MXPA00003175A

MXPA00003175A - Sulfonyl derivatives

Info

Publication number: MXPA00003175A
Application number: MXPA/A/2000/003175A
Authority: MX
Inventors: Shozo Kobayashi; Satoshi Komoriya; Masayuki Ito; Tsutomu Nagata; Akiyoshi Mochizuki; Noriyasu Haginoya; Takayasu Nagahara; Haruhiko Horino
Original assignee: Daiichi Pharmaceutical Co Ltd
Priority date: 1997-09-30
Filing date: 2000-03-30
Publication date: 2001-12-13

Abstract

Sulfonyl derivatives represented by general formula (I), salts of the same, and solvates of both;and application of them as drugs:[wherein R1 is hydrogen, hydroxyl, nitro or the like;R2 and R3 are each independently hydrogen, halogeno or the like;R4 and R5 are each independently hydrogen, halogeno or the like;Q1 is an optionally substituted saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or the like;Q2 is a single bond, oxygen or the like;Q3 is, e.g., a group represented by formula (a);T1 is carbonyl or the like;and X1 and X2 are each independently methylidyne or nitrogen]. These compounds exhibit potent Fxa inhibiting activities and serve as excellent anticoagulants which speedily exert satisfactory and persistent anti-thrombotic effects through oral administration and little cause adverse effects.

Description

SULFONYL DERIVATIVES TECHNICAL FIELD The present invention relates to a novel sulphonyl derivative, or a salt thereof, which can be administered orally and which inhibits an activated coagulation factor (which will be abbreviated hereafter as "FXa"), which is why it exhibits strong anticoagulant action; and a coagulation or prophylactic suppressant and / or remedy for thrombosis or embolism, which comprises the derivative or salt as an effective ingredient.

BACKGROUND OF THE INVENTION Exacerbation of coagulation capacity is an important factor of unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after of valve replacement, reocclusion after revascularization or thrombus formation by extracorporeal circulation. Consequently, there is a demand for an excellent anticoagulant that is very good in dose-response, has long-lasting effects, has a low risk of bleeding, has fewer side effects and exhibits rapid and sufficient effects even by oral administration (Thrombosis Research , 68, 507-512, 1992). Studies on anticoagulants based on various mechanisms of action suggest that an FXa inhibitor has the potential to be an excellent anticoagulant. The coagulation system is a series of reactions in which a large number of thrombi are produced by an amplification step by a multistage enzymatic reaction and induces the formation of insoluble fibrin. In the intrinsic system, after the multi-step reaction following the activation of a contact factor, activated Factor IX activates Factor X on a phospholipid membrane in the presence of activated Factor VIII and a calcium ion; whereas in the extrinsic system, activated Factor Vl activates Factor X in the presence of a tissue factor. In other words, the activation of factor X in FXa in the coagulation system is an essential reaction in the formation of thrombin. The activated Factor X (FXa) in each system carries out limited prothrombin proteolysis thereby forming thrombin. The resulting thrombin activates the coagulation factors in their initial part, thereby further increasing the formation of thrombin. As described above, the initial FXa coagulation system is separated into intrinsic and extrinsic systems such that inhibition of the enzyme from the initial FXa coagulation system does not suppress FXa production sufficiently, resulting in the inevitable production of thrombin. In addition, coagulation occurs as a self-amplification reaction so that suppression of the coagulation system can be achieved more efficiently by inhibiting FXa that exists at the onset of thrombin formation, rather than inhibiting the already formed thrombin (Thrombosis Research, 15, 617-629, 1979)). Another merit of the FXa inhibitor is that an effective dose in a thrombus model is very different from the dose to prolong the bleeding time in an experimental hemorrhage model. From the experimental result, it is presumed that the FXa inhibitor is an anticoagulant with a low risk of hemorrhage. Several compounds are reported as FXa inhibitors. In general, antithrombin III or antithrombin-dependent penta-saccharide III is known to have no inhibitory action against a prothrombinase complex which plays a practical role in the formation of thrombi in vivo (Thrombosis Research, 68, 507-512 (1992 ), Journal of Clinical Investigated, 71, 1383-1389 (1983), Mebio, August edition, 92-97) and also, does not exhibit effectiveness in oral administration. Although the tick anticoagulant peptide (TAP, Science, 248, 593-596 (1990)) or antistain (Journal of Biological Chemistry, 263, 10162-10167 (1988)) isolated from a blood-sucking tick or leech inhibits FXa and exhibits antithrombotic effects on the models of venous thrombi or arterial thrombi, it is not effective when administered orally since it is a high molecular weight peptide. From this consideration, a low molecular weight FXa inhibitor has been developed that directly inhibits a coagulation factor without relying on antithrombin III. An object of the present invention is to provide as an excellent anticoagulant a novel compound which has strong FXa inhibitory action, exhibits fast, sufficient and long-lasting antithrombotic effects even by oral administration, and has fewer side effects.

DESCRIPTION OF THE INVENTION In view of the above, the inventors of the present have conducted extensive research on the synthesis of a novel FXa inhibitor and its pharmacological action. As a result, it has been found that a novel sulfonyl derivative, or its salt or solvate, exhibits strong FXa inhibitory action and strong anticoagulant action, strongly inhibits FXa rapidly and continuously by oral administration, exhibits anticoagulant action and antithrombotic action, is very safe and is useful as a prophylactic or remedy for various diseases caused by a thrombus or plunger, thus leading to the conclusion of the present invention. The present invention provides a sulfonyl derivative represented by the following formula (I): wherein: R1 represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group , an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A1-B1- (wherein A1 represents an amino group which may have one or two substituents, a saturated 5- or 6-membered cyclic hydrocarbon group or unsaturated which may have a substituent, or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group ), R2 and R3 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group, or R2 or R3 may be coupled together with R1 to form an alkylene or alkenylene group of C? -3, R4 and R5 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (with the proviso that R 4 and R 5 do not represent a hydrogen atom at the same time), Q 1 represents a saturated or unsaturated 5 or 6 membered cyclic hydrocarbon group which may have a substituent, a saturated 5- or 6-membered heterocyclic group or unsaturated which may have a substituent, or a saturated or unsaturated bicyclic or tricyclic fused ring group which may have a substituent, Q2 represents a single bond, an oxygen atom, a sulfur atom, a linear C? -6 alkylene group or branched, a linear or branched C2-6 alkenylene group, a linear or branched C2-β alkynylene group, a group -N (R6) -CO- (wherein R6 represents a hydrogen atom or an alkyl group), one GR upo -N (R7) - (CH2) - (wherein R7 represents a hydrogen atom or an alkyl group and m represents an integer from 0 to 6) or a group of the following formula: (which represents a saturated or unsaturated 5 or 6 membered divalent cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5 or 6 membered divalent heterocyclic group which may have a substituent, or a divalent saturated or divalent fused ring dichloric group unsaturated which may have a substituent and < - C means the binding of the carbon atom of this group to Q1), Q3 represents any of the following groups: (in which, when the carbon atom to which each of R3, R9, R10, R11, R12, R13, R15 and R16 is attached is not adjacent to a nitrogen atom, R8, R9, R10, R11, R12 , R13, R15 and R16 each independently represents: a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkyloxy group, a hydroxyalkyl group, a hydroxyalkyloxy group, a hydroxyalkylcarbonyl group, a group hydroxyalkylsulfonyl, a formyl group, a formylalkyl group, a formylalkylcarbonyl group, a formylalkylsulfonyl group, an alkylcarbonyl group, an alkylsulfonyl group, An alkylcarbonylalkyl group, an alkylsulfonylalkyl group, a carboxyl group, a carboxyalkyl group, a carboxyalkyloxy group, a carboxyalkylcarbonyl group, a carboxialquilsulfonilo group, a carboxialquilcarbonilalquilo group, a carboxialquílsulfonilalquilo group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, alcoxicarbonilalquiloxi a alkoxycarbonylalkylcarbonyl group, a alcoxicarbonilalquilsulfonilo group, an amino group which may have one or two substituents, an aminoalkyl group in which the amino moiety may have one or two substituents, one aminoalkyloxy group in which the amino moiety may have one or two substituents, one aminoalkylcarbonyl group in which the amino moiety may have one or two substituents, one aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents, aminocarbonyl group in which the amino moiety may have one or two substituents, aminocarbonyl group one in which the amino moiety may have one or two substituents, one aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents, or A2-B2- group (in which A2 represents a cyclic hydrocarbon group 5 or 6 membered, saturated or unsaturated, which may have a substituent, or a heterocyclic group of 5 or 6 membered, saturated or unsaturated, which may have a substituent and B2 represents a single bond, a carbonyl group or an alkylene group) , when the carbon atom to which each of Rβ is bound, R9, R1 0, R, R1 2, R1 3, R 5 and R 6, is adjacent to a nitrogen atom, then R 8, R 9, R 0, R 1 1, R 12, R 3, R 1 5 and R 1 6 represent, each independently: a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkyl sulfonyl group, a formyl group, a formylalkyl group, a formyl alkylcarbonyl group, a formylalkyl sulfonyl group, an alkylcarbonyl group, an alkylsulfonyl group, a alkylcarbonylalkyl group, an alkylsulfonylalkyl group, a carboxyl group, a carboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonyl alkyl group, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group , an aminoalkyl group in which the amino portion may have one or two substituents an aminoalkylcarbonyl moiety in which the amino moiety may have one or two substituents an aminocarbonyl group in which the amino moiety may have one or two substituents, an aminocarbonylalkyl group in which the amino moiety may have one or two substituents, or a group A -B3- (in which A3 represents a saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group, which may have a substituent, or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent, and B3 represents a single bond, a carbonyl group or an alkylene group), R8 and R9, R10 and R1 1, R12 and R1 3, and R15 and R16 may each be coupled together with a ring carbon atom and represents a 5 to 7 membered saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, or a 5-7 membered heterocyclic group, saturated or unsaturated, which may have a substituent, R14 and R17 represent each independently ntemente: a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkylsulphonyl group, an alkoxy group, an alkoxyalkyl group, an alkoxyalkylcarbonyl group, an alkoxyalkylsulfonyl group, a formyl group, a formylalkyl group, a formyl alkylcarbonyl group , a formylalkylsulfonyl group, an alkylcarbonyl group, an alkylcarbonylalkyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, a carboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group, an amino group which may have one or two substituents, an aminoalkyl group in which the amino portion may have one or two substituents an aminoalkyloxy group in which the amino Amino moiety may have one or two substituents, an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents, an aminoalkyloxycarbonyl group in which the amino moiety may have one or two substituents, an aminocarbonyl group in which the amino moiety may have one or two substituents, an aminocarbonylalkyl group in which the amino moiety may have one or two substituents, an aminocarbonyloxyalkyl group in which the amino moiety may have one or two substituents, R14 and R12 O R13 may be coupled together with a carbon atom of the ring and a nitrogen atom to which R 4 is attached, and represent a 5-7 membered heterocyclic group, saturated or unsaturated, which may have a substituent, R 17 and R 1 5 O R 16 may be coupled together with a carbon atom of the ring and a nitrogen atom to which R17 is attached, and represent a 5-7 membered heterocyclic group, saturated or unsaturated which can have a substituent, a, b, d, e, and g each independently represent an integer of 0 or 1, c represents an integer from 0 to 3, f, hei each independently represent an integer from 1 to 3 , with the proviso that the sum of a, b and c represents an integer of 2 or 3, the sum of d and e represents an integer of 0 or 1, and the sum of f, g, and h represents an integer of 3 to 5), T "! represents a carbonyl group, a group -CH (R''3) - (where R18 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group wherein the amino may have a substituent) or a group -C (= NOR''9) - (wherein R ^ 9 represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group , a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group, wherein the amino portion may have a substituent, and X 1 and X 2 each independently represent a methyl group or a nitrogen atom); and salts or solvates thereof. The present invention also provides a medicament comprising as an effective ingredient, a sulfonyl derivative represented by the formula (1), or a salt or solvate thereof. The present invention also provides a pharmaceutical composition comprising a sulfonyl derivative represented by the formula (1), or a salt or solvate thereof, and a pharmaceutically acceptable carrier. The present invention also provides the use of a sulfonyl derivative represented by the formula (1), or a salt or solvate thereof, as a medicament.

The present invention also provides a method for the treatment of a disease caused by thrombosis or embolism, which comprises administering to the patient suffering it, a sulfonyl derivative represented by the formula (1), or a salt or solvate thereof.

PREFERRED MODALITIES OF THE INVENTION Next, a description will be made of the substituents in the sulfonyl group derivative of the formula (1) according to the present invention. As R1, examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the alkyl group include alkyl groups of C < Linear, branched or cyclic, such as methyl, ethyl, isopropyl and cyclopropyl. The "hydroxyalkyl group" means a group consisting of a hydroxyl group and an alkylene group of linear, branched or cyclic C- | _ß. Examples of the alkylene group include methylene, ethylene, trimethylene, propylene and cyclohexylene. Examples of the hydroxyalkyl group include hydroxymethyl and hydroxyethyl. The "alkoxy group" means a group formed from the above-mentioned C- | 6 alkyl group and an oxygen atom. Examples include methoxy, ethoxy, and sopropoxy.

The "alkoxyalkyl group" means a group formed from the alkoxy group mentioned above and the alkylene group of C-μs mentioned above.

Examples include methoxymethyl, methoxyethoyl and ethoxymethyl. The "carboxyalkyl group" means a group formed of a carboxyl group and the alkylene group of C < | _6 mentioned above. Examples include carboxymethyl and carboxyethyl. The "alkylcarbonyl group" means a group formed from the C-μs alkyl group mentioned above and a carbonyl group. Examples include methylcarbonyl and ethylcarbonyl. The "alkoxycarbonyl group" means a group formed from the C 1-6 alkoxy group mentioned above and a carbonyl group. Examples include methoxycarbonyl and ethoxycarbonyl. The "alkoxycarbonylalkyl group" means a group formed from the alkoxycarbonyl group mentioned above and the alkylene group mentioned above. Examples include methoxycarbonyllethyl and ethoxycarbonylmethyl. The "alkylcarbonyloxy group" means a group formed from the C-μβ alkyl group mentioned above, a carbonyl group and an oxygen atom.

Examples include methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy. In the group A ^ -B ^ -, A ^ represents an amino group which may have one or two substituents, a saturated or unsaturated cyclic hydrocarbon group of 5 or 6, which may have a substituent, or a heterocyclic group of 5 or 6 members, saturated or unsaturated, which may have a substituent.

When A1 represents an amino group which may have one or two substituentsB represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group. Thus, the group A ^ -B ^ - represents, for example, a group such as which is shown in the following class (A): Class (A): an amino group which may have one or two substituents, an aminocarbonyl group in which the amino portion may have one or two substituents, an aminoalkyl group in which amino moiety can have one or two substituents, an aminocarbonylalkyl group in which the amino moiety can have one or two substituents, an aminocarbonylalkyl group in which the amino moiety can have one or two substituents, or an aminoalkylcarbonyl moiety in which the moiety Amino can have one or two substituents, and an aminoalkylcarbonyloxy group in which the amino moiety can have one or two substituents A description of the groups shown in FIG. a Class (A): The "aminocarbonyl group in which the amino portion may have one or two substituents" means a group formed of an amino group which may have one or two substituents, and a carbonyl group. The "aminoalkyl group in which the amino portion may have one or two substituents" means a group formed of an amino group which may have one or two substituents, and the alkylene group of C-j.β mentioned above. Examples of the aminoalkyl group include aminomethyl and aminoethyl. The "aminocarbonylalkyl group in which the amino moiety may have one or two substituents" means a group formed from an aminocarbonyl group mentioned above and the alkylene group from C <.; \ _Q mentioned above. Examples of the aminocarbonylalkyl group include aminocarbonylmethyl and aminocarbonylethyl. The "aminocarbonylalkyloxy group in which the amino portion may have one or two substituents" means a group formed from the aminocarbonylalkyl group mentioned above and an oxygen atom. Examples of the aminocarbonylalkyl group include aminocarbonylmethoxy and aminocarbonylethoxy. The "aminoalkylcarbonyl group in which the amino portion may have one or two substituents" means a group formed from the aminoalkyl group mentioned above and a carbonyl group. Examples of the aminoalkylcarbonyl group include aminomethylcarbonyl and aminoethylcarbonyl. The "aminoalkylcarbonyloxy group in which the amino portion may have one or two substituents" means a group formed from the aminoalkylcarbonyl group mentioned above and an oxygen atom. Examples of the aminoalkylcarbonyloxy group include aminomethylcarbonyloxy and aminoethylcarbonyloxy. Examples of substituents of an amino group include those shown in the following Class (1). Class (1): an alkyl group, an alkenyl group, a halogenoalkyl group, a halogenoalkenyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkylcarbonyl group, an alkoxyalkylsulfonyl group, an formyl group, a formylalkyl group, a formyl alkylcarbonyl group, a fromylalkylsulfonyl group, an alkylcarbonyloxy group, an alkylcarbonylalkyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, a carboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group , an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group, a trifluoromethylsulfonyloxyalkenyl group, and an a ^ -b ^ group (wherein a ^ represents a 5- or 6-membered cyclic hydrocarbon group, saturated or unsaturated, which may have one to three substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group , an alkoxycarbonyl group and an aminocarbonyl group; and b ^ represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group, an alkylenecarbonyloxy group, an alkyleneaminocarbonyl group, an alkyleneaminocarbonylalkyl group, an alkyleneaminesulfonyl group, or an alkyleneaminesulfonylalkyl group). Next, substituents of an amino group of class (1) will be described. The alkyl group has the same meaning as described above. The "alkenyl group" means a linear, branched or cyclic C2-6 alkenyl group. Examples include vinyl and allyl. The "halogenoalkyl group" means a group formed from a halogen atom and the alkylene group mentioned above. Examples include chloromethyl and bromoethyl. The "halogenoalkenyl group" means a group consisting of a halogen atom and a linear or branched C2-6 alkenylene group. Examples include chloroethenyl and bromopropenyl groups. There is no particular limitation on the position of a double bond. The "hydroxyalkyl group" means a group consisting of a hydroxyl group and a linear, branched or cyclic C2-6 alkylene group. Examples include hydroxyethyl and hydroxypropyl. The "hydroxyalkylcarbonyl group" means a group formed from the hydroxyalkyl group mentioned above and a carbonyl group. Examples include hydroxymethylcarbonyl and hydroxyethylcarbonyl. The "hydroxyalkylsulfonyl group" means a group formed from the hydroxyalkyl group mentioned above and a sulfonyl group. Examples include hydroxymethylsulfonyl and hydroxyethylsulfonyl. The "alkoxyl group has the same meaning as described above.

The "alkoxyalkyl group" means a group formed from the alkoxy group mentioned above and a linear, branched or cyclic C2-6 alkylene group. Examples include methoxyethyl, ethoxyethyl and methoxypropyl. The "alkoxyalkylcarbonyl group" means a group formed from the alkoxyalkyl group mentioned above and a carbonyl group. Examples include methoxyethylcarbonyl and ethoxymethylcarbonyl. The "alkoxyalkylsulfonyl group" means a group formed from the alkoxyalkyl group mentioned above and a sulfonyl group. Examples include methoxymethylsulfonyl and ethoxymethylsulfonyl. The "formylalkyl group" means a group formed from a formyl group and the alkylene group of C-μβ mentioned above. Examples include formylmethyl and formyllethyl. The "formylcarbonyl group" means a group formed from the formylalkyl group mentioned above and a carbonyl group. Examples include formylmethylcarbonyl and formylethylcarbonyl. The "formylalkylsulfonyl group" means a group formed from the formylalkyl group mentioned above and a sulfonyl group. Examples include formylmethylsulfonyl and formylethylsulfonyl. The "alkylcarbonyl group" means a group formed of the alkyl group mentioned above and a carbonyl group. Examples include methylcarbonyl and ethylcarbonyl. The "alkylcarbonylalkyl group" means a group formed from the above-mentioned alkylcarbonyl group and the alkylene group of C-μβ mentioned above. Examples include methylcarbonylmethyl and ethylcarbonylmethyl. The "alkylsulfonyl group" means a group formed of the alkyl group mentioned above and a sulfonyl group. Examples include methylsulfonyl and ethylsulfonyl. The "alkylsulfonylalkyl group" means a group formed of the alkylsulfonyl group mentioned above and the alkylene group of C-μ? mentioned above. Examples include methylsulfonylmethyl and ethylsulfonylmethyl. The carboxyalkyl group has the same meaning as described above. The "carboxyalkylcarbonyl group" means a group formed from the carboxyalkyl group mentioned above and a carbonyl group. Examples include carboxymethylcarbonyl and carboxyethylcarbonyl. The "carboxyalkylsulfonyl group" means a group formed from the carboxyalkyl group mentioned above and a sulfonyl group. Examples include carboxymethylsulfonyl and carboxyethyl sulfonyl. The "carboxyalkylcarbonylalkyl group" means a group formed from the carboxyalkylcarbonyl group mentioned above and the alkylene group of C-μβ mentioned above. Examples include carboxymethylcarbonylmethyl and carboxyethylcarbonylmethyl. The "carboxyalkyl sulfonylalkyl group" means a group formed from the carboxyalkyl-sulfonyl group mentioned above and the alkylene group of C-μg mentioned above. Examples include carboxymethysulfonylmethyl and carboxyethyl sulfonylmethyl. The alkoxycarbonyl and alkoxycarbonylalkyl groups have the same meanings described above. The "alkoxycarbonylalkylcarbonyl group" means a group formed from the alkoxycarbonylalkyl group mentioned above and a carbonyl group. Examples include methoxycarbonylethylcarbonyl and ethoxycarbonylmethylmethylcarbonyl. The "alkoxycarbonylalkylsulfonyl group" means a group formed from the alkoxycarbonylalkyl group and a sulfonyl group. Examples include methoxycarbonylethylsulfonyl and ethoxycarbonylmethylsulfonyl. The group "trifluoromethylsulfonyloxyalkenyl" means a group formed of a trifluoromethylsulfonyloxy group and a linear or branched C2-6 alkenylene group. Examples include trifluoromethylsulfonyloxyvinyl and trifluoromethylsulfonyloxyallyl. In the group a ^ -b ^, al represents a 5- or 6-membered, saturated or unsaturated cyclic hydrocarbon group, or a saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent such as a halogen atom . Examples of saturated or unsaturated 5 or 6-membered cyclic hydrocarbon groups include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has several structural isomers, as in cyclopentenyl, it is to be noted that all of them are included in it.

The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one heteroatom. Examples of heteroatoms include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazole, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl. , pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. b1 represents a single bond or a carbonyl, alkylene, carbonylalkyl, alkylenecarbonyloxy, alkyleneaminocarbonyl, alkyleneaminocarbonylalkyl, alkyleneaminesulfonyl, or alkyleneaminesulfonylalkyl group. The alkylene group has the same meaning as described above. The "carbonylalkyl group" means a group formed of a carbonyl group and the alkylene group of C- | a mentioned above. Examples include carbonylmethyl and carbonylethyl. The "carbonylalkyloxy group" means a group formed from the carbonyl alkyl group mentioned above and an oxygen atom. Examples include carbonylmethoxy and carbonylethoxy.

The "alkylenecarbonyloxy group" means a group formed from the alkylene group of C < | 6 mentioned above, a carbonyl group and an oxygen atom. Examples include methylenecarbonyloxy and ethylenecarbonyloxy. The "alkylene aminocarbonyl group" means a group formed from the alkylene group of C 1-6 mentioned above, an amino group and a carbonyl group. Examples include methyleneaminocarbonyl and ethyleneaminocarbonyl. The "alkyleneaminocarbonylalkyl group" means a group formed from the alkyleneaminocarbonyl group mentioned above and the alkylene group of C? _ Mentioned above. Examples include methyleneaminocarbonylmethyl and ethyleneaminocarbonylmethyl. The "alkyleneminosulfonyl group" means a group formed from the alkylene group of C- | _g mentioned above, an amino group and a sulfonyl group. Examples include methylene amino sulfonyl and ethylene amino sulfonyl. The "alkyleneminosulfonylalkyl group" means a group formed from the alkyleneaminesulfonyl group mentioned above and the C-μg alkylene mentioned above. Examples include methylaminosulfonylmethyl and ethylaminosulfonylmethyl. Next, a description will be made of the substituents that can be introduced, such as the above-mentioned a, in a 5- or 6-membered saturated or unsaturated cyclic hydrocarbon group, or in the saturated or unsaturated 5- or 6-membered heterocyclic group. , which may have a substituent. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. The alkoxy, alkyl, alkoxycarbonyl and aminocarbonyl groups have the same meanings as described above. As for the group a ^ -b ^ -, there are several types according to the combination of a ^ and b ^. Examples include: a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group, which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent, and a group carbonyl, a group consisting of a saturated or unsaturated cyclic hydrocarbon group of 5 or 6 members, which may have a substituent, and an alkyl group, a group consisting of a saturated or unsaturated 5 or 6-membered heterocyclic group, which may be having a substituent, and a carbonylalkyl group, a group consisting of a saturated or unsaturated cyclic hydrocarbon group of 5 or 6, which may have a substituent, and a carbonylalkyloxy group, a group formed of a cyclic hydrocarbon group of 5 or 6 members, saturated or unsaturated, which may have a substituent, and an alkylenecarbonyloxy group, a group consisting of a saturated or unsaturated cyclic hydrocarbon group of 5 or 6, which may have a substituent, and an alkylene iminocarbonyl group, a group formed of a 5-6 membered heterocyclic group, saturated or unsaturated, which may have a substituent, and an alkyleneaminocarbonylalkyl group, a group consisting of a saturated or unsaturated cyclic hydrocarbon group of 5 or 6, which may have a substituent, and a alkylene sulfonyl group, a group consisting of a saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent, and an alkylene-amino-sulfonylalkyl group, and the like. In addition to the aforementioned Class (1), the following Class (2) can be given as examples of substituents of the amino group. Class (2): an amino group which may have one or two substituents selected from Class (1), an aminoalkyl group in which the amino portion may have one or two substituents selected from Class (1), an aminocarbonyl group in wherein the amino moiety can have one or two substituents selected from Class (1), an aminocarbonylalkyl group in which the amino moiety can have one or two substituents selected from Class (1), an aminocarbonylalkylcarbonyl group in which the moiety amino can have one or two substituents selected from Class (1), an aminocarbonylalkysulfonyl group in which the amino moiety can have one or two substituents selected from Class (1), an aminoalkylcarbonyl group in which the amino moiety can have one or two substituents selected from Class (1), an aminosulfonyl group in which the amino portion may have one or two substituents selected from Class (1), an aminosulfonylalkyl group in which the amino moiety can have one or two substituents selected from Class (1), an aminoalkylsulfonyl group in which the amino moiety can have one or two substituents selected from Class (1), an aminosulfonylalkylcarbonyl group in wherein the amino moiety can have one or two substituents selected from Class (1), and an aminosulfonylalkyl-sulfonyl group in which the amino moiety can have one or two substituents selected from Class (1). A description of the substituents of Class (2) will be described below. The aminocarbonyl, aminocarbonylalkyl and aminoalkylcarbonyl groups of Class (2) have the meanings described above. The "aminoalkyl group which may have a substituent" means a group formed of an amino group which may have a substituent, and a linear, branched or cyclic C2-6 alkylene group. Examples of the aminoalkyl group include aminoethyl and aminopropyl. The "aminocarbonylalkylcarbonyl group which may have a substituent" means a group formed of an aminocarbonylalkyl group which may have a substituent, and a carbonyl group. Examples of the aminocarbonylalkylcarbonyl group include aminocarbonylmethylcarbonyl and aminocarbonylethylcarbonyl. The "aminocarbonylalkylsulfonyl group which may have a substituent" means a group formed of an aminocarbonylalkyl group which may have a substituent, and a sulfonyl group. Examples of the aminocarbonylalkyl-sulfonyl group include aminocarbonylmethylsulfonyl and aminocarbonylethylsulfonyl. The "aminosulfonyl group which may have a substituent" means a group formed of an amino group which may have a substituent, and a sulfonyl group. The "aminosulfonylalkyl group which may have a substituent" means a group formed of the aminosulfonyl group mentioned above which may have a substituent, and the alkylene group of C 1-6 mentioned above.

Examples of the aminosulfonylalkyl group include aminosulfonylmethyl and aminosulfonylethyl. The "aminoalkylsulfonyl group which may have a substituent" means a group formed of the amino group mentioned above which may have a substituent, the alkylene group of C-μ? mentioned above, and a sulfonyl group. Examples of the aminoalkylsulfonyl group include aminomethylsulfonyl and aminoethylsulfonyl. The "aminosulfonylalkylcarbonyl group which may have a substituent" means a group formed of the aminosulfonylalkyl group mentioned above which may have a substituent, and a carbonyl group. Examples include aminosulfonylmethylcarbonyl and aminosulfonylethylcarbonyl. The "aminosulfonylalkysulfonyl group which may have a substituent" means a group formed from the aminosulfonylalkyl group mentioned above which may have a substituent, and a sulfonyl group. Examples include aminosulfonylmethylsulfonyl and aminosulfonylethylsulfonyl. A ^ also represents a cyclic hydrocarbon group or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent. Examples of the saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl groups. When the group has several structural isomers, as in the cyclopentenyl group, it is to be noted that all of them are included in it. The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one heteroatom. Examples of heteroatoms include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. When ^ represents a cyclic hydrocarbon group or a saturated or unsaturated 5 or 6-membered heterocyclic group, which may have a substituent, β1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyl group or a alkylenecarbonyloxy group. Consequently, the group A ^ -B ^ - represents for example a group as shown in the following Class (B): Class (B): a cyclic hydrocarbon group or a 5- or 6-membered heterocyclic group, saturated or unsaturated , which may have a substituent, a group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent, and a carbonyl group, a group formed from a cyclic hydrocarbon group or a 5 or 6 membered heterocyclic group, saturated or unsaturated, which may have a substituent, and an alkylene group, a group consisting of a cyclic hydrocarbon group or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent, a carbonyl group and an alkylene group, a group consisting of a saturated or unsaturated cyclic hydrocarbon group or a 5- or 6-membered heterocyclic group, which may have a substituent, a carbonyl group, an alkali group, and an oxygen atom, a group consisting of a cyclic hydrocarbon group or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent, an alkylene group and a carbonyl group, a group formed from a hydrocarbon group cyclic or a 5 or 6 membered heterocyclic group, saturated or unsaturated, which may have a substituent, an alkylene group, a carbonyl group and an oxygen atom, and the like. A description of the groups shown in Class (B) will be given below. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and a carbonyl group, examples of the group consisting of the cyclic hydrocarbon group and a carbonyl group include cyclopentylcarbonyl and phenylcarbonyl; while those of the group formed of the heterocyclic group and a carbonyl group, include the furilcarbonyl, thienylcarbonyl and pyridylcarbonyl groups. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and an alkylene group, the "group consisting of a cyclic hydrocarbon group and an alkylene group" means a group formed from the above-mentioned cyclic hydrocarbon group and the above-mentioned C ?_6 alkylene group, for example cyclohexylmethyl and benzyl; while the "group consisting of a heterocyclic group and an alkylene group" means a group formed of the heterocyclic group mentioned above and the alkylene group of C 1-6 mentioned above, for example furylmethyl, thienylethyl and pyridylpropyl. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, a carbonyl group and an alkylene group, the "group consisting of a cyclic hydrocarbon group, a carbonyl group and a "alkylene group" means a group formed from the cyclic hydrocarbon group mentioned above, a carbonyl group and the alkylene group of C 1-6 mentioned above, for example cyclopentadienylcarbonylmethyl and phenylcarbonylethyl; Meanwhile he "group consisting of a heterocyclic group, a carbonyl group and an alkylene group" means a group formed from the heterocyclic group mentioned above, a carbonyl group and the alkylene group of C-μβ mentioned above, for example, furylcarbonylmethyl, thienylcarbonylethyl and pyridylcarbonylpropyl. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5 or 6 membered heterocyclic group which may have a substituent, a carbonyl group, an alkylene group and an oxygen atom, the "group consisting of a cyclic hydrocarbon group, a carbonyl group, an alkylene group and an oxygen atom "means a group consisting of the aforementioned group - which is formed of a cyclic hydrocarbon group, a carbonyl group and an alkylene group - and an oxygen atom, for example cyclopentylcarbonylmethoxy and phenylcarbonyl ethoxy; while the "group consisting of a heterocyclic group, a carbonyl group, an alkylene group and an oxygen atom" means a group composed of the aforementioned group - which is formed of a heterocyclic group, a carbonyl group and an alkylene group - and an oxygen atom, for example, furylcarbonylmethoxy, thienylcarbonyl ethoxy and pyridylcarbonylpropoxy. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, an alkylene group and a carbonyl group, the group consisting of a cyclic hydrocarbon group, an alkylene group and a "carbonyl group" means a group consisting of the aforementioned group - which is formed of a cyclic hydrocarbon group and an alkylene group - and a carbonyl group, for example cyclohexylmethylcarbonyl and phenylethylcarbonyl; while the "group consisting of a heterocyclic group, an alkylene group and a carbonyl group" means a group composed of the aforementioned group - which is formed of a heterocyclic group and an alkyl group - and a carbonyl group, for example furylmethylcarbonyl, thienylethylcarbonyl and pyridylpropylcarbonyl. In the group consisting of a cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, an alkylene group, a carbonyl group and an oxygen atom, the "group consisting of a cyclic hydrocarbon group, an alkylene group, a carbonyl group and an oxygen atom "means a group consisting of the aforementioned group - which is formed of a cyclic hydrocarbon group, an alkylene group and a carbonyl group - and an oxygen atom, for example cyclohexadienylmethylcarbonyloxy and phenylethylcarbonyloxy; while the "group consisting of a heterocyclic group, an alkylene group, a carbonyl group and an oxygen atom" means a group composed of the aforementioned group - which is formed of a heterocyclic group, an alkylene group and a carbonyl group - and an oxygen atom, such as, for example, furylmethylcarbonyloxy, thienylethylcarbonyloxy and pyridylpropylcarbonyloxy. As examples of a substituent for the hydrocarbon group or the saturated or unsaturated 5- or 6-membered heterocyclic group, those shown in Class (3) may be given. Class (3): a hydroxyl group, an alkyl group, an alkoxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group, a formyl group, a heteroaryl group, a heteroarylalkyl group, an alkyl amino group, an amidino group, a guanidino group, an amino (hydroxyimino) alkyl group, an amino (alkoxyimino) alkyl group, an amino (aryloxyimino) alkyl group, an amino group which may have one or two substituents, an aminocarbonyl group in which the amino portion may have one or two substituents, an aminocarbonylalkyl group in which the amino moiety may have one or two substituents, an aminocarbonylalkyl group in which the amino moiety may have one or two substituents, an aminoalkyl group in which the amino moiety can have one or two substituents, an aminoalkyloxy group in which the amino moiety can have one or two substituents, an aminoalkylcarbonyl group in which the amino moiety can have one or two substituents, aminoalkylcarbonyloxy group in which the amine portion may have one or two substituents, and an oxygen atom. The number of replaceable substituents varies from 1 to 3. A description will now be made of the substituents of the saturated or unsaturated 5- or 6-membered heterocyclic group of Class (3).

The alkyl group, the alkyloxy group, the hydroxyalkyl group, the alkoxyalkyl group, the halogen atom and the alkoxycarbonyl group have the same meanings as described above in R1. The "heteroaryl group" means an aromatic monovalent group having at least one heteroatom. Examples include pyridyl, furyl and thienyl. The "heteroarylalkyl group" means a group formed from the heteroaryl group mentioned above and the alkylene group of C-j.β mentioned above.

Examples include pyridylmethyl, furylethyl and thienylmethyl. The "alkylimino group" means a group formed of the alkyl group mentioned above and a nitrogen atom. Examples include methylimino and ethylimino. The "amino (hydroxyimino) alkyl" group means a group in which the amino and hydroxyimino groups are linked to the same carbon atom of the alkyl group mentioned above. Examples include amino (hydroxyimino) methyl and amino (hydroxyimino) ethyl. The "amino (alkoxyamino) alkyl group" means a group in which the amino and alkoxyimino groups are linked to the same carbon atom of the alkyl group mentioned above. Here, the "alkoxyimino group" means a divalent group formed from the alkoxy group mentioned above and an imino group. Examples of the amino (alkoxyimino) alkyl group include amino (methoxyimino) methyl and amino (ethoxyimino) methyl. The "amino (aryloxyimino) alkyl" group means a group in which the amino and aryloxyimino groups are linked to the same carbon atom of the alkyl group mentioned above. Here, the "aryloxyimino group" means a divalent group formed of aryl and imino groups. Examples of the aryl group include phenyl, naphthyl, anthryl and phenanthryl. Examples of the amino (aryloxyimino) alkyl group include amino (penoxyimino) methyl and amino (naphthyloxyimino) methyl. The "aminocarbonyl group in which the amino portion may have one or two substituents" means a group formed of an amino group which may have one or two substituents, and a carbonyl group. The "aminoalkyl group in which the amino portion may have one or two substituents" means a group formed of an amino group which may have one or two substituents, and the alkylene group of C 1-6 mentioned above. Examples of the aminoalkyl group include aminomethyl and aminoethyl. The "aminocarbonoalkyl group in which the amino moiety may have one or two substituents" means a group formed from the aminocarbonyl group mentioned above, in which the amino moiety may have one or two substituents, and the alkylene group of C- | _6 mentioned above. Examples of the aminocarbonylalkyl group include aminocarbonylmethyl and aminocarbonylethyl. The "aminocarbonylalkyloxy" group in which the amino moiety may have one or two substituents "means a group formed from the aminocarbonylalkyl group mentioned above, in which the amino moiety may have one or two substituents, and an oxygen atom. The aminocarbonylalkyloxy group includes aminocarbonylmethoxy and aminocarbonylethoxy The "aminoalkylcarbonyl group in which the amino moiety can have one or two substituents" means a group formed from the aminoalkyl group mentioned above, in which the amino moiety can have one or two substituents, and a moiety Examples of the aminoalkylcarbonyl group include aminomethylcarbonyl and aminoethylcarbonyl The "aminoalkylcarbonyloxy group in which the amino portion may have one or two substituents" means a group formed from the aminoalkylcarbonyl group mentioned above, in which the amino portion may have one or two substituents, and an oxygen atom. Crystals of the aminoalkylcarbonyloxy group include aminomethylcarbonyloxy and aminoethylcarbonyloxy. The "aminoalkyloxy group in which the amino portion may have one or two substituents" means a group formed of an amino group, which may have a substituent, a linear C2-6 alkylene group, branched or cyclic, and an oxygen atom. Examples of the aminoalkyloxy group include aminoethyloxy and aminopropyloxy. In the case of the cyclic hydrocarbon group, an oxygen atom can serve as a substituent when the corresponding keto compound is formed, while in the case of the heterocyclic group or a dichicyclic or tricyclic group of fused rings, an oxygen atom can serve as a substituent when the oxygen atom is linked to a nitrogen or sulfur atom of the ring, and the corresponding compound N-oxide or S-oxide or keto is formed. In the present invention, when R1 is not coupled with R2 or R3 to form an alkylene or alkenylene group of C- | _3, the examples Preferred of R1 include a hydrogen atom, an alkyl group, a hydroxyalkyl group and an Al-β1- group. In R2 and R3, examples of the halogen atom include fluorine, chlorine, bromine and iodine. The "alkyl group" means a linear, branched or cyclic C? _8 alkyl group. Examples include methyl, ethyl, isopropyl, cyclopropyl, heptyl and octyl. The "hydroxyalkyl group" means a group consisting of a hydroxyl group and a linear, branched or cyclic C? _ Al alkylene group. Examples include hydroxymethyl and hydroxyethyl. The "alkoxyalkyl group" means a group formed of the above-mentioned alkyl group, an oxygen atom and a linear, branched or cyclic C-μs alkylene group. Examples include methoxymethyl, methoxyethyl and ethoxymethyl. When R2 or R3 is coupled with R1 to form an alkylene or alkenylene group of C-j_3, the following group in formula (I): means the group described below, or a similar group.

In the present invention, when R2 or R3 is not coupled with R1 to form an alkylene or alkenylene group of C- | _3, they are preferred as R2 or R3 a hydrogen atom and an alkyl group. In the present invention, it is preferred that R1 and R2 or R3 are coupled to form an alkylene or alkenylene group of C-1.3. In R 4 or R 5, examples of the halogen atom include fluorine, chlorine, bromine and iodine. The alkyl and alkoxy groups have the same meanings described above in R1. In the present invention, a halogen atom is preferred as R4 or R5, with fluorine, chlorine and bromine being particularly preferred.

Q1 represents a 5- or 6-membered saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent, or a cyclic or tricyclic ring group merged, saturated or Unsaturated, which may have a substituent. Here, examples of the 5-or 6-membered saturated or unsaturated cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has several structural isomers such as cyclopentenyl, it should be noted that all of them are embedded in it. The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one heteroatom. Examples of heteroatoms include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. The "fused or unsaturated cyclic or tricyclic ring group of fused or unsaturated rings that may have a substituent" means: (1) a group obtained by the condensation of the aforementioned saturated or unsaturated 5 or 6 membered cyclic hydrocarbon groups which may have a substituent, (2) a group obtained by the condensation of the aforementioned saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group which may have a substituent, and the aforementioned saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent; and (3) a group obtained by the condensation of the 5 or 6 saturated or unsaturated heterocyclic groups described above which may have a substituent. Examples of group (1) include indenyl, indanyl, naphthyl, tetrahydronaphthyl, anthryl, and phenanthryl; those of group (2) include benzofuranyl, indolyl, indolinyl, quinolyl, benzodiazinyl and tetrahydroisoquinolyl; and those of group (3) include naphthyridinyl, tetrahydrothienopyridyl, tetrahydrothiazolopyridyl and tetrahydropyridinopyridyl. Examples of the substituent for the cyclic, heterocyclic, cyclic or tricyclic hydrocarbon groups of fused rings include the groups shown in the following Class (4): Class (4): a hydroxyl group, an alkyl group, an alkenyl group, a group halogenoalkyl, a halogenoalkenyl group, an alkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group, a formyl group, a heteroaryl group, a heteroarylalkyl group , an alkylimino group, an amidino group, a guanidino group, an amino (hydroxyimino) alkyl group, an amino (alkoxyimino) alkyl group, an amino (aryloxyimino) alkyl group, an amino group which may have one or two substituents, an aminocarbonyl group in which the amino moiety can have one or two substituents, an aminocarbonylalkyl group in which the amino moiety can have one or two substituents, a moiety an aminocarbonylalkyloxy moiety in which the amino moiety may have one or two substituents, an aminoalkyl group in which the amino moiety may have one or two substituents, an aminoalkyloxy group in which the amino moiety may have one or two substituents, an aminoalkylcarbonyl group wherein the amino portion may have one or two substituents, an aminoalkylcarbonyloxy group in which the amino portion may have one or two substituents, an oxygen atom, a trifluoromethylsulfonyloxy group, a trifluoromethylsulfonyloxyalkenyl group, a boric acid group (-B (OH) 2), a 5 or 6 membered saturated or unsaturated cyclic hydrocarbon group, which may have from 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, alkoxy, alkyl, cyano, nitro, carboxyl , alkoxycarbonyl and aminocarbonyl, and a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have from 1 to 3 substituents selected of the group consisting of halogen, hydroxyl, amino, alkoxy, alkyl, cyano, nitro, carboxyl, alkoxycarbonyl and aminocarbonyl. Incidentally, the number of replaceable substituents varies from 1 to 7. Substituents of Class (4) have the same meanings as described in Classes (1) to (3).

In the present invention, preferred examples of Q1 include a phenyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyrrolidinyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, and a tetrahydrothiazolopyridyl group which may have a substituent. In Q2, examples of the linear or branched C-μ alkylene group include methylene, ethylene, trimethylene, propylene, tetramethylene, butylene, pentamethylene and hexamethylene. Examples of the linear or branched C2-6 alkenylene group include vinylene, propenylene, butenylene and pentenylene. There is no particular limitation on the position of the double bond. Examples of the linear or branched C2-6 alkynylene group include propynylene, butynylene, pentynylene and hexinylene. The following group: means a divalent, saturated or unsaturated cyclic hydrocarbon group of 5 or 6 members which may have a substituent, a divalent, saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent, or a divalent, saturated or saturated fused dichloride group; unsaturated, which may have a substituent; and < -C means the bond of the carbon atom of this group with Q1. Examples of this group include divalent groups derived from thiophene, furan, pyrano, pyrrole, pyrrolidine, pyrroline, imidazole, imidazoline, imidazolidine, pyrazole, pyrazolidine, thiazole, oxazole, oxathiolan, benzene, pyridine, piperidine, piperazine, morpholine, thiomorpholine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, thiadiazine, dithiazine, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, or the like, and may have a substituent. The alkyl group in R6 or R7 of the group -N (R6) -CO- or -N (R7) - (CH2) rrr > means a linear, branched or cyclic C ^ .Q alkyl group. Examples include methyl, ethyl, isopropyl and cyclopropyl. As the group -N (R6) -CO-, a group < -N (R6) -CO- (where «-means the bond of the nitrogen atom of this group with Q1), while a -N (R7) - (CH2) m_ group is preferred (where - means the bond of the nitrogen atom of this group with Q1) as the group -N (R7) - (CH2) m-. In the present invention, preferred examples of Q2 include a single bond, a carbonyl group and groups represented by the following formula: Among the groups represented by the following formula: divalent groups derived from benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazoline, furan, thiophene, pyrrole, oxazole, oxazoline, thiadiazole, cyclopentane, cyclopentene, cyclohexane or cyclohexene are preferred. In Rβ, R 9, R 0, R 1, R 12, R 13, R 15 and R 16, as the substituents in Q 3, the alkyl, alkoxyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, formylalkyl, formylalkylcarbonyl, formylalkyl-sulphonyl, alkylcarbonyl, alkylsulfonyl groups , alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkylcarbonyl, carboxyalkylsulfonyl, carboxyalkylcarbonylalkyl, carboxyalkylsulfonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkysulfonyl, amino which may have one or two substituents, aminoalkyl in which the amino moiety may have one or two substituents, aminoalkylcarbonyl in which the moiety amino can have one or two substituents, aminoalkylcarbonyloxy in which the amino moiety can have one or two substituents, aminocarbonyl in which the amino moiety can have one or two substituents, aminocarbonylalkyl in which the amino moiety can have having one or two substituents, and aminocarbonylalkyloxy in which the amino portion may have one or two substituents, have the same meanings as described above in Rl. The "alkoxyalkyloxy group" means a group formed from the alkoxyalkyl group mentioned above and an oxygen atom, and examples include methoxymethyloxy and ethoxymethyloxy.

The "carboxyalkyl group" means a group formed from a carboxyl group and the alkylene group of C-μβ mentioned above, and examples include carboxymethyl and carboxyethyl. The "carboxyalkyloxy group" means a group formed from the carboxyalkyl group mentioned above and an oxygen atom, and examples include carboxymethoxy and carboxyethoxy. The "alkoxycarbonylalkyloxy group" means a group formed from the alkoxycarbonylalkyl group and an oxygen atom, and examples include methoxycarbonylethyl and ethoxycarbonylethyl. The "aminoalkyloxy group in which the amino moiety may have one or two substituents" means a group formed of an amino group which may have a substituent, a linear, branched or cyclic alkylene group of ^ 2-6- and an oxygen atom , and examples include aminoethoxy and aminopropoxy. In the group A2-B2-, A2 represents a 5- or 6-membered, saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent. Here, examples of the saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has several structural isomers such as cyclopentenyl, they are all covered in it. The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one heteroatom. Examples of the heteroatom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. B2 represents a single bond, a carbonyl group or an alkylene group. The "alkylene group" means a linear, branched or cyclic C? _ Alkylene group. Examples of the group A2-B2- include the following groups: a saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group which may have a substituent, a group consisting of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and a carbonyl group, and a group formed of a saturated or unsaturated 5 or 6 membered cyclic hydrocarbon group which may have a substituent, and an alkylene group.

