WO2002089803A1

WO2002089803A1 - Composition for iontophoresis

Info

Publication number: WO2002089803A1
Application number: PCT/JP2002/004422
Authority: WO
Inventors: Koichi Fujimoto; Naoki Tanaka; Ikuko Shimada; Fumitoshi Asai; Kazuhiro Inoue; Junichi Okada
Original assignee: Sankyo Company, Limited
Priority date: 2001-05-07
Filing date: 2002-05-07
Publication date: 2002-11-14

Abstract

An iontophoresis composition for blood clotting factor X inhibitors which contains either a benzamidine derivative having the general formula (1): (1) (wherein R1 represents hydrogen, halogeno, alkyl, or hydroxy; R2 represents hydrogen, halogeno, or alkyl; R3 represents hydrogen, optionally substituted alkyl, optionally substituted acyl, or optionally substituted alkylsulfonyl; R?4 and R5¿ are the same or different and each represents hydrogen, halogeno, optionally substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, or optionally substituted carbamoyl; R6 represents hydrogen, optionally substituted alkyl, optionally substituted acyl, carbamoyl, alkylsulfonyl, aryl, etc.; R?7 and R8¿ are the same or different and each represents hydrogen, alkyl, etc.; and n is 0, 1, or 2) or a pharmacologically acceptable salt of the derivative. It is useful as a remedy or preventive for thrombus or embolus.

Description

-Cis composition

[Technical field]

Light

The present invention relates to a composition for iontophoresis containing a benzamidine derivative useful as a therapeutic or prophylactic agent for thrombus or emboli, and a pharmacological notice of the composition for iontophoresis.

The present invention relates to a method for treating or preventing thrombus or embolus, which comprises administering an effective amount to a warm-blooded animal.

[Background technology]

As competitive competitive activated blood coagulation factor X inhibitors, JP-A-5-208946 (ΕΡ540051), WO 96/16940 (ΕΡ798295) or WO 00/47553 include aromatic amidine derivatives or amidinonaphthyl derivatives Is described. Further, WO 98/31661 (ΕΡ 976722) includes, for example, Ν— [4-1- [1-acetoimidoyl-1-4-piperidyloxy] phenyl] -Ν- [2- (3-amidinophenoxy) ethyl] sulfamoylacetic acid 2 Amidine derivatives such as trifluoroacetate are described. Furthermore, WO 01/30756 includes, for example, Ν- [4- (1_acetoimidoylpiperidine-1 4-^^ oxy) phenyl] -1N— [3- (3-amidinofenyl) —2 — (E) 1-Propenyl] ethanesulfonamide is described.

Intravenous administration and oral administration are generally used as administration forms of these drugs that act on the blood coagulation system. A formulation has been described. Here, iontophoresis is a percutaneous absorption promotion system that uses electricity. Utilizing the force of the transferred molecules from the cathode to the anode, the drug molecules pass through the skin barrier It is a system to promote. 'However, transdermal preparations of conventionally known blood coagulation factor X inhibitors have not been fully satisfactory with respect to skin permeability.

[Disclosure of the Invention]

The present inventors have conducted intensive studies on a transdermal preparation of a blood coagulation factor X inhibitor, which is useful as a therapeutic or preventive agent for thrombus or emboli, and as a result, have found that certain `` benzamidine derivatives '' can be iontophoresed. The present inventors have found that a cis preparation is efficiently absorbed from the skin, thereby completing the present invention. The present invention provides a composition for iontophoresis containing a benzamidine derivative useful as a therapeutic or prophylactic agent for thrombus or emboli, and administering a pharmacologically effective amount of the iontophoretic composition to a warm-blooded animal. Methods for treating or preventing thrombus or emboli are provided. The composition for iontophoresis of the present invention,

[Where,

R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxyl group, represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms, and represents a hydrogen atom, a carbon atom An alkyl group having 1 to 6 carbon atoms, a hydroxyl-substituted alkyl group having 1 to 6 carbon atoms, a carboxyalkyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms, and a carbon number 7 to 16 aralkyl groups, 2 to 7 carbon atoms Aliphatic acyl group, hydroxyl-substituted aliphatic acyl group having 2 to 7 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms, 2 to 7 carbon atoms A carboxyalkylsulfonyl group or a carboxyalkyl group having 3 to 8 carbon atoms,

R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms A carbonyl group, a carbonyl group having 2 to 7 carbon atoms, a carbamoyl group, a monoalkyl carbamoyl group having 2 to 7 carbon atoms, or a dialkylcarbamoyl group having 3 to 13 carbon atoms,

R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or a carbon atom having 1 to 6 carbon atoms substituted by a heterocyclic ring. Alkyl groups, C2 to C7 carboxyalkyl groups, C3 to C13 alkoxycarbonyl groups, C2 to C7 aliphatic acyl groups, C7 to C11 Aromatic acyl group, carbamoyl group, C1 to C6 alkylsulfonyl group, C6 to C10 aryl group, heterocycle, formimidoyl group, C2 to C7 A 11-iminoalkyl group, an N-alkylformimidyl group having 2 to 7 carbon atoms or an iminoarylmethyl group having 7 to 11 carbon atoms,

R ⁷ and R ⁸ represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

Alternatively, R ⁶ and R ⁷ together or R ⁷ and R ⁸ together represent an alkylene group having 2 to 5 carbon atoms,

n represents 0, 1 or 2. ] Or a pharmacologically acceptable salt thereof.

"Halogen atom" of R \ R ^2, R ⁴ and R ^5, for example, an iodine atom, a bromine atom, a chlorine atom, a fluorine atom and the like, for R ¹ is, preferably, a bromine atom, a chlorine atom Or a fluorine atom, particularly preferably a fluorine atom, and for R ² , preferably a bromine atom, a fluorine atom or a chlorine atom, particularly preferably a fluorine atom, R ⁴ and R ⁵ is a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, Particularly preferably, it is a chlorine atom.

