H-pyrazole-1-carboxyamidine hydrochloride (3.69 g) were added, and the mixture was stirred at room temperature for 12 hours. Diethyl ether (350 ml) was added to the residue obtained by evaporating the solvent, and the supernatant was removed. The obtained oil was dissolved in methanol (20 ml).
In diethyl ether (700 m
l) was added dropwise. The supernatant was removed and dried under reduced pressure to obtain 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4. -Dissolve 50 mg of ethyl carboxylate (10.0 g) in ethanol, add dilute hydrochloric acid, concentrate and dry under reduced pressure to give the title compound (5
5 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.15 (tr, 3H), 1.65-1.80 (m, 2
H), 2.15-2.22 (m, 2H), 2.81 (tr, J = 6.0Hz, 2H), 3.30-3.5
0 (m, 2H), 3.56 (tr, J = 6.0Hz, 2H), 3.95-4.18 (m, 6H), 4.5
3 (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 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Synthesis

Embedded image 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride (9 g) was concentrated. It was dissolved in hydrochloric acid (50 ml) and stirred under reflux for 3 hours. After completion of the reaction, insolubles were filtered off, the solvent was distilled off, and the residue was dried under reduced pressure to give the title compound (9.0 g).
I got ¹ H-NMR (δppm, 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

Embedded image 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride (11 g) was added to water (100 ml). ) And filtered,
A 4N-sodium hydroxide aqueous solution (20 ml) was added dropwise at 50 ° C, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the resulting solid was collected by filtration, washed sequentially with water and ethanol, and dried under reduced pressure to obtain the title compound (7.7 g). ¹ H-NMR (δppm, 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 = 8.3H
z, 1H), 7.09 (d, J = 7.2Hz, 2H), 7.17 (d, J = 8.3Hz, 1H), 8.1
3 (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

Embedded image 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.
ml), and the mixture was heated to 60 ° C., and a 1N aqueous sodium hydroxide solution (2.9 ml) and 1N hydrochloric acid (1 ml) were sequentially added dropwise. The resulting crystals were collected by filtration, washed with water, and dried to give the title compound (4.7 g). ¹ H-NMR (δppm, 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, 2
H), 6.70 (1H), 6.79-6.86 (m, 3H), 7.13 (1H), 7.61 (brs,
4H), 8.14 (2H)

Example 10 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-
Synthesis of dimethylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride Step 1 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image 7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (3 g) was treated with a 1N aqueous solution of sodium hydroxide (46 ml) and tetrahydrofuran (10 m
l), benzyl chlorocarbonate (2.45 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with chloroform, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (3.3 g).

Step 2 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image Under an argon atmosphere, 7-hydroxy-1,2,3,4-
Tetrahydroisoquinoline-2-carboxylic acid benzyl ester (2.5 g) in dimethylformamide (25 m
l) Add 60% sodium hydride (390 m
g) was added and stirred at the same temperature for 30 minutes. 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, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the oil obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate =
8: 1) and dried under reduced pressure to give the title compound (2.7)
g) was obtained. ¹ H-NMR (δppm, 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), 6.6
9 (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

Embedded image Under an argon atmosphere, 7-methylthiomethoxy-1,2,2
3,4-tetrahydroisoquinoline-2-carboxylic acid
Benzyl ester (200mg) in methylene chloride (4m
l) To the solution, add sulfuryl chloride (0.052 ml) under ice-cooling.
Was added dropwise and stirred at the same temperature for 1 hour. The solvent was distilled off by azeotropic distillation with toluene and dried under reduced pressure to obtain the title compound (213 mg). ¹ H-NMR (δppm, 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-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester

Embedded image Ethyl isonipecotate (25.5 g), di-tert
Example 1 from butyl dicarbonate (36.5 g)
The title compound (41.4 g) was obtained in the same manner as in Step 1.

Step 5 7- (1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy) -1,
2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image To a solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl ester (300 mg) in tetrahydrofuran (3 ml) was added dropwise a 1.5 M lithium diisopropylamide-tetrahydrofuran solution (0.97 ml) at -70 ° C, and the mixture was heated at the same temperature. Stir for 50 minutes. Next, a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (213 mg) in tetrahydrofuran (3 ml) was added dropwise at the same temperature, and the temperature was raised to room temperature with stirring for 2 hours. did. After completion of the reaction, an aqueous ammonium chloride solution and water were added under ice cooling, and the mixture was extracted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 7: 1), and dried under reduced pressure to obtain the title compound (170 mg). . ^{1 H-NMR (δppm, CDCl} 3) 1.23 (tr, J = 7.2Hz, 3H), 1.46 (s, 9
H), 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

Embedded image 7- (1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy) -1,
Trichloroacetic acid (0.5 ml) was added to a chloroform (1.5 ml) solution of 2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (165 mg).
Was added dropwise and stirred at room temperature for 1 hour. The solvent was distilled off, and an aqueous solution of sodium hydrogen carbonate was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off and the residue was dried under reduced pressure to obtain the title compound (135 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.23 (tr, J = 7.5 Hz, 3H), 1.50-1.65
(m, 2H), 2.15-2.25 (m, 2H), 2.65-2.90 (m, 4H), 2.95-3.0
5 (m, 2H), 3.69 (m, 2H), 3.93 (s, 2H), 4.19 (q, J = 7.5Hz, 2
H), 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

Embedded image 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), 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 using a pressure-resistant reaction vessel. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol = 4: 1), dried under reduced pressure and dried to obtain the title compound (1).
60 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.26 (tr, J = 6.6 Hz, 3H), 1.70-1.85
(m, 2H), 2.35-2.45 (m, 2H), 2.66 (s, 6H), 2.78 (m, 2H),
3.28-3.37 (m, 2H), 3.70 (m, 2H), 3.80-3.90 (m, 2H), 3.97
(s, 2H), 4.24 (q, J = 6.6Hz, 2H), 4.60 (s, 2H), 5.17 (s, 2
H), 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

Embedded image 7- [1- (2,6-dimethylpyridin-4-yl)-
4-ethoxycarbonylpiperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-25 to carboxylic acid benzyl ester (155 mg)
% Hydrogen bromide acetic acid solution (3 ml) was added and stirred for 10 minutes. After completion of the reaction, diisopropyl ether was added and the resulting solid was collected by filtration. Dimethylformamide (1 ml) and diisopropylethylamine (0.25
ml), 1H-pyrazole-1-carboxamidine hydrochloride (80 mg) was added, and the mixture was stirred at room temperature for 12 hours. The residue obtained by distilling off the solvent was washed with tetrahydrofuran and then separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 4: 1 to 2: 3). The obtained residue was treated with dilute hydrochloric acid and dried under reduced pressure to give the title compound (120 m
g) was obtained.

Example 11 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-
Synthesis of dimethylpyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 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) with 6N-
Hydrochloric acid was added and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insolubles were removed, the solvent was distilled off, and the obtained residue was washed with diethyl ether and dried under reduced pressure to obtain the title compound (76 mg). ¹ H-NMR (δppm, 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 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidin-4-carboxylic acid
Synthesis of methyl ester dihydrochloride Step 1 4-Chloro-2-methylpyridine hydrochloride

Embedded image Journal of Heterocyclic Chemistry, vol. 27, p.
From -methylpyridine N-oxide (5.1 g), the title compound (743 mg) was obtained. ¹ H-NMR (δppm, 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

Embedded image 7- (4-ethoxycarbonylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (100 mg),
4-chloro-2-methylpyridine hydrochloride (40 mg),
The title compound (105 mg) was obtained from triethylamine (0.07 ml) in the same manner as in Step 7 of Example 10.

Step 3 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidine-4-carboxylic acid
Ethyl ester dihydrochloride

Embedded image 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), 1H-pyrazole-1-carboxyamidine hydrochloride (55 mg) from Step 8 of Example 10.
In the same manner as in the above, the title compound (83 mg) was obtained.

Example 13 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidin-4-carboxylic acid
Synthesis of dihydrochloride

Embedded image 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-methylpyridin-4-yl) piperidin-4-carboxylic acid
Example 1 from ethyl ester dihydrochloride (63 mg)
In the same manner as 1, the title compound (53 mg) was obtained. ¹ H-NMR (δppm, 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 (br
s, 1H)

Example 14 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyrimidin-4-yl) piperidine-4-carboxylic acid dihydrochloride Synthesis Step 1 7- [1- (2-chloropyrimidin-4-yl) -4-
Ethoxycarbonylpiperidin-4-ylmethoxy]-
1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image 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), triethylamine (0.
15 ml), 2,4-dichloropyrimidine (150 m
g) was added and the mixture was stirred for 1 hour under reflux. After completion of the reaction, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purify in 2) and dry under reduced pressure to give the title compound (263 mg)
I got ^{1 H-NMR (δppm, 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, 2
H), 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 = 6.1H
z, 1H)

Step 2 1- (Pyrimidin-4-yl) -4- (1,2,3,4
-Tetrahydroisoquinolin-7-yloxymethyl)
Piperidine-4-carboxylic acid ethyl ester

Embedded image 7- [1- (2-chloropyrimidin-4-yl) -4-
Ethoxycarbonylpiperidin-4-ylmethoxy]-
To a solution of 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (263 mg) in ethanol (5 ml) was added 7.5% palladium carbon (1
20 mg) and ammonium formate (200 mg) were added, and the mixture was stirred under reflux for 30 minutes. After completion of the reaction, water was added to the residue obtained by evaporating the solvent, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was dried under reduced pressure to obtain 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

Embedded image 1- (pyrimidin-4-yl) -4- (1,2,3,4
-Tetrahydroisoquinolin-7-yloxymethyl)
Piperidine-4-carboxylic acid ethyl ester (260
mg) in dimethylformamide (1 ml), diisopropylethylamine (0.24 ml), 1H-pyrazole-1-carboxamidine hydrochloride (200 mg).
Was added and stirred at room temperature for 2 hours. After completion of the reaction, the residue obtained by evaporating the solvent was fractionated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 6: 4 to 2: 8),
The obtained residue was refluxed with concentrated hydrochloric acid for 2 hours. After the reaction,
The residue obtained by evaporating the solvent was washed with diethyl ether and dried under reduced pressure to obtain the title compound (51 mg). ¹ H-NMR (δppm, 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), 6.8
1 (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), 8.8
1 (s, 1H)

Example 15 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl] -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
Synthesis of ethyl ester dihydrochloride Step 1 7- (2-Iodoethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.21
g), 2-bromoethanol (5.46 ml), and a solution of triphenylphosphine (20.11 g) in tetrahydrofuran (30 ml), and a 40% diethylazodicarboxylate-toluene solution (33.6 ml) was added.
Stirred for hours. After completion of the reaction, dimethylformamide (30 ml) and sodium iodide (9.6 g) were added to the residue obtained by evaporating the solvent, and the mixture was stirred at 90 ° C. for 15 hours.
After completion of the reaction, the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) and dried under reduced pressure to give the title compound (1.19)
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 2.79 (m, 2H), 3.40 (tr, J = 6.9 Hz, 2
H), 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), 7.26-7.3
8 (m, 5H)

Step 2 7- [2- (1-tert-butoxycarbonyl-4-)
Ethoxycarbonylpiperidin-4-yl) ethoxy]
-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester

Embedded image 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) The title compound (935 mg) was obtained from 2M-lithium diisopropylamide-tetrahydrofuran solution (0.82 ml) in the same manner as in Step 5 of Example 10. ¹ H-NMR (δppm, CDCl ₃ ) 1.25 (tr, J = 6.9 Hz, 3H), 1.60-1.65
(m, 2H), 2.01-2.04 (m, 2H), 2.13-2.19 (m, 2H), 2.77 (m, 2
H), 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

Embedded image 7- [2- (1-tert-butoxycarbonyl-4-
Ethoxycarbonylpiperidin-4-yl) ethoxy]
In the same manner as in Step 6 of Example 10, 7- [2- (4-ethoxycarbonyl) was obtained from -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (935 mg) and trifluoroacetic acid (5 ml). Piperidine-
4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester was obtained. This was combined with 4-chloropyridine hydrochloride (248 m
g) and triethylamine (1.38 ml) to give the title compound (680 mg) in the same manner as in Step 7 of Example 10. However, the reaction time was 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

Embedded image 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), 1H-pyrazole-1-carboxyamidine hydrochloride (214 mg) ) To give the title compound (208 mg) in the same manner as in Step 8 of Example 10.

Example 16 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl] -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
Synthesis of dihydrochloride

Embedded image 4- [2- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy) ethyl] -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
The reaction was carried out in the same manner as in Example 11 from ethyl ester dihydrochloride (200 mg). The obtained residue is subjected to HPLC
(0.05% aqueous trifluoroacetic acid: methanol = 1:
The resulting residue was treated with dilute hydrochloric acid to obtain the title compound (29 mg). ¹ H-NMR (δppm, 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 (S) -4- [N- [5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazole-2]
-Ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl]
Synthesis of benzoic acid dihydrochloride Step 1 4- (4-nitrophenoxy) piperidine-1-carboxylic acid tert-butyl ester

Embedded image 4-hydroxypiperidine-1-carboxylic acid tert
To a solution of -butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under ice-cooling under nitrogen, 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 with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (52.384 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.48 (s, 9H), 1.80 (m, 2H), 1.96
(m, 2H), 3.39 (m, 2H), 3.70 (m, 2H), 4.61 (m, 1H), 6.96
(d, J = 9.3Hz, 2H), 8.20 (d, J = 9.3Hz, 2H)

Step 2 4- (4-aminophenoxy) piperidine-1-carboxylic acid tert-butyl ester

Embedded image 4- (4-Nitrophenoxy) piperidine-1-carboxylic acid tert-butyl ester (53.687 g) was added to tetrahydrofuran (215 ml) and ethanol (21).
7.5% palladium on carbon (8.0 ml) in the mixed solution.
5g) and hydrogenated at 3 atmospheres over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, the solvent was distilled off, hexane was added to the obtained residue, and the obtained solid was collected by filtration and dried under reduced pressure to obtain the title compound (42.157 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 1.71 (m, 2H), 1.86
(m, 2H), 3.27 (m, 2H), 3.71 (m, 2H), 4.26 (m, 1H), 6.63
(d, J = 8.7Hz, 2H), 6.76 (d, J = 8.7Hz, 2H)

Step 3 4- (4-benzyloxycarbonylaminophenoxy) piperidine-1-carboxylic acid tert-butyl ester

Embedded image 4- (4-Aminophenoxy) piperidine-1-carboxylic acid tert-butyl ester (6.63 g), sodium hydrogencarbonate (2.1 g) in tetrahydrofuran (1
(00 ml) -water (100 ml) was added dropwise with benzyl chlorocarbonate (3.24 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by distilling off the solvent was washed with diisopropyl ether, collected by filtration, and dried under reduced pressure to give the title compound (7.189).
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.74 (m, 2H), 1.88
(m, 2H), 3.31 (m, 2H), 3.69 (m, 2H), 4.39 (m, 1H), 5.19
(s, 2H), 6.54 (brs, 1H), 6.86 (2H), 7.26-7.42 (m, 7H)

Step 4 4- [4- (N-benzyloxycarbonyl-N-ethoxycarbonylmethylamino) phenoxy] piperidine-1-carboxylic acid tert-butyl ester

Embedded image To a solution of 4- (4-aminophenoxy) piperidine-1-carboxylic acid tert-butyl ester (42.28 g) in dimethylformamide (254 ml) was added 60% sodium hydride (3.97 g), and the mixture was stirred at room temperature for 20 minutes. did. Then, ethyl bromoacetate (12.1 m
l) was added and the mixture was stirred at room temperature for 15 hours. 60% sodium hydride (3.97 g), ethyl bromoacetate (12.1.
ml) and stirred at room temperature for 4 hours. 60% more
Sodium hydride (1.19 g) and ethyl bromoacetate (3.3 ml) were added, and the mixture was stirred at room temperature for 2 hours. After 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 residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the title compound (49.916 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.28 (3H), 1.47 (s, 9H), 1.75 (m, 2
H), 1.89 (m, 2H), 3.34 (m, 2H), 3.68 (m, 2H), 4.19 (2H),
4.30 (brs, 2H), 4.43 (m, 1H), 5.19,5.17 (2H), 6.86 (2H),
7.13-7.35 (m, 7H)

Step 5 N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-benzyloxycarbonylaminoacetic acid

Embedded image 4- [4- (N-benzyloxycarbonyl-N-ethoxycarbonylmethylamino) phenoxy] piperidine-1-carboxylic acid tert-butyl ester (49.
916 g) in ethanol (102 ml)
An aqueous sodium hydroxide solution (102 ml) and tetrahydrofuran (102 ml) were added, and the mixture was stirred at room temperature for 10 minutes and at 50 ° C for 1 hour. After completion of the reaction, the residue obtained by evaporating the solvent was extracted with ethyl acetate, and washed with a 10% aqueous citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to give the title compound (4).
7.18 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.76 (m, 2H), 1.89
(m, 2H), 3.34 (m, 2H), 3.68 (m, 2H), 4.35 (s, 2H), 4.44
(m, 1H), 5.16 (brs, 2H), 6.86 (2H), 7.15-7.45 (m, 7H)

Step 6 N- (4-cyano-2-nitrophenyl) glycine t
tert-butyl ester

Embedded image 4-chloro-3-nitrobenzonitrile (33.87
g), glycine tert-butyl ester hydrochloride (5
To a solution of 5.98 g) in ethanol (400 ml) was added triethylamine (77.6 ml), and the mixture was added at room temperature for 15 hours.
Stirred at 50 ° C. for 3 hours. After completion of the reaction, the residue obtained by evaporating the solvent was extracted with ethyl acetate, and washed with a 10% aqueous citric acid solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was washed with diisopropyl ether and collected by filtration to give the title compound (3
8.419 g). ^{1 H-NMR (δppm, CDCl} 3) 1.53 (s, 9H), 4.03 (d, J = 5.0Hz, 2
H), 6.75 (d, J = 8.9Hz, 1H), 7.64 (dd, J = 2.0,8.9Hz, 1H),
8.55 (d, J = 2.0Hz, 1H), 8.81 (brs, 1H),

Step 7 N- (2-amino-4-cyanophenyl) glycine t
tert-butyl ester

Embedded image N- (4-cyano-2-nitrophenyl) glycine t
7.5% palladium carbon (3.84 g) was added to ert-butyl ester (17.337 g) in tetrahydrofuran (173 ml) solution using 7.5% palladium carbon (1.73 g) at normal pressure for 2 hours. For another hour. After completion of the reaction, the mixture was filtered through Celite, and the residue obtained by evaporating the solvent was washed with diisopropyl ether.
The crystals were collected by filtration and dried under reduced pressure to give the title compound (8.324 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.51 (s, 9H), 3.84 (s, 2H), 6.45 (1
H), 6.95 (1H), 7.15 (1H)

Step 8 4- [4- [N-benzyloxycarbonyl-N- (2
-Tert-butoxycarbonylmethylamino-5-cyanophenyl) carbamoylmethylamino] phenoxy] piperidine-1-carboxylic acid tert-butyl ester

Embedded image N- (2-amino-4-cyanophenyl) glycine t
tert-butyl ester (21.53 g), N- [4-
(1-tert-butoxycarbonylpiperidine-4-
Yloxy) phenyl] -N-benzyloxycarbonylaminoacetic acid (42.18 g) in chloroform (300
ml) solution, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (23.68 g) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give the title compound (4
4.479 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.76 (m, 2H), 1.90
(m, 2H), 3.34 (m, 2H), 3.67 (m, 2H), 3.78 (brd, 2H), 4.36
(s, 2H), 4.45 (m, 1H), 5.10-5.25 (m, 1H), 5.20 (s, 2H),
6.53 (1H), 6.89 (2H), 7.20-7.31 (m, 7H), 7.40 (2H), 7.9
6 (brs, 1H)

Step 9 2- [N-benzyloxycarbonyl-N- [4- (1
-Tert-Butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid

Embedded image 4- [4- [N-benzyloxycarbonyl-N- (2
A solution of -tert-butoxycarbonylmethylamino-5-cyanophenyl) carbamoylmethylamino] phenoxy] piperidine-1-carboxylic acid tert-butyl ester (44.479 g) in acetic acid (600 ml) was stirred at 90 ° C for 4 days. After the completion of the reaction, the residue obtained by evaporating the solvent (51 g) and sodium carbonate (19.8).
g), di-tert-butyl dicarbonate (13.6)
g) according to a conventional method, and the obtained residue is purified by silica gel column chromatography (chloroform: methanol = 9: 1), dried under reduced pressure, and dried to give the title compound (23.
545 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 1.67 (m, 2H), 1.81
(m, 2H), 3.27 (m, 2H), 3.63 (m, 2H), 4.35 (m, 1H), 5.05 (b
rs, 6H), 6.75 (2H), 7.02-7.27 (m, 7H), 7.30 (d, J = 8.4Hz,
1H), 7.50 (dd, J = 1.1,8.4Hz, 1H), 7.99 (d, J = 1.1Hz, 1H)

Step 10 (S) -2- [N-benzyloxycarbonyl-N-
[4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyano-1- (1-phenylethylcarbamoylmethyl)
Benzimidazole

Embedded image 2- [N-benzyloxycarbonyl-N- [4- (1
-Tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid (583 mg) and 1-hydroxybenzotriazole hydrate (135 mg) in dimethylformamide (5 ml) solution. S) -phenethylamine (0.118 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (193 m
g) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, extraction was performed with ethyl acetate, and water, an aqueous solution of sodium hydrogen carbonate,
The mixture was washed sequentially with a 0% citric acid aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, diisopropyl ether was added to the residue obtained by evaporating the solvent, and the resulting solid was collected by filtration to obtain the title compound (623 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.46-1.48 (s, 12H), 1.70 (m, 2H),
1.86 (m, 2H), 3.30 (m, 2H), 3.65 (m, 2H), 4.38 (m, 1H), 4.
95-5.05 (m, 3H), 5.14 (s, 2H), 5.21 (s, 2H), 6.81 (2H),
7.10-7.30 (m, 12H), 7.48 (d, J = 8.0Hz, 1H), 7.63 (d, J = 8.0
Hz, 1H), 8.06 (s, 1H)

Step 11 (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N
-(4-methoxycarbonylbenzoyl) aminomethyl] -5-cyano-1- (1-phenylethylcarbamoylmethyl) benzimidazole

Embedded image (S) -2- [N-benzyloxycarbonyl-N-
[4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyano-1- (1-phenylethylcarbamoylmethyl)
A solution of benzimidazole (623 mg) in a solution of 7.5% palladium on carbon (310 ml) in tetrahydrofuran (6 ml).
and hydrogenation at 3 atmospheres for 7 hours. After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off, and the residue was dissolved in chloroform (6 ml). Triethylamine (0.176 ml), methyl 4-chloroformylbenzoate (167 mg), 4-dimethylaminopyridine (10
mg) and stirred at room temperature for 18 hours. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 7), and dried under reduced pressure to obtain the title compound (284 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.36 (d, 3H), 1.46 (s, 9H), 1.70
(m, 2H), 1.86 (m, 2H), 3.30 (m, 2H), 3.69 (m, 2H), 3.87
(s, 3H), 4.36 (m, 1H), 5.02-5.09 (m, 3H), 5.15-5.28 (s, 2
H), 5.21 (m, 2H), 6.73 (d, J = 9Hz, 2H), 7.11 (d, J = 9Hz, 2
H), 7.15-7.23 (m, 6H), 7.30 (d, J = 8.4Hz, 2H), 7.40 (1H),
7.51 (1H), 7.82 (d, J = 8.4Hz, 2H), 8.04 (1H)

Step 12 (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N
-(4-methoxycarbonylbenzoyl) aminomethyl] -1- (1-phenylethylcarbamoylmethyl)
Benzimidazole-5-carboxamidine

Embedded image (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N
-(4-Methoxycarbonylbenzoyl) aminomethyl] -5-cyano-1- (1-phenylethylcarbamoylmethyl) benzimidazole (284 mg) in pyridine-triethylamine (5: 1) mixed solution (10 m
Hydrogen sulfide was blown into l) under ice cooling, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, and acetone (6 ml), methanol (6 ml), and methyl iodide (0.229 ml) were added to the residue treated with hydrogen chloride-ethanol.
The mixture was stirred under reflux for 2 hours. After completion of the reaction, the residue obtained by evaporating the solvent was dissolved in ethanol (12 ml), ammonium acetate (43 mg) was added, and the mixture was stirred at 75 ° C for 2 hours. After completion of the reaction, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 95: 5 to 90:10), and dried under reduced pressure to obtain the title compound (113 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.30-1.45 (m, 14H), 1.76 (m, 2
H), 3.07 (m, 2H), 3.57 (m, 2H), 3.80 (s, 3H), 4.40 (m, 1
H), 4.92 (m, 1H), 5.21-5.38 (m, 4H), 6.75 (d, J = 9.0Hz, 2
H), 7.14 (d, J = 9.0Hz, 2H), 7.21-7.33 (m, 7H), 7.63-7.70
(m, 2H), 7.75 (2H), 8.14 (s, 1H), 8.96 (brs, 1H)