Each of R8 and R9, R10 and R1 1, R 2 and R13, and R15 and R16 are coupled together with a ring carbon atom and represents a 5- to 7-membered, saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, or a 5 to 7 membered heterocyclic group, saturated or unsaturated, which may have a substituent. Here, examples of the 5 to 7 membered saturated or unsaturated cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has several structural isomers such as cyclopentenyl, they are all covered in it. The 5-7 membered saturated or unsaturated heterocyclic group is a cyclic group having at least one heteroatom. Examples of the heteroatom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5-7 membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl., oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydripyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. a, b, d, e, and g each independently represent an integer of 0 or 1, c represents an integer from 0 to 3, f, hei each independently represent an integer from 1 to 3, with the proviso that the sum of a, b and c represents an integer of 2 or 3, the sum of d and e represents an integer of 0 or 1, and the sum of f, g, and h represents an integer from 3 to 5. In Rl4 or R "1 7 as in substituent in Q3, the alkyl, alkoxyl, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, alkoxyalkylcarbonyl, alcoxialquilsulfonilo, formylalkyl, formilalquilcarbonilo, formilalquilsulfonilo, alkylcarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkylcarbonyl, carboxialquilsulfonilo, carboxialquilcarbonilalquilo, carboxialquilsulfonilalquilo, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alcoxicarbonilalquilsulfonilo, amino which may have one or two substituents, aminoalkyl in which the amino portion may have one or two substitutes aminoalkylcarbonyl in which the amino moiety can have one or two substituents, aminoalkyloxycarbonyl in which the amino moiety can have one or two substituents, aminocarbonyl in which the amino moiety can have one or two substituents, aminocarbonylalkyl in which the moiety amino can have one or two substituents, and aminocarbonyloxyalkyl in which the amino portion can have one or two substituents, have the same meanings as described above in R "1. The "hydroxylalkyl group" means a group consisting of a hydroxyl group and a linear, branched or cyclic C2-6 alkylene group, and examples include hydroxyethyl and hydroxypropyl. The "alkoxyalkyl group" means a group formed from the alkoxy group mentioned above and a straight, branched or cyclic C2-6 alkylene group, and examples include methoxyethyl and ethoxyethyl. The "aminoalkyl group in which the amino portion may have one or two substituents" means a group formed of the amino group mentioned above, which may have a substituent, and a linear, branched or cyclic C2-6 alkylene group, and examples include aminoethyl and aminopropyl. The "aminoalkyloxy group in which the amino portion may have one or two substituents" means a group formed of the amino group mentioned above, which may have a substituent, a linear, branched or cyclic C2-6 alkylene group, and an atom of oxygen, and examples include aminoethoxy and aminopropoxy. In group A3-B3-, A3 represents a saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group, which may have a substituent, or a saturated or unsaturated 5- or 6-membered heterocyclic group, which may have a substituent. Here, examples of the saturated or unsaturated 5 or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has several structural isomers, such as cyclopentenyl, they are all covered in it. The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one heteroatom. Examples of heteroatoms include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazole, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl., Pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. B3 represents a single bond or a carbonyl group or an alkylene group. The "alkylene group" means a linear, branched or cyclic C-μ-alkylene group. Examples A3-B3- the group include the following groups: saturated heterocyclic group 5 or 6 membered unsaturated or may have a substituent, a group formed of a saturated cyclic hydrocarbon group of 5 or 6 membered unsaturated or may have a substituent, and a carbonyl group, and a group consisting of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and an alkylene group. R14 and R1 2, R14 and R1 3 R1 7 and R1 5 and R1 7 and R1 6 are coupled together with the carbon atom of the ring and the nitrogen atom to which they are attached R 4 or R 7 and represent a 5-7 membered heterocyclic group, saturated or unsaturated, which may have a substituent. Here, examples of the heterocyclic group of 5 to 7 membered saturated or unsaturated, are cyclic groups having at least or nitrogen atom and may have a heteroatom. Examples of the heteroatom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5-7 membered heterocyclic group include, furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, prazrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl. , pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. When the group has several structural isomers, as in pyranyl, it is to be noted that all of them are included in it. In the present invention, Q3 represents a group of the following formula: (wherein R8, R9, R ™, R1 1, R12, R13, RI4, R15, R16, R17; a> b> c> d> g, g, hei have the same meanings described above), with the group of the following formula being preferred: (wherein R8, R9, a, b, and c have the same meanings described above). t1 represents a carbonyl group, a group -CH (R18) - (wherein R ^ 8 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an agroup, an aralkyl group, a heteroagroup, a heteroalkyl group or an aminoalkyl group wherein the amino portion may have a substituent) or a group -C (= NOR19) - (wherein R19 represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an agroup, an aralkyl group, a heteroagroup, a heteroalkyl group or an aminoalkyl group wherein the amino moiety may have a substituent). Here, the alkyl, carboxyalkyl, alkoxycarbonyl, a aralkyl, heteroa heteroalkyl and aminoalkyl groups in which the amino moiety may have a substituent, in R ^ 8 or R ^ 9, have the same meanings described in R1. In the present invention, a carbonyl group such as T ^ is preferred. In the present invention, the group: in the formula (1) it means a group: or another group: Y. R4 represents a halogen atom. In the present invention, a cyclopentyl group which may have a substituent, a cyclohexyl group which may have a substituent, a cyclopentenyl group which may have a substituent, a cyclohexenyl group which may have a substituent, a phenyl group which may having a substituent, a pyrrolidinyl group which may have a substituent, a piperidinyl group which may have a substituent, an imidazolyl group which may have a substituent, a thiazolyl group which may have a substituent, a thiadiazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, a thiazolidinyl group which may have a substituent, a morpholinyl group which may have a substituent, a piperazinyl group which may have a a substituent, a thiomorpholinyl group which may have a substituent, a group or pyrrolyl which may have a substituent, a thienyl group which may have a substituent, a furanyl group which may have a substituent, a tetrahydropyrimidinyl group which may have a substituent, a tetrahydrofuranyl group which may have a substituent, a tetrahydrothienyl group which may have a substituent, a sulfolanyl group which may have a substituent, an imidazolinyl group which may have a substituent, a thiazolinyl group which may have a substituent, an oxazolyl group which may have a substituent, an oxadiazinyl group which may have a substituent, a group triazinyl which may have a substituent, a tetrazinyl group which may have a substituent, a pyrazinyl group which may have a substituent, a pyrazolyl group which may have a substituent, a pyrazolinyl group which may have a substituent, a pyrazolidinyl group which may have a substituent, a thienopyridyl group that can have a substituyent e, a tetrahydrothienopyridyl group which may have a substituent, a thiazolopyridyl group which may have a substituent, and a tetrahydrothiazolopyridyl group which may have a substituent. Preferred substituents of saturated or unsaturated 5 or 6 membered cyclic hydrocarbon groups, each of which may have 1 to 3 substituents selected from the group consisting of a hydroxyl group, alkyl groups, hydroxyalkyl groups, halogen atoms, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, a formyl group, alkylsulfonyl groups, amino groups which may have 1 or 2 substituents, aminosulfonyl groups which may have, in their amino portion, 1 or 2 substituents, aminoalkyl wherein the amino portion may have one or two substituents, an oxygen, a trifluoromethyl group, halogen atoms, a hydroxyl group, amino groups, alkoxyl groups, alkyl groups, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, aminocarbonyl groups which may have 1 or 2 substituents in their portion amino, aminosulfonyl groups which may have 1 or 2 substituents on their amino moiety, aminoalkyl groups which may have 1 or 2 substituents on their amino moiety, and a trifluoromethyl group; and saturated or unsaturated 5 or 6 membered heterocyclic groups which may have 1 to 3 substituents selected from the group consisting of halogen atoms, a hydroxyl group, amino groups, alkoxyl groups, alkyl groups, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, aminocarbonyl groups which may have 1 or 2 substituents on their amino moiety, amine sulfonyl groups which may have 1 or 2 substituents on their amine moiety, aminoalkyl groups which may have 1 or 2 substituents on their amino moiety, and a trifluoromethyl group. In the present invention, preferred examples of Q2 include a single bond, a carbonyl group and groups represented by the following formula: Among the groups represented by the following formula: divalent groups derived from benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazoline, furan, thiophene, pyrrole, oxazole, oxazoline, thiadiazole, cyclopentane, cyclopentene, cyclohexane or cyclohexene are preferred. Particularly preferred is the case in which: Q3 represents the following group: [wherein R8, R9, a, b and c have the same meanings described above]; and Ti represents a carbonyl group. The sulfonyl derivative of the present invention has optical isomers or stereoisomers based on an asymmetric carbon atom. These optical isomers and stereoisomers and their mixtures are all encompassed in the present invention. There is no particular limitation on the salt of the sulfonyl derivative according to the present invention, as long as it is pharmaceutically acceptable. Specific examples include salts of a mineral acid such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and benzoate, and salts of organic sulfonic acids such as methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, and salts of a carboxylic acid organic such as acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate. There is no particular limitation on the solvate, as long as it is pharmaceutically acceptable. Specific examples include hydrates and ethanolates. The following are the preferred compounds of the sulfonyl derivative of the present invention. 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine-2-carboxylic acid hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) nicotinyl] piperazine hydrochloride; 4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide; 1- [4- (2-aminopyridin-5-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- [imidazol-4 (5) -yl] benzoyl] piperazine hydrochloride; 1- [4- [2-aminoimidazol-4-yl] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; N-oxide of 2- [4 - [(4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine; 2- [4 - [[4-] iodide [(6-chloronaphthalen-2-yl) sulfonyl) piperazin-1-yl] carbonyl] phenol] -1-methylpyridinium; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride; 1 - [(E) -4-chlorostyrylsulfonyl] -4- [4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride; N-oxide of 2- [4 - [[4 - [(E) -4-chlorostyrylsulfonyl] p-piperazin-1-yl] carbonyl] phenyl] pyridine; 1 - [(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 3- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] -1-methylpyridinium iodide; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-hydroxy-4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-4- [4- (pyridin-4-yl) benzoyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine-2-carboxylic acid; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-3-yl) benzoyl] piperazine hydrochloride; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; N-oxide of 4- [4 - [[2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] p¡perazin-1-yl] carbonyl] phenyl] pyridine; N-oxide of 4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazin-1-yl] carbonyl] phenyl] pyridine; N-oxide of 4- [4 - [[2-carboxy-4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine; 2-carbamoyl-4 - [(E) -4-chlorostyrylsulfonyl] - [1 - [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 1- [trans-4- (aminomethyl) cyclohexylcarbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [[(6RS) -6-aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl] -4- (6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [(7-aminomethylnaphthalen-2-yl] carbonylj-4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl] sulfonyl] -4 hydrochloride - [4 - [[(3S) -pyrrolidin-3-yl] oxy] benzoyl] piperazine; 1 - [(6-chloronaphthalen-2-yl] sulfonyl] -4- [4 - [(3RS) -pyrrolidin hydrochloride] -3-yl) benzoyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-hydrochloride] il) carbonyl] piperazine; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1 - [(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 hydrochloride] -yl) carbonyl] piperazine; 2-carboxy-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [(4,5,6,7-tetrahydrothieno [3,2-c] pyridine- hydrochloride] 2-yl) carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothione [3,2-c] pyridine -2-yl) carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[5- (1-pyrrolin-2-yl) -4,5,6,7- hydrochloride] tetrahydrothieno [3,2-c] pyridin-2-yl] carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) s hydrochloride ulfonyl] -4 - [(4, 5,6,7-tetrahydro-azolo [5,4-c] pyridin-2-yl] carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl hydrochloride ] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(6-formyl-4,5,6,7-tetrahydroxyzolo [5,4-c] pyridin-2-yl) carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[6-methyl-4,5,6,7-tetrahydroxyzolo [5,4-c] pyridin-2-yl) carbonyl] hydrochloride] piperazine; 2 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6,6-dimethyl-4,5,6,7-tetrahydric acid iodide [5.4 -c] pyridinium; N - oxide of 2 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] pyridine; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- (4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine trifluoroacetate; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl hydrochloride] ) carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[6- (2-hydroxyethyl) -4,5,6,7-tetrahydrothiazole [5,4-c] pyridinyl hydrochloride] 2-yl] carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[6- (pyridin-3-yl) methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- hydrochloride] 2-yl] carbonyl] piperazine; 1 - [(E) -4-chlorostyrylsulfonyl] -4 - [(4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[(1 RS) -4- (pyridin-4-yl) -3-cyclohexenyl] carbonyl] piperazine hydrochloride; cis-, trans-1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [[4- (pyridin-4-yl) -cyclohexanyl] carbonyl] -piperazine hydrochloride; 6 - [[4 - ((6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -2,2-dimethyl-1, 2,3,4-tetrahydroisoquinolinio iodide; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (1, 2,3,6-tetrahydropyridin-4-yl) benzoyl] piperazine hydrochloride; 1 - ([(E) -2- (6-chloropyridin-3-yl) vinyl] sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine; hydrochloride of 1 - [(6 -chloronaphthalen-2-yl) sulfonyl] -4- [2-methyl-4- (pyridin-4-yl) benzoyl] piperazine; N-oxide of 4- [4 - [[4 - [(6-chloronaphthalene-2 -yl) sulfonyl] piperazin-1-yl] carbonyl] -2-methylphenyl] pyridine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-methylpyridin-4-yl hydrochloride] benzoyl] piperazine; 4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -piperazin-1-yl] carbonyl] pheny] -2-methylpyridine N-oxide; N-oxide of 4- [4 - [[4- (6-chloronaphthalen-2-ll) sulfonyl] -2 - [[2- (morpholin-4-yl) ethylamino] carbonyl] p -perazin-1-yl] carbonyl] phenyl] pyridine; 4- [4 - [[4 - ((6-chloronaphthalen-2-yl) sulfonyl] -2 - [[2- (dimethylamino) ethylamino] carbonyl] piperazine N-oxide -1-yl] carbonyl] phenyl] pyridine; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-1- [4- (pyridin-2-yl) benzoyl] piperazine; [(6-chloronaphthalen-2-yl) sulfonyl] -2-carboxymethyl-1 - [4- (pyridin-2-yl) benzoyl] piperazine; 2-carbamoylmethyl hydrochloride l-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [4- (pyridin-2-¡l) benzoyl] piperazine; 1 - [4 - [(3RS) -1-acetimidoylpyrrolidin-3-yl] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-acetoxymethylpyrrolidin-4-yl) benzoyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-hydroxymethylpyridin-4-yl) benzoyl] piperazine hydrochloride; N-oxide of 2-hydroxymethyl-4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl) carbonyl] phenyl] pyridine; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- [4- (2-aminoimidazol-4-yl) benzoyl] piperazine; N - oxide of 2 - [[1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-4-yl] carbonyl-4-phenyl] -6-methylpyridine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (6-methylpyridin-2-yl) benzoyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (3-aminopyridin-2-yl) benzoyl] piperazine hydrochloride; N-oxide of 4- [4 - [[1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-4-yl] carbonyl] -3-methylphenyl] pyridine; 1- [2-tert-butoxycarbonyl-4- (pyridin-4-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine; 1- [2-carboxy-4- (pyridin-4-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine; 1- (4-amidinobenzoyl) -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [4- [imidazol-4 (5) -yl] benzoyl] piperazine hydrochloride; 1- [4- (2-aminopyridin-4-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride; 1- [4- (2-aminothiazol-4-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine; 2-carbamoyl-4 - [(E) -4-chlorostyrylsulfonyl] -1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; N-oxide of 4- [5 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] pyridin-2-yl] pyridine; N-oxide of 2-amino-4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine; N-oxide of 4- [4 - [[4 - [(E) -4-chlorostyrylsulfonyl] piperazin-1-l] carbonyl] phenyl] pyridine; N-oxide of 4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazin-1-yl] carbonyl] phenyl] pyridine; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-1 - [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; 2-carboxymethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; 2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; 2- [4 - [[2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide; N-oxide of 2-methyl-4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl] pyridine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,3-dimethyl-4- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 2- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-hydroxymethyl-3-methylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide; N-oxide of 4- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,3-dimethylpiperazin-1-yl] carbonyl] phenyl] pyridine; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,6-dimethyl-1 - [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,2-dimethyl-1 - [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride; 2- [4 - [[4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,2-dimethylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-oxo-1 - [4- (pyridin-4-yl) benzoyl] piperazine N-oxide; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2,3-dicarbamoyl-4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-methyl-3- (2- (morpholin-4-yl) ethylamino] carbonyl] -4- [4- (pyridin-4-yl) hydrochloride benzoyl] piperazine; 4- [4 - [[4- (6-chloronaphthalen-2-yl) sulfonyl-3-methyl-2 - [[2- (morpholin-4-yl) ethylamino] carbonyl] N-oxide] piperazin-1-yl] carbonyl] phenyl] pyridine; 2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-1- [4- (pyridin-4-yl) benzoyl hydrochloride ] piperazine; 4- [4 - [[2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -6-methylpiperazin-1-yl] carbonyl] phenyl] pyridine N-oxide; N-oxide of 2- [4 - [[2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -6-oxopiperazin-1-yl] carbonyl] phenyl] pyridine hydrochloride 1 - [(6-chloronaphthalene- 2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] -1,2,3,4-tetrahydroquinoxaline; 1 - [(6-chloronaphthalen-2-yl) sulfonyl hydrochloride] -4- [4- (pyridin-4-yl) benzoyl] decahydroquinoxaline; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -3 - [(ethoxycarbonylmethylsulfonyllamino) methyl] -2-methyl hydrochloride -4- [4- (pyridin-2-yl) benzoyl] piperazine; hydrochloride 2-carbamoylmethyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-oxo-1 - [4- (pyridin-2-yl) benzoyl] piperazine; 1 - [(6-chloroanephthalen-2-yl) sulfonyl-3- (imidazol-4-yl) methyl-2-oxo-4- [4- (pyridin-2-yl) benzoyl] piperazine hydrochloride; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [4- (pyridin-4-yl) benzoyl] -7-oxodecahydropyrido [3,4-b] pyrazine hydrochloride; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-1 - [(6-methyl-4,5,6,7-tetrahydrothiazole hydrochloride (5,4-c) ] pyridin-2-yl) carbonyl] piperazine; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -6-methyl-1 - [(6-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine; 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [(6-methyl-4,5) hydrochloride , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2 - [[2- (morpholin-4-yl) ethylamino] carbonyl] piperazine; 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) carbonyl] piperazine hydrochloride; 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-methyl-1 - [(6-methyl-5,6,7,8-tetrahydropyrid-1, 6 hydrochloride. -naphthyridin-2-yl) carbonyl] piperazine. Next, the process for the preparation of the sulfonyl derivative of the present invention will be described. The sulfonyl derivative or salt or solvate thereof according to the present invention can be prepared using conventionally known general chemical methods in combination. Subsequently, typical synthesis procedures will be described. For the synthesis of the sulfonyl derivative of the present invention, when it is necessary to protect a substituent such as a nitrogen atom, a hydroxyl group or a carbonyl group, these can be protected with a conventional conventionally known protecting group that can be removed as necessary. Said protecting group can be removed at will by means of the synthesis method ordinarily employed in organic chemistry which will be described below. The starting materials necessary for the synthesis can be obtained by means of synthesis methods ordinarily employed in organic chemistry and said methods will be described in the Reference Examples. The starting materials can also be synthesized by applying the procedure described in the Reference Examples. Next, a description will be made of a protecting group for a substituent such as the nitrogen atom, the hydroxyl group or the carboxyl group, and a method of deprotection thereof. As a protecting group for the nitrogen atom in an amino or alkylamino group, ordinary acyl-type protecting groups are suitable. Examples include alkanoyl groups such as acetyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; arylmethoxycarbonyl groups such as benzyloxycarbonyl; paramethoxybenzyloxycarbonyl and para- (ortho-) nitrobenzyloxycarbonyl groups; arylmethyl groups such as benzyl- and triphenylmethyl; and aroyl groups such as benzoyl. The removal procedures of said protective group differ with the chemical properties of the protective group adopted. For example, the acyl-type protecting group, such as alkanoyl, alkoxycarbonyl or aroyl, can be removed by hydrogenolysis using an appropriate base such as alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide. The substituted methoxycarbonyl type protecting group such as tert-butoxycarbonyl or para-methoxybenzyloxycarbonyl can be removed using an appropriate acid, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, or combination of them. The arylmethoxycarbonyl group such as benzyloxycarbonyl, para-methoxybenzyloxycarbonyl or para- (ortho-) nitrobenzyloxycarbonyl, or the arylmethyl group such as benzyl, can be removed by hydrogenolysis in the presence of a palladium-carbon catalyst. The benzyl group can also be removed by reduction of Birch in liquid ammonia, in the presence of metallic sodium, by means of which conversion to a nitrogen-hydrogen bond can be effected. The triphenylmethyl group can be removed using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, or combination thereof. It can also be removed by Birch reduction in liquid ammonia, in the presence of metallic sodium or by hydrogenolysis in the presence of a palladium-carbon catalyst. In addition to the amino-protecting group mentioned above, a phthaloyl-type protecting group for a primary amino group can be adopted and can be removed using hydrazine, dimethylaminopropylamine or the like. As the protective group suitable for a hydroxyl group, there are the acyl-type and ether-type groups. Examples of the acyl-type protecting group include alkanoyl groups such as acetyl and aroyl such as benzoyl, while those of the ether-type protecting group include arylmethyl groups such as benzyl, silyl ether such as tert-butyl dimethylsilyl, methoxymethyl and tetrahydropyranyl. The removal of said protective group differs with the chemical properties of the protective group adopted. For example, the acyl group such as alkanoyl or aroyl can be removed by hydrogenolysis using an appropriate base such as an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide. The arylmethyl type protecting group can be removed by hydrogenolysis using a palladium-carbon catalyst. The silyl group such as tert-butyl dimethylsilyl can be removed using a hydrofluoride salt such as tetrabutylammonium fluoride. The methoxymethyl or tetrahydropyranyl group can be removed using acetic acid, hydrochloric acid or the like. The hydroxyl group substituted with an aryl group can be protected with a methyl group and the deprotection can be carried out using a Lewis acid such as aluminum chloride or phosphorus tribromide, trimethylsilyl iodide or hydrogen bromide. A carboxyl group can be protected by its esterification.

A methyl or ethyl ester can be deprotected by hydrogenolysis using an appropriate base such as alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, while the tert-butyl group can be removed from an ester ter. -butyl by treatment with trifluoroacetic acid or hydrochloric acid. The arylmethyl group can be removed from an arylmethyl ester by hydrogenolysis in the presence of a palladium-carbon catalyst.

Preparation process 1 A process for preparing a sulfonyl derivative represented by the following formula (I): [wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings described above], which comprises sulfonating the nitrogen atom of Q3a of the compound represented by the following formula ( ): Ql.Q2.t1.Q3a (| a) [wherein Q1, Q2 and Ti have the same meanings described above and Q3a represents any of the groups represented by the following formulas: (in which R8, R9, R10, R1 1, R12? R13> R14_ R15? R16, 17, a> b, c, d, e, f, g, h, ei, have the same meanings as above) ], with a sulfonyl halide represented by the following formula (Na): [wherein R1, R2, R3, R4, Rβ, γ1 and X2 have the same meanings described above and Halo represents a halogen atom such as chlorine, bromine or iodine].

Synthesis of the compound of formula (la) The compound of formula (la) can be synthesized by a series of operations according to the known technique. For example, a compound of the following formula (Ib): Q1-C2_t1_Q3b (ib) [where Q1, Q2 and T ^ have the same meanings as described above and Q3b represents any of the following groups: (wherein R8, R9, R10, R1 1, R12, R3, R4, R5, R16, R17J a> b> c> d, g, g, h, ei, have the same meanings described above and R21 represents an ordinary nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl or benzyl)], can be synthesized by acylation of the nitrogen atom of the compound represented by the following formula (Illa): Q3 ° -H (Illa) (where Q3 has the same meaning as described above), to whose nitrogen atom the hydrogen atom of O3 3 is bound, with a carboxylic acid in an activated form represented by any of the following formulas (IVa) to (IVd): Ql_Q2b_c00H (IVa) Q1-N (R20) - (CH2) m? -COOH (IVb) Q1-0- (CH2) m1-COOH (IVe) Q -S- (CH2) m1-COOH (IVd) [wherein Q 1 has the same meaning as described above, R 2 represents a linear or branched alkylene or an ordinary nitrogen protecting group such as tert-butoxocarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl or benzyl, Q 2b represents a single bond, a linear or branched alkylene of C-μβ, a linear or branched C 2-6 alkenylene, linear or branched C 2-6 alkynylene or a group of the following formula: [which has the same meaning as described above) and m1 represents an integer from 1 to 6]. When the carbon atom of the compound represented by the formula (Illa) forms an amide bond, the compound of the formula (Ib) can be synthesized by alkylation of the Cfib nitrogen atom of the compound represented by the formula (Illa) with any of the compounds represented by the following formulas (Va) a (Vd): Q1_Q2b_cHLl Rl8 (Va) Q1-N (R20) - (CH2) m? -CHLl Rl8 (Vb) Q -O- (CH2) mi-CHL R18 (Go) Q -S- (CH2) mi-CHLl Rl8 (IVd) [wherein Q ^, Q2b, R ^ 8, R ^ and m1 have the same meaning as described above, and represents an elimination group frequently used in organic chemistry, such as chlorine, bromine, iodine, methylsulfonyloxy, para-toluenesulfonyloxy] . When the Qβb nitrogen atom of the compound represented by the formula (Illa) exists as a primary or secondary amine, the compound of the formula (Ib) can be prepared by reductive alkylation, that is, by forming the corresponding imine with a carbonyl compound depicted by any of the following formulas (Via) to (Vid): Q1-Q2 -C (= O) R18 (Via) Q1-O- (CH2) m? -C (= O) R18 (Vlc) wherein Q1, Q2b, R18, R20 and m1 have the same meanings described above], followed by reduction; by reaction of the compound of formula (Illa) with a reagent such as 1, r-carbonyldiimidazole and a compound containing a primary amine represented by any of the following formulas (Vlla) a (Vlld): Q1-Q2-NH2 (Vlla) Ql -N (R20) - (CH2) m2-NH2 (Vllb) A1-O- (CH2) m2-NH2 (Vllc) Q -S- (CH2) m2-NH2 (Vlld) N- H (Vlle) [where Q1, Q2 and R20 have the same meanings described above and m2 represents an integer from 2 to 6, and a group of the following formula: N- H represents a 5- or 6-membered heterocyclic group which may have a substituent], thereby forming a urea derivative; or by reacting the amine of formula (Illa) with an isocyanate derivative or an isocyanate prepared from a carboxylic acid represented by any of the formulas (IVa) to (IVd). When, in the structure of Q1 of the compound represented by the formula (Ib), an aryl group substituted by halogen or trifluoromethane-sulphonyloxy or a halogen-substituted or alkenyl group is contained, the coupling reaction can be carried out with a substituted aryl compound with boric acid in the presence of a transition metal catalyst. When an alkenyl group is contained in the Q1 structure of the compound represented by the formula (Ib), it can be subjected to a coupling reaction with an aryl group substituted with halogen or substituted with trifluoromethanesulfonyloxy in the presence of a transition metal catalyst. When an aryl group substituted with boric acid is contained in the Q1 structure of the compound represented by the formula (Ib), it can be subjected to a coupling reaction with a halogen-substituted aryl compound or with trifluoromethanesulfonyloxy or a halogen-substituted alkenyl compound or with trifluoromethanesulfonyloxy. When an aryl group substituted by halogen or with trifluoromethanesulfonyloxy is contained in the Q1 structure of the compound represented by the formula (Ib), it can be subjected to coupling reaction with an alkenyl compound in the presence of a transition metal catalyst. If the nitrogen atom of Q3b of the compound (Ib) thus obtained has been protected, the compound of formula (la) can be obtained by deprotection as necessary. Examples of the carboxylic acids of the following formulas (IVa) to (IVd) in an activated form include mixed acid anhydrides, available by reacting any of the carboxylic acids of the formulas (IVA) to (IVd) with an ester chloroformate such as butyl chloroformate, acid halides such as acyl chloride prepared using an acid halide such as thionyl chloride, active esters obtained by reaction with a phenol such as para-nitrophenol or pentafluorophenyl trifluoroacetate, active esters obtained by reaction with N-hydroxybenzotriazole or N-hydroxysuccinimide, reaction products with N, N'-dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, which is usually used for peptide amino acid synthesis, reaction products with diethyl cyanophosphonate (Shiori method) and reaction products with triphenylphosphine and 2,2, -dipyridyl sulfide (Mu method) kaiyama). The resulting carboxylic acid in an activated form is then reacted with the compound of formula (Illa) or salt thereof generally in the presence of an appropriate base in an inert solvent at a temperature of -78 ° C to 150 ° C, with which is obtained the compound of formula (Ib). Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases exemplified by alkyllithium as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine and diazabicyclo [5.4.0] -7-undequene (DBU). Examples of the inert solvent include alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition to them, sulfoxide solvents such as dimethyl sulfoxide and sulfolane and ketone solvents such as acetone and methyl ethyl ketone can be used, if appropriate. When the nitrogen atom of Q3b of the compound represented by the formula (Illa) forms an amide bond, the alkylation of the nitrogen atom is carried out by reacting the compound (Illa) with a compound represented by any of the formulas (Go to (Vd) in the presence of an appropriate base in an inert solvent at a temperature of -78 to 150 ° C, by means of which the compound of formula (Ib) can be obtained.Specific examples of the base include from the base include alkoxides and hydrides of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, organic metal bases exemplified by alkyl lithium such as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; organic solvents such as diazabicyclo [5.4.0] -7-undekene (DBU) Examples of the inert solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and amide solvents. such as N, N-dimethylformamide. When the nitrogen atom of Q3b of the compound represented by the formula (Illa) exists as a primary or secondary amine, the compound of formula (Ib) can be obtained by reacting the compound of formula (Illa) with the carbonyl compound of any of the formulas (Via) to (Vid) to form the corresponding imine, generally in an inert solvent, in the presence of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid, or a Lewis acid such as aluminum chloride at a temperature -20 to 150 ° C; and then hydrogenation of the resulting imine in an inert solvent in the presence of a borohydride reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or a reduction catalyst such as palladium-carbon catalyst at a temperature of 10 to 110 ° C. Preferred examples of the inert solvent include carbohalides such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; solvents such as benzene such as toluene, and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one When the nitrogen atom of Q3 of the compound represented by the formula (Illa) exists as a primary or secondary amine, the reaction product between a compound of any of the formulas (Vlla) to (Vllb) containing a primary amine, or the compound of formula (VIle) containing a secondary amine, and a reagent such such as 1, 1-carbonyldiimidazole, can be reacted with the compound of formula (Illa) to be introduced into the corresponding urea derivative. The derivative can be synthesized by reacting the primary amine compound of any of the formulas (Vlla) to (Vlld) or the secondary amine compound of the formula (Vlle), a reagent such as carbonyldiimidazole and the compound of the formula (Illa) successively in this order, if necessary in the presence of a base, in an inert solvent. Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; solvents such as benzene such as toluene, and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one. Among them, dichloromethane, tetrahydrofuran and toluene are preferred. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU). The reaction is carried out on a temperature scale of -70 to 1 10 ° C. When the nitrogen atom of Q3b of the compound represented by the formula (Illa) exists as a primary or secondary amine, the compound of formula (Ib) can also be obtained by reacting the compound of formula (Illa) with an isocyanate derivative in an inert solvent at a temperature of -20 to 100 ° C. The isocyanate derivative can be synthesized by converting the carboxylic acid of formula (IVa) into the corresponding acid halide using an acid halide such as thionyl chloride or oxalyl chloride in an inert solvent such as tetrahydrofuran, chloroform or toluene, to a temperature from -20 to 110 ° C, by reacting the resulting acid halide with sodium azide in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature range of 0 to 80 ° C, and then heating the reaction mixture to a temperature of from 0 to 80 ° C. 20 to 100 ° C; reacting the carboxylic acid of formula (IVa) with a chloroformate such as isobutyl chloroformate in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature of -20 to 110 ° C to obtain the corresponding mixed acid anhydride, reacting the mixed acid anhydride with sodium azide on a temperature scale from 0 to 80 ° C and then heating the reaction mixture from 20 to 100 ° C; or introducing the carboxylic acid of formula (IVa) into the corresponding hydrazide by an ester in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature of -20 to 110 ° C, reacting the hydrazide with nitric acid or an alkyl ester of the same to convert it into the corresponding acyl azide and then heating the resulting acyl azide in a solvent such as chloroform, dichloroethane, toluene, xylene or N, N-dimethylformamide at a temperature of 20 to 150 ° C. The compound of formula (Ib) can also be prepared by reacting the carboxylic acid of formula (IVa) with diphenylphosphorylazide in the presence of a base such as triethylamine, in an inert solvent such as chloroform, tetrahydrofuran, toluene or N, N-dimethylformamide a a temperature scale of 10 to 140 ° C and then reacting the reaction mixture with the amine of formula (Illa).

When in the Q1 structure of the compound represented by the formula (Ib) a halogen or trifluoromethanesulfonyloxy substituted aryl group or a halogen or trifluoromethanesulfonyloxy substituted alkenyl group is contained, the compound can be subjected to coupling reaction with a substituted aryl derivative with boric acid using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0), in a diphasic solvent such as benzene-water or toluene-water, amide solvent such as N, N-dimethylformamide or ether solvent such as tetrahydrofuran or dimethoxyethane, in the presence of a base such as sodium carbonate, sodium hydroxide, barium hydroxide, potassium phosphate or cesium carbonate at a temperature range of 20 to 150 ° C for 0.5 to 120 hours. When an alkenyl group is contained in the structure of Q1 of the compound represented by the formula (Ib), coupling reaction of the compound with an aryl group substituted with halogen or trifluoromethanesulfonyloxy can be carried out using a transition metal catalyst such as palladium acetate , in the presence of an appropriate base, in an amide solvent such as N, N-dimethylformamide, at a temperature range of 20 to 150 ° C for 0.5 hour to 120 hours. When an aryl group substituted with boric acid is contained in the Q1 structure of the compound represented by the formula (Ib); or coupling reaction of the compound can be carried out with an aryl derivative substituted with halogen or trifluoromethanesulfonyloxy or a substituted alkenyl derivative with halogen or trifluoromethanesulfonyloxy. When an aryl group substituted with halogen or trifluoromethanesulfonyloxy is contained in the Q1 structure of the compound represented by the formula (Ib), coupling reaction of the compound with an alkenyl group using a transition metal catalyst can be carried out. If the nitrogen atom of Q3b of the compound represented by the formula (Ib) has been protected as described above, the compound of the formula (la) can be obtained by deprotection as necessary.

Synthesis of the compound represented by the formula (lia) The sulfonic acid halide of the formula (lia) can be synthesized by means of any of the various conventionally reported procedures ("The Chemistry of Sulfonic Acid Esters and their Derivatives", edited by S. Patai and Z. Rappoport, 1991, John Wiley &Sons Ltd.), for example, halogenation of the corresponding sulfonic acid of the following formula (lb): or halogensulfonation of a n-saturated-bond-containing compound represented by the following formula (lie): [wherein in the above formulas (llb) and (He), R, R2, R3, R4, R5, X1 and X2 have the same meanings described above]. For example, the sulfonic acid halide of formula (Ia) can be obtained by reacting the sulfonic acid of formula (Ib) with a thionyl halide in the presence of N, N-dimethylformamide at a temperature of 0 to 150 ° C for 0.5. to 24 hours. At this time, the reaction system can be diluted with a solvent such as dichloromethane, chloroform, carbon tetrachloride, N-methylpyrrolidin-2-one, dimethyl sulfoxide or sulfolane. The sulfonic acid halide of formula (lia) can also be obtained by reacting the unsaturated-containing compound of formula (I) with a thionyl halide or chlorosulfonic acid in a solvent such as N, N-dimethylformamide at a temperature of 0 to 150 ° C for 0.5 to 24 hours. The compound of formula (I) can be obtained generally by reacting the compound of formula (la), which has been synthesized by the process described above or a similar one, with the sulfonic acid halide of formula (Ia) which has been synthesized by the procedure described above or a similar one, in the presence of an appropriate base, in an inert solvent at a temperature of -78 to 150 ° C.

Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases exemplified by alkyllithium as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU). Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide, sulfolane and acetone.

Preparation procedure 1- (1) When the nitrogen atom of Q3a of the compound represented by the formula (s) to be sulfonated, exists as a primary or secondary amine, preferred examples of the base include carbonates and hydroxides of a alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [ 5.4.0] -7-undequene (DBU); and useful examples of the solvent include, in addition to the inert solvents, alcoholic solvents such as ethanol and butanol and ester solvents such as ethyl acetate.

Preparation procedure 1 (2) When the nitrogen atom of Q3 of the compound represented by the formula (s) to be sulphonated forms an amide group, preferred examples of the base include alkali metal or alkaline earth metal alkoxides and hydrides such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride; organic metal bases exemplified by alkyllithium as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; and organic bases such as diazabicyclo [5.4.0] -7-undequene (DBU). Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane, and N, N-dimethylformamide.

Preparation process 2 A process for preparing the sulfonyl derivative (I) by acylation of the Q3a nitrogen atom of the compound represented by the formula (Villa): [wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings described above], with a carboxylic acid the following formula (IVa): Q1-Q2-COOH (IVa) [wherein Q1 and Q2 have the same meanings described above] or the carboxylic acid in an activated form. The compound of the following formula (Vllb): (Vlllb) [wherein R1, R2, R3, R4, R, X1, X2, and Q3b have the same meanings described above], can be obtained by sulfonation of the nitrogen atom of the primary amine, the secondary amine or the amide of the compound of formula (Illa) with a sulfonic acid halide represented by the following formula (lia): [wherein R1, R2, R3, R4, R1, X1, X2 and Halo represent the same as above] in the presence of an appropriate base in an inert solvent at a temperature of -78 to 150 ° C. Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases exemplified by alkyllithium as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU). Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide, sulfolane and acetone. If the nitrogen atom of Q3b of the resulting compound represented by the formula (Vlllb) has been protected, the compound of the formula (Villa) can be obtained by deprotection as necessary. The compound of formula (Villa) can be obtained by removing the protecting group from the nitrogen atom of the compound represented by the following formula (VI I le): (Vlllc) [wherein R2, R3, R4, Rβ, X1 and X2 have the same meanings as described above and Q3c represents any of the following groups: (Wherein R22 represents a hydrogen atom, an alkyl group, a hydroxyl group protected with methoxymethyl, tetrahydropyranyl or the like, a hydroxyalkyl group protected with methoxymethyl, tetrahydropyranyl or the like, an alkoxyl group, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylamino group, a monoalkylamino group in which the amino moiety has been protected with tert-butoxycarbonyl a dialkylaminoalkyl group, a monoalkylaminoalkyl group in which the amino moiety has been protected with tert-butoxycarbonyl, dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, one dialkylaminoalkyloxy group, a monoalquilaminoaminoalquiloxi group in which the amino moiety has been protected with tert-butoxycarbonyl, one dialquilaminoalquilalquiloxi group, a monoalquilaminoalquiloxi group in which the amino moiety has been protected with tert-butoxycarbonyl, a group dialquilaminocarbonilalquiloxi or the like. When the carbon atom to which R23, R24, R2 ^ or R28 is attached is not adjacent to the nitrogen atom, R23, R24, R2 ^ and R28 each independently represent: a hydrogen atom, an alkyl group, a protected hydroxyl group with methoxymethyl, tetrahydropyranyl or the like, a hydroxyalkyl group protected with methoxymethyl, tetrahydropyranyl or the like, an alkoxyl group, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylamino group, a monoalkylamino group in which the amino moiety has been protected with tert -butoxycarbonyl a dialkylaminoalkyl group, a monoalkylaminoalkyl group in which the amino moiety has been protected with tert-butoxycarbonyl, dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, a dialkylaminoalkyloxy group, a monoalquilaminoaminoalquiloxi group in which the amino moiety has been protected with tert -butoxycarbonyl, a dialkylaminocarbonylalkyloxy group, a monoalkylaminoalkyl group uyloxy in which the amino portion has been protected with tert-butoxycarbonyl, a dialkylaminocarbonylalkyloxy group or the like. When the carbon atom to which R23, R24, R2 ^ or R28 is adjacent to the nitrogen atom, R23, R24, R2 ^ and R28 each independently represent: a hydrogen atom, an alkyl group, a hydroxyalkyl group protected with methoxymethyl, tetrahydropyranyl or the like, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylaminoalkyl group, a monoalkylaminoalkyl group in which the amino portion has been protected with tert-butoxycarbonyl, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, a dialkylaminoalkyloxy group, or the like. R23 and R24, as well as R25 and R28, may be coupled together to form a 5-7 membered saturated or unsaturated cyclic hydrocarbon group which may have a substituent, or a 5-7 membered saturated or unsaturated heterocyclic group that can have a substituent. R2 represents: an alkyl group, a hydroxyalkyl group in which the hydroxyl portion has been protected, a hydroxyalkylcarbonyl group in which the hydroxyl portion has been protected, a hydroxyalkylsulfonyl group in which the hydroxyl portion has been protected, an alkoxyalkyl group, an alkoxyalkylcarbonyl group, an alkoxyalkylsulfonyl group, an alkylcarbonyl group, an alkylcarbonylalkyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group, a dialkylaminoalkyl group, a monoalkylaminoalkyl group in which the amino portion has been protected with tert-butoxycarbonyl, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, or similar. R25 and R27_ or R26 and R27 may be coupled together to form a 5-7 membered saturated or unsaturated heterocyclic group which may have a substituent. R28 represents a tert-butoxycarbonyl, benzyl or triphenylmethyl group, j and k each independently represent an integer of 0 or 1 and I represents an integer from 1 to 3, with the proviso that the sum of k and I represents an integer from 1 to 4 )]. The compound represented by the formula (VI I le) can be obtained by reacting an amino compound which is available by the known process thereof and is represented by the following formula (IIIb): Q3c-H (IIIb) [wherein Q3c has the same meaning as mentioned above] with an alkylsulfonic acid halide in the presence of an appropriate base; by reacting the resulting sulfonamide represented by the following formula (IXa): [wherein R3 and Q3c have the same meaning as mentioned above] with a carbonyl compound represented by the following formula (Xla): [wherein R2, R3, R4, R22, X "! and X2 have the same meanings described above] in an inert solvent, in the presence of an appropriate base to obtain the alcohol product represented by the following formula (Xlla): [wherein R2, R3, R4, R22, Q3c,? 1 and X2 have the same meanings described above]; converting the alcohol moiety of the alcohol product (Xlla) to a methanesulfonyloxy group or the like in the presence of an appropriate base, or converting the alcohol moiety to a halogen atom by a phosphorus halide or triphenylphosphine / carbon tetrahalogenide, thereby forming an elimination group; and then removing methanesulfonic acid or hydrogen halide in the presence of an appropriate base. The sulfonamide compound of formula (IXa) can be obtained by reacting the available amino compound of formula (IIIb) by the known method or application thereof, with an alkylsulfonic halide which can have a substituent, in the presence of an appropriate base, in an inert solvent at a temperature of -78 to 150 ° C. Examples of the base include carbonates of an alkali metal or alkaline earth metal such as sodium carbonate and potassium carbonate, and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine and diazabicyclo [ 5.4.0] -7-undequene (DBU). Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one. Dimethyl sulfoxide, sulfolane, acetone or the like can be used, although it depends on the type of bases used. The alcohol compound of formula (Xlla) can be obtained by reacting the sulfonamide of formula (IXa) with a carbonyl of formula (Xla) in the presence of an appropriate base in an inert solvent at a temperature of -78 to 110 ° C. Examples of the base include alkali metal or alkaline earth metal hydrides such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, and organic metal bases such as n-butyllithium and lithium diisopropylamide. Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane and dioxane. The compound of formula (Vlllc) can be obtained by treating the hydroxyl group of the alcohol of formula (Xlla) with a phosphorus halide such as phosphorus pentachloride or a triphenylphosphine-halogen complex such as triphenylphosphine dibromide, in the presence of an appropriate base, example, alkali metal or alkaline earth metal carbonate such as sodium or potassium carbonate, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] - 7-undekene (DBU), in a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene or NN-dimethylformamide at -20 -110 ° C, thus obtaining the corresponding halide, and then removing the hydrogen halide from the resulting halide under basic conditions, for example, treating at a temperature of -78 to 110 ° C, with a carbonate, alkoxide, hydroxide or alkali metal hydride or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, an organic metal base such as n-butyllithium and lithium diisopropylamide, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU), in dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran , 1, 2-dimethoxyethane, dioxane, toluene or NN-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulfoxide. The compound of formula (VI I le) can also be obtained by treating the hydroxy group of the alcohol represented by the formula (Xlla) with an alkyl- or arylsulfonic acid chloride such as methanesulfonic acid chloride in the presence of an appropriate base, for example, an alkali metal or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7 -undequene (DBU), in a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene or NN-dimethylformamide, at a temperature of -20 to 110 ° C, to obtain the alkyl derivative - or corresponding arisulfonate; and then removing the alkyl- or arylsulfonic acid from the corresponding derivative under basic conditions, specifically, treating the resulting alkyl- or aryisulfonate derivative at a temperature of -78 to 150 ° C in the presence of an alkali metal carbonate, alkoxide, hydroxide or hydride. or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, an organic metal base such as n-butyllithium and lithium diisopropylamide, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine or diazabicyclo [5.4.0] -7-undequene (DBU), in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene or NN-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulfoxide. The compound of formula (VI I le) can also be obtained by treating the sulfonamide of formula (IXa) with a silyl halide such as trimethylsilyl chloride, in the presence of an appropriate base, in an inert solvent, to convert it to the corresponding compound of silyl, reacting the resulting silyl with a carbonyl compound of formula (Xla) in the presence of a base in an inert solvent, and then treating the reaction product under aqueous acidic to basic conditions (Peterson reaction). Specifically, the compound of formula (Vlllc) can be obtained by treating the sulfonamide of formula (IXa) with an alkylsilyl chloride such as trimethylsilyl chloride at a temperature of -78 to 110 ° C in the presence of an alkali metal or alkaline earth metal hydroxide such as sodium ethoxide, potassium butoxide, sodium hydride or potassium hydride, or an organic metal base such as lithium n-butyllithium or diisopropylamide, in an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, to convert it into the corresponding silyl compound, condensing with the carbonyl compound of formula (Xla) under the same conditions and then treating the condensate under aqueous conditions of basic acids. The protecting group for the nitrogen atom of the compound represented by the formula (Vlllc) can be removed by the method ordinarily employed. Specifically, when the protecting group is a tert-butoxycarbonyl group, it can be removed using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or acidic trifluoromethanesulfonic acid, or combinations thereof. The aryl-methyl group, such as benzyl, can be removed by hydrogenolysis in the presence of a palladium-carbon catalyst. The triphenylmethyl group can be removed using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or acidic trifluoromethanesulfonic acid, or combinations thereof. It can also be removed by reduction of Birch with metallic sodium in liquid ammonia or by hydrogenolysis in the presence of a palladium-carbon catalyst. In this way, the compound of formula (Villa) can be obtained by removal of the protective group of the compound of formula (Vlllc). Examples of the carboxylic acid of formula (IVa) in an appropriate activated form include mixed acid anhydrides, available by reacting the carboxylic acid of formula (IVa) with a chloroformate ester such as isobutyl chloroformate, thereby converting it into the corresponding acid anhydride; acyl halides such as acyl chloride, prepared by treating with an inorganic acid halide such as thionionyl chloride, active esters obtained by reacting with a phenol such as para-nitrophenol or pentafluorophenyl-trifluoroacetate, active esters obtained by reacting with N-hydroxybenzotriazole or N-hydroxysuccinimide; reaction products with N, N'-dicylohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, which is commonly used in the synthesis of an amino acid; reaction products with diethyl cyanophosphonate (Shiori method) and reaction products with triphenylphosphine and 2,2'-dipyridyl sulfide (Mukaiyama method). The resulting carboxylic acid in an activated form is then reacted with the compound of formula (Villa) at a temperature of -78 to 150 ° C, generally in the presence of an appropriate base in an inert solvent, whereby the sulfonyl derivative of formula (I). Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases exemplified by alkyllithium as n-butyllithium and lithium dialkylamine as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine and diazabicyclo [5.4.0] -7-undequene (DBU). Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide and sulfolane and acetone.

Preparation procedure 2 (1) When the carbon atom of Q3 of the compound of formula (Villa): (Villa) [wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings described above] to be acylated, exists as a primary or secondary amine, preferred examples of the base include carbonates and hydroxides of alkaline or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine and diazabicyclo [5.4.0 ] -7-undequene (DBU); and solvent examples include, in addition to inert solvents, alcohol solvents such as ethanol and butanol, and ester solvents such as ethyl acetate.

Preparation procedure 2 (2) When the carbon atom of Q3 of the compound of formula (Villa): (Villa) [wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings described above] to be acylated, forms an amide bond, examples of the base include alkali metal or alkaline earth metal alkoxides and hydrides such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, organic metal bases such as n-butyllithium or lithium diisopropylamide, and organic bases such as diazabicyclo [5.4.0] -7-undekene (DBU), and Preferred examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane and N, N-dimethylformamide.

Preparation Process 3 A process for preparing the sulfonyl derivative of the present invention, in the case in which the nitrogen atom of Q3a of the compound represented by the following formula (Villa): [wherein R1, R2, R3, R4, Rβ,? 1, X2 and Q3a have the same meanings described above] forms an amide, by alkylation of the nitrogen atom of the compound represented by the formula (Villa), with the compound represented by any of the following formulas (Va) to (Vd): Ql_Q2b_cHL1R18 (Va) Q -N (R20) - (CH2) m? -CHL1R18 (Vb) Q -O- (CH2) m? - CHL1R18 (Go) Q1 -S- (CH2) m? - CHL1R18 (IVd) [where Q1, Q2b, R18, R20 m1 and L have the same meanings described above]. When the nitrogen atom of Q3a of the compound represented by the formula (Villa) forms an amide bond, the sulfonyl derivative of formula (I) can be synthesized by alkylation of the nitrogen atom with the compound of any of the formulas (Va) (Vd), specifically, by reacting the compound of formula (Villa) with a compound of any of formulas (Va) to (Vd), at a temperature of -78 to 150 ° C, in the presence of an appropriate base in an inert solvent for 0.5 to 120 hours, thus alkylating the nitrogen atom. Examples of the base include alkali metal or alkaline earth metal alkoxides and hydrides such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, organic metal bases such as n-butyllithium or lithium düsopropylamide, and organic bases such as diazabicyclo [ 5.4.0] -7-undequene (DBU). Preferred examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, toluene, dioxane and N, N-dimethylformamide.

Preparation Method 4 A process for preparing the sulfonyl derivative (I), in the case in which the nitrogen atom of Q3 of the compound represented by the following formula (Villa): (Villa) [wherein R, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings described above] exists as a primary or secondary amine, by formation of the corresponding imine with the carbonyl compound of any of the following formulas ( Via) to (Vid): Ql_Q2b_c (= 0) R18 (Via) Ql-N (R20) - (CH2) mi- C (= O) R18 (Vlb) Ql-O- (CH2) mi-C (= O) R18 (Vlc) Ql-S- (CH2) mi- C (= O) R18 (Vid) [where Ql, Q2b, R18, R20 and m1 have the same meanings described above], followed by reduction. When the nitrogen atom of Q3a of the compound of formula (Villa) exists as an amine, the sulfonyl derivative of formula (I) can be obtained by reacting the compound of formula (Villa) with the carbonyl compound of any of the formulas (Via) to (Vid) at a temperature of - 20 to 150 ° C for 0.5 to 120 hours, generally in an inert solvent and, if necessary, in the presence of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid or a Lewis acid such as aluminum chloride, forming the corresponding imine; and hydrogenating the resulting imine at a temperature of 10 to 110 ° C for 0.5 to 120 hours in an inert solvent in the presence of a boron hydride reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or a reducing catalyst. like palladium-carbon. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, M-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide and sulfolane Preparation Method 5 A process using the reaction in which a urea derivative is formed by reacting, when Q3a of the compound of the following formula (Villa): (Villa) [wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings described above] exists as a primary or secondary amine, the compound of formula (Villa) with the primary amine-containing compound of any of the formulas (Vlla) a (Vlld): Ql_Q2b_MH2 (Vlla) Ql -N (R20) - (CH2) m2- NH2 (Vllb) Q1 -O- (CH2) m2-NH2 (VMc) Q1 -S- (CH2) m2-NH2 (Vlld) or the secondary amine-containing compound of the formula (VI le): Q1- C N-H (Vite) [where in the previous formulas Q1, Q2 * 3, and R20 and m2 have the same meanings described above], and a group of the following formula: - C N- H has the same meaning as described above] using a reagent such as carbonyldiimidazole. When Q3a of the compound represented by the formula (Villa) is an amine, the primary amine-containing compound of any of the formulas (Vlla) a (Vlld), or the secondary amine-containing compound of the formula (Vlle) and a reagent such as 1,1'-carbonyldiimidazole are reacted with the compound of the formula (Villa) to introduce therein the sulfonyl derivative of the formula (I) of the present invention, which is a urea derivative. The derivative can be synthesized by reacting the primary amine-containing compound of any of the formulas (Vlla) to (Vlld) or the secondary amine-containing compound of the formula (Vlle) and then the compound of the formula (Villa), successively with a reagent such as carbonyldiimidazole and, if necessary, in the presence of a base in an inert solvent. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide. and sulfolane. Among them, dichloromethane, tetrahydrofuran and toluene are preferred. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU). It is only necessary to carry out the reaction within a temperature range of -70 ° C to 110 ° C.

Preparation process 6 A process for preparing the urea-containing sulfonyl derivative of the formula (I). In the case where the nitrogen atom of Q3a of the compound represented by the formula (Villa): (Villa) [where R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above], exists as a primary or secondary aminereacting the amine of the formula (Villa) with a known isocyanate derivative (Q1-Q2b-N = C = O) [where Q1 and Q2b have the same meanings as described above] or a socianate prepared from of the carboxylic acid of any of the following formulas (Iva) - (lvd): Q1-Q2b-COOH (IVa) Q1-N (R20MCH2) mi-COOH (IVb) Q1-O- (CH2) mrCOOH (IVe) Q1- S- (CH2) mi-COOH (IVd) [wherein Q1, Q2b, R20 and m1 have the same meanings as described above]. When Q3a of the compound represented by the formula (Villa) is an amine, the sulfonyl derivative of the formula (I) can be obtained by reacting the compound of the formula (Villa) with a known isocyanate derivative in an inert solvent of - 20 to 100 ° C for 0.5 to 120 hours. The isocyanate derivative can also be synthesized from the carboxylic acid of any of the formulas (IVa) to (IVd), specifically described, by converting the carboxylic acid of any of the formulas (IVa) to (IVd), into the halogenide of corresponding acid using thionyl chloride or oxalyl chloride, by reacting the resulting acid halide with sodium azide in an inert solvent at a temperature range from 0 to 60 ° C, and then heating the reaction mixture; reacting the carboxylic acid of the formula (IVa) with a chloroformate such as isobutyl chloroformate to obtain the corresponding mixed acid anhydride, reacting the resulting anhydride with sodium azide and then heating; or by introducing the carboxylic acid of any of the formulas (IVa) to (IVd) into the corresponding hydrazide through an ester in an inert solvent such as tetrahydrofuran, chloroform or toluene of -20 to 1 10 ° C, reacting the hydrazide with nitric acid or alkyl ester thereof, thus introducing it into the corresponding acylazide and then heating the acylazide from 20 to 150 ° C in a solvent such as chloroform, dichloroethane, toluene, xylene or N, N-dimethylformamide. The sulfonyl derivative of the formula (I) can also be prepared by reacting the carboxylic acid of any of the formulas (IVa) to (IVd) with diphenylphosphoryl azide in the presence of a base such as triethylamine, in a solvent inert to a temperature scale from 10 to 100 ° C, and then reacting the resulting compound with the amine of the formula (Villa).

Preparation process 7 A process for synthesizing the sulfonyl derivative represented by the formula (I): [wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings as described above] by coupling reaction using a transition metal catalyst. When the Q1 structure of the sulfonyl derivative represented by the formula (I) contains an aryl group substituted with halogen or trifluoromethanesulfonyloxy, or a halogen or trifluoromethanesulfonyl substituted alkenyl group, the coupling reaction with an aryl compound substituted with boric acid is It can be carried out in the presence of a transition metal catalyst. When an alkenyl group is contained in the Q1 structure of the sulfonyl derivative of the formula (I), the coupling reaction can be carried out with an aryl group substituted with halogen or trifluoromethanesulfonyloxy in the presence of a transition metal catalyst. When an aryl group substituted with boric acid is contained in the structure of Q1 of the sulfonyl derivative of the formula (I), the coupling reaction can be carried out with an aryl compound substituted with halogen or trifluoromethanesulfonyloxy or a substituted alkenyl compound with halogen or trifluoromethanesulfonyloxy.

When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), an aryl group substituted with halogen or trifluoromethanesulfonyloxy is contained, the coupling reaction can be carried out with an alkenyl compound in the presence of a transition metal catalyst , whereby the sulfonyl derivative of the formula (I) can be obtained. The sulfonyl derivative of the formula (I) obtained in this way is subjected to deprotection, as necessary, whereby the compound of the formula (la) can be obtained. When in the Q1 structure of the sulfonyl derivative represented by the formula (I), an aryl group substituted with halogen or trifluoromethanesulfonyloxy or a halogen or trifluoromethanesulfonyloxy substituted alkenyl group is contained, the coupling reaction with an aryl derivative substituted with acid boricone can be made using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (O), in two phase solvent such as benzene-water or toluene-water, an amide solvent such as N, N-dimethylformamide or a ether solvent such as tetrahydrofuran or dimethoxyethane, in the presence of a base such as sodium carbonate, sodium hydroxide, barium hydroxide, potassium phosphate or cesium carbonate, at a temperature range of 20 to 150 ° C for 0.5 to 120 hours When in the Q1 structure of the sulfonyl derivative represented by the formula (I), an aryl group substituted with boric acid is contained, the coupling region can be carried out with an aryl compound substituted with halogen or trifluoromethanesulfonyloxy or an alkenyl derivative substituted with halogen or trifluoromethanesulfonyloxy. When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), an alkenyl group is contained, the coupling reaction can be carried out with an aryl group substituted with halogen or trifluoromethanesulfonyloxy using a transition metal catalyst such as acetate of palladium, in the presence of an appropriate base, in an amide solvent such as N, N-dimethylformamide at a temperature range of 20 to 150 ° C for 0.5 to 120 hours. When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), an aryl group substituted with boric acid is contained, the coupling reaction can be carried out with an aryl derivative substituted with halogen or trifluoromethanesulfonyloxy or an alkenyl derivative substituted with halogen or trifluoromethanesulfonyloxy. When in the Q1 structure of the sulfonyl derivative represented by the formula (I), an aryl group substituted with halogen or trifluoromethanesulfonyloxy, the coupling reaction can be carried out with an alkenyl compound by the use of a transition metal catalyst, whereby the sulfonyl derivative of the formula (I) can be obtained. From the sulfonyl derivative of the formula (I) obtained in this way, the sulfonyl derivative of the formula (I) with a substituted substituent can be obtained by deprotection, as necessary.

Preparation method 8 A process for preparing a sulfonamide product of amidoxime type: When T1-Q3 of the sulfonyl derivative represented by the following formula (I): [wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings as described above] represents any of the following formulas: [wherein R8, R9, R12, R13 and R14 have the same meanings as described above, n means an integer of 1 or 2, p means an integer from 1 to 3, and q means an integer from 0 to 3, with the condition that the sum of py 1 means an integer of 3 or 4] and none of the substituents containing amine, alkylamine, amido, hydroxyl and carboxylic acid exist in R1, Q1 or Q2, or R8, R9, R12, R13 or R14 or Q3, or a substituent replaceable therewith, the sulfonyl derivative of the formula (I) is reacted with a halogenating agent such as phosphorus pentachloride or an alkylating agent such as Meerwein reagent in an inert solvent of -30 to 140 ° C, preferably, in a halogen solvent such as chloroform from 0 to 80 ° C, to obtain the corresponding imino chloride or imino ether, and then the imino chloride or resulting methyl ether is it reacts with hydroxylamine or alkoxyamine, which may have a substituent or salt thereof from 0 to 80 ° C, preferably from 20 to 60 ° C, if necessary, in the presence of a base catalyst, whereby the objective sulfonyl derivative of the formula (I) can be obtained . Examples of the inert solvent include alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and aromatic solvents such as benzene and toluene. Among them, alkyl halide solvents are particularly preferred. Examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU).

Preparation Process 9 N-oxide Formation When in the sulfonyl derivative of the formula (I), there is an aliphatic tertiary amine or heterocyclic aromatic ring containing nitrogen in R1, Q1, Q2, Q3 or T1 or a substitutable substitutable with the same, the sulfonyl derivative of the formula (I) is reacted with a peroxide such as hydrogen peroxide, metachloroperbenzoic acid or tertiary butyl hydroperoxide of from -40 to 60 ° C for 0.5 to 120 hours, preferably from -20 to 20 ° C in water, acetic acid, a ketone solvent such as acetone, benzene solvent such as benzene, toluene or xylene, ether solvent such as tetrahydrofuran or dimethoxyethane or an alkyl halide solvent such as dichloromethane, chloroform or tetrachloride of carbon, whereby the sulfonyl derivative of the formula (I) can be obtained as an N-oxide derivative.

Preparation procedure 10 Quaternization of a nitrogen atom When in the sulfonyl derivative of the formula (I), there exists an aliphatic tertiary amine or heterocyclic aromatic group containing nitrogen in R1, Q1, Q2, Q3 or T1 or a replaceable substituent with them, the sulfonyl derivative of the formula (I) is reacted with an alkyl halide such as methyl iodide or ethyl iodide in an ether solvent such as 1,2-dimethoxyethane or dioxane, an aromatic solvent such as benzene or toluene, an amide solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidin-2-one or a sulfoxide solvent such as dimethyl sulfoxide or sulfolane of -10 to 150 ° C, preferably from 0 to 80 ° C, whereby the sulfonyl derivative of the formula (I) can be obtained as a quaternary amine product.

Preparation procedure 11 Sulfoxide or sulphone formation When there is an aliphatic or heteroaryl thioether containing sulfur in the sulfonyl derivative of the formula (I) in R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the derivative of sulfonyl of the formula (I) is reacted with a peroxide such as hydrogen peroxide, metachloroperbenzoic acid or tertiary butyl hydroperoxide of from -40 to 60 ° C for 0.5 to 120 hours, preferably from -20 to 20 ° C in water, acetic acid, a ketone solvent such as acetone, a benzene solvent such as benzene, toluene or xylene, an ether solvent such as tetrahydrofuran or dimethoxyethane or an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride , whereby the sulfonyl derivative (I) can be obtained in the form of sulfoxide or sulfone.

Preparation procedure 12 Amidino-1 formation When in the sulfonyl derivative of the formula (I), a nitrile group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substitutent therewith, it can be converted into a group amidino by the commonly used method. The amidino-containing sulfonyl derivative of the formula (I) can be obtained, for example, by allowing an amount equal to the large excess of a C-alcohol such as methanol, ethanol or propanol, to act on the sulfonyl derivative of the formula (I) from -10 to 60 ° C for 3 to 120 hours in an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform or dichloromethane, or an aprotic solvent such as benzene or a mixed solvent thereof, in the presence of a hydrogen halogenide such as hydrogen chloride or hydrogen bromide, thereby converting it to the corresponding imino ether; then reacting the resulting imino ether product with ammonium, a monoalkylamine which may have a substituent, or a dialkylamine which may have a substituent or a carbonate or acetate thereof of from -10 to 140 ° C for 0.5 to 200 hours in an alcohol of C? -4 such as ethanol or propanol, an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform, an aprotic solvent such as benzene, a solvent such as dimethylformamide or dimethyl or a mixed solvent thereof, preferably from -8 to 30 ° C for 10 to 96 hours in ethanol.

Preparation procedure 13 Formation of amidino-2 When in the sulfonyl derivative of the formula (I), a primary or secondary amino group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, it can be converted in an amidino group substituted by the commonly used method. Specifically described, the amidino-containing sulfonyl derivative of the formula (I) can be obtained by reacting the sulfonyl derivative of the formula (I) with an imino ether, imino chloride or salt thereof, which has been synthesized from an amide compound or nitrile compound, in an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform or dichloromethane, or an aprotic solvent such as benzene or a mixed solvent of the same, if necessary, in the presence of a base catalyst, from -10 to 140 ° C for 0.5 to 200 hours, preferably from 0 to 80 ° C for 10 to 96 hours. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and organic bases such as pyridine, 2,6-lutidine, collidine, -dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU).

Preparation Process 14 N-Nitrile Formation When in the sulfonyl derivative of the formula (I), a primary or secondary amine group exists in R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, may be cyanated by the commonly used process. Specifically described, the sulfonyl derivative of the formula (I) is reacted with cyanogen bromide in an alcohol solvent such as methanol, ethanol or propanol in the presence of a salt such as sodium acetate or a base of -10. at 10 ° C, preferably 0 to 60 ° C, whereby the sulfonyl derivative (I) having a nitrile group on its nitrogen atom can be obtained. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU).

Preparation procedure 15 Introduction of amidoxime or carboxamido-O-alkyloxime When in the sulfonyl derivative of the formula (I), a nitrile group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, it can be converted to an amidoxime or carboxamido-O-alkyloxime group by the commonly used method. Specifically described, the sulfonyl derivative of the formula (I) is reacted with hydroxylamine or an alkoxyamine, which may have a substituent or salt thereof in an alcohol solvent such as methanol, ethanol or propanol, a solvent of ether such as diethyl ether or tetrahydrofuran, a halogenated hydrocarbon such as chloroform or dichloromethane, an aprotic solvent such as toluene, an amide solvent such as N, N-dimethylformamide or a solvent such as dimethyl sulfoxide, or a mixed solvent of same from -10 to 100 ° C, preferably from 0 to 60 ° C, if necessary, in the presence of a base catalyst, whereby the sulfonyl derivative of the formula (I) having a group can be obtained amidoxime or carboxamido-O-alkyloxime. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU).

Preparation procedure 16 Introduction of quanidino When in the sulfonyl derivative of the formula (I), a primary or secondary amino group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, it can be converted into a Guanidino group substituted or unsubstituted by the commonly used process. Specifically described, the sulfonyl derivative of the formula (I) having a primary or secondary amino group is reacted with N, N'-di (tert-butoxy) carbonyl thiourea using a condensing agent, N, N ' dicyclohexylcarbodiimide in an aliphatic ether solvent such as diethyl ether, a halogenated hydrocarbon such as chloroform or dichloromethane, or an aprotic solvent such as benzene, or a mixed solvent thereof at -10 to 140 ° C for 0.5 to 200 hours, preferably from 0 to 80 ° C for 10 to 96 hours, if necessary, in the presence of a base catalyst, and then, as usual, the tertiary butoxycarbonyl group is removed, whereby the sulfonyl derivative can be synthesized of the formula (I) as a guanidino compound. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] -7-undequene (DBU).

Preparation procedure 17 Deprotection of the protected nitrogen atom When in the sulfonyl derivative of the formula (I), an acylamino or alkoxycarbonylamino group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, the derivative may to be hydrolyzed from 0 to 80 ° C in a solvent such as water, a lower alcohol or tetrahydrofuran, or a mixed solvent thereof, in the presence of a base such as an alkali metal hydroxide, for example, lithium hydroxide, sodium or potassium hydroxide, whereby the amino-containing derivative can be obtained. The nitrogen atom to which a protective group of the acyl type such as paramethoxybenzyloxycarbonyl or tertiary butoxycarbonyl has been attached can be converted into a nitrogen-hydrogen bond by the use of an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid , sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, or a combination thereof, and removing the acyl type protecting group from the nitrogen atom from 0 to 80 ° C in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, or an aromatic solvent such as benzene or toluene. The nitrogen atom to which an arylmethoxycarbonyl group such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl or para (ortho) -nitrobenzyloxycarbonyl has been attached can be converted to a nitrogen-hydrogen bond by removing the arylmethoxycarbonyl group from the protected nitrogen through hydrogenolysis in the presence of a palladium-carbon catalyst in a solvent such as ethanol, tetrahydrofuran, acetic acid or N, N-dimethylformamide. The nitrogen atom to which a protecting group of the silyl type such as trimethylsilyl or tertiary butyl dimethylsilyl, has been attached, can be converted into a nitrogen-hydrogen bond by reaction with hydrochloric acid or a hydrofluoride such as tetrabutylammonium fluoride from 0 to 80 ° C in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, or an aromatic solvent such as benzene or toluene, stirring in this way the silyl group of the protected nitrogen atom. The nitrogen atom to which a benzyl group has been attached can be converted into a nitrogen-hydrogen bond by removing the benzyl group through catalytic reduction with a palladium-carbon catalyst or its like, from 0 to 80 ° C in a solvent such as ethanol, tetrahydrofuran or acetic acid, or by reduction of Birch with sodium metal in liquid ammonia. The nitrogen atom to which a triphenyl group has been attached can be converted into a nitrogen-hydrogen bond by removing the triphenyl group by catalytic reduction with a palladium-carbon catalyst or its like, from 0 to 80 ° C in a solvent such as ethanol, tetrahydrofuran or acetic acid, or through reduction of Birch with sodium metal in liquid ammonia. The removal of the triphenylmethyl group and its conversion into a nitrogen-hydrogen bond can be carried out using an appropriate acid, such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid, or a combination thereof, from 0 to 80 ° C.