Examples of the “alkyl group having 1 to 6 carbon atoms” of RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s —Butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,

1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, etc. ¹ is preferably a methyl group, R ² is preferably a methyl or ethyl group, particularly preferably a methyl group, and R ³ is preferably methyl and ethyl. Or an isopropyl group, particularly preferably an isopropyl group, R ⁴ and R ⁵ are preferably a methyl group, and R ⁶ is preferably a methyl, ethyl, isopropyl or butyl group. group, particularly preferably methyl, Echiru or isopropyl group, for R ⁷ is preferably a methyl group, R ⁸ information, preferably, der methyl You. Examples of the alkyl portion of the `` hydroxyl-substituted alkyl group having 1 to 6 carbon atoms '' include the same as those described above for the `` alkyl group having 1 to 6 carbon atoms ''. Preferably, the alkyl portion is It is a group having 1 to 3 carbon atoms, more preferably an ethyl group, and a preferable "hydroxyl-substituted alkyl group having 1 to 6 carbon atoms" is a 2-hydroxyethyl group.

As the alkyl moiety of the “C 2 to C 7 alkyl group” for R ³ , the same as those described above for the “C 1 to C 6 alkyl group” can be mentioned. The moiety is one to three, more preferably a methyl group, and a preferred “C 2-7 carboxyalkyl group” is a carboxymethyl group. The alkyl portion (including the alkyl portion of the alkoxy portion) of the “alkoxycarbonylalkyl group having 3 to 13 carbon atoms” in the above is mentioned in the above “alkyl group having 1 to 6 carbon atoms”. Preferably, the alkyl moiety is one having 1 to 4 carbon atoms, and a preferred "alkoxycarbonylalkyl group having 3 to 13 carbon atoms" is methoxycarbonyl. A methyl group, an X ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, more preferably a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, and particularly preferably an ethoxycarbonylmethyl group. You.

Examples of the “aralkyl group having 7 to ¹⁶ carbon atoms” for R ³ and R ⁶ include, for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl group and the like, preferably benzyl or It is a phenethyl group.

Examples of the “aliphatic acryl group having 2 to 7 carbon atoms” for R ³ and R ⁶ include, for example, acetyl, propionyl, butyryl, isoptyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl, and oxanolyl groups. And preferably an acetyl group.

The “C2-C7 hydroxyl-substituted aliphatic acyl group” for R ³ is the above-mentioned “C2-C7 aliphatic aliphatic acyl group” which is substituted with a hydroxyl group. It is a cetyl group. Examples of the alkyl moiety of the “C2 to C7 carpoxyalkylsulfonyl group” include the same as those described above in the above “C1 to C6 alkyl group”. The moiety has 1 to 4 carbon atoms, more preferably a methyl group, and a preferable "carboxyalkylsulfonyl group having 2 to 7 carbon atoms" is a carboxymethanesulfonyl group.

As the alkyl moiety of the “C1 to C6 alkylsulfonyl group” for R ³ , the same as those described above for the “C1 to C6 alkyl group” can be mentioned, and preferably, an alkyl moiety Is a group having 1 to 4 carbon atoms, more preferably an ethyl group, and The “alkylsulfonyl group having a prime number of 1 to 6” is an ethanesulfonyl group. The alkyl portion (including the alkyl portion of the alkoxy portion) of the "alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms" in the above is the same as the above-mentioned "alkyl group having 1 to 6 carbon atoms" Preferably, the alkyl moiety has 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, and preferably has 3 to 13 carbon atoms. The “alkoxycarbonylalkylsulfonyl group” is an ethoxycarbonylmethanesulfonyl group. Examples of the alkyl portion of the “C 3 -C 8 alkyl group” include the same as those described above in the “C 1 -C 6 alkyl group”. The moiety is one having 1 to 4 carbon atoms, more preferably one having 1 carbon atom, and a preferred “carboxyalkylcarbonyl group having 3 to 8 carbon atoms” is carboxyacetyl. Group.

The alkyl portion of the `` halogen-substituted alkyl group having 1 to 6 carbon atoms '' of R ⁴ and R ⁵ is preferably the same as that described in the above-mentioned `` alkyl group having 1 to 6 carbon atoms ''. The alkyl moiety has 1 to 2 carbon atoms, and a preferable "halogen-substituted alkyl group having 1 to 6 carbon atoms" is a trifluoromethyl group.

The alkyl moiety of the `` alkoxy group having 1 to 6 carbon atoms '' of R ⁴ and R ⁵ includes the same as those described in the above `` alkyl group having 1 to 6 carbon atoms ''. The alkyl moiety has 1 to 4 carbon atoms, more preferably has 1 carbon atom, and a preferred "alkoxy group having 1 to 6 carbon atoms" is a methoxy group.

The alkyl part of the "number 2 to 7 alkoxy Cal Poni Le group atoms" of R ⁴ and R ⁵ are the same as those listed above Symbol "having 1 to 6 alkyl group having a carbon" and the like, preferably Represents an alkyl moiety having 1 to 2 carbon atoms. Examples of the “xycarbonyl group” include an ethoxycarbonyl group.

The alkyl part of the "number 2 to 7 monoalkyl force Rubamoiru group atoms" of R ⁴ and R ⁵ are the same as those listed above, "having 1 to 6 alkyl group having a carbon" and the like, preferably The alkyl moiety has 1 to 2 carbon atoms, and a preferable “monoalkylcarbamoyl group having 2 to 7 carbon atoms” is an N-methylcarbamoyl group.