Step 13 (S) -4- [N- [5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazole-2]
-Ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl]
Benzoic acid dihydrochloride

Embedded image (S) -2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N
-(4-methoxycarbonylbenzoyl) aminomethyl] -1- (1-phenylethylcarbamoylmethyl)
Benzimidazole-5-carboxamidine (113
mg)) in chloroform (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 5 minutes. The solvent was distilled off, and the obtained residue was treated with a 4N aqueous sodium hydroxide solution (1.
1 ml) and stirred for 5 hours. After completion of the reaction, dilute hydrochloric acid was added to distill off the solvent, followed by drying under reduced pressure to obtain a residue. The obtained residue was dissolved in methanol (2 ml), and triethylamine (0.2 ml) and ethylacetoimidate hydrochloride (89 mg) were added, followed by stirring at room temperature for 18 hours. After the reaction was completed, insolubles were removed, and the solvent was distilled off. The residue obtained was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). After dilute hydrochloric acid was added to the obtained residue, the solvent was distilled off and the residue was dried under reduced pressure to give the title compound (78 m
g) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.37 (d, J = 7.2 Hz, 3H), 1.63 (m, 2
H), 1.94 (m, 2H), 2.25 (s, 3H), 3.43 (m, 2H), 3.72 (m, 2
H), 4.56 (m, 1H), 4.91 (quint, J = 7.2Hz, 1H), 5.23-5.39
(m, 4H), 6.80 (2H), 7.16-7.37 (m, 9H), 7.72-7.74 (m, 4
H), 8.17 (s, 1H), 8.73 (brs, 1H), 9.09 (brs, 2H), 9.20
(d, J = 7.2Hz, 1H), 9.31 (brs, 3H)

Example 18 4- [N- [5-amidino-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole-2]
-Ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl]
Synthesis of benzoic acid dihydrochloride Step 1 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid

Embedded image 2- [N-benzyloxycarbonyl-N- [4- (1
-Tert-Butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid (7.037 g) in a solution of 7.5% palladium on carbon (3.5 ml) in a solution of ethanol (70 ml).
2g) for 3 hours at 3 atm. After completion of the reaction, the mixture was filtered through celite, and the solvent was distilled off. The obtained residue was washed with diisopropyl ether, collected by filtration, and dried under reduced pressure to give the title compound (4.189 g). ¹ H-NMR (δppm, CD ₃ OD) 1.44 (s, 9H), 1.58 (m, 2H), 1.84
(m, 2H), 3.25 (m, 2H), 3.66 (m, 2H), 4.29 (m, 1H), 4.60
(s, 2H), 5.23 (s, 2H), 6.67 (d, J = 6.6Hz, 2H), 6.77 (d, J =
6.6Hz, 2H), 7.59 (d, J = 6.6Hz, 1H), 7.63 (d, J = 6.6Hz, 1H),
8.02 (s, 1H)

Step 2 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -5-
Cyanobenzimidazole-1-acetic acid

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] aminomethyl] -5-cyanobenzimidazole-1-acetic acid (3.
36g), sodium hydrogen carbonate (1.67g) in water (3
4 ml) and tetrahydrofuran (34 ml) were mixed with methyl 4-chloroformylbenzoate (1.32 g), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and washed sequentially with water, a 10% aqueous citric acid solution and saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (2.907 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.45 (s, 9H), 1.63 (m, 2H), 1.80
(m, 2H), 3.25 (m, 2H), 3.63 (m, 2H), 3.83 (s, 3H), 4.31
(m, 1H), 5.28 (s, 2H), 5.32 (s, 2H), 6.65 (d, J = 9.0Hz, 2
H), 6.90 (d, J = 9.0Hz, 2H), 7.23 (d, J = 8.4Hz, 2H), 7.37 (1
H), 7.55 (1H), 7.64 (d, J = 8.4Hz, 2H), 7.99 (1H)

Step 3 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -5-
Cyano-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -5-
Cyanobenzimidazole-1-acetic acid (632 mg),
1-hydroxybenzotriazole hydrate (128 m
g), 4-benzyloxyaniline hydrochloride (223 m
g), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (182 mg), N-methylmorpholine (0.104 ml), Step 1 of Example 17
The reaction was carried out in the same manner as in Example 1, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 7 to 2: 8) to give the title compound (605 m
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 1.85 (m, 2H), 3.29
(m, 2H), 3.66 (m, 2H), 3.84 (s, 3H), 4.35 (m, 1H), 4.98
(s, 2H), 5.23 (s, 2H), 5.31 (s, 2H), 6.72 (d, J = 9.0Hz, 2
H), 6.80 (d, 2H), 7.07 (d, J = 9.0Hz, 2H), 7.27 (d, J = 8.4H
z, 2H), 7.30-7.41 (m, 7H), 7.56 (s, 2H), 7.73 (d, J = 8.4H
z, 2H), 8.06 (s, 1H), 8.72 (brs, 1H)

Step 4 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
(4-benzyloxyphenylcarbamoylmethyl) benzimidazole-5-carboxyamidine

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -5-
Cyano-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole (605 mg) in pyridine-triethylamine (5: 1) mixed solution (15 ml)
Hydrogen sulfide was blown into the mixture under ice cooling, followed by stirring at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was collected by filtration and washed with toluene. Acetone (1) was added to the obtained solid.
5 ml) and methyl iodide (0.443 ml) were added, and the mixture was stirred under reflux for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was dried under reduced pressure to obtain a crude product (804 mg). 434 mg of the obtained crude product was dissolved in ethanol (10 ml), and ammonium acetate (44 mg) was added at room temperature to give 75 mg.
Stirred at 3.5 ° C. for 3.5 hours. After the completion of the reaction, the residue obtained by evaporating the solvent is subjected to silica gel column chromatography (chloroform: methanol = 95: 5 to 90:10).
And dried under reduced pressure to give the title compound (141 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.38 (s, 9H), 1.75 (m, 2H), 3.05
(m, 2H), 3.60 (m, 2H), 3.79 (s, 3H), 4.40 (m, 1H), 5.06 (s,
2H), 5.35 (brs, 4H), 6.77 (2H), 6.97 (2H), 7.25-7.50 (1
0H), 7.65-7.76 (4H), 8.13 (1H)

Step 5 4- [N- [5-amidino-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole-2]
-Ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl]
Benzoic acid dihydrochloride

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
(4-benzyloxyphenylcarbamoylmethyl) benzimidazole-5-carboxyamidine (141 m
g), trifluoroacetic acid (1 ml), 4N-aqueous sodium hydroxide solution (0.973 ml), triethylamine (0.226 ml), ethylacetimidate hydrochloride (100 mg) in the same manner as in step 13 of Example 17 The title compound (59 mg) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.63 (m, 2H), 1.95 (m, 2H), 2.27
(s, 3H), 3.45 (m, 2H), 4.57 (m, 1H), 5.06 (s, 2H), 5.39 (br
s, 2H), 5.45 (brs, 2H), 6.82 (d, 2H), 6.97 (d, 2H), 7.18
(d, 2H), 7.27-7.45 (m, 8H), 7.53 (d, 2H), 7.65 (d, 2H),
7.75 (d, J = 8.4Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 8.19 (s, 1
H), 8.74 (brs, 1H), 9.09 (brs, 2H), 9.30-9.33 (m, 3H)

Example 19 Synthesis of 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine dihydrochloride Step 14 4- (1-tert) -Butoxycarbonylpyrrolidine-
3-yloxy) benzaldehyde

Embedded image 3-hydroxypyrrolidine-1-carboxylic acid tert
-Butyl ester (3.07 g), 4-hydroxybenzaldehyde (2 g), triphenylphosphine (4.
To a solution of 51 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (2.7 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: acetone = 5: 1), and dried under reduced pressure to obtain the title compound (3.2 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 2.19 (m, 2H), 3.59
(m, 4H), 4.99 (m, 1H), 6.98 (d, J = 9.0Hz, 2H), 7.85 (d, J =
9.0Hz, 2H), 9.89 (s, 1H)

Step 2 4- (1-tert-butoxycarbonylpyrrolidine-
3-yloxy) phenol

Embedded image 4- (1-tert-butoxycarbonylpyrrolidine-
To a solution of 3-yloxy) benzaldehyde (500 mg) in methylene chloride (10 ml) was added 70% 3-chloroperbenzoic acid (712 mg) under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate were added, and the mixture was extracted with methylene chloride.
Washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was dissolved in methanol (3.4 ml), 1N aqueous sodium hydroxide solution (1.7 ml) was added, and the mixture was stirred at room temperature for 1 hour. did. After completion of the reaction, a 10% aqueous solution of citric acid was added, extracted with chloroform, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the solid obtained by evaporating the solvent was washed with diethyl ether, collected by filtration, and dried under reduced pressure to obtain the title compound (350 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 2.09 (m, 2H), 3.54
(m, 4H), 4.75 (m, 1H), 6.71-6.79 (m, 4H)

Step 3 4- (1-tert-butoxycarbonylpyrrolidine-
3-yloxy) phenoxyacetic acid ethyl ester

Embedded image 4- (1-tert-butoxycarbonylpyrrolidine-
Ethyl bromoacetate (1.1 ml) and 60% sodium hydride (368 m) were added to a solution of 3-yloxy) phenol (2.14 g) in tetrahydrofuran (43 ml) under ice-cooling.
g) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted with ethyl acetate, and washed with a 10% aqueous citric acid solution. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and dried under reduced pressure to obtain the title compound (2.605 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.30 (tr, J = 7.2 Hz, 3H), 1.46 (s, 9
H), 2.13 (m, 2H), 3.54 (m, 4H), 4.27 (q, J = 7.2Hz, 2H), 4.
57 (s, 2H), 4.79 (brs, 1H), 6.78-6.87 (m, 4H)

Step 4 4- (1-tert-butoxycarbonylpyrrolidine-
3-yloxy) phenoxyacetic acid

Embedded image 4- (1-tert-butoxycarbonylpyrrolidine-
To a mixed solution of 3-ethyloxy) phenoxyacetic acid ethyl ester (2.5 g) in tetrahydrofuran (5 ml) and ethanol (5 ml) was added a 1N aqueous solution of lithium hydroxide (7.5 ml) under ice-cooling, followed by stirring at room temperature for 30 minutes. . After completion of the reaction, ice water was added to the residue obtained by evaporating the solvent,
A 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain the title compound (2.30 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 2.14 (m, 2H), 3.54
(m, 4H), 4.61 (brs, 2H), 4.79 (m, 1H), 6.80-6.89 (m, 4H)

Step 5 4- (2-hydroxyethylamino) -3-nitrobenzonitrile

Embedded image 4-chloro-3-nitrobenzonitrile (10.13
g), a mixed solution of ethanolamine (3.52 ml) in ethanol (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours, and then ethanolamine (3.35 ml) was added. (3.35 ml) was added and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solid obtained by distilling off the solvent was washed with isopropanol, collected by filtration and dried under reduced pressure to obtain the title compound (7.25 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 3.48 (m, 2H), 3.63 (m, 2H), 5.00
(brs, 1H), 7.22 (d, J = 9.0Hz, 1H), 7.81 (dd, J = 1.8, 9.0H
z, 1H), 8.50 (d, J = 1.8Hz, 1H), 8.62 (brtr, 1H),

Step 6 3-Amino-4- (2-hydroxyethylamino) benzonitrile

Embedded image 4- (2-hydroxyethylamino) -3-nitrobenzonitrile (3.11 g), tin chloride dihydrate (16.9)
A solution of 4 g) in ethanol (50 ml) was stirred at 70 ° C. for 1 hour. After completion of the reaction, tetrahydrofuran and a 15% aqueous sodium hydroxide solution were added to the residue obtained by evaporating the solvent, and the mixture was stirred. The insoluble material, and then the organic layer obtained by removing the aqueous layer were dried over anhydrous magnesium sulfate. After drying, the solid obtained by evaporating the solvent was washed with chloroform, collected by filtration, and dried under reduced pressure to obtain the title compound (2.08 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 3.17 (q, J = 5.6Hz, 2H), 3.58 (q, J
= 5.6Hz, 2H), 4.74 (tr, J = 5.6Hz, 1H), 4.93 (brs, 2H), 5.3
4 (tr, J = 5.6Hz, 2H), 6.49 (1H), 6.77 (1H), 6.91 (1H)

Step 7 3- [4- [5-Cyano-2- (2-hydroxyethylamino) phenylcarbamoylmethoxy] phenoxy]
Pyrrolidine-1-carboxylic acid tert-butyl ester

Embedded image To a solution of 3-amino-4- (2-hydroxyethylamino) benzonitrile (1.21 g) and 4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxyacetic acid (2.30 g) in chloroform (50 ml). 1-Ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (2.19 g) was added, and the mixture was added at room temperature for 15 hours.
Stirred for hours. After completion of the reaction, the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 4) gave the title compound (2.56).
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 2.13 (m, 2H), 3.31
(m, 2H), 3.55 (m, 4H), 3.73 (m, 2H), 4.64 (s, 2H), 4.82
(m, 1H), 6.73 (1H), 6.85-6.94 (m, 4H), 7.41-7.50 (2H),
7.99 (1H), 8.10 (1H)

Step 8 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -5-cyano-1- (2-hydroxyethyl) benzimidazole

Embedded image 3- [4- [5-cyano-2- (2-hydroxyethylamino) phenylcarbamoylmethoxy] phenoxy]
A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g) in acetic acid (15.4 ml) was heated to 65 ° C.
For 4 hours. After completion of the reaction, the residue obtained by evaporating the solvent was extracted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4-ethyl acetate) to give the title compound (1.356 g). Obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.44 (s, 9H), 2.11 (m, 2H), 3.44-
3.54 (m, 4H), 3.75 (brs, 1H), 4.06 (m, 2H), 4.46 (m, 2H),
4.77 (m, 1H), 5.32 (s, 2H), 6.77 (2H), 6.93 (2H), 7.49 (2
H), 7.79 (1H)

Step 9 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -5-cyano-1- (2-methoxyethyl) benzimidazole

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

Step 10 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -1- (2
-Methoxyethyl) benzimidazole-5-carboxyamidine

Embedded image 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -5-cyano-1- (2-methoxyethyl) benzimidazole (195 mg), methyl iodide (1 ml), ammonium acetate ( 37 mg) to give the title compound (119 mg) in the same manner as in Step 4 of Example 18. ¹ H-NMR (δppm, CDCl ₃ ) 1.45 (s, 9H), 2.10 (m, 2H), 3.24
(s, 3H), 3.54 (m, 4H), 3.69 (brtr, 2H), 4.47 (brtr, 2H),
4.76 (m, 1H), 5.32 (s, 2H), 6.79 (2H), 6.94 (2H), 7.48 (1
H), 7.66 (1H), 8.08 (1H)

Step 11 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine dihydrochloride

Embedded image 2- [4- (1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenoxymethyl] -1- (2
To a solution of (-methoxyethyl) benzimidazole-5-carboxyamidine (115 mg) in chloroform (3 ml) was added trifluoroacetic acid (3 ml), and the mixture was stirred for 5 minutes. The residue obtained by distilling off the solvent was added with 1N hydrogen chloride-
After adding diethyl ether (2 ml), the solvent was distilled off. The obtained residue was washed with tetrahydrofuran and dried under reduced pressure to obtain the title compound (97 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 2.10 (m, 2H), 3.18 (s, 3H), 3.28
-3.42 (m, 4H), 3.69 (brtr, 2H), 4.59 (brtr, 2H), 5.02 (m,
1H), 5.43 (s, 2H), 6.94 (d, J = 9.0Hz, 2H), 7.07 (d, J = 9.0H
z, 2H), 7.60 (d, J = 9.0Hz, 1H), 7.87 (d, J = 9.0Hz, 1H), 8.2
3 (s, 1H), 9.08 (brs, 2H), 9.34 (brs, 2H)

Example 20 2- [4- (1-acetimidoylpyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine
Synthesis of dihydrochloride

Embedded image 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine dihydrochloride (44 mg)
Sodium hydrogencarbonate (38 mg) and ethyl acetimidate hydrochloride (33 mg) were added to a mixed solution of the above in tetrahydrofuran (2 ml) and water (0.6 ml), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, insolubles were removed, and the residue obtained by evaporating the solvent was subjected to HPLC (50% methanol-water,
(0.05% trifluoroacetic acid). After dilute hydrochloric acid was added to the obtained residue, the solvent was distilled off and the residue was dried under reduced pressure to obtain the title compound (40 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 2.12-2.28 (m, 5H), 3.18 (s, 3H),
3.35-3.95 (m, 6H), 4.59 (brs, 2H), 5.06-5.13 (m, 1H),
5.43 (s, 2H), 6.94 (dd, J = 2.9, 9.0Hz, 2H), 7.07 (dd, J = 2.
9, 9.0Hz, 2H), 7.77 (1H), 7.88 (1H), 8.24 (1H), 8.47,
8.54 (1H), 9.13 (2H), 9.27,9.31 (1H), 9.36 (2H)

Example 21 7- [1- (2-hydroxyethyl) piperidine-4-
Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 N, N′-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydro Isoquinoline-2-carboxamidine

Embedded image To a suspension of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (500 mg) in acetonitrile (5 ml) was added triethylamine (0.3
ml), and the mixture was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration. The obtained solid was washed with dimethylformamide (5 m
1) Dissolved and 1H-pyrazol-1- (N, N'-bis-tert-butoxycarbonyl) carboxamidine (synthesis, p.579, 1994) (742 mg)
Was added and stirred at room temperature for 2 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and dried under reduced pressure to obtain the title compound (700 mg). Was. ¹ H-NMR (δppm, 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

Embedded image Under a argon atmosphere, a solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10 g) obtained in the same manner as in Step 1 of Example 10 in tetrahydrofuran (100 ml) was obtained from isonipecotic acid (15.5 g).
Triethylamine (5.56 ml) and isobutyl chlorocarbonate (5.2 ml) were added dropwise at 15 ° C., and the mixture was stirred at the same temperature for 20 minutes. After the completion of the reaction, the reaction solution was filtered, and the filtrate was added dropwise to an aqueous solution of sodium borohydride (4.3 g) under ice cooling. The mixture was stirred at the same temperature for 15 minutes and at room temperature for 2 hours. After the completion of the reaction, water was added to remove insolubles, a part of the solvent was distilled off, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide, water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was dried under reduced pressure to obtain the title compound (7.2 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.05-1.30 (m, 2H), 1.55-1.80 (m, 3
H), 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

Embedded image 4-hydroxymethylpiperidine-1-carboxylic acid benzyl ester (1.11 g), carbon tetrabromide (1.77)
To a solution of g) in methylene chloride (11 ml) was added triphenylphosphine (1.4 g) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 10: 1), and dried under reduced pressure to obtain the title compound (1.25 g). ¹ H-NMR (δ ppm, CDCl ₃ ) 1.05-1.30 (m, 2H), 1.70-1.90 (m, 3
H), 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

Embedded image N, N'-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (50 mg), 4-bromomethylpiperidine-1-carboxylic acid benzyl ester (120 mg) To a solution of dimethyl sulfoxide (1 ml) was added a 4N aqueous solution of sodium hydroxide (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 with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 5: 1) and dried under reduced pressure to obtain the title compound (55 mg). . ¹ H-NMR (δppm, 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 (1
H), 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

Embedded image 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-carboxylic acid benzyl ester (500 mg) in tetrahydrofuran (5 ml) and 7.5% palladium on carbon (150 mg) in a mixed solution of ethanol (100 ml) was hydrogenated at 3 atm for 3 hours. After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (815 mg). ¹ H-NMR (δppm, 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), 3.1
0-3.20 (m, 2H), 3.65-3.85 (m, 4H), 4.67 (s, 2H), 6.62 (1
H), 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

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
To a mixed solution of tetrahydroisoquinoline-2-carboxyamidine (100 mg) in tetrahydrofuran (1 ml) and dimethylformamide (1 ml), 9.1 N aqueous sodium hydroxide solution (0.027 ml) and ethyl bromoacetate (0.027 ml) were added. Stirred at room temperature for 1 hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate.
Washed sequentially with saturated saline. The organic layer was dried over anhydrous sodium sulfate and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: acetone =
4: 1) and dried under reduced pressure to give the title compound (100 m
g) was obtained. ^{1 H-NMR (δppm, CDCl} 3) 1.28 (tr, J = 5.2Hz, 3H), 1.51 (s, 18
H), 1.60-1.85 (m, 5H), 2.17-2.23 (m, 2H), 2.85-3.05 (m, 4
H), 3.22 (s, 2H), 3.55-3.95 (m, 4H), 4.19 (q, J = 5.2Hz, 2
H), 4.86 (brs, 2H), 6.61 (1H), 6.71 (1H), 7.03 (1H), 1
0.22 (brs, 1H)

Step 7 N, N'-di-tert-butoxycarbonyl-7-
[1- (2-hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine

Embedded image 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-acetic acid ethyl ester (155 mg) in tetrahydrofuran ( 2 ml) and methanol (0.008 ml), lithium borohydride (11 mg) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: hexane).
Purification with acetone = 3: 1) and drying under reduced pressure gave the title compound (65 mg). ¹ H-NMR (δppm, 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, 1
H)

Step 8 7- [1- (2-Hydroxyethyl) piperidine-4-l
Ilmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
To a solution of [1- (2-hydroxyethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (60 mg) in chloroform (0.6 ml) was added trifluoroacetic acid (0. 3m
l) was added and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off, and a residue obtained by adding an ethanol solution of hydrogen chloride to remove insolubles was concentrated and dried under reduced pressure to obtain the title compound (40 mg). ¹ H-NMR (δppm, 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, 2
H), 3.75-3.83 (m, 6H), 4.54 (s, 2H), 6.71 (1H), 6.83 (1
H), 7.14 (1H), 7.59 (4H), 10.08 (1H)

Example 22 7- [1- (Pyridin-4-ylmethyl) piperidine-
Synthesis of 4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine trihydrochloride Step 1 N, N′-di-tert-butoxycarbonyl-7-
[1- (pyridin-4-ylmethyl) piperidin-4-
Ilmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
To a mixed solution of tetrahydroisoquinoline-2-carboxyamidine (100 mg) in tetrahydrofuran (1 ml) and dimethylformamide (1 ml), 9.1 N sodium hydroxide (0.068 ml) and 4-picolyl chloride hydrochloride (51 mg) were added. And stirred at 50 ° C. for 5 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate.
Washed sequentially with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to preparative thin-layer chromatography (chloroform: methanol = 2).
0: 1) and dried under reduced pressure to give the title compound (93 m
g) was obtained.

Step 2 7- [1- (Pyridin-4-ylmethyl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine trihydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (pyridin-4-ylmethyl) piperidin-4-
Ilmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (88 mg), trifluoroacetic acid (0.45 ml) from Example 8 Step 8.
In the same manner as in the above, the title compound (65 mg) was obtained. ¹ H-NMR (δppm, 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), 7.6
0 (4H), 8.19 (d, J = 6.0Hz, 2H), 8.88 (d, J = 6.0Hz, 2H), 11.
63 (1H)

Example 23 Synthesis of 7- [1- (2-hydroxy-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride Step 1 N, N'-di-tert-butoxycarbonyl-7-
(1-phenacylpiperidin-4-ylmethoxy)-
1,2,3,4-tetrahydroisoquinoline-2-carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
Tetrahydroisoquinoline-2-carboxyamidine (200 mg), phenacyl bromide (90 mg),
From 9.1 N sodium hydroxide (0.054 ml),
The title compound (125m) was prepared in the same manner as in Step 6 of Example 21.
g) was obtained.

Step 2 N, N'-di-tert-butoxycarbonyl-7-
[1- (2-hydroxy-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(1-phenacylpiperidin-4-ylmethoxy)-
Sodium borohydride (11 mg) was added to a mixed solution of 1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (120 mg) in tetrahydrofuran (1 ml) and methanol (0.2 ml), and the mixture was stirred at room temperature for 2 hours. . After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent 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). ) Got. ¹ H-NMR (δppm, 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), 4.6
0-4.77 (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-carboxyamidine dihydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (2-Hydroxy-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (85 m
g) The title compound (55 mg) was obtained in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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, 2
H), 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 24 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Synthesis of 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

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
Tetrahydroisoquinoline-2-carboxamidine (1 g), benzyl chloroacetate (0.34 m
l), 9.1 N sodium hydroxide (0.025 ml)
From the title compound (8) in the same manner as in Step 6 of Example 21.
10 mg).