Preparation procedure 18 Ester hydrolysis When in the sulfonyl derivative of the formula (I), an alkoxycarbonyl group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, the alkoxycarbonyl group protected in the ester form Methyl or ethyl, can be converted into the corresponding carboxylic acid by hydrolysis with an appropriate base, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. In the case of protection in the form of a tertiary butyl ester, the tertiary butyl group can be removed by treatment with trifluoroacetic acid or hydrochloric acid, while in the case of protection in the form of an ester of the arylmethyl type such as benzyl, the Carboxylic acid can be obtained by removing the arylmethyl group by hydrogenolysis in the presence of a palladium-carbon catalyst.

Preparation procedure 19 When in the sulfonyl derivative of the formula (I), an acyloxy, arylmethyloxy, silyl ether, methoxymethyl or tetrahydropyranyl group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, the group Acyl such as alkanoyl or aroyl can be removed by hydrolysis with an appropriate base, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The protecting group of the arylmethyl type can be removed by hydrogenolysis with a palladium-carbon catalyst. The silyl ether group such as tertiary butyl dimethylsilyl can be removed by a hydrofluoride salt such as tetrabutylammonium fluoride. The methoxymethyl or tetrahydropyranyl group can be removed by acetic acid or hydrochloric acid.

Preparation procedure When in the sulfonyl derivative of the formula (I), an amino group exists in R1, Q1, Q2, Q3 or T1 or a substitutable substitutent therewith, it can be acylated by the commonly used process, which use an acyl halide or carboxylic acid in activated form. Alternatively, it can be rented by reductive alkylation or a similar method. The sulfonyl derivative of the formula (I), which is a urea derivative, can be prepared by sulfonylation through sulfonic acid chloride, or by reaction with an isocyanate or an isocyanate derivative of a carboxylic acid.

Preparation procedure 21 When there is a carboxyl group in the sulfonyl derivative of the formula (I) in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, it can be converted into a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group by the commonly used active ester method or the mixed acid anhydride method, and then converted to a hydroxyl or aldehyde group by reduction. The resulting hydroxyl or aldehyde group can be subjected to conversion of a functional group, such as ether linkage formation, conversion to an amino group or conversion to an alkylamino group by the process commonly used in organic chemistry. The carboxyl group, after conversion to its ester or mixed acid anhydride directly or by the usual procedure, is reduced, whereby the corresponding alcohol can be obtained.

Preparation 22 Phenol Formation When there is a methoxy group substituted with aryl in the sulfonyl derivative of the formula (I) in R1, Q1, Q2, Q3 or T1 or a substitutable substituent therewith, it can be converted into a hydroxyl group by stirring the methyl group using trimethylsilyl iodide in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, or a benzene solvent such as toluene, a Lewis acid such as aluminum chloride or phosphorus tribromide, a solvent of alkyl halide or an ether solvent of -78 to 110 ° C. In accordance with the present invention, the sulfonyl derivative of the formula (I), salt thereof or solvate thereof, has peculiar and excellent FXa inhibitory activity, and is therefore useful as a coagulation suppressant or a preventive and / or remedy for thrombosis or embolism. The sulfonyl derivative of the present invention exhibits effects even by oral administration, so that it can be administered orally or parenterally. The dose of the sulfonyl derivative can be modified as necessary, depending on the symptom, age, weight and / or similar of a patient. It is necessary to administer the derivative in an amount of 1 to 1000 mg / day, preferably 5 to 300 mg / day per adult. Although no particular limitation is imposed on the dosage form, examples include tablets, capsules, powders, granules, suspensions, syrups and dry syrups. The derivative together with the commonly used additives such as excipient, lubricant or binder, can be formulated into the dosage forms described above in accordance with the known formulation technique. No particular limitation is imposed on the dosage form in the case of parenteral administration, but examples include ointments, plasters, injections and suppositories. As an injection, the derivative can be administered subcutaneously or intravenously, or by intravenous drip in an amount of 0.1 to 100 mg / day, preferably 0.5 to 30 mg / day per adult. The present invention will now be described more specifically by reference examples, examples and tests, but it should nevertheless be taken into account that the present invention is not limited thereto or by them.

EXAMPLES A detailed description will now be made of the sulfonyl derivative of the present invention, and of the method of preparation thereof. Some of the raw materials used to prepare the sulfonyl derivative of the present invention are novel compounds. These compounds and the process for preparing them will be described in the reference examples. After preparing the compound, Merck silica gel 60 or Yamazen silica gel was used for moderate pressure liquid chromatography for silica gel column chromatography. In the nuclear magnetic resonance (NMR) spectrum, tetramethylsilane was used as the internal standard.

REFERENCE EXAMPLE 1 1-r (6-Chloronaphthalen-2-Psulphonylpiperazine Hydrochloride and Trifluoroacetate In dichloromethane (20 ml), tert-butyl 1-piperazine carboxylate (856 mg) was dissolved. To the resulting solution, triethylamine (0.77 ml) and 6-chloro-2-naphthylsulfonyl chloride (1.20 g) were added, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting mixture was washed with 1 N hydrochloric acid. The extracted organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled under reduced pressure. The residue was dissolved in saturated ethanol hydrochloride (10 ml), followed by concentration under reduced pressure and washing with ethyl acetate, whereby the hydrochloride (1.662 g, quantitative) of the title compound was obtained as a colorless solid. . 1 H-NMR (DEMO-d 6) d: 3.1-3.4 (8H, m), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.86 (1 H, dd, J = 8.8, 1.5 Hz), 8.22 (1 H, d, J = 8.8 Hz), 8.26-8.32 (2H, m), 8.56 (1 H, s), 8.63 (2H, br s). MS (FAB) m / z: 31 1 [(M + H) +, Cl 35], 313 [(M + H) +, Cl37]. Elemental analysis for C14H15CIN2? 2S HCI 0.1 H2O Calculated: C, 48.17; H, 4.68, Cl, 20.31; N, 8.03; S, 9.19. Found: C, 47.91; H, 4.68; Cl, 20.41; N, 7.80; S, 9.21. Instead of the saturated ethanol hydrochloride, the treatment was carried out using trifluoroacetic acid, whereby the trifluoroacetate was obtained. Elemental analysis for C? 4H? 5CIN2? 2S CF3C? 2H Calculated: C, 45.24; H, 3.80, Cl, 8.35; F, 13.42; N, 6.59; S, 7.55. Found: C, 44.84; H, 3.80; Cl, 8.27; F, 13.72; N, 6.29; S, 7. fifty.

REFERENCE EXAMPLE 2 4- (4-pyridyl) benzoic acid hydrochloride At room temperature, 4-bromopyridine hydrochloride (1.7 g) and 4-carboxybenzanboronic acid (10.0 g) were dissolved in toluene (250 ml) and water (250 ml). To the resulting solution, tetrakys (triphenylphosphine) palladium (O) (5.00 g) and anhydrous sodium carbonate (25.4 g) were successively added, followed by reflux under heat at 120 ° C for 19 hours.

After allowing to cool, the reaction mixture was added with ethyl acetate and water, whereby the aqueous layer was separated. The organic layer was extracted twice with water. All the aqueous layers obtained in this manner were combined, and to the resulting solution concentrated hydrochloric acid was added to make it acid, followed again by washing with ethyl acetate. The solvent was distilled from the aqueous layer until it decreased to 100 ml. The colorless solid precipitated in this way was collected by filtration, and dried under reduced pressure, whereby the title compound was obtained (8.37 g, 59%). 1H-NMR (DEMO-de) d: 8.1 1 (2H, d, J = 8.8 Hz), 8.14 (2H, d, J = 8.8 Hz), 8.35 (2H, d, J = 6.6 Hz), 8.97 (2H , d, J = 6.6 Hz). Elemental analysis for C12H9NO2 HCl 0.3H2O Calculated: C, 59.79; H, 4.43, N, 5.81; Found: C, 59.87; H, 4.35; N, 5.53. MS (FAB) m / z: 200 (M + H) +.

REFERENCE EXAMPLE 3 1-tert-Butoxycarbonyl-4-r4- (4-pyridyl) benzoippyrazine In N, N-dimethylformamide (40 ml), 4- (4-pyridyl) benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374 mg) and N-methylmorpholine (336 μl) were added. The resulting mixture was cooled in ice, followed by the addition of 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg) After stirring at room temperature for 7 hours, the solvent was distilled.The residue was purified by chromatography on a silica gel column. (2% methanol-dichloromethane), followed by washing with hexane, whereby the title compound was obtained (905 mg, 89%). 1 H-NMR (CDCl 3) d: 1.48 (9H, s), 3.40-3.91 (8H, m), 7.51 (2H, d, J = 5.9 Hz), 7.53 (2H, d, J = 8.1 Hz), 7.69 (2H, d, J = 8.1 Hz), 8.69 (2H, d, J = 5.9 Hz) Elemental analysis for C2iH25N3O3 Calculated: C, 68.64; H, 6.86, N, 11.44. Found: C, 68.48; H, 6.84; N, 11.17.

REFERENCE EXAMPLE 4 1-r4- (4-pyridyl) benzoylpiperazine ditrifluoroacetate In dichloromethane (30 ml), 1-tert-butoxycarbonyl-4- [4- (4-pyridyl) benzoyl] piperazine (944 mg) was dissolved. Under cooling on ice, trifluoroacetic acid (30 ml) was added to the resulting solution, followed by stirring at room temperature for 1 hour. The solvent was distilled. Tetrahydrofuran was added to the residue to solidify it, whereby the title compound (1.28 g, 100%) was obtained as a colorless amorphous solid. 1H-NMR (DEMO-de) d: 3.1-3.3 (4H, br s), 3.5-4.0 (4H, m), 7.65 (2H, d, J = 7.8 Hz), 7.95-8.05 (4H, m), 8.79 (2H, d, J = 5.4 Hz), 8.95-9.10 (1 H, br s).

REFERENCE EXAMPLE 5 4-tert-Butoxycarbonyl-2-ethoxycarbonyl-1-r4- (4-pyridyl) benzoinpiperazine In toluene (150 ml), 1,2-dibromopropionic acid (58.0 g) was dissolved. To the resulting solution, a solution of N, N'-dibenzylethylenediamine (53.5 g) and triethylamine (53 ml) in toluene (toluene: 50 ml) was added dropwise while cooling on ice. Toluene (100 ml) was added again to the reaction mixture, followed by stirring at room temperature for 14 hours, again adding toluene (100 ml) and stirring at 60 to 80 ° C for 4 hours. The insoluble material was filtered. The filtrate was washed with water and dried over anhydrous potassium carbonate. The solvent was then distilled under reduced pressure. The residue was dissolved in acetic acid (200 ml). To the resulting solution, 10% carbon-palladium (water content: about 50%, 40 g) was added, followed by catalytic reduction under atmospheric pressure for 4 hours. The catalyst was filtered, and the filtrate was distilled under reduced pressure. To the residue, dichloromethane and a saturated aqueous solution of potassium carbonate were added to separate the organic layer, followed by drying over anhydrous potassium carbonate. The solvent was distilled under reduced pressure. The residue was dissolved in dichloromethane (350 ml), followed by the addition of 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (46.5 g) under cooling on ice. The reaction mixture was gradually heated to room temperature, at which temperature the stirring was carried out for 14 hours. The solvent was distilled under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane ~ 2% methanol-dichloromethane), whereby 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (5.82 g, 10%) was obtained. In a similar manner to reference example 3, except for the use of the resulting product and 4- (4-pyridyl) benzoic acid hydrochloride as raw materials, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.2-1.4 (3H, m), 1.46 (9H, s), 2.7-5.4 (7H, m), 7.51 (2H, d, J = 5.2 Hz), 7.59 (2H, d , J = 7.6 Hz), 7.69 (2H, d, J = 7.6 Hz), 8.69 (2H, d, J = 5.2 Hz).

MS (FAB) m / z: 440 (M + H) +.

REFERENCE EXAMPLE 6 6- (4-Pyridyl) nicotinic acid hydrochloride In tetra hyd break not (20 ml), 6-chloronicotinic acid (535 mg) and diethyl (4-pyridyl) borane (500 mg) were dissolved. To the resulting solution, tetrabutylammonium bromide (546 mg), potassium hydrochloride (570 mg), tetrakis (triphenylphosphine) palladium (O) (392 mg) and water (0.5 ml) were added, followed by heating under reflux for 6 hours. . Dilute hydrochloric acid was added to the reaction mixture to make it acidic. Water and ethyl acetate were poured into the resulting mixture for extraction. The aqueous layer extracted in this way was distilled under reduced pressure. The residue was purified by chromatography through a synthetic adsorbent ("Diaion HP-20", water ~ 50% acetonitrile-water). To the resulting fraction, dilute hydrochloric acid was added to make it acidic. Then the solvent was distilled. Tetrahydrofuran was added to the residue, and the precipitate was collected by filtration, whereby the title compound (269 mg, 32%) was obtained. 1H-NMR (DEMO-de) d: 8.45-8.55 (2H, m), 8.65 (2H, d, J = 6.8 Hz), 9.03 (2H, d, J = 6.8 Hz), 9.27 (1 H, s) . MS (FAB) m / z: 201 (M + H) + REFERENCE EXAMPLE 7 Methyl 4- (3-pyridyl) benzoate In tetrahydrofuran (100 ml), methyl 4-bromobenzoate (5.04 g) and diethyl 3-pyridyl borane (2.30 g) were dissolved, followed by the addition of tetrabutylammonium bromide (2.51 g), potassium hydroxide (2.63 g) tetrakis. (triphenylphosphine) palladium (O) (1.8 g) and water (1 ml) under an argon atmosphere. The resulting mixture was heated under reflux for 2 hours. After cooling on ice, an aqueous solution of ammonium chloride and ethyl acetate was added to the reaction mixture. The organic layer separated in this way was dried over anhydrous magnesium sulfate. The residue obtained by distillation of the solvent was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 1: 1). Then, the solvent was distilled. To the residue, methanol and ethanolic hydrochloric acid were added at 1 N. The solvent was distilled again. Tetrahydrofuran was added to the residue, and the solid precipitated in this way was collected by filtration. After drying, the title compound (1.76 g, 45%) was obtained as a colorless solid. 1 H-NMR (DEMO-de) d: 3.91 (3H, s), 8.0-8.1 (3H, m), 8.1-8.15 (2H, m), 8.75-8.85 (1H, m), 8.85-8.95 (1 H, m), 9.25-9.3 (1 H, m).

REFERENCE EXAMPLE 8 4- (3-Pyridyl) benzoic acid hydrochloride At room temperature, methyl 4- (3-pyridyl) benzoate (1.76 g) was dissolved in a mixed solvent of hydrochloric acid at 1 N (50 ml) and dioxane (50 ml), followed by heating under reflux for 4 hours. The solvent was then distilled under reduced pressure. Tetrahydrofuran was added to the residue, followed by washing, whereby the title compound (1.55 g, 93%) was obtained as a colorless solid. 1 H NMR (DEMO-de) d: 7.95-8.0 (3H, m), 8.10 (2H, d, J = 8.3 Hz), 8. 65-8.75 (1 H, m), 8.8-8.9 (1 H, m), 9.22 (1 H, d, J = 2.0 Hz) REFERENCE EXAMPLE 9 Methyl 4- (2-Aminopyridin-5-yl) benzoate In a similar manner to Example 2, except for the use of 5-bromo-2-aminopyridine and 4-carboxyphenylboronic acid as raw materials, the reaction was carried out, whereby 4- (2-aminopyridin-5-) acid was obtained il) benzoic. The resulting 4- (2-aminopyridin-5-yl) benzoic acid (684 mg) was dissolved in methanol (50 ml) at room temperature, followed by the addition of concentrated sulfuric acid (1 ml). After heating under reflux for 2 hours, the reaction mixture was made weakly alkaline with an aqueous solution of sodium bicarbonate. Water and ethyl acetate were added to the resulting mixture to separate the organic layer. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled. Hexane was added to the residue for crystallization, whereby the title compound (243 mg, 23%) was obtained. H-NMR (CDCl 3) d: 3.94 (3H, s), 4.57 (2H, br s), 6.60 (1 H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.72 ( 1 H, dd, J = 8.8, 2.4 Hz), 8.09 (2 H, d, J = 8.8 Hz), 8.38 (1 H, d, J = 2.4 Hz). MS (FAB) m / z: 229 (M + H) +. Elemental analysis for: C? 3H? 2N2O2 Calculated: C, 68.41; H, 5.30, N, 12.27. Found: C, 68.78; H, 5.45; N, 12.09.

REFERENCE EXAMPLE 10 methyl 4-r2- (tert-butoxycarbonylamino) pyridin-5-benzoate At room temperature, methyl 4- (2-aminopyridin-5-yl) benzoate (200 mg) was suspended in tert-butanol (20 ml). To the resulting suspension, di-tert-butyl dicarbonate (286 mg) was added, and the resulting mixture was stirred for 24 hours. After the solvent was distilled off, the residue was purified by chromatography on a column of silica gel (1% methanol-dichloromethane), whereby the title compound (155 mg, 54%) was obtained as a colorless solid. . 1 H-NMR (CDCl 3) d: 1.55 (9H, s), 3.95 (3H, s), 7.63 (2H, d, J = 8.3 Hz), 7.92 (1 H, dd, J = 8.8, 2.4 Hz), 8.07 (1 H, d, J = 8.8 Hz), 8.09 (1 H, br s), 8.12 (2 H, d, J = 8.3 Hz), 8.55 (1 H, d, J = 2.4 Hz). MS (FAB) m / z: 329 (M + H) +. Elemental analysis for: Ci8H2oN204 Calculated: C, 65.84; H, 6.14, N, 8.53; Found: C, 65.67; H, 6.02; N, 8.40.

REFERENCE EXAMPLE 11 4-r2- (tert-butoxycarbonylamino) pyridin-5-benzoic acid At room temperature, methyl 4- (2- (tert-butoxycarbonylamino) pyridin-5-yl] benzoate (250 mg) was suspended in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), followed by the addition of an aqueous solution of sodium hydroxide at 1 N (8 ml). The resulting mixture was stirred for 5 hours. The reaction mixture became weakly acidic with an aqueous solution of citric acid, followed by the addition of saturated saline solution and n-butanol to separate the organic layer. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled, whereby the title compound (120 mg, 49%) was obtained as a crude purified product. 1H-NMR (DEMO-d6) d: 1.49 (9H, s), 7.83 (2H, d, J = 8.3 Hz), 7.91 (1 H, d, J = 8.8 Hz), 8.02 (2H, d, J = 8.3 Hz), 8.13 (1 H, dd, J = 8.8, 2.4 Hz), 8.65 (1 H, d, J = 2.4 Hz), 9.95 (1 H, s), 12.99 (1 H, br s).

REFERENCE EXAMPLE 12 1-r4- [2- (tert-Butoxycarbonylamino) pyridin-5-inbenzoin-4 - [(6-chloronaphthalen-2-dsulfoninpiperazine In a mixed solvent of dichloromethane (20 ml) and N, N-dimethylformamide (1 ml), 4- [2- (tert-butoxycarbonyl) -amino] pyridin-5-yl] benzoic acid (74 mg) and trifluoroacetate were suspended. of 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine (10 mg). To the resulting suspension, 1-hydroxybenzotriazole (35 mg) and N-methylmorpholine (34 μl) were added, followed by the addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (68 mg) under ice cooling. After stirring at room temperature for 6 hours, the solvent was distilled. The residue was purified by chromatography on a column of silica gel (1% methane-dichloromethane). The solvent was then distilled, whereby the title compound (128 mg, 90%) was obtained. 1 H-NMR (CDCl 3) d: 1.54 (9H, s), 3.00-3.30 (4H, m), 3.50-4.10 (4H, m), 7.39 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.8 Hz), 7.60 (1 H, dd, J = 8.8, 2. 0 Hz), 7.71 (1 H, dd, J = 8.8, 1.5 Hz), 7.84 (1 H, dd, J = 8.8, 2.4 Hz), 7.88 (1 H, br s), 7.9-8.0 (3 H, m ), 8.03 (1 H, d, J = 8.8 Hz), 8.31 (1 H, s), 8.46 (1 H, d, J = 2.4 Hz).

REFERENCE EXAMPLE 13 4- (4-aminophenyl) benzoic acid hydrochloride In a similar manner to reference example 2, except for the use of 4-bromoaniline and 4-carboxyphenylboronic acid as raw materials, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (DEMO-de) d: 7.31 (2H, d, J = 7.3 Hz), 7.75-7.85 (4H, m), 8.09 (2H, d, J = 8.3 Hz). MS (FAB) m / z: 213 (M +). Elemental analysis for: C? 3H-nN02? CI Calculated: C, 62.53; H, 4.84, N, 5.61; Cl, 14.20. Found: C, 62.33; H, 4.83; N, 5.50; Cl, 14.14.

REFERENCE EXAMPLE 14 4- [4- (tert-Butoxycarbonylamino) phenylbenzoate methyl) In a manner similar to reference examples 9 and 10, except for the use of 4- (4-aminophenyl) benzoic acid hydrochloride as the raw material, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.54 (9H, s), 3.94 (3H, s), 6.56 (1 H, br s), 7. 46 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.3 Hz), 8.08 (2H, d, J = 8.3 Hz). MS (FAB) m / z: 328 (M + H) +.

Elemental analysis for: C19H21NO4 Calculated: C, 69.71; H, 6.47, N, 4.28. Found: C, 69.49; H, 6.44; N, 4.42.

REFERENCE EXAMPLE 15 4-r4- (tert-butoxycarbonylamino) phenyl-1-benzoic acid In a similar manner to reference example 11, except for the use of methyl 4- [4- (tert-butoxycarbonylamino) phenylbenzoate (501 mg), the reaction was carried out, whereby the title compound was obtained (426). mg, 89%). 1 H-NMR (CDCl 3) d: 1.54 (9H, s), 6.57 (1 H, br s), 7.47 (2 H, d, J = 8.3 Hz), 7.59 (2 H, d, J = 8.3 Hz), 7.66 ( 2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz). MS (FAB) m / z: 314 (M + H) +. Elemental analysis for: C18H-19NO4 Calculated: C, 68.99; H, 6.11, N, 4.47. Found: C, 68.91; H, 6.27; N, 4.24.

REFERENCE EXAMPLE 16 1-r4-f4- (tert-Butoxycarbonylamino) phennbenzoin-4-r (6-chloronaphthalen-2-dsulfonylpiperazine In a manner similar to reference example 12, except for the use of 4- [4- (tert-butoxycarbonylamino) phenylbenzoic acid (150 mg) and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] trifluoroacetate] Perazine (203 mg) as raw materials, the reaction was carried out, whereby the title compound (303 mg, 100%) was obtained. 1 H-NMR (CDCl 3) d: 1.53 (9H, s), 2.90-3.30 (4H, m), 3.50-4.10 (4H, m), 6.56 (1 H, s), 7.35 (2H, d, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.76 (1 H, dd, J = 8.8, 2.0 Hz), 7.90-7.95 (3H, m) , 8.30 (1 H, br s).

REFERENCE EXAMPLE 17 4-Acetylbenzoate methyl In a mixed solvent of tetrahydrofuran (100 ml) and methanol (7 ml), methyl 4-acetylbenzoate (3.28 g) was dissolved at room temperature, followed by the addition of trimethylsilyldiazomethane (to a solution of hexane at 2.0 M, 12 ml. ) in portions under ice cooling. After warming to room temperature and stirring for 30 minutes, the solvent was distilled. To the residue, an aqueous solution of sodium bicarbonate and ether was added. The organic layer separated in this way was dried over anhydrous magnesium sulfate. After the solvent was distilled, the residue was crystallized from hexane, whereby the title compound (2.90 g, 82%) was obtained. 1 H-NMR (CDCl 3) d: 2.65 (3 H, s), 3.96 (3 H, s), 8.01 (2 H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz). MS (EI) m / z: 178 M +. Elemental analysis for: C? 0H? OO3 Calculated: C, 67.41; H, 5.66. Found: C, 67.28; H, 5.53.

REFERENCE EXAMPLE 18 4-Methyl Bromoacetylbenzoate At 15 ° C, methyl 4-acetylbenzoate (2.23 g) was dissolved in a solution of acetic acid and hydrobromic acid (30%, 10 ml). Bromine was gradually added dropwise to the reaction mixture to maintain its temperature at 15 ° C. After stirring for 10 minutes, the reaction mixture was cooled to 4 ° C. A mixed solvent of methanol (50 ml) and water (50 ml) was added to the reaction mixture for crystallization, followed by washing with hexane. By filtration through filtration, the title compound (2.29 g, 71%) was obtained as a colorless solid. 1 H-NMR (CDCl 3) d: 3.96 (3H, s), 4.47 (2H, s), 8.05 (2H, d, J = 8.8 Hz), 8.16 (2H, d, J = 8.8 Hz). MS (FAB) m / z: 257 [(M + H) +, 79Br], 259 [(M + H) +, 81Br]. Elemental analysis for: C? OH9BrO3 Calculated: C, 46.72; H, 3.53. Found: C, 46.36; H, 3.63.

REFERENCE EXAMPLE 19 Methyl 4- (2-aminothiazol-4-yl) benzoate At room temperature, methyl 4-bromoacetylbenzoate (1.00 g) and thiourea (296 mg) were dissolved in isopropanol (100 ml), followed by heating under reflux for 15 minutes. Under stirring at the same temperature, anhydrous sodium carbonate (206 mg) was added to the reaction mixture. The resulting mixture was heated under reflux for 20 minutes. After the completion of the reaction, water (50 ml) was added under cooling on ice, and the solid precipitated in this way was collected by filtration. The solid was dissolved in water and dichloromethane. The organic layer separated in this way was dried over anhydrous sodium sulfate. Then, the solvent was distilled. The pale yellow solid precipitated in this manner was washed with ether, whereby the title compound (634 mg, 70%) was obtained. 1 H-NMR (CDCl 3) d: 3.93 (3 H, s), 4.96 (2 H, br s), 6.88 (1 H, s), 7.85 (2 H, d, J = 8.8 Hz), 8.05 (2 H, d, J = 8.8 Hz).

MS (FAB) m / z: 235 (M + H) +.

REFERENCE EXAMPLE 20 4- (2-aminothiazol-4-yl) benzoic acid At room temperature, methyl 4- (2-aminothiazol-4-yl) benzoate (300 mg) was suspended in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5 ml), followed by the addition of an aqueous solution of sodium hydroxide at 1 N (10 ml). The resulting mixture was stirred for 1 hour. To the reaction mixture, N, N-dimethylformamide (5 ml) was added, followed by heating under reflux for 6 hours. After the reaction was complete, the solvent was distilled. To the residue, water and hydrochloric acid were successively added at 1 N, and the pale yellow solid precipitated in this way was collected by filtration, whereby the title compound (229 mg, 69%) was obtained as a white solid. pale yellow color. 1 H-NMR (DEMO-d 6) d: 7.30 (1 H, br s), 7.87 (2 H, d, J = 8.3 Hz), 7.95-8.00 (2 H, m). MS (FAB) m / z: 221 (M + H) +. Elemental analysis for: C? 0H8N2O2S 0.75 HCl 0.6H2O Calculated: C, 46.48; H, 3.88, N, 10.84; Cl, 10.29; S, 12.41. Found: C, 46.36; H, 4.12, N, 10.64; Cl; 10.05; S, 12.33.

REFERENCE EXAMPLE 21 4- (lmidazol-4-yl) methyl benzoate At room temperature, methyl 4-bromoacetyl benzoate (2 g) was dissolved in formamide (100 ml), followed by stirring at 180 ° C for 90 minutes. After the reaction was complete, the reaction mixture was cooled in ice and dissolved in water and 1N hydrochloric acid. The resulting solution was purified by chromatography through a synthetic adsorbent ("Diaion HP-20", water ~ 50% acetonitrile - water). The crude product obtained in this way was again purified by chromatography on a column of silica gel (5% methanol-dichloromethane), whereby the title compound (844 mg, 54%) was obtained as a solid of color pale yellow. 1 H-NMR (CDCl 3) d: 3.93 (3 H, s), 7.46 (1 H, s), 7.75 (1 H, s), 7.86 (2 H, m), 8.07 (2 H, d, J = 8.3 Hz). MS (FAB) m / z: 203 (M + H) +.

REFERENCE EXAMPLE 22 methyl 4-ri-Trifenilmetilimidazol-4 (5) -ylbenzoate Methyl 4- (imidazol-4-yl) benzoate (828 mg) was dissolved in dichloromethane (50 ml), followed by the addition of diisopropylethylamine (856 μl) and triphenylmethyl chloride (1.37 g) under ice cooling. The resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled. The residue was purified by chromatography on a column of silica gel (dichloromethane), whereby the title compound (1.08 g, 59%) was obtained as a colorless glassy solid. 1 H-NMR (CDCl 3) d: 3.90 (3H, s), 7.15-7.22 (6H, m), 7.23 (1H, d, J = 1.5 Hz), 7.30-7.40 (15H, m), 7.52 (1 H, d, J = 1.5 Hz), 7.79 (2H, d, J = 8.3 Hz), 8.01 (2H, d, J = 8.3 Hz ). MS (FAB) m / z: 445 (M + H) +.

REFERENCE EXAMPLE 23 4-M -triphenylmethylimidazol-4 (5) -yl-1-benzoic acid At room temperature, methyl 4- (1-triphenylmethylmethyl-4 (5) yl] benzoate (1.04 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml). To the resulting solution, an aqueous solution of 3N sodium hydroxide (6 ml) was added, followed by stirring for 5 hours. Tetrahydrofuran and methanol were subjected to solvent removal by distillation under reduced pressure. An aqueous solution of citric acid was added to the residue to make it weakly acidic, followed by the addition of water and dichloromethane. The organic layer separated in this way was washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled, whereby the title compound (1.13 g, quantitative) was obtained as a crude purified product in the form of a colorless glassy solid. 1 H-NMR (CDCl 3) d: 7.15-7.22 (6H, m), 7.23 (1 H, d, J = 1.5 Hz), 7.30-7.40 (9H, m), 7.69 (1 H, d, J = 1.5 Hz ), 7.81 (2H, d, J = 8.3 Hz), 8.10 (2H, d, J = 8.3 Hz).

REFERENCE EXAMPLE 24 1-r (6-Chloronaphthalen-2-yl) sulfonin-4-r4-p-triphenylmethyl-4-f5) - D-benzoylpiperazine In a manner similar to reference example 12, except for the use of 4- [1-triphenylmethylimidazol-4 (5) -yl] benzoic acid (371 mg) and 1 - [(6-chloronaphthalen-2-yl) sulfonyl hydrochloride ] piperazine (300 mg) as raw materials, the reaction was carried out, whereby the title compound (560 mg, 90%) was obtained as a colorless glassy solid. 1 H-NMR (CDCl 3) d: 2.90-3.30 (4H, m), 3.50-4.10 (4H, m), 7.15-7.20 (6H, m), 7.28 (2H, d, J = 8.3 Hz), 7.30-7.40 (9H, m), 7.49 (1 H, d, J = 1.0 Hz), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.75 (1 H , dd, J = 8.8, 1.5 Hz), 7.90-7.95 (3H, m), 8.29 (1 H, br s). MS (FAB) m / z: 723 (M + H) +.

REFERENCE EXAMPLE 25 4-r2-aminoimidazole-4-p-benzoic acid hydrochloride At room temperature, methyl 4-bromoacetylbenzoate (1.37 g) and acetylguanidine (1.62 g) were suspended in acetonitrile, followed by heating under reflux for 16 hours. The solvent was then distilled under reduced pressure. Water was added to the residue. The insoluble matter precipitated in this manner was collected by filtration, followed by washing with ethanol, whereby methyl 4- [2-aminoimidazol-4-yl] benzoate was obtained. The resulting product was dissolved in a mixed solvent of dioxane (10 ml) and hydrochloric acid at 1 N (10 ml)., followed by heating under reflux for 8 hours. The residue obtained by distilling the solvent was solidified by tetrahydrofuran, and then collected by filtration, whereby the title compound (500 mg, 39%) was obtained. 1H-NMR (DEMO-de) d: 7.55-7.65 (3H, m), 7.80 (2H, d, J = 8.3 Hz), 7.98 (2H, d, J = 8.3 Hz), 12.2-13.3 (3H, m ). MS (FAB) m / z: 204 (M + H) +. Elemental analysis for: C10H9N3O2 HCI O.5H2O Calculated: C, 48.30; H, 4.46; N, 16.90; Cl, 14.26. Found: C, 48.03; H, 4.10; N, 16.49; Cl, 14.12.

REFERENCE EXAMPLE 26 1 -f4-Bromo-2- (tert-butoxycarbonyl) benzoin-4-r (6-chloronaphthalen-2-Psulfonylpiperazine In dichloromethane (200 ml), 4-bromophthalic anhydride (1.96 g) and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (3.00 g) were suspended under ice cooling. To the resulting suspension, diisopropylethylamine (3.76 ml) was added, followed by stirring for 20 minutes. To the reaction mixture, dilute hydrochloric acid and dichloromethane were added. The organic layer separated in this way was dried over anhydrous sodium sulfate. The solvent was concentrated, so that the volume was reduced to 200 ml. To the concentrate, N, N'-diisopropyl-O-tert-butylisarea (2.6 g) was added under cooling on ice, and the resulting mixture was stirred at room temperature for 3 days. Dilute hydrochloric acid and dichloromethane were added to the reaction mixture. The organic layer separated in this way was dried over anhydrous sodium sulfate. The residue was purified by chromatography on a silica gel column (hexane: ethyl acetate = 3: 1 ~ 1: 1), whereby the title compound (1.78 g, 35%) was obtained as a colorless solid. 1 H-NMR (CDCl 3) d: 1.30 (9H, s), 2.90-3.40 (6H, m), 3.80-4.00 (2H, m), 7.01 (1 H, d, J = 8.3 Hz), 7.59 (1 H, dd, J = 8.3, 2.0 Hz), 7.61 (1 H, dd, J = 8.3, 2.0 Hz), 7.76 (1 H, dd, J = 8.8, 2.0 Hz), 7.85-7.95 (3H, m), 8.00 (1 H, d, J = 2.0 Hz), 8.29 (1 H, br s).

REFERENCE EXAMPLE 27 1-r2-tert-Butoxycarbonyl-4- (pyridin-4-yl) benzoyl-1-4-y (6-chloronaphthalen-2-yl) sulfonylpiperidine hydrochloride In a similar manner to reference example 7, except for the use of 1- [4-bromo-2- (tert-butoxycarbonyl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] -piperazine and (4) -pyridyl) diethyl borane as raw materials, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.37 (9H, s), 2.80-3.50 (6H, m), 3.80-4.00 (2H, m), 7.40 (1 H, d, J = 7.8 Hz), 7.60 (1 H , dd, J = 8.8, 2.0 Hz), 7.77 (1 H, dd, J = 8.3, 1.5 Hz), 7.87 (1 H, dd, J = 7.8, 2.0 Hz), 7.90-7.95 (3H, m), 8.10 (2H, d, J = 6.8 Hz), 8.25 (1 H, d, J = 2.0 Hz), 8.31 (1 H, br s), 8.90 (2 H, d, J = 6.8 Hz). MS (FAB) m / z: 592 (M + H) +. Elemental analysis for: C3? H3oCIN3O5S HCI 0.2H2O THF Calculated: C, 59.69; H, 5.64; N, 5.97; Cl, 10.07; S, 4.55. Found: C, 59.55; H, 5.45; N, 5.87; Cl, 9.97; S, 4.68.

REFERENCE EXAMPLE 28 5- (4-Pyridyl) thiophene-2-carboxylic acid hydrochloride In a similar manner to reference example 6, except for the use of 5-bromothiophen-2-carboxylic acid and diethyl (4-pyridyl) borane acid, the reaction was carried out, whereby the compound of Title. 1 H-NMR (DEMO-d 6) d: 7.87 (1 H, d, J = 3.9 Hz), 8.17 (1 H, d, J = 3.9 Hz), 8.29 (2 H, d, J = 6.8 Hz), 8.88 ( 2H, d, J = 6.8 Hz). MS (FAB) m / z: 206 (M + H) +. Elemental analysis for: C? 0H7NO2S HCI 0.8H2O Calculated: C, 46.90; H, 3.78; N, 5.47; Cl, 13.84; S, 12.52. Found: C, 46.77; H, 3.76; N, 5.27; Cl, 13.83; S, 12.56.

REFERENCE EXAMPLE 29 5- (4-pyridyl) furan-2-carboxylic acid hydrochloride In a similar manner to reference example 6, except for the use of 5-bromofuran-2-carboxylic acid and diethyl (4-pyridyl) borane as raw materials, the reaction was carried out, whereby the compound of Title. 1H-NMR (DEMO-de) d: 7.49 (1 H, d, J = 3.4 Hz), 7.80-7.90 (1 H, m), 8.20-8.30 (2H, m), 8.85-8.95 (2H, m) .

REFERENCE EXAMPLE 30 4- (2-Pyridyl) benzoic acid hydrochloride To water (200 ml), 2- (p-tolyl) pyridine (17.2 g) was added. To the resulting mixture, potassium permanganate (21.0 g) was added, followed by heating under reflux for 18 hours. After the precipitate was filtered, dichloromethane was added to the filtrate to remove the aqueous layer. The aqueous layer was then made acidic with 2N hydrochloric acid. The aqueous acid solution was concentrated. The precipitate was collected by filtration, followed by washing with water and ethyl acetate, whereby the title compound (7.07 g, 35%) was obtained as a white solid. 1H-NMR (DEMO-de) d: 7.60 (1 H, t, J = 5.9 Hz), 8.08 (2H, d, J = 7.8 Hz), 8.17 (2H, m), 8.21 (2H, d, J = 7.8 Hz), 8.78 (1 H, d, J = 4.9 Hz). MS (EI) m / z: 199 M +.

REFERENCE EXAMPLE 31 1-F (E) -4-chlorostyrylsulfonyl) piperazine hydrochloride In a similar manner to reference example 1, except for the use of tert-butyl 1-piperazinecarboxylate and (E) -4-chlorostyrylsulfonyl chloride as raw materials, the reaction was carried out, whereby the compound of Title. 1H-NMR (DEMO-d6) d: 3.20 (4H, br s), 3.33-3.38 (4H, m), 7.47 (2H, s), 7.53 (1 H, d, J = 8.8 Hz), 7.82 (1 H, d, J = 8.8 Hz). Elemental analysis for: C12H-15CIN2O2S Calculated HCI: C, 44.59; H, 4.99, Cl, 21.94; N, 8.67; S, 9.92. Found: C, 44.42; H, 4.78, Cl, 21.83; N, 8.68; S, 9.87.

REFERENCE EXAMPLE 32 4- (2,4-Diamino-6-pyrimidinyl) benzoic acid hydrochloride In toluene (9 ml), 6-chloro-2,4-diamnopyrimidine (434 mg) was dissolved, followed by the addition of 4-carboxyphenylboronic acid (667 mg), ethanol (2.5 ml), sodium carbonate (635 mg), water (3.0 ml) and bis (triphenylphosphine) palladium (II) dichloride (65 mg). The resulting mixture was heated under reflux for 24 hours under an atmosphere of argon gas. Ethyl acetate and water were added to the reaction mixture. The aqueous layer separated in this way was made acidic with 2N hydrochloric acid. The insoluble matter was collected by filtration, washed with water and tetrahydrofuran and then dried, whereby the title compound (371 mg, 54%) was obtained. 1 H-NMR (DEMO-de) d: 6.43 (1 H, s), 7.30-7.80 (2 H, br), 7.96 (2 H, d, J = 7.8 Hz), 8.12 (2 H, d, J = 7.8 Hz) , 8.27 (2H, br s), 12.77 (1 H, br), 13.33 (1 H, br). MS (El) m / z: 230 M +. Elemental analysis for: CnH? ON4? 2S 0.95HCM .9H2O Calculated: C, 44.17; H, 4.97; Cl, 11.26; N, 18.73. Found: C, 44.33; H. 4.97; Cl, 11.32; N, 18.65.

REFERENCE EXAMPLE 33 1-tert-butoxycarbonyl-4-r4- (2-pyridyl) benzoylpiperazine In a similar manner to reference example 3, except for the use of 4- (2-pyridyl) benzoic acid hydrochloride obtained in reference example 30, and tert-butyl 1-piperazinecarboxylate as raw materials, the reaction, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9 H, s), 3.43 (4 H, br), 3.51 (2 H, br), 3.76 (2 H, br), 7.28 (1 H, d, J = 5.9 Hz), 7.52 (2H, d, J = 7.8 Hz), 7.76 (1 H, m), 7.79 (1 H, m), 8.05 (2 H, d, J = 7.8 Hz), 8.71 (1 H, d, J = 4.9) . MS (FAB) m / z: 368 (M + H) +. Elemental analysis for: C2iH25N3O30.1 Calculated H2O: C, 68.31; H, 6.88; N, 11.38 Found: C, 68.26; H, 6.86; N, 11.42.

REFERENCE EXAMPLE 34 N-oxide of 2-f4-r4- (tert-butoxycarbonyl) piperazin-1-illcarbonylphenylpyridine At -10 ° C, methachloroperbenzoic acid (789 mg) was added to a solution of 1-tert-butoxycarbonyl-4- [4- (2-pyridyl) benzoyl] piperazine (517 mg) in dichloromethane (dichloromethane: 8 ml). The resulting mixture was stirred for 24 hours, followed by dilution with dichloromethane. A small amount of an aqueous solution of sodium thiosulfate and saturated saline was added to the diluted solution. The organic layer thus separated was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (dichloromethane: methanol = 20: 1), whereby the title compound (415 mg, 77%) was obtained. 1 H-NMR (CDCl 3) d: 1.48 (9 H, s), 3.47 (6 H, br), 3.76 (2 H, br), 7.29 (1 H, m), 7.34 (1 H, t, J = 7.8 Hz), 7.44 (1 H, dd, J = 7.8, 2.0 Hz), 7.52 (2 H, d, J = 7.8 Hz), 7.90 (2 H, d, J = 7.8 Hz), 8.35 (1 H, d, J = 5.9 Hz ). MS (FAB) m / z: 384 (M + H) +.

REFERENCE EXAMPLE 35 N-oxide of 2-r4-r (1-piperazinyl) carboninfenillpyridine In dichloromethane (2.5 ml), 2- [4 - [[4- (tert-butoxycarbonyl) piperazin-1-yl] carbonyl] phenyl] pyridine N-oxide was dissolved. To the resulting solution, a saturated solution of ethanol hydrochloride (2.5 ml) was added, followed by stirring at room temperature for 1 hour. After the solvent was distilled under reduced pressure, water was added to the residue, whereby an aqueous solution was obtained. Acetone was added to the aqueous solution until the solution became cloudy. The precipitate was collected by filtration and washed with acetone, whereby the title compound (274 mg, 81%) was obtained. 1 H-NMR (DEMO-d 6) d: 3.17 (4 H, br s), 3.50-3.95 (4 H, br), 7.43 (1 H, d, J = 3.9 Hz), 7.44 (1 H, d, J = 3.9 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.66 (1 H, t, J = 3.9 Hz), 7.92 (2H, d, J = 8.8 Hz), 8.36 (1 H, t, J = 3.9 Hz), 9.21 (2H, br). MS (FAB) m / z: 284 (M + H) +.

REFERENCE EXAMPLE 36 1- (tert-Butoxycarbonyl) -4- [4- (3-pyridyl) benzoyl-1-piperazine In a similar manner to reference example 3, except for the use of 4- (3-pyridyl) benzoic acid hydrochloride obtained in reference example 8, and tert-butyl 1-piperazinecarboxylate as raw materials, the reaction, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 3.35-3.85 (8H, br), 7.38 (1H, dd, J = 7.8, 4.9 Hz), 7.52 (2H, d, J = 8.3 Hz) , 7.63 (2H, d, J = 8.3 Hz), 7.88 (1 H, m), 8.62 (1 H, dd, J = 1.5, 4.9 Hz), 8.84 (1 H, d, J = 2.0 Hz).

EXAMPLE OF REFERENCE 37 N-oxide of 3-f4-rf4- (tert-butoxycarbonyl) piperazin-1-illcarbonylphenipyridine In a manner similar to reference example 34, except for the use of 1- (tert-butoxycarbonyl) -4- [4- (3-pyridyl) benzoyl] piperazine as a starting material, the title compound was obtained as a colorless solid. 1 H-NMR (CDCl 3) d: 1.48 (9H, s), 3.35-4.83 (8H, br), 7.38 (1 H, m) 7.47 (1 H, m), 7.49-7.65 (4H, m), 8.23 ( 1 H, dd, J = 6.4, 1.5 Hz), 8.47 (1 H, t, J = 1.5 Hz). MS (FAB) m / z: 384 (M + H) +. Elemental analysis for: C21H25N3O4 O.25H2O Calculated: C, 65.02; H, 6.63; N, 10.83. Found: C, 65.30; H, 6.65; N, 10.43.

REFERENCE EXAMPLE 38 2-Hydroxy-4- (4-pyridyl) benzoic acid In water (22.5 ml) and an aqueous solution at 47% hydrobromic acid (22.5 ml), 4-amino-2-hydroxybenzoic acid (5.04 g) was dissolved. While the mixture of the resulting solution was kept at 5 ° C or less, an aqueous solution (water: 15.0 ml) of sodium nitrite (2.26 g) was added dropwise thereto, followed by stirring for 30 minutes under cooling in ice. The reaction mixture was added, in portions, to a solution of cuprous bromide (5.63 g) dissolved in an aqueous solution at 47% hydrobromic acid (15 ml) under ice-cooling. The resulting mixture was stirred at room temperature for 150 minutes. Ethyl acetate was added to the reaction mixture for extraction. The organic layer obtained in this way was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (dichloromethane ~ 10% methanol-dichloromethane), whereby 4-bromo-2-hydroxybenzoic acid (5.51 g) was obtained as a crudely purified product. The crudely purified product (298 mg) was reacted as in Reference Example 6, whereby the title compound (70 mg, 21%) was obtained. 1H-NMR (DEMO-d6) d: 7.30-7.40 (2H, m), 7.78 (2H, d, J = 4.4 Hz), 7.92 (1 H, d, J = 6.3 Hz), 8.69 (2H, d, J = 5.9 Hz).

MS (FAB) m / z: 216 (M + H) +.

REFERENCE EXAMPLE 39 4-Bromo-3-hydroxybenzoic acid In acetic acid (24.5 ml), 3-hydroxybenzoic acid (5.00 g) was suspended. To the resulting suspension, a solution of bromine (1.9 ml) in acetic acid (acetic acid: 5 ml) was added dropwise while cooling on ice, followed by stirring at room temperature for 33 hours. The reaction mixture was cooled in ice. The crystals precipitated in this way were collected by filtration and then washed with acetic acid, whereby the title compound was obtained (1.68 g, 21%). 1 H-NMR (DEMO-de) d: 7.28 (1 H, dd, J = 7.8, 2.0 Hz), 7.51 (1 H, d, J = 2.0 Hz), 7.59 (1 H, d, J = 8.3 Hz) , 10.54 (1 H, br s), 12.84 (1 H, br).

REFERENCE EXAMPLE 40 Methyl 4-bromo-3-methoxy benzoate In a similar manner to reference example 17, except for the use of 4-bromo-3-hydroxybenzoic acid as raw material, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 3.92 (3H, s), 3.96 (3H, s), 7.51 (1 H, dd, J = 8.3, 2.0 Hz), 7.55 (1 H, d, J = 2.0 Hz), 7.61 (1 H, d, J = 8.8 Hz).

REFERENCE EXAMPLE 41 3-Methoxy-4- (4-pyridyl) benzoic acid In a manner similar to Reference Example 7, except for the use of methyl 4-bromo-3-methoxybenzoate and diethyl (4-pyridyl) borane, the reaction was carried out. The crude product obtained in this manner was reacted as in Reference Example 8, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 3.93 (3H, s), 7.65-7.75 (3H, m), 8.20 (2H, d, J = 5.4 Hz), 8.94 (2H, d, J = 6.3 Hz). MS (FAB) m / z: 230 (M + H) +.

REFERENCE EXAMPLE 42 4-tert-butoxycarbonyl-1-r (6-chloronaphthalen-2-yl) sulfonyl-2-ethoxycarbonylpiperazine In dichloromethane (18 ml), 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and 6-chloro-2-naphthylsulfonyl chloride (588 mg) were dissolved under ice cooling. To the resulting solution, dipropylethylamine (0.59 ml) was added, followed by stirring at room temperature for 63 hours. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1), whereby the title compound (688 mg, 71%) was obtained. 1 H-NMR (CDCl 3) d: 1.05 (3 H, t, J = 7.1 Hz), 1.38 (9 H, s), 2.80-4.70 (9 H, m), 7.55 (1 H, dd, J = 8.6, 2.2 Hz) , 7.77 (1H, dd, J = 8.6, 1.7 Hz), 7.85-7.90 (3H, m), 8.33 (1 H, s). MS (FAB) m / z: 483 [(M + H) Cl 35], 485 [(M + H) Cl 37].

REFERENCE EXAMPLE 43 4-tert-butoxycarbonyl-2-ethoxycarbonyl-1-r4- (3-pyridyl) benzo-piperazine In a similar manner to reference example 12, except for the use of 4- (3-pyridyl) benzoic acid and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine as raw materials, the reaction was carried out, whereby the composed of the title. 1 H-NMR (CDCl 3) d: 1.20-1.40 (3H, m), 1.46 (9H, s), 2.70-4.80 (8H, m), 5.35 (1H, br), 7.35-7.70 (5H, m), 7.85-7.95 (1H, m), 8.64 (2H, dd, J = 4.6, 1.7 Hz), 8.86 (1 H, s). MS (FAB) m / z: 440 (M + H) +.

REFERENCE EXAMPLE 44 Methyl N-tert-butoxycarbonyltranexamate To methanol (20 ml), thionyl chloride (1 ml) was added dropwise under cooling on ice, followed by the addition of tranexamic acid (2.04 g). The resulting mixture was heated under reflux for 3 hours. The residue obtained by distilling the reaction mixture under reduced pressure was pulverized in ether, and then collected by filtration, whereby colorless crystals (2.31 g) were obtained. The resulting crystals (2.10 g) were dissolved in dichloromethane (40 ml), followed by the addition of N-methylmorpholine (1.2 ml). To the resulting mixture, a solution of di-tert-butyl dicarbonate (2.51 g) in dichloromethane (dichloromethane: 3 ml) was added under ice-cooling. The resulting mixture was stirred at room temperature for 18 hours. After dilution with dichloromethane, the reaction mixture was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 10: 1 ~ 3: 1), followed by recrystallization from a mixed solvent of hexane and ethyl acetate. ethyl, whereby colorless crystals were obtained (2.09 g, 65%). 1 H-NMR (CDCl 3) d: 0.90-1.10 (2H, m), 1.40-1.60 (12H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 2.24 (1H, m ), 2.98 (2H, m), 3.66 (3H, s), 4.58 (1H, br).

Elemental analysis for: CUH25NO4 Calculated: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.15; H, 9.42; N, 5.12.

REFERENCE EXAMPLE 45 Trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylmethanol Methyl N-tert-butoxycarbonyltranexamate (1.00 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (2 ml). To the resulting solution, sodium borohydride (0.44 g) was added under cooling on ice, followed by stirring at room temperature for 24 hours. After the addition of water, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and dilute hydrochloric acid were added to the concentrate. The organic layer separated in this way was dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a repeating silica gel column (first time, dichloromethane ~ dichloromethane: methanol = 20: 1, second time, hexane: ethyl acetate = 3: 1), whereby colorless crystals were obtained (0.74 g, 82%). A portion of the crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained. 1 H-NMR (CDCl 3) d: 0.90-1.10 (4H, m), 1.30-1.60 (12H, m), 1.80-2.00 (4H, m), 2.98 (2H, m), 3.45 (2H, d, J = 6.4 Hz), 4.59 (1 H, br).

Elemental analysis for: C13H25NO3 Calculated: C, 64.17; H, 10.35, N, 5.76. Found: C, 64.31; H, 10.03; N, 5.74.

REFERENCE EXAMPLE 46 trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexanecarboxaldehyde In dichloromethane (5 ml), trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylmethanol (0.20 g) was dissolved, followed by the addition of pyridinium chlorochromate (0.23 g). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1), whereby the title compound (0.15 g, 76%) was obtained. 1 H-NMR (CDCl 3) d: 1.00 (2H, m), 1.27 (2H, m), 1.40-1.60 (1 H, m), 1.44 (9H, s), 1.88 (2H, m), 2.02 (2H, m), 2.18 (1 H, m), 3.00 (2 H, t, J = 6.4 Hz), 4.61 (1 H, br), 9.62 (1 H, s). MS (FAB) m / z: 242 (M + H) +.

REFERENCE EXAMPLE 47 1-rtrans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylmethyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine In dichloromethane (7 ml), trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexane carboxaldehyde (0.13 g) was dissolved, followed by the addition of 1 - [(6-chloronaphthalen-2-yl) sulfonyl trifluoroacetate. ] piperazine (0.24 g), triethylamine (78 μl) and sodium triacetoxyborohydride (0.17 g). The resulting mixture was stirred at room temperature for 11 hours under an atmosphere of argon gas. To the reaction mixture, an aqueous solution of sodium bicarbonate was added, followed by dilution with dichloromethane. The organic layer separated in this way was dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2: 1), whereby the title compound was obtained (0.29 g, 100%). 1 H-NMR (CDCl 3) d: 0.70-0.90 (4H, m), 1.30-1.50 (2H, m), 1.42 (9H, s), 1.70-1.80 (4H, m), 2.09 (2H, d, J = 7.3 Hz), 2.46 (4H, m), 2.92 (2H, m), 3.08 (4H, m), 4.53 (1 H, br), 7.56 (1 H, dd, J = 8.8, 2.0 Hz), 7.78 ( 1 H, dd, J = 8.8, 2.0 Hz), 7.80-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 536 [(M + H) +, Cl 35], 538 [(M + H)? Cl37].

REFERENCE EXAMPLE 48 1-rtrans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was carried out as in the reference examples 11 and 12, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 0.80-1.00 (2H, m), 1.40-1.60 (3H, m), 1.42 (9H, s), 1.60-1.70 (2H, m), 1.70-1.90 (2H, m) , 2.30 (1 H, m), 2.95 (2H, m), 3.07 (4H, m), 3.58 (2H, br), 3.70 (2H, br), 4.57 (1H, m), 7.58 (1H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.30 (1 H, s). MS (FD) m / z: 549 (M +, Cl35), 551 (M \ Cl37).

REFERENCE EXAMPLE 49 Benzyl ester of N-frans-4-N-tert-butoxycarbonylaminomethylD-cyclohexylcarbonylIglycine In a manner similar to reference examples 11 and 12, except for the use of methyl N-tert-butoxycarbonyltranexamate and glycine benzyl ester as raw materials, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 0.96 (2H, m), 1.44 (9H, s), 1.40-1.60 (3H, m), 1.80-1.90 (2H, m), 1.90-2.00 (2H, m), 2.10 (1 H, m), 2.98 (2 H, m), 4.08 (2 H, d, J = 4.9 Hz), 4.57 (1 H, m), 5.19 (2 H, s), 5.97 (1 H, m), 7.30 -7.40 (5H, m).

Elemental analysis for: C22H32N2O5 Calculated: C, 65.32; H, 7.97; N, 6.93. Found: C, 65.05; H, 7.89; N, 7.16.

REFERENCE EXAMPLE 50 1-fN-rans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl-glycine-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazine In tetrahydrofuran (11 ml), N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycine benzyl ester (0.22 g) was suspended. To the resulting suspension, 10% palladium on carbon (water content: about 50%, 50 mg) was added, followed by catalytic reduction at normal pressure and room temperature for 14 hours. After removal of the catalyst, the solvent was distilled under reduced pressure. The residue obtained in this way was reacted as in reference example 12, whereby the title compound (0.32 g, 98%). 1 H-NMR (CDCl 3) d: 0.80-1.00 (2H, m), 1.30-1.50 (3H, m), 1.43 (9H, s), 1.80-2.00 (4H, m), 2.06 (1H, m), 2.95 (2H, m), 3.10-3.20 (4H, m), 3.52 (2H, m), 3.74 (2H, m), 3.94 (2H, d, J = 4.4 Hz), 4.54 (1 H, m), 6.40 (1 H, m), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.74 (1 H, dd, J = 8.8, 1.5 Hz), 7.80-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 607 [(M + H)? Cl35], 609 [(M + H)? Cl37].

REFERENCE EXAMPLE 51 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-1homopiperazine hydrochloride Homopiperazine (5 g) was dissolved in tetrahydrofuran (100 ml) at room temperature. To the resulting solution, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (12.3 g) was added in portions, followed by stirring for 3 hours. After concluding the reaction, the solvent was distilled. The residue was purified by chromatography on a column of silica gel (10 to 20% methanol-dichloromethane), followed by the addition of ethanolic hydrochloric acid to 1 N. The solvent was then distilled off. The residue was solidified by the addition of ethanol, whereby powders (7.46 g) were obtained. The resulting powders were reacted as in reference example 1, whereby the title compound was obtained. 1H-NMR (DEMO-de) d: 2.00 (2H, br s), 3.10-3.30 (4H, m), 3.30-3.50 (2H, m), 3.55-3.65 (2H, m), 7.72 (1H, d, J = 8.8 Hz), 7.89 (1 H, d, J = 8.3 Hz), 8.17 (1 H, d, J = 8.8 Hz), 8.22-8.28 (2H, m), 8.56 (1 H, s) , 9.29 (2H, br s). MS (FAB) m / z: 325 (M + H) +. Elemental analysis for: C? 5H? 7CIN2? 2S Calculated HCI: C, 49.89; H, 5.02; N, 7.75; Cl, 19.63. Found: C, 49.94; H, 5.05; N, 7.47; Cl, 19.65.

REFERENCE EXAMPLE 52 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl-1-4-r (6-chloronaphthalen-2-yl) sulfonyl-homopiperazine In a similar manner to reference example 48, except for the use of methyl N-tert-butoxycarbonyltranexamate and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 0.80-1.00 (2H, m), 1.40-1.60 (3H, m), 1.43 (9H, s), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m) , 2.30-2.40 (1 H, m), 2.97 (2H, m), 3.30-3.50 (4H, m), 3.60-3.80 (4H, m), 4.64 (1 H, br), 7.50-7.60 (1 H , m), 7.70-7.80 (1 H, m), 7.80-8.00 (3H, m), 8.33 and 8.35 (1 H, each s). MS (FAB) m / z: 564 [(M + H) +, Cl 35], 566 [(M + H)? Cl37].

REFERENCE EXAMPLE 53 Methyl 4- (N-tert-butoxycarbonylaminomethyl) benzoate In a similar manner to reference example 44, except for the use of 4-aminomethylbenzoic acid as raw material, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 3.91 (3H, s), 4.37 (2H, d, J = 5.4 Hz), 4.92 (1 H, br), 7.35 (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.3 Hz). Elemental analysis for: C? H? 9 NO 4 Calculated: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.20; H, 7.02; N, 5.58.