The alkyl moiety of the `` dialkyl alkamoyl group having 3 to 13 carbon atoms '' of R ⁴ and R ⁵ is the same as the above-mentioned `` alkyl group having 1 to 6 carbon atoms '', and is preferably In the above, the alkyl moiety has 1 to 2 carbon atoms, and a preferable "dialkyl carbamoyl group having 3 to 13 carbon atoms" is an N, N-dimethylcarbamoyl group.

Examples of the “cyclic alkyl group having 3 to 8 carbon atoms” for R ⁶ include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, and the like. is there. The alkyl portion of the `` alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic ring '' of the above is preferably the same as the above-mentioned `` alkyl group having 1 to 6 carbon atoms ''. Is an alkyl moiety having 1 to 2 carbon atoms, and a heterocyclic moiety is a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms or Z and nitrogen atoms. , Furyl, chenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl Aromatic heterocyclic groups and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazo Examples thereof include partial or completely reduced groups corresponding to these groups such as dinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, and piperazinyl, and preferably include at least one nitrogen atom, Or a 5- to 7-membered heterocyclic group which may contain a sulfur atom, for example, pyrrolyl, azepi Aromatic ring such as nil, hinolazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3,1oxadazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and morphoyl such as aromatic ring Partially or completely reduced groups corresponding to these groups such as pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl (for example, 4,5-dihydro-3H-pyrroyl-2-i) 2,3,4,5-tetrahydropyridine-1-yl, 4,5-dihydrooxazolu-2-yl, 5,6-dihydro-2H— [1,4] thiazine-3-yl ) And “5 The `` 7-membered heterocyclic group '' may be condensed with another cyclic group, for example, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, Groups such as isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carporinyl, acridinyl, and isoindolinyl; and the like, preferably a pyridyl group, and preferably a carbon atom substituted by a heterocycle. Examples of the “to 6 alkyl groups” include 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl group or 2- (2-pyridyl) ethyl, 2- (3-pyridyl) X tyl or 2- (4-pyridyl) An ethyl group. Examples of the alkyl portion of the `` C2 to C7 carboxyalkyl group '' include the same as those described above for the `` C1 to C6 alkyl group ''. Preferably, the alkyl portion is A carboxyl group having 1 to 2 carbon atoms, and a preferred "carboxyalkyl group having 2 to 7 carbon atoms" is a carboxymethyl group.

The alkyl portion of the `` C3-C13 alkoxycarbonylalkyl group '' for R ⁶ includes the same ones as those described in the above-mentioned `` C1-C6 alkyl group ''. The alkyl moiety has 1 to 2 carbon atoms, and a preferred "alkoxycarbonylalkyl group having 3 to 13 carbon atoms" is a methoxycarbonylmethyl group. The “aromatic acyl group having 7 to 11 carbon atoms” for R ⁶ includes, for example, benzoyl, 1.1-naphthylcarbonyl, 21-naphthylcarbonyl and the like, and is preferably a benzoyl group.

The alkyl portion of the “alkylsulfonyl group having 1 to 6 carbon atoms” for R ⁶ includes the same as those described above for the “alkyl group having 1 to 6 carbon atoms”, and preferably the alkyl portion Has 1 to 2 carbon atoms, and a preferable “alkylsulfonyl group having 1 to 6 carbon atoms” is a methanesulfonyl group. Examples of the "aryl group having 6 to 10 carbon atoms" include phenyl, 1.1-naphthyl, 2-naphthyl, phenanthryl and the like, and preferably a phenyl group.

As the “heterocycle” for R ^6, the same as those described above in the aforementioned “heterocycle-substituted alkyl group having 1 to 6 carbon atoms” can be mentioned. That is, 4,5-dihydro-3H-pyrrol-2-yl (A), 2,3,4,5-tetrahydropyridine_6-yl (B), 4,5-dihydrooxa Zol-2-yl (C), 5,6-dihydro-2H— [1,4] thiazin-3-yl (D) or 4-pyridyl group.

(A) (Β) (C) (D)

The alkyl moiety of the “1-iminoalkyl group having 2 to 7 carbon atoms” of R ⁶ is the same as the above-mentioned “alkyl group having 1 to 6 ′ carbon atoms”. The alkyl moiety has 2 or 3 carbon atoms, and a preferred "1-iminoalkyl group having 2 to 7 carbon atoms" is a 1-iminoethyl group (hereinafter, referred to as an acetimidoyl group). Is a 1-iminopropyl group, particularly preferably an acetimidoyl group.

The alkyl moiety of the “N-alkylformimidoyl group having 2 to 7 carbon atoms” for R ⁶ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”, and is preferably The alkyl moiety has 1 to 2 carbon atoms, and a preferable "N-alkylformimidoyl group having 2 to 7 carbon atoms" is an N-ethylformimidoyl group. .

Examples of the “iminoarylmethyl group having 7 to 11 carbon atoms” for R ⁶ include, for example, iminophenylmethyl, iminonaphthylmethyl and the like, and preferably an iminophenylmethyl group.