Step 2 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-acetic acid

Embedded image 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-acetic acid benzyl ester (735 mg) was added to tetrahydrofuran ( 7 ml) and a mixed solution of methanol (14 ml)
3% at normal pressure using 7.5% palladium carbon (220 mg)
Hydrogenated over time. After completion of the reaction, the mixture was filtered through celite to evaporate the solvent, and dried under reduced pressure to give the title compound (600 mg).
I got ¹ H-NMR (δppm, 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

Embedded image 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-acetic acid (120 mg), glycine ethyl ester hydrochloride To a solution of the salt in methylene chloride (1.5 ml) was added triethylamine (0.031 ml) and 4-dimethylaminopyridine (2 ml).
7 mg), 1- (3-dimethylaminopropyl) -3-
Ethylcarbodiimide hydrochloride (42 mg) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 5: 2) and dried under reduced pressure to obtain the title compound (100 mg). . ¹ H-NMR (δppm, CDCl ₃ ) 1.29 (tr, J = 7.2 Hz, 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 (1
H), 7.04 (1H), 7.70 (brtr, 1H), 10.20 (brs, 1H)

Step 4 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Ilacetylglycine ethyl ester dihydrochloride

Embedded image From 4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidin-1-ylacetylglycine ethyl ester (100 mg) The title compound (75) was obtained in the same manner as in Step 8 of Example 21.
mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.20 (tr, J = 7.0 Hz, 3H), 1.58-2.
1 (m, 5H), 2.82 (m, 2H), 3.00-3.20 (m, 2H), 3.51 (m, 2H),
3.82 (m, 2H), 3.9.-3.98 (m, 4H), 4.11 (q, J = 7.0Hz), 4.56
(s, 2H), 6.72 (d, J = 2.1Hz, 1H), 6.83 (dd, J = 2.1,8.3Hz, 1
H), 7.15 (d, J = 8.3Hz, 1H), 7.68 (brs, 4H), 9.24 (brtr, 1H
H), 10.07 (brs, 1H)

Example 25 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Synthesis of 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

Embedded image 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 m
g) From N-methylmorpholine (0.24 ml), the title compound (25 mg) in the same manner as in Step 3 of Example 24.
Obtained.

Step 2 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Acetic acid N-methylamide dihydrochloride

Embedded image From 4- [2- (N ', N "-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine-1-acetic acid N-methylamide (20 mg) The title compound (15 mg) was obtained in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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 26 7- (1-Acetylpiperidin-4-ylmethoxy)-
Synthesis of 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

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
To a solution of tetrahydroisoquinoline-2-carboxyamidine (100 mg) in tetrahydrofuran (1.5 ml), acetic anhydride (0.021 ml) and pyridine (0.0
25 ml) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (100 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.20-1.40 (m, 2H), 1.45-1.65 (m, 2
0H), 1.80-2.10 (m, 6H), 2.59 (m, 1H), 2.90 (brtr, 2H),
3.08 (m, 2H), 3.85-3.90 (m, 4H), 4.67 (brs, 2H), 6.62 (1
H), 6.72 (1H), 7.04 (1H)

Step 2 7- (1-Acetylpiperidin-4-ylmethoxy)-
1,2,3,4-tetrahydroisoquinoline-2-carboxamidine hydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(1-acetylpiperidin-4-ylmethoxy) -1,
The title compound (60 mg) was obtained from 2,3,4-tetrahydroisoquinoline-2-carboxyamidine (94 mg) in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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, 2
H), 3.02 (m, 1H), 3.57 (tr, J = 6.0Hz, 2H), 3.75-3.90 (m, 3
H), 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 27 Synthesis of 7- (1-benzylsulfonylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine hydrochloride Step 1 N, N′-di-tert- Butoxycarbonyl-7-
(1-benzylsulfonylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2
-Carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
To a solution of tetrahydroisoquinoline-2-carboxyamidine (100 mg) in tetrahydrofuran (1.5 ml), pyridine (0.02 ml), 4-dimethylaminopyridine (12 mg) and alpha-toluenesulfonyl chloride (43 mg) were added, and the mixture was added at room temperature. After stirring for 12 hours, the mixture was stirred at 50 ° C. for 6 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 3: 1) and dried under reduced pressure to obtain the title compound (48 mg). . ¹ H-NMR (δ ppm, CDCl ₃ ) 1.20-1.40 (m, 2H), 1.45-1.60 (m, 2
0H), 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-carboxyamidine hydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(1-benzylsulfonylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2
-The title compound (30 mg) was obtained from -carboxyamidine (43 mg) in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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 (d
d, J = 2.7, 8.3Hz, 1H), 7.13 (d, J = 8.3Hz, 1H), 7.35-7.40
(m, 5H), 7.53 (s, 4H)

Example 28 7- [1- (2-Naphthylsulfonyl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine hydrochloride Step 1 N, N′-di-tert-butoxycarbonyl-7-
[1- (2-Naphthylsulfonyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
Example 2 from tetrahydroisoquinoline-2-carboxyamidine (100 mg), 2-naphthalenesulfonyl chloride (51 mg), pyridine (0.02 ml).
The title compound (75 mg) was obtained in the same manner as in Step 1 of Step 7.

Step 2 7- [1- (2-Naphthylsulfonyl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine hydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (2-Naphthylsulfonyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (70 mg) and the title compound (55 mg) in the same manner as in Step 8 of Example 21 I got ¹ H-NMR (δppm, 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 = 8.4H
z, 1H), 7.50 (brs, 4H), 7.66-7.77 (m, 3H), 8.07-8.20 (m,
3H), 8.43 (s, 1H)

Example 29 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-
Synthesis of 2-carboxyamidine dihydrochloride Step 1 N, N′-di-tert-butoxycarbonyl-7-
(1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2
-Carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
Tetrahydroisoquinoline-2-carboxyamidine (100 mg) in tetrahydrofuran (1.5 ml),
To a mixed solution of 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 to remove insolubles, then the solvent was distilled off and the residue was dried under reduced pressure to obtain the title compound (120 mg). ¹ H-NMR (δppm, 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 (1
H), 6.70 (1H), 7.04 (1H)

Step 2 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-
2-carboxyamidine dihydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2
-The title compound (80 mg) was obtained from -carboxyamidine (120 mg) in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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, 2
H), 3.00-3.29 (m, 2H), 3.59 (tr, J = 4.4Hz, 2H), 3.85 (m, 2
H), 3.92-4.20 (m, 2H), 4.56 (s, 2H), 6.72 (d, J = 1.7Hz, 1
H), 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 30 7- (1-Phenylacetimidoylpiperidin-4-
Synthesis of ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine dihydrochloride Step 1 Ethyl phenylacetimidate hydrochloride Benzyl cyanide (5.8 ml) in diethyl ether (10 ml) was ice-cooled. Under hydrogen chloride gas was blown in, and the mixture was left at room temperature for 12 hours. After the completion of the reaction, the solid obtained by evaporating the solvent was washed with diethyl ether and collected by filtration.
Drying under reduced pressure gave 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

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
The title compound (105 mg) was obtained from tetrahydroisoquinoline-2-carboxyamidine (105 mg) and ethyl phenylacetimidate hydrochloride (64 mg) in the same manner as in Step 1 of Example 29.

Step 3 7- (1-Phenylacetimidoylpiperidine-4-
Ilmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-7-
The title compound (70 mg) was obtained from (1-phenylacetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (100 mg) in the same manner as in Step 8 of Example 21. Was. ¹ H-NMR (δppm, 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, 1
H), 2.80 (m, 2H), 3.05-3.25 (m, 2H), 3.56 (m, 2H), 3.74
(m, 2H), 3.93-4.26 (m, 2H), 4.07 (s, 2H), 4.53 (s, 2H),
6.66 (1H), 6.77 (1H), 7.12 (1H), 7.25-7.42 (m, 5H), 7.6
2 (brs, 4H), 9.13 (brs, 1H), 9.75 (brs, 1H)

Example 31 N- [2- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-5-yl] acetamide Synthesis of hydrochloride Step 1 N, N′-di-tert-butoxycarbonyl-7-
[1- (5-nitropyridin-2-yl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
(Piperidin-4-ylmethoxy) -1,2,3,4-
Tetrahydrofuran (1.2 ml) of tetrahydroisoquinoline-2-carboxyamidine (120 mg),
Triethylamine (0.068 ml) and 2-chloro-5-nitropyridine (58 mg) were added to a dimethylformamide (1.2 ml) mixed solution, 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 with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 4: 1) and dried under reduced pressure to obtain the title compound (120 mg). . ¹ H-NMR (δppm, 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) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (5-nitropyridin-2-yl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1 ml), methanol (2 ml)
Was hydrogenated using 7.5% palladium on carbon (30 mg) at 2.5 atm for 4 hours. After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off, and the residue obtained was purified by preparative thin-layer chromatography (chloroform: methanol = 10: 1), dried under reduced pressure, and dried under reduced pressure to give the title compound (9).
0 mg).

Step 3 N- [2- [4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine- 1-yl] pyridin-5-yl] acetamide

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (5-aminopyridin-2-yl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) was added with acetic anhydride (0.017 ml) and pyridine (0.017 ml). Stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (hexane: hexane).
(Acetone = 2: 1). The obtained residue was dissolved in methanol, treated with activated carbon, and dried under reduced pressure to obtain the title compound (75 mg). ¹ H-NMR (δppm, 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), 7.0
4 (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 salt

Embedded image N- [2- [4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidin-1-yl] pyridine -5-yl] acetamide (7
0 mg) to give the title compound (50 mg) in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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, 2
H), 6.71 (1H), 6.83 (1H), 7.13 (1H), 7.39 (1H), 7.57 (b
rs, 4H), 8.00 (1H), 8.46 (1H), 10.49 (1H)

Example 32 N- [2- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-5-yl] benzamide Synthesis of hydrochloride Step 1 N- [2- [4- [2- (N, N′-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidine -1-yl] pyridin-5-yl] benzamide

Embedded image N, N'-di-tert-butoxycarbonyl-7-
[1- (5-aminopyridin-2-yl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine (100 mg),
Benzoyl chloride (0.021 ml), pyridine (0.0
17 ml) to give the title compound (90 mg) in the same manner as in Step 3 of Example 31.

Step 2 N- [2- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-5-yl] benzamide dihydrochloride salt

Embedded image N- [2- [4- [2- (N, N'-di-tert-butoxycarbonylamidino) -1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl] piperidin-1-yl] pyridine -5-yl] benzamide (8
4 mg) to give the title compound (70 mg) in the same manner as in Step 8 of Example 21. ¹ H-NMR (δppm, 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, 2
H), 3.57 (tr, J = 5.8Hz, 2H), 3.86 (m, 2H), 4.29-4.36 (m, 2
H), 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), 7.51-7.6
4 (7H), 8.02 (2H), 8.30 (1H), 8.63 (1H), 10.65 (1H)

Example 33 3- [4- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-3-yl] -2 Synthesis of -propenoic acid ethyl ester dihydrochloride Step 1 4- (2-tert-butoxycarbonyl-1,2,2
3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-carboxylic acid benzyl ester

Embedded image 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (1.2 g), 4-hydroxymethylpiperidine-1-
Triphenylphosphine (2.52 g) and diisopropyl azodicarboxylate (1.90 ml) were added to a solution of benzyl carboxylate (2.39 g) in tetrahydrofuran (30 ml), and the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (hexane: acetone = 6: 6).
Purify in 1) and dry under reduced pressure to give the title compound (1.82 g)
I got ¹ H-NMR (δppm, 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 te
rt-butyl ester

Embedded image 4- (2-tert-butoxycarbonyl-1,2,2
3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-carboxylic acid benzyl ester (1.3 g) in a mixed solution of tetrahydrofuran (10 ml) and methanol (20 ml), 7.5% palladium carbon (300 mg) For 3 hours at 3 atm. After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (815 mg). ¹ H-NMR (δppm, 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), 6.7
1 (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

Embedded image 7- (piperidin-4-ylmethoxy) -1,2,3,
4-tetrahydroisoquinoline-2-carboxylic acid te
rt-butyl ester (442 mg) in ethanol (3
ml) solution, triethylamine (0.3 ml), 4-
Chloro-3-formylpyridine (Journal of Heterocyclic Chemistry, 25, 81, 1
988) (150 mg) and stirred under reflux for 27 hours. After completion of the reaction, tetrahydrofuran and diethyl ether were added to remove insolubles, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), dried under reduced pressure, and dried. The compound (430 mg) was obtained. ¹ H-NMR (δppm, 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 (1
H), 6.84 (d, J = 6.0Hz, 1H), 7.05 (1H), 8.42 (d, J = 6.0Hz, 1
H), 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] pyridine-3
-Yl] -2-propenoic acid ethyl ester

Embedded image Triethyl phosphonoacetate under ice cooling (0.05m
1) To a solution of tetrahydrofuran (1 ml) was added sodium hydride (12 mg), and the mixture was stirred at the same temperature for 1 hour.
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)
The solution was added dropwise and stirred for 2 hours. After completion of the reaction, an aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted with ethyl acetate.
Washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol = 20: 1 to 10: 1), and dried under reduced pressure to give the title compound (100 mg). ) Got. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.35 (tr, J = 6.4 Hz, 3H), 1.49 (s, 9
H), 1.50-1.80 (m, 2H), 1.95-2.10 (m, 3H), 2.75-2.95 (m, 4
H), 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, 1
H)

Step 5 3- [4- [4- (1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-3-yl] -2-propenoic acid ethyl ester

Embedded image 3- [4- [4- (2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine-3
-Yl] -2-propenoic acid ethyl ester (100 m
To a solution of g) 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 residue obtained by evaporating the solvent was added with an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate.
Washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (70 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.35 (tr, J = 7.1 Hz, 3H), 1.50-1.65
(m, 2H), 1.90-2.10 (m, 3H), 2.70-2.90 (m, 4H), 3.13 (m, 2
H), 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 = 2.3H
z, 1H), 6.72 (dd, J = 2.3,8.2Hz, 1H), 6.83 (d, J = 6.0Hz, 1
H), 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

Embedded image Dimethyl 3- [4- [4- (1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-3-yl] -2-propenoic acid ethyl ester (70 mg) Diisopropylethylamine (0.032 ml) in formamide (1 ml) solution,
1H-pyrazole-1-carboxamidine hydrochloride (2
7 mg) and stirred at room temperature for 12 hours. Diethyl ether was added to the residue obtained by evaporating the solvent, and the supernatant was removed. An ethanol solution of hydrogen chloride was added to the residue obtained by repeating this operation twice, and the insolubles were removed.
Drying under reduced pressure gave the title compound (50 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.25 (tr, J = 7.3 Hz, 3H), 1.40-1.
55 (m, 2H), 1.82-2.05 (m, 3H), 2.76-2.96 (m, 4H), 3.42
(m, 2H), 3.57 (m, 2H), 3.90 (m, 2H), 4.18 (q, J = 7.3Hz, 2
H), 4.53 (s, 2H), 6.63 (d, J = 16.1Hz, 1H), 6.73 (1H), 6.8
5 (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 34 Methyl 4- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine-3-carboxylate dihydrochloride Step 1 7- [1- (3-Methoxycarbonylpyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4
-Tetrahydroisoquinoline-2-carboxylic acid tert
-Butyl ester

Embedded image 7- [1- (3-Formylpyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (50 mg) in chloroform (0.5 ml) ),
Sodium cyanide (8 mg), manganese dioxide (250 mg), and acetic acid (0.003 ml) were added to a mixed solution of methanol (0.2 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was filtered and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 15: 1), and dried under reduced pressure to obtain the title compound (50 mg). ¹ H-NMR (δppm, 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

Embedded image 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
trifluoroacetic acid (0.15 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, an aqueous solution of sodium hydrogen carbonate was added to the residue obtained by evaporating the solvent, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off and dried under reduced pressure to obtain 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

Embedded image 4- [4- (1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine-3-carboxylic acid methyl ester (30 mg)
From the title compound (1) in the same manner as in Step 6 of Example 33.
5 mg). ¹ H-NMR (δppm, 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), 6.8
2 (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 35 Synthesis of 4- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine-3-carboxylic acid dihydrochloride

Embedded image 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 ( 0.2ml)
A 1N aqueous solution of sodium hydroxide (0.1 ml) was added to the solution, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the mixture was neutralized with 1N-hydrochloric acid and then the solvent was distilled off. The resulting residue was subjected to reverse-phase preparative thin-layer chromatography (40% aqueous acetonitrile, 1%
The obtained residue was treated with a hydrogen chloride ethanol solution and dried under reduced pressure to give the title compound (15).
mg). ¹ H-NMR (δppm, 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 (1
H), 7.34 (d, J = 7.4Hz, 1H), 7.44 (brs, 4H), 8.27 (d, J = 7.4
Hz, 1H), 8.59 (s, 1H)

Example 36 Synthesis of 6- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride Step 1 6-hydroxy -1,2,3,4-tetrahydroisoquinoline hydrobromide

Embedded image 6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.89 g) was treated with a 48% aqueous hydrogen bromide solution (70 m
1) and refluxed for 2 hours. Ethanol and diethyl ether were added to the residue obtained by evaporating the solvent, and the residue was collected by filtration and dried under reduced pressure to give the title compound (3.93 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 2.90 (tr, J = 6.3 Hz, 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

Embedded image 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (350 mg), di-tert-
The title compound (325 mg) was obtained from butyl dicarbonate (365 mg) in the same manner as in Step 1 of Example 1. ¹ H-NMR (δppm, CDCl ₃ ) 1.49 (s, 9H), 2.76 (tr, J = 6.0 Hz, 2
H), 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

Embedded image 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (320 mg), 4-hydroxymethyl-1- (pyridin-4-yl) piperidine (247 mg) in tetrahydrofuran (15 ml) To a mixed solution of methylene chloride (5 ml), triphenylphosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml) were sequentially added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 3: 2-1: 1, 1% triethylamine), dried under reduced pressure, and dried under reduced pressure to give the title compound (400
mg). ¹ H-NMR (δppm, 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

Embedded image 6- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (4
00 mg) and trifluoroacetic acid (1.5 ml) in the same manner as in Step 5 of Example 33, to give the title compound (265 m
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.36-1.50 (m, 2H), 1.90-2.15 (m, 3
H), 2.80 (tr, J = 6.0Hz, 2H), 2.93 (m, 2H), 3.15 (tr, J = 6.0
Hz, 2H), 3.80 (d, 2H), 3.92-3.99 (m, 4H), 6.62 (1H), 6.6
7-6.70 (m, 3H), 6.93 (1H), 8.24 (2H)

Step 5 6- [1- (Pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride

Embedded image 6- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline (70 mg), diisopropylethylamine (0.
042 ml) and the title compound (60 mg) was obtained from 1H-pyrazole-1-carboxamidine hydrochloride (35 mg) in the same manner as in Step 6 of Example 33. ¹ H-NMR (δppm, 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, 2
H), 3.56 (tr, J = 5.8Hz, 2H), 3.85 (m, 2H), 4.23-4.28 (m, 2
H), 4.48 (s, 2H), 6.80 (2H), 7.05 (1H), 7.19 (2H), 7.60
(4H), 8.19 (2H), 13.65 (1H)

Example 37 7- [2- [4-Cyano-1- (pyridin-4-yl)
Piperidin-4-yl] ethoxy] -1,2,3,4-
Tetrahydroisoquinoline-2-carboxamidine
Synthesis of dihydrochloride Step 1 4-Carbamoylpiperidine-1-carboxylic acid benzyl ester

Embedded image 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.5 g) in tetrahydrofuran (100 m
1) N-methylmorpholine (4.6 ml) and isobutyl chlorocarbonate (5.
4 ml) was added dropwise and stirred at the same temperature for 10 minutes. 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 distilled off, water was added, and the mixture was extracted with ethyl acetate.
The mixture was washed sequentially with a 10% aqueous citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (8.3 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.58-1.75 (m, 2H), 1.80-1.95 (m, 2
H), 2.25-2.40 (m, 1H), 2.75-2.95 (m, 2H), 4.05-4.30 (m, 2
H), 5.13 (s, 2H), 5.30-5.90 (brd, 2H), 7.26-7.62 (m, 5H)

Step 2 4-carbamoylpiperidine-1-carboxylic acid ter
t-butyl ester

Embedded image 4-carbamoylpiperidine-1-carboxylic acid benzyl ester (8.3 g) in tetrahydrofuran (50 m
1) In a mixed solution of methanol (50 ml) and 7.5% palladium carbon (2 g), hydrogenation was performed at 3 atm for 2 hours. After completion of the reaction, the mixture was filtered through celite, and di-tert-butyl dicarbonate (7.6 g) was added to the obtained solution, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After evaporating the solvent, hexane was added and the mixture was collected by filtration and dried under reduced pressure to give the title compound (5.6 g). ¹ H-NMR (δppm, 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

Embedded image 4-carbamoylpiperidine-1-carboxylic acid ter
Triphenylphosphine (24.4 g) was added to a mixed solution of t-butyl ester (5.6 g) in tetrahydrofuran (110 ml) and carbon tetrachloride (90 ml), and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, the mixture was filtered and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and dried under reduced pressure to obtain the title compound (3.5 g). ¹ H-NMR (δppm, 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

Embedded image Under argon, a solution of 2-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.5 g) in tetrahydrofuran (15 ml) was added to a solution of 2M lithium diisopropylamide-tetrahydrofuran solution (9.96 ml) in tetrahydrofuran (20 ml) at -78 ° C. ) The solution was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then, allyl bromide (2.15 ml) was added at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes 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 saline and dried over anhydrous sodium sulfate.
The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and dried under reduced pressure to obtain 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

Embedded image 4-allyl-4-cyanopiperidine-1-carboxylic acid
Tert-butyl ester (3.5 g) in acetone (1
N-methylmorpholine N-oxide (2.5 g) and osmium tetroxide (5% tert-butanol solution, 8 ml) were added to a mixed solution of 60 ml) and water (20 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 filtered. The solvent was distilled off. Water was added to the obtained residue, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate) and dried under reduced pressure to obtain the title compound (3.65 g). ¹ H-NMR (δppm, 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

Embedded image 10% aqueous solution of sodium periodate (100 ml) in a solution of tert-butyl 4-cyano-4- (2,3-dihydroxypropyl) piperidine-1-carboxylate (3.65 g) in tetrahydrofuran (100 ml)
Was added and stirred at room temperature for 40 minutes. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent (3.3 g) was added to tetrahydrofuran (10
0 ml), and sodium borohydride (3
60 mg) and methanol (20 ml).
Stirred for 0 minutes. After completion of the reaction, 10% aqueous citric acid was added, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol = 95: 5), and dried under reduced pressure to give the title compound (3.13 g). Obtained. ¹ H-NMR (δppm, 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] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxylic acid
Benzyl ester

Embedded image 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 a solution of tetrahydrofuran (40 ml) were added to the solution under ice-cooling. Diethyl dicarboxylate (2 g) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and dried under reduced pressure to obtain the title compound (1.6 g). ¹ H-NMR (δppm, 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, 2
H), 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

Embedded image 7- [2- (1-tert-butoxycarbonyl-4-
Cyanopiperidin-4-yl) ethoxy] -1,2,2.
3,4-tetrahydroisoquinoline-2-carboxylic acid
Benzyl ester (1.2 g), trifluoroacetic acid (1
0 ml) to give the title compound (1 g) in the same manner as in Step 6 of Example 10. ¹ H-NMR (δppm, CDCl ₃ ) 1.53-1.64 (m, 2H), 1.99-2.05 (m, 2
H), 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

Embedded image 7- [2- (4-cyanopiperidin-4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxylic acid benzyl ester (850 mg), 4-
The title compound (590 mg) was obtained in the same manner as in Step 7 of Example 10 from chloropyridine hydrochloride (300 mg) and triethylamine (0.84 ml). ¹ H-NMR (δppm, CDCl ₃ ) 1.68-1.78 (m, 2H), 2.08-2.16 (m, 4
H), 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, 2
H), 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, 2
H)

Step 10 7- [2- [4-cyano-1- (pyridin-4-yl)
Piperidin-4-yl] ethoxy] -1,2,3,4-
Tetrahydroisoquinoline

Embedded image 7- [2- [4-cyano-1- (pyridin-4-yl)
Piperidin-4-yl] ethoxy] -1,2,3,4-
7.5% palladium carbon (220 mg) and ammonium formate (220 mg) were added to a solution of benzyl tetrahydroisoquinoline-2-carboxylate (585 mg) in ethanol (5 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the mixture was filtered and the solvent was distilled off. To the resulting residue was added aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was dried under reduced pressure to give the title compound (385 m
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.68-1.84 (m, 2H), 2.02-2.21 (m, 4
H), 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