REFERENCE EXAMPLE 54 1 -r4- (N-tert-butoxycarbonylaminomethyl) benzoin-4-r (6-chloronaphthalen-2-dsulfonylpiperazine In a manner similar to reference example 48, except for the use of methyl 4- (N-tert-butoxycarbonylaminomethyl) benzoate and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride, it was The reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.45 (9H, s), 3.00-3.30 (4H, br), 3.40-4.00 (4H, br), 4.31 (2H, d, J = 5.9 Hz), 4.90 (1 H, br), 7.27 (4H, m), 7.59 (1 H, dd, J = 8.8, 1.5 Hz), 7.75 (1 H, d, J = 8.8 Hz), 7.90-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 544 [(M + H)? Cl35], 546 [(M + H) +, Cl37].

REFERENCE EXAMPLE 55 3- (N-tert-butoxycarbonylaminomethyl) benzoate methyl Methyl 3-methylbenzoate (1.00 g) was dissolved in carbon tetrachloride (10 ml), followed by the addition of N-bromosuccinic imide (1.22 g) and 2,2'-azobisisobutyronitrile (catalytic amount). The resulting mixture was heated under reflux for 1 hour under exposure to a mercury lamp.

After the insoluble matter was filtered, the residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 20: 1), whereby a colorless oil was obtained ( 1.34 g). The colorless oil (0.62 g) obtained in this way was dissolved in N, N-dimethylformamide (10 ml), followed by the addition of sodium azide (0.38 g). The resulting mixture was stirred at room temperature for 20 hours. After concentration of the reaction mixture under reduced pressure, the concentrate was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was dissolved in tetrahydrofuran (15 ml). Triphenylphosphine (0.75 g) was added to the resulting solution, followed by stirring at an external temperature of about 50 ° C for 5 hours. After the addition of aqueous ammonia at approximately 28% (7 ml) and stirring for another two hours, the reaction mixture was concentrated under reduced pressure. The concentrate was extracted with ether. Dilute hydrochloric acid was added to the extract to make it acidic. To the aqueous layer separated in this manner, a dilute aqueous solution of sodium hydroxide was added to make it alkaline, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was dissolved in dichloromethane (7 ml). To the resulting solution, di-tert-butyl carbonate (0.45 g) was added under cooling on ice, followed by stirring at room temperature for 3 days. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 5: 1), whereby the title compound was obtained (0.29 g, 35%). 1 H-NMR (CDCl 3) d: 1.46 (9 H, s), 3.91 (3 H, s), 4.36 (2 H, d, J = 5.9 Hz), 4.97 (1 H, br), 7.40 (1 H, t, J = 7.8 Hz), 7.49 (1 H, d, J = 7.8 Hz), 7.90-8.00 (2H, m). MS (FAB) m / z: 266 (M + H) +.

REFERENCE EXAMPLE 56 methyl 4-cyanomethylbate In dichloromethane (20 ml), methyl 4-hydroxymethylbate (1.00 g) was dissolved followed by the addition of triethylamine (0.9 ml). Under cooling on ice, a solution of methanesulfonyl chloride (0.70 g) in dichloromethane (dichloromethane: 5 ml) was added to the resulting solution. The resulting mixture was stirred at room temperature for 15 hours. After dilution with dichloromethane, the reaction mixture was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was dissolved in acetonitrile (12 ml). To the resulting solution, potassium cyanide (0.80 g) and 18-crown-6 (0.16 g) were added, followed by stirring at room temperature for 40 hours. After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (dichloromethane), whereby colorless crystals (0.91 g, 86%) were obtained. A portion of the resulting crystals was recrystallized from the mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained. 1 H-NMR (CDCl 3) d: 3.82 (2H, s), 3.93 (3H, s), 7.42 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.3 Hz). Elemental analysis for: C10H9NO2 Calculated: C, 68.56; H, 5.18; N, 8.00 Found: C, 68.39; H, 5.29; N, 8.08.

REFERENCE EXAMPLE 57 methyl 4-r2- (tert-butoxycarbonylamino) ethylenbate Methyl 4-cyanomethylbate (0.20 g) was dissolved in a mixed solvent of methanol (15 ml) and chloroform (0.4 ml). To the resulting solution, platinum dioxide (33 mg) was added, followed by catalytic reduction at room temperature under atmospheric pressure for 3 hours. The catalyst was removed by filtration through Celite, and the solvent was distilled under reduced pressure. The residue was suspended in dichloromethane (5 ml), followed by the addition of triethylamine (160 μl). After the addition of a solution of di-tert-butyl dicarbonate (0.29 g) in dichloromethane (dichloromethane: 2 ml) under ice cooling, the resulting solution was stirred at room temperature for 13 hours. The reaction mixture was diluted with dichloromethane, washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 10: 1 ~ 5: 1), whereby the title compound was obtained (0.28 g, 88%). 1 H-NMR (CDCl 3) d: 1.43 (9H, s), 2.86 (2H, t, J = 6.8 Hz), 3.39 (2H, m), 3.91 (3H, s), 4.53 (1 H, br), 7.27 (2H, d, J = 8.3 Hz), 7.98 (2H, d, J = 8.3 Hz). Elemental analysis for: C15H21NO4 Calculated: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.43; H, 7.35; N, 4.97.

REFERENCE EXAMPLE 58 1-f4-f2- (tert-butoxycarbonylamino) ethylbenzoin-4-r (6-chloronaphthalen-2-dsulfonylpiperazine In a similar manner to reference example 48, except for the use of methyl 4- [2- (tert-butoxycarbonylamino) ethyl] benzoate and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as raw materials , the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.42 (9H, s), 2.79 (2H, t, J = 6.8 Hz), 3.10 (4H, br), 3.35 (2H, m), 3.40-4.00 (4H, br), 4.50 (1 H, br), 7.18 (2 H, d, J = 8.3 Hz), 7.24 (2 H, d, J = 8.3 Hz), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 558 [(M + H) +, Cl 35], 560 [(M + H) +, Cl 37].

REFERENCE EXAMPLE 59 (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1, 2,3,4-tetrahydronaphthalene In a manner similar to Reference Example 55, except for the use of (2RS) -6-methoxycarbonyl-2-p-toluenesulfonyloxymethyl-1, 2,3,4-tetrahydronaphthalene as raw material, the reaction was carried out, which was obtained the title compound. 1 H-NMR (CDCl 3) d: 1.40-1.60 (1 H, m), 1.46 (9 H, s), 1.90-2.10 (2 H, m), 2.50 (1 H, dd, J = 17.1, 10.7 Hz), 2.70 -3.00 (3H, m), 3.10-3.30 (2H, m), 3.89 (3H, s), 4.68 (1 H, br), 7.12 (1 H, d, J = 7.8 Hz), 7.70-7.80 (2H , m). Elemental analysis for: C? 8H25NO4 Calculated: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.78; H, 7.61; N, 4.12.

REFERENCE EXAMPLE 60 1-rr (6RS) -6- N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-incarbonin-4-f (6-chloronaphthalen-2-ylsulfonylpiperazine In a similar manner to reference example 48, except for the use of (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1, 2,3,4-tetrahydronaphthalene and hydrochloride of 1 - [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine, the reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.30-1.60 (1 H, m), 1.45 (9 H, s), 1.80-2.00 (2 H, m), 2.43 (1 H, dd, J = 16.6, 10.7 Hz), 2.70 -2.90 (3H, m), 3.00-3.20 (6H, m), 3.50-3.90 (4H, br), 4.69 (1H, br), 6.90-7.10 (3H, m), 7.59 (1H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 598 [(M + H)? Cl 35], 600 [(M + H)? Cl37].

REFERENCE EXAMPLE 61 (2RS) -2- N-tert-butoxycarbonylaminomethyl-6-hydroxymethyl-1, 2,3,4-tetrahydronaphthalene In dichloromethane (10 ml), (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1, 2,3,4-tetrahydronaphthalene (0.47 g) was dissolved, followed by the addition, dropwise, of diisobutylaluminum hydride (a solution of hexane at 0.95 M, 3.6 ml) at an external temperature of -78 ° C. The resulting mixture was stirred for 90 minutes without changing the temperature.

Methanol was added to the reaction mixture, followed by heating to room temperature. Insoluble matter was filtered through Celite. The filtrate was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1), whereby colorless crystals (0.31 g, 72%) were obtained. A portion of the crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained. 1 H-NMR (CDCl 3) d: 1.40-1.60 (1 H, m), 1.46 (9H, s), 1.60-1.70 (1 H, m), 1.90-2.00 (2H, m), 2.45 (1 H , dd, J = 16.6, 10.7 Hz), 2.70-2.90 (3H, m), 3.10-3.30 (2H, m), 4.62 (2H, d, J = 5.9 Hz), 4.67 (1 H, br), 7.00 -7.20 (3H, m). Elemental analysis for: C-? 7H25NO3 Calculated: C, 70.07; H, 8.65; N, 4.81. Found: C, 70.21; H, 8.49; N, 4.75.

REFERENCE EXAMPLE 62 1-rr (6RS) -6- (N-tert-butoxycarbonylaminomethylP-5,6,7,8-tetrahydronaphthalen-2-Hmetip-4-r (6-chloronaphthalen-2-ylsulphonopiperazine In a manner similar to reference examples 46 and 47, except for the use of (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-hydroxymethyl-1, 2,3,4-tetrahydronaphthalene as raw material, it was The reaction was carried out, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.30-1.50 (1 H, m), 1.44 (9 H, s), 1.80-2.00 (2 H, m), 2.40 (1 H, m), 2.51 (4 H, br), 2.60 -2.90 (3H, m), 3.09 (6H, br), 3.39 (2H, s), 4.67 (1 H, br), 6.90-7.00 (3H, m), 7.56 (1 H, d, J = 8.8 Hz ), 7.77 (1 H, d, J = 8.8 Hz), 7.80-8.00 (3H, m), 8.28 (1 H, s). MS (FAB) m / z: 584 [(M + H) +, Cl 35], 586 [(M + H)? Cl37].

REFERENCE EXAMPLE 63 (2RS) -2- (tert-butyldimethylsilyloxymethiD-6-methoxycarbonyl-1, 2,3,4-tetrahydronaphthalene) In N, N-dimethylformamide (5 ml), (2RS) -2-hydroxymethyl-6-methoxycarbonyl-1, 2,3,4-tetrahydronaphthalene (1.71 g) was dissolved, followed by the addition of imidazole (0.81 g). ) and tert-butyldimethylsilyl chloride (1.81 g) under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After the addition of methanol, the mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 50: 1), whereby a yellow solid (2.20 g, 85%) was obtained. 1 H-NMR (CDCl 3) d: 0.06 (6H, s), 0.91 (9H, s), 1.14-1.60 (1 H, m), 1.90-2.10 (2H, m), 2.53 (1 H, dd, J = 17.1, 10.3 Hz), 2.80-3.00 (3H, m), 3.58 (2H, d, J = 5.9 Hz), 3.89 (3H, s), 7.14 (1 H, d, J = 7.8 Hz), 7.70 -7.80 (2H, m). MS (FAB) m / z: 335 (M + H) +.

EXAMPLE OF REFERENCE 64 (2RS) -2- (tert-butyldymethylsilyloxymethyl) -6-hydroxyethyl-1,2,3,4-tetrahydronaphthalene In a similar manner to reference example 61, except for the use of (2RS) -2- (tert-butyldimethylsilyloxymethyl) -6-methoxycarbonyl-1, 2,3,4-tetrahydro-naphthalene as raw material, the compound of Title. 1 H-NMR (CDCl 3) d: 0.07 (6H, s), 0.91 (9H, s), 1.30-1.50 (1 H, m), 1.50-1.60 (1 H, m), 1.90-2.10 ( 2H, m), 2.48 (1 H, m), 2.70-2.90 (3H, m), 3.58 (2H, m), 4.62 (2H, d, J = 5.9 Hz), 7.09 (3H, m). MS (FAB) m / z: 307 (M + H) +.

REFERENCE EXAMPLE 65 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl) -1, 2,3,4-tetrahydronaphthalene In dichloromethane (10 ml), (2RS) -2- (tert-butyldimethylsilyloxymethyl) -6-hydroxymethyl-1, 2,3,4-tetrahydronaphthalene (1.00 g) was dissolved. To the resulting solution, triethylamine (0.5 ml) was added, followed by cooling on ice. After the addition of a solution of methanesulfonyl chloride (0.39 g) in dichloromethane (dichloromethane: 1 ml), the resulting mixture was stirred at room temperature for 9 hours. The reaction mixture was washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was treated as in Reference example 59, whereby the title compound was obtained (1.10 g, 83%). 1 H-NMR (CDCl 3) d: 0.06 (6H, s), 0.91 (9H, s), 1.40-1.60 (1 H, m), 1.46 (9H, s), 1.90-2.00 (2H, m), 2.45 ( 1 H, m), 2.70-2.90 (3H, m), 3.57 (2H, m), 4.24 (2H, m), 4.76 (1 H, br), 7.00-7.10 (3H, m). MS (FAB) m / z: 406 (M + H) +.

REFERENCE EXAMPLE 66 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1.2.3.4- tetrahydronaphthalene In tetrahydrofuran (10 ml), (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl-1, 2,3,4-tetrahydro-naphthalene (1.09 g) was dissolved in the resulting solution. , tetrabutylammonium fluoride (a solution of tetrahydrofuran at 1.0 M, 4.0 ml) was added, followed by stirring at room temperature for 2 hours.After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and dried on anhydrous sodium sulfate The residue, obtained by distilling off the solvent under reduced pressure, was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1 ~ 2: 1). a colorless solid (0.77 g, 98%) A portion of the solid was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained H-NMR (CDCl 3) delta: 1.40-1.60 (2H , m), 1.46 (9H, s), 1.90-2.10 (2H, m), 2.48 (1H, dd, J = 16.6.10.7Hz), 2.70-3.00 (3H, m), 3.6-3.7 (2H, m), 4.24 (2H, d, J = 5.4Hz) , 4.78 (1 H, br), 7.00-7.10 (3H, m). Elemental analysis for C17H25NO3 Calculated: C, 70.07; H, 8.65; N, 4.81. Found, 70.02; H, 8.61; N, 4.46.

REFERENCE EXAMPLE 67 1-rr (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1.2.3.4-tetrahydronaphthalen-2-pmet-p-4-r (6-chloronaphthalen-2-yl) sulfonyl perazine (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1, 2,3,4-tetrahydronaphthalene (0.17 g) was dissolved in dichloromethane (5 ml), followed by the addition of N-N-oxide. -methylmorpholine (0.13 g) and molecular sieves of 4A (activated powder, 0.18 g). Under ice-cooling, tetrapropylammonium ruthenium-tetraoxylammonium salt (10 mg) was added to the resulting mixture, followed by stirring at room temperature for 1 hour. Ether was added to the reaction mixture and the insoluble matter was removed by filtration through Celite. The filtrate was distilled off under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane), whereby the corresponding aldehyde compound was obtained. The reaction was carried out in a manner similar to Reference Example 47, except for the use of the resulting aldehyde compound, whereby the title compound (0.14 g, 41%) was obtained. 1 H-NMR ((CDCl 3) delta: 1.20-1.40 (1 H, m), 1.44 (9H, s), 1.80-2.00 (2H, m), 2.20-2.40 (3H, m), 2.50-2.60 (4H, m), 2.60-2.80 (3H, m) 3.11 (4H, m), 4.20 (2H, d, j = 5.4Hz) , 4.79 (1 H, br), 6.94 (3H, m), 7.57 (1 H, dd, j = 8.8,1.5Hz), 7.79 (1 H, dd, j = 8.8,1.5Hz), 7.90-8.00 ( 3H, m), 8.31 (1 H, s). MS (FAB) m / z: 584 [(M + H), CI35], 586 [(M + H) +, CI37].

REFERENCE EXAMPLE 68 1-rr (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1.2.3.4-tetrahydronaphthalen-2-incarbonin-4-f (6-chloronaphthalen-2-yl) sulfonylpiperazine (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1, 2,3,4-tetrahydronaphthalene (0.21 g) was dissolved in carbon tetrachloride (2 ml), acetonitrile (2 ml) and water ( 3 ml), followed by the addition of sodium periodate (0.48 g) and hydrated ruthenium trichloride (4 mg). The resulting mixture was stirred for 90 minutes. The reaction mixture was diluted with dichloromethane. The organic layer thus separated was dried over anhydrous sodium sulfate. The residue obtained by removing the solvent by distillation under reduced pressure was added with ether and the insoluble matter was removed by filtration. The filtrate was then distilled under reduced pressure. The reaction was carried out in a manner similar to Reference Example 12, except for the use of the carboxylic acid compound thus obtained, whereby the title compound (0.11 g, 25%) was obtained. 1 H-NMR (CDCl 3) delta: 1.45 (9H, s), 1.70-2.00 (2H, m), 2.60-2.90 (4H, m), 2.95 (1H, m), 3.11 (4H, m), 3.64 (2H, m), 3.76 (2H, m) 4.22 (2H, d, j = 5.4Hz), 4.82 (1H , br), 6.90-7.10 (3H, m), 7.59 (1H, d, j = 8.8Hz), 7.77 (1H, d, J = 8.8Hz), 7.90-8.00 (3H, m), 8.31 (1 H, s). MS (FD) m / z: 597 [M +, CI35], 599 [M +, CI37].

REFERENCE EXAMPLE 69 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene The reaction was performed in a manner similar to Reference Example 65, except for the use of 2-hydroxymethyl-7-methoxycarbonylnaphthalene (1.01 g) as a starting material, thereby obtaining the title compound. 1 H-NMR (CDCl 3) delta: 1.49 (9H, s), 3.98 (3H, s), 4.50 (2H, d, J = 5.4Hz), 4.99 (1H, br), 7.53 (1H, d, J = 8.3Hz), 7.80-7.90 (3H, m), 8.04 (1H, dd, J = 8.3.1.0Hz), 8.57 (1H, s). Elemental analysis for C18H21 O4 Calculated: C, 68.55; H, 6.71; N, 4.44.

Found: C, 68.54; H, 6.70; N, 4.46.

REFERENCE EXAMPLE 70 1-rf7- (N-tert-butoxycarbonylaminomethyl) naphthalene-2-illcarbonyl-4-r (6-chloronaphthalen-2-yl) sulfonippiperazine The title compound was obtained in a manner similar to Reference Example 48, except for the use of 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as the starting material. 1 H-NMR (CDCl 3) delta: 1.46 (9H, s), 3.12 (4H, br), 3.50-4.00 (4H, br), 4.45 (2H, d, J = 5.9Hz), 5.01 (1H, br ), 7.34 (1 H, d, J = 7.8 Hz), 7.45 (1 H, d, J = 8.3 Hz), 7.50-7.60 (1 H, m), 7.66 (1 H, s), 7.70-7.8 80 (4H, m), 7.90-8.00 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 594 [(M + H) +, CI35], 596 [(M + H) +, Cl37].

REFERENCE EXAMPLE 71 1 -ff7- (N-tert-Butoxycarbonylaminomethyl) naphthalene-2-immetn-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazine The reaction was performed in a manner similar to Reference Examples 61 and 67, except for the use of 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as the starting material, thereby obtaining the title compound. 1 H-NMR (CDCl 3) delta: 1.47 (9H, s), 2.50-2.70 (4H, m), 3.10 (4H, br), 3.61 (2H, s), 4.44 (2H, d, J = 5.4Hz) , 4.92 (1 H, br), 7.30-7.40 (2H, m), 7.50-.70 (3H, m), 7.70-7.90 (3H, m), 7.90-8.00 (3H, m), 8.29 (1 H , s). MS (FAB) m / z: 580 [(M + H) +, CI35], 582 [(M + H) +, CI37].

REFERENCE EXAMPLE 72 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene The reaction was performed in a manner similar to Reference Examples 45 and 65, except for the use of dimethyl-2,6-naphthalenedicarboxylate as a starting material, thereby obtaining the title compound. 1 H-NMR (CDCl 3) delta: 1.48 (9H, s), 3.98 (3H, s), 4.50 (2H, d, J = 5.4Hz), 4.99 (1H, br), 7.47 (1H, d, J = 8.3Hz), 7.75 (1H, s), 7.84 (1H, d, J = 8.8 Hz), 7.92 (1 H, d, J = 8.8 Hz), 8.06 (1 H, d, J = 8.3 Hz), 8.58 (1 H, s). Elementary analysis for C- | 8H21 NO4 Calculated: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.93; H, 6.70; N, 4.29.

EXAMPLE OF REFERENCE 73 4-y (3S) -1-tert-butoxycarbonyl-3-pyrrolidinipoxy Methylbenzoate Methyl 4-hydroxybenzoate (1.01 g), (3R) -1-tert-butoxycarbonyl-3-pyrrolidinol (1.36 g) and triphenylphosphine (1.73 g) were dissolved in tetrahydrofuran (50 ml), followed by the addition, dropwise , of a solution at 40% of diethyl azodicarboxylate (2.87 ml) in toluene under cooling with ice. The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture was added ethyl acetate and 10% aqueous solution of potassium carbonate to separate the organic layer. The organic layer thus separated was washed with a 10% aqueous solution of potassium carbonate and water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2: 1), whereby the title compound was obtained (1.60 g, 76%). 1 H-NMR (CDCl 3) delta: (9H, s), 2.00-2.20 (2H, m), 3.40-3.70 (4H, m), 3.89 (3H, s), 4.96 (1 H, br s), 6.68 (2H, d, J = 8.8Hz), 7.90-8.00 (2H, m).

REFERENCE EXAMPLE 74 4-rr (3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl-methylbenzoic acid The reaction was carried out in a manner similar to Reference Example 11, except for the use of methyl 4 - [[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as the starting material, by means of which was obtained the title compound. 1 H-NMR (CDCI3) delta: 1.45 and 1.47 (9H, each s), 2.10-2.20 (2H, m), 3.40-3.70 (4H, m), 5.00-5.10 (1H, m), 6.98 (2H, d, J = 8.8Hz), 7.97 (2H, d, J = 8.8Hz).

REFERENCE EXAMPLE 75 1-r4-rr (3S) -1-tert-butoxycarbonyl-pyrrolidin-3-yl-p-benzoyl-4-r (6-chloronaphthalen-2-yl) sulfoninpiperazine The reaction was performed in a manner similar to Reference Example 12, except for the use of 4 - [[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid and 1 - [(6- chloronaphthalen-2-yl) sulfonyl] piperazine as the starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) delta: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.00-3.20 (4H, m), 3.40-3.80 (8H, m), 4.88 (1 H, br s), 6.82 (2H, d, J = 8.3Hz), 7.20-7.30 (2H, m), 7.60 (1H, dd, J = 8.7.1.9Hz), 7.76 (1H, dd, J = 8.5.1.7Hz), 7.90-7.95 (3H, m), 8.30 (1H, s). Elemental analysis for C3OH34CI3O6S Calculated: C.60.04; H, 5.71; N, 7.00. Found: C, 60.05; H, 5.69; N, 6.80.

REFERENCE EXAMPLE 76 3-IT (3S) -1 -ter-B? Toxicarbonyl-3-pyrrolidinyl-methylbenzoate methyl The reaction was performed in a manner similar to Reference Example 73, except for the use of methyl 3-hydroxybenzoate, whereby the title compound was obtained. 1 H-NMR (CDCI3) delta: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m), 3.40-3.70 (4H, m), 3.92 (3H, s), 4.96 (1H, br s), 7.07 (1 H, d, J = 7.8 Hz), 7.30-7.40 (1 H, m), 7.53 (1 H, d, J = 2.0 Hz), 7.65 (1 H, m). MS (FAB) m / z: 322 (M + H) +.

REFERENCE EXAMPLE 77 3-rr (3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl-methylbenzoic acid The title compound was obtained in a manner similar to Reference Example 74, except that methyl 3 - [[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate was used as the starting material. 1H-NMR (CDCI3) delta: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m), 3.35-3.65 (4H, m), 5.04 (1 H, br s), 7.05-7.15 (1 H, m), 7.30-7.40 (1 H, m), 7.53 (1 H, s ), 7.62 (1 H, d, J = 7.3 Hz). MS (FAB) m / z: 308 (M + H) +.

REFERENCE EXAMPLE 78 1-r3-r [(3S) -1-tert-Butoxycarbonylpyrrolidin-3-chloro-1-benzoyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The title compound was obtained in a manner similar to Reference Example 75, except for the use of 3 - [[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as starting material.

H-NMR (CDCI3) delta: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m), 2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (1 H, br s), 6.80-6.90 (3H, m), 7.20-7.30 (1 H, m ), 7.60 (1 H, dd, J = 8.8,1.5Hz), 7.76 (1 H, dd, J = 8.5,1.7Hz), 7.90-7.95 (3H, m), 8.30-8.35 (1 H, m) . MS (FAB) m / z: 600 [(M + H) +. CI35], 602 [(M + H) +, CI37].

REFERENCE EXAMPLE 79 4-rr (3R) -1-tert-Butoxycarbonyl-3-pyrrolidininoxylbenzoate methyl The title compound was obtained in a manner similar to Reference Example 73, except for the use of methyl 4-hydroxybenzoate and (3S) -1-tert-butoxycarbonyl-3-pyrrolidinol as the starting materials. H-NMR (CDCl 3) delta: 1.47 (9H, s) 2.05-2.25 (2H, m), 3.40-3.70 (4H, m), 3.89 (3H, s), 4.96 (1 H, br s), 6.88 (2H, d, J = 8.8Hz), 7.90-8.00 (2H, m). MS (FAB) m / z: 322 (M + H) +.

REFERENCE EXAMPLE 80 4-yr (3R) -1-tert-butoxycarbonyl-3-pyrrolidin-H-oxy-1-benzoic acid The title compound was obtained in a manner similar to Reference Example 74, except for the use of methyl 4 - [[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as the starting material. 1 H-NMR (CD3OD) delta: 1.47 and 1.48 (9H, each s), 2.10-2.25 (2H, m), 3.40-3.70 (4H, m), 4.98 (1 H, br s), 6.91 ( 2H, d, J = 8.8Hz), 8.00-8.10 (2H, m), MS (FAB) m / z: 308 (M + H) +.

REFERENCE EXAMPLE 81 1 -4-rr (3R) -1-tert-Butoxycarbonylpyrrolidin-3-inoxpbenzoin-4-r-chloronaphthalen-2-yl) sulfoninpiperazine The title compound was obtained in a manner similar to Reference Example 75, except for the use of 4 - [[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as the starting material. 1 H-NMR (CDCl 3) delta: 1.46 (9H, s), 2.00-2.20 (3.00-3.20 (4H, m), 3. 40-3.80 (8H, m), 4.89 (1 H, br s), 6.82 (2H, d, J = 8.3Hz), 7.20-7.30 (2H, m), 7.58 (1 H, dd, J = 8.8, 2.0Hz), 7.74 (1 H, dd, J = 8.5.1.7Hz), 7.90-7.95 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 600 [(M + H) +. CI35], 602 [(M + H) +. CI37].

EXAMPLE OF REFERENCE 82 3-FT (3R) -1-tert-Butoxycarbonyl-3-pyrrolidininoxylbenzoate methyl The title compound was obtained in a manner similar to Reference Example 73, except for the use of methyl 3-hydroxybenzoate and (3S) -1-tert-butoxycarbonyl-3-pyrrolidinol as the starting materials. 1 H-NMR (CDCl 3) delta: 1.47 (9H, s), 2.05-2.25 (2H, m), 3.40-3.70 (4H, m), 3.92 (3H, s), 4.95 (1 Hbr s), 7.07 ( 1 H, d, J = 7.8 Hz), 7.30-7.40 (1 Hmm), 7.50-7.55 (1 H, m), 7.60-7.70 (1 H, m). MS (FAB) m / z: 322 (M + H) +.

EXAMPLE OF REFERENCE 83 3-rF (3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl-methylbenzoic acid The title compound was obtained in a manner similar to Reference Example 74, except for the use of methyl 3 - [[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoate as the starting material. 1 H-NMR (CDCl 3) delta: 1.48 (9H, s), 2.05-2.25 (2H, m), 3.45-3.70 (4H, m), 4.97 (1 H, br s), 7.10-7.15 (1 H, n), 7.35-7.45 (1 H, m), 7.58 (1 H, s), 7.70-7.75 (1 H, m). MS (FAb) m / z: 308 (M + H) +.

REFERENCE EXAMPLE 84 1 -f3-rI (3R) -1-tert-butoxycarbonyl-1-pyrrolidin-3-yloxy-1-benzoyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The title compound was obtained in a manner similar to Reference Example 75, except for the use of 3 - [[(3R) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] benzoic acid as starting material. 1 H-NMR (CDCl 3) delta: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m), 2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (1 H , br s), 6.80-6.90 (3H, m), 7.20-7.30 (1H, m), 7.60 (1H, dd, J = .5.1.7Hz), 7.76 (1H, dd, J = 8.5 , 2.0hz), 7.90-7.95 (3H, m), 8.30-8.35 (1 H, m). MS (FAB) m /: 600 [(M + H) +, CI35], 602 [(M + H) +, CI37].

REFERENCE EXAMPLE 85 4-f2-amino-5-pyrimidyl) benzoic acid The title compound was obtained in a manner similar to Reference Example 2, except for the use of 2-amino-5-bromopyrimidine as the starting material. 1 H-NMR (CDCl 3) delta: 7.81 (2H, d, J = 8.8Hz), 8.00 (2H, d, J = 8.8Hz), 8.84 (2H, s). MS (FAB) m / z: 216 (M + H) +.

REFERENCE EXAMPLE 86 1-tert-Butoxycarbonyl-4-y (methoxycarbonyl) methylen-1-piperidine Methyl dimethylphosphonoacetate (1.8 ml) was dissolved in tetrahydrofuran (40 ml). To the resulting solution was added under cooling with ice, 60% oily sodium hydride (450 mg), followed by stirring under the same condition. After the addition of a solution of 1- (tert-butoxycarbonyl) -4-piperidone (2.05 g) in tetrahydrofuran (tetrahydrofuran: 10 ml) and stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate. 2N hydrochloric acid was added to the diluted solution. The organic layer was separated and washed with an aqueous saturated solution of sodium bicarbonate and saturated aqueous saline, and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 6: 1), whereby the title compound was obtained (2.35 g, 92%). 1 H-NMR (CDCl 3) delta: 1.47 (9H, s), 2.28 (2H, t, J = 5.9Hz), 2.94 (2H, t, J = 5.9Hz), 3.48 (2H, t, J = 5.9Hz) ), 3.50 (2H, t, J = 5.9Hz), 3.70 (3H, s), 5.72 (1H, s). Elemental analysis for C-13H21 NO4 Calculated: C, 61.16; H, 8.29; N, 5.49. Found: C, 61.14; H, 8.34; N, 5.20.

REFERENCE EXAMPLE 87 (methyl 1-tert-butoxycarbonylpiperidin-4-yl) acetate 1-tert-butoxycarbonyl-4 - [(methoxycarbonyl) methyl] piperidine (875 mg) was dissolved in ethanol (10 ml), followed by the addition of 10% palladium / carbon. (water content approximately 50%, 730 mg). The resulting mixture was subjected to catalytic reduction under normal pressure at room temperature for 3 days. After removing the catalyst by filtration, the solvent was removed by distillation under reduced pressure, whereby the title compound (871 mg, 99%) was obtained. 1 H-NMR (CDCl 3) delta: 1.16 (2H, m), 1.45 (9H, s), 1.65 (2H, m), 1. 93 (1 H, m), 2.25 (2H, d, J = 6.8Hz), 2.72 (2H, br), 3.68 (3H, s), 4.08 (2H, br). MS (FAB) m / z: 258 (M + H) +.

EXAMPLE OF REFERENCE 88 Acid (1-tert-butoxycarbonylpiperidin-4-yl) acetic acid The title compound was obtained in a manner similar to Reference Example 11, except that methyl (1-tert-butoxycarbonylpiperidin-4-yl) acetate was used as the starting material. 1 H-NMR (CDCl 3) delta: 1.18 (H, m), 1.45 (9H, s), 1.73 (2H, m), 1. 94 (1H, m), 2.29 (2H, d, J = 6.8Hz), 2.72 (2H, m), 4.10 (2H, br). MS (El) m / z: 243 M +.

REFERENCE EXAMPLE 89 1-r (1-tert-Butoxycarbonylpiperidin-4-yl) acetyn-4-r (6-chloronaphthalen-2-dsulfonylpiperazine The reaction was carried out in a manner similar to Reference Example 12, except that (1-tert-butoxycarbonylpiperidin-4-yl) acetic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used, which was obtained the title compound. 1 H-NMR (CDC) d: 1.05 (2H, m), 1.43 (9H, s), 1.63 (2H, m), 1.91 (1 H, m), 2.14 (2H, d, J = 6.8 Hz), 2.66 (2H, m), 3.07 (4H, br s), 3.56 (2H, br s), 3.67 (2H, br s), 4.02 (2H, br), 7.58 (1 H, dd, J = 8.8, 2.0 Hz ), 7.75 (1 H, d, J = 8.8 Hz), 7.91 (1 H, d, J = 8.8 Hz), 7.93 (1 H, d, J = 8.8 Hz), 7.92 (1 H, s), 8.30 (1 H, s). MS (FAB) m / z: 536 [(M + H) +, Cl 35], 538 [(M + H) +, Cl37].

REFERENCE EXAMPLE 90 3- (1-tert-Butoxycarbonylpiperidin-4-yl) propionic acid The reaction was performed in a manner similar to the Reference Example 61, except that ethyl 1-tert-butoxycarbonylisonispecotinate was used as the starting material, whereby the corresponding aldehyde derivative was obtained. The resulting derivative was treated as in Reference Examples 86, 87 and 88, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.10 (2H, m), 1.41 (1 H, m), 1.45 (9H, s), 1.60 (2H, q, J = 7.8 Hz), 1.66 (2H, m), 2.39 (2H, t, J = 7.8 Hz), 2.67 (2H, m), 4.09 (2H, br). MS (FAB m / z: 258 (M + H) +.

REFERENCE EXAMPLE 91 1-r3- (1-tert-Butoxycarbonylpiperidin-4-yl) propionin-4-r (6-chloronaphthalen-2-ylsulphonylpiperazine The reaction was performed in a manner similar to the Reference Example 12, except that 3- (1-tert-butoxycarbonylpiperidin-4-yl) propionic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as raw materials, thereby obtaining the title compound. 1 H-NMR (CDCl 3) d: 1.04 (2H, m), 1.35 (1 H, m), 1.44 (9H, s), 1.47 (2H, q, J = 7.8 Hz), 1.57 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.61 (2H, m), 3.07 (4H, br s), 3.50 (2H, br s), 3.71 (2H, br s), 4.04 (2H, br), 7.58 (1 H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.90 (1 H, d, J = 8.8 Hz), 7.91 (1 H, s), 7.92 (1 H, d, J = 8.8 Hz), 8.30 (1 H, s). MS (FAB) m / z: 550 [(M + H) Cl 35], 552 [(M + H) +, Cl37].

REFERENCE EXAMPLE 92 Acid (E) -3- (4-pyridyl) acrylic The title compound was obtained in a manner similar to Reference Examples 86 and 88, except that isonicotinic aldehyde was used as the starting material. 1 H-NMR (DEMO-d 6) d: 6.79 (1 H, d, J = 16.6 Hz), 7.56 (1 H, d, J = 16.6 Hz), 7.66 (2 H, d, J = 5.9 Hz), 8.62 ( 2H, d, J = 5.9 Hz), 12.72 (1 H, br s).

MS (El) m / z: 149M +.

REFERENCE EXAMPLE 93 1-Methoxycarbonyl-3-pyrrolinia 3-Pyrroline (1.1 ml) was dissolved in dichloromethane (20 ml), followed by the addition of triethylamine (2.6 ml) and methyl chloroformate (1.2 ml) under ice-cooling. The resulting mixture was stirred at room temperature for 17 hours. The residue obtained by distilling the reaction mixture under reduced pressure was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 4: 1), whereby the title compound was obtained (0.95 g, 52 %). H-NMR (CDCl 3) Ü: 3.73 (3H, s), 4.00-4.20 (4H, m), 5.70-5.90 (2H, m).

REFERENCE EXAMPLE 94 4-Methyl trifluoromethanesulfonyloxybenzoate Methyl 4-hydroxybenzoate (1.99 g) was dissolved in dichloromethane (20 ml), followed by the addition of pyridine (2.4 ml) and trifluoromethanesulfonic anhydride (3.0 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was added with pyrridine (1.5 ml) and again trifluoromethanesulfonic anhydride (1.0 ml). The resulting mixture was stirred for 5 hours. Dichloromethane and an aqueous solution of sodium bicarbonate were added to the reaction mixture. The organic layer thus separated was washed with an aqueous solution of 10% citric acid and saturated saline and dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation under reduced pressure was purified by chromatography on a column of silica gel (5% ethyl acetate-hexane), whereby the title compound was obtained (3.22). g, 86%). 1 H-NMR (CDCl 3) d: 3.95 (3H, s), 7.36 (2H, d, J = 8.8 Hz), 8.15 (2H, d, J = 8.8 Hz). MS (FAB) m / z: 285 (M + H) +.

REFERENCE EXAMPLE 95 Methyl 4- (1-methoxycarbonylpyrrolidin-3-yl) benzoate Methyl 4-trifluoromethanesulfonyloxybenzoate (1.05 g), 1-methoxycarbonyl-3-pyrroline (1.0 g), lithium chloride (0.51 g), palladium (II) acetate (53 mg) and tri (2-furyl) phosphine were dissolved. (100 mg) in N, N-dimethylformamide (25 ml), followed by the addition of diisopropylethylamine (2.8 ml). Under an atmosphere of argon gas, the resulting mixture was stirred at 90 ° C for 11 hours and then at 100 ° C for 7 hours. The residue obtained by removing the solvent by distillation under reduced pressure was added with dichloromethane and water. The organic layer thus separated was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 9: 1 ~ 5: 1). The purified product was dissolved in methanol (30 ml), followed by the addition of 10% palladium / carbon (water content approximately 50%, 186 mg) and ammonium formate (197 mg). The resulting mixture was heated under reflux for 2 hours. After removing the catalyst by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate-toluene 10%), whereby the title compound (241 mg, 25%) was obtained. 1 H-NMR (CDCl 3) d: 1.95-2.10 (1 H, m), 2.25-2.35 (1 H, m), 3.30-3.35 (4 H, m), 3.55-3.75 (1 H, m), 3.72 and 3.73 (3H, each s), 3.80-3.90 (1H, m), 3.91 (3H, s), 7.30 (2H, d, J = 3.8 Hz), 8.00 (2H, d, J = 8.3 Hz). MS (FAB) m / z: 264 (M + H) +.

REFERENCE EXAMPLE 96 4- (1-tert-Butoxycarbonylpyrrolidin-3-yl) benzoic acid Methyl 4- (1-methoxycarbonylpyrrolidin-3-yl) benzoate (0.24 g) was dissolved in methanol (10 ml). The resulting solution was added with 8N hydrochloric acid (30 ml), followed by heating under reflux for 40 hours. The residue obtained by removing the solvent by distillation under reduced pressure was dissolved in N, N-dimethylformamide (30 ml). To the resulting solution, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (0.30 g) and then diisopropylethylamine (0.40 ml) were added, followed by stirring at room temperature for 15 hours. The residue obtained by removing the solvent by distillation under reduced pressure was distributed between ethyl acetate and an aqueous solution of 10% citric acid. The organic layer thus separated was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane ~ 10%, methanol-dichloromethane), whereby the title compound (234 mg) was obtained. 1 H-NMR (CDCl 3) d: 1.48 (9H, m), 1.90-2.00 (1 H, m), 2.20-2.30 (1 H, m), 3.20-3.90 (5H, m), 7.20-7.30 (2H, m), 8.00-8.10 (2H, m). MS (EI) m / z: 291 M +.

REFERENCE EXAMPLE 97 1-r4- (3RS) -1-tert-Butoxycarbonylpyrrolidin-3-inbenzoon-4-r (6-chloronaphthalene-2-ylsulfonippiperazine The reaction was performed in a manner similar to Reference Example 12, except that 4- (1-tert-butoxycarbonylpyrrolidin-3-yl) benzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] p hydrochloride were used Perazine as the starting materi whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 and 1.60 (9H "each s), 1.80-2.00 (1 H, m), 2.10-2.20 (1 H, m), 3.00-4.00 (13H, m), 7.10-7.30 (4H, m), 7.55-7.65 (1 H, m), 7.70-7.80 (1 H, m), 7.85-8.00 (3H, m), 8.30 (1 H, s).

REFERENCE EXAMPLE 98 Methyl 5-benzimidazolecarboxylate hydrochloride The reaction was carried out in a manner similar to Reference Example 44, except that 5-benzimidazolecarboxylic acid was used as the starting material, whereby the title compound was obtained. 1H-NMR (DEMO-d6) d: 3.93 (3H, s), 7.96 (1 H, d, J = 8.8 Hz), 8.12 (1 H, d, J = 8.8 Hz), 8.40 (1 H, s) , 9.66 (1 H, s). Elemental analysis for C9H8N2O2? CI Calculated: C, 50.84; H, 4.27; N, 13.17; Cl, 16.67. Found: C, 50.64; H, 4.22; N, 13.12; Cl, 16.59.

REFERENCE EXAMPLE 99 Methyl N-Trifenylmethyl-5-benzimidazolecarboxylate The title compound was obtained in a manner similar to Reference Example 22, except that methyl 5-benzimidazolecarboxylate hydrochloride was used as the starting material, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 3.75 (2H, s), 3.89 (1 H, s), 6.49 (1 / 3H, d, J = 8.8 Hz), 7.1-7.4 (16H, m), 7.61 (1 / 3H, dd, J = 8.8, 1.5 Hz), 7.78 (2 / 3H, d, J = 8.8 Hz), 7.87 (2 / 3H, dd, J = 8.8, 1.5 Hz), 7.96 (1 / 3H, s) , 8.02 (2 / 3H, s). MS (FAB) m / z: 419 (M + H) +.

REFERENCE EXAMPLE 100 Tiazolor 5,4-clpyridine-2-carboxylate sodium Ethyl thiazolo [5,4-c] pyridine-2-carboxylate (0.61 g) was dissolved in tetrahydrofuran (12 ml), followed by the addition of an aqueous solution of 1 N sodium hydroxide (3 ml). After stirring at room temperature for 30 minutes, the insoluble material was removed by filtration. The filtrate was supplied without purification for the subsequent reaction. 1 H-NMR (DEMO-d6) d: 7.95 (1 H, d, J = 5.9 Hz), 8.57 (1 H, d, J = 5.9 Hz), 9.27 (1 H, s).

REFERENCE EXAMPLE 101 1-r (5-tert-Butoxycarbonyl-4.5.6.7-tetrahydrothienor3.2-clpyridin-2-inmetim-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was performed in a manner similar to Reference Example 47, except that 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and hydrochloride of 1 [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine as the starting materi whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.53-2.62 (4H, m), 2.72 (2H, br s), 3.10 (4H, br s), 3.59 (2H, s), 3.66 (2H , br s), 4.38 (2H, s), 6.54 (1 H, s), 7.57 (1 H, dd, J = 8.8, 2.0 Hz), 7.76 (1 H, dd, J = 8.8, 2.0 Hz), 7.87-7.94 (3H, m), 8.29 (1 H, s). MS (FAB) m / z: 562 [(M + H) +, Cl 35], 564 [(M + H)? Cl37].

REFERENCE EXAMPLE 102 3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor 3,2-clpyridin-2-ylpropionic acid The reaction was performed in a manner similar to Reference Examples 86, 87 and 88, except that 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine was used as starting material, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.48 (9H, s), 2.70 (2H, t, J = 7.3 Hz), 2.76 (2H, br s), 3.09 (2H, t, J = 7.3 Hz), 3.70 (2H , s), 4.40 (2H, s), 6.51 (1 H, s). MS (FD) m / z: 311 M +.

REFERENCE EXAMPLE 103 Acid (E) -3- 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothienor 3,2-c-pyridin-2-ylacrylic The reaction was performed in a manner similar to Reference Examples 86 and 88, except that 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine was used as the starting, with which the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.49 (9 H, s), 2.85 (2 H, br s), 3.73 (2 H, br s), 4.47 (2 H, s), 6.12 (1 H, d, J = 15.4 Hz) , 6.98 (1 H, s), 7.77 (1 H, d, J = 15.4 Hz). EM (FD) m / z: 309M +.

REFERENCE EXAMPLE 104 1-r (E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothienor3.2-c1pyridin-2-yl) propenop-4-r (6-chloronaphthalene-2- il) sulfonippiperazine The reaction was performed in a manner similar to the Reference Example 12, except that (E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) acrylic acid and 1 - [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine as the starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.80 (2H, br s), 3.12 (4H, t, J = 4.9 Hz), 3.46-3.86 (6H, m), 4.41 (2H, s) , 6.39 (1 H, d, J = 15.1 Hz), 6.83 (1 H, s), 7.55-7.78 (3H, m), 7.89-7.92 (3H, m), 8.30 (1 H, s). MS (FD) m / z: 601 (M +, Cl35), 603 (M +, Cl37).

REFERENCE EXAMPLE 105 1- [3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno [3,2-c1pyridin-2-yl] propion] -1-4-r (6 -chloronaphthalen-2-yl) sulfonyl-1-piperazine 3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionic acid (445 mg) was dissolved in tetrahydrofuran (10 ml), followed by dropwise addition of N-methylmorpholine (170 μl) and isobutyl chloroformate (210 μl) successively at -20 ° C. After stirring at -20 ° C for 10 minutes, 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (607 mg) previously dissolved in dichloromethane (10 ml) was added to the reaction mixture. . The reaction mixture was stirred at -20 ° C for 10 minutes and then warmed to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloroethane. The resulting solution was washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 4: 1 ~ 2: 1), whereby the title compound (625 mg, 72%) was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.53 (2H, t, J = 7.5 Hz), 2.68 (2H, br s), 2.99-3.10 (6H, m), 3.51-355 (2H, m), 3.64 (2H, br s), 3.72-3.77 (2H, m), 4.34 (2H, s), 6.43 (1 H, s), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.74 (1 H, dd, J = 8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 604 [(M + H)? Cl35], 606 [(M + H) +, Cl37].

REFERENCE EXAMPLE 106 3- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienof3.2-c1pyridin-2-yl) propanal It was dissolved in dichloromethane (100 ml) ethyl 3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydroxy-thieno [3,2-c] pyridin-2-yl) propionate (1.68 g), obtained in Reference Example 102. After stirring at -78 ° C for 10 minutes, diisobutylaluminum hydride (7.50 ml of a 0.98 M hexane solution) was slowly added dropwise to the reaction mixture. The resulting mixture was stirred at -78 ° C for 10 minutes, followed by the addition of methanol (50 ml). The resulting mixture was heated to room temperature. The reaction mixture was concentrated under reduced pressure. To the residue were added dichloromethane and a saturated aqueous solution of ammonium chloride, and the resulting mixture was filtered through Celite. The separated organic layer of the filtrate was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then removed by distillation. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 5: 1), whereby the title compound (935 mg, 55%) was obtained. 1 H-NMR (CDCl 3) d: 1.48 (9H, s), 2.76 (2H, br s), 2.81 (2H, t, J = 7.3 Hz), 3.09 (2H, t, J = 7.3 Hz), 3.69 (2H, br s), 4.39 (2H, s), 6.49 (1 H, s), 9.81 (1 H, s). MS (FAB) m / z: 295M +.

REFERENCE EXAMPLE 107 1 -f3- (5-tert-Butoxycarbonyl-4.5.6.7-tetrahydrothienor-3, 2-clpyridin-2-yl) propin-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was performed in a manner similar to Reference Example 47, except that 3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propanal and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as the starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 1.69-1.79 (2H, m), 2.36 (2H, t, J = 7.3 Hz), 2.49-2.54 (4H, m), 2.65-2.75 (4H, m), 3.10 (4H, br s), 3.67 (2H, br s), 4.37 (2H, s), 6.39 (1 H, s), 7.57 (1 H, dd, J = 8.8, 2.0 Hz ), 7.78 (1 H, dd, J = 8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.30 (1 H, s). MS (FD) m / z: 589 (M +, Cl35), 591 (M +, Cl37).

REFERENCE EXAMPLE 108 2-Aminomethyl-5-tert-butoxycarbonyl-4.5.6.7-tetrahydrothienor3.2-clpyridine -tert-Butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (2.10 g) was dissolved in tetrahydrofuran (100 ml), followed by the addition of triphenylphosphine (2.66 g) and phthalimide (1.15 g). After the dropwise addition of diethyl azodicarboxylate (1.28 ml), the resulting mixture was stirred at room temperature for 5 hours. After concentration under reduced pressure, the residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 4: 1), whereby a colorless solid was obtained. The resulting solid was dissolved in ethanol (40 ml). To the solution was added hydrazine hydrate (0.39 ml), followed by heating under reflux for 5 hours. After the solid thus precipitated was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 25: 1), whereby the title compound (448 mg, 21%) was obtained. 1 H-NMR (DMSO-d 6) d: 1.42 (9H, s), 2.72 (2H, m), 3.60 (2H, m), 3.80 (2H, s), 6.64 (1 H, s). EM (FD) m / z: 268M +.

REFERENCE EXAMPLE 109 1-rN- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor3.2-c1pyridin-2-yl) methypcarbamop-4-r (6-chloronaphthalene-2) il) sulfon¡ppiperaz¡na -tert-Butoxycarbonyl-2-aminomethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (150 mg) was dissolved in tetrahydrofuran (100 ml). To the resulting solution, carbonyldiimidazole (136 mg) was added under cooling with ice, followed by stirring at room temperature for 1 hour. After concentrating under reduced pressure, the residue was dissolved in toluene (50 ml). To the resulting solution was added triethylamine (0.23 ml) and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (356 mg), followed by stirring overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was removed by filtration under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1-1: 1), whereby the title compound was obtained (303 mg, 89%). 1 H-NMR (CDCl 3) d: 1.46 (9H, s), 2.70 (2H, br s), 3.07 (4H, t, J = 4.9 Hz), 3.48 (4H, t, J = 4.9 Hz), 3.66 (2H , br s), 4.36 (2H, br s), 4.39 (2H, d, J = 5.4 Hz), 4.69 (1 H, t, J = 5.4 Hz), 6.58 (1 H, s), 7.58 (1 H , dd, J = 8.8, 2.0 Hz), 7.74 (1 H, dd, J = 8.8, 2.0 Hz), 7.87-7.93 (3H, m), 8.30 (1 H, s). MS (FD) m / z: 604 (M +, Cl35), 606 (M +, Cl37).

REFERENCE EXAMPLE 110 1-f (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor3.2-c1pyridin-2-yl) carbonin-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazine The title compound was obtained in a manner similar to Reference Example 12, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydroxy [3,2-c] pyridine-2-carboxylic acid was used and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as the starting materials. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.79 (2H, br s), 3.12 (4H, t, J = 4.9 Hz), 3.68 (2H, br s), 3.84 (4H, t, J = 4.9 Hz), 4.42 (2H, br s), 6.91 (1 H, s), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz) , 7.90-7.97 (3H, m), 8.30 (1 H, s). MS (SD) m / z: 575 (M +, Cl35), 577 (M \ Cl37).

REFERENCE EXAMPLE 111 1-r (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor3.2-c1pyridin-2-yl) carbonill-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-2-ethoxycarbonylpiperazine The title compound was obtained in a manner similar to Reference Example 12, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-ethoxycarbonylpiperazine hydrochloride as starting materials. 1 H-NMR (CDCl 3) d: 1.32 (3 H, t, J = 7.3 Hz), 1.47 (9 H, s), 2.35-2.46 (1 H, m), 2.55-2.64 (1 H, m), 2.80 (2 H, br s), 3.15-3.20 (1 H, m), 3.69 (2 H, br s), 3. 75-3.85 (1 H, m), 4.12 (2H, q, J = 7.3 Hz), 4.20-4.36 (2H, m), 4.39-4.48 (3H, m), 6.69 (1 H, s), 7.59 ( 1 H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.32 (1 H, s). MS (FAB) m / z: 648 [(M + H)? Cl35], 650 [(M + H)? Cl37].

REFERENCE EXAMPLE 112 1-r (6-chloronaphthalen-2-yl) sulfonin-4-f (5-cyano-4,5,6,7-tetrahydro-thienor-3,2-c1-pyridin-2-yl) -carbonopiperazine 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine hydrochloride was suspended. (195 mg), triethanolamine (0.2 ml) and sodium acetate (118 mg) in ethanol, followed by the addition of cyanogen bromide (114 mg). The resulting mixture was stirred at room temperature for 2 hours. The residue obtained by concentration of the reaction mixture under reduced pressure was added with dichloromethane, followed by washing with water. After drying over anhydrous sodium sulfate, the residue obtained by removing the solvent by distillation under reduced pressure was purified by chromatography on a column of silica gel (dichloromethane: methanol = 100: 1), whereby the compound of the title (51 mg, 28%). 1 H-NMR (CDCl 3) d: 2.93-2.98 (2H, m), 3.11-3.14 (4H, m), 3.49-3.55 (2H, m), 3.81-3.84 (4H, m), 4.29 (2H, s) , 6.89 (1 H, s), 7.59 (1 H, dd, J = 8.8, 2.0 Hz), 7.75 (1 H, dd, J = 8.8, 2.0 Hz), 7.90-7.94 (3H, m), 8.30 ( 1 H, s). MS (FAB) m / z: 501 [(M + H) +, Cl 35], 503 [(M + H) +, Cl37].

REFERENCE EXAMPLE 113 1-fN- (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor3.2-c1pyridin-2-yl) carbamop-4-r (6-chloronaphthalen-2-yl) sulfonyl] piperazine -tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (283 mg) was dissolved in benzene (10 ml), followed by the addition of triethylamine (0.14 ml) ) and diphenylphosphorylazide (0.21 g). The resulting mixture was heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was added with 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (347 mg), followed by heating under reflux overnight. After cooling the reaction mixture to room temperature, dichloromethane and a 3 N aqueous sodium hydroxide solution were added to extract the organic layer. The organic layer thus extracted was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1 - 2: 1), whereby the title compound (284 mg, 48%) was obtained. 1 H-NMR (CDCl 3) d: 1.45 (9H, s), 2.65 (2H, br s), 3.10 (4H, t, J = 4.9 Hz), 3.57 (4H, t, J = 4.9 Hz), 3.64 (2H , br s), 4.27 (2H, s), 6.15 (1 H, br s), 7.58 (1 H, dd, J = 8.8, 2.0 Hz), 7.73 (1 H, dd, J = 8.8, 2.0 Hz) , 7.87-7.93 (3H, m), 8.28 (1 H, s). MS (FAB) m / z: 591 [(M + H)? Cl35], 593 [(M + H) +, Cl37].

REFERENCE EXAMPLE 114 1-rN- (5-tert-Butoxycarbonyl-4.5.6.7-tetrahydrothienor3.2-c1pyridin-2-yl) -N-methylcarbamoyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine It was dissolved 1 - [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl] -4 - [(6-chloronaphthalen-2-yl ) sulfonyl] piperazine (147 mg) in N, N-dimethylformamide (10 ml). After the addition of 60% oily sodium hydride (22 mg), the resulting mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes. To the residue obtained by concentrating the reaction mixture under reduced pressure, ethyl acetate was added. The resulting mixture was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2: 1), whereby the title compound (43 mg) was obtained. 1 H-NMR (CDCl 3) d: 1.49 (9H, s), 2.63 (2H, br s), 3.01 (4H, t, J = 4.9 Hz), 3.13 (3H, s), 3.40 (4H, t, J = 4.9 Hz), 3.67 (2H, br s), 4.31 (2H, s), 6.21 (1 H, br s), 7.58 (1 H, dd, J = 8.8, 2.0 Hz), 7.72 (1 H, dd, J = 8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.27 (1 H, s). MS (FAB) m / z: 605 [(M + H)? Cl35], 607 [(M + H)? Cl37].

REFERENCE EXAMPLE 115 1 -r (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazole-5,4-clpyridin-2-yl) carbonin-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The title compound was obtained in a manner similar to Reference Example 12, except that 6-tert-butoxycarbonyl-4,5,6,7-tetrahydroxyzolo [5,4-c] pyridine-2-carboxylic acid was used and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as starting materials. 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.84 (2H, br s), 3.19 (4H, br), 3.72 (2H, t, J = 5.4 Hz), 3.87 (2H, br s), 4.54 (2H, s), 4.63 (2H, br s), 7.57 (1 H, dd, J = 8.8, 2.0 Hz), 7.76 (1 H, dd, J = 8.8, 2.0 Hz), 7.87-7.94 (3H , m), 8.30 (1 H, s). MS (FAB) m / z: 577 [(M + H) +, Cl 35], 579 [(M + H) +, Cl37].

REFERENCE EXAMPLE 116 l-Ke-tert-Butoxycarbonyl ^ .S.e -tetrahydrothiazoloid ^ -cypyridin ^ -yl) carbonin-4-r (6-chloronaphthalen-2-yl) sulfonyl-2-ethoxycarbonylpiperazine 6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazo [5,4-c] pyridine-2-carboxylic acid (742 mg), 1 - [(6-chloronaphthalen-2-yl) sulfonyl hydrochloride were dissolved. ] -3-ethoxycarbonylpiperazine (1.00 g) and benzotriazole-1-yl-oxytris (pyrrolidino) phosphonium hexafluorophosphate ("PyBOP", trademark, 1.50 g) in N, N-dimethylformamide (30 ml), followed by the addition of triethylamine (0.40 ml). The resulting mixture was stirred overnight at room temperature. After concentrating the reaction mixture reaction mixture under reduced pressure, ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 4: 1), whereby the title compound was obtained (505 mg, 30%). 1 H-NMR (CDCl 3) d: 1.24-1.37 (3H, m), 1.47 (9H, s), 2.45-2.60 (1 H, m), 2.62-2.71 (1 H, m), 2.75-2.90 (2H, m), 3.65-3.94 (3H, m), 4.19-4.31 (2H, m), 4.45-4.72 (4H, m), 5.35 (1 / 2H, br s), 5.71-5.77 (1 / 2H, m) , 6.72 (1 H, br s), 7.58 (1 H, dd, J = 8.8, 2.0 Hz), 7.77 (1 H, dd, J = 8.8, 2.0 Hz), 7.88-7.92 (3H, m), 8.33 (1 H, s). MS (FAB) m / z: 649 [(M + H) +, Cl 35], 651 [(M + H) +, Cl37].