Examples of the “alkylene group having 2 to 5 carbon atoms” formed when R ⁶ and R ^{7 are}緖 or R ⁷ and R ^{8 are}緖 are, for example, ethylene, trimethylene, tetra A methylene group, a pentamethylene group or the like, and preferably, an ethylene or trimethylene group. n is preferably 1. The benzamidine derivative having the general formula (1), which is contained in the composition for iontophoresis of the present invention, is treated with an acid according to a conventional method to give a corresponding “pharmacologically acceptable salt”. be able to. For example, the compound (1) is treated with a corresponding acid for 1 minute to 30 minutes at room temperature in a solvent (for example, ethers, esters or alcohols, preferably ethers or alcohols), It can be obtained by filtering the precipitated crystals or distilling off the solvent under reduced pressure. Such salts include carbonates; mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; Sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; acetate, trifluoroacetate, propionate, butyrate, fumarate Carboxylates such as monolate, succinate, citrate, tartrate, oxalate or maleate or benzoate; Or an amino acid salt such as glutamate or aspartate. The benzamidine derivative having the general formula (1), which is contained in the composition for iontophoresis of the present invention, is treated with a base according to a conventional method, for example, when R ³ , RR ⁵ or R ⁶ contains a hydroxyl group. By doing so, the corresponding “pharmacologically acceptable salts” can be obtained. For example, compound (1) is treated with a corresponding base in a solvent (eg, ethers, esters or alcohols, preferably alcohols) at room temperature for 1 minute to 30 minutes, and the precipitated crystals are filtered. Or by distilling off the solvent under reduced pressure. Such salts include, for example, alkali metal salts such as sodium, potassium and lithium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts Metal salts such as salts, nickel salts, cobalt salts, etc .; ammonium salts; , Getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt, N-benzylphenethylamine salt, Perazine salt, tetramethylammonium salt, tris (hydro It is an organic amine salt such as Shimechiru) Aminometan salt, in good Suitable alkali metal salts (especially sodium or potassium salts). The benzamidine derivative having the general formula (1) or a pharmaceutically acceptable salt thereof, which is contained in the composition for iontophoresis of the present invention, has an asymmetric carbon atom in the molecule. There are stereoisomers that are S-coordinated, and each of them, or any compound thereof in any proportion, is encompassed by the present invention. Such stereoisomers may be prepared, for example, by synthesizing the compound (1) using the optically resolved starting compound, or subjecting the synthesized compound (1) to optical synthesis using a usual optical resolution or separation method as desired. Can be split. A benz having the general formula (1), which is contained in the composition for iontophoresis of the present invention. Amidine derivatives or pharmacologically acceptable salts thereof may absorb moisture, become adsorbed, or become hydrated when left in the air or recrystallized. Compounds and salts containing are also included in the active ingredient of the composition for iontophoresis of the present invention. In the composition for iontophoresis containing the benzamidine derivative having the general formula (1) or a pharmaceutically acceptable salt thereof according to the present invention,

(1) R ¹ is a hydrogen atom or a hydroxyl group, a composition for iontophoresis,

(2) a composition for iontophoresis, wherein R ¹ is a hydrogen atom,

(3) a composition for iontophoresis, wherein R ² is a hydrogen atom, a bromine atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group;

(4) is a hydrogen atom, a fluorine atom or a methyl group, a composition for iontophoresis,

(5) is a hydrogen atom, a composition for iontophoresis,

(6) R ² is a fluorine atom or a methyl group, a composition for iontophoresis,

(7) R ² is a fluorine atom, a composition for iontophoresis,

(8) R ³ is an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms or a carboxyalkylsulfonyl group having 2 to 7 carbon atoms, a composition for iontophoresis,

(9) is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group. A composition for iontophoresis,

(10) Iontophore wherein R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms, or a rubamoyl group A composition for one cis,

(11) a composition for iontophoresis, wherein R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a chlorine atom, a methyl group, a methyl group of trifluorene or a rubamoyl group;

(12) a composition for iontophoresis, wherein R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group or a sorbamoyl group;

(13) is a hydrogen atom, and R ⁵ is a hydrogen atom or a levamoyl group, a composition for iontophoresis,

(14) R ⁶ is an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or 1 to 6 carbon atoms substituted with a heterocyclic ring An alkyl group, an aryl group having 6 to 10 carbon atoms, a heterocycle, a formimidoyl group, a 1-iminoalkyl group having 2 to 7 carbon atoms, an iminoarylmethyl group having 7 to 11 carbon atoms or a carbon atom having 2 carbon atoms From 7 to 7 N-alkylformimidoyl groups, for iontophoretic compositions;

(15) R ⁶ is methyl, ethyl or isopropyl, cyclopentyl, benzyl or phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 2- ( 3-pyridyl) ethyl or 2- (4-pyridyl) ethyl group, phenyl group, 4,5-dihydro-3H-pyrroyl-2-yl, 2,3,4,5-tetrahydropyridine-1-6- 4,5-dihydrooxazole-2-yl, 5,

6-dihydro-2H- [1,4] thiazin-3-yl or 4-pyridyl group, formimi A composition for iontophoresis, which is a doyl group, an acetimidoyl group, a 1-iminopropyl group, an iminophenylmethyl group, or an N-ethylformimidoyl group;

(16) a composition for iontophoresis, wherein R ⁶ is a 4,5-dihydro-3H-pyrroyl-2-yl or acetimidoyl group;

(17) is an acetoimidoyl group, a composition for iontophoresis,

(18) a composition for iontophoresis, wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

(19) R ⁷ and R ⁸ are the same or different and are each a hydrogen atom or a methyl group, a composition for iontophoresis,

(20) R ⁷ and R ⁸ are hydrogen atoms, a composition for iontophoresis,

(21) a composition for iontophoresis, wherein R ⁶ and R ⁷ are joined together, or R ⁷ and R ⁸ are linked to form an alkylene group having 2 to 5 carbon atoms,

(22) a composition for iontophoresis, wherein R ⁶ and R ⁷ are together, or R ⁷ and R ⁸ are together and are an ethylene or trimethylene group; and

(23) n is 1, can be mentioned composition for iontophoresis, is related to R ^1, it raises the order in a suitable order of from (1) (2), with respect to R ² is , (3) from the forward in raises the preferred order of (7), with respect to R ^3, Ri is above order in a suitable order of from (8) (9), with respect to R ⁴ and R ^5, (10 ) from the forward in raises the preferred order of (13), in respect R ^6, raises the order in a suitable order of (14) to (17), is then opened to R ⁷ and R ^8, (18) from the order in raises the preferred order of (20), R ⁶ and R ⁷ or R ⁷ and R ^8, together such connexion, § Those showing a alkylene group are more preferably ranked in the order of (21) to (22). The iontophoresis composition of the present invention containing the benzamidine derivative having the general formula (1) or a pharmacologically acceptable salt thereof includes (1)-(2), (3)-(7 ), (8)-(9), (10)-(13), (14)-(17), (18)-(20), (21) (22) , And any combination thereof. Preferred examples of the combination include, for example,