Embedded image 7- [2- [4-cyano-1- (pyridin-4-yl)
Piperidin-4-yl] ethoxy] -1,2,3,4-
Diisopropylethylamine (0.1 ml) and 1H-pyrazole-1-carboxyamidine hydrochloride (85 mg) were added to a solution of tetrahydroisoquinoline (70 mg) in dimethylformamide (5 ml), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the residue obtained by distilling off the solvent was purified by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 1: 1). The obtained residue was treated with dilute hydrochloric acid and dried under reduced pressure to obtain the title compound (67 mg). ¹ H-NMR (δppm, 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, 2
H), 4.17 (tr, J = 6.0Hz, 2H), 4.27-4.34 (m, 2H), 4.56 (s, 2
H), 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, 4
H), 8.26 (d, J = 7.5Hz, 1H), 13.80 (brs, 1H)

Example 38 Synthesis of ethyl 4- (2-amidino-8-chloronaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylate dihydrochloride Step 17 -Methoxy-2-trifluoromethanesulfonyloxynaphthalene

Embedded image 2-hydroxy-7-methoxynaphthalene (12.34
g) and trifluoromethanesulfonic anhydride (20 g) were added to a chloroform (185 ml) solution of triethylamine (9.87 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, aqueous sodium hydrogen carbonate was added, the mixture was extracted with chloroform, and washed sequentially with water and saturated saline.
The organic layer was dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent 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). I got ¹ H-NMR (δppm, CDCl ₃ ) 3.96 (s, 3H), 7.14 (d, J = 2.4Hz, 1
H), 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

Embedded image A solution of 7-methoxy-2-trifluoromethanesulfonyloxynaphthalene (2.23 g) in dimethylformamide (8.9 ml) was added at room temperature to zinc cyanide (598 m
g) and tetrakis (triphenylphosphine) palladium (337 mg) were added, and the mixture was stirred at 80 ° C for 1 hour.
After the reaction, water and ethyl acetate were added to remove insolubles,
The organic layer was separated and concentrated, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1).
9: 1) and dried under reduced pressure to give the title compound (965 m
g) was obtained. ¹ H-NMR (δppm, 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 = 9.0H
z, H), 7.83 (1H), 8.11 (1H),

Step 3 7-Hydroxynaphthalene-2-carbonitrile

Embedded image 7-methoxynaphthalene-2-carbonitrile (6 g)
To a solution of chlorobenzene (60 ml) was added aluminum chloride (15.3 g) at room temperature, and the mixture was heated under reflux for 30 minutes.
After the completion of the reaction, the mixture was ice-cooled, and ice, ethyl acetate and concentrated hydrochloric acid were added thereto, followed by stirring. The organic layer was separated and concentrated. Hexane was added to the obtained residue, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (5.21 g). ¹ H-NMR (δppm, 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

Embedded image 7-hydroxynaphthalene-2-carbonitrile (2.
23g) in chloroform (120 ml) under ice cooling.
tert-Butyl hypochlorite (1.64 ml) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.88 g). ¹ H-NMR (δ ppm, DMSO-d ₆ ) 7.49 (d, J = 9.0 Hz, 1 H), 7.68 (1
H), 7.94 (d, J = 9.0Hz, 1H), 8.19 (1H), 8.46 (1H)

Step 5 8-Chloro-7-methylthiomethoxynaphthalene-2-
Carbonitrile

Embedded image The title compound (1.31 g) was obtained from 8-chloro-7-hydroxynaphthalene-2-carbonitrile (1.88 g) in the same manner as in Step 2 of Example 10. ¹ H-NMR (δppm, 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

Embedded image 8-chloro-7-methylthiomethoxynaphthalene-2-
The title compound (939 mg) was obtained from carbonitrile (1.28 g) in the same manner as in Step 3 of Example 10. ¹ H-NMR (δppm, CDCl ₃ ) 6.04 (s, 2H), 7.61-7.67 (2H), 7.8
8 (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

Embedded image 8-chloro-7-chloromethoxynaphthalene-2-carbonitrile (295 mg), 1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (6
03 mg) to give the title compound (128 mg) in the same manner as in Step 5 of Example 10. ¹ H-NMR (δppm, CDCl ₃ ) 1.28 (tr, J = 7.1 Hz, 3H), 1.78-1.88
(m, 2H), 2.41-2.48 (m, 2H), 3.16-3.25 (m, 2H), 3.75-3.8
5 (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), 7.8
1 (d, J = 9.0Hz, 1H), 7.88 (1H), 8.27 (dd, J = 1.4, 5.1Hz, 2
H), 8.61 (1H),

Step 8 4- (2-Amidino-8-chloronaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester dihydrochloride

Embedded image 4- (8-Chloro-2-cyanonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester (124 mg), pyridine (2.5 ml), triethylamine ( 0.5m
l) Hydrogen sulfide was blown into the mixed solution under ice cooling,
Stir for 2 hours. After completion of the reaction, the solvent was distilled off, and acetone (2 ml), methanol (2 ml) and methyl iodide (0.172 ml) were added to the residue treated with hydrogen chloride ethanol, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the residue obtained by evaporating the solvent was dissolved in ethanol (4 ml), ammonium acetate (106 mg) was added, and the mixture was stirred at 75 ° C for 2 hours. After the completion of the reaction, the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (chloroform:
The residue was treated with ethanol and hydrogen chloride and dried under reduced pressure to give the title compound (9).
2 mg).

Example 39 Synthesis of 4- (2-amidino-8-chloronaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 4- (2-amidino-8-chloronaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester dihydrochloride (78
mg) in concentrated hydrochloric acid was stirred at 50-100 ° C for 3 hours. After completion of the reaction, the residue obtained by distilling off the solvent was purified by HPL.
C (0.05% aqueous trifluoroacetic acid: methanol = 1:
The sample was collected in 1). The obtained residue was treated with hydrogen chloride ethanol and dried under reduced pressure to obtain the title compound (49 mg). ¹ H-NMR (δppm, 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 (2
H), 7.78 (2H), 8.12 (1H), 8.18-8.25 (m, 3H), 8.56 (s, 1
H), 9.34 (brs, 2H), 9.62 (brs, 2H), 12.98 (brs, 1H), 13.
65 (brs, 1H)

Example 40 Synthesis of ethyl 4- (2-amidinonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylate dihydrochloride Step 1 7-methylthiomethoxynaphthalene -2-carbonitrile

Embedded image 7-hydroxynaphthalene-2-carbonitrile (1.
From 12 g), the title compound (907 mg) was obtained in the same manner as in Step 2 of Example 10.

Step 2 7-chloromethoxynaphthalene-2-carbonitrile

Embedded image The title compound (567 mg) was obtained from 7-methylthiomethoxynaphthalene-2-carbonitrile (647 mg) in the same manner as in Step 3 of Example 10.

Step 3 4- (2-Cyanonaphthalen-7-yloxymethyl)
-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester

Embedded image 7-chloromethoxynaphthalene-2-carbonitrile (314 mg), 1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (743 mg),
The title compound (430 mg) was obtained in the same manner as in Step 5 of Example 10 from a 2M-lithium diisopropylamide-tetrahydrofuran solution (1.73 ml).

Step 4 4- (2-Amidinonaphthalen-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester dihydrochloride

Embedded image 4- (2-cyanonaphthalen-7-yloxymethyl)
From 1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (51 mg) and methyl iodide (0.6 ml), the title compound (36 mg) was obtained in the same manner as in Step 8 of Example 38. Was. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.14 (tr, J = 7.1 Hz, 3H), 1.75-1.
88 (m, 2H), 2.19-2.31 (m, 2H), 3.44 (m, 2H), 4.00-4.20
(m, 4H), 4.27 (s, 2H), 7.21 (d, J = 7.0Hz, 2H), 7.34 (d, J =
8.9Hz, 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 (br
s, 1H)

Example 41 4- (2-amidino-2,3,4,5-tetrahydro-
1H-benzo [c] azepin-8-yloxymethyl)
Synthesis of -1- (pyridin-4-yl) piperidin-4-carboxylic acid ethyl ester dihydrochloride Step 18-Methoxy-2,3,4,5-tetrahydrobenzo [c] azepin-1-one

Embedded image To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one (5.21 g) in concentrated hydrochloric acid (26 ml) was added sodium azide (1.98 g) little by little under ice-cooling, and at the same temperature. The mixture was stirred for 2 hours and at room temperature for 2 hours. After completion of the reaction, the reaction solution was opened in ice water, aqueous potassium carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate), and dried under reduced pressure to obtain the title compound (470 mg). ¹ H-NMR (δ ppm, CDCl ₃ ) 1.98 (quint, J = 6.9 Hz, 2H), 2.80 (t
r, J = 6.9Hz, 2H), 3.13 (q, J = 6.9Hz, 2H), 3.83 (s, 3H), 6.9
6 (1H), 7.09 (1H), 7.26 (1H)

Step 2 8-Methoxy-2,3,4,5-tetrahydro-1H-
Benzo [c] azepine

Embedded image To a solution of lithium aluminum hydride (3.07 g) in tetrahydrofuran (60 ml) was added 8-methoxy-
2,3,4,5-tetrahydrobenzo [c] azepine-
1-one (4.42 g) in 1,4-dioxane (30 m
l) The solution was added dropwise and refluxed for 20 hours. After the completion of the reaction, a 20% aqueous sodium hydroxide solution was added dropwise under ice-cooling,
Stirred for hours. The reaction solution was filtered, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (4.05 g). ¹ H-NMR (δppm, 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
-Benzo [c] azepine hydrobromide

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-
Benzo [c] azepine (3.65 g) was dissolved in a 48% aqueous hydrogen bromide solution (36 ml) and refluxed for 2 hours. Ethanol and diethyl ether were added to the residue obtained by evaporating the solvent, and the mixture was filtered and dried under reduced pressure to give the title compound (4.56).
g) was obtained. ¹ H-NMR (δppm, 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, 1
H), 8.80 (brs, 2H), 9.42 (brs, 1H)

Step 4 8-Hydroxy-2,3,4,5-tetrahydro-1H
-Benzo [c] azepine-2-carboxylic acid tert-
Butyl ester

Embedded image 8-hydroxy-2,3,4,5-tetrahydro-1H
-Benzo [c] azepine hydrobromide (3 g), 2N
-Sodium hydroxide aqueous solution (30 ml), di-tert
From -butyl dicarbonate (3.2 g), the title compound (2.64 g) was obtained in the same manner as in Step 1 of Example 1. ¹ H-NMR (δppm, 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), 5.1
9,5.91 (1H), 6.63 (1H), 6.70,6.85 (1H), 6.98 (1H)

Step 5 8-Methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo [c] azepine-2-carboxylic acid t
tert-butyl ester

Embedded image 8-hydroxy-2,3,4,5-tetrahydro-1H
-Benzo [c] azepine-2-carboxylic acid tert-
The title compound (1.07 g) was obtained from butyl ester (1.06 g), 60% sodium hydride (195 mg) and chloromethyl methyl sulfide (0.41 ml) in the same manner as in Step 1 of Example 6. ¹ H-NMR (δppm, 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- (pyridine-4-
Yl) piperidin-4-ylmethoxy] -2,3,4
5-tetrahydro-1H-benzo [c] azepine-2-
Carboxylic acid tert-butyl ester

Embedded image Under an argon atmosphere, 8-methylthiomethoxy-2,3,
4,5-tetrahydro-1H-benzo [c] azepine-
2-carboxylic acid tert-butyl ester (530 m
g) and 8-chloromethoxy-2,3 from sulfuryl chloride (0.145 ml) in the same manner as in Step 2 of Example 6.
4,5-tetrahydro-1H-benzo [c] azepine-
2-carboxylic acid tert-butyl ester (850 m
g) was obtained. Then, the title compound (755 mg) was obtained in the same manner as in Step 3 of Example 6. ¹ H-NMR (δppm, CDCl ₃ ) 1.27 (tr, J = 6.9 Hz, 3H), 1.39 (s, 9
H), 1.64-1.78 (m, 4H), 2.30-2.36 (m, 2H), 2.85-2.88 (m, 2
H), 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, 3
H), 6.72,6.84 (1H), 7.02 (1H), 8.25 (2H)

Step 7 1- (Pyridin-4-yl) -4- (2,3,4,5-
Tetrahydro-1H-benzo [c] azepin-8-yloxymethyl) piperidine-4-carboxylic acid ethyl ester

Embedded image 8- [4-ethoxycarbonyl-1- (pyridine-4-
Yl) piperidin-4-ylmethoxy] -2,3,4
5-tetrahydro-1H-benzo [c] azepine-2-
Carboxylic acid tert-butyl ester (750 m
g), trifluoroacetic acid (2.5 ml), Example 6
In the same manner as in Step 4, the title compound (600 mg) was obtained.

Step 8 4- (2-amidino-2,3,4,5-tetrahydro-
1H-benzo [c] azepin-8-yloxymethyl)
-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride

Embedded image 1- (pyridin-4-yl) -4- (2,3,4,5-
From tetrahydro-1H-benzo [c] azepin-8-yloxymethyl) piperidine-4-carboxylic acid ethyl ester (200 mg), diisopropylethylamine (0.105 ml), and 1H-pyrazole-1-carboxyamidine hydrochloride (90 mg) Step 5 of Example 6
In the same manner as in the above, the title compound (200 mg) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.16 (tr, J = 7.2 Hz, 3H), 1.75 (m,
4H), 2.20 (m, 2H), 2.89 (m, 2H), 3.41 (m, 2H), 4.04 (m, 4
H), 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), 1
3.60 (brs, 1H)

Example 42 4- (2-amidino-2,3,4,5-tetrahydro-
1H-benzo [c] azepin-8-yloxymethyl)
Synthesis of -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 4- (2-amidino-2,3,4,5-tetrahydro-
1H-benzo [c] azepin-8-yloxymethyl)
-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride (150 mg) in 6N
-Dissolved in hydrochloric acid (2 ml) and stirred under reflux for 3 hours. After completion of the reaction, insolubles were removed, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (140 mg). ¹ H-NMR (δppm, 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, 4
H), 4.59 (s, 2H), 6.76 (1H), 7.12 (1H), 7.19-7.23 (m, 3
H), 7.54 (brs, 4H), 8.23 (2H), 13.70 (brs, 1H)

Example 43 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridine-
Synthesis of 4-yl) piperidine-4-carboxylic acid dihydrochloride Step 1 4-ethoxycarbonyl-4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester

Embedded image 1-tert-butoxycarbonyl isonipecotic acid
To a solution of ethyl ester (7.14 g) in tetrahydrofuran (140 ml) was added a 2M lithium diisopropylamide-tetrahydrofuran solution (16.6) at -78 ° C.
ml) and diiodomethane (2.7 ml) were added dropwise.
Stirred for hours. After completion of the reaction, a 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent 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). I got ¹ H-NMR (δppm, CDCl ₃ ) 1.27-1.33 (m, 3H), 1.38-1.45 (m, 1
0H), 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, 2
H)

Step 2 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester

Embedded image 2-acetyl-7-chlorosulfonyl-1,2,3,4
-Tetrahydroisoquinoline (U.S. Pat. No. 3,725,388)
Specification) (7.68 g), tin chloride dihydrate (25.3)
g), from Journal of Medicinal Chemistry,
The crude crystals of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol obtained according to the method described in Vol. 23, No. 8, page 837, 1980 are dissolved in dimethylformamide (120 ml). Potassium carbonate (4.27 g) and 4-ethoxycarbonyl-4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (3.71 g) were added, and the mixture was stirred at 100 ° C for 1 hour. After completion of the reaction, the mixture was filtered, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: hexane:
The residue was purified with ethyl acetate (2: 8 to ethyl acetate) and dried under reduced pressure to obtain the title compound (3.92 g). ¹ H-NMR (δppm, 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- (pyridine-
4-yl) piperidine-4-carboxylic acid ethyl ester

Embedded image 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)
To the solution was added trifluoroacetic acid (1 ml) and the mixture was added at room temperature for 1 hour.
Stirred for 0 minutes. After completion of the reaction, the solvent was distilled off, and the residue obtained was ethanol (3 ml) and triethylamine (0.
39 ml) and 4-chloropyridine hydrochloride (70 mg) were added, and the mixture was stirred at 150 ° C. for 2 days using a pressure-resistant reaction vessel. After completion of the reaction, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (5% methanol-chloroform), dried under reduced pressure and dried under reduced pressure to give the title compound (63 m
g) was obtained. ¹ H-NMR (δppm, 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- (pyridine-
4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -1- (pyridine-
Concentrated hydrochloric acid (2 ml) was added to 4-yl) piperidine-4-carboxylic acid ethyl ester (63 mg).
Stir for 1 hour. After completion of the reaction, the solvent was distilled off, and a 1N-sodium hydroxide aqueous solution (0.7 ml), acetone (2 ml), 1H-pyrazole-1-carboxyamidine hydrochloride (61 mg) were added to the obtained residue, and the mixture was stirred for 12 hours. did. After completion of the reaction, the mixture was acidified by adding dilute hydrochloric acid, and the solvent was distilled off. Methanol was added to the obtained residue, followed by filtration. The residue obtained by distilling off the solvent was separated by HPLC (25% to 40% methanol-water, 0.05% trifluoroacetic acid), treated with dilute hydrochloric acid, dried under reduced pressure, and dried to give the title compound (47 m
g) was obtained. ¹ H-NMR (δppm, 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, 2
H), 3.95-4.10 (m, 2H), 4.57 (s, 2H), 7.14-7.20 (m, 5H),
7.66 (brs, 4H), 8.22 (2H)

Example 44 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridin-4-yl) piperidine-4-carboxylic acid Synthesis of hydrochloride Step 1 4-Allyl-4-ethoxycarbonylpiperidine-1-
Carboxylic acid tert-butyl ester

Embedded image 1-tert-butoxycarbonyl isonipecotic acid
Ethyl ester (6 g) in tetrahydrofuran (120
2M-lithium diisopropylamide-tetrahydrofuran solution (14 ml) and allyl bromide (2.42 ml) were added dropwise to the solution at −78 ° C., and the mixture was stirred for 3 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and washed with water. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and dried under reduced pressure to obtain the title compound (5.07 g).

Step 2 1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylacetic acid

Embedded image Sodium periodate (14.69 g) in water (90 m
l), carbon tetrachloride (50 ml), acetonitrile (50
After adding ruthenium chloride (111 mg) to the mixed solution, 4-allyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (5.
07g) of carbon tetrachloride (10 ml) and acetonitrile (10 ml) were added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was filtered and the residue was washed with ethyl acetate to remove the aqueous layer of the obtained filtrate, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate), and dried under reduced pressure to obtain the title compound (4.23 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.26 (tr, J = 7.0 Hz, 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

Embedded image A solution of 1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylacetic acid (2.34 g) in tetrahydrofuran (60 ml) was added at −78 ° C. to a 1M borane tetrahydrofuran solution (7.42 ml).
The mixture was stirred for 15 hours while heating. After completion of the reaction, water and potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was extracted with ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to give the title compound (1.9).
2 g) were obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.28 (tr, J = 7.1 Hz, 3H), 1.35-1.75
(m, 11H), 1.82 (tr, J = 6.7Hz, 2H), 2.10-2.20 (m, 2H), 2.9
1 (m, 2H), 3.68 (tr, J = 6.7Hz, 2H), 3.75-4.00 (m, 2H), 4.1
8 (q, J = 7.1Hz, 2H)

Step 4 4-ethoxycarbonyl-4- (2-methanesulfonyloxyethyl) piperidine-1-carboxylic acid tert
-Butyl ester

Embedded image Triethoxyamine of 4-ethoxycarbonyl-4- (2-hydroxyethyl) piperidine-1-carboxylic acid tert-butyl ester (1.92 g) (1.15 g)
l) To a methylene chloride (40 ml) solution was added methanesulfonyl chloride (0.592 ml) at −78 ° C.
Stirred for hours. After completion of the reaction, an aqueous sodium hydrogen carbonate solution was added to separate an organic layer, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and dried under reduced pressure to obtain the title compound (2.38 g). ¹ H-NMR (δppm, 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, 3
H), 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

Embedded image 4-ethoxycarbonyl-4- (2-methanesulfonyloxyethyl) piperidine-1-carboxylic acid tert
Sodium iodide (4.77 g) was added to dimethylformamide (24 ml) of -butyl ester (2.38 g), and the mixture was stirred at 70 ° C for 7 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent 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). I got ¹ H-NMR (δppm, CDCl ₃ ) 1.28 (tr, J = 7.1 Hz, 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

Embedded image Crude crystals of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol (1.26 g) were dissolved in dimethylformamide (15 ml), and 60% sodium hydride (243 mg), 4-ethoxycarbonyl- 4-
(2-iodoethyl) piperidine-1-carboxylic acid t
tert-butyl ester (1 g) was added and
Stirred for hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 7), and dried under reduced pressure to give the title compound (53).
5 mg). ^{1 H-NMR (δppm, 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

Embedded image 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), triethylamine (0.4 ml) from Example 43, step 3
In the same manner as in the above, the title compound (98 mg) was obtained.

Step 8 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride salt

Embedded image 4- [2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (94 mg), concentrated Hydrochloric acid (2 ml), 1N aqueous sodium hydroxide solution (1 ml), 1H-pyrazole-
The title compound (53 mg) was obtained from 1-carboxyamidine hydrochloride (88 mg) in the same manner as in Step 4 of Example 43. ¹ H-NMR (δppm, 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), 3.17-3.3
4 (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 45 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Synthesis Step 1 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -4-ethoxycarbonylpiperidine-1-carboxylic acid tert-
Butyl ester

Embedded image A solution of tert-butyl 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl) -4-ethoxycarbonylpiperidine-1-carboxylate (252 mg) in methylene chloride (5 ml) was added at room temperature. 70% 3-chloroperbenzoic acid (260 mg)
Was added and stirred for 12 hours. After completion of the reaction, an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium thiosulfate are added, and
Stir for minutes and extract with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate), and dried under reduced pressure to obtain the title compound (203 mg). ¹ H-NMR (δppm, 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 Ethyl 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -1- (pyridin-4-yl) piperidine-4-carboxylate

Embedded image 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) to give the title compound (120 mg) in the same manner as in Step 3 of Example 43.

Step 3 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 4- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (200 mg), concentrated hydrochloric acid (10 ml) ), A 1N aqueous solution of sodium hydroxide (2.06 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (181 mg) in the same manner as in Step 4 of Example 43 to give the title compound (12
0 mg). ¹ H-NMR (δppm, 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, 2
H), 7.54 (1H), 7.65 (1H), 7.72-7.76 (m, 5H), 8.23 (d, J =
(7.5Hz, 2H)

Example 46 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl] -1
Synthesis of-(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 t
tert-butyl ester

Embedded image 4- [2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -4-ethoxycarbonylpiperidine-1-carboxylic acid tert-
The title compound (173 mg) was obtained from butyl ester (295 mg) and 70% 3-chloroperbenzoic acid (297 mg) in the same manner as in Step 1 of Example 45.

Step 2 4- [2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl] -1
-(Pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester

Embedded image 4- [2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl] -4
-Ethoxycarbonylpiperidine-1-carboxylic acid t
tert-butyl ester (173 mg), trifluoroacetic acid (1 ml), 4-chloropyridine hydrochloride (60 m
g) and triethylamine (0.28 ml) to give the title compound (97 mg) in the same manner as in Step 3 of Example 43.