REFERENCE EXAMPLE 117 1-r (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolof5.4-c1pyridin-2-yl) carbonip-2-carbamoyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine 1 - [(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl was dissolved ] -2-Ethoxycarbonylpiperazine (487 mg) in tetrahydrofuran (5 ml). After the addition of methanol (5 ml) and 1 N aqueous solution of sodium hydroxide (3 ml), the resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 1N hydrochloric acid to adjust its pH from 1 to 2, followed by the addition of ethyl acetate. The organic layer thus separated was dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was dissolved in tetrahydrofuran (5 ml), followed by the addition, dropwise, of N-methylmorpholine (0.09 ml) and sobutyl chloroformate (0.11 ml) to - 20 ° C. After stirring at -20 ° C for 10 minutes, the reaction mixture was added with a solution of ammonia-dichloromethane (0.50 ml). The resulting solution was stirred at -20 ° C for 10 minutes and 1N hydrochloric acid (10 ml) in aq. Then, the reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane, followed by washing with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 1), whereby the title compound was obtained (317 mg, 68%). 1 H-NMR (DMSO-d 6) d: 1.41 (9H, s), 2.39-2.86 (4H, m), 3.60-3.80 (4H, m), 4.25-4.34 (1H, m), 4.36-4.44 (1 / 2H, m), 4.62 (2H, br s), 4.97 (1 / 2H, br s), 5.44-5.52 (1 / 2H, m), 6.19 (1 / 2H, br s), 7.30-7.39 (1 H, m), 7.63-7.85 (3H, m), 8.15 (1 H, d, J = 8.8 Hz), 8.20-8.29 (2H, m), 8.48 (1 H, s). MS (FAB) m / z: 620 [(M + H)? Cl35], 622 [(M + H) +, Cl37].

REFERENCE EXAMPLE 118 1- (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c1pyridn-2-l) carbonin-4-r (E ) -4-chlorostyrylsulfonylpiperazine The title compound was obtained in a manner similar to Reference Example 12, except that 6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid and hydrochloride were used. 1 - [(E) -4-chlorostyrylsulfonyl] piperazine as the starting materials. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 2.87 (2H, br s), 3.31 (4H, m), 3.75 (2H, br s), 3.90 (2H, br s), 4.57 (2H, br s), 4.68 (2H, s), 6.64 (1 H, d, J = 15.6Hz), 7.28-7.35 (5H, m). MS (FAB) m / z: 553 [(M + H) Cl 35], 555 [(M + H) +, Cl37].

REFERENCE EXAMPLE 119 (3S) -3-Amino-1-tert-butoxycarbonylpyrrolidine The title compound was obtained in a manner similar to Reference Example 59, except that (3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (1.50 g) was used as the starting material. 1 H-NMR (CDCl 3) d 1.46 (9H, s), 1.98-2.11 (2H, m), 2.95-3.10 (1 H, m), 3.26-3.60 (4H, m). MS (FAB) m / z: 187 [(M + H) +.

REFERENCE EXAMPLE 120 (3S) -3-r (6-chloronaphthalen-2-yl) sulfonamide-1-pyrrolidine trifluoroacetate The reaction was carried out in a manner similar to Reference Example 1, except that (3S) -3-amino-1-tert-butoxycarbonylpyrrolidine was used as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d 6) d: 1.69-1.80 (1 H, m), 1.88-1.99 (1 H, m) 2.95-3.28 (4H, m), 3.75-3.84 (1 H, m), 7.71 ( 1 H, m), 7.91 (1 H, m), 8.10-8.30 (4H, m), 8.53 (1 H, s), 8.91 (1 H, br s), 9.06 (1 H, br s).

REFERENCE EXAMPLE 121 (3S) -1-r (5-tert-butoxycarbonyl-4.5.6.7-tetrahydrothienor-3, 2-c1pyridin-2-yl) metin-3 - [(6-chloronaphthalen-2-yl) sulfonamide-1-pyrrolidine The reaction was performed in a manner similar to the Reference Example 47, except that 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and (3S) -3 - [(6-chloronaphthalene-2-trifluoroacetate] were used. il) sulfonamide] pyrrolidine as the starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d 1.49 (9H, s), 1.52-1.63 (1 H, m), 2.03-2.12 (1 H, m), 2.19-2.27 (1 H, m), 2.35-2.54 (2H, m), 2.73-2.85 (3H, m), 3.59 (1H, d, J = 13.9Hz), 3.66 (1H, d, J = 13.9Hz), 3.70 (2H, br s), 3.88-3.95 ( 1 H, m), 4.39 (2 H, s), 4.99 (1/2 H, s), 5.02 (1/2 H, s), 6.49 (1 H, s), 7.55 (1 H, dd, J = 8.8, 2.0Hz), 7.82-7.90 (4H, m), 8.40 (1 H, s). MS (FD) m / z: 561 [(M \ Cl35), 563 (M + Cl37).

REFERENCE EXAMPLE 122 (3S) -1-r (5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor 3,2-clpyridin-2-yl) carbonill-3-f 6-chloronaphthalen-2-yl) sulfonamide-1-pyrrolidine The title compound was obtained in a manner similar to Reference Example 12, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydroxy [3,2-c] pyridine-2-acid was used. carboxylic acid and (3S) -3 - [(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine trifluoroacetate as the starting materials. 1 H-NMR (CDCl 3) d 1.50 (9H, s), 1.80-2.08 (2H, m), 2.75 (2H, br s), 3.48-3.87 (6H, m), 3.88-4.05 (1 H, m), 4.37 (2H, br s), 6.09 (1 H, br s), 7.05-7.15 (1 H, m), 7.55 (1 H, dd, J = 8.8,1.5 Hz), 7.79-7.91 (4 H, m) , 8.41 (1 H, s). MS (FAB) m / z: 576 [(M + H) +, Cl 35], 578 [(M + H) +, Cl37].

REFERENCE EXAMPLE 123 (3S) -3-Amino-1-f (6-chloronaphthalen-2-yl) sulfonylpyrrolidine (3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine was dissolved in trifluoroacetic acid. After concentrating the resulting solution under reduced pressure, diethyl ether was added to the concentrate, followed by removal of the supernatant. The residue was reacted as in Reference Example 1, whereby the corresponding sulfonamide derivative was obtained as a crude product. The crude product was subjected to azide formation and reduction as in Reference Example 55, whereby the title compound was obtained. 1 H-NMR (DMSO-d 6) d: 1.38-1.53 (3H, m), 1.72-1.83 (1 H, m) 2.81-2.89 (1 H, m), 3.20-3.39 (4H, m), 7.69 (1 H, dd, J = 8.8.1.9Hz), 7.87 (1 H, d, J = 8.8Hz), 8.12 (1 H, d, J = 8.8Hz), 8.21 (1 H, s), 8.26 (1 H , d, J = 8.8 Hz), 8.39 (1 H, s). MS (FAB) m / z: 3.11 [(M + H) +, Cl 35], 313 [(M + H)? Cl37].

REFERENCE EXAMPLE 124 (3S) -1-rr (5-tert-Butoxycarbonyl-4.5.6.7-tetrahydrothienor3.2-c1pyridin-2-M) metMlaminol-1-r (6-chloronaphthalen-2-yl) sulfonyl] pyrrolidi na The reaction was performed in a manner similar to the Reference Example 47, except that 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and (3S) -3-amino-1 - [(6-) chloronaphthalen-2-yl) sulfonyl] pyrrolidine as starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 1.60-1.69 (1 H, m), 1.95-2.05 (1 H, m), 2.72 (2H, br s), 3.11 (1 H, dd, J = 10.3.4.4Hz), 3.30-3.46 (4H, m), 3.68 (2H, br s), 3.72 (2H, s), 4.36 (2H, s) 6.44 (1 H, s), 7.56 (1 H, dd, J = 8.8.2.0Hz), 7.86-7.91 (4H, m), 8.36 (1H, s). MS (FAB) m / z: 561 M + CI35), 563 (M + Cl37).

REFERENCE EXAMPLE 125 (3S) -3-rr (5-tert-Butoxycarbonyl-4.5.6.7-tetrahydrothienor3.2-c1pyridin-2-yl) carbonylamino1-1-r (6-chloronaphthalen-2-yl) sulfonylpyrrolidine The title compound was obtained in a manner similar to Reference Example 12, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydroxy [3,2-c] pyridine-2-carboxylic acid was used and (3S) -3-amino-1 - [(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as starting materials. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 1.90-2.00 (1 H, m), 2.1 1 (1 H, m), 2. 22 (1 H, m), 2.80 (2 H, br s), 3.32-3.42 (1 H, m), 3.44-3.57 (3 H, m), 3.71 (2 H, br s), 4.38 (2 H, d, J = 1.5Hz), 4.40-4.49 (1 H, m), 5.80-5.87 (1 H, m), 6.96 (1 H, s), 7. 54 (1 H, dd, J = 8.8,1.5 Hz), 7.83-7.89 (3 H, m), 7.90 (1 H, d, J = 8.8 Hz), 8.37 (1 H, s). MS (FD) m / z: 576 [(M + H) Cl 35], 578 [(M + H) +, Cl37].

REFERENCE EXAMPLE 126 1 - [(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothienor3,2-c1pyridin-2-yl) carbonn-4-r (6-chloronaphthalene-2-yl) sulfon Phomopiperazine The title compound was obtained in a manner similar to Reference Example 12, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid and hydrochloride were used. 1 - [(6-chloronaphthalen-2-yl) sulfonyl] homopyperazine as starting materials. 1 H-NMR (CDCl 3) d 1.47 (9H, s), 2.01 (2H, br s), 2.78- (2H, br s), 3.37-3.54 (4H, m), 3.68 (2H, br s), 3.78 ( 2H, t, J = 6.1 Hz), 3.86 (2H, t, J = 6.1 Hz), 4.39 (2H, s), 6.88 (1 H, br s), s), 7.55 (1 H, dd, J = 8.8.2.0Hz), 7.75-7.80 (1 H, m), 7.83-7.90 (3H, m), 8.33 (1 H, s). MS (FD) m / z: 589 (M \ Cl35), 591 (M +, Cl37).

REFERENCE EXAMPLE 127 4-Benzylamino-1-tert-butoxycarbonylpiperidine 1-tert-Butoxycarbonyl-4-piperidone (7.00 g) was dissolved in dichloromethane (500 ml), followed by the addition of benzylamine (4.03 ml) and sodium triacetoxyborohydride (1.91 g). The resulting mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethyl acetate. The resulting mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 1: 1), whereby the title compound was obtained (7.46 g, 76%). 1 H-NMR (CDCl 3) d 1.24-1.37 (2H, m), 1.45 (9H, s), 1.80-190 (2H, m), 2.62-2.70 (1 H, m), 2.75-2.85 ( 1 H, m), 2.98-3.07 (1 H, m), 3.78-3.90 (3H, m), 3.95-4.10 (1 H, m), 7.21-7.34 (5H, m). EM (FD) m / z: 290M + REFERENCE EXAMPLE 128 4-Amino-1-tert-butoxycarbonylpiperidine acetate 4-Benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was dissolved in methanol (2 ml) and acetic acid (30 ml), followed by the addition of 10% palladium-carbon (water content: approximately 50%, 3.06 g). The resulting mixture was subjected to catalytic reduction overnight under medium pressure (3 atmospheres pressure). After removing the catalyst by means of filtration, the filtrate was subjected to distillation under reduced pressure. The residue was solidified in ethyl acetate, whereby the title compound was obtained (2.23 g, 57%). 1 H-NMR (DMSO-d6) d: 1.10-1.23 (2H, m), 1.39 (9H, s) 1.69-1.77 (2H, m), 1.80 (3H, s), 2.50 (2H, s), 2.67- 2.88 (2H, m), 3.80-3.90 (1 H, m). Elemental analysis for C-? OH2oN2? 2 * CH3CO2H Calculated: C, 53.16; H, 9.37; N, 10.33 Found: C, 53.51; H, 9.10; N. 9.93 REFERENCE EXAMPLE 129 4-R (6-chloronaphthalen-2-yl) sulfonamido-piperidine trifluoroacetate The title compound was obtained in a manner similar to Reference Example 1, except that 4-amino-1-tert-butoxycarbonylpiperidine hydrochloride and 6-chloro-2-naphthylsulfonyl chloride were used as the starting materials. 1 H-NMR (DMSO-d 6) d: 1.47-1.60 (2H, m), 1.68-1.78 (2H, m) 2. 81-2.95 (2H, m), 3.10-3.20 (2H, m), 3.29-3.40 (1H, m), 7.70 (1H, dd, J = 8.8.2.0Hz), 7.91 (1H, dd, J = 8.8.2.0Hz), 8.11-8.15 (2H, m), 8.21 (1 H, s), 8.31 (1 H, br s), 8.50 (1 H, s), 8.55 (1 H, br s) MS (FAB) m / z: 325 [(M + H) +, Cl 35], 327 [(M + H)? Cl37].

REFERENCE EXAMPLE 130 1-r (6-Chloronaphthalen-2-yl) sulfonyl-4-r (6-cyanobenzofuran-2-D-carbonylpiperazine The reaction was carried out in a manner similar to Reference Example 12, except that 6-cyanobenzofuran-2-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as the starting materials, with which was obtained the title compound. 1 H-NMR (CDCl 3) d 3.21 (4 H, s), 3.95 (4 H, s), 7.32 (1 H, d, J = 1.0 Hz), 7.55 (1 H, dd, J = 8.3.1.0 Hz), 7.59 (1 H, dd, J = 8.8.2.0Hz), 7.72 (1 H, d, J = 8.3Hz), 7.77 (1 H, dd, J = 8.8.2.0Hz), 7.81 (1 H, s), 7.88-7.95 (3H, m), 8.32 1 H, s). MS (FAB) m / z: 480 [(M + H)? Cl35], 482 [(M + H) +, Cl37].

REFERENCE EXAMPLE 131 1-r (6-Chloronaphthalen-2-yl) sulfonin-4-f (5-cyanobenzothiophen-2-ylcarbonylpiperazine The reaction was carried out in a manner similar to Reference Example 12, except that 5-cyanobenzothiophene-2-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, which was obtained the title compound. 1 H-NMR (CDCl 3) d 3.18 (4 H, s), 3.89 (4 H, s), 7.43 (1 H, d, J = 2.0 Hz), 7.60 (1 H, d, J = 8.8 Hz), 7.73-7.80 (2H, m), 7.85-7.95 (4H, m), 8.10 (1 H, s), 8.32 (1 H, s). MS (FAB) m / z: 496 [(M + H) +, Cl 35], 4.98 [(M + H)? Cl37].

REFERENCE EXAMPLE 132 (1 RS) -4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylate ethyl Diisopropylamine (0.99 ml) was dissolved in tetrahydrofuran (50 ml), followed by the dropwise addition of n-butyllithium (1.59 M solution in hexane, 3.70 ml) at -78 ° C. After the dropwise addition of ethyl 4-oxocyclohexanecarboxylate (1.00 g) dissolved in tetrahydrofuran (5 ml) to the reaction mixture, and stirring for 15 minutes, N was added dropwise to the reaction mixture. phenyltrifluoromethanesulfonimide (2.10 g) dissolved in tetrahydrofuran (5 ml). The reaction mixture was warmed to 0 ° C, stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by chromatography on a neutral alumina column (hexane: ethyl acetate = 9: 1), whereby the title compound was obtained (838 mg, 47%). 1 H-NMR (CDCl 3) d 1.27 (3 H, t, J = 7.3 Hz), 1.88-199 (1 H, m), 2.10-2.18 (1 H, m), 2.38-2.50 (4 H, m), 2.55- 2.64 (1 H, m), 4.16 (2 H, q, J = 7.3 Hz), 5.77 (1 H, br s). s) MS (FAB) m / z: 303 (M + H) +.

REFERENCE EXAMPLE 133 (1RS) -4- (4-pyridyl) -3-cyclohexenecarboxylate ethyl The reaction was carried out in a manner similar to Reference Example 7, except that ethyl (1 RS) -4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylate was used as the starting material, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d 1.28 (3 H, t, J = 7.3 Hz), (9 H, s), 1.80-191 (1 H, m), 2. 19-2.25 (1 H, m), 2.40-2.57 (4H, m), 2.59-2.67 (1 H, m), 4.17 (2H, q, J = 7.3Hz), 6.36 (1 H, br s), 7.26 (2H, dd, J = 4.9.1.5Hz), 8.53 (2H, dd, J = 4.9.1.5Hz). MS (FAB) m / z: 232 (M + H) +.

REFERENCE EXAMPLE 134 Acid (1 RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid The title compound was obtained in a manner similar to Reference Example 8, except that ethyl (1 RS) -4- (4-pyridyl) -3-cyclohexenecarboxylate was used as the starting material. 1 H-NMR (DMSO-d 6) d: 1.70-1.82 (1 H, m), 2.10-2.19 (1 H, m), 2.42-2.65 (5H, m), 6.99 (1 H, br s), 8.02 ( 2H, d, J = 6.8Hz), 8.80 (2H, d, J = 6.8Hz). MS (FAB) m / z: 204 (M + H) +.

REFERENCE EXAMPLE 135 cis-acid. trans-4- (4-pyridyl) cyclohexanecarboxylic The title compound was obtained in a manner similar to Reference Example 87, except that (1 RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid was used as the starting material. MS (FAB) m / z: 206 (M + H) +.

REFERENCE EXAMPLE 136 6-Methoxy-3,4-dihydroisoquinoline 3-Methoxyphenethylamine (75.0 g) was dissolved in tetrahydrofuran (100 ml), followed by the addition of formic acid (60 ml) and acetic anhydride (108 ml) under ice-cooling. The resulting mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic layer thus separated was washed with saturated saline and dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was dissolved in benzene (200 ml), followed by the dropwise addition of phosphorus oxychloride (140 ml) under ice-cooling. After stirring at 70 ° C for 15 minutes, ice and then 2 N hydrochloric acid were added. The resulting mixture was stirred under ice-cooling for one hour. The aqueous layer was separated and neutralized with potassium carbonate. After extracting with dichloromethane, the extract was dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 1), whereby the title compound was obtained (13.5 g, %). 1 H-NMR (CDCl 3) d 2.72 (2 H, t, J = 7.3 Hz), 3.72 (2 H, t, J = 7.3 Hz), 3.83 (3 H, s), 6.68 (1 H, d, J = 2.4 Hz) , 6.79 (1 H, dd, J = 8.3.2.4 Hz), 7.22 (1 H, d, J = 8.3 Hz), 8.25 (1 H, s). MS (FAB) m / z: 162 (M + H) +.

REFERENCE EXAMPLE 137 6-Methoxy-1.2.3.4-tetrahydroisoquinoline 6-methoxy-3,4-dihydroisoquinoline (10.4 g) was dissolved in methanol (100 ml). After the addition of water (10 ml) and then sodium borohydride (6.10 g), the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water. The organic layer thus separated was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 15), whereby the title compound (7.95 g, 76%) was obtained. 1 H-NMR (CDCl 3) d 2.79 (2 H, t, J = 5.9 Hz), 3.12 (2 H, t, J = 5.9 Hz), 3.76 (3 H, s), 3.96 (2 H, s), 6.62 (1 H, s), 6.70 (1 H, dd, J = 8.3.2.4 Hz), 6.92 (1 H, d, J = 8.3 Hz), MS (FAB) m / z: 164 (M + H) + \ REFERENCE EXAMPLE 138 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 6-Methoxy-1, 2,3,4-tetrahydroisoquinoline (7.75 g) was dissolved in dimethyl sulfide (20 ml), followed by the addition of aluminum chloride (19.0 g) under ice-cooling. The resulting mixture was stirred at room temperature for 3 hours. Dichloromethane and dilute hydrochloric acid were added to the reaction mixture. A saturated aqueous solution of sodium bicarbonate was added to the water layer thus separated to make it weakly alkaline, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The residue was dissolved in saturated hydrochloric acid in ethanol (100 ml) and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid thus precipitated was collected by filtration, whereby the title compound was obtained (7.91 g, 90%). 1 H-NMR (DMSO-d6) d: 3.06 (2H, T, J = 5.9Hz), 3.43 (2H, m), 4.25 (2H, s), 6.76 (1H, d, J = 2.0Hz), 6.83 (1 H, dd, J = 8.3.2.0Hz), 7.15 (1 H, d, J = 8.3Hz), 9.71 (3H, br s). MS (FAB) m / z: 150 (M + H) +.

REFERENCE EXAMPLE 139 2-tert-Butoxycarbonyl-6-hydroxy-1.2.3.4-tetrahydroisoquinoline 6-Hydroxy-1, 2,3,4-tetrahydroisoquinoline hydrochloride (7.87 g) was dissolved in methanol (100 ml), followed by the addition of triethylamine (4.67 ml) and di-tert-butyl dicarbonate (13.95 g). The resulting mixture was stirred at room temperature for 3 hours. To the residue, obtained by concentrating the reaction mixture under reduced pressure, ethyl acetate was added. The resulting mixture was washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 10: 1 ~ 3: 1), whereby the title compound was obtained (9.96 g, 94%). 1 H-NMR (CDCl 3) d: 1.49 (9H, s), 2.75 (2H, t, J = 5.9Hz), 3.61 (2H, t, J = 5.9Hz), 4.48 (2H, s), 6.25 (1H , br, s), 6.64 (1 H, d, J = 2.4 Hz), 6.70 (1 H, br, s), 6.93 (1 H, d, J = 7.8 Hz).

REFERENCE EXAMPLE 140 2-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-1, 2,3,4-tetrahydroisoquinoline The title compound was obtained in a manner similar to Reference Example 94, except that 2-tert-butoxycarbonyl-6-hydroxy-1, 2,3,4-tetrahydroisoquinoline was used as the starting material. 1 H-NMR (CDCl 3) d 1.49 (9H, s), 2.87 (2H, t, J = 5.9Hz), 3.66 (2H, t, J = 5.9Hz), 4.59 (2H, s), 7.06 (1H, br s), 7.08 (1 H, d, J = 8.3 Hz), 7.17 (1 H, d, J = 8.3 Hz). Elemental analysis for C-15H-18F3NO5S Calculated: C, 47.24; H, 4.76; F, 14.94; N, 3.67; S.8.41. Found: N, 3.42; S, 8.65.

REFERENCE EXAMPLE 141 2-tert-Butoxycarbonyl-6-methoxycarbonyl-1.2.3.4-tetrahydroisoquinoline 2-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-1, 2,3,4-tetrahydroisoquinoline (1.34 g) was dissolved in methanol (50 ml), followed by the addition of triethylamine (0.73 ml), palladium (II) acetate ( 40 mg) and 1, 3- (diphenylphosphino) propane (145 mg). The resulting mixture was stirred overnight at 70 ° C under a stream of carbon monoxide gas. After concentrating the reaction mixture under reduced pressure, the residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 15: 1), whereby the title compound (665 mg, 65%) was obtained. %). 1 H-NMR (CDCl 3) d 1.50 (9 H, s), 2.88 (2 H, m), 3.66 (2 H, br s), 3.91 (3 H, s), 4.62 (1 H, s), 7.17 (1 H, d , J = 7.8 Hz), 7.83 (1 H, s), 7.84 (1 H, d, J = 7.8 Hz).

REFERENCE EXAMPLE 142 1-r (2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-Piperazine The title compound was obtained in a manner similar to Reference Example 48, except that 2-tert-butoxycarbonyl-6-methoxycarbonyl-1, 2,3,4-tetrahydroisoquinoline and 1 - [(6-chloronaphthalene-2-hydrochloride -yl) sulfonyl] piperazine as the starting materials. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 2.76 (2H, t, J = 5.4Hz), 3.09 (4H, br), 3.60 (2H, t, J = 5.4Hz), 3.77 (4H, br ), 4.52 (2H, s) 7.12-7.25 (3H, m), 7.59 (1H, dd, J = 8.8.2.0Hz), 7.75 (1H, dd, J = 8.8.2.0Hz), 7.88-7.95 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 570 [(M + H)? Cl35], 572 [(M + H)? Cl37].

REFERENCE EXAMPLE 143 4- (1-tert-Butoxycarbonyl-1, 2,3,6-tetrahydropyridin-4-yl) benzoic acid 4- (1-tert-Butoxycarbonyl-4-trifluoromethanesulfonyloxy-1, 2,3,6-tetrahydropyridine (3.59 g) was dissolved in 1,2-dimethoxyethane (30 ml), followed by the addition of 4-carboxyphenylboronic acid (3.60). g), lithium chloride (1.38 g), palladium tetrakistriphenylphosphine (0.62 g) and an aqueous solution of sodium carbonate (2 M, 16.3 ml) The resulting mixture was heated under reflux for 2 hours under an atmosphere of Argon gas 1 N hydrochloric acid was added to the reaction mixture The resulting mixture was extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 1) The purified product was pulverized and washed in a mixed solvent of hexane and ethyl acetate (hexane: ethyl acetate = : 1), whereby the title compound was obtained (462 mg, 14%). 1 H-NMR (CDCl 3) d 1.50 (9H, s), 2.56 (2H, br s), 3.66 (2H, m), 4.12 (2H, br s), 6.19 (1 H, br s), 7.47 (2H, d, J = 8.3Hz), 8.07 (2H, d, J = 8.3Hz). MS (FAB) m / z: 304 (M + H) +.

EXAMPLE OF REFERENCE 144 4- (1-tert-Butoxycarbonylpiperidin-4-yl) benzoic acid The title compound was obtained in a manner similar to Reference Example 87, except that 4- (1-tert-butoxycarbonyl-1, 2,3,6-tetrahydropyridin-4-yl) benzoic acid was used as the starting material. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 1.60-1.71 (2H, m), 1.80-1.89 (2H, m), 2.69-2.90 (3H, m), 4.20-4.35 (2H, m), 7.31 (2H, d, J = 8.3Hz), 8.05 (2H, d, J = 8.3Hz). MS (FAB) m / z: 306 (M + H) +.

EXAMPLE OF REFERNCIA 145 1 -f4- (1-tert-Butoxycarbonyl-1, 2,3,6-tetrahydropyridin-4-yl) benzoyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was carried out in a manner similar to Reference Example 12, except that 4- (1-tert-butoxycarbonyl-1, 2,3,6-tetrahydropyridyl-4-yl) was used. benzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as the starting materials, by means of which the title compound was obtained. 1 H-NMR (CDCl 3) d 1.49 (9H, s), 2.48 (1 H, br s), 3.10 (4H, br), 3.62 (2H, t, J = 5.90Hz), 3.70 (4H, br), 4.08 (2H, br), 6.05 (1H, br s), 7.25 (2H, d, J = 8.3Hz), 7.34 (2H, d, J = 8.3 Hz), 7.59 (1 H, dd, J = 8.8.2.0Hz), 7.75 (1 H, dd, J = 8.8.2.0Hz), 7.90-7.96 (3H, m), 8.30 (1 H, s).

MS (FAB) m / z: 596 [(M + H) Cl 35], 598 [(M + H) +, Cl37].

REFERENCE EXAMPLE 146 1-r4- (1-tert-Butoxycarbonylpiperidin-4-yl) benzoyl-4-r (6-chloronaphthalen-2-dsulfoninpiperazine The reaction was performed in a manner similar to Reference Example 12, except that 4- (1-tert-butoxycarbonylpiperidin-4-yl) benzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used. as the starting materials, whereby the title compound was obtained. 1 H-NMR (CDCl 3) d 1.47 (9H, s), 1.49-1.63 (2H, m), 1.72-1.80 (2H, m), 2.59-2.68 (1 H, m), 2.71-2.86 (2H, m) , 2.92-3.30 (4H, m), 3.45-4.95 (4H, m), 4.16-4.31 (2H, m), 7.18 (2H, d, J = 8.3Hz), 7.24 (2H, d, J = 8.3Hz ), 7.59 (1 H, dd, J = 8.8.2.0 Hz), 7.75 (1 H, dd, J = 8.8.2.0 Hz), 7.90-7.94 (3 H, m), 8.30 (1 H, S). MS (FAB) m / z: 598 [(M + H) +, Cl 35], 600 [(M + H)? Cl37].

EXAMPLE OF REFERENCE 147 (3RS) -3-Amino-1-tert-butoxycarbonylpyrrolidine 3-Aminopyrrolidine (0.54 g) was dissolved in methanol (30 ml) under cooling with ice, followed by the addition of diisopropylethylamine (720 μl) and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (0.84 g). The resulting mixture was gradually warmed to room temperature and stirred for 11 hours. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ 5% methanol-dichloromethane), whereby the title compound was obtained (0.59 g, 94%). . H-NMR (CDCl 3) d: 1.45 (9H, s), 2.00-2.30 (2H, m), 3.10-4.00 (5H, m).

REFERENCE EXAMPLE 148 (3RS) -1-tert-Butoxycarbonyl-3-r (6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine The title compound was obtained in a manner similar to Reference Example 1, except that (3RS) -3-amino-1-tert-butoxycarbonylpyrrolidine was used as the starting material. 1 H-NMR (CDCl 3) d 1.37 (9H, s), 1.60-2.10 (2H, m), 3.00-3.50 (4H, m), 3.88 (1 H, br), 4.96 (1 H, br), 7.50- 7.60 (1 H, m), 7.80-7.90 (4H, m), 8.43 (1 H, s) MS (FAB) m / z: 411 [(M + H) Cl 35], 413 [(M + H) \ Cl37].

REFERENCE EXAMPLE 149 (3RS) -1-tert-Butoxycarbonyl-3-r4- (4-pyridyl) benzamido] pyrrolidine The title compound was obtained in a manner similar to Reference Example 12, except that (3RS) -3-amino-1-tert-butoxycarbonylpyrrolidine and 4- (4-pyridyl) benzoic acid were used as the starting materials. 1 H-NMR (CDCl 3) d 1.48 (9H, s), 1.90-2.10 (1 H, m), 2.20-2.30 (1 H, m), 3.30-3.40 (1 H, m), 3.40-3.60 (2H, m), 3.70-3.80 (1 H, m), 4.65-4.75 (1 H, m), 6.25-6.35 (1 H, m), 7.52 (2 H, d, J = 5.9 Hz), 7.71 (2 H, d , J = 8.3Hz), 7.88 (2H, d, J = 8.3Hz), 8.70 (2H, d, J = 5.4Hz). MS (FAB) m / z: 368 (M + H) +.

REFERENCE EXAMPLE 150 6-Chloro-N-methoxy-N-methylnicotinamide Under cooling with ice, 6-chloronicotinic acid (5.00 g) was suspended in dichloromethane (150 ml), followed by the addition of a catalytic amount of N, N-dimethylformamide and oxalyl chloride (5.30 ml). The resulting mixture was stirred at room temperature for 23 hours. The residue, obtained by concentrating the reaction mixture, was dissolved in dichloromethane (100 ml), followed by the addition of N, O-dimethylhydroxylamine hydrochloride (6.18 g) and triethylamine (13.3 ml) under cooling with ice. After stirring at room temperature for 6 hours, the reaction mixture was diluted with dichloromethane (150 ml), washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, and then dried over anhydrous sodium sulfate. . The residue, obtained by elimination of the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2: 1), whereby the title compound (6.08 g, 96%). 1 H-NMR (CDCl 3) d 3.39 (3 H, s), 3.56 (3 H, s), 7.39 (1 H, d, J = 8.3 Hz), 8.03 (1 H, dd, J = 8.3.2.4 Hz), 8.78 (1 H, d, J = 2.4Hz).

EXAMPLE OF REFERENCE 151 6-Chloronicotinaldehyde 6-Chloro-N-methoxy-N-methylnicotinamide (500 mg) was dissolved in tetrahydrofuran (8 ml), followed by the dropwise addition of diisobutylaluminium hydride (0.95 M solution in haxane, 2.88 ml) to - 78 ° C in an atmosphere of argon gas. The resulting mixture was stirred for 3 hours and then at room temperature for 2 hours. After cooling the reaction mixture to -20 ° C, saturated saline (2 ml) was added thereto, followed by stirring for 30 minutes. The insoluble material was removed by filtration. The residue was washed with ethyl acetate. The filtrate and the washing were combined. The mixture was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, whereby the title compound (346 mg, 98%) was obtained as a crude product. The product was supplied without purification for the subsequent reaction. 1 H-NMR (CDCl 3) d: 7.52 (1 H, d, J = 8.3 Hz), 8.14 (1 H, dd, J = 8.3, 2.2 Hz), 8.87 (1 H, d, J = 2.2 Hz), 10.10 (1 H, s).

REFERENCE EXAMPLE 152 1-tert-Butoxycarbonyl-4-methanesulfonylpiperazine N-tert-butoxycarbonylpiperazine (2.00 g) was dissolved in dichloromethane (40 ml), followed by the addition of triethylamine (1.78 ml). To the resulting solution, methanesulfonyl chloride (0.91 ml) was added dropwise under cooling with ice. After stirring for one hour under ice-cooling, the reaction mixture was diluted with dichloromethane (20 ml), washed with an aqueous solution of 5% citric acid, water and saturated saline, and dried over magnesium sulfate. anhydrous. The residue, obtained by removing the solvent by distillation under reduced pressure, was recrystallized from a mixed solvent of ethyl acetate and hexane, whereby the title compound was obtained (2.58 g, 91%). 1 H-NMR (CDCl 3) d: 1.47 (9H, s), 2.79 (3H, s), 3.19 (4H, t, J = 5.1 Hz), 3.55 (4H, t, J = 5.1 Hz).

REFERENCE EXAMPLE 153 1-tert-Butoxycarbonyl-4-rr (2RS) -2- (6-chloropyridin-3-yl) -2- hydroxyethylsulfonylpiperazine 1-tert-Butoxycarbonyl-4-methanesulfonylpiperazine (838 mg) was dissolved in tetrahydrofuran (8 ml), followed by the addition of tert-butyllithium (1.7 M solution in pentane, 1.72 ml) at -78 ° C under an atmosphere of Argon gas The resulting mixture was stirred for 2 hours. After the dropwise addition of a solution of 6-chloronicotinaldehyde (346 mg) in tetrahydrofuran (tetrahydrofuran: 4 ml) and stirring at -78 ° C for 3 hours, the reaction mixture was added with isopropanol (1 ml). The resulting mixture was warmed to room temperature and diluted with ethyl acetate. The diluted solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was recrystallized from ethyl acetate, whereby the title compound (532 mg, 54%) was obtained. 1 H-NMR (CDCl 3) d 1.46 (9H, s), 3.11 (1 H, dd, J = 14.1, 2.2Hz), 3.21 (1 H, dd, J = 14.1, 9.8Hz), 3.23-3.33 (4H, m), 3.52-3.57 (4H, m), 3.70 (1 H, br s), 5.37 (1 H, br), 7.36 (1 H, d, J = 8.3 Hz), 7.72 (1 H, dd, J = 8.3.2.4Hz), 8.41 (1 H, d, J = 2.4Hz). MS (FAB) m / z: 405 (M + H) +.

EXAMPLE OF REFERENCE 154 1-tert-Butoxycarbonyl-4-rr (E) -2- (6-chloropyridin-3-yl) ethynylsulfonylpiperazine 1-tert-Butoxycarbonyl-4 - [[(2RS) -2- (6-chloropyridin-3-yl) -2-hydroxyethyl] sulfonyl] piperazine (465 mg) was dissolved in dichloromethane (10 ml), followed by the addition of N-methylmorpholine (0.152 ml) and N, N-dimethyl-4-aminopyridine (14.1 mg). Under cooling with ice, p-toluenesulfonyl chloride (263 mg) was added under an argon atmosphere. After stirring at room temperature for 2 hours, N, N-dimethyl-4-aminopyridine (141 mg) was added and the resulting mixture was stirred at room temperature for 3 hours. After diluting with dichloromethane (20 ml), the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline and then dried over anhydrous sodium sulfate. The residue, obtained by removal of the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane: methanol = 100: 1), whereby the title compound was obtained (414 mg, 93% ). 1 H-NMR (CDCl 3) delta: 1.45 (9H, s), 3.19 ((4H, br), 3.55 (4H, br), 6. 73 (1 H, d, J = 15.6 Hz), 7.40 (1 H, d, J = 8.3 Hz), 7.43 (1 H, d, J = 15.6 Hz), 7.76 (1 H, dd, J = 8.3, 2.5Hz), 8.50 (1 H, d, J = 2.5Hz). Elemental analysis for C16H22CIN3O3S Calculated: C, 49.54; H, 5.72; N, 10.83; Cl, 9.14; S, 8.27. Found: C, 49.54; H, 5.73; N, 10.63; Cl, 9.44; S, 8.15.

REFERENCE EXAMPLE 155 1 - (4-Bromo-2-methylbenzoyl) -4-f (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was carried out in a manner similar to Reference Example 12, except that 4-bromo-2-methylbenzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, which was obtained the title compound. 1 H-NMR (CDCl 3) delta: 2.13 (3H, s), 2.80-4.10 (8H, m), 6.89 (1 H, d, J = 8.3Hz), 7.30 (1 H, dd, J = 8.3.2.OHz), 7.35 (1 H, d, J = 2.OHz), 7.60 (1 H, dd, J = 8.8.2.OHz), 7.74 (1 H, dd, J = 8.8.2.OHz), 7.90-7.95 (3H, m), 8.30 (1 H, br s). MS (FAB) m / z: 507 [(M + H) +, Br79], 509 [(M + H) +, Br81].

REFERENCE EXAMPLE 156 3-Methyl-4- (4-pyridyl) benzoic acid hydrochloride The reaction was carried out in a manner similar to Reference Example 6, except that 4-bromo-3-methylbenzoic acid was used as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO -dβ) delta: 2.36 (3H, s), 7.50 (1 H, d, J = 7.8Hz), 7. 92 (1 H, d, J = 7.8 Hz), 7.97 (1 H, s), 8.08 (2 H, d, J = 6.4 Hz), 8.99 (2 H, d, J = 6.4 Hz). MS (FAB) m / z: 214 (M + H) +.

REFERENCE EXAMPLE 157 4- (2-Methyl-4-pyridyl) benzoic acid hydrochloride The reaction was carried out in a manner similar to Reference Example 2, except that 4-bromo-2-methylpyridine was used as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 2.81 (3H, s), 8.10-8.16 (4H, m), 8.23 (1 H, dd, J = 6.4.1.5 Hz), 8.36 (1 H, d, J = 1.5 Hz), 8.85 (1 H, d, J = 6.4 Hz). MS (FAB) m / z: 214 (M + H) +.

REFERENCE EXAMPLE 158 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine N, N'-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved in toluene, followed by the dropwise addition of methyl 3-bromocrotonate (7.0 ml) under ice-cooling. The resulting mixture was stirred at room temperature for 24 hours. After the addition of triethylamine (2.0 ml), the resulting mixture was stirred at room temperature for 71 hours. The insoluble material was removed by filtration and the filtrate was distilled under reduced pressure. The residue was added with 10% hydrochloric acid (300 ml) and the crystals thus precipitated were removed by filtration. Ethyl acetate was added to the filtrate. Potassium carbonate was added to the water layer thus separated to make it alkaline. Ethyl acetate was added to the resulting mixture. The organic layer thus separated was washed with saturated saline and dried over anhydrous potassium carbonate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 4: 1), whereby the title compound was obtained (1.07 g, 62%). 1 H-NMR (CDCl 3) delta: 2.30-2.70 (8H, m), 3.11 (1 H, br s), 3.40- 3.80 (4H, m), 3.60 (3H, s), 7.20-7.40 (10H, m ). MS (FAB) m / z: 339 (M + H) +.

REFERENCE EXAMPLE 159 1-r (6-Chloronaphthalen-2-yl) sulfonin-3-methoxycarbonylmethylpiperazine 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine (2.04 g) was dissolved in acetic acid (40 ml), followed by the addition of 10% palladium-carbon (water content: approximately 50%, 2.00 g). The resulting mixture was subjected to catalytic reduction at room temperature for 4 hours under 4 atmospheres of pressure. After removing the catalyst by filtration, the residue, obtained by distilling the filtrate under reduced pressure, was mixed with dichloromethane and a saturated aqueous solution of sodium bicarbonate. The insoluble material thus precipitated was removed by filtration. The organic layer thus separated was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (30 ml), followed by the addition of 6-chloro-2-naphthylsulfonyl chloride (782 mg). The resulting mixture was stirred at 0 ° C for 2 hours. Triethylamine (410 μl) was added to the reaction mixture, followed by stirring at 0 ° C for three more hours. The residue, obtained by removal of the solvent by distillation r reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane-3% methanol-dichloromethane), whereby the title compo(759 mg, 33%). 1 H-NMR (CDCl 3) delta: 1.71 (1 H, br s), 2.15-2.55 (4 H, m), 2.90- 3.05 (2 H, m), 3.15-3.25 (1 H, m), 3.60-3.70 ( 5H.m), 7-55-7.60 (1 H, m), 7.75-7.80 (1 H, m), 7.85-7.95 (3H, m), 8.30 (1 H, s). MS (FAB) m / z: 383 [(M + H) +, CI35], 385 [(M + H) +, CI37].

REFERENCE EXAMPLE 160 4-tert-Butoxycarbonyl-1-f 3-chloro-1-propylsulfonylpiperazine Under argon, 1-tert-butoxycarbonylpiperazine (3.00 g) and triethylamine (2.24 ml) were dissolved in dichloromethane (40 ml) under ice-cooling, followed by the addition of 3-chloro-1-propanesulfonic acid chloride. (1.96 g). The resulting mixture was stirred for 20 minutes under cooling with ice, and then at room temperature for 10 minutes. The reaction mixture was diluted with dichloromethane, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane, whereby the title compound was obtained (4.36 g, 83%). 1 H-NMR (CDCl 3) delta: 1.41 (9H, s), 2.27-2.33 (2H, m), 3.08 (2H, t, J = 7.3Hz), 3.26 (4H, t, J = 4.9Hz), 3.53 (4H, t, J = 4.9Hz), 3.69 (2H, t, J = 6.1 Hz). MS (FAB) m / z: 327 (M + H) + Elemental analysis for C 12 H 23 CIN 2 O 4 S Calculated: C, 44.10; H, 7.09, Cl, 10.85; N, 8.57; S, 9.81. Found: C, 44.18; H, 7.11; Cl, 10.69; N, 8.23; S, 9.76.

REFERENCE EXAMPLE 161 4-tert-Butoxycarbonyl-1-r (3-hydroxy-1-propyl) sulfonylpiperazine 4-tert-Butoxycarbonyl-1 - [(3-chloro-1-propyl) sulfonyl] piperazine (1.18 g) was dissolved in N, N-dimethylformamide (10 ml), followed by the addition of potassium acetate (1.06 g) . After stirring at room temperature for 2 hours, the reaction mixture was stirred under heating at 100 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate, followed by the addition of water and a saturated aqueous solution of sodium bicarbonate. After stirring, the organic layer thus separated was washed with an aqueous solution of 5% citric acid, water and saturated saline. After drying over anhydrous sodium sulfate, the residue, obtained by removing the solvent by distillation under reduced pressure, was dissolved in tetrahydrofuran (20 ml). To the resulting solution was added water and lithium hydroxide monohydrate (221 mg), followed by stirring at room temperature for 18 hours. Ethyl acetate and saturated saline were added to the reaction mixture to separate an organic layer. Another organic layer was extracted from the aqueous layer with ethyl acetate. The organic layers were combined, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane, whereby the title compound (944 mg, 84%) was obtained. 1 H-NMR (CDCl 3) delta: 1.47 (9H, s), 2.04-2.11 (2H, m), 3.06 (2H, t, J = 7.6Hz), 3.25 (4H, t, J = 4.9Hz), 3.53 (4H, t, J = 4.9Hz), 3.80 (2H, q, J = 5.4Hz). MS (FAB) m / z: 309 (M + H) +. Elemental analysis for C-12H24N2O5S Calculated: C, 46.74; H, 7.84; N, 9.08; S, 10.40. Found: C, 46.80; H, 7.92; N, 9.05; S, 10.59.

EXAMPLE OF REFERENCE 162 4-tert-Butoxycarbonyl-1-f (3-methoxymethyloxy-1-propyl) sulfonylpiperazine 4-tert-Butoxycarbonyl-1 - [(3-hydroxy-1-propyl) sulfonyl] piperazine (3.00 g) was dissolved in dichloromethane (60 ml). To the resulting solution was added diisopropylethylamine (2.72 ml), followed by the addition of methoxymethyl chloride (1.11 ml) under ice-cooling. After stirring at room temperature for 20 hours, the reaction mixture was diluted with dichloromethane, washed with water, an aqueous solution of 5% citric acid and saturated saline, and then dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2: 1), whereby the title compound was obtained (3.32 g, 97%). 1 H-NMR (CDCl 3) delta: 1.47 (9H, s), 2.06-2.13 (2H, m), 3.03 (2H, m), 3.25 (4H, t, J = 4.9Hz), 3.36 (3H, s), 3.52 (4H, t, J = 4.9Hz), 3.63 (2H, t, J = 5.4Hz), 4.61 (2H, s). MS (FAB) m / z: 353 (M + H) +. Elemental analysis for C 14 H 28 N 2 O 6 S Calculated: C, 47.71; H, 8.01; N, 7.95; S, 9.10. Found: C, 47.77; H, 8.18; N, 7.97; S, 9.16.

REFERENCE EXAMPLE 163 4-tert-Butoxycarbonyl-1-r (E) -4-chloro-β-r 2 -methoxymethyloxy) etin-β-styrylsulphonylpiperazine and 4-tert-butoxycarbonyl-1-y (Z) -4-chloro- ß-r2-methoxymethyloxy) etill-ß-styrylsulfonippiperazine Under an atmosphere of argon gas, 4-tert-butoxycarbonyl-1- [3-methoxymethoxy-1-propyl) sulfonyl] piperazine (800 mg) was dissolved in tetrahydrofuran (10 ml), followed by the addition , dropwise, of ter-butyllithium (1.7 M solution in hexane, 1.47 ml) at -78 ° C. The resulting mixture was stirred at -78 ° C for one hour. After the addition of trimethylsilyl chloride (0.317 ml) and stirring at -78 ° C for 90 minutes, tear drop, tert-butyllithium (1.7 M solution in hexane, 1.47 ml) was added to the reaction mixture and it was stirred at -78 ° C for 90 minutes. Drop by drop, a solution of p-chlorobenzaldehyde (352 mg) in tetrahydrofuran (tetrahydrofuran: 8 ml) was added to the reaction mixture at -78 ° C. After stirring for 2 hours, the temperature of the mixture was allowed to reach, at room temperature, 15 hours, and at this temperature it was stirred for 6 hours. Under cooling with ice, 5% citric acid solution (20 ml) and ethyl acetate (150 ml) were added to the reaction mixture. The organic layer thus separated was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3: 1 ~ 2: 1), whereby the title compound was obtained as an E form (307 mg, 28%) and a Z form (751 mg, 70%). Form E: H-NMR (CDCl 3) delta: 1.42 (9H, s), 2.87 (2Ht, J = 7.3Hz), 3.21- 3.28 (4H, m), 3.35 (3H, s), 3.46-3.56 (4H, m), 3.80 (2H, t, J = 7.3Hz), 4.60 (2H, s), 7.40 (2H, d, J = 8.5Hz), 7.46; d, J = 8.5Hz), 7.54 (1H, s ). Form Z 1 H-NMR (CDCl 3) delta: 1.43 (9H, s), 2.77 (2H, dt, J = 6.4.1.0Hz), .91-2.98 (4H, m), 3.19-3.25 (4H, m) , 3.38 (3H, s), 3.82 (2H, t, J = 6.4Hz), 4.66 (2H, s), 7.07 (1H, s), 7.32 (2H, d, J = 8.6Hz), 7.35 (2H , d, J = 8.6Hz).

EXAMPLE 1 1-r (6-Chloronaphthalen-2-yl) sulfonyl-4-r4-pyridin-4-Mbenzoylpiperazine hydrochloride At room temperature, 1- [4- (4-pyridyl) benzoyl] piperazine ditrifluoroacetate (1.19 g) in dichloromethane (100 ml) was suspended, followed by the addition of dipropylethylamine (1.68 ml) and 6-chloro-2-chloride. -naphthylsulfonyl (691 mg). After stirring at room temperature for 2 hours, the reaction mixture was purified by chromatography on a column of silica gel (2% methanol-dichloromethane). To the resulting fraction, 1 N ethanolic hydrochloric acid was added to make it slightly acidic. Then, the solvent was removed by distillation. The resulting colorless solid was washed with tetrahydrofuran, whereby the title compound (1.05 g, 81%) was obtained as a colorless solid. 1 H-NMR (CDCl 3) d: 2.95-3.25 (4H, m), 3.43 (2H, br s), 3.60 (2H, br s), 7.56 (2H, d, J = 8.3Hz), 7.74 / 1 H , dd, J = 8.8.2.5Hz), 7.83 (1H, dd, J = 8.8.2.0Hz), 8.01 (2H, d, J = 8.3Hz), 8.19 (1H, d, J = 8.8Hz) , 8.25-8.40 (4H, m), 8.51 (1H, s), 8.94 (2H, d, J = 6.8Hz). MS (FAB) m / z: 492 [(M + H) +, CI35], 494 [(M + H) +, Cl37]. Elemental analysis for C26H22N3O3CIS.HCLO.5H2O Calculated: C, 58.10; H, 4.50; N, 7.82; Cl, 13.19; S, 5.97.

Found: C, 58.12; H, 4.67; N, 7.66; Cl, 13.12; S, 6.10.

EXAMPLE 2 4-R (6-Chloronaphthalen-2-yl) sulfonyl-2-ethoxycarbonyl-1 - [4- (pyridin-4-yl) benzoin piperazine hydrochloride 4-tert-Butoxycarbonyl-2-ethoxycarbonyl-1- [4- (4-pyridyl) benzoyl] piperazine (514 mg) was dissolved in dichloromethane (30 ml), followed by the addition of trifluoroacetic acid (30 ml) under cooling with ice. After stirring at room temperature for 45 minutes, the residue, obtained by solvent removal by distillation, was suspended in dichloromethane (100 ml) under cooling with ice, followed by the addition of diisopropylethylamine (1.02 ml) and 6-chloro chloride -2-naphthylsulfonyl (366 mg). After stirring at room temperature for one hour, the reaction mixture was purified by chromatography on a column of silica gel (1% methanol-dichloromethane). To the resulting fraction, 1 N ethanolic hydrochloric acid was added to make it slightly acidic. Then, the solvent was removed by distillation. The resulting colorless solid was washed with ethanol, whereby the title compound (308 mg, 43%) was obtained as a colorless solid. 1 H-NMR (CDCl 3) delta: 1.15-1.30 (3H, m), 2.60-5.40 (9H, m), 7.50 (2 / 3Hd, J = 8.3Hz), 7.57 (4 / 3H, d, J = 7.8Hz), 7.74 (1H, dd, J = 9.0.1.7Hz), 7.83 (1H, d, J = 8.8 Hz), 8.00 (2 / 3H, d, J = 7.8Hz), 8.04 (4 / 3H, d, J = 8.3Hz), 8.19 (1H, d, J = 8.8Hz), 8.25-8.35 (4H, m), 8.55 (1 H, s), 8.92 (2 H, d, J = 4.9 Hz). MS (FAB) m / z: 564 [(M + H) +, CI35], 566 [(M + H) +, Cl37]. Elemental analysis for C29H26N3O5CIS.HCI.O.5H2O Calculated: C, 57.15; H, 4.63; N, 6.89; Cl, 11.63; S, 5.26. Found: C, 56.95; H, 4.68; N, 6.70; Cl, 11.36; S, 5.30.

EXAMPLE 3 4-R (6-Chloronaphthalen-2-yl) sulfonylH-1-r4- (pyridin-4-yl) benzoyl-1-piperazine-2-carboxylic acid hydrochloride In a mixed solvent of eatnol (1 ml), tetrahydrofuran (1 ml) and water (1 ml), 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl hydrochloride was dissolved under ice cooling. -1- [4- (pyridin-4-yl) benzoyl] piperazine (152 mg), obtained in Example 2, followed by the addition, dropwise, of a 1 N aqueous solution of sodium hydroxide. The reaction mixture was stirred at room temperature for 90 minutes. After concentrating under reduced pressure, 1 N hydrochloric acid was added to the reaction mixture to make it slightly acidic. The colorless solid thus precipitated was collected by filtration and dried, whereby the title compound (62 mg, 42%) was obtained as a colorless solid. 1 H-NMR (DMSO -d6) delta: 2.65-5.30 (7H, m), 7.49 (4 / 5H, d, J = 7.7Hz), 7.56 (6 / 5H, d, J = 8.3Hz), 7.74 (1H, dd, J = 8.8.2.0Hz), 7.82 (1H, d, J = 8.3Hz), 7.95-8.05 (2H, m), 8.19 (1H, d, J = 8.3Hz), 8.20-8.35 (4H, m), 8.53 (1 H, s), 8.92 (2H, d, J = 5.4Hz). MS (FAB) m / z: 536 [(M + H) +, CI35], 538 [(M + H) +, CI37]. Calculated: C, 54.92; H, 4.32; N, 7.12; Cl, 11.41; S, 5.43. Found: C 54.94; H, 4.42; N, 6.83; Cl, 11.31; S, 5.33.

EXAMPLE 4 1-f 6-Chloronaphthalen-2-yl) sulfonyl-4-f4- (pyridin-4-Dnicotinylpiperazine hydrochloride 6- (4-Pyridyl) nicotinic acid hydrochloride (96 mg) and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetate (150 mg) were suspended in dichloromethane (10 ml), followed by the addition of 1-hydroxybenzotriazole (48 mg) and N-methylmorpholine (155 μl). After the addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (102 mg) under ice-cooling, the resulting mixture was stirred at room temperature for 16 hours. Due to the slow reaction, N, N-dimethylformamide (10 ml) was added to the reaction mixture and the resulting mixture was stirred for 3 days. After finishing the reaction, the solvent was removed by distillation. The residue was purified by chromatography on a column of silica gel (1% methanol-dichloromethane). The solvent was removed by distillation. To the residue was added tetrahydrofuran and 1 N ethanolic hydrochloric acid, and the solid thus precipitated was collected by filtration and dried, whereby the title compound (105 mg, 55%) was obtained as a colorless solid. 1 H-NMR (DMSO -d6) delta: 3.00-3.25 (4H, m), 3.46 (2H, br s), 7. 74 (1 H, dd, J = 8.5,1.7 Hz), 7.83 (1 H, d, J = 8.8 Hz), 8.07 (1 H, dd, J = 7.8,1.5 Hz), 8.19 (1 H, d, J = 8.8 Hz), 8.28 (1 H, s), 8.29 (1 H, d, J = 8.8 Hz), 8.42 (1 H, d, J = 8.3 Hz), 8.51 (1 H, s), 8.65 ( 2H, d, j) = 6.4Hz), 8.80 (1H, m), 9.01 (2H, d, J = 5.9Hz). MS (FAB) m / z: 493 [(M + H) +, CI35], 495 [(M + H) +, CI37]. Elemental analysis for C25H21 N4O3CIS. Calculated: C, 54.85; H, 4.42; N, 10.23; Cl, 12.95; S, 5.86. Found: C, 54.57; H. 4.51; N, 10.06; Cl, 13.08; s, 5.87.

EXAMPLE 5 1 -r (6-Chloronaphthalen-2-yl) sulfonin-4-r4- (pyridin-3-p-benzoylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (3-pyridyl) benzoic acid hydrochloride and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetate were used as starting materials , whereby the title compound was obtained as a colorless solid. 1 H-NMR (DMSO -d6) delta: 3.00-3.25 (4H, m), 3.47 (2H, br s), 3. 73 (2H, br s), 7.51 (2H, d, J = 8.3Hz), 7.73 (1H, dd, J = 8.8.2.0Hz), 7.8-7.9 (3H, m), 7.92 (1H, dd , J = 7.8.5.4Hz), 8.19 (1H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.50 (1 H, s), 8.55-8.66 (1 H, m), 8.75 -8.85 (1 H, m), 9.14 (1 H, d, J = 2.0 Hz); MS (FAB) m / z: 492 [(M + H) +, CI35], 494 [(M + H) +, CI37]. Elemental analysis for C26H22N3 ° 3CIS 0-85 CI 2 ° Calculated: C, 57.72; H, 4.63; N, 7.77; Cl, 12.12; S, 5.93. Found: C, 57.44; H, 4.62; N, 7.68; Cl, 11.99; S, 5.83.

EXAMPLE 6 N-oxide of 4-r4-IT4-r (6-chloronaphthalen-2-yl) sulfonyl-piperazin-1-illcarboniphenylpyrydine 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine (300 mg), obtained in Example 1, was dissolved in dichloromethane (10 ml) , followed by the addition of 3-chloroperbenzoic acid (382 g) at -20 ° C. The resulting mixture was stirred at -20 ° C for 21 hours. An aqueous solution of sodium sulfite was added to decompose the excess peroxide. Dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to separate an organic layer. After drying the organic layer over anhydrous magnesium sulfate, the residue, obtained by removing the solvent by distillation, was purified by chromatography on a column of silica gel (2-5% methanol-dichloromethane). After removing the solvent by distillation, ether was added to the residue to solidify it, followed by collection by filtration, whereby the title compound (200 mg, 63%) was obtained as a colorless solid. 1 H-NMR (CDCl 3) delta: 2.90-3.40 (4H, m), 3.40-4.20 (4H, m), 7.43 (2H, d, J = 8.3Hz), 7.47 (2H, d, J = 7.3Hz) , 7.55-7.65 (3H, m), 7.76 (1H, dd, J = 8.8,1.5Hz), 7.90-8.00 (3H, m), 8.26 (2H, d, J = 7.3Hz), 8.31 (1H, s). MS (FAB) m / z: 508 [(M + H) +, CI35], 510 [(M + H) +, CI37]. Elemental analysis for C26H22N3 ° 4CIS.O.8H2? Calculated: C, 59.78; H, 4.55; N, 8.04; Cl, 6.79; S, 6.14. Found: C, 59.82; H, 4.45; N, 7.94; Cl, 6.85; S, 6.29.

EXAMPLE 7 1-r4- (2-Aminopyridin-5-yl) benzoin-4-f (6-chloronaphthalen-2-Psulphonylpiperazine hydrochloride In a mixed solvent of dichloromethane (1 ml) and ethanol (1 ml), 1- [4- [2-tert-butoxycarbonylamino) pyridin-5-yl) benzoyl] -4 - [(6-chloronaphthalene-2- il) sulfonyl] piperazine (128 mg), followed by the addition of a saturated solution of hydrochloric acid in ethanol (10 ml) under ice-cooling. After stirring at room temperature for 1 minute, the solvent was removed by distillation. Isopropanol was added to the residue for crystallization. The crystals thus obtained were collected by filtration and dried, whereby the title compound (88 mg, 68%) was obtained as a colorless solid. H-NMR (DMSO -d6) delta: 3.00-3.20 (4H, m), 3.30-3.90 (4H, m), 7.05 (1 / 2H, d, J = 8.8Hz), 7.06 (1 / 2H, d, J = 8.8Hz), 7.43 (2H, d, J = 8.3Hz), 7.67 (2H, d, J = 8.3Hz), 7.73 (1 H, d, J = 8.3Hz), 7.82 (1 H, d, J = 8.8Hz), 7.90-8.10 (2H, br), 8.18 (1H, d, J = 8.3Hz), 8.25-8.35 (4H, m), 8.50 (1H, s). MS (FAB) m / z: 507 [(M + H) +, CI35], 509 [(M + H) +, CI37]. Elemental analysis for C26H23CIN4O3S.HCI. 1.2H2O.O.8¡PrOH Calculated: C, 55.56; H, 5.52; N, 9.13; Cl, 11.55; S, 5.22. Found: C, 55.40; H, 5.24; N, 8.85; Cl, 11.79; S, 5.50.