(24) R ¹ is a hydrogen atom or a hydroxyl group,

R ² is a hydrogen atom, a bromine atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group,

R ³ is an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms or a carboxyalkylsulfonyl group having 2 to 7 carbon atoms,

R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms or a rubamoyl group;

R ⁶ is an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic ring An aryl group having 6 to 10 carbon atoms, a heterocyclic ring, a formimidoyl group, a 1-iminoalkyl group having 2 to 7 carbon atoms, an iminoarylmethyl group having 7 to 11 carbon atoms, or a C2 to Ί N-alkylformimidyl groups;

A composition for iontophoresis, wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

(25) R ¹ is a hydrogen atom or a hydroxyl group,

R ² is a hydrogen atom, a fluorine atom or a methyl group,

R ³ is a methoxycarbonyl sulfonyl group or a carbonyloxy sulfonyl group,

R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group or a levamoyl group; and-R ⁶ is a methyl, ethyl or isopropyl group, a cyclopentyl group, benzyl or phenyl. Tyl group, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl or 2- (4-pyridyl) ethyl group, phenyl group, 4 , 5-Dihydro-1 3H-pyrrole-12-yl, 2,3,4,5-tetra.hydropyridine-1-6-yl, 4,5-dihydrooxazoyl-2-yl, 5,6-dihi Dro-2H- [1,4] thiazin-3-yl or 4-pyridyl group, formimidoyl group, acetimidoyl group, 1-iminopropyl group, iminophenylmethyl group or N-ethylformimidoyl group;

R ⁷ and R ⁸ are the same or different and are a hydrogen atom or a methyl group, a composition for iontophoresis,

(26) R ¹ is a hydrogen atom,

Is a hydrogen atom, a fluorine atom or a methyl group,

Is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,

Is a hydrogen atom, R ⁵ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group,

R ⁶ is a 4,5-dihydro-3H-pyrroyl-2-yl or acetimidoyl group, and R ⁷ and R ⁸ are hydrogen atoms, a composition for iontophoresis,

(27) R ¹ is a hydrogen atom,

Is a fluorine atom or a methyl group,

R ³ is an ethoxycarbonylmethylsulfonyl group or a carboxymethanesulfonyl group,

Is a hydrogen atom, R ⁵ is a hydrogen atom or a rubamoyl group,

R ⁶ is an acetimidoyl group,

R ⁷ and R ⁸ may be hydrogen atoms, for example, a composition for iontophoresis, and the preferred order increases from (24) to (27). In the composition for iontophoresis containing the benzamidine derivative having the general formula (1) or a pharmaceutically acceptable salt thereof of the present invention, particularly preferred are:

N- [3 -— (3-Amidinophenyl) -2- (E) 1-probenyl] -N- [3-chloro-4— [1- (4-Pyridyl) piperidine—4-yloxy] phenyl] Sulfamoylethyl ester ,

N— [3- (3-Amidinophenyl) -2- (E) 1-probenyl] -N- [3-chloro 4- (1-formimidoylpiperidine-4_yloxy) phenyl] sulfamoyl Ethyl acetate,

N— [3 -— (3-amidinofenyl) -1- (E) —probenyl] —N— [3-chloro-4— [1- (1-iminopropyl) piperidine—4-yloxy] phenyl] sulfamoylacetic acid Ethil,

N— [3- (3-Amidinophenyl) -2- (E) 1-probenyl] —N— [3—chloro mouth_4—1 [1 -— (4,5-dihydro_3H—pyrrole—1—2—yl ) Pyridine-4-4-yloxy] phenyl] sulfamoyl acetate

N— [3 -— (3-amidinofenyl) -2- (E) -probenyl] -N- [4-1- [1-(4,5-dihydro-3H-pyrroyl-2-yl)]ぺ lysine-1 4-yloxy] -3-methylphenyl] sulfamoyl acetate

N— [3- (3-Amidinophenyl) -1-2- (E) -propidinyl] —N— [4-1-1 [1- (4,5-dihydro-3H-pyrroyl-2-yl) piperidine—4 1-yloxy] ― 3-trifluoromethylphenyl] sulfamoyl acetate,

N— [3- (3-Amidinophenyl) —2— (E) 1-probenyl] 1-N— [3-Chloro4-1- (1_isopropylpiperidine-1-4-yloxy) phenyl] sulfamoyl acetic acid

N— [3- (3-Amidinophenyl) -2- (E) 1-probenyl] -N- [3-chloro-4— [1- (4-pyridyl) piperidine—4-yloxy] phenyl] sulfamo Acetic acid,

N— [3 -— (3-amidinofenyl) -1-2- (E) -propidinyl] -1-N— [3-—Mouth—41- (1-cyclopentylbiperidine-1-41-yloxy) phenyl] sulfamoi Acetic acid,

N— [3 -— (3-Amidinophenyl) —2 -— (E) —probenyl] —N— [3-chloroau 4- (indolizine-1-7-yloxy) phenyl] sulfamoylacetic acid, '

N— [3- (3-Amidinophenyl) 1-2— (E) —Probenyl] N—N— [3-Chloro4-1 (1-formimidoylpiperidine-1-4yloxy) phenyl] sulfamoyl Acetic acid,

N— [3 -— (3-Amidinophenyl) -1- (E) -probenyl] —N— [3-chloro-4— [1- (1-f ^ aminopropyl) piperidine-1-4-yloxy] phenyl] sul Famoyl acetic acid,