Step 3 4- [2- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl] -1
-(Pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride

Embedded image 4- [2- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl) ethyl] -1
-(Pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (97 mg), concentrated hydrochloric acid (2 ml), 1
N-sodium hydroxide aqueous solution (0.97 ml), 1H-
Pyrazole-1-carboxamidine hydrochloride (86 m
From g), the title compound (57 mg) was obtained in the same manner as in Step 4 of Example 43. ¹ H-NMR (δppm, 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, 4
H), 3.66 (m, 2H), 3.95-4.10 (m, 2H), 4.71 (s, 2H), 7.17 (2
H), 7.53 (1H), 7.67-7.82 (m, 6H), 8.20 (2H)

Example 47 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid methyl ester dihydrochloride Synthesis of salt Step 1 1- (pyridin-4-yl) piperidin-4-one

Embedded image 4-chloropyridine hydrochloride (10 g), 1,4-dioxa-8-azaspiro [4,5] decane (10 g), triethylamine (29 ml) in ethanol (10 ml),
The mixed solution of water (30 ml) was prepared using a pressure-resistant reaction vessel for 150 minutes.
Stirred at C for 22 hours. After the completion of the reaction, the solvent was distilled off and 5
An N-sodium hydroxide aqueous solution (25 ml) was added, and the mixture was extracted with a mixed solvent of chloroform-methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and concentrated hydrochloric acid (30 ml) was added dropwise to the residue obtained under ice-cooling, followed by stirring at the same temperature for 10 minutes. After completion of the reaction, sodium hydroxide (15 g) was added, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 9: 1, 1% aqueous ammonia), and dried under reduced pressure to obtain the title compound (6.1 g). ^{1 H-NMR (δppm, 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

Embedded image 1- (pyridin-4-yl) piperidin-4-one (1
g) in a methanol solution of ammonium acetate (880 m
g), aqueous sodium cyanide solution (560 mg / 5 m
l), aqueous ammonia (5 ml) and acetic acid (2 ml) were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off and aqueous ammonia (3 ml) was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a residue. Hydrogen chloride gas was blown into a 10% methanol solution of hydrochloric acid (25 ml) under ice-cooling, and the mixture was allowed to stand at room temperature for 12 hours. After completion of the reaction, 2N-hydrochloric acid (25 ml) was added to the residue obtained by evaporating the solvent, and 2
After stirring for an hour, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. Evaporate the solvent,
Drying under reduced pressure gave the title compound (760 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.55-1.65 (m, 2H), 2.08-2.17 (m, 2
H), 3.46-3.50 (m, 4H), 3.74 (s, 3H), 6.66 (dd, J = 1.5, 4.5
Hz, 2H), 8.25 (dd, J = 1.5,4.5Hz, 2H)

Step 3 1- (Pyridin-4-yl) -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) piperidine-4-carboxylic acid methyl ester

Embedded image 4-amino-1- (pyridin-4-yl) piperidine-
To a solution of methyl 4-carboxylate (330 mg) in chloroform (5 ml) was added 7-chlorosulfonyl-2.
-Trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Journal of Medicinal Chemistry, Vol. 23, No. 8, page 837, 1980) (500)
mg) and pyridine (0.23 ml).
Stirred for hours. After completion of the reaction, water was added, extracted with chloroform, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (627 mg). ¹ H-NMR (δppm, 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)

4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)
-1- (pyridin-4-yl) piperidine-4-carboxylic acid methyl ester dihydrochloride

Embedded image 1- (Pyridin-4-yl) -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) piperidine-4-carboxylic acid methyl ester (627 mg) in chloroform ( 5N), 2N-
An aqueous sodium hydroxide solution (1.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2N-hydrochloric acid (1.1 m
l) was added, and the residue obtained by concentration was subjected to dimethylformamide (3 ml) and diisopropylethylamine (0.9%).
(1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (305 mg) were sequentially added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the mixture was filtered, the filtrate was added dropwise to diethyl ether, and the resulting solid was separated by HPLC (0.05% aqueous trifluoroacetic acid: methanol = 4: 1 to 3: 2).
Treat with dilute hydrochloric acid and dry under reduced pressure to give the title compound (480 mg)
I got ¹ H-NMR (δppm, 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, 2
H), 7.17 (d, J = 7.1Hz, 2H), 7.47 (1H), 7.56 (1H), 7.62 (1
H), 7.82 (brs, 4H), 8.22 (d, J = 7.1Hz, 2H), 8.56 (s, 1H),
13.89 (brs, 1H)

Example 48 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Synthesis

Embedded image 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino) -1- (pyridin-4-yl) piperidine-4-carboxylic acid methyl ester dihydrochloride (415 mg) has 6N -Hydrochloric acid (2 m
l) was added and the mixture was stirred under reflux for 4 hours. After completion of the reaction, insolubles were removed and the solvent was distilled off. The solid formed by adding diethyl ether was collected by filtration, dried under reduced pressure, and dried under reduced pressure to give the title compound (363
mg). ¹ H-NMR (δppm, 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, 2
H), 7.16 (d, J = 7.3Hz, 2H), 7.44 (1H), 7.56 (1H), 7.67 (1
H), 7.80 (brs, 4H), 8.20 (d, J = 7.3Hz, 2H), 8.35 (s, 1H)

Example 49 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
Synthesis of ethyl ester dihydrochloride Step 1 4-benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert
-Butyl ester

Embedded image 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 diphenylphosphate azide (1.1 ml) at room temperature. 30 minutes at 70 ° C, 1 minute at 90 ° C
The mixture was stirred for 0 minutes and benzyl alcohol (0.58 m
l) was added and stirred for 20 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography and dried under reduced pressure to obtain the title compound (1.35 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.26 (tr, J = 7.0 Hz, 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), 5.0
9 (s, 2H), 7.26-7.40 (m, 5H)

Step 2 4-Benzyloxycarbonylaminomethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester

Embedded image 4-benzyloxycarbonylaminomethyl-4-ethoxycarbonylpiperidine-1-carboxylic acid tert
-Butyl ester (851 mg) in chloroform (5 m
l) To the solution was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off and the residue obtained was ethanol (5 ml), 4-chloropyridine hydrochloride (304 mg), and triethylamine (1.69 m).
l) was added, and the mixture was stirred at 150 ° C. for 2 days using a pressure-resistant reaction vessel. After completion of the reaction, the solvent was distilled off and the residue
An aqueous solution of N-sodium hydroxide was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol = 93: 7) and dried under reduced pressure to obtain the title compound (738 mg). . ¹ H-NMR (δppm, CDCl ₃ ) 1.27 (tr, J = 7.0 Hz, 3H), 1.50-1.70
(m, 2H), 2.05-2.22 (m, 2H), 3.10-3.22 (m, 2H), 3.35-3.4
5 (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

Embedded image 4-Benzyloxycarbonylaminomethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester (331 mg) in chloroform (0.5 m
1) 25% Hydrogen bromide acetic acid (2 ml) was added to the solution, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, hexane, diisopropyl ether and diethyl ether were added, and the supernatant was removed. Next, dimethylformamide (1 ml) was added, and the resulting solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the title compound (423 mg).

Step 4 1- (Pyridin-4-yl) -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) piperidin-4-
Carboxylic acid ethyl ester

Embedded image 4-Aminomethyl-1- (pyridin-4-yl) piperidine-4-carboxylic acid ethyl ester To dihydrobromide (423 mg), pyridine (2 ml), 7-chlorosulfonyl-2-trifluoroacetyl-1, 2,3,4-
Tetrahydroisoquinoline (273 mg) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol = 4: 1), and dried under reduced pressure to dry the title compound (2).
22 mg). ¹ H-NMR (δppm, 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

Embedded image 1- (pyridin-4-yl) -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) piperidin-4-
From the carboxylic acid ethyl ester (222 mg), diisopropylethylamine (0.28 ml), and 1H-pyrazole-1-carboxamidine hydrochloride (117 mg), the title compound (75
mg). ^{1 H-NMR (δppm, 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), 7.9
4 (brtr, 1H), 8.22 (2H)

Example 50 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
Synthesis of dihydrochloride

Embedded image 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl) -1-
(Pyridin-4-yl) piperidine-4-carboxylic acid
Example 4 from ethyl ester dihydrochloride (59 mg)
In a similar manner to 8, the title compound (52 mg) was obtained. ¹ H-NMR (δppm, 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 (1
H), 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 52 Synthesis of 1- [2- (benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5-carboxyamidine hydrochloride Step 1 N- (4-cyano-2) -Phenoxyacetamidophenyl) glycine tert-butyl ester

Embedded image N- (2-amino-4-cyanophenyl) glycine t
tert-butyl ester (5.97 g), phenyloxyacetic acid (3.44 g), 1-ethoxycarbonyl-2-
Ethoxy-1,2-dihydroxyquinoline (6.15
From g), the title compound (6.66 g) was obtained in the same manner as in Step 8 of Example 17. ¹ H-NMR (δppm, CDCl ₃ ) 1.49 (s, 9H), 3.81 (d, J = 4.8Hz, 2
H), 4.72 (s, 2H), 4.95 (brtr, 1H), 6.58 (d, J = 8.7Hz, 1H),
7.02 (d, J = 7.5Hz, 2H), 7.08 (tr, J = 7.5Hz, 1H), 7.36 (d, J
= 7.5Hz, 1H), 7.39 (d, J = 7.5Hz, 1H), 7.44 (dd, J = 1.5,8.7
Hz, 1H), 7.57 (d, J = 1.5Hz, 1H), 8.06 (brs, 1H)

Step 2 5-cyano-2-phenoxymethylbenzimidazole-1-acetic acid

Embedded image N- (4-cyano-2-phenoxyacetamidophenyl) glycine tert-butyl ester (6.61
A solution of g) in acetic acid (250 ml) was stirred at 80 ° C. for 12 hours. After completion of the reaction, trifluoroacetic acid (60 ml) was added to the residue obtained by evaporating the solvent, and the mixture was stirred at 50 ° C for 30 minutes. After completion of the reaction, chloroform and acetone were added to the residue obtained by evaporating the solvent, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (5.0 g). ¹ H-NMR (δ ppm, CDCl ₃ ) 5.25 (s, 2H), 5.43 (s, 2H), 6.97 (1
H), 7.05 (2H), 7.27-7.33 (2H), 7.68 (dd, J = 1.3,8.4Hz,
1H), 7.82 (d, J = 8.4Hz, 1H), 8.23 (d, J = 1.3Hz, 1H)

Step 3 N-methoxy-N-methyl-5- (cyano-2-phenoxymethylbenzimidazole) -1-acetamide

Embedded image 5-cyano-2-phenoxymethylbenzimidazole-1-acetic acid (2.14 g), N, O-dimethylhydroxylamine hydrochloride (815 mg), N-methylmorpholine (0.919 ml), 1-hydroxybenzotriazole hydrate (1.13 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.6
From g), the title compound (1.83 g) was obtained as a white solid in the same manner as in Step 10 of Example 17. ¹ H-NMR (δppm, CDCl ₃ ) 3.22 (s, 3H), 3.77 (s, 3H), 5.27
(s, 2H), 5.41 (s, 2H), 6.98-7.03 (3H), 7.26-7.36 (3H),
7.54 (1H), 8.11 (1H)

Step 4 N-methoxy-N-methyl- [5- (N ', N "-di-
tert-butoxycarbonylamidino) -2-phenoxymethylbenzimidazole] -1-acetamide

Embedded image Step 12 of Example 17 from N-methoxy-N-methyl- (5-cyano-2-phenoxymethylbenzimidazole) -1-acetamide (893 mg), methyl iodide (1.6 ml), ammonium acetate (295 mg).
N-methoxy-N-methyl- (5-amidino-2-phenoxymethylbenzimidazole) -1
-Acetamide was obtained. From this compound and di-tert-butyl dicarbonate (1.11 g), the title compound (144 mg) was obtained in the same manner as in Step 1 of Example 1. However,
The solvent used was tetrahydrofuran (10 ml) and 1N-
A saturated aqueous sodium hydrogen carbonate solution (10 ml) was used instead of the aqueous sodium hydroxide solution. ¹ H-NMR (δppm, CDCl ₃ ) 1.57 (s, 9H), 3.22 (s, 3H), 3.70-
3.80 (m, 3H), 5.25 (s, 2H), 5.40 (s, 2H), 6.90-7.05 (m, 3
H), 7.25-7.35 (m, 3H), 7.94-8.19 (m, 2H)

Step 5 N, N'-di-tert-butoxycarbonyl-1-
[2- (benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5
-Carboxamidine

Embedded image To a solution of benzothiazole (42 mg) in tetrahydrofuran (5 ml), a 1.66 M n-butyllithium-hexane solution (0.204 ml) was added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 10 minutes. Then, a solution of N-methoxy-N-methyl-5-[(N ', N "-di-tert-butoxycarbonylamidino) -2-phenoxymethylbenzimidazole] -1-acetamide (144 mg) in tetrahydrofuran (1 ml) was added dropwise. After completion of the reaction, an aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3), and dried under reduced pressure to obtain the title compound (25 mg) ¹ H-NMR (δppm, CDCl ₃ ) 1.57 (s, 9H), 5.45 (s, 2H), 6.07
(s, 2H), 6.898-6.95 (3H), 7.17-7.22 (2H), 7.34 (1H),
7.63 (2H), 7.97 (1H), 8.03 (1H), 8.22-8.25 (2H)

Step 6 1- [2- (Benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5-carboxyamidine hydrochloride

Embedded image N, N'-di-tert-butoxycarbonyl-1-
[2- (benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5
-The title compound (18 mg) was obtained from carboxamidine (25 mg) and trifluoroacetic acid (1 ml) in the same manner as in Step 11 of Example 19. ¹ H-NMR (δppm, DMSO-d ₆ ) 5.52 (s, 2H), 6.32 (s, 2H), 6.84
-6.88 (m, 3H), 7.13-7.18 (m, 2H), 7.69-7.76 (m, 3H), 7.9
3 (d, 1H), 8.28-8.34 (m, 3H), 9.01 (brs, 2H), 9.32 (brs, 2
H)

Example 53 trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
Synthesis of amidinobenzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride Step 1 Ethyl 4-benzyloxyphenoxyacetate

Embedded image To a solution of 4-benzyloxyphenol (18.34 g) in tetrahydrofuran (150 ml) was added 60% sodium hydride (4.76 g) under ice-cooling, followed by stirring at the same temperature for 15 minutes, followed by ethyl bromoacetate (14.2 ml). ) Was added dropwise and stirred at room temperature for 16 hours. After completion of the reaction, 5% hydrochloric acid was added, extracted with hexane, and dried over anhydrous magnesium sulfate. The solid obtained by evaporating the solvent was collected by filtration with hexane, and dried under reduced pressure to obtain the title compound (21.78 g) as a white solid. ^{1 H-NMR (δppm, CDCl} 3) 1.29 (tr, J = 7.2Hz, 3H), 4.26 (q, J =
7.2Hz, 2H), 4.56 (s, 2H), 5.01 (s, 2H), 6.84-6.92 (m, 4
H), 7.26-7.43 (m, 5H)

Step 2 Ethyl 4-hydroxyphenoxyacetate

Embedded image Ethyl 4-benzyloxyphenoxyacetate (21.78
g) in a solution of g) in tetrahydrofuran (220 ml).
Hydrogenation was performed using 5% palladium carbon (3.2 g) at 3 atm for 7 hours. After completion of the reaction, the reaction mixture was filtered through celite, the solvent was distilled off, and the solid obtained was filtered with diisopropyl ether and dried under reduced pressure to give the title compound (13.88 g) as a white solid. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.19 (tr, J = 7.2 Hz, 3H), 4.14 (q,
J = 7.2Hz, 2H), 4.61 (s, 2H), 6.63-6.76 (m, 4H), 8.95 (s, 1
H)

Step 3 4- (1-tert-butoxycarbonylpiperidine-
Ethyl 4-yloxy) phenoxyacetate

Embedded image 4-hydroxypiperidinecarboxylic acid tert-butyl ester (35.59 g), ethyl 4-hydroxyphenoxyacetate (5 g), triphenylphosphine (4
6.4 g), diethyl azodicarboxylate (27.8 m
From 1), the title compound (23.71 g) was obtained in the same manner as in Step 7 of Example 37. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.30 (tr, J = 7.2 Hz, 3H), 1.47 (s, 9
H), 1.73 (m, 2H), 1.88 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2
H), 4.27 (q, J = 7.2Hz, 2H), 4.33 (m, 1H), 4.56 (s, 2H), 6.
85 (s, 4H)

Step 4 4- (1-tert-butoxycarbonylpiperidine-
4-yloxy) phenoxyacetic acid

Embedded image 4- (1-tert-butoxycarbonylpiperidine-
Ethyl 4-yloxy) phenoxyacetate (23.71
To a mixed solution of g) in tetrahydrofuran (34 ml) and ethanol (34 ml) was added dropwise a 1N aqueous solution of lithium hydroxide (68.7 ml) under ice-cooling, followed by stirring at room temperature for 20 minutes. After completion of the reaction, 10% was added to the residue obtained by evaporating the solvent.
An aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained solid was collected by filtration with hexane and dried under reduced pressure to obtain the title compound (19.09 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.40 (s, 9H), 1.49 (m, 2H), 1.83
(m, 2H), 3.15 (m, 2H), 3.63 (m, 2H), 4.40 (m, 1H), 4.58 (s,
2H), 6.83 (d, J = 9.2Hz, 2H), 6.91 (d, J = 9.2Hz, 2H)

Step 5 N- [4-cyano-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetamido] phenyl] glycine tert-butyl ester

Embedded image N- (2-amino-4-cyanophenyl) glycine t
ert-butyl ester (9.11 g), 4- (1-t
Example 17 from tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetic acid (12.94 g).
In the same manner as in Step 8, the title compound (17.11 g) was obtained as a white solid. ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.50 (s, 9H), 1.71
(m, 2H), 1.88 (m, 2H), 3.31 (m, 2H), 3.71 (m, 2H), 3.82 (b
rd, 2H), 4.37 (m, 1H), 4.66 (s, 2H), 4.99 (brtr, 1H), 6.5
8 (d, J = 8.7Hz, 1H), 6.89-6.97 (m, 4H), 7.45 (d, J = 8.7Hz, 1H
H), 7.57 (s, 1H), 8.07 (brs, 1H)

Step 6 5-cyano-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] benzimidazole-1-acetic acid

Embedded image A solution of N- [4-cyano-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxyacetamido] phenyl] glycine tert-butyl ester (16.91 g) in acetic acid (500 ml) at 75 ° C. After stirring for 12 hours, trifluoroacetic acid (100 ml) was added to the residue obtained by evaporating the solvent, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, ice was added to the residue obtained by evaporating the solvent, and then an aqueous solution of sodium hydroxide was added. The resulting solid was collected by filtration, washed with water and ethyl acetate, and washed with N- [4- Cyano-2- [4- (piperidine-4-
Illoxy) phenoxyacetamido] phenyl] glycine (8.642 g) was obtained. This and di-tert-
The title compound (9.506 g) was obtained from butyl dicarbonate (6.96 g) and 1N aqueous sodium hydroxide solution (23.4 ml) in the same manner as in Step 1 of Example 1. ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 1.64 (m, 2H), 1.79
(m, 2H), 3.25 (m, 2H), 3.63 (m, 2H), 4.28 (m, 1H), 5.12
(s, 2H), 5.33 (s, 2H), 6.77 (d, J = 9.1Hz, 2H), 6.88 (d, J =
9.1Hz, 2H), 7.43 (d, J = 8.4Hz, 1H), 7.59 (dd, J = 1.2,8.4H
z, 1H), 8.10 (d, J = 1.2Hz, 1H)

Step 7 Trans-4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride

Embedded image The title compound (8.8 g) was obtained from trans-4-aminomethylcyclohexanecarboxylic acid (7 g) and thionyl chloride (11.6 ml) according to a conventional method. ¹ H-NMR (δppm, DMSO-d ₆ ) 0.98 (m, 2H), 1.29 (m, 2H), 1.55
(m, 1H), 1.82 (m, 2H), 1.91 (m, 2H), 2.25 (m, 1H), 2.26 (m,
2H), 3.59 (s, 3H), 8.07 (brs, 3H)

Step 8 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyano-1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole

Embedded image 5-cyano-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] benzimidazole-1-acetic acid (1.1 g), trans-4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride (452 mg), N-methylmorpholine (0.263 ml), 1-hydroxybenzotriazole hydrate (293 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4
37 mg) to give the title compound (1.37 g) in the same manner as in Step 10 of Example 17. ¹ H-NMR (δppm, CDCl ₃ ) 0.79 (m, 2H), 1.27 (m, 3H), 1.46
(s, 9H), 1.55 (m, 2H), 1.72 (m, 2H), 1.85 (m, 4H), 2.09
(m, 1H), 3.02 (tr, 2H), 3.30 (m, 2H), 3.64 (s, 3H), 3.67
(m, 2H), 4.35 (m, 1H), 4.97 (s, 2H), 5.37 (s, 2H), 5.66 (b
rtr, 1H), 6.87 (d, J = 9.0Hz, 2H), 6.95 (d, J = 9.0Hz, 2H),
7.48 (1H), 7.61 (1H), 8.14 (1H)

Step 9 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxyamidine

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyano-1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole (1.1 g) pyridine- Triethylamine (5: 1)
Hydrogen sulfide was blown into the mixed solution (30 ml) under ice cooling,
Stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was collected by filtration with toluene. To the obtained solid were added acetone (30 ml) and methyl iodide (1.3 ml), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, the solvent was distilled off.
Dry under reduced pressure to give 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carbothioimidic acid methyl ester (1.8
19g) was obtained. 606 mg of ethanol (1
0 ml) and ammonium acetate (80 m
g) was added and the mixture was stirred at 75 ° C for 3 hours. After completion of the reaction, the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform: methanol = 95: 5-9).
3: 7) and dried under reduced pressure to give the title compound (341m).
g) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 0.91 (m, 2H), 1.20-1.55 (m, 14
H), 1.70 (m, 2H), 1.86 (m, 4H), 2.18 (m, 1H), 2.94 (brtr,
2H), 3.15 (m, 2H), 3.58 (s, 3H), 3.62 (m, 2H), 4.40 (m, 1
H), 5.10 (s, 2H), 5.30 (s, 2H), 6.91 (d, J = 9.0Hz, 2H), 6.
99 (d, J = 9.0Hz, 2H), 7.70 (1H), 7.78 (1H), 8.21 (1H), 8.3
5 (brtr, 1H), 8.79 (brtr, 1H), 9.26 (brtr, 1H)

Step 10 trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
Amidinobenzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxyamidine (341 mg), trifluoroacetic acid (5m
From l), in the same manner as in step 11 of Example 19, 2-
[4- (Piperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxyamidine (299 mg) was obtained. To a solution of this (205 mg) in methanol (1 ml) was added a 1N aqueous sodium hydroxide solution (1.57 ml) at room temperature, and the mixture was stirred for 15 hours. After completion of the reaction, 1N hydrochloric acid (0.
944 ml), and the solvent was distilled off. The residue obtained by drying under reduced pressure was added with methanol (5 ml), triethylamine (0.439 ml) and ethylacetimidate hydrochloride (195 mg), and the mixture was stirred at room temperature for 15 hours. . After completion of the reaction, the residue obtained by distilling off the solvent was subjected to HPLC (40
% Methanol-water, 0.05% trifluoroacetic acid). Dilute hydrochloric acid was added, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (78 mg).