EXAMPLE 8 1-r4- (4-amnofenyl) benzop-4 - [(6-chloronaphthalen-2-ylsulfon-piperazine) hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1- [4- [4- (tert-butoxycarbonylamino) phenyl] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as the starting material, whereby the title compound was obtained as a colorless solid. 1 H-NMR (DMSO -d6) delta: 2.90-3.20 (4H, m), 3.25-3.80 (4H, m), 6. 68 (2H, d, J = 8.3Hz), 7.32 (2H, d, J = 8.3Hz), 7.39 (2H, d, J = 8.3Hz), 7.54 (2H, d, J = 8.3Hz), 7.73 ( 1H, dd, J = 8.8.2.0Hz), 7.82 (1H, dd, J = 8.8.2.0Hz), 8.18 (1H, dd, J = 8.8Hz), 8.25-8.40 (2H, m), 8.50 (1 H, br s). MS (FAB) m / z: 506 [(M + H) +, LC35], 508 [(M + H) +, CI37]. Elemental analysis for C27H24CIN3O3S.O.2HCI Calculated: C, 63.18; H, 4.75; N, 8.19; Cl, 8.29; EM, 6.25. Found: C, 62.93; H, 4.93; N, 7.91; Cl, 7.99; S, 6.36.

EXAMPLE 9 1-r4- (2-aminothiazol-4-yl) benzoyl l-4-r (6-chloronaphthalen-2-dsulfonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (2-aminothiazol-4-yl) benzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials , whereby the title compound was obtained. 1 H-NMR (DMSO-dβ) delta: 2.90-3.20 (4H, m), 3.30-3.90 (4h, m), 7. 26 (1 H, s), 7.41 (2 H, d, J = 8.3 Hz), 7.73 (1 H, dd, J = 8.8.2.0 Hz), 7.79 (2 H, d, J = 8.3 Hz), 7.82 (1 H, dd, J = 8.8.2.0Hz), 8.18 (1H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.50 (1 H.br s).

MS (FAB) m / z: 513 [(M + H) +, CI35], 515 [(M + H) +, CI37]. Elemental analysis for C24H21 N4O3CIS2.HCI.O.3H2O Calculated: C, 51.95; H. 4.1 1; N, 10.10; Cl, 12.78; S, 1 1.56. Found: C, 51.99; H, 4.19; N, 10.03; Cl, 12.61; S, 1 1.45.

EXAMPLE 10 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r4-fimidazol-4 (5) -I-l-benzoylpiperazine hydrochloride 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4- [4- [1 -triphenylmethylimidazol-4 (5) -yl] benzoyl] piperazine (303 mg) was dissolved in dichloromethane (5 ml), followed by the addition of a saturated solution of hydrochloric acid in ethanol (30 ml) under cooling with ice. After stirring at room temperature for 3 hours, the solvent was removed by distillation. Ether was added to the residue to crystallize and the resulting crystals were collected by filtration, whereby the title compound was obtained as a colorless solid (307 mg, 76%). 1 H-NMR (DMSO -d6) delta: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m), 7. 47 (2H, d, J = 8.3Hz), 7.74 (1H, dd, J = 8.8.2.0Hz), 7.82 (1H, dd, J = 8.8.2.0Hz), 7.89 (2H, d, J = 8.3Hz), 8.19 (1H, d, J = 8.8Hz), 8.22 (1H, d, J = 1.0Hz), 8.25-8.30 (2H, m), 8.50 (1H, m), 9.22 (1 H, d, J = 1.0Hz).

MS (FAB) m / z: 481 [(M + H) +, CI35], 483 [(M + H) +, CI37]. Elemental analysis for C24H21 CIN4O3S.HCI.O.4H2O Calculated: C, 54.94; H, 4.38; N, 10.68; Cl, 13.52; S, 6.1 1. Found: C, 54.98; H, 4.29; N, 10.62; Cl, 13.56; S, 6.14.

EXAMPLE 11 1-r4- (2-Aminoimidazol-4-yl) benzoyl-4-r 6-chloronaphthalen-2-Psulphonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (2-aminoimidazol-4-yl) benzoic acid hydrochloride and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as the starting materials, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m), 7. 39 (2H, d, J = 8.3Hz), 7.47 (1H, s), 7.49 (2H, br s), 7.67 (2H, d, J = 8.3Hz), 7.73 (1H, dd.J = 8.8 , 2.5Hz), 7-82 (1H, dd, J = 8.8.2.OHz), 8.18 (1H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.50 (1H br s). MS (FAB) m / z: 496 [(M + H) +, CI35], 498 [(M + H) +, CI37]. Elemental analysis for C24H22N5O3CIS.HCI Calculated: C.54.14; H, 4.35; N, 13.15; Cl, 13.32; S, 6.02.

Found: C, 53.94; H, 4.39; N, 12.82; Cl, 13.27; S, 6.07.

EXAMPLE 12 4-r4-rr4-f (6-chloronaphthalen-2-yl) sulfonyl-piperazin-1-ylcarbonyl-phenyl-1-methylpyridinium iodide In a mixed solvent of benzene (10 ml) and methanol (10 ml), 1 - [(6-chloronaphthalen-2-yl) -4- [4- (pyridin-4-yl) benzoyl] piperazine was dissolved at room temperature. (300 mg) obtained in Example 1, followed by the addition of methyl iodide (1 ml). To the resulting mixture, the same amount of methyl iodide was added three times at 24 hour intervals, followed by heating at reflux for 4 days. The reaction mixture was distilled under reduced pressure and the residue was washed with methanol, collected by filtration and dried, whereby the title compound was obtained as a yellow solid (229 mg, 58%). H-NMR (DMSO -d6) delta: 3.03 (2H, br s), 3.13 (2H, br s), 3.43 (2H, br s), 3.75 (2H, br s), 4.34 (3H, s), 7.59 (2H, d, J = 8.8Hz), 7.74 (1H, dd, J = 8.8Hz), 7.85 (1 H, dd, J = 8.8.2.OHz), 8.08 (2H, d, J = 8.8Hz), 8.19 (1H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.45-8.55 (3H, m), 9.03 (2H, d, J = 6.8Hz). Elemental analysis for C27H25N3O3CIIS.H2O Calculated: C, 49.74; H, 4.17; N, 6.45. Found: C, 49.60; H, 4.09; N, 6.23.

EXAMPLE 13 N-Oxide of 3-r4-rr4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazin-1-illcarboniphenyl-pyridine The reaction was carried out in a manner similar to Example 6, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine was used as the starting material, obtained in Example 6, whereby the title compound was obtained. 1 H-NMR (CDCl 3) delta: 2.90-3.40 (4H, m), 3-40-4.20 (4H, m), 7.50-7.60 (1 H, m), 7.40-7.45 (3H, m), 7.54 ( 2H, d, J = 8.3Hz), 7.60 (1 H, dd, J = 8.8.2.OHz), 7.76 (1 H, dd, J = 8.8.2.OHz), 7.90-8.00 (3H, m) , 8.22 (1 H, d, J = 5.9 Hz), 8.31 (1 H, d, J = 2.OHz), 8.43 (1H, br s). MS (FAB) m / z: 508 [(M + H) +, CI35], 510 [(M + h) +, CI37]. Elemental analysis for C26H22N3O4CIS.H2O Calculated: C, 59.37; H, 4.60; N, 7.99; Cl, 6.74; S, 6.10. Found: C, 59.48; H, 4.69; N, 7.74; Cl, 6.73; S, 6.07.

EXAMPLE 14 1 -f2-Carboxy-4- (pyridin-4-yl) benzoin-4-r (6-chloronaphthalen-2-dsulfonylpiperazine 1- [2-tert-Butoxycarbonyl-4- (pyridin-4-yl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (250 mg) in dichloromethane (50 ml) was dissolved. , followed by the dropwise addition of trifluoroacetic acid (50 ml) under ice-cooling. After stirring at room temperature for 5 hours, the solvent was removed by distillation. The residue was dissolved in methanol and the resulting solution was allowed to stand one day in a refrigerator. The colorless solid thus precipitated was collected by filtration and dried, whereby the title compound was obtained as a colorless solid (550 mg, 28%). 1 H-NMR (delta-DMSO): 2.90-3.40 (6H, m), 3.65-3.75 (2H, m), 7.41 (1 H, d, J = 7.8Hz), 7.70-7.75 (3H, m) , 7.82 (1 H, dd, J = 8.8.2.OHz), 8.00 (1 H, dd, J = 7.8.1.5Hz), 8.15-8.30 (4H, m), 8.50 (1 H, br s), 8.67 (2H, d, J = 5.9Hz), 13.29 (1 H, br s). MS (FAB) m / z: 536 [(M + H) +, CI35], 538 [(M + H) +, CI37]. Elemental analysis for C27H22CIN3O5S.O.5H2O Calculated: C, 59.50; H, 4.25; N, 7.71; Cl, 6.50; S, 5.88. Found: C, 59.54; H, 4.30; N, 7.37; Cl, 6.35; S, 5.89.

EXAMPLE 15 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-IT5- (pyridin-4-yl) thiophenyl-2-pcarbonylpiperazine hydrochloride The reaction was performed in a manner similar to Example 4, except that 5- (pyridin-4-yl) thiophene-2-carboxylic acid hydrochloride obtained in Reference Example 28, and 1 - [(6-chloronaphthalene hydrochloride -2-yl) sulfonyl] piperazine as the starting materials, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 3.11 (4H, s), 3.74 (4H, br s), 7.52 (1 H, d, J = 3.9 Hz), 7.73 (1 H, dd, J = 8.8.2.5 Hz), 7.83 (1 H, dd, J = 8.8.2.OHz), 8.03 (1 H, d, J = 3.9Hz), 8.10-8.15 (2H, m), 8.18 (1H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.51 (1H, s), 8.88 (2H, d, J = 6.8Hz). MS (FAB) m / z: 498 [(M + H) +, Cl 35], 500 [(M + H) +, Cl37]. Elemental analysis for C24H20CIN3O3S2.HCI.H2O Calculated: C, 52.17; H, 4.20; N, 7.61; Cl, 12.83; S, 11.61. Found: C, 52.04; H, 4.22; N, 7.22; Cl, 12.74; S, 11.57.

EXAMPLE 16 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-rr5- (pyridin-4-yl) furan-2-ylcarbonylpiperazine hydrochloride The reaction was performed in a manner similar to Example 4, except that 5- (pyridin-4-yl) furan-2-carboxylic acid hydrochloride, obtained in Reference Example 29, and 1 - [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine as starting materials, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 3.13 (4H, br s), 3.30-4.00 (4H, m), 7. 21 (1 H, d, J = 3.9 Hz), 7.71 (1 H, d, J = 8.8 Hz), 7.75-7.80 (1 H, m), 7.83 (1 H, d, J = 8.8 Hz), 8.10 -8.30 (5H, m), 8.51 (1 H, s), 8.85-8.90 (2H, m), MS (FAB) m / z: 482 [(M + H) +, CI35], 484 [(M + H) +, CI37]. Elemental analysis for C24H20CIN3O4S.HCI.H2O Calculated: C, 53.74; H, 4.32; N, 7.83; Cl, 13.22; S, 5.98. Found: C, 53.51; H, 4.36; N, 7.57; Cl, 13.21; S, 5.97.

EXAMPLE 17 1-r (6-chloronaphthalen-2-yl) sulfonyl-4-lT4- (pyridin-2-Obenzoylpiperazine hydrochloride The reaction was performed in a manner similar to Example 4, except that 4- (pyridin-2-yl) benzoic acid hydrochloride, obtained in Reference Example 30, and 1 - [(6-chloronaphthalene-2-hydrochloride il) sulfonyl] piperazine as starting materials, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 3.07 (4H, br), 3.60-4.00 (4H, br), 7.46 (3H, br), 7.73 (1 H, dd, J = 8.8.2.OHz), 7.82 81 H, dd, J = 8.8.2.OHz), 7.94-8.05 (2H, br), 8.08 (2H, d, J = 8.8 Hz), 8.18 (1 H, d, J = 8.8 Hz), 8.28 (2 H, d, J = 8.8 Hz), 8.50 (1 H, s), 8.70 (1 H, br). MS (FAb) m / z: 492 [(M + H) +, CI35, 494 [(M + H) +, CI37]. Elemental analysis for C26H22CIN3 ° 3S .O.9HCI.H2O Calculated: C, 57.53; H. 4.62; Cl, 12.41; N, 7.74; S, 5.91. Found: C, 57.55; H, 4.52; Cl, 12.64; N, 7.61; S, 6.03.

EXAMPLE 18 1-r (E) -4-Chloroestiryl sulfonin-4-f4- (pyridin-2-dihydrazylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 17, except that 4- (2-pyridyl) benzoic acid hydrochloride and 1 - [(E) -4-chlorostyrylsulfonyl] piperazine hydrochloride, which had been obtained, were used as starting materials. in Reference Example 31, whereby the title compound was obtained. 1 H-NMR (DMSO-de) delta: 3.19 (4H, br), 3.46 (2H, br), 3.75 (2H.br), 7.36 (1H, d, J = 15.6Hz), 7.44 (1H, d, J = 15.6Hz), 7.50-7.58 (1H, br), 8.13 (2H, m), 8.15 (2H, d, J = 7.8Hz), 8.75 (1H, d, J = 4.9Hz). MS (FAB) m / z: 468 [(M + H) +, CI35], 470 [(M + H) +, CI37]. Elemental analysis for C24H22CIN3O3S.HCI.O. 3EtOH.O.3H2O Calculated: C, 56.42 H, 4.89; Cl, 13.54; N, 8.02; S, 6.12. Found: C, 56.51 H, 4.83; Cl, 13.46; N, 8.10; S, 5.99.

EXAMPLE 19 N-oxide of 2-r4-rf4-r (6-chloronaphthalen-2-yl) sulfonylpiperazin-1-Qcarboniphenillpyridine The reaction was carried out in a manner similar to Example 6, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine, which was obtained in Example 17, as starting material, whereby the title compound was obtained. 1 H-NMR (CDCl 3) delta: 3.11 (4 H, br), 3.63 (2 H, br), 3.87 (2 H, br), 7.27 (1 H, m), 7.33 (1 H, t, J = 8.8 Hz) , 7.39-7.41 (1 Hbr), 7.40 (2H, d, J = 7.8Hz), 7.60 (1H, d, J = 8.8Hz), 7.77 (1H, d, J = 8.8Hz), 7.83 82H, d, J = 7.8 Hz), 7.93 (1 H, d, J = 3.8 Hz), 7.94 (1 H, s), 8.31 (1 H, s), 8.33 (1 H, d, J = 5.9 Hz). MS (FAB) m / z: 508 [(M + H) +, CI35], 510 [(M + H) +, CI37]. Elemental analysis for C26H22CIN3O4S Calculated: C, 61.47; H, 4.37; Cl, 6.98; N, 8.27; S, 6.31. Found: C, 61.32; H, 4.46; Cl, 7.21; N, 8.13; S, 6.02.

EXAMPLE 20 2-r4-rf4-r (6-chloronaphthalen-2-yl) sulfonylpiperazin-1-yl) carbonyl-1-phenyl-1-methylpyridinium iodide The reaction was carried out in a manner similar to Example 12, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-2-yl) benzoyl] piperazine, which had been obtained, was used. in Example 17, as starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-de) delta: 2.93-3.23 (4H, br), 3.54 (2H, br), 3.82 (2H, br), 4.30 (3H, s), 7.50 (2H, d, J = 8.8 Hz), 7.53 (1 H, m), 7.70 (2 H, d, J = 8.8 Hz), 7.70 (1 H, br), 7.84-7.92 (4 H, m), 8.15 (1 H, t, J = 6.8 Hz), 8.26 (1 H, s), 8.52 (1 H, t, J = 6.8 Hz), 9.29 (1 H, dJ = 5.9 Hz). Elemental analysis for C27H25CIIN3O3S.I.6H2O Calculated: C, 48.93; H, 4.29; N, 6.34. Found: C, 48.81; H, 4.06; N, 6.31.

EXAMPLE 21 1-F (6-Chloronaphthalen-2-yl) sulfonyl-4-r4- (2,4-diaminopyrimidin-6-yl) benzoyl] piperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (2,4-diamino-6-pyrimidyl) benzoic acid hydrochloride, obtained in Reference Example 32, and 1 - [(6-) hydrochloride were used. chloronaphthalen-2-yl) sulfonyl] piperazine as starting materials, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 3.14 (4H, br), 3.45 (2H, br s), 3.73 (2H, br s), 6.36 (1 H, s), 7.54 (2H, d, J = 7.8Hz), 7.74 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, d, J = 8.8Hz), 7.83 (1H, s), 7.84 (2H, d, J = 7.8Hz), 8.18 (1H, J = 8.8Hz), 8.18-8.35 (3H, br), 8.27 (1H , s), 8.28 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s), 12.64 (1 H.br s). MS (FAB) m / z: 523 [(M + H) +, CI35], 525 [(M + H) +, CI37]. Elemental analysis for C25H23CIN6O3S.HCI.I.4H2O Calculated: C, 51.36; H. 4.62; Cl, 12.13; N, 14.37; S, 5.48. Found: C, 51.38; H, 4.54; Cl, 12.24; N, 14.23; S, 5.55.

EXAMPLE 22 1 -r (E) -4-chlorostyril-sulfonyl-4-r4- (2,4-diaminopyrimidin-6-D-benzoylpiperazine hydrochloride The reaction was performed in a manner similar to Example 21, except that 4- (2,4-diamino-6-pyrimidyl) benzoic acid hydrochloride, obtained in Reference Example 33, and hydrochloride 1 - [(E) -4-chlorostyrylsulfonyl] piperazine, which had been obtained in Reference Example 31, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 3.18 (4H, br), 3.43 (2H, br), 3.76 (2H, br), 4.0 (2H, br), 6.37 (1H, s), 7.84 (2H , d, J = 15.6Hz), 7.44 (1 H, J = 15.6Hz), 7.53 (2H, d, J = 8.8Hz), 7.63 (2H, d, J = 8.8Hz), 7.82 (1H, d , J = 8.8 Hz), 7.88 (1 H, d, J = 8.8 Hz), 8.23 (1 H, br s), 8.32 (1 H, br s), 12.58 (1 H, br s). MS (FAb) m / z: 499 [(M + H) +, CI35, 501 [(M + H) +, CI37]. Elemental analysis for C23H23CIN6O3S.I.2HCI.I.4H2O Calculated: C, 48.64; H, 4.79; Cl, 13.73; N, 14.80; S, 5.65. Found: C, 48.46; H4.56; Cl, 13.53; N, 14.54; S, 5.72.

EXAMPLE 23 N-oxide of 2-r4-IT4- (E) -4-chlorostyrylsulfonippiperazin-1-yl) carbonylphenyl1pyridine The reaction was carried out in a manner similar to Example 1, except that 2- [4 - [(1-piperazyl) carbonyl] phenyl] pyridine N-oxide hydrochloride, obtained in Reference Example 35, was used as starting materials. and (E) -4-chlorostyrylsulfonyl chloride, whereby the title compound was obtained. H-NMR (CDCl 3) delta: 3.10-3.40 (4H, br), 3.66 (2H, br), 3.89 (2H, br), 6.65 (1H, d, J = 15.6Hz), 7.28 (1H, m), 7.34 (1H, t, J = 7.8Hz), 7.39-7.48 (6H, m), 7.50 (1 H, d, J = 7.8 Hz), 7.88 (2 H, d, J = 7.8 Hz), 8.34 (1 H, d, J = 5.9 Hz). MS (FD) m / z: 483 (M +, CI35), 485 (M +, CI37).

Elemental analysis for C24H22CIN3O4S.O.5H2O Calculated: C, 58.47; H, 4.70; Cl, 7.19; N, 8.52; S, 6.50. Found: C, 58.49; H, 4.80;, Cl, 7.29; N, 8.31; S, 6.34.

EXAMPLE 24 1-r (E) -4-chlorostyrylsulfonyl-p-4-r4- (pyridin-4-D-benzoylpiperazine hydrochloride Under cooling with ice, piperazine (727 mg) was dissolved in dichloromethane (10 ml), followed by portionwise addition of (E) -4-chlorostyrylsulfonyl chloride (500 mg). After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane (100 ml), washed with a saturated aqueous solution of sodium bicarbonate, an aqueous solution of citric acid, water, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was suspended in N, N-dimethylformamide (10 ml), followed by the addition of 4- (4-pyridyl) benzoic acid (420 mg), obtained in Reference Example 2, and N, N-dimethyl-4-aminopyridine (309 mg). Under cooling with ice, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidate hydrochloride (405 mg) was added thereto, and the resulting mixture was stirred at room temperature for 68 hours. After concentrating, the residue was purified by chromatography on a column of silica gel (dichloromethane: methanol = 70: 1). The colorless solid thus obtained was recrystallized from a mixed solvent of ethyl acetate and hexane, followed by recrystallization from ethyl acetate to obtain colorless needle crystals (185 mg). On the other hand, saturated hydrochloric acid-ethanol solution (4 ml) was added to the filtrate. After concentrating, the residue was recrystallized from methanol-ethyl acetate, whereby the title compound was obtained as colorless needle crystals (200 mg). 1 H-NMR (DMSO -d6) delta: 3.17 (2H, br s), 3.23 (2H, br s), 3.48 (2 H, br s), 3.77 (2 H, br s), 7.36 (1 H, d, J = 15.3Hz), 7.44 (1H, d, J = 15.3Hz), 7.53 (2H, d, J = 8.8Hz), 7.64 (2H, d, J = 8.3Hz), 7.82 (2H, d, J = 8.3Hz), 8.06 (2H, d, J = 8.8Hz), 8.32 (2H, d, J = 6.6Hz), 8.95 (2H, d, J = 6.6Hz). MS (FAB) m / z: 468 [(M + H) +, CI35], 470 [(M + H) +, CI37]. Elemental analysis for C23H22CIN3O3S.HCI.O.2H2O.O.22CH3CO2CH2CH3 Calculated: C, 56.66; H, 4.81; Cl, 13.44; N, 7.97; S, 6.08. Found: C, 56.68; H, 4.79; Cl, 13.43; N, 8.04; S, 6.14.

EXAMPLE 25 4-r4-IT4-r (E) -4-chlorostyrylsulfonylpiperazin-1 -Dcarboniphenyl] -1-methylpyridinium iodide The reaction was carried out in a manner similar to Example 12, except that 1 - [(E) -4-chlorostyrylsulfonyl] -4- [4- (pyridin-4-yl) benzoyl] piperazine, which was obtained in Example 1, was used. 24, as starting material, whereby the title compound was obtained. 1 H-NMR (delta-DMSO): 3.04-3.87 (8H, br), 4.35 (3H, s), 7.35 (1H, d, J = 15.6Hz), 7.44 (1H, d, J = 15.6 Hz), 7.53 (2H, d, J = 8.3Hz), 7.67 2H, d, J = 8.3Hz), 7.82 (2H, d, J = 8.8Hz), 8.13 (2H, d, J = 8.3Hz), 8.53 (2H, d, J = 6.8Hz), 9.05 (2H, d, J = 7.3Hz), Elemental analysis for C25H25CIIN3O3S.O.5H2O Calculated: C, 48.52; H, 4.23; N, 6.79. Found: C, 48.68; H, 4.13; N, 6.41.

EXAMPLE 26 N-oxide of 3-r4-fr4-f (E) -4-chlorostyrylsulfonylpiperazin-1-pcarbonylphenylpyridine After removing the protecting group as in the reaction in Example 7, the reaction was carried out with (E) -4-chlorostyrylsulfonyl chloride in a manner similar to Example 23, whereby the title compound was obtained.

H-NMR (CDCl 3) delta: 3.26 (4H, br), 3.52-4.00 (4H, br), 6.64 (1 H, d, J = 15.6Hz), 7.45-7.52 (7H, m), 7.52 (2H, d, J = 2.0Hz), 7.57 (2H, d, J = 2.0Hz), 8.22 (1H, dt, J = 6.3.1.6Hz), 8.44 (1 H, t, J = 1.6Hz). MS (FAB) m / z: 484 [(M + H) +, CI35], 486 [(M +, CI37].) Elemental analysis for C 24 H 22 CIN 3 O 3 S. O 5 H 2 O Calculated: C, 58.47; H, 4.70; Cl, 7.19; N, 8.52; S, 6.50, Found: C, 58.49; H, 4.66; Cl, 7.40; N, 8.54; S, 6.56.

EXAMPLE 27 1-((E) -4-chlorostyrylsulfonyl-1-4-r4- (pyridin-3-Q-benzoylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 17, except that 4- (3-pyridyl) benzoic acid hydrochloride, obtained in Reference Example 8, and 1 - [(E) -4 hydrochloride were used as starting materials. -chlorostyrylsulfonyl] piperazine, obtained in Reference Example 31, whereby the title compound was obtained. H-NMR (DMSO-d6) delta: 3.08-3.29 (4H, br), 3.42-3.85 (4H, br), 7. 35 (1 H, d, J = 15.6Hz), 7.43 (1 H, d, J = 15.6Hz), 7.52 (2H, d, J = 8.3hz), 7.59 ((2H, d, J = 8.3Hz) , 7.80-7.93 (5H, m), 8.54 (1 H, d, J = 6.8 Hz), 8.78 (1 H, d, J = 4.5 Hz), 9.13 (1 H, d, J = 2.OHz).

MS (FAB) m / z): 468 [(M + H) +, CI35], 470 [(M + H) +, CI37]. Elemental analysis for C24H22CIN3O3S.HCI.I.3H2O Calculated: C, 54.61; H. 4.89; N, 7.96; Cl, 13.43; S, 6.07. Found: C, 54.82; H, 4.80; N, 7.91; Cl, 13.14; S, 6.14.

EXAMPLE 28 3-r4-rf4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazin-1-illcarboniphenyl-1-methylpyridinium iodide The reaction was carried out in a manner similar to Example 12, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (pyridin-3-yl) benzoyl] piperazine was used as the starting material, obtained in Example 5, whereby the title compound was obtained. 1 H-NMR (DMSO-de) delta: 2.50-3.80 (8H, m), 4.44 (3H, s), 7.57. (2H, d, J = 8.3Hz), 7.74 (1H, dd, J = 8.8.2.OHz), 7.84 (1H, dd, J = 8.8.1 .5Hz), 7.94 (2H, d, J = 8.3Hz), 8.10-8.30 (4h, m), 8.51 (1 H, s), 8.90 (1 H, d, J = 7.8H = 7.8Hz), 9.01 (1 H, d, J = 5.9Hz) , 9.45 (1 H, s). MS (FAB) m / z: 506 [(M + H) +, CI35], 508 [(M + H) +, CI37].

EXAMPLE 29 1-R (6-Chloronaphthalen-2-yl) sulfonyl-1-4- [2-hydroxy-4- (pyridin-4-D-benzoylpiperazine hydrochloride The reaction was performed in a manner similar to Example 4, except that 2- (hydroxy-4- (4-pyridyl)) benzoic acid, obtained in Reference Example 38, and 1 - [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. H-NMR (DMSO -d6) delta: 2.90-3.40 (8H, m), 7.25-7.40 (3H, m), 7. 70-7.80 (1 H, m), 7.80-7.90 (1 H, m), 8.15-8.25 (3H, m), 8.25-8.35 (2H, m), 8.50-8.60 (1 H, m), 8.91 ( 2H, d, J = 6.4Hz), 10.41 (1h, br s). MS (FAB) m / z: 535 [(M + H) +, CI35], 537 [(M + H) +, CI37]. Elemental analysis for C26H22CIN3 ° 4S .I.IHCI.I.7H2O Calculated: C, 53.96; H, 4.62; N, 7.26; Cl, 12.86; S, 5.54. Found: C, 53.62; H, 4.58; N, 7.34; Cl, 13.10; S, 5.94.

EXAMPLE 30 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r3-methoxy-4- (pyridin-4-D-benzoylpiperazine hydrochloride The reaction was performed in a manner similar to Example 4, except that 3-methoxy-4- (4-pyridyl) benzoic acid, obtained in Reference Example 41, and 1 - [(6-) hydrochloride were used as starting materials. chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d 6) d: 3: 00-4.00 (8H, m), 3.81 (3H, S), 7.08 (1 h, d, J = 8.8Hz), 7.17 (1 H, s), 7.55 ( 1 H, d, J = 8.8 Hz), 7.74 (1 H, dd, J = 8.8, 2.0 Hz), 7.83 (H, d, J = 8.3 Hz), 8.04 (2 H, d, J = 6.3 Hz) , 8.19 (1 H, d, J = 8.8 Hz), 8.25-8.30 (2 H, m), 8.52 (1 H, s), (.85 (2 H, d, J = 6.3 Hz) EM (FAB) m / z: 522 [(M + H) Cl 35], 524 [(M + H) +, Cl 37] Elemental analysis for C 27 H 24 CIN 3 O 4 S 0 8 HCl 1. 7 H 2 O Calculated: C, 55.74; H, 4.89; N, 7.22; Cl, 10.97; S, 5.51, Found: C, 55.59; H, 4.90; N, 7.23; Cl, 10.90; S, 5.52.

EXAMPLE 31 1 -r (6-Chloronaphthalen-2-yl) sulfonin-4- [3-hydroxy-4- (pyridyl-4-ylbenzoylpiperazine hydrochloride Boron tribromide (115 μl) was dissolved in dichloromethane (1 ml), followed by dropwise addition of a solution of 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-methoxy-4-] (pyridin-4-yl) benzoylpiperazine (105 mg), obtained in Example 30, in dichloromethane (dichloromethane: 4 ml), at an external temperature of about -78 ° C. While gradually warming to room temperature, the resulting mixture was stirred for 23 hours. After adding dichloromethane and water to the reaction mixture, the resulting mixture was stirred for a moment and sodium bicarbonate was added to make it alkaline, whereby an organic and an aqueous layer were separated. From the aqueous layer, another organic layer was extracted with dichloromethane. These organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ 3% methanol-dichloromethane). The crude purified product thus obtained was dissolved in tetrahydrofuran. Ethanolic hydrochloric acid was added to the resulting solution to solidify. The resulting solid was collected by filtration and then dissolved in a mixed solvent of water and methanol. After removing the insoluble matter by filtration, the filtrate was distilled under reduced pressure, whereby the title compound (36 mg, 30%) was obtained. 1 H NMR (DMSO-d6) d: 3.00-3.80 (8H, m), 6.85-6.95 (1 H, m), 7.01 (1 H, d, J = 1.4Hz), 7.49 (1 H, d, J = 8.8Hz), 7.72 (1H, dd, J = 8, 8.2, Ohz), 7.81 (1H, dd, J = 8.5, 1.7Hz), 7.94 (2H, d, J = 6.4Hz), 8.19 (1 H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.51 (1 H, s), 8.75 (2H, d, J = 5.9Hz), 10.67 (1 H, s) ,. MS (FAB) m / z: 508 [(M + H) +, Cl 35, 510 [(M + H) 35, Cl37].

EXAMPLE 32 1-r (6-Chloronaphthalen-2-yl) sulfonyl-2-ethoxycarbonyl-4-r4- (pyridin-4-ylbenzoylpiperazine The protecting group was removed in a reaction similar to Example 7, except that 4-tert-butoxycarbonyl-1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine was used as the starting material. Then, the residue was reacted with 4- (4-pyridyl) benzoic acid hydrochloride as in Example 4, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 0.80-1.10 (3H, m), 3.00-4.00 (8H, m), 4.60-4.80 (iH, m), 7.42 (2H, d, J = 7.8 Hz), 7.47 ( 2H, d, J = 5.9Hz), 7.50-7.60 (1H, m), 7.64 (2H, d, J = 8.3Hz), 7.70-7.80 (1H, m), 7.85-7.95 (3H, m) , 8.33 (1 H, s), 8.69 (2H, s). MS (FAB) m / z: 564 [(m + H) +, Cl 35, 566 [(M + H) 35, Cl37] Elemental analysis for C 29 H 26 CIN 3 O 5 S 0 3H 2 O Calc'd: C, 60.78; H, 4.70; N, 7.33; Cl, 6.80; S, 5.60. Found: C, 60.84; H, 4.84; N, 6.98; Cl, 7.03; S, 5.70.

EXAMPLE 33 1-f (6-Chloronaphthalen-2-yl) sulfonin-4-r4- (pyridin-4-yl) benzoyl-piperazine-2-carboxylic acid The title compound was obtained in a manner similar to Example 3, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-4- [4- (pyridin-4-yl) benzoyl] was used. piperazine as starting material. 1 H NMR (DMSO-d6) d: 2.70-5.00 (7H, m), 7.40-7.50 (2H, m), 7.65-7-7-5 (2H.m), 7.85-8.25 (8H, m), 8.50 -8.60 (2H, m), 8.80-8.95 (2H, m). MS (FAB) m / z: 536 [(M + H) Cl 35], 538 [(M + H) +, Cl37] Elemental analysis for C 27 H 22 CIN 3 O 5 S 0 3 HCl 1. H 2 O Calculated: C, 57.40; H, 4.34; N, 7.44; Cl, 8.16; S, 5.68. Found: C, 57.16; H, 4.35; N, 7.36; Cl, 7.92; S, 6.08.

EXAMPLE 34 4-r (6-Coronaphthalen-2-yl) sulfonyl-1-2-ethoxycarbonyl-1-r4- (pyridin-3-Q-benzoylpiperazine The reaction was carried out in a manner similar to Example 2, whereby the title compound was obtained. 1 H NMR (CDCl 3) d: 1.15-1.30 (3H, m), 2.60-4.60 (8H, m), 5.33 (1 H, br), 7.40-7.55 (3H, m), 7.70-7.85 (4H, m) , 8.05 + 8.10 (1 H, m), 8.19 (1 H, d, J = 8.8 Hz), 8.25-8.30 (2H, m), 8.50-8.65 (2H, m), 8.91 (1 H, s). MS (FAB) m / z: 564 [(M + H) +, Cl 35], 566 [(M + H)? Cl37]. Elemental analysis for C29H26CIN3O5S 0 1 HCl 1. 5H2O Calculated: C, 60.40; H, 4.74; N, 7.29; Cl, 6.76, S, 5.56. Found: C, 60.67; H, 4.61; N, 7.30; Cl, 6.89; S, 5.51.

EXAMPLE 35 2-Carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl-1-y4- (pyridin-3-d-benzoylpiperazine hydrochloride In a manner similar to Example 3, with 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1- [4-pyridin-3-yl) benzoyl] piperazine (426 mg) as starting material, a crude product was obtained by hydrolysis of the ester, followed by suspension in N, N-dimethylformamide (35 ml). Under cooling with ice, di-tert-butyl dicarbonate (646 mg), pyridine (370 μl) and ammonium bicarbonate (196 mg) were added to the resulting solution. The resulting mixture was stirred at room temperature for 19 hours. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (4% methanol-dichloromethane) and the eluted fraction was dissolved in tetrahydrofuran. Ethanolic hydrochloric acid was added to the resulting solution to solidify. The resulting solid was collected by filtration and dissolved in a mixed solvent of water and methanol. The insoluble material was removed by filtration and the filtrate was distilled under reduced pressure, whereby the title compound was obtained (302 mg, 65%). 1 H NMR (DMSO-d 6) d: 2.30-4.50 (6H, m), 5.08 (1 H, br), 7.40-7.60 (2H, m), 7.65-7.85 (3H, m), 7.92 (2H, d, J = 7.8Hz), 8.00-8.10 (1H, m), 8.20 (2H, d, J = 8.8Hz), 8.25-8.35 (2H, m) 8.49 (1 H, s), 8.80 (1 H, d , J = 7.8 Hz), 8.88 (1 H, d, J = 5.4 Hz), 9.25 (1 H, s). MS (FAB) m / z: 508 [(M + H) +, Cl 35], 537 [(M + H)? Cl37]. Elemental analysis for C27H23CIN4O4S 1 1 HCl 1. 7H2O Calculated: C, 53.54; H, 4.58; N, 9.25; Cl, 12.29; S, 5.29. Found: C, 53.36; H, 4.71; N, 9.07; Cl, 12.17; S, 5.50.

EXAMPLE 36 2-Carbamoyl-4-f (6-chloronaphthalen-2-yl) sulfonyl-1-r4- (pyridin-4-di-benzoMI-piperazine hydrochloride The title compound was obtained in a manner similar to Example , except that 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1- [4- (pyridin-4-yl) benzoyl] pperazine was used as the starting material. 1 H NMR (DMSO -d6) d: 2.30-2.70 (2H, m), 3.20-3.80 (2H, m), 4. 10-4.50 (2H, m), 5.07 (1 H, br, s), 7.40-7.55 (2H, m), 7.60-7.65 (1 H, m), 7.67 (1 H, s), 7.72 (1 H , dd, J = 8.8, 2.4Jz), 7.78 (1H, dd, J = 8.8, 2.4Hz), 8.4 (2H, d, J = 8. 8Hz), 8.20 (1 H, d, J = 8.8Hz), 8.25-8.35 (4H, m), 8.49 (1 H, s), 8.95 (2H, d, J = 5.4Hz). MS (FAB) m / z: 535 [(M + H) +, Cl 35], 537 [(M + H)? Cl37]. Elemental analysis for C27H23CIN4O4S 0 HCl 1. 8H2O Calculated: C, 53.70; H, 4.61; N, 9.28; Cl, 11.74; S, 5.31. Found: C, 53.87; H, 4.40; N, 8.89; Cl, 11.81; S, 5.23.

EXAMPLE 37 N-oxide of 4-f4-ff2-carbamoyl-4-f (6-chloronaphthalen-2-yl) sulfonylpiperazin-1-illcarboniphenillpyridine The reaction was carried out in a manner similar to Example 7, except that 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1- [4-pyridin-4-yl] benzoyl] piperazine was used as the material starting, with which the title compound was obtained. 1 H NMR (DMSO-d 6) d: 2.30-4.50 (6H, m), 5.04 (1 H, br), 7.30-7.90 (10H, m), 8.10-8.30 (5H, m), 8.48 (1H, s) ). MS (FAB) m / z: 551 [(M + H) +, Cl 35], 553 [(M + H) 35, Cl37]. Elemental analysis for C27H23CIN4O5S 0 8H2O Calculated: C, 57.35; H, 4.39; N, 9.91; Cl, 6.27; S, 5.67. Found: C, 57.64; H, 4.50; N, 9.48; Cl, 6.37; S, 5.71.

EXAMPLE 38 N-oxide of 4-r4-rr4-r (6-chloronaphthalen-2-yl) sulfonin-2-ethoxycarbonylpiperazin-1 -Mlcarbonylpheniripyridine The reaction was carried out in a manner similar to Example 37, whereby the title compound was obtained. 1 H NMR (CDCl 3) d: 1.30-1.40 (3H, m), 2.30-4.70 (8H, m), 5.47 (1 H, br, s), 7.40-7.80 (8H, m), 7.92 (1 H , s), 7.94 (2H, s), 8.26 (2H, d, 6.8Hz), 8.48 (1H, s). MS (FAB) m / z: 580 [(M + H)? Cl35], 582 [(M + H) +, Cl37] Elemental Analysis for C29H26CIN3O6S 1 3H2O Calculated: C, 57.72; H, 4.78; N, 6.96; Cl, 5.87; S, 5.31. Found: C, 57.99; H, 4.75; N, 6.56; Cl, 5.98; S, 5.43.

EXAMPLE 39 N-oxide of 4-r4-IT2-carboxy-4-r (6-chloronaphthalen-2-iDsulfonippiperazin-1-illcarbonylphenylpyridine) The reaction was carried out in a manner similar to Example 3, whereby the title compound was obtained. 1 H NMR (CDCl 3) d: 2.30-4.50 (6H, m), 5.22 (1 H, br, s), 7.35-7.50 (2H, m), 7.70-7.90 (6H, m), 8.19 (1 H, d , J = 8.8Hz), 8.25-8.30 (4H, m), 8.53 (1H, s), 13.42 (1H, br). Elemental analysis for C27H22CIN3O6S 0 2HCI 1. 7H2O Calculated: C, 54.97; H, 4.37; N, 7.12; Cl, 7.21; S, 5.44. Found: C, 55.07; H, 4.40; N, 6.82; Cl, 7.16; S, 5.47.

EXAMPLE 40 2-Carbamoyl-4 - [(E) -4-chlorostyrylsulfonyl-1 - [4- (pyridin-4-Q-benzoylpiperazine hydrochloride and 2-carbamoyl-4-IT2- hydrochloride -chlorophenyl) -2- ethoxy-ethylsulfonin-1-f4- (pyridin-4-yl) benzo-piperazine The reaction was carried out in a manner similar to Example 2 and 35, whereby the title compounds were obtained respectively. 2-Carbamoyl-4 - [(E) -4-chlorostyril sulfonyl] - [1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride: 1 H NMR (CD3OD) d: 2.80-4.80 ( 6H, m), 5.32 (1H, br), 7.04 (1H, d, J = 15.6Hz), 7.40-7.50) 3H, m), 7.60-7.80 (4H, m), 7.95-8.05 (2H, m), 8.20 (2H, br), 8.81 (2H, br). MS (FAB) m / z: 51 1 [(M + H) +, Cl 35], 513 [(M + H) 35, Cl 37]. Elemental analysis for C25H23CIN4O4S 0 9HCI 1. 8H2O Calculated: C, 52.1 1; H, 4.81; N, 9.72; Cl, 1 1.69. Found: C, 52.28; H, 4.83; N, 9.44; Cl, 1 1.51 2-Carbamoyl-4 - [[2- (4-chlorophenyl) -2-ethoxyethyl] sulfonyl] - [1- [4- (pyridin-4-yl) benzoyl] piperazine hydrochloride: 1 H NMR (CD3OD) ) d: 1.10-1.20 (3H, m), 2.95-4.70 (6H, m), 5.34 (1H, br), 7.38 (4H, s), 7.65-7.85 (2H, m), 8.05-8.15 (2H , m), 8.40-8.50 (2H, m), 8.91 (2H, d, J = 5.9Hz), MS (FAB) m / z: 557 (M + H) \ Cl35], 559 [(M + H) 35, Cl37] Elemental analysis for C27H29CIN4O5S 0 HCl 2. 5H2O Calculated: C, 50.78; H, 5.52; N, 8.77; Cl, 11.10; S, 5.02. Found: C, 50.61; H, 5.38; N, 8.68; Cl, 11.27; S, 5.07.

EXAMPLE 41 1-Transrans-4- (aminomethyl) cyclohexylmethyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, whereby the title compound was obtained. 1 H NMR (DMSO-d 6) d: 0.80-1.00 (4H, m), 1.48 (1 H, m), 1.60-1.90 (5H, m), 2.60 (2H, m), 2.90-3.10 (4H, m) , 3.14 (2H, m), 3.52 (2H, m), 3.77 (2H, m), 7.75 (1H, dd, J = 8.8-2.0Hz), 7.85 (1H, d, J = 8.8Hz), 7.99 (3H, br), 8.21 (1 H, d, J = 8.8 Hz), 8.30-8.40 (2H, m), 8.56 (1 H, s), 10.46 (1 H, br). MS (FAB) m / z: 436 (M + H) +, Cl 35], 438 [(M + H) +, Cl37]. Elemental analysis for C22H3OCIN3O2S 0 2HCI 3 / 4H2O Calculated: C, 50.58; H, 6.46; N, 8.04; Cl, 20.36; S, 6.14. Found: C, 50.74; H, 6.48; N, 7.76; Cl, 20.09; S, 6.19.

EXAMPLE 42 1-Frans-4- (amnomethyl) cyclohexylcarbonyl-4-f (6-chloronaphthalen-2-yl) sulfonyl-1-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) -cyclohexylcarbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] was used. piperazine as starting material. 1 H NMR (DMSO-d 6) d: 0.90-1.00 (2H, m), 1.20-1.40 (2H, m), 1.48 (1 H, m), 1.50-1.70 (2H, m), 1.70-1.90 (2H, m), 2.44 (1 H, m), 2.59 (2H, m), 2.96 (4H, m), 3.55 (4H, m), 7.72 (1 H, dd, J = 8.8, 2.0Hz), 7.81 (1 H, d, J = 8.3HZ), 7.90 (3H, br), 8.16 (1H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.49 (1H, s). MS (FAB) m / z: 450 [(M + H) Cl 35], 452 [(M + H) 35, Cl37]. Elemental analysis for C22H28CIN3O3S 0 9HCI 1. 5H2O Calculated: C, 51.83; H, 6.31; N, 8.24; Cl, 13.21; S, 6.29. Found: C, 51.63; H, 6.22; N, 7.97; Cl, 13.32; S, 6.17.

EXAMPLE 43 1-rN-rtrans-4- (aminomethyl) cyclohexylcarbonylphenylcyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine hydrochloride The reaction was performed in a manner similar to Example 7, except that 1- [N- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] glycyl]] - 4 - [(6-chloronaphthalen-2-yl) was used. sulfonyl] piperazine as starting material, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 0.80-1.00 (2H, m), 1.20-1.40 (2H, m), 1. 50 (1 H, m), 1.60-1.80 (4H, m), 2.62 (2H, m), 2.90-3.10 (4H, m), 3.40-3.60 (4H, m), 3.83 (2H, d, J = 5.4Hz), 7.70-7.90 (3H, m), 7.93 (3H, br), 8.17 (1H, d, J = 8.3Hz), 8.20-8.30 (2H, m), 8.49 (1H, s). MS (FAB) m / z: 507 [(MH) \ Cl35], 509 [(M + H) 35, Cl37]. Elemental analysis for C 24 H 3iCIN 4 O 4 S Calculated HCl: C, 53.04; H, 5.93; N, 10.31; Cl, 13.05; S, 5.90. Found: C, 52.90; H, 5.98; N, 10.29 Cl, 12.98; S, 5.91.

EXAMPLE 44 1-rtrans-4- (aminomethyl) -cyclohexylcarbonyl-4-IY6-chloronaphthalen-2-yl) sulfonyl-homopiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [trans-4- (N-tert-butoxycarbonylaminomethyl) cyclohexylcarbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine was used as the departure. 1 H NMR (DMSO-d6) d: 0.90-1.10 (2H, m), 1.30-1.50 (2H, m), 1.50-1.90 (7H, m), 2.40-2.80 (3H, m), 3.20-3.70 (8H , m), 7.60-7.70 (1 H, m), 7.80-8.00 (4H, m), 8.10-8.20 (1 H, m), 8.20-8.30 (2H, m), 8.52 and 8.53 (1 H, each s). MS (FAB) m / z: 464 [(M + H) +, Cl 35], 466 [(M + H) 35, Cl 37]. Elemental analysis for C237H30CIN3O3S Calculated HCl: C, 55.20; H, 6.24; N, 8.40; Cl, 14.17; S, 6.41. Found: C, 55.42; H, 6.18; N, 8.26; Cl, 14.11; S, 6.53.

EXAMPLE 45 1-R4- (Aminomethyl) benzoyl-4-f (6-chloronaphthalen-2-iPsulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4- (N-tert-butoxycarbonylaminomethyl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as the departure. ? NMR (DMSO-dβ) d: 3.00-3.20 (4H, br), 3.30-3.80 (4H, br), 4.03 (2H, s), 7.37 (2H, d, J = 7.3Hz), 7.50 (2H, d) , J = 7.3Hz), 7.72 (1H, d, J = 8.8Hz), 7.82 (1H, d, J = 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.20-8.40 ( 2H, m), 8.43 (3H, br), 8.49 (1H, s). MS (FAB) m / z: 444 [(M + H)? Cl35], 446 [(M + H) 35, Cl37]. Elemental analysis for C22H22CIN3O3S HCl 1. Calculated H2O: C, 53.02; H, 5.06; N, 8.43; Cl, 14.23; S, 6.43. Found: C, 53.06; H, 5.30; N, 8.32; Cl, 14.20; S, 6.44.

EXAMPLE 46 1-R3- (aminomethyl) benzoyl-4-r (6-chloronaphthalen-2-dsulfonylpiperazine hydrochloride The ester was hydrolyzed in a manner similar to Example 3, except that methyl 3- (N-tert-butoxycarbonylaminomethyl) benzoate was used as the starting material. The reaction was then carried out as in Examples 4 and 7, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 3.07 (4H, br), 3.20-3.80 (4H, br), 4.00 (2H, s), 7.30-7.60 (4H, m), 7.73 (1H, d, J = 8.8Hz), 7.83 (1H, d, J = 8.8Hz), 8.10-8.60 (7H, m). MS (FAB) m / z: 444 [(m + Hf, Cl 35], 446 [(M + H) 35, Cl37] Elemental analysis for C22H22CIN3O3S HCl 1 / 4H2O Calculated: C, 54.49; H, 4.88; N, 8.67; Cl, 14.62; S, 6.61, Found: C, 54.64; H, 4.95; N, 8.52; Cl, 14.59; S, 6.70.

EXAMPLE 47 1-R (6-Chloronaphthalen-2-yl) Sulfonin-4-r3-rN- (1-pyrrolin-2-Daminomethylbenzoylpiperazine hydrochloride 2-Methoxy-1-pyrroline (35 mg) was dissolved in dimethylformamide (2 ml), followed by the addition of 1 - [3- (aminomethyl) benzoyl] -4 - [(6-chloronaphthalen-2-yl) hydrochloride sulfonyl] piperazine (0.10 g) and triethylamine (44 μl). The resulting mixture was stirred at room temperature for 3 days. After concentrating the reaction mixture under reduced pressure, the concentrate was diluted with methanol, followed by the addition of 1 N hydrochloric acid. Then, the solvent was distilled off under reduced pressure. The residue was purified by gel penetration chromatography ("Sephadex LH-20", diameter 15 x 300 mm, methanol), followed by solidification in a mixed solvent of methanol and ether, whereby a colorless solid was obtained (0.1 1 g, 91%). NMR (DMSO -d6) d: 2.04 (2H, m), 2.81 (2H, t, J = 7.8Hz), 3.18 (4H, br), 3.20-3.80 (5H, m), 4.10 (1H, br), 4.51 (2H, d, J = 5.9Hz), 7.30-7.50 (4H, m), 7.72 (1H, dd , J = 8.8.2.0Hz), 7.82 (1H, d, J = 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.50 (1 H, s ), 10.01 (1 H, t, J = 5.9Hz), 10.06 (1 H, s). MS (FAB) m / z: 51 1 (M + H) +, Cl 35], 513 [(M + H) 35, Cl 37]. Elemental analysis for C26H27CIN4O3S HCl CH3OH 4 / 5H2O Calculated: C, 54.60; H, 5.70; N, 9.43; Cl, 1.94; S, 5.40 Found: C, 54.84; H, 5.47; N, 9.13; Cl, 11.86; S, 5.48.

EXAMPLE 48 1-4- (2-Aminoethyl) benzop-4-f (6-chloronaphthalen-2-dsulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4- (2- (tert-butoxycarbonylamino) ethyl] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used. 1H NMR (DMSO -d6) d: 2.90-3.20 (8H, m), 3.40-3.90 (4H, br), 7.28 (4H, s), 7.72 (1H, dd, J = 8.8, 2.4Hz), 7.81 (1H, dd, J = 8.8.2.0Hz), 8.02 (3H, br), 8.17 (1H, d, J = 8.3Hz), 8.20-8.30 (2H, m), 8.49 (1 H, s) .MS (FAB) m / z: 458 (M + H) +, Cl35], 460 [(M + H) 35, Cl37] Elemental analysis for C23H24CIN3O3S HCl 1/2 CH3OH 1 / 2H2O Calculated : C, 54.34; H, 5.43; N, 8.09; Cl, 13.65; S, 6.17, Found: C, 54.43; H, 5.26; N, 7.92; Cl, 13.58; S, 6.24.

EXAMPLE 49 1-rr (6RS) -6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl-1-carbonyl-1-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine The title compound was obtained in a manner similar to Example 7, except that 1 - [[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl) sulfonyl was used ] piperazine as starting material. 1 H NMR (DMSO -d6) d: 1.30-1.50 (1 H, m), 1.90-2.10 (2H, m), 2.40-2.60 (1 H, m), 2.60-3.00 (5H, m), 3.03 (4H , m), 3.40-3.80 (4H, br), 7.00-7.10 (3H, m), 7.73 (1H, dd, J = 8.8, 2.0Hz), 7.81 (1H, dd, J = 8.8, 1.5Hz ), 8.05 (3H, br), 8.18 (1 H, d, J = 8.3Hz), 8.20-8.30 (2H, m), 8.49 (1 H, s). MS (FAB) m / z: 498 [(M + H) +], Cl 35, 500 [(M + H) 35, Cl37]. Elemental analysis for C26H28CIN3O3S HCl 3 / 2H2O Calculated: C, 55.61; H, 5.74; N, 7.48; Cl, 12.63; S, 5.71. Found: C, 55.64; H, 5.53; N, 7.77; Cl, 12.79; S, 5.76.

EXAMPLE 50 1 -rr (6RS) -6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-illmethyl-1-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] methyl was used. -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d6) d: 1.30-1.50 (1 H, m), 2.00-2.10 (2H, m), 2.40-2.60 (1 H, m), 2.60-3.00 (7H, m), 3.00-3.20 (2H, m), 3.30-3.50 (2H, m), 3. 82 (2H, m), 4.22 (2H, br), 7.00-7.10 (1H, m), 7.25 (2H, s), 7.73 (1H, dd, J = 8.8, 2.4Hz), 7.81 (1H, dd, J = 8.8, 1.5Hz), 8.00-8.40 (6H, m), 8.52 (1H, s), 11. 08 (1 H, br). MS (FAB) m / z: 484 [(M + H) +, Cl 35], 486 [(M + H) 35, Cl37]. Elemental analysis for C26H3oCIN3? 2S 2HCI Calculated: C, 56.07; H, 5.79; N, 7.54; Cl, 19.10; S, 5.76. Found: C, 56.04; H, 5.79; N, 7.52; Cl, 18.95; S, 5.80.

EXAMPLE 51 1-rr 2 RS) -6-aminomethyl-1, 2,3,4-tetrahydronaphthalen-2-ipmethyl-1-4-r (6-chloronaphthalen-2-yl) sulfonippiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [[2RS] -6- (N-tert-butoxycarbonylaminomethyl) -1, 2,3,4-tetrahydronaphthalen-2-yl] methyl was used] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d6) d: 1.30-1.50 (1 H, m), 2.00-2.20 (1 H, m), 2.20-2.40 (1 H, m), 2.40-2.60 (1 H, m), 2.75 (2H, m), 2.90-3.30 (7H, m), 3.60-3.70 (2H, m), 3.70-4.00 (4H, m), 7.04 (1H, d, J = 7.8Hz), 7.10-7.30 ( 2H, m), 7.74 (1H, m), 7.86 (1H, d, J = 8.8Hz), 8.20-8.50 (6H, m), 8.56 (1H, s), 10.69 (1H, br) . MS (FAB) m / z: 484 [(M + H) Cl 35], 486 [(M + H) 35, Cl37]. Elemental analysis for C 26 H 30 CIN 3 O 2 S 2 HCl 1 / 2H 2 O Calculated: C, 55.18; H, 5.88; N, 7.42; Cl, 18.79; S, 5.66. Found: C, 55.34; H, 5.70; N, 7.31; Cl, 18.76; S, 5.85.

EXAMPLE 52 1 -rr (2RS) -6-aminomethyl-1, 2,3,4-tetrahydronaphthalen-2-ylcarbonyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [[2RS] -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] carbonyl] was used. -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d 6) d: 1.55 (1 H, m), 1.80-1.90 (1 H, m), 2.60-2.90 (4H, m), 2.90-3.10 (5H, m), 3.50-3.80 (4H , m), 3.90 (2H, s), 7.05 (1H, d, J = 7.8Hz), 7.10-7.20 (2H, m), 7.71 (1H, d, J = 8.8Hz), 7.82 (1H , d, J = 8.3Hz), 8.10-8.40 (6H, m), 8.50 (1 H, s). MS (FAB) m / z: 498 [(M + H)? Cl35], 500 [(M + H) 35, Cl37]. Elemental analysis for C 26 H 28 CIN 3 O 3 S 1 2 HCl 1. 8 H 2 O Calculated: C, 56.15; H, 5.58; N, 7.55; Cl, 14.02; S, 5.76. Found: C, 55.93; H, 5.22; N, 7.37; Cl, 14.26; S, 5.70.

EXAMPLE 53 1- (7-aminomethylnaphthalene-2-yl) carbonyl-4-r (6-chloronaphthalen-2-yl) sulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [[7-N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] carbonyl] -4 - [(6-chloronaphthalen-2-yl) was used. sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d6) d: 3.10 (4H, br), 3.30-3.90 (4H, br), 4.18 (2H, s), 7.46 (1 H, d, J = 8.8Hz), 7.69 (1H, d, J = 8.8Hz), 7.73 (1H, d, J = 8.8Hz), 7.83 (1H, d, J = 8.8Hz), 7.89 (1H, s), 7.90-8.00 (3H, m), 8.19 (1 H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.50 (4H, br, s). MS (FAB) m / z: 494 [(M + H)? Cl35], 496 [(M + H) 35, Cl37]. Elemental analysis for C26H24CIN3O3S HCl 1. 3 / 4H2O Calculated: C, 57.41; H, 4.91; N, 7.72; Cl, 13.03; S, 5.89. Found: C, 57.40; H, 4.87; N, 7.71; Cl, 13.09; S, 5.89.

EXAMPLE 54 1-R (7-aminomethylnaphthalen-2-yl) methyl 1-4-r (6-chloronaphthalen-2-ylsulfonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [[7-N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] methyl] -4 - [(6-chloronaphthalen-2-yl) was used sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d6) d: 2.92 (2H, m), 3.22 (2H, m), 3.83 (2H, m), 4.20 (2H, d, J = 5.4Hz), 4.51 (2H, d, J = 5.4Hz), 4.51 (2H, br), 7.60-7.90 (4H, m), 7.90-8.40 (7H, m), 8.52 (1 H, s), 8.57 (3H, br), 1 1.52 (1 H, br). MS (FAB) m / z: 480 [(M + H) +, Cl 35], 482 [(M + H) 35, Cl37]. Elemental analysis for C 26 H 26 CIN 3 O 2 S 2 HCl 1. 1 / 4H 2 O Calculated: C, 56.02; H, 5.15; N, 7.54; Cl, 19.08; S, 5.75. Found: C, 55.88; H, 5.45; N, 7.34; Cl, 18.90; S, 5.69.