N— [3- (3-Amidinophenyl) -2- (E) 1-prodenyl] 1-N— [3-chloro-4-1-1- (4,5-Dihydro-3H-pyrroyl-2-yl ) Pyridine—4-yloxy] phenyl] sulfamoylacetic acid,

N— [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] -N- [4- [1- (4,5-dihydro-3H-pyrroyl-2-yl) piperidine— 4-yloxy] -3-methylphenyl] sulfamoylacetic acid,

N— [3--(3-Amidinophenyl) 1 2-— (E) 1-probenyl] -N- [4- 1- (1- (4,5-dihydro-3H-pyrroyl-2-yl) piperidine— 4-yloxy] phenyl] sulfamoylacetic acid,

N— [3 -— (3-Amidinophenyl) —2 -— (E) 1-Probenyl] N— [4 -— (1-Methylpiperidine-14-yloxy) -1-3-trifluoromethylphenyl] sulfamoylacetic acid ,

N- [3- (3-amidinofenyl) 1 2- (E) 1-probenyl] 1 N— [4- 1 [1 (4,5-dihydro-3H-pyrroyl-2-yl) piperidine 1-41-yloxy] 1-3-trifluoromethylphenyl] sulfamoylacetic acid,

N— [3-(3-Amidinophenyl) —2— (E) 1-Propenyl] -N- [3-carbamoyl— 4 -— [1- (4,5-dihydro-3H-pyrrole—2-yl) Piperidine-41-yloxy] phenyl] sulfamoylacetic acid,

N— [3 -— (3-amidinofenyl) -1-2- (E) -propidinyl] —N— [3-chloro Rho 4— [1- (4,5-dihydrooxazolyl 21-yl) piperidine-1_4-yloxy] phenyl] sulfamoylacetic acid,

N— [3- (3-amidinofenyl) -2- (E) —probenyl] -N- [4- [1- (4,5-dihydrooxazole-2-yl) piperidine-1 4 1-yloxy] phenyl] sulfamoylacetic acid,

N— [3- (3-Amidinophenyl) -1-2_ (E) —probenyl] —N— [3-chloro-4-1- [1- (N-ethylformimidoyl) piperidine-1-4-yloxy] Phenyl] sulfamoyl acetic acid, '

N— [4- (1_acetimidoylpiperidine-4_yloxy) phenyl] -N- [3- (3_amidinophenyl) -2- (E) -probenyl] ethyl sulfamoyl acetate,

N— [4- (1-Acetimidoylpiperidine-1-yloxy) —3-chlorophenyl] —N— [3- (3-Amidinophenyl) —2 -— (E) 1-probenyl] Ethyl sulfamyl acetate,

N— [4- (1_ (acetoimidoylpiperidine-1-4-yloxy) -1-3-methylphenyl] -N- [3- (3-amidinofenyl) —2— (E) 1-probenyl] sulfamo Ethyl acetate,

N— [4- (1-Acetimidoylpiperidine-1-4-yloxy) -13-force rubamoyl phenyl) —N— [3- (3_ (amidinophenyl) —2 -— (E) monopropenyl] sulf Ethyl famoyl acetate,

N— [4- (1-acetimidoylpiperidine—4-yloxy) phenyl] —N—

[3- (3-amidinophenyl) -2- (E) -probenyl] sulfamoylacetic acid,

N— [4- (1-acetoimidoylpiperidine—4-yloxy) -1-3-fluorophenyl] -N- [3- (3-amidinofenyl) 1-2— (E) 1-probenyl] sulfamoylacetic acid,

N— [4- (1-Acetimidoylpiperidin-1-41-yloxy) —3-chlorophenyl] -N- [3- (3-Amidinophenyl) -2- (E) -propenyl] Sulfamylacetic acid, N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-methylphenyl] N— [3- (3-amidinofenyl) -2- (E) —probenyl] sulfamoy Acetic acid,

N— [4- (1_acetoimidoylpiperidine-1 4-yloxy) -13-trifluoromethylphenyl) N— [3- (3-Amidinophenyl) 1-2— (E) 1-probenyl] sulfamoyl Acetic acid,

N— [4- (1-Acetimidoylpiperidin-1-yloxy) —3-—Rubamoyl ulfenyl] — N— [3 -— (3-Amidinophenyl) —2 -— (E) 1-propenyl) sulf Famoyl acetic acid,

N— [4- (1 _acetimidoylpiperidine _ 4 _yloxy) —3,5-dioctylphenyl] 1 Ν— [3— (3-amidinofenyl) 1 2— (Ε) —probe2 Le] sulfamoyl acetate,

Ν— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-dichloromouth phenyl] Ν— [3- (3-amidinofenyl) —2 -— (Ε) —probenyl ] Sulfamoyl acetic acid,

Ν— [4- (1-acetoimidoylpiperidin-1-41-yloxy) phenyl] -Ν- [3- (3-amidinophenyl) -1-2-fluoro-2- (Ζ) -probenyl] sulfamoylacetic acid ,

Ν— [4 -— (1-acetoimidoylpiperidine-1-41-yloxy) phenyl] mono- [3-(3-amidinofenyl) -1-2-methyl-2 -— (Ε) -probenyl] sulfamoy Acetic acid or

Ν— [4- (1_acetoimidoylpiperidine-1-41-yloxy) -1-3-potassium rubenyl] — Ν— [3- (3-amidinofenyl) 1-2-fluoro-2 -— (Ζ) [Benzyl] sulfamoylacetic acid, or a composition for iontophoresis containing a pharmacologically acceptable salt thereof (especially hydrochloride).