Example 54 Trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
Synthesis of (N-methylamidino) benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride Step 1 N-methyl-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl ] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxyamidine

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carbothioimidic acid methyl ester (606 mg), methyl Amine hydrochloride (70mg), sodium acetate (85mg)
From the title compound (4) in the same manner as in Step 9 of Example 53.
47 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 0.91 (m, 2H), 1.16-1.55 (m, 14
H), 1.70 (m, 2H), 1.85 (m, 4H), 2.18 (m, 1H), 2.94 (brtr,
2H), 3.03 (s, 3H), 3.16 (m, 2H), 3.58 (s, 3H), 3.61 (m, 2
H), 4.42 (m, 1H), 5.10 (s, 2H), 5.30 (s, 2H), 6.91 (d, J =
9.0Hz, 2H), 6.99 (d, J = 9.0Hz, 2H), 7.64 (dd, J = 1.5,8.5H
z, 1H), 7.77 (d, J = 7.77Hz, 1H), 8.11 (d, J = 1.5Hz, 1H), 8.
34 (brtr, 1H)

Step 2 trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
(N-methylamidino) benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride

Embedded image N-methyl-2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxyamidine (447 mg) Trifluoroacetic acid (5 ml), 1N aqueous sodium hydroxide solution (2.15 ml), triethylamine (0.599 m
l) and ethylacetimidate hydrochloride (265 mg) in the same manner as in Step 10 of Example 53 to give the title compound (1
49 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 0.8-1.0 (m, 2H), 1.12-1.42 (m, 3
H), 1.71 (m, 4H), 1.86 (m, 2H), 1.92-2.18 (m, 3H), 2.30
(s, 3H), 2.95 (m, 2H), 3.05 (d, 3H), 3.42-3.88 (m, 4H),
4.58 (m, 1H), 5.19 (s, 2H), 5.37 (s, 2H), 6.96 (d, J = 9.3H
z, 2H), 7.04 (d, J = 9.3Hz, 2H), 7.74 (d, J = 8.7Hz, 1H), 7.8
5 (d, J = 8.7Hz, 1H), 8.18 (s, 1H), 8.63 (brtr, 1H), 8.87 (b
rs, 1H), 9.01 (brs, 1H), 9.43 (brs, 1H), 9.53 (brs, 1H),
9.94 (brs, 1H)

Example 55 trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
Synthesis of [amino (hydroxyimino) methyl] benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride Step 1 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl]- 1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxamide oxime

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carbothioimidic acid methyl ester (606 mg), hydroxy Amine hydrochloride (72 mg), sodium acetate (85 m
From g), the title compound (181 mg) was obtained in the same manner as in Step 9 of Example 53. ¹ H-NMR (δppm, DMSO-d ₆ ) 0.90 (m, 2H), 1.15-1.55 (m, 14
H), 1.70 (m, 2H), 1.86 (m, 4H), 2.19 (m, 1H), 2.94 (tr, 2
H), 3.16 (m, 2H), 3.58 (s, 3H), 3.65 (m, 2H), 4.40 (m, 1
H), 5.00 (s, 2H), 5.26 (s, 2H), 5.92 (brs, 1H), 6.91 (d, J
= 9.0Hz, 2H), 7.00 (d, J = 9.0Hz, 2H), 7.49 (1H), 7.63 (1
H), 7.95 (1H), 8.27 (brtr, 1H), 9.59 (brs, 1H)

Step 2 trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
[Amino (hydroxyimino) methyl] benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid dihydrochloride

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1- (trans-4-methoxycarbonylcyclohexylmethylcarbamoylmethyl) benzimidazole-5-carboxamide oxime (181 mg), trifluoroacetic acid (5 ml) and a 1N aqueous solution of sodium hydroxide (0.
669 ml), triethylamine (0.187 ml),
The title compound (22 mg) was obtained from ethylacetimidate hydrochloride (83 mg) in the same manner as in Step 10 of Example 53.
I got ¹ H-NMR (δppm, DMSO-d ₆ ) 0.8-1.0 (m, 2H), 1.12-1.42 (m, 3
H), 1.71 (m, 4H), 1.86 (m, 2H), 2.04 (m, 3H), 2.29 (s, 3
H), 2.94 (m, 2H), 3.45-3.60 (m, 2H), 4.58 (m, 1H), 5.14
(s, 2H), 5.34 (s, 2H), 6.95 (d, J = 9.0Hz, 2H), 7.02 (d, J =
9.0Hz, 2H), 7.64 (d, J = 8.7Hz, 1H), 7.81 (d, J = 8.7Hz, 1H),
8.10 (s, 1H), 8.49 (brtr, 1H), 8.74 (brs, 1H), 8.98 (br
s, 1H), 9.29 (brs, 2H), 11.20 (brs, 1H), 12.86 (brs, 1H)

Example 56 2- [4- (Piperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine dihydrochloride Step 1 3,4-diaminobenzonitrile

Embedded image Hydrogenation was performed using 7.5% palladium on carbon (320 mg) in a solution of 2-nitro-4-cyanoaniline (2.21 g) in ethanol (44 ml) at normal pressure for 2 hours.
After completion of the reaction, the reaction mixture was filtered through celite, the solvent was distilled off, and the residue was added with chloroform. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (474 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 4.82-4.85 (2H), 5.41-5.43 (2
H), 6.54 (d, J = 8.1Hz, 1H), 6.75 (d, J = 2.1Hz, 1H), 6.79 (d
d, J = 2.1, 8.1Hz, 1H)

Step 2 4- [4- (2-Amino-5-cyanophenylcarbamoylmethoxy) phenyloxy] piperidine-1-carboxylic acid tert-butyl ester

Embedded image 3,4-diaminobenzonitrile (474 mg), 4-
(1-tert-butoxycarbonylpiperidine-4-
To a solution of (yloxy) phenoxyacetic acid (1.25 g) in tetrahydrofuran (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (1.06 g) under ice-cooling, followed by stirring at room temperature for 16 hours. After completion of the reaction, chloroform and hexane were added to the residue obtained by evaporating the solvent, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (1.55 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.74 (m, 2H), 1.90
(m, 2H), 3.32 (m, 2H), 3.70 (m, 2H), 4.28 (brs, 2H), 4.38
(m, 1H), 4.64 (s, 2H), 6.80 (d, J = 8.4Hz, 1H), 6.92 (s, 4
H), 7.37 (dd, J = 1.8,8.4Hz, 1H), 7.56 (d, J = 1.8Hz, 1H),
8.10 (brs, 1H)

Step 3 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyanobenzimidazole

Embedded image The title compound (4- (4-amino-2-cyanophenylcarbamoylmethoxy) phenyloxy] piperidine-1-carboxylic acid tert-butyl ester (1.52 g) was obtained in the same manner as in Step 8 of Example 19 (1.58 g). 1.
04g). ¹ H-NMR (δppm, CDCl ₃ ) 1.47 (s, 9H), 1.73 (m, 2H), 1.88
(m, 2H), 3.30 (m, 2H), 3.69 (m, 2H), 4.35 (m, 1H), 5.36
(s, 2H), 6.86-6.96 (m, 4H), 7.54 (s, 1H)

Step 4 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyano-1-phenacylbenzimidazole

Embedded image 60% sodium hydride (90 mg) in a solution of 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyanobenzimidazole (915 mg) in dimethylformamide (15 ml) under ice-cooling. And stirred at the same temperature for 20 minutes.
Phenacyl bromide (426 mg) was added and the mixture was added at room temperature for 15 minutes.
Stirred for hours. After completion of the reaction, the mixture was extracted with ethyl acetate,
Washed sequentially with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
Purification by C (hexane: ethyl acetate = 2: 3) gave the title compound (385 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.46 (s, 9H), 1.68 (m, 2H), 1.83
(m, 2H), 3.27 (m, 2H), 3.66 (m, 2H), 4.29 (m, 1H), 5.34
(s, 2H), 5.79 (s, 2H), 6.75-6.82 (m, 4H), 7.27 (1H), 7.54
(1H), 7.59 (2H), 7.72 (tr, 1H), 8.02 (2H), 8.15 (1H)

Step 5 2- [4- (Piperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine dihydrochloride

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -5-cyano-1-phenacylbenzimidazole (182 m
g), hydrogen sulfide, methyl iodide (0.204 ml), ammonium acetate (38 mg) from step 9 of Example 53
In the same manner as in the above, 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carbothioimidic acid methyl ester (127 mg) was obtained.
Trifluoroacetic acid (1 ml) was added to a chloroform (1 ml) solution, and the mixture was stirred for 5 minutes. The solvent was distilled off, and the obtained residue was dissolved in methanol.
Methanol (0.5 ml) was added, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (109 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.77 (m, 2H), 2.00 (m, 2H), 3.01
(m, 2H), 3.15 (m, 2H), 4.45 (m, 1H), 5.37 (s, 2H), 6.18 (s,
2H), 6.78-6.86 (m, 4H), 7.59-7.84 (m, 5H), 8.09 (d, 2H),
8.26 (s, 1H), 8.80-9.10 (m, 4H), 9.33 (brs, 2H)

Example 57 Synthesis of 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine dihydrochloride

Embedded image 2- [4- (piperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine dihydrochloride (85 mg), triethylamine (0.128 ml), ethylacetimidate hydrochloride (57 mg) To 2- [4- (1-acetimidoylpiperidine-4) in the same manner as in Step 1 of Example 29.
-Yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine. The solid formed by adding isopropanol to this was collected by filtration and dried under reduced pressure to obtain the title compound (17 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.69 (m, 2H), 1.95 (m, 2H), 2.27
(s, 3H), 3.50 (m, 2H), 3.71 (m, 2H), 4.52 (m, 1H), 5.37 (s,
2H), 6.19 (s, 2H), 6.80 (d, J = 9.0Hz, 2H), 6.86 (d, J = 9.0H
z, 2H), 7.63 (tr, 2H), 7.71-7.79 (m, 2H), 7.83 (1H), 8.1
0 (2H), 8.26 (s, 1H), 8.60, 8.95, 9.20, 9.31 (6H)

Example 58 2- [2- [4-Ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -1-
Synthesis of (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride Step 1 4-ethoxycarbonyl-4- [2- (1,3-dioxolan-2-yl) ethyl] piperidine-1-carboxylic acid tert- Butyl ester

Embedded image 1-tert-butoxycarbonyl isonipecotic acid
Ethyl ester (500 mg), 1.5 M-lithium diisopropylamide-tetrahydrofuran solution (1.6
ml) and 2- (2-bromoethyl) -1,3-dioxolane (0.27 ml) in the same manner as in Step 5 of Example 10 to obtain the title compound (520 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.26 (tr, J = 7.2 Hz, 2H), 1.35 (m, 2
H), 1.44 (s, 9H), 1.62 (m, 4H), 2.07-2.11 (m, 2H), 2.88
(m, 2H), 3.81-3.97 (m, 6H), 4.17 (q, J = 7.2Hz, 2H), 4.81 (t
(r, 1H)

Step 2 4-ethoxycarbonyl-4- [2- (1,3-dioxolan-2-yl) ethyl] piperidine-1-carboxylic acid benzyl ester

Embedded image To a solution of tert-butyl 4-ethoxycarbonyl-4- [2- (1,3-dioxolan-2-yl) ethyl] piperidine-1-carboxylate (450 mg) in chloroform (2 ml) was added trifluoroacetic acid (2 ml).
Was added and stirred for several minutes. After completion of the reaction, the solvent was distilled off, and an aqueous solution of sodium hydrogen carbonate was added to the obtained residue. The mixture was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 4- [2-
(1,3-Dioxolan-2-yl) ethyl] piperidine-4-carboxylic acid ethyl ester was obtained. Then
Example 10 was prepared from sodium hydrogen carbonate (127 mg) and benzyloxycarbonyl chloride (0.22 ml).
The title compound (460 mg) was obtained in the same manner as in Step 1 of.

Step 3 4-ethoxycarbonyl-4- (2-formylethyl)
Piperidine-1-carboxylic acid benzyl ester

Embedded image 4-Ethoxycarbonyl-4- [2- (1,3-dioxolan-2-yl) ethyl] piperidine-1-carboxylic acid benzyl ester (460 mg) was dissolved in tetrahydrofuran (5 ml) and concentrated hydrochloric acid (5 ml) under ice-cooling. ) Was added dropwise and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was opened in an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: acetone = 5: 1) to obtain the title compound (300 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.27 (tr, J = 7.2 Hz, 3H), 1.36 (m, 2
H), 1.85 (tr, J = 8.0Hz, 2H), 2.10 (m, 2H), 2.43 (tr, J = 8.0
Hz, 2H), 2.94 (m, 2H), 3.98 (m, 2H), 4.18 (q, J = 7.2Hz, 2
H), 5.12 (s, 2H), 7.28-7.38 (m, 5H), 9.74 (s, 1H)

Step 4 Cyclohexylcarbamoylmethylcarbamic acid benzyl ester

Embedded image N- (benzyloxycarbonyl) glycine (13.2
1g), a solution of 1-hydroxybenzotriazole hydrate (9.39 g) in dimethylformamide (92 ml) was added to cyclohexylamine (7.95 ml),
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.32 g) was added, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and washed sequentially with water, an aqueous solution of sodium hydrogen carbonate, 10% hydrochloric acid, and saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by distilling off the solvent was recrystallized from ethyl acetate and hexane to obtain the title compound (16.799 g). ¹ H-NMR (δppm, CDCl ₃ ) 1.13 (m, 3H), 1.35 (m, 2H), 1.67
(m, 3H), 1.86 (m, 2H), 3.76 (m, 1H), 3.82 (d, J = 5.7Hz, 2
H), 5.13 (s, 2H), 5.41 (brs, 1H), 5.81 (brs, 1H), 7.32-
7.37 (m, 5H)

Step 5 4- (Cyclohexylcarbamoylmethylamino) -3
-Nitrobenzonitrile

Embedded image Cyclohexylcarbamoylmethylcarbamic acid benzyl ester (16.359 g) was added to ethanol (164
7.5% palladium on carbon in solution (3.24 g)
And hydrogenated at normal pressure for 8 hours. After the reaction,
The residue obtained by filtering through Celite and evaporating the solvent was dissolved in a mixed solution of ethanol (50 ml) and isopropanol (50 ml), and 4-chloro-3-nitrobenzonitrile (8.23 g) and triethylamine (7. 1 ml) and stirred under reflux for 6 hours. After completion of the reaction, water was added under reflux and the mixture was cooled on ice. The resulting solid was collected by filtration, washed with water and diisopropyl ether in that order, and the title compound (10.221)
g) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 1.13 (m, 3H), 1.38 (m, 2H), 1.70
(m, 3H), 1.91 (m, 2H), 3.84 (m, 1H), 4.01 (d, J = 5.4Hz, 2
H), 5.76 (brd, 1H), 6.81 (d, J = 8.7Hz, 1H), 7.65 (dd, J = 2.
1, 8.7Hz, 1H), 8.54 (d, J = 2.1Hz, 1H), 8.81 (brtr, 1H)

Step 6 3-Amino-4- (cyclohexylcarbamoylmethylamino) benzonitrile

Embedded image 4- (cyclohexylcarbamoylmethylamino) -3
-Nitrobenzonitrile (3.64 g) was hydrogenated in tetrahydrofuran (100 ml) solution using 7.5% palladium on carbon (1.1 g) at normal pressure for 40 minutes.
After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (3.274 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.21 (m, 5H), 1.52-1.72 (m, 5H),
3.57 (m, 1H), 3.70 (d, J = 5.7Hz, 2H), 4.97 (brs, 2H), 5.7
4 (d, J = 5.7Hz, 1H), 6.30 (d, J = 8.4Hz, 1H), 6.82 (d, J = 1.8H
z, 1H), 6.92 (dd, J = 1.8,8.4Hz, 1H), 7.80 (brd, 1H)

Step 7 4- [2- [5-Cyano-2- (cyclohexylcarbamoylmethylamino) phenylcarbamoyl] ethyl]
-4-ethoxycarbonylpiperidine-1-carboxylic acid benzyl ester

Embedded image 4-ethoxycarbonyl-4- (2-formylethyl)
Piperidine-1-carboxylic acid benzyl ester (50
mg) in tert-butanol (1 ml), sodium dihydrogen phosphate aqueous solution (25 mg / 0.5 ml),
Amylene (0.06 ml) and an aqueous solution of sodium chlorite (40 mg / 0.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, hydrochloric acid and a 5% aqueous solution of sodium thiosulfate were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was distilled off with dimethylformamide (1 m
l), 3-amino-4- (cyclohexylcarbamoylmethylamino) benzonitrile (39 mg),
1-hydroxybenzotriazole hydrate (21 m
g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30 mg) was added, and the mixture was added at room temperature for 1 hour.
Stir for 2 hours. After completion of the reaction, an aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was recrystallized from ethyl acetate.
Drying under reduced pressure gave the title compound (51 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.29 (tr, J = 7.2 Hz, 3H), 0.95-1.76
(m, 12H), 1.99 (m, 2H), 2.18 (m, 2H), 2.44 (tr, 2H), 2.96
(m, 2H), 3.74 (m, 1H), 3.90 (d, J = 6.3Hz, 2H), 4.00 (m, 2
H), 4.17 (q, J = 7.2Hz, 2H), 5.12 (s, 2H), 5.22 (tr, J = 6.3H
(z, 1H), 6.59 (1H), 6.82 (1H), 7.31-7.44 (m, 8H)

Step 8 2- [2- (1-benzyloxycarbonyl-4-ethoxycarbonylpiperidin-4-yl) ethyl] -5-
Cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole

Embedded image 4- [2- [5-cyano-2- (cyclohexylcarbamoylmethylamino) phenylcarbamoyl] ethyl]
Acetic acid (10 ml) of -4-ethoxycarbonylpiperidine-1-carboxylic acid benzyl ester (300 mg)
The solution was stirred at 100 C for 24 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) and dried under reduced pressure to obtain the title compound (200 mg). Was. ¹ H-NMR (δppm, CDCl ₃ ) 0.8-1.75 (m, 13H), 1.80 (m, 2H),
2.22 (m, 4H), 2.84 (tr, 2H), 3.01 (m, 2H), 3.77 (m, 1H),
3.85-4.05 (m, 4H), 4.72 (s, 2H), 5.13 (s, 2H), 5.91 (d, 1
H), 7.26-7.45 (m, 6H), 7.54 (1H), 8.01 (1H)

Step 9 2- [2- (4-ethoxycarbonylpiperidine-4-l
Yl) ethyl] -5-cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole

Embedded image 2- [2- (1-benzyloxycarbonyl-4-ethoxycarbonylpiperidin-4-yl) ethyl] -5-
Cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole (200 mg), 7.5% palladium on carbon (100 mg), ammonium formate (105 mg)
Then, the title compound (1) was obtained in the same manner as in Step 2 of Example 14.
50 mg). ¹ H-NMR (δppm, CDCl ₃ ) 0.9-1.85 (m, 12H), 1.26 (tr, J = 7.2
Hz, 3H), 2.15-2.25 (m, 4H), 2.68 (m, 2H), 2.85 (tr, 2H),
2.90-3.00 (m, 2H), 3.79 (m, 1H), 3.98 (q, J = 7.2Hz, 2H),
4.73 (s, 2H), 6.04 (d, 1H), 7.37 (1H), 7.53 (1H), 8.01 (1
H)

Step 10 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -5-cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole

Embedded image 2- [2- (4-ethoxycarbonylpiperidine-4-
Yl) ethyl] -5-cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole (150 m
g), 4-chloropyridine hydrochloride (48 mg), triethylamine (0.14 ml) from Step 7 of Example 10
In the same manner as in the above, the title compound (110 mg) was obtained. ¹ H-NMR (δppm, CDCl ₃ ) 0.95-1.40 (m, 6H), 1.28 (tr, J = 7.2
Hz, 3H), 1.82 (m, 2H), 2.25 (tr, J = 7.6Hz, 2H), 2.32 (m, 2
H), 2.87 (tr, J = 7.6Hz, 2H), 3.02 (m, 2H), 3.69 (m, 2H),
3.80 (m, 1H), 4.03 (q, J = 7.2Hz, 2H), 4.73 (s, 2H), 5.97
(d, 1H), 6.65 (d, J = 6.6Hz, 2H), 7.35 (1H), 7.54 (1H), 8.
01 (1H), 8.26 (d, J = 6.6Hz, 2H)

Step 11 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -1-
(Cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride

Embedded image 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -5-cyano-1- (cyclohexylcarbamoylmethyl) benzimidazole (100 mg), methyl iodide ( 1m
l), ammonium acetate (22 mg) and sodium acetate (23 mg), to give the title compound (60 mg) in the same manner as in Step 8 of Example 38. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.10-1.38 (m, 8H), 1.50-1.70
(m, 7H), 2.10 (m, 2H), 2.22 (m, 2H), 2.77 (m, 2H), 3.26
(m, 2H), 3.51 (m, 1H), 4.92 (s, 2H), 7.20 (d, J = 7.0Hz, 2
H), 7.66 (s, 2H), 8.08 (s, 1H), 8.22 (d, J = 7.0Hz, 2H), 8.
37 (d, 1H), 8.94 (s, 2H), 9.20 (s, 2H), 13.34 (brs, 1H)

Example 59 4- [2- [5-Amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-yl] ethyl] -1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride Salt synthesis

Embedded image 2- [2- [4-ethoxycarbonyl-1- (pyridin-4-yl) piperidin-4-yl] ethyl] -1-
(Cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride (50 m
g) and concentrated hydrochloric acid (1.5 ml) to give the title compound (20 mg) in the same manner as in Example 7. However, purification was performed by preparative HPLC (30 to 50% methanol-water). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.19 (m, 5H), 1.65 (m, 7H), 2.17
(m, 4H), 2.87 (m, 2H), 3.29 (m, 2H), 4.08 (m, 2H), 5.01 (s,
2H), 7.19 (2H), 7.72 (d, J = 8.7Hz, 1H), 7.77 (d, J = 8.7Hz,
1H), 8.14 (s, 1H), 8.21 (2H), 8.56 (d, 1H), 9.07 (brs, 2
H), 9.34 (brs, 2H), 13.56 (brs, 1H)

Example 60 1- (cyclohexylcarbamoylmethyl) -2- [N
Synthesis of-[1- (pyridin-4-yl) piperidin-4-yl] -N-ethoxalylaminomethyl] benzimidazole-5-carboxyamidine dihydrochloride Step 1 1- (Pyridin-4-yl) piperidin- 4-carbamic acid benzyl ester

Embedded image 1- (pyridin-4-yl) piperidine-4-carboxylic acid (11.18 g), triethylamine (11.3 m
l) Diphenylformamide (12.9 ml) was added to a suspension of dimethylformamide (110 ml) at room temperature, and the mixture was stirred at 80 ° C for 30 minutes. Then, benzyl alcohol (6.17 ml) was added at the same temperature for 12 hours. Stirred. After completion of the reaction, the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform: methanol =
99: 1 to 95: 5) and dried under reduced pressure to give the title compound (9.46 g). ¹ H-NMR (δppm, 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

Embedded image In a solution of 1- (pyridin-4-yl) piperidine-4-carbamic acid benzyl ester (9.46 g) in ethanol (95 ml), 7.5% palladium on carbon (3.5%) was used.
7g) for 3 hours at 3 atmospheres. After completion of the reaction, the mixture was filtered through Celite, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (5.38 g). ¹ H-NMR (δppm, 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

Embedded image Under a nitrogen atmosphere, sodium methoxide (3.29 g) was added to a solution of chloroacetonitrile (3.9 ml) in methanol (166 ml), and the mixture was stirred at room temperature for 40 minutes. Then methanesulfonic acid (7.91 ml), 3-amino-
4- (Cyclohexylcarbamoylmethylamino) benzonitrile (8.3 g) was added and 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 mixed solution of hexane and tetrahydrofuran, filtered and dried under reduced pressure. The title compound (9.30 g) was obtained. ¹ H-NMR (δppm, 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) piperidine-4
-Ylaminomethyl] benzimidazole

Embedded image 4-amino-1- (pyridin-4-yl) piperidine (1.91 g), 2-chloromethyl-1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (3.25 g), triethylamine (2.74 m)
A solution of 1) in dimethylformamide (15 ml) was stirred at room temperature for 1 day. After completion of the reaction, the solvent was distilled off, and the obtained residue was extracted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent 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 (δppm, 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, 3
H), 3.68 (m, 1H), 3.89 (m, 2H), 4.17 (s, 2H), 4.87 (s, 2
H), 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

Embedded image 1- (cyclohexylcarbamoylmethyl) -5-cyano-2- [1- (pyridin-4-yl) piperidine-4
-Ylaminomethyl] benzimidazole (203 m
g) and a solution of triethylamine (0.18 ml) in chloroform (5 ml) was added to ethyl oxalate (0.119 ml).
ml) and stirred at room temperature for 2 hours. After completion of the reaction, water was added, extracted with chloroform, and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was subjected to 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 (δppm, CDCl ₃ ) 1.04-1.36 (m, 6H), 1.39 (tr, J = 7.2
Hz, 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), 4.7
3 (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-carboxyamidine dihydrochloride

Embedded image 1- (cyclohexylcarbamoylmethyl) -5-cyano-2- [N- [1- (pyridin-4-yl) piperidin-4-yl] -N-ethoxylylaminomethyl] benzimidazole (205 mg), hydrogen sulfide, The title compound (87 mg) was obtained from methyl iodide (5 ml), ammonium acetate (138 mg) and sodium acetate (59 mg) in the same manner as in Step 8 of Example 38. ¹ H-NMR (δppm, 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), 7.76-7.7
5 (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 61 N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
Synthesis of-[1- (pyridin-4-yl) piperidin-4-yl] aminooxalic acid dihydrochloride

Embedded image 1- (cyclohexylcarbamoylmethyl) -2- [N
-[1- (Pyridin-4-yl) piperidin-4-yl] -N-ethoxalylaminomethyl] benzimidazole-5-carboxyamidine dihydrochloride (50 mg)
Was added to a methanol (1 ml) solution and a 2N aqueous solution of sodium hydroxide (0.107 ml) was added, followed by stirring for 10 minutes. After completion of the reaction, dilute hydrochloric acid was added, and the solvent was distilled off. The obtained residue was subjected to 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 (δppm, 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, 2
H), 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 62 2- [N- [4- (1-acetimidoylpiperidine-
Synthesis of 4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride Step 1 2- [4- (1-tert-butoxycarbonylpiperidine) -4-yloxy) phenylaminomethyl] -1-
(Cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole

Embedded image 4- (4-aminophenoxy) piperidine-1-carboxylic acid tert-butyl ester (8.21 g), 2-
Chloromethyl-1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (9.29 g),
A solution of diisopropylethylamine (9.8 ml) in dimethylformamide (93 ml) was stirred at 60 ° C. for 14 hours. After completion of the reaction, the residue obtained by distilling off the solvent was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Ethyl acetate and hexane were added to the obtained residue, and the resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (15.726 g). ¹ H-NMR (δppm, CDCl ₃ ) 0.75 (m, 2H), 0.97 (m, 1H), 1.23
(m, 2H), 1.46-1.73 (m, 16H), 1.85 (m, 2H), 3.27 (m, 2H),
3.65 (m, 3H), 4.28 (m, 1H), 4.61 (s, 2H), 4.90 (s, 2H), 5.
63 (d, 1H), 6.74 (d, J = 8.7Hz, 2H), 6.82 (d, J = 8.7Hz, 2H),
7.44 (d, J = 8.4Hz, 1H), 7.57 (dd, J = 1.2,8.4Hz, 1H), 8.10
(d, J = 1.2Hz, 1H)