EXAMPLE 55 1-R (6-Am'nomethylnaphthalen-2-yl) carbonn-4-f (6-chloronaphthalene-2-yl) sulfonyl-1-piperazine hydrochloride The reaction was performed in a manner similar to Examples 3, 4 and 7, except that 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene was used as starting material, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 3.09 (4H, br), 3.40-3.90 (4H, br), 4.19 (4H, s), 7.47 (1H, d, J = 8.3Hz), 7.66 (1H, d, J = 8.3Hz), 7.73 (1H, d, J = 9.3Hz), 7.83 (1H, d, J = 8.8Hz), 7.90-8.10 (4H, m), 8.19 (1H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.40-8.60 (4H, m). MS (FAB) m / z: 494 [(M + H) +, Cl 35], 496 [(M + H) 35, Cl37]. Elemental analysis for C26H24CIN3O3S HCl 3 / 4H2O 1 / 5Et2O Calculated: C, 57.60; H, 5.14; N, 7.52; Cl, 12.69; S, 5.74. Found: C, 57.64; H, 5.10; N, 7.12; Cl, 12.69; S, 5.82.

EXAMPLE 56 1 -r (6-chloronaphthalen-2-illsulfonin-4-r4-rr (3S) -pyrrolidin-3-p-alkylbenzoyl-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4 - [[(3S) -1-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4 - [(6 -chloronaphthalen-2-yl) sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d 6) d: 2.05-2.25 (2H, m), 3.00-3.10 (4H, m), 3.20-3.70 (8H, m), 5.16 (1 H, br, s), 6.95 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.3Hz), 7.70-7.75 (1H, m), 7.82 (1H, dd, J = 8.8Hz), 8.20-8.30 (3H, m ), 8.50 (1 H, s). MS (FAB) m / z: 500 [(M + H) +, Cl35], 502 [(M + H) 35, Cl37].

EXAMPLE 57 1-R (6-Chloronaphthalen-2-yl-1-sulfonyl-4-r3-rr (3S) -pyrrolidin-3-ylmethylbenzoMI-piperazine hydrochloride The title compound was obtained in a manner similar to Example 56, except that 1- [3 - [[(3S) -1-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4 - [(6-chloronaphthalene -2-yl) sulfonyl] piperazine as starting material. ? NMR (DMSO -d6) d: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m), 3.20-3.80 (8H, m), 5.11 (1H, br, s), 6.90-6.95 (3H , m), 7.00-7.05 (1 H, m), 7.30-7.35 (1 H, m), 7.72 (1 H, dd, J = 8.8.2.0Hz), 7.81 (1 H, dd, J = 8.5, 1.7Hz), 8.18 (2H, d, J = 8.8Hz), 8.25-8.30 (2H, m), 8.50 (1H, s). MS (FAB) m / z: 500 [(M + H) +, Cl35], 502 [(M + H) 35, Cl37]. Elemental analysis for C25H26CIN3O4S HCl Calculated H2O: C, 54.15; H, 5.27; N, 7.58; Cl, 12.79; S, 5.78. Found: C, 53.94; H, 5.19; N, 7.33; Cl, 12.72; S, 5.86.

EXAMPLE 58 1 -r (6-Chloronaphthalen-2-illsulfonyl-4-r4- [r (3R) -pyrrolidin-3-yldoxybenzoylpiperazine hydrochloride] The title compound was obtained in a manner similar to Example 56, except that 1- [4 - [[(3R) -1-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as the departure. 1 H NMR (DMSO-d6) d: 2.05-2..25 (2H, m), 3.00-3.10 (4H, m), 3.20-3.70 (8H, m), 5.16 (1H, br s), 6.96 (2H , d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.74 (1H, dd, J = 8.8, 2.0Hz), 7.82 (1H, dd, J = 8.8, 1.5Hz) , 8.18 (1 H, d, J = 8.8 Hz), 8.25-8.30 (2 H, m), 8.50 (1 H, s). MS (FAB) m / z: 500 [(M + H) +, Cl35], 502 [(M + H) 35, Cl37]. Elemental analysis for C 25 H 26 CIN 3 O 4 S 1 2 HCl 0. 8 H 2 O Calculated: C, 53.80; H, 5.20; N, 7.53; Cl, 13.97; S, 5.74. Found: C, 53.84; H, 5.05; N, 7.51; Cl, 13.79; S, 5.74.

EXAMPLE 59 1 -r (6-Chloronaphthalen-2-yl-1-sulfonyl-1-4-r3-rr (3R) -pyrrolidin-3-hexylbenzoylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 56, except that 1- [3 - [[(3R) -1-tert-butoxycarbonylpyrrolidin-3-yl] oxy] benzoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as the departure. 1 H NMR (DMSO-d 6) d: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m), 3.20-3.80 (8H, m), 5.11 (5H, br s), 6.91-6.95 (8H, m), 5.11 (1 H, br s), 6.90-6.95 (2H, m), 7.00-7.05 (1H, m), 7.30-7.35 (1H, m), 7.74 (1H, dd, J = 8.8, 2.0Hz), 7. 82 (1 H, dd, J = 8.8, 1.5 Hz), 8.18 (2 H, d, J = 8.8 Hz), 8.25-8.30 (2 H, m), 8.50 (1 H, s). MS (FAB) m / z: 500 [(M + H) +, Cl35], 502 [(M + H) 35, Cl37]. Elemental analysis for C25H26CIN3O4S HCl Calculated H2O: C, 54.15; H, 5.27; N, 7.58; Cl, 12.79; S, 5.78. Found: C, 53.91; H, 5.14; N, 7.37; Cl, 12.62; S, 5.67.

EXAMPLE 60 1-r4- (2-aminopyrimidin-5-yl) benzoyl-4-r (6-chloronaphthalen-2-psulfonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (2-amino-5-pyrimidyl) benzoic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] p hydrochloride were used as starting materials. Perazine, whereby the title compound was obtained.1H NMR (DMSO-d6) d: 3.06 (4H, br), 3.56 and every 2H, br), 4.70-5.45 (3H, br), 7.40 (2H, d, J = 8.8Hz), 7.67 (2H, d, J = 8.8Hz), 3.73 (1H, dd, J = 8.8, 2.0Hz), 7.82 (1H, d, J = 8.8Hz), 8.18 ( 1H, d, J = 8.8Hz), 8.27 (1H, s), 8.28 (1H, d, J = 8.8Hz), 8.50 (1H, s), 8.72 (1H, s). MS (FAB) m / z: 508 [(M + H) +, Cl 35], 510 [(M + H) 35, Cl37]. Elemental analysis for C 25 H 22 CIN 5 O 3 S 1 1 HCl 7 H 2 O Calculated: C, 53.55; H, 4.40; N, 13.28 Cl, 12.49; S, 5.72. Found: C, 53.59; H, 4.58; N, 13.02 Cl, 12.58 S, 5.89.

EXAMPLE 61 1-l (6-Chloronaphthalen-2-ylsulfonyl-4-r (piperidin-4-Dacetylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(1-tert-butoxycarbonylpiperidin-4-yl) acetyl] -4 - [(6-chloronaphthalen-2-yl] sulfonyl] piperazine was used as starting material. 1H NMR (DMSO -d6) d: 1.25 (2H, m), 1.71 (2H, m), 1.87 (1H, m), 2. 20 (2H, d, J = 6.8Hz), 2.78 (2H, br), 2.96 (4H, br s), 3.14 (2H, m), 3.52 (4H, br s), 4.02 (2H, br), 7.73 (1 H, dd, J = 88, 2.0 Hz), 7.81 (1 H, d, J = 8.8 Hz), 8.17 (1 H, d, J = 8.8 Hz), 8.28 (1 H, d, J = 8.8 Hz), 8.26 (1 H, s), 8.50 (1 H, s), 8.54 (1 H, br), 8. 75 (1 H, br). MS (FAB) m / z: 436 [(M + H) +, Cl 35], 438 [(M + H) 35, Cl37]. Elemental analysis for C2? H26CIN3O3S 1 1 HCl 1 1 H2O Calculated: C, 50.86; H, 5.96; N, 15.01; Cl, 8.47; S, 6.47. Found: C, 51.07; H, 5.74; N, 14.75; Cl, 8.36; S, 6.50.

EXAMPLE 62 1 -r (6-Chloronaphthalen-2-yl-1-sulfonyl-4-r3- (piperidin-4-dpropioninpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [3- (1-tert-butoxycarbonylpiperidin-4-yl) propionyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] was used. piperazine as starting material: 1 H NMR (CD3OD) d: 1.29 (2H, m), 1.50 (1 H, m), 1.51 (2H, m), 1.89 (2H, m), 2.36 (2H, m), 2.88 (2H, m), 3.08 (4H, m), 3.64 (4H, m), 4.04 (2H, br), 7.58 (1H, dd, J = 8.8, 2.0Hz), 7.82 (1H, dd, J = 8.8, 2.0Hz), 8.05 (1 H, d, J = 8.8Hz), 8.06 (1 H, s), 8.09 (1 H, d, J = 8.8Hz), 8.42 (1 H, s). (FAB) m / z: 450 [(M + H) Cl 35], 452 [(M + H) 35, Cl37] Elemental analysis for C 26 H 28 CIN 3 O 3 S 1 8 HCl 0 9 H 2 O Calculated: C, 49.68; H, 5.69; N, 18.66; Cl, 7.90; S, 6.03, Found: C, 49.45; H, 5.70; N, 18.63; Cl, 7.72; S, 6.04.

EXAMPLE 63 1 -r (6-Chloronaphthalen-2-illsulfonyl-4-r (E) -3- (pyridin-3-iPpropenoylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 4, except that (E) -3- (3-pyridyl) acrylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl hydrochloride were used as starting materials. ] piperazine. ? NMR (DMSO-d6) d: 3.03 (4H, m), 3.69 (2H, br), 3.85 (2H, br), . 71 (2H, s), 7.70 (1 H, dd, J = 8.8, 2.0Hz), 7.83 (1H, dd, J = 8.8, 2.0Hz), 7.89 (1H, dd, J = 7.8, 5.4Hz ), 8.16 (1 H, d, J = 8.8 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.26 (1 H, d, J = 8.8 Hz), 8.51 (1 H, s), 8.67 ( 1 H, d, J = 7.8 Hz), 8.77 (1 H, d, J = 5.4 Hz), 9.13 (1 H, s). MS (FAB) m / z: 442 [(M + H) +, Cl 35], 444 [(M + H) 35, Cl37]. Elemental analysis for C22H20CIN3O3S HCl 1 / 4H2O Calculated: C, 54.72; H, 4.49; N, 8.70; Cl, 14.68; S, 6.64. Found: C, 54.81; H, 4.43; N, 8.54; Cl, 14.68; S, 6.74.

EXAMPLE 64 1-r (6-Chloronaphthalen-2-α-sulfonin-4-r E) -3- (pyridin-4-yl) propenoyl] piperazine hydrochloride The title compound was obtained in a manner similar to Example 4, except that (E) -3- (4-pyridyl) acrylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl hydrochloride were used as starting materials. ] piperazine. 1 H NMR (DMSO-d 6) d: 3.03 (3 H, m), 3.68 (2 H, br), 3.82 (2 H, br), 5.76 (1 H, s), 7.48 (1 H, d, J = 15.1 Hz) , 7.65 (1 H, d, J = 15.1 Hz), 7.72 (1 H, dd, J = 8.8, 2.0Hz), 7.83 (1 H, dd, J = 15.1 Hz), 8.11 (2H, br s), 8.16 (1 H, d, J = 8.8 Hz), 8.24 (1 H, s), 8.27 (1 H, d, J = 8.8 Hz), 8.52 (1 H, s), 8.82 (2 H, d, J = 5.9Hz). MS (FAB) m / z: 442 [(M + H) +, Cl 35], 444 [(M + H) 35, Cl37]. Elemental analysis for C22H2oCIN3O3S HCl 1 / 5H2O Calculated: C, 54.82; H, 4.48; N, 14.71; Cl, 8.72; S, 6.65; Found: C, 54.77; H, 4.41; N, 14.71; Cl, 8.50; S, 6.77.

EXAMPLE 65 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-f (pyridyl-4-diacetylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 4, except that 4-pyridylacetic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials. 1 H NMR (DMSO-d 6) d: 2.99 (2H, br), 3.04 (2H, br), 3.57 (2H, br), 3. 62 (2H, br), 4.00 (2H, s), 7.71 (2H, d, J = 5.9Hz), 7.74 (1H, dd, J = 8.8, 3.0Hz), 7.83 (1H, dd, J = 8.8, 2.0Hz), 8.18 (1H, d, J = 8.8Hz), 8.27 (1H, s), 8.29 (1H, d, J = 8.8 Hz), 8.27 (1 H, s), 8.29 (1 H, d, J = 8.8 Hz), 8.53 (1 H, s), 8.72 (2 H, d, J = 5.9Hz). MS (FAB) m / z: 430 [(M + H) +, Cl 35], 432 [(M + H) 35, Cl37]. Elemental analysis for C21H20CIN3O3S HCl 0 3H2O Calculated: C, 53.46; H, 4.61; N, 15.03; Cl, 8.91; S, 6.80; Found: C, 53.28; H, 4.49; N, 15.18; Cl, 8.91; S, 6.75.

EXAMPLE 66 1-F (6-Chloronaphthalen-2-yl) sulfonyl-4-r4-r (3RS) -pyrrolidin-3-PbenzoiH-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4 - [(3RS) -1-tert-butoxycarbonyl-pyrrolidin-3-yl] benzoyl] -4 - [(6- chloronaphthalen-2-yl) sulfonyl] piperazine as starting material. 1 H NMR (DMSO-d 6) d: 1.85-1.95 (1 H, m), 2.30-2.40 (1 H, m), 3.82 (2 H, br), 3.00-3.90 (13 H, m), 7.72 (1 H, dd, J = 8.6, 2.2Hz), 7.80 (1H, dd, J = 8.8, 2.0Hz), 7.29 (2H, d, J = 8.3Hz), 7.35 (1H, d, J = 8.3Hz), 8.18 (1 H, d, J = 8.8 Hz), 8.25-8.30 (2 H, m), 8.49 (1 H, s). MS (FAB) m / z: 484 [(M + H) +, Cl 35], 486 [(M + H) 35, Cl37]. Elemental analysis for C25H26CIN3O3S HCl 3 / 2H2O Calculated: C, 54.84; H, 5.52; N, 7.67; Cl, 12.95 S, 5.86; Found: C, 55.00; H, 5.53; N, 7.48; Cl, 13.23; S, 5.97.

EXAMPLE 67 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r (isoquinolin-7-) D-carbonylpiperazine hydrochloride Methyl 7-isoquinolinecarboxylate (206 mg) was dissolved in 4N hydrochloric acid, followed by heating under reflux for 4 hours. The reaction was carried out in a manner similar to Example 4, except that the residue obtained by removing the solvent by distillation under reduced pressure, and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials. , whereby the title compound was obtained (298 mg, 62%). 1 H NMR (DMSO-d6) d: 2.95-3.25 (4H, m), 3.40-3.60 (2H, m), 3.70-3.90 (2H, m), 7.73 (1 H, dd, J = 8.8, 2.0Hz) , 7.84 (1 H, d, J = 8.8 Hz), 8.05 (1 H, d, J = 7.3 Hz), 8.20 (1 H, d, J = 8.8 Hz), 8.25-8.35 (3 H, m), 8.41 (1 H, d, J = 6.4 Hz), 8.45 (1 H, s), 8.52 (1 H, s), 8.71 (1 H, d, J = 6.4 Hz), 9.79 (1 H, s). MS (FAB) m / z: 465 [(M + H) Cl 35], 467 [(M + H) 35, Cl37]. Elemental analysis for C 24 H 2 o CIN 3 O 3 S HCl 2 2 H 2 O Calculated: C, 53.18; H, 4.72; N, 7.75; Cl, 13.08; S, 5.92; Found: C, 53.1 1; H, 4.70; N, 7.60; Cl, 13.01; S, 6.16.

EXAMPLE 68 1 -r (6-chloronaphthalen-2-yl) sulfonip-4-f (quinolyl-2-dicarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that quinoline-2-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, whereby the composed of the title. 1 H NMR (DMSO-d 6) d: 3.05 (2 H, m), 3.17 (2 H, m), 3.62 (2 H, m), 3.83 (2 H, m), 7.61 (1 H, d, J = 8.3 Hz), 7.60-7.80 (2H, m), 7.80-7.90 (2H, m), 7.95 (1H, d, J = 8.3Hz), 8.00 (1H, d, J = 7.3Hz), 8.18 (1H, d , J08.3Hz), 8.51 (1 H, s). Elemental Analysis for C24H2oCIN3O3S Calculated: C, 61.87; H, 4.33; N, 9.02; Cl, 7.61; S, 6.88; Found: C, 61.76; H, 4.20; N, 8.73; Cl, 7.65; S, 6.99.

EXAMPLE 69 1 -r (6-chloronaphthalen-2-yl) sulfonyl-4 - [(4-hydroxyquinol-2-dicarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4-hydroxyquinoline-2-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, obtained the title compound. NMR (DMSO -d6) d: 3.00-3.30 (4H, br), 3.53 (2H, br), 3.77 (2H, br), 6.45 (1H, s), 7.48 (1H, t, J = 7.3Hz ), 7.70-7.90 (4H, m), 8.10-8.40 (4H, m), 8.52 (1H, s). MS (FAB) m / z: 482 [(M + H) Cl 35], 484 [(M + H) 35, Cl37]. Elemental analysis for C24H2oCIN3O4S 9 / 10HCI 1 / 3CH3OH 3/2 2H2O Calculated: C, 52.90; H. 4.60; N, 7.61; Cl, 12.19; S, 5.80; Found: C, 53.17; H, 4.59; N, 7.39; Cl, 12.31; S, 6.07.

EXAMPLE 70 1 - [(6-Chloronaphthalen-2-yl) sulfonyl-4-yl (8-hydroxyquinolin-7-D-carbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that d-hydroxyquinoline-7-carboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, obtained the title compound. 1 H NMR (DMSO-d6) d: 2.90-3.30 (4H, br), 3.35 (2H, br), 3.79 (2H, br), 7.39 (1H, d, J = 8.3Hz), 7.53 (1H, d, J = 8.3Hz), 7.60-7.90 (3H, m), 8.10-8.40 (3H, m), 8.50 (3H, s), 8.60 (1H, d, J = 7.8Hz), 8.96 (1H , d, J = 4.4Hz). MS (FAB) m / z: 482 [(M + H) +, Cl 35], 484 [(M + H) 35, Cl37]. Elemental Analysis for C24H2oCIN3O4S HC3OH 1 / 4H2O Calculated: C, 54.11, H, 4.63; N, 7.57; Cl, 12.78; S, 5.78; Found: C, 54.40; H, 4.84; N, 7.66; Cl, 13.04; S, 5.99.

EXAMPLE 71 1-R (Benzimidazol-5-yl) carbonn-4-r (6-chloronaphthalen-2-Qsulfonylpiperazine hydrochloride The reaction was performed in a manner similar to Examples 3, 4 or , except that methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride were used as starting materials, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 3.08 (4H, br), 3.30-4.00 (2H, br), 7.48 (1H, d, J = 8.3Hz), 7.60-7.90 (4H, m), 8.10-8.30 (3H, m), 8.50 (1 H, s), 9.51 (1 H, s). MS (FAB) m / z: 455 [(M + H) +, Cl 35], 457 [(M + H) 35, Cl37]. Elemental analysis for C22H? 9CIN4O3S HCl 5 / 4H2O Calculated: C, 51.42; H, 4.41; N, 10.90; Cl, 13.80; S, 6.24; Found: C, 51.53; H, 4.40; N, 10.71; Cl, 13.61; S, 6.40.

EXAMPLE 72 1-R (Benzimidazol-5-yl) carbonyl 1-4-r (6-chloronaphthalen-2-yl) sulfonophomopiperazine hydrochloride The reaction was carried out in a manner similar to Example 71, except that methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride were used as the starting material, the title compound was obtained. 1 H NMR (DMSO-d 6) d: 1.67 (1 H, m), 1.93 (1 H, m), 3.20-3.90 (8H, m), 7.44 (1 / 2H, m), 7.54 (1 / 2H, m ), 7.68 (1 H, m), 7.80-8.00 (3H, m), 8.10-8.30 (3H, m), 8.49 (1 / 2H, s), 8.55 (1 / 2H, s), 9.56 and 9.57 ( 1 H, each s). MS (FAB) m / z: 469 [(M + H) +, Cl 35], 471 [(M + H) 35, Cl 37]. Elemental analysis for C23H2? CIN4O3S HCl 0 3CH3OH H2O Calculated: C, 52.50; H. 4.76; N, 10.51; Cl, 13.30; S, 6.01; Found: C, 52.31; H, 4.66; N, 10.50; Cl, 13.34; S, 6.01.

EXAMPLE 73 1 -r (6-chloronaphthalen-2-yl) sulfonin-4-r (thiazolor-5,4-clpyridin-2-dicarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that sodium tiazole [5,4-c] pyridine-2-carboxylate and 1 - [(6-chloronaphthalen-2-yl) hydrochloride were used as starting materials. ) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 3.10-3.30 (4H, m), 3.84 (2H, m), 4.32 (2H, m), 7.69 (1 H, dd, J = 8.8, 2.0Hz), 7.83 (1 H, dd, J = 8.8, 2.0Hz), 8.10-8.30 (4H, m), 8.51 (1 H, s), 8.79 (1 H, d, J = 5.9Hz), 9.62 (1 H, s). MS (FAB) m / z: 473 [(M + H) +, Cl 35], 467 [(M + H) 35, Cl37]. Elemental analysis for C2iH-? 7CIN4O3S2 Calculated HCl: C, 49.51; H, 3.56; N, 11.00; Cl, 13.92; S, 12.59; Found: C, 49.45; H, 3.71; N, 11.20; Cl, 13.67; S, 12.55.

EXAMPLE 74 1 -r (E) -4-chlorostylsulfonyl-4-r (t) azoloyl 5-chlorpyridin-2-dicarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that thiazolo [5,4-c] pyridine-2-carboxylate sodium and 1 - [(E) -4-chlorostyrylsulfonyl) piperazine hydrochloride were used as starting materials, whereby the title compound was obtained. 1 H NMR (DMSO-d 6) d: 3.30 (4H, m), 3.87 (2H, m), 4.35 (2H, m), 7.35 (1 H, d, J = 15.6Hz), 7.40-7.50 (3H, m ), 7.79 (1 H, d, J = 8.3 Hz), 8.2 (1 H, d, J = 5.9 Hz), 8.77 (1 H, d, J = 5.9 Hz), 9.59 (1 H, s). MS (FAB) m / z: 449 [(M + H)? Cl35], 451 [(M + H) 35, Cl37]. Elemental analysis for C19Hi7CIN4O3S2 1 / 2HCI Calculated: C, 48.85; H, 3.78; N, 11.99; Cl, 11.38; S, 13.73; Found: C, 49.18; H, 3.80; N, 12.20; Cl, 11.05; S, 13.84.

EXAMPLE 75 1-r (6-Chloronaphthalen-2-yl) sulfonyl-4-r (4.5.6.7-tetrahydrothienor-3-c-pyridin-2-yl) methynpiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl was used as the starting material. ) methyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 2.82-2.88 (4H, m), 2.91-2.99 (4H, m), 3.28-3.36 (2H, m), 3.47-3.55 (4H, m), 4.02 (2H, br s), 6.58 (1 H, s), 7.71 (1 H, dd, J = 8.8, 2.0Hz), 7.81 (1 H, d, J = 8.8, 2.0Hz), 7.23-7.28 (3H, m), 8.49 (1 H, s), 9.42 (1 H, br s). MS (FAB) m / z: 462 [(M + H) +, Cl 35], 464 [(M + H) 35, Cl37]. Elemental analysis for C22H2Cl4N3O2S2 2HCI 1 5H2O Calculated: C, 47.02; H, 5.20; N, 18.93; Cl, 7.48; S, 11.41; Found: C, 47.18; H, 5.41; N, 18.59; Cl, 7.37; S, 11.33.

EXAMPLE 76 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-rans-3- (4.5.6.7-tetrahydrothienor-3, 2-c1pyridin-2-yl) propenoxypiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1- [trans-3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin was used as starting material. -2-yl) propenoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 2.95-3.10 (6H, m), 3.32-3.51 (3H, m), 3.60-3.80 (3H, m), 4.12 (2H, s), 6.75 (1H, d, J = 15.1 Hz), 7.19 (1 H, s), 7.50 (1 H, d, J = 15.1 Hz), 7.70 (1 H, dd, J = 8.8, 2.4 Hz), 7.81 (1 H, dd, J = 8.8, 2.0 Hz), 8.15 (1 H, d, J = 8.8 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.50 (1 H, s), 9.53 (1 H, br s). MS (FAB) m / z: 502 [(M + H) +, Cl 35], 504 [(M + H) 35, Cl37]. Elemental analysis for C 24 H 24 CIN 3 O 3 S 2 HCl 0 5H 2 O Calculated: C, 52.65; H, 4.79; N, 12.95; Cl, 7.67; S, 11.71; Found: C, 52.36; H, 4.88; N, 12.63; Cl, 8.01; S, 11.39.

EXAMPLE 77 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r3- (4.5.6.7- tetrahydrothienor3.2-clpyridin-2-yl) propionylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1- [3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 was used as the starting material. -yl) propionyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 2.80-3.60 (16H, m), 4.12 (2H, br, s), 7.11 (1 H, br s), 7.74 (1 H, dd, J = 8.8, 2.0Hz) , 7.83 (1 H, dd, J = 8.8, 2.0Hz), 8.20 (1 H, s), 8.25-8.30 (2H, m), 8.53 (1 H, s), 9.67 (2H, br s). MS (FAB) m / z: 504 [(M + H) +, Cl 35], 506 [(M + H) 35, Cl37]. Elemental analysis for C 24 H 26 CIN 3 O 3 S 2 1 2 HCl 1 3 H 2 O Calculated: C, 50.46; H, 5.26; N, 13.65; -N, 7.36; Found: C, 50.83; H, 5.26; Cl, 13.43; N, 6.97.

EXAMPLE 78 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r3- (4.5,6.7-tetrahydrothio-3,2-clpyridin-2-yl) propi-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothione [3,2-c] was used as the starting material. ] pyridin-2-yl) propyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H NMR (DMSO-d6) d: 1.90-2.07 (2H, m), 2.72-2.80 (2H, m), 2.82-3.21 (8H, m), 3.35 (2H, br s), 3.51 (2H, d, J = 11.5Hz), 3.82 (2H, d, J = 11.5Hz), 4.06 (2H, s), 6.66 (1H, s), 7.74 (1H, dd, J = 8.8, 1.5Hz), 7.85 (1H, dd, J = 8.8, 1.5Hz) , 7.85 (1 H, dd, J = 8.8, 1.5 Hz), 8.20 (1 H, d, J = 8.8 Hz), 8.25- 8.39 (2 H, m), 8.55 (1 H, s), 9.50 (2 H, br s), 11.26 (1 H, br s). MS (FAB) m / z: 490 [(M + H)? Cl35], 492 [(M + H) 35, Cl37]. Elemental analysis for C 24 H 28 CIN 3 O 2 S 2 2 HCl 1 6 H 2 O Calculated: C, 48.71; H, 5.65; N, 17.97; N, 7.10; S, 10.84; Found: C, 49.01; H, 5.77; N, 17.62; N, 6.96; S, 10.82.

EXAMPLE 79 1-R (6-Chloronaphthalen-2-sulfonyl-4-rN-r 4,5,6,7-tetrahydrothienor-3-c-pyridin-2-yl) methancarbamoyl-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thieno [3,2-c] was used as the starting material. ] pyridin-2-yl) methyl] carbamoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H NMR (DMSO-d6) d: 2.78-2.86 (4H, br s), 2.88-2.94 (4H, m), 3.29-3.35 (2H, m), 3.37-3.42 (4H, m), 4.03 (2H, br s), 4.19 (2H, d, J = 5.4Hz), 6. 62 (1 H, s), 7.25 (3H, t, J = 5.4Hz), 7.72 (1 H, dd, J = 8.8, 2.0Hz), 7.82 (1 H, dd, J = 8.8, 2.0Hz), 8.16 (1H, d, J = 8.8Hz), 8.22-8.26 (2H, m) 8.50 (1 H, s), 9.27 (2H, br s). Elemental analysis for C23H25CIN4O3S2 HCl 1 3H2O Calculated: C, 48.90; H, 5.10; N, 12.55; N, 9.92 Found: C, 49.02; H, 5.20; Cl, 12.50; N, 9.76 EXAMPLE 80 1-rf6-Chloronaphthalen-2-yl sulfonyl-4-r (4,5,6,7-tetrahydrothienor 3,2-clpyridin-2-yl) carbonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 was used as the starting material. -yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H NMR (DMSO-d6) d: 2.99-3.05 (2H, m), 3.08 (4H, t, J = 4.6Hz), 3.35-3.40 (2H, m), 3.71 (4H, t, J = 4.6Hz) , 4.11 (2H, s), 7.17 (1 H, s), 7.71 (1 H, dd, J = 8.8, 2.0Hz), 7.82 (1 H, dd, J = 8.8, 2.0Hz), 8.22-8.28 ( 3H, m), 8.50 (1 H, s), 9.38 (2H, br s). MS (FAB) m / z: 476 [(M + H) +, Cl 35], 478 [(M + H) 35, Cl37]. Elemental analysis for C22H23CIN3O3S2 HCl 3 / 2H2O Calculated: C, 48.98; H, 4.86; Cl, 13.14; N, 7.79; S, 11.89; Found: C, 48.96; H, 4.67; N, 13.21; N, 7.74; S, 11.93.

EXAMPLE 81 4-R (6-Chloronaphthalen-2-yl) sulfonyl-2-ethoxycarbonyl-1 - | (4,5,6,7-tetrahydrothienor-3,2-clpyridin-2-yl) carbonippiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydroxy] [3,2-c] pyridine-2 was used as the starting material. -yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d 6) d: 1.22 (3 H, t, J = 7.0 Hz), 2.38-2.58 (1 H, m), 2.65-2.72 (1 H, m), 3.04 (2 H, br s), 3.29- 3.43 (3H, m), 3.70 (1 H, br s), 4.01-4.30 (6H, m), 5.18 (1 H, br s), 7.27 (1 H, s), 7.73 (1 H, dd, J = 8.8, 2.0Hz), 7.82 (1 H, d, J = 8.8Hz), 8.26 (1 H, s), 8.29 (1 H, s), 8.54 (1 H, s), 9.59 (2H, br s ). MS (FAB) m / z: 548 [(M + H) +, Cl 35], 550 [(M + H) 35, Cl 37]. Elemental analysis for C25H26N3CIO5S2 1 2HCI 0 6H20 Calculated: C, 49.83; H, 4.75; Cl, 12.94; N, 6.978; S, 10.64; Found: C, 49.62; H, 4.71; Cl, 13.30; N, 7.19; S, 10.56.

EXAMPLE 82 2-Carboxy-4-r (6-chloronaphthalen-2-M) sulfonyl-1-r (4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-2-yl) carbon hydrochloride Llpiperazine The reaction was carried out in a manner similar to Example 3, except that 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1 - [(4,5,6, 7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 2.30-2.53 (1 H, m), 2.58-2.69 (1 H, m), 3.04 (2 H, br s), 3.29-3.83 (4 H, m), 4.07-4.32 ( 4H, m), 4.90-5.20 (1H, m), 7.03-7.30 (1H, m), 7.71 (1H, dd, J = 8.8, 2.4Hz), 7.81 (1H, d, J = 8.8Hz ), 8.81 (1H, d, J = 8.8Hz), 8.20-8.29 (2H, m), 8.52 (1H, s), 9.58 (1H, br s). MS (FAB) m / z: 520 [(M + H) +, Cl 35], 522 [(M + H) 35, Cl37]. Elemental analysis for C23H22N3CIO5S2 1 2HCI 0 8H2O Calculated: C, 47.78; H, 4.32; Cl, 13.49;; N, 7.27; S, 11.09; Found: C, 47.41; H, 4.36; Cl, 13.81; N, 7.141; S, 11.01 EXAMPLE 83 1-r (6-Chloronaphthalen-2-yl) sulfonin-4-r (5-aminohydroxyiminomethyl, 4,5,6,7-tetrahydrothienor 3, 2-c1pyridin-2-yl) carboninpiperazine A solution of 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(5-cyano-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine- 2-yl) carbonyl] piperazine (41 mg) in dichloromethane (dichloromethane: 1 ml) to methanol (4 ml), followed by the addition of hydroxylamine hydrochloride (28 mg) and triethylamine (0.55 ml). The resulting mixture was stirred at room temperature for 2 hours. The residue, obtained by concentration of the reaction mixture under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 3), whereby the title compound (14 mg , 32%). 1 H NMR (DMSO-d6) d: 2.74-2.79 (2H, m), 3.06 (4H, s), 3.35-3.38 (2H, m), 3.71 (4H, s), 4.07 (2H, s), 5.32 ( 2H, s), 7.08 (1 H, s), 7.71 (1 H, dd, J = 8.8, 1.6 Hz), 7.81 (1 H, d, d J = 8.8, 1.6 Hz), 8.16 (1 H, s ), 8.23-8.25 (2H, m), 8.33 (1H, br s), 8.49 (1 H, s). MS (FAB) m / z: 534 [(M + H) +, Cl 35], 536 [(M + H) 35, Cl37].

EXAMPLE 84 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-rN- (4,5,6,7-tetrahydrothio-3,2-clpyridin-2-yl) carbamoylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 was used as the starting material. -yl) carbamoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO-d6) d: 2.83 (2 H, br s), 2.99 (4 H, br s), 3.30 (2 H, br s), 3.54 (4 H, br s), 4.00 (2 H, s), 6.33 ( 1 H, s), 7.70 (1 H, dd, J = 8.8, 2.0 Hz), 7.82 (1 H, d, J = 8.8 Hz), 8.16 (1 H, d, J = 8.8 Hz), 8.22 (1 H , s), 8.26 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s), 9.18 (2 H, br s), 9.82 (1 H, s). MS (FAB) m / z: 491 [(M + H) +, Cl 35], 493 [(M + H) 35, Cl 37]. Elemental analysis for C22H23N4CIO3S2 HCl 0 3H2O Calculated: C, 49.59; H, 4.65; Cl, 13.31; N, 10.51; S, 12.03; Found: C, 49.32; H, 4.63; Cl, 13.34; N, 10.81; S, 12.03.

EXAMPLE 85 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-rN-methyl-N- (4,5,6,7-tetrahydrothio-3,3-c1-pyridin-2-yl) carbamoin piperazine hydrochloride The reaction was carried out in a manner similar to Example 7, except that 1- [N- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothione [3,2-c] pyridine was used as the starting material. -2-yl) -N-methylcarbamoyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine, whereby the title compound was obtained. 1 H NMR (DMSO -d6) d: 2.83 (2H, t, J = 5.4Hz), 2.97 (4H, br s), 3.10 (3H, s), 3.28-3.41 (6H, m), 4.00 (2H, s ), 6.35 (1 H, s), 7.72 (1 H, dd, J = 8.8, 2.0 Hz), 7.81 (1 H, dd, J = 8.8, 2.0 Hz), 8.17 (1 H, d, J = 8.8 Hz), 8.23-8.31 (2H, m), 8.50 (1 H, s), 9.28 (2H, br s). MS (FAB) m / z: 505 [(M + H) +, Cl35], 507 [(M + H) 35, Cl37]. Elemental analysis for C23H25N4CIO3S2 1 1 HCl 0 5H2O Calculated: C, 49.85; H, 4.93; Cl, 13.43; N, 10.11; S, 11.57; Found: C, 49.55; H, 4.92; N, Cl, 13.23 N, 10.13 S, 11.83 EXAMPLE 86 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-rr5- (1-pyrrolin-2-yl) -4,5,6,7-tetrahydrothienor-3-clpyridin-2-hydrochloride il) carbon¡pp¡perazina The title compound was obtained in a manner similar to Example 47, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydro-thieno [3,2-c] pyridin hydrochloride was used as starting material. -2-yl) carbonyl] piperazine. 1 H NMR (DMSO-d6) d: 2.07-2.18 (2H, m), 2.90-3.11 (8H, m), 3.62 (2H, t, J = 6.8Hz), 3.72 (4H, br), 3.80 (2H, t, J = 5.9Hz), 3.99 (2H, t, J = 5.9Hz), 4.62 (1 H, br s), 4.73 (1 H, br s), 7.10 (1 H, s), 7.50 (1 H, s), 7.72 (1 H, dd, J = 8.8 , 2.0Hz), 7.82 (1H, dd, J = 8.8, 2.0Hz), 8.18 (1H, d, J = 8.8Hz), 8.22- 8.28 (2H, m), 8.51 (1H, s), 10.37 (1 H, br s), 10.53 (1 H, br s) .. MS (FAB) m / z: 542 [(M + H) +, Cl 35], 544 [(M + H) 35, Cl 37] . Elemental analysis for C26H27CIN4? 3S2 1 3HCI 0 4H2O Calculated: C, 52.25; H. 4.91; Cl, 13.64; N, 9.37; S, 10.73; Found: C, 52.34; H, 5.03; Cl, 13.56; N, 9.36; S, 10.74.

EXAMPLE 87 1-R (6-Chloronaphthalen-2-yl) sulfonip-4-r (4,5,6,7-tetrahydrothiazole-5,4-clpyridin-2-yl) carbonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2 was used as the starting material. -yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H-NMR (DMSO -d6) delta: 3.01 (2H, t, J = 5.9Hz), 3.11 (4Hbr), 3.44 (2H, br s), 3.74 (2H, br s), 4.32-4.46 (4H, m), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.83 (1 H, dd, J = 8.8Hz, 2.OHz), 8.15 (1 H, d, J = 8.8Hz), 8.23 (1 H, s), 8.26 (1 H, d, J = 8.8 Hz), 8.30 (1 H, s). MS (FAB) m / z: 477 [(M + H) +, CI35], 479 [(M + H) +, CI37]. Elemental Analysis for C21 H21 CIN4O3S2.HCI.O.2H2O Calculated: C, 48.78; H, 4.37; Cl, 13.71; N, 10.84; S, 12.40. Found: C, 48.60; H, 4.50; Cl, 13.58; N, 10.62; S, 12.29.

EXAMPLE 88 1-R (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r (6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolor-5,4-clpyridin-2-dicarbonyl-piperazine hydrochloride and 1 -r (6- carbamoyl-4,5,6,7-tetrahydrothiazolof5,4-c1pyridin-2-yl) carbonin-4-f (6-chloronaphthalen-2-yl) sulfonylpiperazine The reaction was performed in a manner similar to Reference Example 112 and Example 83, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-) hydrochloride was used. tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine as a starting material, whereby 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(6-) hydrochloride was obtained aminohydroxymeminomethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine and 1 - [(6-carbamoyl-4,5,6,7-tetrahydric acid [5] 4-c] pyridin-2-yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4 - [( 6-Aminohydroxy-minomethyl-4,5,6,7-tetrahydroxyzolo [5,4-c] pyridin-2-yl] carbonyl] piperazine: 1 H-NMR (DMSO-de) delta: 2.77 (2H, br s), 3.09 (4H, br), 3.48 (2H, t, J = 5.4Hz), 3.73 (2H, br s), 4.30-4.50 (4H, m), 5.61 (1 H, br s), 7.71 (1 H, dd, J = 8.8.2. OHz), 7.82 (1 H, dd, J = 8.8 Hz, 2.OHz), 8.15 (1 H, d, J = 8.Hz), 8.22 (1 H, d, J = 1.5Hz), 8.25 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s), 8.53 (1 H, br s). MS (FAB) m / z: 535 [(M + H) +, CI35], 537 [(M + H) +, Cl37]. 1 - [(6-Carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine: H-NMR (DMSO-de) delta: 2.75 (2H, br s), 3.09 (4H, br), 3.63 (2H, t, J = 5.9Hz), 3.73 (2H, br s), 4.39 (2H, br s), 4.59 (2H, s), 6.17 (2H, s), 7.70 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8Hz, 2.OHz), 8.14 (1 H, d, J = 8.8Hz), 8.21 (1 H, d, J = 1.5Hz), 8.25 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s). MS (FAB) m / z: 520 [(M + H) +, CI35], 522 [(M + H) +, CI37]. Elemental analysis for C22H22CIN5O4S2.H2O Calculated: C, 49.11; H, 4.50; 13.02. Found: C, 48.98; H, 4.12; N, 12.83.

EXAMPLE 89 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r (6- (1-pyrrolin-2-yl) -4,5,6,7-tetrahydrothiazole-5,4-c1pyridin-2-hydrochloride incarbonnpiperazine The title compound was obtained in a manner similar to Example 47, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothiazolo [5] hydrochloride was used. 4-c] pirridin-2-yl) carbonyl] piperazine as starting material. H-NMR (DMSO -d6) delta: 2.07-2.15 (2H, m), 2.94-3.16 (8Hm), 3. 63 (2H, t, J = 7.3Hz), 3.75 (2H, br s), 3.90 (2H, br s), 4.39 (2H, br s), 4.93 (2H, s), 7.70 (1 H, dd, J = 8.8.2.OHz), 7.83 (1 H, dd, J = 8.8Hz, 2.OHz), 8.15 (1 H, d, J = 8.8Hz), .22 (1 H, d, J = 2 .OHz), 8.25 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s).

MS (FAB) m / z: 544 [(M + H) +, CI35], 546 [(M + H) +, CI37]. Elemental analysis for C25H26CIN5O3S2.I.4HCI.CH3OH Calculated: C, 49.79; H, 5.05; Cl, 13.57; N, 1 1.17; S, 10.23. Found: C, 49.44; H, 4.78; Cl, 13.63; N, 10.83; S, 10.15.

EXAMPLE 90 1 -r (6-Chloronaphthalen-2-insulfonin-4-r (6-formyl-4,5,6,7-tetrahydrothiazole-5,4-clpyridin-2-illcarboninpiperazine The reaction was carried out in a manner similar to Example 4, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothiazolo [hydrochloride]] was used as starting materials. 5,4-c] pyridin-2-yl) carbonyl] piperazine and formic acid, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 2.74-2.88 (2H, m), 3.10 (4H, br), 3.31 (2H, s), 3.66-3.86 (4H, m), 4.64-4.73 (2H, m), 7.69 (1H, dd, J = 8.8.2.OHz), 7.82 (1H, dd, J = 8.8 , 2.OHz), 8.14 (1 H, d, J = 8.8Hz), 8.15-8.22 (2H, m), 8.24 (1 H, d, J = 8.8Hz), 8.50 (1 H, s). MS (FAB) m / z: 505 [(M + H) +, CI35], 507 [(M + H) +, CI37]. Elemental analysis for C22H21 CIN4O4S2.I / 5H2O Calculated: C, 51.95; H. 4.24; Cl, 6.97; N, 1.02; S, 12.61.

Found: C, 52.18; H, 4.30; Cl.6.69; N, 10.71; S, 12.21.

EXAMPLE 91 1-R (6-Chloronaphthalen-2-yl) sulfonin-4-r (6-methyl-4,5,6,7-tetrahydrothiazolof 5,4-c 1-pyridin-2-yl) carbon n-piperazine hydrochloride 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) cabonyl] piperazine (400 mg) was suspended in dichloromethane (10 ml), followed by the addition of triethylamine (0.22 ml) and acetic acid (0.05 ml). The resulting mixture was stirred at room temperature for 5 minutes. An aqueous solution of 30% formaldehyde (0.08 ml) and sodium triacetoxyborohydride (264 mg) was added to the reaction mixture, followed by stirring at room temperature for 10 minutes. After concentrating the reaction mixture under reduced pressure, the residue was added to ethyl acetate. The resulting mixture was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was dissolved in a saturated solution of hydrochloric acid in ethanol (1 ml) and then the resulting solution was concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate, whereby the title compound was obtained (298 mg, 71%). 1 H-NMR (DMSO -d6) delta: 2.89 (3H, s), 3.10 (6H, br), 3.32-3.81 (4H, m), 4.30-4.81 (4H, m), 7.71 (1H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8.2.OHz), 8.15 (1 H, dd, J = 8.8Hz), 8.20-8.28 (2H, m), 8.50 (1 H, s), 11.28 (1H, br s). MS (FAB) m / z: 491 [(M + H) +, CI35], 493 [(M + H) +, CI37]. Elemental analysis for C22H23CIN4O3S2.HCI.O.6H2O Calculated: C, 49.09; H, 4.72; Cl, 13.17; N, 10.41; S, 11.91. Found: C, 48.88; H, 4.78; Cl, 13.26; N, 10.42; S, 12.03.

EXAMPLE 92 2-IT4-R (6-chloronaphthalen-2-yl) sulfonyl-piperazin-1-trimcarbonyl-6,6-dimethyl-4,5,6,7-tetrahydrothiazole-5,4-pyridinium iodide 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4 - [(6-methyl-4-hydrochloride was dissolved., 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (200 mg) in NN-dimethylformamide (20 ml), followed by the addition of methyl iodide (0.05 ml) ) and potassium carbonate (79 mg). The resulting mixture was stirred overnight at 80 ° C. After concentrating the reaction mixture under reduced pressure, the residue was added with water and the resulting precipitate was collected by filtration. The precipitate was then dissolved in a mixed solvent (1: 1) of dichloromethane and methanol, followed by the addition of ethyl acetate. The resulting precipitate was collected by filtration, whereby the title compound (144 mg, 56%) was obtained. 1 H-NMR (DMSO-dβ) delta: 3.05-3.23 (12H, m), 3.77 (2H, t, J = 5.9Hz), 4.40 (2H, br s), 4.79 (2H, br s), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.83 (1 H, dd, J = 8.8.2.OHz), 8.15 (1 H, d, J = 8.8Hz), 8.20-8.27 (2H, m), 8.52 (1 H, s). MS (FD) m / z: 505 (M +, CI35), 507 (M +, CI37). Elemental analysis for C23H26CIIN4O3S2.

I / 2CH3CO2CH2CH3 Calculated: C, 44.35; H, 4.47; N, 8.28. Found: C, 44.52; H, 4.23; N, 8.01.

EXAMPLE 93 N-oxide of 2-rr4-r (6-chloronaphthalen-2-yl) sulfonyl-1-piperazin-1-ylcarbonyl-6-methyl-4,5,6,7-tetrahydrothiazole-5,4-clpyridine 1 - [(6-Chloronaphthalen-2-yl) sulfonyl] -4 - [(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl hydrochloride was dissolved. ] piperazine (400 mg) in acetone (10 ml), followed by the addition of an aqueous solution of 1 N sodium hydroxide (0.38 ml) and 30% aqueous hydrogen peroxide (3.50 ml). The resulting mixture was stirred at room temperature for 8 days. After concentrating the reaction mixture under reduced pressure, the residue was purified by chromatography through a synthetic adsorbent ("Diaion HP-20", water ~ water: acetonitrile = 2: 5), whereby the compound of title (84 mg, 39%). 1 H-NMR (DMSO-dβ) delta: 2.83-2.90 (1 H, m), 3.10 (5H, br), 3.20- 3.47 (4H, m), 3.61 (3H, m), 4.28-4.50 (3H, m), 4.78-4.85 (1 H, m), 7.69 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8.2, OHz), 8.14 (1 H; d, J = 8.8 Hz), 8.19-8.27 (2H, m), 8.50 (1 H, s). MS (FD) m / z: 506 (M +, CI35), 508 (M +, CI37).

EXAMPLE 94 2-Carbamoyl-4-r (6-chloronaphthalen-2-yl) sulfonyl-1-r (4,5,6,7-tetrahydrothiazole-5,4-c1pyridin-2-yl) carbonnpiperazine trifluoroacetate A solution of 1 - [(6-tert-butoxycarbonyl-4,5,6,7-tetrahydroxyzolo [5,4-c] pyridin-2-yl) carbonyl] -2-carbamoyl-4 - [( 6-chloronaphthalen-2-yl) sulfonyl] piperazine (303 mg) dissolved in dichloromethane (1 ml) to trifluoroacetic acid (1 ml), followed by concentration under reduced pressure. The resulting precipitate was collected by filtration and washed with diethyl ether, whereby the title compound (263 mg, 83%) was obtained. 1 H-NMR (DMSO-dβ) delta: 2.39-2.70 (2H, m), 2.92-3.06 (2H, m), 3. 42-3.77 (4H, m), 4.25-4.50 (7 / 2H, m), 4.97 (1 H / 2H, br s), 5.35-3.77 (4H, m), 4.25-4.50 (7 / 2H, m) , 4.97 (1 H, br s), 5.35-5.44 (1 / 2H, m), 6.14 (1 / 2H, br s), 7.30-7.39 (1 H, m), 7.66-7.73 (2H, m), 7.77-7.82 (1 H, m), 8.16 (1 H, d, J = 8.8 Hz), 8.21-8.28 (2 H, m), 8.49 (1 H, s), 9.26 (2 H, br s). MS (FAB) m / z: 520 [(M + H) +, CI35], 522 [(M + H) +, CI37]. Elemental analysis for C22H22CIN5O4S2. CF3CO2H.O.6H2O Calculated: C, 44.29; H, 3.73; Cl, 5.40; F, 9.55; N, 10.67; S, 9.77. Found: C, 44.59; H, 3.79; Cl, 5.26; F, 9.54; N, 1028; S, 9.72.

EXAMPLE 95 2-Carbamoyl-4-r (6-chloronaphthalen-2-yl) sulfonin-1 -r (6-methyl-4,5,6,7-tetrahydrothiazole-5,4-clpyridin-2-yl) carbonippiperazine hydrochloride The title compound was obtained in a manner similar to Example 91, except that 2-carbamoyl-4 - [(6-chloronaphthalen-2-yl) sulfonyl] -1 - [(4,5,6,7-tetrahydroxyzolo [5,4-c] pyridin trifluoroacetate was used. -2-yl) carbonyl] piperazine as starting material. 1 H-NMR (DMSO -d6) delta: 2.37-2.70 (2H, m), 2.91 (3H, s), 3.00-3.78 (6H, m), 4.28-4.77 (7 / 2H, m), 4.97 (1 H, br s), 5.40-5.50 (1 / 2H, m), 6.14 (1 / 2H, br s), 7.32-7.40 (1 H, m), 7.68-7.75 (2H, m), 7.77-7.83 ( 1 H, m), 8.15 (1 H, d, J = 8.8 Hz), 8.21 -8.28 (2 H, m), 8.49 (1 H, s). MS (FAB) m / z: 534 [(M + H) +, CI35], 536 [(M + H) +, CI37]. Elemental analysis for C23H24CIN5O4S2.HCI.2.5H2O Calculated: C, 44.88; H, 4.91; Cl, 1 1 .52; N, 11.38; S, 10.42. Found: C, 44.83; H, 4.89; Cl, 1 1.65; N, 1 1.31; S, 10.46.

EXAMPLE 96 1-R (6-Chloronaphthalen-2-yl) sulfonyl-1-4-rr6- (2-hydroxyethyl) -4,5,6,7-tetrahydrothiazole-5,4-c] pyridin-2-pcarbon hydrochloride Hp¡peraz¡na The reaction was carried out in a manner similar to Example 91, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothiazolo [hydrochloride]] was used as starting materials. 5,4-c] pyridin-2-yl) carbonyl] piperazine (132 mg) and glyoxylic acid hydrate (82 mg), whereby a crude product was obtained. The product was suspended in tetrahydrofuran (50 ml), followed by the addition of triethylamine (0.22 ml) and ethyl chloroformate (0.03 ml) under cooling with ice. After stirring at room temperature for 15 minutes, sodium borohydride (50 mg) and water (10 ml) were added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with saturated saline and then dried over anhydrous sodium sulfate. The residue, obtained by removing the solvent by distillation under reduced pressure, was purified by chromatography on a column of silica gel (dichloromethane ~ dichloromethane: methanol = 100: 3). The purified product was dissolved in saturated hydrochloric acid in ethanol (1 ml), followed by concentration under reduced pressure. The concentrate was pulverized and washed in ethyl acetate, whereby the title compound (52 mg, 33%) was obtained. 1 H-NMR (DMSO -d6) delta: 3.11 (4H, br s), 3.20-3.57 (6H, m), 3.69-3.87 (4H, m), 4.34-4.82 (4H, m), 5.38 (1 H , br s), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8Hz, 2.OHz), 8.15 (1 H, d, J = 8.8Hz) , 8.22 (1 H, s), 8.25 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s), 10.48 (1 H, br s). MS (FAB) m / z): 521 [(M + H) +, CI35], 523 [(M + H) +, Cl37]. In a manner similar to Example 91, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(4,5,6,7-tetrahydrothiazole [5,4] hydrochloride was used. -c] pyridin-2-yl] carbonyl] piperazine as the starting material, the compounds of Examples 97, 98 and 99 were obtained.

EXAMPLE 97 1-F (6-Chloronaphthalen-2-yl) sulfonyl-4-r (6-pyridin-2-yl) methyl-4,5,6,7-tetrahydrothiazole-5,4-c1pyridin-2-hydrochloride il) carboninpiperazine H-NMR (DMSO -d6) delta: 3.07-3.17 (6H, m), 3.63 (2H, t, J = 6.3Hz), 3.74 (2Hbr s), 4.39 (2H, br s), 4.58 (2H, s ), 4.61 (2H, s), 7.50-7.64 (1 H, m), 7.67-7.73 (2H, m), 7.82 (1 H, dd, J = 8.8,1.5Hz), 7.97 (1 H, m) , 8.15 (1 H, d, J = 8.8 Hz), 8.22 (1 H, d, J = 1.5 Hz), 8.25 (1 H, d, J = 8.8 Hz), 8.50 (1 H, s), 8.69 ( 1 H, d, J = 4.9 Hz). MS (FAB m / z: 568 [(M + H) +, CI35], 570 [(M + H) +, CI37]. Elemental Analysis for C27H26CIN5O3S2.2HCI.O.8H2O Calculated: C, 49.48; H, 4.55; CII6.23; N, 10.68; S, 9.78, Found: C, 49.72; H, 4.48; Cl, 16.31; N, 10.86; S, 9.53.

EXAMPLE 98 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r (6-pyridin-3-yl) methyl-4,5,6,7-tetrahydrothiazole-5,4-c1pyridin-2-hydrochloride il) carboninpiperazine 1 H-NMR (DMSO -d6) delta: 3.03-3.27 (6H, m), 3.40-3.81 (4H, m), 3. 74 (2H, br s), 4.40 (2H, br s), 4.50 (2H, s), 4.70 (2H, s), 7.70 (1 H, dd, J = 8.8.2.4Hz), 7.82 (1 H, dd, J = 8.8), 8.15 (1 H, d, J = 8.8Hz), 8.22 (1 H, s), 8.25 (1 H.dJ = 8.8Hz), 8.50 (1 H, s), 8.73 (1 H, d, J = 7.8 Hz), 8.93 (1 H, d, J = 4.4 Hz). MS (FAB) m / z: 568 [(M + H) +, CI35], 570 [(M + H) +, CI37]. Elemental analysis for C27H26CLN5O3S2.2.9HCI.45H2O Calculated: C, 42.96; H, 5.06; Cl, 18.32; N, 9.28. Found: C, 42.97; H, 4.84; Cl, 18.19; N, 9.23.

EXAMPLE 99 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r (6- (pyridin-4-yl) methyl-4,5,6,7-tetrahydrozothiazolo hydrochloride [5,4-c] ] pyridin-2-yl) carbonnpiperazine 1 H-NMR (DMSO -ÚQ) delta: 3.1 1 (4H, br s), 3.19 (2H, br s), 3.64 (2H, br s), 3.74 (2H, br s), 4.41 (2H, br s) ), 4.49 (2H, s), 4.80 (2H, s), 7.69 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8.2.OHz), 8.15 (1 H, d, J = 8.8 Hz), 8.21 (1 H, d, J = 2.OHz), 8.25 (1 H, d, J = 8.8 Hz), 8.41 (2 H, d, J = 6.3 Hz ), 8.50 (1 H, s), 9.04 (2H, d, J = 6.3Hz). MS (FAB) m / z: 568 [(M + H) +, CI35], 570 [(M + H) +, CI37]. Elemental analysis for C27H26CIN5O3S2.2.7HCI.6.OH2O Calculated: C, 41.86; H, 5.30; Cl, 16.93; N, 9.04; S, 8.28. Found: C, 42.05; H, 4.98; Cl, 16.92; N, 9.37; S, 8.61.

EXAMPLE 100 1-r (E) -4-chlorostyrosulfonyl-1-4-r (4,5,6,7-tetrahydro-azole-5,4-clpyrid-2-yl) carbonyl | - | piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl was used. -4 - [(E) -4-Chlorostyrylsulfonyl] piperazine as starting material 1 H-NMR (DMSO -ÓQ) delta: 3.04 (2H, br s), 3.23 (4H, br), 3.47 (2H, br s), 3.77 (2H, br s), 4.35-4.50 (2H, m), 7.33 (1 H, d, J = 15.6Hz), 7.43 (1 H, d, J = 15.6Hz), 7.49 (1H , d, J = 8.3Hz), 7.79 (1 H, d, J = 8.3Hz), 9.57 (2H, br s) .MS (FAB) m / z: 453 [(M + H) +, CI35], 455 [(M + H) +, CI37] Elemental analysis for C19H21CIN4O3S2.HCI.O.3H2O Calculated: C, 46.12; H, 4.60; Cl, 14.33; N, 11.32; S, 12.96 Found: C, 46.42; H, 4.66; Cl, 14.38; N, 11.02; S, 13.02.

EXAMPLE 101 1 -r (E) -4-chlorostyrylsulfonyl 1-4 - [(6-methyl-4,5,6-tetrahydrothiazolor-5,4-clpyridin-2-yl) carbonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 91, except that [(E) -4-chlorostyrylsulfonyl] -4 - [(4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride was used as the 1 H-NMR (DMSO -d6) delta: 2.92 (3H, s), 3.01-3.32 (6H, br), 3.35-3.88 (4H, m), 4.29-4.84 (4H, m), 7.33 (1 H, d, J = 15.6 Hz), 7.49 (1 H, d, J = 15.6 Hz), 7.49 (1 H, d, J = 8.3 Hz), 7.79 (1 H, d, J = 8.3 Hz), 1 1.31 (1 H, br s) .MS (FAB) m / z: 467 [(M + H) +, CI35], 469 [(M + H) +, CI37] Elemental analysis for C20H23CIN4O3S2.HCI.O. 2H2O Calculated: C, 47.37, 4.85, Cl, 13.98, N, 1.05, S, 12.65, Found: C, 47.30, H, 4.92, Cl, 14.05, N, 1.03, S, 12.49.