Ν- [4- (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] —Ν— [3- (3-amidinofenyl) -12- (Ε) 1-probenyl] sulfamoylacetic acid,

Ν- [4- (1-acetoimidoylpiperidine-1-41-^-loxy)-3-cloth Nyl] -N- [3- (3-Amidinophenyl) -2- (E) -Propenyl] sulfamoylacetic acid,

N— [4- (1-acetoimidoylpiperidine—4-yloxy) -1-3-methylphenyl] -N- [3- (3-amidinofenyl) 1-2— (E) —probenyl] sulfamo Acetic acid,

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-trifluoromethylphenyl] N— [3- (3-amidinofenyl) -2- (E) 1-probenyl] sulfamoylacetic acid ,

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -13-potassium rubenyl] -N- [3- (3-amidinophenyl) 1-2- (E) 1-probenyl] sul Famoyl acetic acid,

N— [4- (1-Acetimidoylpiperidin-1-41-yloxy) phenyl] -1-N— [3- (3-Amidinophenyl) -1-2-fluoro-2 -— (Z) -propionyl] sulfamoylacetic acid ,

N— [4- (1-Acetimidoylpiperidin-1-41-yloxy) phenyl] -N- [3- (3-amidinofenyl) —2-methyl_2- (E) -propionyl] sulfamoyl Acetic acid or

N— [4- (1-Acetimidoylpiperidine-1_4_yloxy) -1-3-Rubamoyl lfenyl] -N- [3- (3-Amidinophenyl) -2-fluoro-2- (Z) [Benyl] sulfamoylacetic acid, or a composition for iontophoresis containing a pharmacologically acceptable salt thereof (particularly hydrochloride).

Benzamidine derivatives or pharmacologically acceptable salts thereof contained in the composition for iontophoresis of the present invention are described in WO 01/30756 and Z or Japanese Patent Application No. 2002-102486 (Japanese Patent Application No. 2001-107615). It can be produced by the method described, for example, by the following method. method A

(twenty five)

method C

(2)

(Ten)

(11) method D

11

14 12

In the above process chart, RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and n are as defined above, &, R ³ a, R ⁴ a, R ⁵ a and R ⁶ a are each a substituent on R ¹ or R RR ³ substituents is protected on ^one or R ³ on R ³ substituent is protected in, R ⁴ or R ⁴ is a protected R ^4, R ⁵ or R ⁵ substituents on R ⁵ are protected, and indicates the R ⁶ substituents on R ⁶ or R ⁶ is protected, R ⁶ b is a R ⁶ a or amino group Indicates a protecting group, Pro represents a hydroxyl-protecting group,

X represents a halogen atom or a hydroxyl group.

Method A is a method for producing the compound (1) of the present invention. 1st step

This step is a step for producing a compound having the general formula (4). The compound having the general formula (2) is prepared by reacting a compound having the general formula (2) Is achieved by condensation with a compound having the formula: The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, halogenated hydrocarbons such as cyclobenzene or dichlorobenzene; or getyl ether; It may be an ether such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably a halogenated hydrocarbon (dichloromethane) or an ether (especially getyl ether or tetrahydrofuran). It is. Phosphines used are, for example, trimethylphosphine, tri E chill phosphine, tripropyl phosphine, Bok-butyl phosphine, tri one c ₆ alkyl phosphines such as hexyl phosphine to tripentyl phosphine or tri; triphenyl phosphine, preparative Riindeniru Tri-c ₆ -c ₁₀ aryl phosphines such as phosphine or trinaphthyl phosphine; C ₄ alkyl and which may tri C have a substituent ₆ - be a C ₁₀ 7 Riruhosufi down, preferably tri C "C ₆ alkyl phosphines (particularly trimethylphosphine, Re C ₆ —. Aryl phosphine (particularly triphenyl phosphine, triindenyl phosphine or trinaphthyl phosphine), more preferably tributyl phosphine or triphenyl phosphine. § zone compounds used is, for example, a Azojikarubo two Rujipiperijin or Azojikaru Bonn dimethyl, Azojikarubon acid Jechiru, Azoji force Rupon Sanjiichi ci one c ₄ alkyl, such as Azoji force Rupon acid dipropyl or Azoji carboxylic dibutyl give Preferably, it is azodiphenol dipiperidine, dimethyl azodicarboxylate or getyl azodicarboxylate. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from −50 ° C. to 100 ° C., preferably from 0 ° C. to 60 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, if there is any insoluble matter, it is removed by filtration and the solvent is distilled off.Or, after the reaction is completed, the solvent is distilled off and water is poured into the obtained residue. After adding a solvent that is immiscible with water (eg, benzene, ether, ethyl acetate, etc.) and extracting, the extract is washed with water, the organic layer is dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound. can get. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. Second step

This step is a step of producing a compound having the general formula (1),

(a) a reaction for converting a cyano group to an amidino group, If desired

(b) a reaction for removing the protecting group of the protected amino group,

(c) a reaction for introducing a desired substituent to an amino group,

(d) an ester hydrolysis reaction,

(e) Reaction for removing the protecting group of the protected hydroxyl group

Can be achieved by appropriately changing the order and combining them. The essential reaction (a), the “reaction to convert a cyano group to an amidino group”, generally follows a method well known in the art.

(1) reacting the starting compound with an alcohol in an inert solvent or in the absence of a solvent (preferably in an inert solvent), in the presence of an acid, and subjecting the iminoether compound produced as an intermediate to ammonialysis; Or