Step 2 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) -5-cyanobenz Imidazole

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylaminomethyl] -1-
To a solution of (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (247 mg) in dimethylformamide (2.5 ml) was added potassium carbonate (175 m2).
g) and ethyl bromoacetate (0.07 ml), and the mixture was stirred at room temperature for 24 hours.
Ethyl bromoacetate (0.07 ml) was added and the mixture was added at room temperature for 24 hours.
Stirred for hours. Furthermore, ethyl bromoacetate (0.07m
l) was added and the mixture was stirred at room temperature for 24 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 residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (12
4 mg). ¹ H-NMR (δppm, CDCl ₃ ) 0.88-1.35 (m, 10H), 1.46 (s, 9H),
1.67 (m, 5H), 1.86 (m, 2H), 3.29 (m, 2H), 3.67 (m, 3H), 4.
01-4.07 (m, 4H), 4.32 (m, 1H), 4.69 (s, 2H), 4.93 (s, 2H),
6.50 (d, 1H), 6.81 (d, J = 9.1Hz, 2H), 6.88 (d, J = 9.1Hz, 2
H), 7.44 (1H), 7.54 (1H), 8.03 (1H)

Step 3 2- [N- [4- (1-acetimidoylpiperidine-
4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (247 mg), Hydrogen sulfide, methyl iodide (1m
l) and ammonium acetate (21 mg) in the same manner as in Step 8 of Example 38, to give 2- [N- [4- (1-tert)
-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine (47 mg)
I got Next, in the same manner as in Step 10 of Example 53,
The title compound (28 mg) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.17 (tr, J = 7.2 Hz, 3H), 1.10-1.
35 (m, 5H), 1.50-1.80 (m, 7H), 1.99 (m, 2H), 2.28 (s, 3H),
3.40-3.60 (m, 3H), 4.10 (q, J = 7.2Hz, 2H), 4.18 (m, 2H),
4.46 (m, 1H), 4.86 (s, 2H), 5.07 (s, 2H), 6.74 (d, J = 9.0H
z, 2H), 6.85 (d, J = 9.0Hz, 2H), 7.73 (1H), 7.80 (1H), 8.1
5 (1H), 8.47 (1H), 8.70 (1H), 9.04 (2H), 9.25 (1H), 9.31
(2H)

Example 63 N- [5-Amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
Synthesis of-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid Step 1 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N − (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
(Cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole

Embedded image 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylaminomethyl] -1-
To a solution of (cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (331 mg) and triethylamine (0.118 ml) in chloroform (10 ml) was added methyl 4-chloroformylbenzoate (112 m2).
g) and 4-dimethylaminopyridine (15 mg) were added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the residue obtained by evaporating the solvent was extracted with ethyl acetate, and washed sequentially with a 10% aqueous citric acid solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was washed with chloroform-diisopropyl ether, collected by filtration, and dried under reduced pressure to obtain the title compound (333 mg). ¹ H-NMR (δppm, CDCl ₃ ) 1.09-1.23 (m, 7H), 1.46 (s, 9H),
1.50-1.94 (m, 7H), 3.29 (m, 2H), 3.69 (m, 3H), 3.87 (s, 3
H), 4.36 (m, 1H), 5.07 (s, 2H), 5.25 (s, 1H), 6.38 (d, 1
H), 6.72 (d, J = 8.9Hz, 2H), 7.08 (d, J = 8.9Hz, 2H), 7.34
(d, J = 8.4Hz, 2H), 7.48 (d, J = 8.6Hz, 1H), 7.57 (dd, J = 1.2,
8.6Hz, 1H), 7.84 (d, J = 8.4Hz, 2H), 8.06 (d, J = 1.2Hz, 1H)

Step 2 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
(Cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
(Cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (333 mg), hydrogen sulfide, methyl iodide (0.277 ml), ammonium acetate (51 m)
From g), the title compound (201 mg) was obtained in the same manner as in Step 12 of Example 17. ¹ H-NMR (δppm, CDCl ₃ ) 1.08 (m, 3H), 1.23 (m, 2H), 1.46
(s, 9H), 1.52-1.80 (m, 7H), 1.86 (m, 2H), 3.29 (m, 2H),
3.67 (m, 3H), 3.87 (s, 3H), 4.36 (m, 1H), 5.07 (s, 2H), 5.
25 (s, 2H), 6.41 (d, 1H), 6.72 (d, J = 8.9Hz, 2H), 7.08 (d, J
= 8.9Hz, 2H), 7.34 (d, J = 8.3Hz, 2H), 7.47 (1H), 7.56 (1
H), 7.84 (d, J = 8.3Hz, 2H), 8.05 (1H)

Step 3 2- [N- [4- (piperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine Dihydrochloride

Embedded image 2- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (4-
Methoxycarbonylbenzoyl) aminomethyl] -1-
Trifluoroacetic acid (1 ml) was added to a chloroform (1 ml) solution of (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine (201 mg), and the mixture was stirred for 5 minutes. After the completion of the reaction, the solvent was distilled off, and a 1N hydrogen chloride-diethyl ether solution was added to the obtained residue. The obtained solid was collected by filtration and dried under reduced pressure to obtain the title compound (175 mg). ^{1 H-NMR (δppm, DMSO} -d 6) 1.21 (m, 5H), 1.50-1.84 (m, 7H),
2.00 (m, 2H), 2.99 (m, 2H), 3.14 (m, 2H), 3.53 (m, 1H),
3.81 (s, 3H), 4.52 (m, 1H), 5.18 (s, 2H), 5.35 (s, 2H), 6.
82 (d, J = 9.0Hz, 2H), 7.21 (d, J = 9.0Hz, 2H), 7.40 (d, J = 8.4
Hz, 2H), 7.75 (s, 2H), 7.79 (d, J = 8.4Hz, 2H), 8.19 (s, 1
H), 8.57 (d, 1H), 9.05 (brs, 2H), 9.10 (brs, 2H), 9.33 (b
rs, 2H)

Step 4 N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid

Embedded image 2- [N- [4- (piperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride (93 mg ) In methanol (1 ml)
An aqueous solution of N-sodium hydroxide (0.629 ml) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 1N-hydrochloric acid (0.377 ml) was added, the solvent was distilled off, and the residue was dried under reduced pressure to obtain a residue. The obtained residue was dissolved in methanol (2 ml), and triethylamine (0.175 ml) and ethylacetimidate hydrochloride (78 mg) were used.
In the same manner as in Step 1, the title compound (28 mg) was obtained as a white solid. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.20 (m, 5H), 1.46-1.60 (m, 7H),
1.96 (m, 2H), 2.27 (s, 3H), 3.35-3.60 (m, 3H), 4.57 (m, 1
H), 5.17 (s, 2H), 5.34 (s, 2H), 6.82 (d, J = 5.6Hz, 2H), 7.
20 (d, J = 5.6Hz, 2H), 7.37 (2H), 7.70-7.80 (m, 4H), 8.19
(s, 1H), 8.56 (1H), 8.75 (brs, 1H), 9.11 (brs, 2H), 9.33
(brs, 3H)

Example 64 2- [N- [4- (1-Amidinopiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole- Synthesis of 5-carboxyamidine dihydrochloride

Embedded image 2- [N- [4- (piperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride (220 mg ) Was dissolved in 10% methanol (2 ml), neutralized with an ion exchange resin (IRA-410), filtered, and the filtrate was concentrated. A solution of the residue obtained in dimethylformamide (2 ml) was added at room temperature to diisopropylethylamine. (0.053 ml), 1H-pyrazole-1-carboxamidine hydrochloride (44 mg) was added, and the mixture was stirred for 20 hours. After completion of the reaction, the residue obtained by distilling off the solvent was fractionated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid), dilute hydrochloric acid was added thereto, and the solvent was distilled off. The title compound (155 mg) was obtained. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.20 (m, 5H), 1.45-1.75 (m, 7H),
1.87 (m, 2H), 3.27 (m, 2H), 3.45-3.65 (m, 3H), 3.80 (s, 3
H), 5.16 (s, 2H), 5.33 (s, 2H), 6.80 (d, J = 9.0Hz, 2H), 7.
19 (d, J = 9.0Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 7.52 (brs, 4
H), 7.74 (s, 2H), 7.78 (d, J = 8.1Hz, 2H), 8.18 (s, 1H), 8.5
6 (d, 1H), 9.11 (brs, 2H), 9.32 (brs, 2H)

Example 65 N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-amidinopiperidin-4-yloxy)
Synthesis of phenyl] carbamoylbenzoic acid dihydrochloride

Embedded image 2- [N- [4- (1-amidinopiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonylbenzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine dihydrochloride Salt (130mg) in methanol (2m
1) Add 1N-sodium hydroxide aqueous solution (0.7 m
l) was added and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the residue obtained by distilling off the solvent was fractionated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid), dilute hydrochloric acid was added thereto, and the solvent was distilled off. The title compound (10
0 mg). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.19 (m, 5H), 1.45-1.75 (m, 7H),
1.90 (m, 2H), 3.27 (m, 2H), 4.51 (m, 1H), 5.17 (s, 2H),
5.33 (s, 2H), 6.80 (d, J = 5.7Hz, 2H), 7.18 (d, J = 5.7Hz, 2
H), 7.36 (2H), 7.52 (s, 4H), 7.74-7.77 (m, 4H), 8.18 (s,
1H), 8.55 (1H), 9.10 (brs, 2H), 9.32 (brs, 2H)

Example 66 N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
Synthesis of-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride Step 1 2- [4- [N- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylsulfonylaminomethyl] -1-
(Cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole

Embedded image To a solution of chlorosulfonylacetyl chloride (2 g) in chloroform (40 ml) was added ethanol (0.
696 ml) and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain a residue of chloroform (10%).
ml) solution with 2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenylaminomethyl] -1- (cyclohexylcarbamoylmethyl)
A solution of -5-cyanobenzimidazole (5.1 g) and pyridine (2.1 ml) in chloroform (88 ml) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water was added, extracted with chloroform, and washed sequentially with water and saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 7 → 2:
Purify in 8) and dry under reduced pressure to give the title compound (4.25 g)
I got ¹ H-NMR (δ ppm, CDCl ₃ ) 1.14-1.44 (m, 5H), 1.37 (tr, J = 7.2
Hz, 3H), 1.46 (s, 9H), 1.55-1.78 (m, 5H), 1.80-2.00 (m, 4
H), 3.32 (m, 2H), 3.65 (m, 2H), 3.77 (m, 1H), 4.10 (s, 2
H), 4.34 (q, J = 7.2Hz, 2H), 4.39 (m, 1H), 4.99 (s, 2H), 5.
21 (s, 2H), 6.04 (d, 1H), 6.84 (d, J = 8.9Hz, 2H), 7.32 (d, J
= 8.9Hz, 2H), 7.53 (s, 2H), 7.94 (s, 1H)

Step 2 N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride

Embedded image 2- [4- [N- (1-tert-butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethoxycarbonylmethylsulfonylaminomethyl] -1-
(Cyclohexylcarbamoylmethyl) -5-cyanobenzimidazole (3.34 g) in ethanol (33 m
1) Hydrochloric acid gas was blown into the solution under ice cooling, and the mixture was stirred at room temperature for 15 hours. The residue obtained by distilling off the solvent was dissolved in methanol (30 ml) and ethanol (33 ml), ammonium acetate (3.49 g) was added, and the mixture was stirred at room temperature for 15 hours. After the completion of the reaction, a 4N hydrogen chloride-dioxane solution (7.9 ml) was added, the resulting insolubles were removed, the solvent was distilled off, and the residue was dried under reduced pressure to obtain a residue. The obtained residue was dissolved in methanol (33 ml), and triethylamine (8.
1 ml), ethylacetimidate hydrochloride (4.48)
From g), the reaction was carried out in the same manner as in Step 1 of Example 29.
After completion of the reaction, insolubles were removed and the solvent was distilled off. To the residue obtained, 2N-hydrochloric acid (50 ml) was added, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the residue obtained by distilling off the solvent was purified by HP
Separation by LC (37-45% methanol-water, 0.05% trifluoroacetic acid), dilute hydrochloric acid was added, and the solvent was distilled off.
Drying under reduced pressure gave the title compound (1.76 g). ¹ H-NMR (δppm, DMSO-d ₆ ) 1.23 (m, 5H), 1.50-1.85 (m, 7H),
2.00 (m, 2H), 2.29 (s, 3H), 3.52 (m, 3H), 3.75 (m, 2H),
4.37 (s, 2H), 4.66 (m, 1H), 5.10 (s, 2H), 5.22 (s, 2H), 6.
97 (d, J = 8.9Hz, 2H), 7.42 (d, J = 8.9Hz, 2H), 7.72 (s, 2H),
8.13 (s, 1H), 8.57 (d, 1H), 8.82 (brs, 1H), 9.15-9.50 (5
H)

Example 67 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid methanesulfonate Synthesis of

Embedded image 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidine-4-carboxylic acid (10 g) is suspended in water (50 ml). Cloudy, methanesulfonic acid (1.6
ml) and heated to 50 ° C. to dissolve. Next, acetone (150 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and allowed to cool to room temperature. The precipitated crystals were collected by filtration to give the title compound (11.56 g). ¹ H-NMR (δppm, D ₂ O) 1.60 (m, 2H), 2.19 (m, 2H), 2.72 (s, 3
H), 2.77 (tr, J = 5.8Hz, 2H), 3.34 (m, 2H), 3.45 (tr, J = 5.8
Hz, 2H), 3.84-3.92 (m, 4H), 4.38 (s, 2H), 6.72 (s, 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 Examples 1 to 67, the compounds of Examples 68 to 115 were obtained. These are shown in Tables 1 to 8. Example 68 7- [1- (Pyridin-4-ylacetyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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, 2
H), 6.71 (s, 1H), 6.82 (d, J = 8.4Hz, 1H), 7.14 (d, J = 8.4H
z, 1H), 7.61 (brs, 4H), 7.90 (d, J = 6.6Hz, 2H), 8.83 (d, J =
(6.6Hz, 2H)

Example 69 7- [1- (3-Aminobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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 70 7- [1- (2-hydroxybenzyl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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 (1
H), 7.13 (1H), 7.26 (t, 1H), 7.46 (1H), 7.56 (brs, 4H),
9.94 (brs, 1H), 10.25 (brs, 1H)

Example 71 7- [1- (Pyridin-2-ylmethyl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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 = 8.4H
z, 1H), 7.55 (1H), 7.63 (brs, 4H), 7.69 (1H), 7.99 (1H),
8.74 (1H), 10.35 (brs, 1H)

Example 72 2- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-ylmethyl] indole-1-carboxylic acid methyl ester dihydrochloride ¹ H-NMR (δppm, 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, 2
H), 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 73 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Acetic acid benzyl ester dihydrochloride ¹ H-NMR (δppm, 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 (br
s, 1H)

Example 74 N-benzyl-4- (2-amidino-1,2,3,4-
Tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-carboxamide hydrochloride ¹ H-NMR (δppm, 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 = 6.4H
z, 1H), 7.00-7.31 (m, 6H), 7.61 (brs, 4H)

Example 75 7- [1- (Indol-2-ylmethyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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), 1
1.50 (s, 1H)

Example 76 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Acetic acid dihydrochloride ¹ H-NMR (δppm, 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 77 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, 4
H), 9.26 (tr, J = 5.8Hz, 1H), 9.97 (brs, 1H)

Example 78 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-
Ilacetylaminoacetic acid dihydrochloride ¹ H-NMR (δppm, 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, 4
H), 9.06 (m, 1H), 10.00 (brs, 1H)

Example 79 7- [1- (5-Nitropyridin-2-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride ¹ H-NMR (δppm, 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 = 9.6H
z, 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 80 7- [1- (2-Nitrobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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 (1
H), 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 81 7- [1- (2-Aminobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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), 7.1
3 (2H), 7.34 (1H), 7.51 (1H), 7.61 (4H)

Example 82 7- (1-hexaneimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 0.87 (tr, 3H), 1.31 (m, 6H), 1.5
2 (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 = 8.4
Hz, 1H), 7.64 (brs, 4H), 8.79 (1H), 9.25 (1H)

Example 83 N-benzyl-4- (2-amidino-1,2,3,4-
Tetrahydroisoquinolin-7-yloxymethyl) piperidine-1-sulfonamide hydrochloride ¹ H-NMR (δppm, 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 (d
d, 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 84 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, 6
H), 1.84 (m, 2H), 2.64 (m, 2H), 2.84 (m, 4H), 3.56 (m, 4
H), 3.81 (m, 2H), 4.53 (s, 2H), 6.69 (1H), 6.81 (m, 2H),
7.10-7.14 (m, 2H), 7.55 (brs, 4H)

Example 85 N-Cyclohexyl-4- (2-amidino-1,2,2
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, 2
H), 2.81 (m, 2H), 2.95 (m, 1H), 3.56 (m, 4H), 3.81 (m, 2
H), 4.53 (s, 2H), 6.70 (1H), 6.81 (1H), 7.13 (m, 2H), 7.
54 (brs, 4H)

Example 86 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), 7.3
4-7.42 (m, 2H), 7.55 (brs, 4H), 7.66 (1H), 7.94 (1H), 9.
62 (s, 1H)

Example 87 7- [1- (Benzimidazol-2-yl) piperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine 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, 2
H), 7.59 (brs, 4H), 13.46 (s, 2H)

Example 88 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 (δppm, DMSO-d ₆ ) 1.14 (tr, J = 7.2 Hz, 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 89 3- [4- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridin-3-yl] propionic acid Dihydrochloride ¹ H-NMR (δppm, 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, 4
H), 8.25 (m, 2H)

Example 90 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-aminopyridin-5-ylcarbonyl) piperidine-4-carboxylic acid Dihydrochloride ¹ H-NMR (δppm, 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 = 9.2H
z, 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 91 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (3-aminopropionyl) piperidine-4-carboxylic acid dihydrochloride ¹ H -NMR (δppm, 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, 2
H), 6.68 (s, 1H), 6.81 (d, J = 8.4Hz, 1H), 7.13 (d, J = 8.4H
z, 1H), 7.66 (brs, 4H), 7.98 (brs, 3H)

Example 92 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (imidazol-4-ylacetyl) piperidine-4-carboxylic acid dihydrochloride ¹ H-NMR (δppm, 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, 2
H), 6.70 (s, 1H), 6.81 (d, J = 8.6Hz, 1H), 7.14 (d, J = 8.6H
z, 1H), 7.43 (s, 4H), 7.55 (s, 1H), 7.62 (brs, 4H), 9.01
(s, 1H), 14.36 (brs, 1H)

Example 93 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (piperidin-4-ylsulfamoyl) piperidine-4-carboxylic acid hydrochloride ¹ H-NMR (δppm, 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 94 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1-dimethylaminoacetylpiperidine-4-carboxylic acid dihydrochloride ¹ H-NMR ( δppm, 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, 3
H), 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 95 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-3-ylcarbamoyl) piperidine-4-carboxylic acid ethyl ester Hydrochloride ¹ H-NMR (δppm, DMSO-d ₆ ) 1.16 (tr, J = 6.9 Hz, 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 = 6.9
Hz, 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 96 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, 10
H), 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 (1
H), 7.14 (1H), 7.58 (brs, 4H), 9.65 (brs, 1H)

Example 97 4- [4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -4-carboxypiperidin-1-yl] -1-methylpyridinium chloride hydrochloride Salt ¹ H-NMR (δppm, DMSO-d ₆ ) 1.15 (tr, J = 7.2 Hz, 3H), 1.72 (m,
2H), 2.17 (m, 2H), 2.81 (m, 2H), 3.40 (m, 2H), 3.57 (m, 2
H), 3.89 (s, 3H), 4.00-4.07 (m, 4H), 4.14 (q, J = 7.2Hz, 2
H), 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 98 Ethyl 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (4-amidinophenyl) piperidine-4-carboxylate dihydrochloride ¹ H-NMR (δppm, DMSO-d ₆ ) 1.14 (tr, J = 6.9 Hz, 3H), 1.69 (m,
2H), 2.14 (m, 2H), 2.81 (m, 2H), 3.14 (m, 2H), 3.56 (m, 2
H), 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
H), 8.97 (brs, 2H)

Example 99 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2,6-
Dimethylpyridin-4-yl) piperidine-4-carboxylic acid ethyl ester dihydrochloride ¹ H-NMR (δppm, DMSO-d ₆ ) 1.16 (tr, J = 7.0 Hz, 3H), 1.71 (m,
2H), 2.17 (m, 2H), 2.44 (m, 6H), 2.82 (m, 2H), 3.56 (m, 2
H), 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
H), 7.15 (d, J = 8.3Hz, 1H), 7.59 (brs, 4H), 13.41 (brs, 1H
H)

Example 100 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 (δppm, DMSO-d ₆ ) 1.17 (tr, J = 7.0 Hz, 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 101 Ethyl 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylate Ester trihydrochloride ¹ H-NMR (δppm, 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, 2
H), 4.16 (q, 2H), 4.53 (s, 2H), 6.71 (1H), 6.82 (1H), 7.
14 (1H), 7.57 (brs, 4H)

Example 102 4- (2-Amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid Hydrochloride ¹ H-NMR (δppm, DMSO-d ₆ ) 1.25 (tr, 3H), 2.00-2.45 (m, 10
H), 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 103 7- [2- (4-Cyanopiperidin-4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-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)
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 104 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 (δppm, DMSO-d ₆ ) 1.19 (tr, J = 7.1 Hz, 3H), 1.62 (m,
2H), 2.05 (m, 2H), 2.20 (m, 2H), 2.82 (m, 2H), 3.27 (m, 2
H), 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 (1
H), 7.19 (d, J = 7.6Hz, 2H), 7.60 (brs, 4H), 8.22 (d, J = 7.6H
(Hz, 2H)

Example 105 4- (2-amidino-6-methoxy-1,2,3,4-
Tetrahydroisoquinolin-7-yloxymethyl)-
1- (pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride ¹ H-NMR (δppm, 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 106 4- (2-Amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1
-(Pyridin-4-yl) piperidine-4-carboxylic acid dihydrochloride ¹ H-NMR (δppm, 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 107 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -1-benzylbenzimidazole-5-carboxyamidine dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.70 (m, 2H), 2.00 (m, 2H), 2.29
(s, 3H), 3.52 (m, 2H), 3.73 (m, 2H), 4.56 (m, 1H), 5.42 (s,
2H), 5.69 (s, 2H), 6.93 (s, 4H), 7.17 (d, 2H), 7.28-7.33
(m, 3H), 7.71 (s, 2H), 8.23 (s, 1H), 8.77 (brs, 1H), 9.12
(brs, 2H), 9.31-9.32 (m, 3H)

Example 108 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -1- (3-oxo-3
-Piperidinopropyl) benzimidazole-5-carboxyamidine dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.30 (m, 4H), 1.49 (m, 2H), 1.70
(m, 2H), 1.99 (m, 2H), 2.27 (s, 3H), 2.90 (brtr, 2H), 3.21
(brtr, 2H), 3.34 (m, 2H), 3.53 (m, 2H), 4.60 (m, 3H), 5.4
7 (s, 2H), 6.96 (d, J = 9.0Hz, 2H), 7.04 (d, J = 9.0Hz, 2H),
7.75 (d, J = 8.4Hz, 1H), 7.91 (d, J = 8.4Hz, 1H), 8.23 (s, 1
H), 9.01 (brs, 2H), 9.25 (brs, 1H), 9.30 (brs, 2H)

Example 109 N- [5-amidino-1- (3-phenyl-2-propenyl) benzimidazol-2-ylmethyl] -N-
[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.61 (m, 2H), 1.92 (m, 2H), 2.25
(s, 3H), 3.35-3.50 (m, 2H), 3.60-3.83 (m, 2H), 5.24 (s, 2
H), 5.41 (s, 2H), 6.40-6.60 (m, 2H), 6.82 (2H), 7.20-7.3
8 (m, 9H), 7.73-7.76 (m, 3H), 7.87 (1H), 8.24 (s, 1H), 8.
74 (brs, 1H), 9.10 (brs, 2H), 9.29 (brs, 3H)

Example 110 N- [5-Amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- [1- [Amino (benzylimino) methyl] piperidin-4-yloxy] phenyl] carbamoylbenzoic acid dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.19 (m, 5H), 1.43- 1.75 (m, 7H),
1.89 (m, 2H), 3.32 (m, 2H), 4.45 (d, 2H), 4.52 (m, 1H),
5.16 (s, 2H), 5.32 (s, 2H), 6.80 (d, J = 5.7Hz, 2H), 7.18 (d,
J = 5.7Hz, 2H), 7.25-7.38 (m, 7H), 7.70-7.78 (m, 6H), 8.1
8 (s, 1H), 8.41 (m, 1H), 8.56 (d, 1H), 9.11 (brs, 2H), 9.3
2 (brs, 2H)