EXAMPLE 102 (3S) -3-r (6-Chloronaphthalen-2-yl) sulfonamide1-1-1 (4.5.6,7-tetrahydro-tene [3,2-c1pyridin-2-yl] hydrochloride) methynpyrrolidine The title compound was obtained in a manner similar to Example 7, except that (3S) -1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 was used. -yl] methyl] -3 - [(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine as starting material. [a] D = -69.72 ° (25 ° C, c = 1.00, CH 3 OH). 1 H-NMR (DMSO-de) at 100 ° C) delta: 1 88-1.89 (1 H, m), 2.10- 2.25 (1 H, m), 3.02-3.07 (2H, m), 3.10-3.50 ( 6H, m), 4.02 (1 H, s), 4.12 (2H, s), 4.45 (2H, s), 7.12 (1 H, s), 7.65 (1 H, d, J = 8.3Hz), 7.91 ( 1 H, d, J = 8.3 Hz), 8.10 (1 H, d, J = 8.3 Hz), 8.14 (1 H, s), 8.16 (1 H, d, J = 8.3 Hz), 8.18 (1 H, br s), 8.48 (1 H, s), 9.65 (2H, br s), MS (FD) m / z: 461 (M +, CI35), 463 (M +, CI37). Elemental analysis for C22H24CIN3O2S2.2.I HCI.H2O Calculated: C, 47.47; H, 5.09; Cl, 19.74; N, 7.55; S, 11.52. Found: C, 47.55; H, 5.13; Cl, 19.85; N7.45; S, 1 1.48.

EXAMPLE 103 (3S) -3-r (6-chloronaphthalen-2-yl) sulfonamide1-1-K4,5.6,7- tetrahydrothienor3,2-c1pyridin-2-yl) carboninpyrrolidine hydrochloride The title compound was obtained in a manner similar to Example 7, except that (3S) -1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2 was used. -yl] carbonyl] -3 - [(6-chloronaphthalen-2-yl) sulfonamide] pyrrolidine as starting material. [α] D = -62.70 ° (25 ° C, c = 1.00, CH 3 OH). 1 H-NMR (DMSO -d6) at 100 °) delta: 1.82-1.90 (1 H, m), 1.96-2.05 (1 H, m), 3.05 (2H, t, J = 6, OHz), 3.42-3.57 (2H, m), 3.60-3.72 (2H, m), 3.84-3.90 (1 H, m), 4.12 ( 2H, s), 4.45 (2H, s), 7.25 (1 H, s), 7.64 (1 H, dd, J = 8.3.1.6Hz), 7.90 (1 H, dd, J = 8.3.1.6Hz), 7.97 (1 H, d, J = 5.6 Hz), 8.08 (1 H, d, J = 8.7 Hz), 8.12 (1 H, s), 8.14 (1 H, d, J = 8.7 Hz), 8.47 (1 H, s), 9.55 (2H, br s). MS (FAB) m / z: 476 [(M + H) +, CI35], 478 [(M + H) +, CI37]. Elemental analysis for C22H22CIN3O3S2.HCI Calculated: C, 51.56; H. 4.52; Cl, 13.84; N, 8.20; S, 12.51. Found: C, 51.25; H, 4.61; Cl, 13.68; N, 7.98; S, 12.36.

EXAMPLE 104 Hydrochloride of (3S1-1 -r (6-chloronaphthalen-2-yl) sulfonyl-3-rr (4,5,6,7-tetrahydro-inof3,2-c1pyridin-2-yl) methyl1-amino-1-pyrrolidine The title compound was obtained in a manner similar to Example 7, except that (3S) -3 - [[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine- 2-yl] methyl] amino] -1 - [(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as starting material [a] = + 34.82 ° (25 ° C, c = 1.00, CH3OH). -NRM (DMSO-del) delta: 1.98-2.20 (2H, m), 2.99-3.04 (2H, m), 3. 19-3.26 (1 H, m), 3.30-3.50 (3H, m), 3.61-3.72 (1 H, m), 3.52-3.60 (1 H, m), 4.13 (2H, s), 4.29 (2H, s), 7.09 (1 H, s), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.89 (1 H, dd, J = 8.8.2.OHz), 817 (1 H, d, J = 8.8 Hz), 8.25 (1 H, d, J = 2.OHz), 8.30 (1 H, s), 8.57 (1 H, s), 9.55 (2 H, br s), 9.7-10.0 (1 H , m). MS (FD) m / z: 461 (M +, CI35), 463 (M +, CI37). Elemental analysis for C22H24CIN3O2S2.2HCI.O.2H2O Calculated: C, 49.06; H, 4.94; Cl, 19.75; N, 7.80; S, 1 1.91. Found: C, 48.88; H, 4.97; Cl, 19.65; N, 7.67; S, 11.84.

EXAMPLE 105 (3S) -3-r (4,5,6,7-tetrahydrothienor-3-c-pyridin-2-yl) carbonylaminol-1-r (6-chloronaphthalen-2-yl) sulfonylpyrrolidine hydrochloride The title compound was obtained in a manner similar to Example 7, except that (3S) -3 - [[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyrid] was used. n-2-yl] carbonylamino] -1 - [(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidone as starting material. [a] D = + 33.56 ° (25 ° C, c = 1.00, CH3OH). 1 H-NMR (DMSO -d6) delta: 1.85-1.95 (1 H, m), 1.95-2.05 (1 H, m), 3. 04 (2H, m), 3.24-3.40 (1 H, m), 3.41-3.53 (3H, m), 4.04-4.24 (3H, m), 7.34 (1 H, s), 7.67 (1 H, d, J = 8.8 Hz), 7.84 (1 H, d, J = 8.8 Hz), 8.03 (1 H, d, J = 8.8 Hz), 8.17 (1 H, s), 8.22 (1 H, d, J = 8.8 Hz), 8.27 (1 H, d, J = 5.7 Hz), 8.50 (1 H, s), 9.59 (1 H, br s9; 9.71 (1 H, br s) .MS (FAB) m / z: 476 [(M + H) +, CI35], 478 [(M + H) +, CI37].

EXAMPLE 106 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r (4,5,6,7-tetrahydrothienor-3, 2-clpyridin-2-yl) carbonylnomopiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]] pyridin-2-yl was used) carbonyl] -4 - [(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine as starting material. 1 H-NMR (DMSO -dβ) delta: 1.83 (2H, br s), 3.04 (2H, t, J = 5.4Hz), 3. 30-3.59 (6H, m), 3.60-3.88 (4H, m), 4.14 (2H, s), 7.20 (1 H, br s), 7.69 (1 H, dd, J = 8.8.2.OHz), 7.84 (1 H, d, J = 8.8Hz), 8.10 (1 H, d, J = 8.8Hz), 8.17-8.21 (2H, m), 8.50 (1 H, s), 9.57 (2H, br s) . MS (FAB) m / z: 490 [(M + H) +, CI35], 492 [(M + H) +, CI37]. Elemental analysis for C23H25CIN3O3S2.I .I HCI.O.2H2O Calculated: C, 51.66; H, 4.99; Cl, 13.92; N, 7.86. Found: C, 51.46; H, 4.61; Cl, 13.55; N, 8.05.

EXAMPLE 107 4-R (6-Chloronaphthalen-2-yl) sulfonamido1-1-r (4,5,6,7-tetrahydrothienor-3, 2-clpyridin-2-yl) carbonylpiperidine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid and trifluoroacetate were used as starting materials. 4 - [(6-chloronaphthalen-2-yl) sulfonamido] piperidine, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 1.26-1.38 (2H, m), 1.58-1.65 (2H, m), 2. 98-3.13 (4H, m), 3.29-3.40 (3H, m), 3.90-4.05 (2H, m), 4.11 (2H, s), 7.16 (1 H, s), 7.68 (1 H, dd, J = 8.0.2.OHz), 7.92 (1 H, dd, J = 8.8.2.OHz), 8.07 (1 H, d, J = 7.3Hz), 8.13 (2H, d, J = 8.8Hz), 8.20 (1 H, d, J = 7.3 Hz), 8.23 (1 H, s), 8.51 (1 H, s), 9.71 (2 H, br s). MS (FAB) m / z: 490 [(M + H) +, CI35], 492 [(M + H) +, CI37]. Elemental analysis for C23H25CIN3O3S2.2.4HCI.3H2O Calculated: C, 43.67; H, 5.32; Cl, 19.05; N, 6.64. Found: C, 43.85; H, 5.10; Cl, 07.07; N, 6.63.

EXAMPLE 108 1-r (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r (6-aminohydroxy-imino-methylbenzofuran-2-yl) carbonnpiperazine The title compound was obtained in a manner similar to Example 83, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(6-cyanobenzofuran-2-yl) carbonyl] piperazine was used as the departure. 1 H-NMR (DMSO-dβ) delta: 3.11 (4H, s), 3.83 (4H, br), 5.90 (2H, br s), 7.34 (1 H, s), 7.64-7.75 (3H, m), 7.83 (1 H, dd, J = 8.8.2.OHz), 7.89 (1 H, s), 8.17 (1 H, d, J = 8.8 Hz), 8.23 (1 H, d, J = 1.5 Hz), 8.26 (1 H, d, J = 8.8 Hz), 8.51 (1 H, s), 9.77 (1 H, s). MS (FAB) m / z: 513 [(M + H) +, CI35], 515 [(M + H) +, CI37]. Elemental analysis for C24H21 CIN4O5S.I / 5H2O Calculated: C, 55.80; H, 4.18; Cl, 6.86; N, 10.70; S, 6.21. Found: C, 55.65; H, 4.25; Cl, 6.81; N. 10.70; S, 6.37.

EXAMPLE 109 1-r (6-Chloronaphthalen-2-yl) sulfonin-4-f (5-aminohydroxyiminomethyl-benzothiophen-2-yl) carbon-piperazine The title compound was obtained in a manner similar to Example 83, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(5-cyanobenzothiophen-2-yl) carbonyl] piperazine was used as the departure. 1 H-NMR (delta-DMSO): 3.11 (4H, s), 3.77 (4H, s), 5.87 (2H, br s), 7.67 (1 H, s), 7.71 (1 Hd, J = 2.0Hz ), 7.75 (1 H, d, J = 8.8 Hz), 7.83 (1 H, dd, J = 8.8.2.0 Hz), 7.94 (1 H, d, J = 8.8 Hz), 8.15 (1 H, s) , 8.17 (1 H, d, J = 8.8 Hz), 8.25 (1 H, d, J = 8.8 Hz), 8.29 (1 H, d, J = 8.3 Hz), 8.50 (1 H, s), 9.68 ( 1 H, s). MS (FAB) m / z: 529 [(M + H) +, CI35], 531 [(M + H) +, CI37]. Elemental analysis for C24H21 N4CIO4S2.O.3H2O Calculated: C, 53.94; H, 4.07; N, 10.48. Found: C, 54.22; H, 4.17; N, 10.23.

EXAMPLE 110 1-R (6-Chloronaphthalen-2-yl) sulfonip-4-rr (1 RS) -4- (pyridin-4-yl) -3-cyclohexenolcarbonylpiperazine hydrochloride The reaction was performed in a manner similar to Example 12, except that (1 RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl were used as starting materials. ] piperazine, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 1.50-1.60 (1 H, m), 1.80-1.90 (1 H, m), 2.25-2.58 (5H, m), 2.80-2.90 (1 H, m) 2.91 -3.10 (1 H, m), 3.46-3.72 (4H, m), 6.94 (1 H, br s), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.82 (1 H, dd, J = 8.8.2.OHz), 7.96 (2H, d, J = 6.8Hz), 8.15 (1H, J = 8.8Hz), 8.24 (1H, J = 2.OHz), 8.27 (1H, J = 8.8Hz), 8.50 (1 H, s), 8.76 (2H, d, J = 6.8Hz). MS (FAB) m / z: 496 [(M + H) +, CI35], 498 [(M + H) +, CI37]. Elemental analysis for C26H26CIN3 ° 3S HCI.1.3H2O Calculated: C, 56.18; H, 5.37; Cl, 12.75; N, 7.56; S, 5.77. Found: C, 56.03; H, 5.29; Cl, 12.67; N, 7.41; S, 5.77.

EXAMPLE 111 1 -r (E) -4-chlorostyrylsulfonin-4-rr 1 RS) -4- (pyridin-4-yl) -3-cyclohexenolcarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 12, except that (1 RS) -4- (4-pyridyl) -3-cyclohexenecarboxylic acid and 1 - [(E) -4-chlorostyrylsulfonyl] piperazyl were used as starting materials. na, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 1.59-1.70 (1 H, m), 1.90-1.98 (1 H, m), 2.31-2.56 (4H, m), 2.90-3.00 (1 H, m), 3.13 (4H, br s), 3.50-3.63 (4H, m), 6.98 (1 H, br s), 7.35 (1 H, d, J = 15.6 Hz), 7.44 (1 H, d, J = 15.6 Hz ), 7.51 (2H, d, J = 8.3Hz), 7.80 (1 H, J = 8.3Hz), 7.97 (1 H, J = 6.8Hz), 8.77 (1 H, J = 6.8Hz). MS (FAB) m / z: 472 [(M + H) +, CI35], 474 [(M + H) +, CI37]. Elemental analysis for C24H26CIN3O3S.O.9HCI.2.3H2O Calculated: C, 52.77; H, 5.81; Cl, 12.33; N, 7.69; S, 5.87. Found: C, 52.61; H, 5.80; Cl, 12.54; N, 7.44; S, 6.05.

EXAMPLE 112 cis-, trans-1-r (6-chloronaphthalen-2-yl) sulfonyl-4-IT-4- (pyridin-4-D-cyclohexanolcarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 12, except that cis-, trans-4- (4-pyridyl) cyclohexanecaboxylic acid and 1 - [(6-chloronaphthalen-2-yl) sulfonyl] were used as starting materials. piperazine, whereby the title compound was obtained. MS (FAB) m / z: 498 [(M + H) +, CI35], 500 [(M + H) +, CI37]. Elemental analysis for C26H28CIN3O3S.1.3H2O Calculated: C, 53.71; H, 5.77; Cl, 14.02; N, 7.23; S, 5.51. Found: C, 53.70; H, 5.70; Cl, 14.21; N, 7.13; S, 5.72.

EXAMPLE 113 cis-, trans-1 -r (E) -4-chlorostyrylsulfonyl-1-4-IT-4- (pyridin-4-d-cyclohexanolcarbonylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 12, except that cis-, trans-4- (4-pyridyl) cyclohexanecaboxylic acid and 1 - [(E) -4-chlorostyrylsulfonyl] piperazine were used as starting materials, with which was obtained the title compound.

MS (FAB) m / z: 474 [(M + H) +, CI35], 476 [(M + H) +, CI37]. Elemental analysis for C24h28CIN3? 3S.1.2HCI.O8H2? Calculated: C, 54.17; H, 5.83; Cl, 14.66; N, 7.80; S, 6.03. Found: C, 54.21; H, 6.20; , CI, 15.03; N, 7.51; S, 6.18.

EXAMPLE 114 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r (1, 2,3,4-tetrahydroisoquinolin-6-yl) carbonylpiperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1 - [(2-tert-butoxycarbonyl-1, 2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] -4- was used as the starting material. [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H-NMR (DMSO-dβ) delta: 2.89-3.29 (4H, m), 3.20-3.83 (8H, m), 4. 25 (2H, s), 7.10-7.25 (3H, m), 7.71 (1 H, d, J = 8.3Hz), 7.81 (1 H, d, J = 8.3Hz), 8.17 (1 H, d, J = 8.8Hz), 8.15-8.25 (2H, m), 8.49 (1 H, s), 9.54 (2H, brs). MS (FAB) m / z: 470 [(M + H) +, CI35], 472 [(M + H) +, CI37]. Elemental analysis for C24H24CIN3O3S.HCI.2.OH2O Calculated: C, 53.14; H, 5.39; Cl, 13.07; N, 7.75; S, 5.91. Found: C, 53.43; H, 5.43: Cl, 13.15; N, 8.07; S, 5.55.

EXAMPLE 115 1-F (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r (2-methylene-1, 2,3,4-tetrahydroisoquinolin-6-yl) carboninpiperazine hydrochloride The reaction was carried out in a manner similar to Example 91, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(1, 2,3,4-tetrahydroisoquinoline-6 il) carbonyl] piperazine, whereby the title compound was obtained. 1 H-NMR (DMSO -d6) delta: 2.88 (3H, s), 2.90-3.80 (13H, m), 4.12-4.56 (1 H, m), 7.19 (1 H, s), 7.20 (2H, d) , J = 6.8Hz), 7.72 (1 H, dd, J = 8.8.2.OHz), 7.81 (1 H, d, J = 8.8Hz), 8.17 (1 H, d, J = 8.8 Hz), 8.24-8.28 (2H, m), 8.49 (1 H, s), 10.93 (1 H, brs). MS (FAB) m / z: 484 [(M + H) +, CI35], 486 [(M + H) +, CI37]. Elemental analysis for C24H24CIN3O3S.HCI.2.3H2O Calculated: C, 53.44; H, 5.67; Cl, 12.62; N, 7.48; S, 5.71. Found: C, 53.71; H, 5.81; Cl, 12.37; N, 7.26; S, 5.62.

EXAMPLE 116 6-lT4-r (6-Chloronaphthalen-2-yl) sulfoniphopperazin-1-carboxyH-2,2-dimethyl-1, 2,3,4-tetrahydroisoquinoline iodide The title compound was obtained in a manner similar to Example 92, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4 - [(2-methyl-1, 2,3,4-tetrahydroisoquinolin-6-yl) carbonyl hydrochloride was used as the starting material. ] piperazine. 1 H-NMR (DMSO-d6) delta: 2.90-3.85 (18, m), 4.61 (2H, s), 7.19 (1 H, d, J = 7.8 Hz), 7.24 (1 H, d, J = 7.8 Hz), 7.28 (1 H, s), 7.72 (1 H, dd, J = 8.8,1.5 Hz), 7.81 (1 H, d, J = 8.8 Hz); 8.17 (1 H, d, J = 8.8Hz), 8.20-8.31 (2H, m), 8.50 (1 H, s), Elemental Analysis for C26H29CI IN3O3S.H2O Calculated: C, 48.49; H, 4.85; N, 6.53. Found: C, 48.66; H, 4.96; N, 6.39.

EXAMPLE 117 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r4- (1, 2,3,6-tetrahydropyridin-4-yl) benzoyl-1-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4- (1-tert-butoxycarbonyl-1, 2,3,6-tetrahydropyridin-4-yl) benzoyl] - was used as the starting material. 4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine. 1 H-NMR (DMSO-d6) delta: 2.67 (2H, br s), 3.05 (4H, br), 3.30 (2H, br s), 3.35-3.78 (6H, m), 6.24 (1 H, br s ), 7.32 (2H, d, J = 8.3Hz), 7.47 (2H, d, J = 8.3Hz), 7.71 (1 H, dd, J = 8.8.2.OHz), 7.81 (1 H, dd, J = 8.8.2.OHz), 8.17 (H, d, J = 8.8Hz), 8.22-8.28 (2H, m), 8.49 (1 H, s), 9.25 (2H, br s). MS (FAB) m / z: 496 [(M + H) +, Cl 35], 498 [(M + H) +, Cl37]. Elemental analysis for C27H26CIN3O3S.HCI.2 / 5H2O Calculated: C, 57.86; H, 5.19; Cl, 13.14; N, 7.79; S, 5.94. Found: C, 57.91; H, 5.19; Cl, 12.91; N, 7.75; S, 5.78.

EXAMPLE 118 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r4- (piperidin-4-PbenzoiH-piperazine hydrochloride The title compound was obtained in a manner similar to Example 7, except that 1- [4- (1-tert-butoxycarbonylpiperidin-4-yl) benzoyl] -4 - [(6-chloronaphthalene-2 il) sulfonyl] piperazine. 1 H-NMR (DMSO-d6) delta: 1.78-1.94 (4H, m), 2.80-3.21 (7H, m), 3. 30-3.84 (6H, m), 7.23 (2H, d, J = 8.3Hz), 7.28 (2H, d, J = 8.3Hz), 7.71 (1H, dd, J = 8.8.2.OHz), 7.80 (1 H, dd, J = 8.8.2.OHz), 8.17 (1 H, d, J = 8.8Hz), 8.22-8.27 (2H, m), 8.49 (1 H, s), 8.78-9.00 (2H , m). MS (FAB) m / z: 498 [(M + H) +, Cl 35], 500 [(M + H) +, Cl37]. Elemental analysis for C26H28CI N3O3S.HCI .3 / 5H2O Calculated: C, 57.27; H, 5.58; Cl, 13.00; N, 7.71; S, 5.88. Found: C, 57.23; H, 5.52; Cl, 12.90; N, 7.60; S, 5.83.

EXAMPLE 119 3RS-3-r (6-chloronaphthalen-2-yl) sulfonamido1-1 -r4- (pyridin-4-ylbenzoylpyrrolidine hydrochloride) In saturated ethanolic hydrochloric acid, (3RS) -1-tert-butoxycarbonyl-3 - [(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine was dissolved, followed by stirring at room temperature for 8 hours. Then, the solvent was removed by distillation under reduced pressure. The reaction was performed in a manner similar to Example 4, except that the resulting residue and 4- (4-pyridyl) benzoic acid were used as starting materials. 1 H-NMR (DMSO-d6) delta: 1.70-2.10 (2H, m), 3.00-3.65 (4H, m), 3. 75-3.90 (1 H, m), 7.50-8.40 (13H, m), 8.95-9.05 (2H, m). MS (FAB) m / z: 492 [(M + H) +, Cl 35], 494 [(M + H) +, Cl37]. Elemental analysis for C26H22CI N3O3S.HCI .I.8H2O Calculated: C, 55.68; H, 4.78; N, 7.49; Cl, 12.64; S, 5.72. Found: C, 55.62; H, 4.94; N, 7.67; EXAMPLE 120 (3RS) -1-R (6-Chloronaphthalen-2-yl) sulfonyl-1-3-r4- (pyridin-4-D-benzamidolpyrrolidine hydrochloride (3RS) -1-tert-Butoxycarbonyl-3- [4- (4-pyridyl) benzamido] pyrrolidine was dissolved in saturated ethanolic hydrochloric acid, followed by stirring at room temperature for 4 hours. The solvent was then removed by distillation under reduced pressure. The reaction was carried out in a manner similar to Example 1, except that the resulting residue and 6-chloro-2-naphthylsulfonyl chloride were used as starting materials. 1 H-NMR (DMSO-dβ) delta: 1.90-2.10 (2H, m), 3.00-3.60 (4H, m), 4-15-4.25 (1 H, m), 7.57 (1 H, dd, J = 8.8.2.OHz), 7.73 (2 H, d, J = 8.8 Hz), 7.85 (1 H, dd, J = 8.8 , 2.OHz), 7.90 (2H, d, J = 8.8Hz), 7.95-8.05 (2H, m), 8.18 (1H, d, J = 8.8Hz), 8.30-8.40 (3H, m), 8.50 (1 H, s), 8.98 (2H, d, J = 6..4Hz). MS (FAB) m / z: 492 [(M + H) +, Cl 35], 494 [(M + H) +, Cl37]. Elemental analysis for C26H22C1 N3 ° 3S O.8HCI .O.8H2O Calculated: C, 58.31; H, 4.59; N, 7.85; Cl, 1 1.92; S, 5.99. Found: C, 58.27; H, 4.68; N, 7.80; Cl, 1.94; S, 6.04.

EXAMPLE 121 1-rr (E) -2- (6-Chloropyridin-3-yl) ethylene-sulfonin-4-r4- (pyridin-4-D-benzoylpiperazine The tert-butoxycarbonyl group was removed in a similar manner to Example 7, except that 1-tert-butoxycarbonyl-4 - [[(E) -2- (6-chloropyridin-3-yl) ethylene] sulfonyl] piperazine was used as the starting material. The residue was subjected to the reaction as in Reference Example 116, whereby the title compound was obtained. 1 H-NMR (DMSO-dβ) delta: 3.10-3.31 (4H, br), 3.40-3.84 (4H, br), 7. 50 (1 H, d, J = 15.9Hz), 7.52 (1 H, d, J = 15.9Hz), 7.46 (3H, d, J = 8.3Hz), 8.06 (2H, d, J = 8.3Hz), 8.28-8.33 (3H, m), 8.79 (1 H, d, J = 2.OHz), 8.94 (2H, d, J = 6.4Hz). MS (FAB) m / z: 469 [(M + H) +, Cl 35], 471 [(M + H) +, Cl37]. Elemental analysis for C23H21 CI N4O3S.HCLO.4H2O Calculated: C, 53.89; H, 4.48; N, 10.93; Cl, 13.83; S, 6.26. Found: C, 53.95; H, 4.47; N, 11.02; Cl, 13.91; S, 6.39.

EXAMPLE 122 1-R (6-Chloronaphthalen-2-yl) sulfonyl-4-r 2 -methyl-4- (pyridin-4-Q-benzoylpiperazine hydrochloride The reaction was performed in a manner similar to the Reference Example 7, except that 1- (4-bromo-2-methylbenzoyl) -4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine was used as starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.20 (3H, s), 2.80-4.00 (8H, m), 7.36 (1 H, d, J = 8.3Hz), 7.73 (1 H, dd, J = 8.8 , 2.4Hz), 7.75-7.85 (2H, m), 7.88 (1 H, s), 8.18 (1 H, d, J = 8.8Hz), 8.20-8.30 (4H, m), 8.50 (1 H.br s), 8.90 (2H, d, J = 6.8Hz). MS (FAB) m / z: 506 [(M + H) +, Cl 35], 508 [(M + H) +, Cl37].

EXAMPLE 123 N-oxide of 4-r4-IT4-r (6-chloronaphthalen-2-yl) sulfonippiperazin-1 -carbonyl-3-methylphenylpyridine The reaction was carried out in a manner similar to Example 6, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [2-methyl-4- (pyridin-4-yl) was used as the starting material benzoyl] piperazine, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.27 (3H, s), 2.80-4.20 (8H, m), 7.16 (1 H, d, J = 8.3 Hz), 7.38 (1 H, J = 8.3 Hz), 7.41 (1 H, br s), 7.48 (2 H, d, J = 6.8 Hz), 7.61 (1 H, dd , J = 8.8.1.5Hz), 7.75 81H, d, J = 8.8Hz), 7.91-7.97 (3H, m), 8.28 (2H, d, J = 6.8Hz), 8.31 (1H, br s) . MS (FAB) m / z: 522 [(M + H) +, C? 0), 524 [(M + H) +, C? 3 ']. Elemental analysis for C27H24CI N3O4S.H2O Calculated: C, 60.05; H, 4.85; Cl, 6.56; N, 7.78; S, 5.94. Found: C, 59.98; H, 4.89; Cl, 6.51; N, 7.48; S, 5.92.

EXAMPLE 124 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-4-r3-methyl-4- (pyridin-4-D-benzoylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 3-methyl-4- (4-pyridyl) benzoic acid hydrochloride was used as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.27 (3H, s), 3.08 (4H, br), 3.47 (2H, br), 3.72 (2H, br), 7.26-7.37 (3H, m), 7.73 (1H, dd, J = 8.8.2.OHz), 7.83 (1H, dd, J = 8.8.2 .OHz), 7.86 (2H, d, J = 6.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.25-8.29 (2H, m), 8.50 (1 H, br s), 8.87 (2H , d, J = 6.8Hz). MS (FAB) m / z: 506 [(M + H) +, Cl 35], 508 [(M + H) +, Cl37]. Elemental analysis for C27H24CI N3O3S.O.9HCI .I JH2O Calculated: C, 56.95; H, 5.01; Cl, 1 1.83; N, 7.38; S, 5.63.

Found: C, 57.08; H, 5.04; Cl, 11.75; N, 7.37; S, 5.49.

EXAMPLE 125 N-oxide of 4-r4-IT4-r (6-chloronaphthalen-2-yl) sulfonip-piperazin-1-picarbonyl-2-methylphenylpyridine The reaction was performed in a manner similar to Example 6, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [3-methyl-4- (pyridin-4-yl) benzoyl] piperazine was used as starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.28 (3H, s), 3.13 (4H, br), 3.63 (2H, br), 3.86 (2H, br), 7.15-7.28 (5H, m), 7.60 ( 1 H, d, J = 8.8 Hz), 7.76 (1 H, d, J = 8.8 Hz), 7.90-7.96 (3 H, m), 8.26 (2 H, d, J = 6.8 Hz), 8.31 (1 H, s). MS (FAB) m / z: 522 [(M + H) +, Cl 35], 524 [(M + H) +, Cl 35]. Elemental analysis for C27H24CI N3O4S.H2O Calculated: C, 60.05; H, 4.85; Cl, 6.56; N, 7.78; S, 5.94. Found: C, 59.71; H, 4.68; Cl, 6.87; N, 7.63; S, 5.91.

EXAMPLE 126 1 -r (6-Chloronaphthalen-2-yl) sulfonyl-1-4-r4- (2-methylpyridin-4-p-benzoylpiperazine hydrochloride The reaction was carried out in a manner similar to Example 4, except that 4- (2-methyl-4-pyridyl) benzoic acid hydrochloride was used as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.76 (3H, s), 3.00-3.90 (8H, m), 7.56 (2H, d, J = 8.3Hz), 7.74 (1H, dd, J = 8.8.2.4Hz), 7.83 (1H, dd, J = 8.8.2.OHz), 8.00 (2H, d, J = 8.3 Hz), 8.14 (1 H, d, J = 6.4 Hz), 8.19 (1 H, d, J = 8.8 Hz), 8.22-8.29 (3 H, m), 8.51 (1 H, br s), 8.80 ( 1 H, d, J = 6.4 Hz). MS (FAB) m / z: 506 [(M + H) +, CI35], 508 [(M + H) +, CI35. Elemental analysis for C27H24CI N3O3S.HCI .2H2O Calculated: C, 56.06; H, 5.05; Cl, 12.26; N, 7.26; S, 5.54. Found: C, 55.84; H, 5.03; Cl, 12.26; N, 6.87; S, 5.54.

EXAMPLE 127 N-oxide of 4-r4-IT4-r 6-chloronaphthalen-2-yl) sulfonyl-piperazin-1-pcarbonipheniH-2-methylpyridine The reaction was carried out in a manner similar to Example 6, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -4- [4- (2-methylpyridin-4-yl) benzoyl] piperazine was used as the starting, with which the title compound was obtained. 1 H-NMR (DMSO-dβ) delta: 2.58 (3H, s), 3.13 (4H.br), 3.65 (2H, br), 3.84 (2H, br), 7.34 (1H, dd, J = 6.8, 2.4Hz), 7.41 (2H, d, J = 8.3Hz), 7.45 (1H, d, J = 2.4Hz), 7.56-7.62 (3H, m), 7.76 (1H, dd, J = 8.8.2 .OHz), 7.91-7.96 (3H, m), 8.28-8.32 (2H, m). MS (FAB) m / z: 522 [(M + H) +, Cl 35], 524 [(M + H) +, Cl37]. Elemental analysis for C27H24CI N3O4S.H2O.O.O5CH2CI2 Calculated: C, 59.69; H, 4.83; Cl, 7.16; N, 7.72; S, 5.89. Found: C, 59.47; H, 4.87; Cl, 6.98; N, 7.48; S, 6.10.

EXAMPLE 128 N-oxide of 4-r4-rr4-r 6-chloronaphthalen-2-yl) sulfonyl-2-rr-2-morpholin-4-yl) ethylamino-1-carbon-1-piperazine-1-carbonylphenylpyridine The reaction was performed in a manner similar to Example 4, except that 4- [4 - [[2-carboxy-4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] phenyl was used ] pyridine as starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.22 (4H, s), 2.35-2.80 (6H, br), 3.20-3.90 (3H, br), 3.74 (4H, s), 4.20-4.60 (1H, br), 5.25-5.50 (1 H, br), 6.80-7.20 (1 H, br), 7.45-7.70 (7H, m), 7.76 (1 H, d, J = 8.8Hz), 7.85-7.95 (3H , m), 8.26 (2H, d, J = 6.9Hz), 8.32 (1 H, s). MS (FAB) m / z: 664 [(M + H) +, Cl 35], 666 [(M + H) +, Cl37].

EXAMPLE 129 N-oxide of 4-r4-rr4-r (6-chloronaphthalen-2-yl) sulfonyl-2-rr2- (dimethylamino) ethylamino-1-carbon-N-piperazin-1-H-carbon-phenyl-pyridine The reaction was carried out in a manner similar to Example 4, except that 4- [4 - [[2-carboxy-4 - [(6-chloronaphthalen-2-yl) sulfonyl] piperazine- N-oxide were used as starting materials. 1 -yl] carbonyl] phenyl] pyridine and 2- (dimethylamino) ethylamine, whereby the title compound was obtained. 1 H-NMR (DMSO-d 6) delta: 2.29 (6H, s), 2.35-2.75 (6Hbr), 3.35- 3.90 (3H, br), 4.40-4.60 (1H, br), 5.25-5.50 (1H, br), 7.00-7.20 (1 H, br), 7.45-7.65 (7H, m), 7.77 (1 H, dd, J = 8.8.1.4Hz), 7.85-7.95 (3H, m), 8.26 (2H, d, J = 7.3 Hz), 8.34 (1 H, s), 7.85-7.95 (3 H, m), 8.26 (2 H, d, J = 7.3 Hz), 8.34 (1 H, s). MS (FAB) m / z: 622 [(M + H) +, Cl 35], 624 [(M + H) +, Cl37]. Elemental analysis for C31 H32N5O5S.O.O5CH2CI2.2H2O Calculated: C, 56.30; H, 5.49; N, 10.57; Cl, 5.89; S, 4.84. Found: C, 56.27; H, 5.37; N, 10.39; Cl, 6.01; S, 4.91.

EXAMPLE 130 4-r (6-Chloronaphthalen-2-yl) sulfonin-2-methoxycarbonylmethyl-1-y4- (pyridin-2-p-benzoylpiperazine The reaction was performed in a manner similar to the Reference Example 116, except that 1 - [(6-chloronaphthalen-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine and 4- (2-pyridyl) benzoic acid hydrochloride were used, whereby the title compound was obtained . 1 H-NMR (DMSO-d6) delta: 2.30-4.50 (11 H, m), 5.06 (1 H, br s), 7.30-7.50 (3 H, m), 7-72 (1 H, dd, J = 8.8.2.OHz), 7.80-7.85 (1 H, m), 7.85-7.95 (1 H, m), 7.98 (1 H, d, J = 7.8 Hz), 8.10 (2 H, d, J = 8.3 Hz ), 8.18 (1 H, d, J = 8.8 Hz), 8.25-8.30 (2 H, m), 8.51 (1 H, s), 8.65-8.70 (1 H, m). MS (FAB) m / z: 564 [(M + H) +, Cl 35], 566 [(M + H) +, Cl37].

Elemental analysis for C29H26CIN3O5S .IH2O Calculated: C, 59.66; H, 4.87; N, 7.20; Cl, 6.07; S, 5.49. Found: C, 59.53; H, 4.61; N, 7.05; Cl, 6.33; S, 5.70.

EXAMPLE 131 4-R (6-Chloronaphthalen-2-yl) sulfonyl-2-carboxymethyl-1 - [4- (pyridin-2-yl) benzoylpiperazine hydrochloride The reaction was carried out in a manner similar to Reference Example 3, except that 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-methoxycarbonylmethyl-1 - [4- (pyridin-2-yl) was used. benzoyl] pperazine as the starting material, whereby the title compound was obtained. 1 H-NMR (DMSO-d6) delta: 2.30-4.50 (8H, m), 5.05 (1 H, br s), 7. 35-7.40 (1 H, m), 7.43 (2 H, d, J = 8-8 Hz), 7.72 (1 H, d, J = 8.3 Hz), 7.81 (1 H, d, J = 8.8 Hz), 7.85 -7.90 (1 H, m), 7.97 (1 H, d, J = 7.8 Hz), 8.49 (1 H, s), 8.65-8.70 (1 H, m). MS (FAB) m / z: 550 [(M + H) +, Cl 35], 552 [(M + H) +, Cl37]. Elemental analysis for C28H24CIN3O5S.O.4HCI.O.9H2O Calculated: C, 57.90; H, 4.55; N, 7.23; Cl, 8.55; S, 5.52. Found: C, 57.76; H, 4.26; N, 7.02; Cl, 8.44; S, 5.27.

EXAMPLE 132 2-Carbamoylmethyl-4-r (6-chloronaphthalen-2-yl) sulfonyl-H - 1 - [4- (pyridin-2-yl) benzoylpiperazine hydrochloride The reaction was performed in a manner similar to Reference Example 35, except that 4 - [(6-chloronaphthalen-2-yl) sulfonyl] -2-carboxymethyl-1- [4- (pyridin-2-yl) was used. benzoyl] piperazine as starting material, whereby the title compound was obtained. H-NMR (DMSO-d6) delta: 2.20-4.50 (8H, m), 5.10 (1 H, br s), 6.96 (2H, br s), 7.45-7.55 (3H, m), 7.70-7.85 (3H, m), 8.05-8.35 (6H, m), 8.50 (1 H, s), 8.81 (1 H, d, J = 4.9Hz). MS (FAB) m / z: 549 [(M + H) +, Cl 35], 551 [(M + H) +, Cl37]. Elemental analysis for C28H25CIN4O4S.I.3HCI.I.5H2O Calculated: C, 53.94; H, 4.74; N, 8.99; Cl, 13.08; S, 5.14. Found: C, 53.85; H, 4.87; N, 8.80; Cl, 13.19; S, 5.27.

EXAMPLE 133 1 -r (Z) -4-Chloro-β- (2-hydroxyethan-1-yl) -β-styrylsulfonyl-4-r4- (pyridin-2-yl) benzoylpiperazine hydrochloride Under ice-cooling, 4-tert-butoxycarbonyl-1- [(Z) -4-chloro-β- [2- (methoxymethoxy) ethyl] -β-styrylsulfonyl] piperazine (355 mg) was dissolved in ethanol (3 ml) , followed by the addition of saturated ethanolic hydrochloric acid (6 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the residue was supplied for a reaction similar to that of Example 4, whereby the title compound (285 mg, 65%) was obtained. H-NMR (DMSO-d6) delta: 2.58 (2H, t, J = 6.6Hz), 3.06 (4H, br s), 3. 15-3.60 (4H, br), 3-68 (2H, t, J = 6.6Hz), 7.24 (1H, s), 7.38 (2H, d, J = 8.6Hz), 7.40 (2H, d, J = 8.6Hz), 7.47-7.57 (3H, m), 8.02-8.10 (2H, m), 8.14 (2H, d, J = 8.3Hz), 8.74 (1H, d, J = 4.4Hz). MS (FAB) m / z: 512 (M + H).

EXAMPLE 134 1 -r (E) -4-Chloro-β- (2-hydroxy-1-yl) -β-styrylsulfonyl-4-r4- (pyridin-2-yl) -benzo-piperazine hydrochloride The title compound was obtained in a manner similar to Example 133, except that 4-tert-butoxycarbonyl-1 - [(E) -4-chloro-β- [2- (methoxymethyloxy) ethyl] -β-styrylsulfonyl] piperazine was used as the starting material. 1 H-NMR (DMSO-d6) delta: 2.74 (2H, t, J = 7.3Hz), 3.27 (4H, br s), 3. 37-3.85 (6H, m), 7.45 (1 H, s), 7.50-7.60 (5H, m), 7.68 (2H, d, J = 8.3Hz), 8.06-8.17 (4H, m), 8.75 (1H , d, J = 4.9Hz). MS (FAB) m / z: 512 (M + H) +. Elemental analysis for C26H26CIN3O4S.I.IH2O Calculated: C, 55.12; H, 5.11; N, 7.42; Cl, 13.14; S, 5.66. Found: C, 55.22; H, 5.21; N, 7.20; Cl, 12.97; S, 5.66.

PROOF 1 Measurement of Ki value against FXa In a 96-well microtiter plate, 5 μl of a sample solution, 5 μl of purified water, 40 μl of a 100 mM tris buffer - 200 mM sodium chloride - 0.2% BSA (pH: 7.4) were discarded μl of human FXa, 0.05 U / ml (product of Enzyme Research, dissolved and diluted with the same buffer), followed by the addition of 40 μl of S2222 (product of Chromogenix, final concentration: 75, 150, 300 and 600 μM) . The increase in absorbance at 405 nm was measured at room temperature for 15 minutes. From the reciprocal of the reaction rate and the concentration of the inhibitor, four primary regression equations were found (Y = aX + b) (Dixon plot). The mean of six values, obtained by solving simultaneous equations, was designated as a Ki value. The Ki values of the compounds obtained in Examples 91 and 93 against FXa were 6.6 nM and 10.9 nM, respectively.

TEST 2 Measuring the Ki against thrombin value In a 96-well microtiter plate, 5 μl of a sample solution, 5 μl of purified water, 40 μl of a 100 mM tris buffer - 200 mM sodium chloride - 0.2% BSA were discharged in portions (pH: 7.4 ) and 10 μl of human thrombin, 5 U / ml (product of Sigma Chemical, dissolved and diluted with a measuring buffer), followed by the addition of 40 μl of S2226 (Chromogenix product, final concentration: 50, 100, 200 and 400 μM). The increase in absorbance at 405 nm was measured at room temperature for 15 minutes. From the reciprocal of the reaction rate and the concentration of the inhibitor, four primary regression equations were found (Y = aX + b) (Dixon plot). The measure of six values, obtained by solving simultaneous equations, was designated as a value of K i. The Ki values of the compounds obtained in Examples 91 and 93 against thrombin were 0.4 μM and 10.9 μM, respectively.

TEST 3 Measurement of the inhibitory action of FXa (C n) 1) Reaction rate method In a 96-well microtiter plate, 10 μl of a sample solution, 40 μl of a 100 mM tris buffer - 200 mM sodium chloride - 0.2% BSA were discharged in portions (pH: 7.4) and 10 μl of human FXa, 0.05 U / ml ("Cosmobío-ERL HFXa-1011", dissolved and diluted with the same buffer), followed by the addition of 40 μl of S2222 (product of Chromogenix). The increase in absorbance (mDO / min) at 405 nm was measured at room temperature. From the following equation, an inhibitory proportion (%) of each sample was determined. The final concentration of the sample and the inhibitory proportion (%) were plotted on a logarithmic probability paper along the abscissa and the ordinate, respectively; With this, a 50% inhibitory concentration (Clso) was determined. Inhibitory ratio (%) = (1-DO of the sample / control OD) x 100 The compound of Example 29 showed a 50% inhibitory concentration of FXa of 7.8 nM. 1) End point method A sample solution (100 μl), 280 μl of a 100 mM tris buffer - 200 mM sodium chloride (pH 7.4) and 100 μl of 1 mM S2222 solution were mixed and heated at 37 ° C. (Chromogenix Corp.). To the resulting mixture, 20 μl of human FXa 0.625 U / ml ("Cosmobio-ERL HFXa-1011", dissolved and diluted with a measuring buffer) were added, followed by heating at 37 ° C for 15 minutes. To the resulting mixture was added 100 μl of 1 M citric acid and then its absorbance at 405 nm was measured. A mixture was used as a target to which only the solvent for the sample was added, while the mixture to which 1 M citric acid was added before the addition of FXa was used as control. The concentration of the sample (Cl50) at which 50% of the FXa activity was inhibited was determined and was designated as an index of FXa inhibitory action. The compounds of Examples 6 and 19 exhibited a 50% inhibitory concentration of 125 nM and 72 nM, respectively.

TEST 4 Measurement of thrombin inhibitory action (Clgo) 1) Reaction rate method In a 96-well microtiter plate, 10 μl of a sample solution, 40 μl of a 100 mM tris buffer - 200 mM sodium chloride - 0.2% BSA were discharged in portions (pH: 7.4) and 10 μl of human thrombin, 4 U / ml (Sigma Chemical, dissolved and diluted with a measuring buffer), followed by the addition of 40 μl of S2266 500 μM (product of Chromogenix). The increase in absorbance (mDO / min) at 405 nm was measured at room temperature. From the following equation, an inhibitory proportion (%) of each sample was determined. The final concentration of the sample and the inhibitory proportion (%) were plotted on a logarithmic probability paper along the abscissa and the ordinate, respectively; with this, the 50% inhibitory concentration (Cl50) was found. Inhibitory ratio (%) = (1-OD of the sample / control OD) x 100 The compound of Example 19 showed a 50% thrombin inhibiting concentration of 1.9 μM. 1) End point method A sample solution (100 μl), 280 μl of a 100 mM tris buffer - 200 mM sodium chloride (pH 7.4) and 100 μl of 1 mM S2238 solution were mixed and heated at 37 ° C. (Chromogenix) To the resulting mixture, 20 μl of 1 U / ml human thrombin (Sigma Chemical, dissolved and diluted with a measuring buffer) was added, followed by heating at 37 ° C for 10 minutes. To the resulting mixture was added 100 μl of 1 M citric acid and then its absorbance at 405 nm was measured. A mixture was used as a target to which only the solvent for the sample was added, while the mixture to which 1 M citric acid was added before the addition of thrombin was used as control. The concentration of the sample (IC50) at which 50% of thrombin activity was inhibited was determined and was designated as an index of thrombin inhibitory action. The compound of Example 92 exhibited a 50% inhibitory concentration of thrombin not less than 200 μM.

TEST 5 Measurement of the coagulation delay action (Prothrombin time measurement) Plasma (20 μl) and 20 μl of a sample solution were mixed. To the resulting mixture, 40 ml of cinplastine (product of Organon Teknika) was added and the coagulation time was measured. The concentration of the sample was found at which the plasma coagulation time (CT2) was increased twice and designated as an anticoagulant action index.

The compound of Example 92 showed CT2 of 0.35 μM.

PROOF 6 ORAL ADMINISTRATION 1) Method A sample was dissolved or suspended in a 0.5% (w / v) methyl cellulose solution and the resulting solution or suspension was orally administered to rats 8 to 11 weeks of age (10 ml / kg) (male Wistar rats) , Nippon SLC Co., Ltd.), who had fasted overnight. After administering the sample, the blood to which 1/10 parts by weight of sodium citrate 3.13% (w / v) was added was drawn from the cervical vein. The rats were awake except during the extraction of the blood. The feeding was started again 6 hours after the blood extraction. From each blood sample the plasma was separated by centrifugation and the anti-FXa activity in the blood and the prothrombin time delay action were measured. 1) Measurement method 2.1) Measurement of anti-FXa activity in plasma In a 96-well plate, 5 μl of plasma was drained portionwise followed by the addition of 55 μl of a 100 mM tris buffer - 200 mM sodium - 0.2% BSA (pH 7.4), water and human factor Xa 0.1 U / ml solution (dissolved and diluted with a measuring buffer) and 40 μl of S2222. After stirring for 10 seconds in a plate mixer, the increase in absorbance (mDO / min) at 405 nm was measured at room temperature. The inhibitory ratio was calculated as follows: Inhibitory proportion (%) = (1-DO of the sample / OD of the control on average in relation to the blood coagulation time of the sample) x 100 2-2) Measurement of the coagulation delay action by oral administration (prothrombin time measurement) To 20 μl of the plasma, 40 μl of cinplastin was added.

(Organon Teknika / USA) and the prothrombin time was measured. The proportion of the prothrombin time after the administration of the sample with respect to the prothrombin time before the administration of the sample, was designated as the index of the action of delay of the coagulation action 1) Result The compound of Example 110 showed a 70% anti-FXa activity in the plasma one hour after the administration of 30 mg / kg of the sample. It delayed the prothrombin time 1.18 times.

TEST 7 Test method for antithrombotic effects in a rat model of tissue-derived thromboplastin DIC A rat was anesthetized with halothane. After the blood extraction (to measure the number of platelets, anti-FXa and TAT activity) of his cervical vein using 1/10 of parts by weight of sodium citrate 3.13% (w / v), the sample was administered orally. At an appropriate time after administration, the rat was anesthetized intraperitoneally (1 mg / kg) with Nembutal (50 mg / ml sodium pentobarbital, Abott Laboratories), followed by intravenous drip of tissue thromboplastin 0.2 U / ml (Thromboplastin C plus, Dade Diagnostics from PR Inc.) of the femoral vein for one minute at a rate of 2.5 to 3.0 ml / kg / min. Blood was drawn (to measure the number of platelets and anti-FXa activity) from the cervical vein 10 minutes after the intravenous drip and blood was drawn (to measure TAT) from the cervical vein 20 minutes after the blood draw . The number of platelets, anti-FXa activity in the plasma and TAT concentration of each blood sample were measured. The number of platelets was measured by means of an automatic cytometer, while the anti-FXa activity in the plasma was measured in a manner similar to that described in test 7. For the measurement of TAT (thrombin-anti-thrombin complex), it was used an EnzygnostR TAT micro kit (boering Verke).

As a result of oral administration of 30 mg / kg of the compound of Example 95, apparent anti-FXa action was recognized in the plasma and a reduction in the number of platelets and an increase in TAT concentration (tissue thromboplastin was suppressed it was administered one hour after the administration of the sample).

Industrial Application Capability The sulfonyl derivative according to the present invention exhibits anticoagulant action based on an excellent FXa inhibitory action, such that, without acting on platelets, it can treat or prevent various diseases caused by thrombi or emboli such as infarction. cerebral, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization, thrombus formation by extracorporeal circulation or coagulation after blood extraction.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A sulfonyl derivative represented by the following formula (I): wherein: R1 represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group , an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A1-B1- (wherein A1 represents an amino group which may have one or two substituents, a saturated 5- or 6-membered cyclic hydrocarbon group) or unsaturated which may have a substituent, or a saturated or unsaturated 5 or 6 membered heterocyclic group which may have a substituent, and B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonyl alkyloxy group or a alkylenecarbonyloxy group), R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group lo, or R2 or R3 can be coupled together with R1 to form an alkylene or alkenylene group of C? -3, R4 and R5 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group (with the proviso that R4 and R5 do not represent a hydrogen atom at the same time), Q1 represents a saturated or unsaturated 5 or 6 membered cyclic hydrocarbon group which may have a substituent, a heterocyclic group of 5 or 6 saturated or unsaturated member which may have a substituent, or a bicyclic or tricyclic group of fused saturated or unsaturated rings which may have a substituent, Q2 represents a single bond, an oxygen atom, a sulfur atom, an alkylene group of C- ? Linear or branched, a linear or branched C2-6 alkenylene group, a linear or branched C2-6 alkynylene group, a group -N (R6) -CO- (wherein R6 represents a hydrogen atom or a alkyl group), a group -N (R7) - (CH2) m- (wherein R7 represents a hydrogen atom or an alkyl group and m represents an integer from 0 to 6) or a group of the following formula: (which represents a saturated or unsaturated divalent 5 or 6 membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered divalent heterocyclic group which may have a substituent, or a divalent saturated or unsaturated which may have a substituent and < - C means the binding of the carbon atom of this group to Q1), Q3 represents any of the following groups: (in which, when the carbon atom to which each of R8, R9, R10, R11, R12, R13, R15 and R16 is attached is not adjacent to a nitrogen atom, R8, R9, R10, R11, R12 , R13, R15 and R16 each independently represents: a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkyloxy group, a hydroxyalkyl group, a hydroxyalkyloxy group, a hydroxyalkylcarbonyl group, a group hydroxyalkylsulfonyl, a formyl group, a formylalkyl group, a formylalkylcarbonyl group, a formylalkysulfonyl group, an alkylcarbonyl group, an alkylsulfonyl group, an alkylcarbonylalkyl group, an alkylsulfonylalkyl group, a carboxyl group, a carboxyalkyl group, a carboxyalkyloxy group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxy group carbonylalkyloxy, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group, an amino group which may have one or two substituents, an aminoalkyl group in which the amino moiety may have one or two substituents, an aminoalkyloxy group in which the amino moiety may have one or two substituents, an aminoalkylcarbonyl group in which the amino portion may have one or two substituents, an aminoalkylcarbonyloxy group in which the amino portion may have one or two substituents, an aminocarbonyl group in which the amino portion may have one or two substituents, aminocarbonylalkyl group in which the amino moiety can have one or two substituents, an aminocarbonylalkyl group in which the amino moiety can have one or two substituents, or an A2-B2- moiety (in which A2 represents a cyclic hydrocarbon group of 5 or 6 members, saturated or unsaturated, which may have a substituent, or a 5- or 6-membered heterocyclic group, saturated or unsaturated, which may have a substituent, and B2 represents a single bond, a carbonyl group or an alkylene group ); when the carbon atom to which each of R8 is attached, R, R10, R1 1, R1, R13, R15 and R16, is adjacent to a nitrogen atom, then R8, R9, R0, R1, R12, R 13, R 5 and R 6 represent, each independently: a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, a formyl group, a formylalkyl group, a formyl alkylcarbonyl group, a formylalkyl sulfonyl group, an alkylcarbonyl group, an alkylsulfonyl group, an alkylcarbonylalkyl group, an alkylsulfonylalkyl group, a carboxyl group, a carboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group, an alkoxyalkyl group, an alkoxycarbonyl group, a group alkoxycarbonylalkyl, an alkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group, an aminoalkyl group in which the amino moiety may have r one or two substituents, an aminoalkylcarbonyl group in which the amino moiety can have one or two substituents, an aminocarbonyl group in which the amino moiety can have one or two substituents, an aminocarbonylalkyl group in which the amino moiety can have one or two substituents, or a group A8-B8- (in which A8 represents a 5- or 6-membered saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, or a 5- or 6-membered heterocyclic, saturated or Unsaturated, which may have a substituent, and B8 represents a single bond, a carbonyl group or an alkylene group); R8 and R9, R ^ O and R11, R12 and R ^, and R15 and R16 may each be coupled together with a ring carbon atom and represent a 5- to 7-membered, saturated or unsaturated cyclic hydrocarbon group, which may have a substituent, or a heterocyclic group of 5 to 7 membered, saturated or unsaturated, which may have a substituent, R14 and R17 each independently represent: a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkylcarbonyl group, a alcoxialquilsulfonilo group, a formyl group, a formylalkyl group, a formilalquilcarbonilo group, a formilalquilsulfonilo group, an alkylcarbonyl group, an alkylcarbonylalkyl group, an alkylsulfonyl group, alkylsulfonylalkyl, a carboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, a group c arboxialquilsulfonilalquilo, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylcarbonyl group, an alcoxicarbonilalquilsulfonílo group, an amino group which may have one or two substituents, an aminoalkyl group in which the amino moiety may have one or two substituents, a group aminoalkyloxy in which amino moiety can have one or two substituents, an aminoalkylcarbonyl group in which the amino moiety can have one or two substituents, an aminoalkyloxycarbonyl group in which the amino moiety can have one or two substituents, an aminocarbonyl group in which amino moiety may have one or two substituents, one aminocarbonyl group in which the amino moiety may have one or two substituents, one aminocarbonyloxyalkyl group in which the amino moiety may have one or two substituents, R and R12 0 R13 may be coupled together with a carbon atom of the ring and with a nitrogen atom to which is R14 attached? and represent a 5 to 7 membered heterocyclic group, saturated or unsaturated, which may have a substituent, R 7 and R 15 O R 16 may be coupled together with a ring carbon atom and with a nitrogen atom to which R is attached 7 to form a 5 to 7 membered heterocyclic group, saturated or unsaturated, which may have a substituent, a, b, d, e, and g each independently represent an integer of 0 or 1, c represents an integer of 0 to 3, f, hei each independently represent an integer from 1 to 3, with the proviso that the sum of a, b and c represents an integer of 2 or 3, the sum of d and e represents an integer of 0 or 1, and the sum of f, g, and h represents an integer from 3 to 5); T ^ represents a carbonyl group, a group -CH (R "8) - (wherein R ^ 8 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group wherein the amino moiety may have a substituent) or a -C (= N0R19) - group (wherein R 9 represents a hydrogen atom , alkyl group, carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent), X1 and X2 each represent independently a methyl group or a nitrogen atom]; and salts or solvates thereof.

2. A sulfonyl derivative in accordance with the claim 1, further characterized in that in the following group: in the formula (I) is a group of the following formula: (wherein R2, R4, R5, X1 and X2 have the same meanings defined above), and salts or solvates thereof.

3. A sulfonyl derivative according to claim 1 or 2, further characterized in that R4 represents a halogen atom, and salts or solvates thereof.

4. A sulfonyl derivative according to any of claims 1 to 3, further characterized in that Q1 represents a phenyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyrrolidinyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent or a tetrahydrothiazolopyridyl group which may have a substituent; and salts or solvates thereof.

5. A sulfonyl derivative according to any of claims 1 to 4, further characterized in that Q2 represents a single bond, a phenylene group, a cyclohexylene group or a cyclohexenylene group, and salts or solvates thereof.

6. A derivative of sulfonyl according to any of claims 1 to 5, further characterized in that Q3 represents a group of the following formula: [wherein R8, R9, a, b and c have the same meanings defined above], and salts and solvates thereof.

7. A sulfonyl derivative according to any of claims 1 to 6, further characterized in that T1 represents a carbonyl group, and salts and solvates thereof.

8. - A medicament comprising as an effective ingredient a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof.

9. An inhibitor of activated coagulation factor X comprising as an effective ingredient a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof.

10. An activated coagulation inhibitor comprising as an effective ingredient a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof.

11. A prophylactic and / or remedy for thrombosis or embolism comprising as an effective ingredient a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof.

12.- A prophylactic and / or remedy for cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization, thrombus formation by extracorporeal circulation or coagulation after blood extraction, which comprises as an active ingredient a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof.

13. - A pharmaceutical composition comprising a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof, and a pharmaceutically acceptable carrier.

14. The use of a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof, for the manufacture of a medicament for treating a disease caused by a thrombosis or embolism in a patient.

15. The use of a sulfonyl derivative according to any of claims 1 to 7, or a salt or solvate thereof, for the manufacture of a medicament for treating cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization, thrombus formation by extracorporeal circulation or coagulation after blood extraction in a patient.

16. The use according to claim 15, wherein said sulfonyl derivative or salt or solvate thereof, is also useful as an inhibitor of activated coagulation factor X.

17. The use according to claim 15, wherein said sulfonyl derivative, or salt or solvate thereof, is also useful as a coagulation inhibitor.

18. The use according to claim 15, wherein said sulfonyl derivative, or salt or solvate thereof, is also useful as a prophylactic and / or remedy for thrombosis or embolism. / / / S *** ^ _ _ ^ Í_¡ ^^^ S¡ _ ^^^ _ ^^^^ _? ^^ _ SUMMARY OF THE INVENTION A sulfonyl derivative represented by the following formula (I) is described: wherein: R1 represents a hydrogen atom, a hydroxyl group, a nitro group or the like, R2 and R3 each independently represent a hydrogen atom, a halogen atom or the like, R4 and R5 each independently represents a hydrogen atom , a halogen atom or the like, Q1 represents a saturated or unsaturated 5 or 6 membered cyclic hydrocarbon group which may have a substituent or the like, Q2 represents a single bond, an oxygen atom or the like, Q3 represents any of the following groups : T ^ represents a carbonyl group or the like, X1 and X2 each independently represent a methyl group or a nitrogen atom]; or salts or solvates thereof; the sulfonyl derivative, or salt or solvate thereof according to the present invention, is novel as an excellent anticoagulant and has strong FXa inhibitory action, rapidly exhibits sufficient long-lasting antithrombotic effects after oral administration and has fewer side effects. P00 / 329F