Example 111 N- [5-Amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.21 (m, 5H), 1.45-1.80 (m, 5H ),
5.18 (s, 2H), 5.40 (s, 2H), 6.98 (m, 4H), 7.35-7.42 (m, 4
H), 7.75 (s, 2H), 7.82 (m, 4H), 8.20 (s, 1H), 8.61 (brd, 1
H), 9.13 (m, 4H), 9.32 (brs, 4H)

Example 112 N- [5-Amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- [1- (N-ethylamidino) piperidine-4
-Yloxy] phenyl] carbamoylbenzoic acid dihydrochloride ¹ H-NMR (δppm, DMSO-d ₆ ) 1.07-1.20 (m, 8H), 1.42-1.75
(m, 7H), 1.87 (m, 2H), 3.15-3.35 (m, 4H), 4.50 (m, 1H),
5.20 (s, 2H), 5.36 (s, 2H), 6.80 (2H), 7.18 (2H), 7.39 (2
H), 7.62-7.85 (m, 7H), 8.18,8.20 (1H), 8.55,8.65 (1H),
9.09,9.19,9.32,9.38 (4H)

Example 113 1- (Cyclohexylcarbamoylmethyl) -2- [4
-Methoxycarbonyl-1- (pyridin-4-yl) piperidin-4-ylaminomethyl] benzimidazole-5-carboxyamidine 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, 1
H), 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, 2
H), 9.23 (brs, 2H), 13.38 (brs, 1H)

Example 114 1- (Cyclohexylcarbamoylmethyl) -2- [4
-Methoxycarbonyl-1- (pyridin-4-yl) piperidin-4-ylcarbamoyl] benzimidazole-5-carboxyamidine 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), 3.41-3.6
2 (m, 6H), 3.95 (m, 2H), 5.32 (s, 2H), 7.23 (2H), 7.80 (1
H), 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) Example 115 (S) -N- [5-amidino-1-[(1-phenylethyl) carbamoylmethyl] benzimidazole-2-
Ilmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.41 (d, 3H), 1.70 (m, 2H), 2.00
(m, 2H), 2.28 (s, 3H), 3.50 (m, 2H), 3.72 (m, 2H), 4.37 (s,
2H), 4.66 (m, 1H), 4.90 (m, 1H), 5.19 (brs, 4H), 6.95 (2
H), 7.18-7.42 (m, 7H), 7.71 (s, 2H), 8.12 (s, 1H), 8.78
(brs, 1H), 9.09 (brs, 2H), 9.18 (brd, 1H), 9.30-9.33 (3
H)

[0399]

[Table 1]

[0400]

[Table 2]

[0401]

[Table 3]

[0402]

[Table 4]

[0403]

[Table 5]

[0404]

[Table 6]

[0405]

[Table 7]

[0406]

[Table 8]

[Test Example] Next, the biological activity of the compound of the present invention was tested. As a control compound, (2S)
-2- [4-[(3S) -1-acetimidoylpyrrolidin-3-yloxy] phenyl] -3- [7-amidinonaphthalen-2-yl] propionic acid hydrochloride pentahydrate

Embedded image Comparative Example 1 was used to compare with the compound of the present invention. Enzyme inhibition experiments using synthetic substrates (Test Examples 1-2)

Test Example 1 Measurement of Anti-Factor Xa (FXa) Activity 0.1 M Tris (Tris-h) containing 0.2 M sodium chloride
ydroxymethyl-aminomethane) buffer (pH 8.4)
(Hereinafter referred to as 0.1 Mtris-0.2 M NaCl buffer.) 40 μl of human FXa at a concentration of 0.16 U / ml
[Enzyme Research Laboratory (USA)] 40 µl of the enzyme and 40 µl of the test compound prepared at each concentration were added to 3 parts.
After incubation at 7 ° C. for 10 minutes, 40 μl of a synthetic substrate S-2222 (Daiichi Pure Chemicals) adjusted to 0.8 mM was added, and the mixture was incubated at 37 ° C. for 10 minutes. The reaction was stopped by adding 40 μl of 60% acetic acid and measuring the absorbance at 405 nm. The measurement was performed using 3550 of BIO-RAD company model.
As a control, a compound using a solvent was used instead of the test compound. The control was taken as 100%, and the drug concentration showing 50% absorbance of the control was taken as the IC ₅₀ value.
Table 9 shows the results.

Test Example 2 Measurement of Anti-Factor IIa (FIIa) Activity 0.1 M Tris-0.2 M NaCl buffer (pH 8.
4) A concentration of 3.2 U / ml human FIIa (sigm
a) 40 μl of enzyme and test compound 40 prepared at each concentration
After incubating μl at 37 ° C. for 10 minutes, 0.8 μm
M prepared synthetic substrate S-2238 (Daiichi Pure Chemicals)
and incubated at 37 ° C. for 20 minutes. The reaction was stopped by adding 40 μl of 60% acetic acid and measuring the absorbance at 405 nm. The measurement was performed using 3550 of BIO-RAD company model. As a control, a compound using a solvent was used instead of the test compound. The control was taken as 100%, and the drug concentration showing the absorbance of 50% of the control was taken as the IC ₅₀ value (μM). Table 9 shows the results.

[0410]

[Table 9]

Test Example 3 Measurement of Prothrombin Time (PT) Citrate blood was collected from mice, rats, cynomolgus monkeys, and healthy volunteers, and centrifuged at 4 ° C. and 2000 G for 15 minutes to obtain normal plasma from various animals. Plasma 45μl
To which 5 μl of purified water containing various concentrations of the test compound was added to prepare a sample. Thrombin reagent (Baxter)
After heating at 37 ° C. for 5 minutes, thrombin reagent 1 was prepared.
50 μl of the sample was mixed with 00 μl, and the time until fibrin precipitation (PT) was measured. The drug concentration to prolong the PT time of the drug untreated group doubling was calculated as CT _2.
Table 10 shows the results.

[0412]

[Table 10]

Intravenous Administration Test (Test Examples 4 to 5) Test Example 4 Intravenous Administration Test in Mice Test compounds dissolved in physiological saline were intravenously administered to ICR mice (body weight 20 to 30 g, 4 to 6 weeks old). After that, the activity of the test compound was evaluated using the human FXa inhibitory activity in the serum as an index. At 10, 30, 60 and 120 minutes after intravenous administration, blood was collected from the fundus using a hematocrit tube, and 900
The serum obtained by centrifugation at 0 G for 5 minutes was used for the measurement. The measurement of human FXa inhibitory activity was performed by the following method. 0.1M
tris-0.2 M NaCl buffer (pH 8.4) 40
40 μl of a 0.5 U / ml concentration of human FXa [Enzyme Research Laboratory (USA)] enzyme and 40 μl of a 4-fold diluted preparation of a plasma sample were added at 37 ° C.
After 10 minutes incubation, 40 μl of a synthetic substrate S-2222 (Daiichi Pure Chemicals) adjusted to 0.8 mM was added.
Incubated at 5 ° C for 5 minutes. The reaction was stopped by adding 40 μl of 60% acetic acid and measuring the absorbance at 405 nm. The measurement was performed using 3550 of BIO-RAD company model. The control was measured using serum or plasma obtained by blood collection in advance, and the human FXa inhibitory activity was the inhibition rate (%) relative to the control.
Was calculated. Table 11 shows the results.

[0414]

[Table 11]

Test Example 5 Intravenous Administration Test in Monkeys A test compound dissolved in physiological saline was intravenously administered to monkeys (cynomolgus monkey, body weight 3.5 to 4.5 kg), and the human FXa inhibitory activity in plasma was measured. The activity of the test compound was evaluated. Intravenous administration 10, 30, 60, 120, 18
0 minutes later, blood was collected from the saffener vein with time, and 2000 times.
G and centrifugation for 10 minutes to obtain citrated plasma, which was used for measurement. The measurement of the human FXa inhibitory activity was performed in the same manner as in the mouse. Table 12 shows the results.

[0416]

[Table 12]

Oral Administration Test (Test Examples 6 to 7) Test Example 6 Mouse Oral Administration Test To an ICR mouse (body weight: 20 to 30 g, 4 to 6 weeks old), a test compound dissolved in distilled water was orally administered, and then serum The activity of the test compound was evaluated using the human FXa inhibitory activity as an index. 30, 60, 120, and 180 minutes after oral administration, blood was collected from the fundus using a hematocrit tube, and 9000 G,
The serum obtained by centrifugation for 5 minutes was used for the measurement. Human FX
a The inhibitory activity was measured in the same manner as in the case of intravenous administration. Table 13 shows the results.

[0418]

[Table 13]

Test Example 7 Oral Administration Test of Monkeys A test compound dissolved in distilled water was orally administered to monkeys (cynomolgus monkey, body weight 3.5 to 4.5 kg), and the test compound was evaluated using human FXa inhibitory activity in plasma as an index. Was evaluated for activity. At 30, 60, 120, 240, and 480 minutes after oral administration, blood was collected over time from the safener vein, and 2000 G,
Centrifugation was performed for 10 minutes to obtain citrated plasma, which was used for measurement. The human FXa inhibitory activity was measured in the same manner as in the case of intravenous administration. Table 14 shows the results.

[0420]

[Table 14]

Test Example 8 Blood Coagulation Model Using Rats Thromboplastin (sigm
Intravenous administration of (company a) promotes the coagulation system, reduces platelet count and increases fibrin degradation product (FDP). Therefore, the test compound was intravenously administered 10 minutes before the administration of thromboplastin, and the inhibitory effects of thromboplastin on platelet reduction and FDP production were examined.
The concentration of thromboplastin to be administered was such that adding 1 dose of plasma to 2 doses of thromboplastin produced a clot within 20 seconds and administered at a dose of 1 ml / kg.
After 10 minutes, the platelet count (PLT value) is
The FDP was measured 30 minutes later using an FDP latex reagent for serum (Imperial Organs) using a smexF-800 (Toa Medical Electronics). Table 15 shows the results. In each example, the PLT value of the group not treated with thromboplastin was (106 ± 1).
3) × 10 ⁴ and the FDP value was 0 ± 0 μg / ml.

[0422]

[Table 15]

[0423]

The compound represented by the general formula [I] according to the present invention has excellent blood coagulation factor Xa inhibitory activity, as is clear from the above Test Examples. Therefore, various diseases caused by blood coagulation and thrombus, such as cerebral infarction,
Diseases in cerebrovascular disorders such as cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), subarachnoid hemorrhage, ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis,
Diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial embolism, deep vein thrombosis, general intravascular coagulation syndrome, thrombosis after vascular prosthesis or valve replacement, and after coronary artery bypass surgery Restenosis or restenosis, percutaneous transluminal coronary angioplasty (PTCA) or coronary thrombolysis (PTC
Reocclusion or restenosis after revascularization therapy such as R),
Diseases in various vascular disorders such as thrombosis during extracorporeal circulation, glomerulonephritis, nephrotic syndrome, diabetic retinopathy,
It is considered to be effective in preventing and / or treating obstructive arteriosclerosis, Buerger's disease, tumor thrombosis, thrombus associated with atrial fibrillation, and the like. Therefore, it is expected to be a very useful therapeutic agent for these diseases.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/506 A61K 31/506 A61P 7/02 A61P 7/02 9/00 9/00 43/00 43/00 C07D 401/04 C07D 401/04 401/12 401/12 403/12 403/12 417/06 417/06 (56) References J.I. Heterocycl. Chem. , 33 (4), p. 1393-7 J.C. Med. Chem. , 21 (7), p. 613-23 Bioorg. Khim. , 20 (6), p. 650-68 Chemical Abstracts, vol. 104, abstracts no. 101983 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 401/14 C07D 401/04 C07D 401/12 C07D 403/12 C07D 417/06 CA (STN) REGISTRY (STN)

Claims (14)

(57) [Claims] 1. A compound of the general formula [I] Wherein R is [Where R ⁴ is a hydrogen atom, a hydroxyl group, a lower alkyl group,
Represents a lower alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom, a cyano group, a carboxy group or a lower alkoxycarbonyl group, R ⁶ represents a hydrogen atom, a cycloalkyl group,
Hydroxyl group, carboxy group, lower alkoxycarbonyl group,
An aralkyloxycarbonyl group (the aralkyloxycarbonyl group is a halogen atom, a nitro group, an alkyl group,
Optionally substituted with an alkoxy group or a trifluoromethyl group), a nitro group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an aryl group, a heteroaryl group (the aryl or heteroaryl group is Alkyl group, hydroxyl group, lower alkoxy group, carboxy group,
A lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a nitro group, an amino group, an acylamino group, an amidino group or a substituent selected from a hydroxyamidino group;
Or 3 may be substituted. ) A 5- to 7-membered saturated heterocyclic ring containing at least one nitrogen atom (the saturated heterocyclic ring may be substituted by a lower alkyl group, an acyl group, a di-lower alkylamino lower alkanoyl group or an imidoyl group) ) Or (Where Ak represents a lower alkyl group, Hal represents a halogen atom), X ² represents an oxygen atom, a sulfur atom, —SO ₂ —, —SO ₂ NH—, or a single bond;
³ _{- (CH 2) m - (} . Here, m represents an integer of 0 or 1 to 3) represent, X ⁴ is -CO-, -C (= N
_{H) -, -SO 2 -,} -CONH-, -CSNH-, -SO 2 NH-, - (CH 2) r C
_{ONH-, - (CH 2) r} CH (OH) -, ## STR4 ## (Where r represents 0 or an integer of 1 to 3) or a single bond; X ⁵ represents an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or a single bond; ⁷
Is a hydrogen atom, a lower alkyl group or ｛Where R ⁹ is an oxygen atom, a sulfur atom, an NH group, NR
¹¹ [where R ¹¹ is a lower alkyl group, an aralkyl group (the aralkyl group is a halogen atom, a lower alkyl group,
A hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, an acyloxy group, which may be substituted by 1 to 3) or a hydroxyl group. R ¹⁰ represents a lower alkyl group, a lower alkoxy group, an amino group, a lower alkylamino group or a di-lower alkylamino group . Represents}, R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group (the cycloalkyl group may be substituted with a lower alkyl group or a carboxy group),
A carboxy group, a lower alkoxycarbonyl group, an aryl group, a heteroaryl group; the aryl group or the heteroaryl group is a halogen atom, a lower alkyl group (the lower alkyl group may be substituted with a halogen atom), a hydroxyl group,
It may be mono- to tri-substituted with a substituent selected from a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group. An aralkyl group (the aralkyl group is a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a haloalkyl group , A cyano group, a nitro group, an amino group, may be substituted with 1 to 3 substituents selected from an acyloxy group), or a 5- to 7-membered saturated heterocyclic ring containing at least one nitrogen atom, Y ¹ is an oxygen atom or —NR ¹² — where R ¹² is —Y ⁶ —R ^13, wherein R ¹³ is a hydrogen atom, a lower alkyl group or an aryl group (the lower alkyl group or the aryl group is Group,
Y ⁶ may be substituted with a lower alkoxycarbonyl group or an aralkyloxycarbonyl group).
, -CO _2- , -COCO _2- , -SO _2-
, —SO ₂ (CH ₂ ) _r − or — (CH ₂ ) _r − (where,
r represents 0 or an integer of 1 to 3. ). Represents｝. > Represents, Y ² is an oxygen atom, a sulfur atom or a single bond, Y ³ is embedded image (Where s and t are the same or different and are 1 to 3
Represents an integer. ) Or a single bond, and Y ⁴ is an oxygen atom, —CO—, —CO ₂ —, —SO ₂ —, —CO
NH-, represents -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 (Where Ak and Ak ′ are the same or different and each represent a lower alkyl group, p represents 0 or an integer of 1 to 3,
p ′ and p ″ are the same or different and are 0 or 1 to 2
Represents an integer. Wherein ring A is Here, R ¹⁴ is a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group (the aralkyloxycarbonyl group may be substituted with a halogen atom, a nitro group, an alkyl group, an alkoxy group or a trifluoromethyl group) Represents Represents j, j represents 1 or 2, k represents 0 or 1, m and n are the same or different, and each represents 0 or an integer of 1 to 3. However, at the same time, R ⁸
Is a hydrogen atom, Y ⁴ is a single bond, Y ⁵ is — (CH ₂ ) _p −, except that p represents 0 and n represents 0. ], R ¹ ,
R ² and R ³ are the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkyl group or an aryl group. Or a salt thereof. 2. In the general formula [I], R is The amidine compound according to claim 1, wherein R ⁴ , R ⁵ , R ⁶ , X ² , X ³ , X ⁴ , X ⁵ , j and k each have the same meaning as described above . 3. In the general formula [I], R is The amidine compound according to claim 2, wherein R ⁴ , R ⁵ , R ⁶ , X ² , X ³ , X ⁴ , X ⁵ , j and k have the same meanings as described above . 4. In the general formula [I], R is Amidine compound or a salt thereof according to claim ^{3 (R 4, R 5,} R 6, X 2, X 3, X 4, X 5, j, k represent. The same as defined above, respectively) is. 5. In the general formula [I], X ³ is — (CH ₂ )
_m − (m represents the same meaning as described above), and X ⁴ represents 5. The compound according to claim 4, wherein j is 1, or a salt thereof. 6. The amidine compound or a salt thereof according to claim ⁵ , wherein in the general formula [I], R ⁶ is a hydrogen atom, X ² is an oxygen atom, and X ⁵ is a single bond . 7. In the general formula [I], R is (R ⁷ , R ⁸ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , ring A,
m and n each have the same meaning as described above. The amidine compound or a salt thereof according to claim 1, wherein 8. In the general formula [I], the ring A is The amidine compound or a salt thereof according to claim 7, which is: 9. 9- [1- (pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (quinoline-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-tetrahydroisoquino 2-carboxyamidine, 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) piperidin-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) piperidin-4-carboxylic acid, 4- [N- [5-amidino-1- (1-phenylethylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N- [4- (1- Acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl] benzoic acid, 4- [N- [5-amidino-1- (4-benzyloxyphenylcarbamoylmethyl) benzimidazole-2]
-Ylmethyl] -N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoyl]
Benzoic acid, 2- [4- (pyrrolidin-3-yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine, 2- [4- (1-acetimidoylpyrrolidine-3-) Yloxy) phenoxymethyl] -1- (2-methoxyethyl) benzimidazole-5-carboxyamidine, 7- [1- (2-hydroxyethyl) piperidine-4-
Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-4-ylmethyl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (2-hydroxy-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4 -Tetrahydroisoquinoline-2-carboxyamidine, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-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) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-
2-carboxyamidine, 7- (1-phenylacetimidoylpiperidine-4-
Ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N- [2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine -1-yl] pyridin-5-yl] acetamide, N- [2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine -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) piperidine-1- Methyl] 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-carboxyamidine, 7- [2- [4-cyano-1- (pyridine) -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- (pyridine-
4-yl) piperidin-4-carboxylic acid, 4- [2- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridin-4-yl) piperidin- 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) piperidin-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) piperidin-4-carboxylic acid, 1- [2- (benzothiazol-2-yl) -2-oxoethyl] -2-phenoxymethylbenzimidazole-5-carboxyamidine, trans-4- [ 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
Amidinobenzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
(N-methylamidino) benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, trans-4- [2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -5-
[Amino (hydroxyimino) methyl] benzimidazol-1-ylacetylaminomethyl] cyclohexanecarboxylic acid, 2- [4- (piperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine, 2- [4- (1-acetimidoylpiperidin-4-yloxy) phenoxymethyl] -1-phenacylbenzimidazole-5-carboxyamidine, 2- [2- [4-ethoxycarbonyl-1- (pyridine-4) -Yl) piperidin-4-yl] ethyl] -1-
(Cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine, 4- [2- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-yl] ethyl] -1- (pyridin-4-yl) piperidine -4-carboxylic acid, 1- (cyclohexylcarbamoylmethyl) -2- [N
-[1- (pyridin-4-yl) piperidin-4-yl] -N-ethoxalylaminomethyl] benzimidazole-5-carboxyamidine, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazole- 2-ylmethyl] -N
-[1- (pyridin-4-yl) piperidin-4-yl] aminooxalic acid, 2- [N- [4- (1-acetimidoylpiperidin-
4-yloxy) phenyl] -N-ethoxycarbonylmethylaminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazole-2- Ylmethyl] -N
-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] carbamoylbenzoic acid, 2- [N- [4- (1-amidinopiperidin-4-yloxy) phenyl] -N- (4-methoxycarbonyl Benzoyl) aminomethyl] -1- (cyclohexylcarbamoylmethyl) benzimidazole-5-carboxyamidine, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-amidinopiperidin-4-yloxy)
Phenyl] carbamoylbenzoic acid, N- [5-amidino-1- (cyclohexylcarbamoylmethyl) benzimidazol-2-ylmethyl] -N
-[4- (1-acetimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid, 7- [1- (pyridin-4-ylacetyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline -2-carboxyamidine, 7- [1- (3-aminobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (2-hydroxybenzyl) ) Piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-2-ylmethyl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine- 1-ylmethyl] indole-1-carboxylic acid methyl 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) piperidine-1-
Ylacetylaminoacetic acid, 7- [1- (5-nitropyridin-2-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (2 -Nitrobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinolin-2-carboxyamidine, 7- [1- (2-aminobenzyl) piperidin-4-ylmethoxy] -1,2,3 , 4-tetrahydroisoquinoline-2-carboxyamidine, 7- (1-hexaneimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 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-1,2,2,
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-carboxyamidine, 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] propion Acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-aminopyr -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-methyl Pyridinium 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-methylpyridine-4 -Yl) piperidine-4-carboxylic acid
Ethyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid ethyl ester, 4 -(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid, 7- [2- (4 -Cyanopiperidin-4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxyamidine, 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-1,2,2,
3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-
A compound selected from carboxylic acids or a salt thereof. 10. 7- [1- (Pyridin-4-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (quinoline-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-tetrahydroisoxyl Phosphorus-2-carboxyamidine, 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) piperidin-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) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (2-hydroxy-2-phenylethyl) piperidin-4-ylmethoxy] -1,2,3,4 -Tetrahydroisoquinoline-2-carboxyamidine, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine-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) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- (1-acetimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-
2-carboxyamidine, 7- (1-phenylacetimidoylpiperidine-4-
Ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, N- [2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine -1-yl] pyridin-5-yl] acetamide, N- [2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidin-1-yl] pyridine -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) piperidine-1- Methyl] 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-carboxyamidine, 7- [2- [4-cyano-1- (pyridine) -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- (pyridine-
4-yl) piperidin-4-carboxylic acid, 4- [2- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio) ethyl] -1- (pyridin-4-yl) piperidin- 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) piperidin-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) piperidin-4-carboxylic acid, 7- [1- (pyridin-4-ylacetyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7 -[1- (3-aminobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (2-hydroxybenzyl) piperidine-4
-Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 7- [1- (pyridin-2-ylmethyl) piperidine-
4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, 2- [4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) piperidine- 1-ylmethyl] indole-1-carboxylic acid methyl 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) piperidine-1-
Ylacetylaminoacetic acid, 7- [1- (5-nitropyridin-2-yl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 7- [1- (2 -Nitrobenzyl) piperidin-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinolin-2-carboxyamidine, 7- [1- (2-aminobenzyl) piperidin-4-ylmethoxy] -1,2,3 , 4-tetrahydroisoquinoline-2-carboxyamidine, 7- (1-hexaneimidoylpiperidin-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxyamidine, 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-1,2,2,
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-carboxyamidine, 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] propion Acid, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (2-aminopyr -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-methyl Pyridinium 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-methylpyridine-4 -Yl) piperidine-4-carboxylic acid
Ethyl ester, 4- (2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid ethyl ester, 4 -(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (1-ethylpiperidin-4-yl) piperidin-4-carboxylic acid, 7- [2- (4 -Cyanopiperidin-4-yl) ethoxy] -1,2,3,4-tetrahydroisoquinoline-2
-Carboxyamidine, 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-1,2,2,
3,4-tetrahydroisoquinolin-7-yloxymethyl) -1- (pyridin-4-yl) piperidin-4-
The compound according to claim 3, which is selected from carboxylic acids, or a salt thereof. 11. A pharmaceutical composition comprising the amidine compound or a salt thereof according to any one of claims 1 to 10 , and a pharmaceutically acceptable additive. 12. A blood coagulation inhibitor comprising the amidine compound or a salt thereof according to any one of claims 1 to 10 as an active ingredient. 13. A factor Xa inhibitor comprising the amidine compound or a salt thereof according to any one of claims 1 to 10 as an active ingredient. 14. A therapeutic agent for a disease caused by blood coagulation or thrombus, comprising an amidine compound or a salt thereof according to any one of claims 1 to 10 as an active ingredient.