(2) The compound is obtained by reacting a starting compound with hydroxylamine in an inert solvent in the presence or absence of a base, and subjecting the amidoxime compound produced as an intermediate to hydrogenolysis. Reaction (a) (1) is a two-step reaction. First, the first step is a reaction in which a nitril group is reacted with an alcohol in the presence of an acid to obtain an imino ether compound. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.Examples include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or ethers such as diethylene glycol dimethyl ether; ketones such as acetone or methylethyl ketone; esters such as methyl acetate or ethyl acetate; nitro compounds such as nitromethane; formamide, N, N-dimethylformamide; N, N— An amide such as dimethylacetamide or N-methyl-2-pyrrolidinone; a sulfoxide such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above-mentioned organic solvents, preferably an aromatic hydrocarbon ( In particular, benzene) or halogenated hydrocarbons (particularly, dichloromethane, particularly preferably, halogenated hydrocarbons (particularly, dichloromethane). In this reaction, the solvent also serves as a solvent in excess alcohol (for example, , Methanol, ethanol, propanol, 2-propanol, butanol or isobutanol, etc., and preferably methanol or ethanol.) In addition, alcohols are usually used as long as there is no problem. The acid used is, for example, hydrogen chloride, hydrochloric acid, hydrobromic acid Mineral acids such as hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or , Boron trifluoride, aluminum chloride, iron chloride (111), zinc chloride, mercury (II) chloride, etc., preferably a mineral acid or a Lewis acid, particularly preferably hydrogen chloride. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 1 hour to 15 hours, depending on the starting compounds, reagents and reaction temperature. The method of distilling off the solvent) Although taken from response mixture, also in monkey it is used in the next reaction without particular isolation and purification. The second step of the reaction (a) (1) is a reaction in which the iminoether compound produced in the first step is subjected to ammonia decomposition. This reaction is usually performed in an inert solvent in the presence of ammonia. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol are used. Water; or a mixed solvent of alcohols and water, preferably methanol, ethanol, water, hydrated methanol or hydrated ethanol, and particularly preferably hydrated methanol or hydrated ethanol. The source of ammonium ions of the ammonium ions used may be, for example, aqueous ammonia, ammonium chloride, ammonium carbonate or a mixture thereof, preferably ammonium chloride. The pH in the reaction is neutral to weakly basic, and is preferably 7 to 9 using aqueous ammonia and hydrochloric acid. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 to 10 ° C, preferably from 0 to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 48 hours, preferably from 1 hour to 15 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or after completion of the reaction, water is added to the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to obtain the desired compound. After extraction, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound. The target compound obtained is necessary The product can be further purified by a conventional method, for example, recrystallization, reprecipitation, or chromatography. Reaction (a) (2) is a two-step reaction. First, the first step is a reaction in which an amidoxime compound is obtained by reacting a nitrile group with hydroxylamine in an inert solvent in the presence of a base, if desired. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; methanol, ethanol; Propanol, 2-propanol, bushanol or Alcohols such as isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-oxide; or water, preferably alcohols (particularly methanol Or ethanol). Sources of hydroxylamine used may include aqueous solutions of hydroxylamine, solutions of organic solvents or salts with acids. The base to be used is not particularly limited as long as it can neutralize a hydroxylamine salt with an acid. (Also, when a hydroxylamine solution is used directly, Not necessarily required.), For example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; sodium hydrogen carbonate, hydrogen carbonate or potassium carbonate Alkali metal bicarbonates such as lithium hydrogen; Alkali metal acetates such as sodium acetate; Alkali metal hydroxides such as sodium hydroxide, hydroxide or lithium hydroxide; Sodium methoxy Alkali metal alkoxides such as sodium ethoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N —Dimethylamino) pyridine, N, N—dimethylaniline, N, N—getylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4 diazabicyclo [2.2.2] octane (DAB CO) or organic bases such as 1,8-diazabic mouth [5.4.0] dex-7-ene (DBU). , The alkali metal carbonates (particularly sodium carbonate) or alkali metal alkoxides (potassium especially t one-butoxide). The reaction temperature varies depending on the starting compounds, reagents and the like, but is generally 0 to 150 ° C, preferably 50 to 10 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 24 hours, preferably 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent), but can be used for the next reaction without isolation and purification. Reaction (a) The second step of (2) is a reaction that hydrolyzes the amidoxime compound produced in the first step. Usually, prior to hydrogenolysis, the hydroxyl group is modified with an eliminable group, but an acetyl group is commonly used for convenience. The acetylation is usually carried out in acetic acid using acetic anhydride, but may be carried out in a solvent if necessary. The solvent used for acetylation is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.Examples include hexane, cyclohexane, heptane, ligroin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyle Ethers such as one ter; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; or nitriles such as acetonitrile or isopyronitrile; Include halogenated hydrocarbons (especially di- Rorometan) or E one ethers (in particular tetrahydrofuran). The reaction temperature for acetylation varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., and preferably 10 ° C. to 50 ° C. The reaction time of the acetylation varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 1 hour to 24 hours, preferably from 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent after completion of the reaction). it can. Hydrogenolysis of the amidoxime compound (deacetoxylation when the hydroxyl group is acetylated) is usually performed continuously without changing the reaction solvent. If desired, the solvent can be distilled off once, and the resulting residue can be dissolved again in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Without limitation, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, lignin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, Halogenated hydrocarbons such as carbon form, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol Ethers such as dimethyl ether; ketones such as acetone or methylethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; methanol, ethanol, propanol, 2-propanol, butanol Are alcohols such as isoptanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-oxide; carboxylic acids such as formic acid or acetic acid; water; And preferably an alcohol (particularly methanol or ethanol), acetic acid, or a mixed solvent thereof. The catalyst used in the hydrogenolysis is not particularly limited as long as it is used in a usual catalytic reduction reaction. For example, palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon , Raney nickel, rhodium aluminum monoxide, palladium-barium sulfate, platinum oxide or platinum black, preferably palladium-carbon. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 ° C to 10 ° C, preferably from 0 ° C to 80 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 1 hour to 24 hours, preferably from 5 hours to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is removed by filtration and then the solvent is distilled off, or after completion of the reaction, the catalyst is removed by filtration. Then, water is added to the reaction mixture, and a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and dried over anhydrous magnesium sulfate. After drying with dimethyl ether or the like, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. The desired reaction (b), “reaction to remove the protected amino group” is generally carried out as follows according to a method well known in the art of synthetic organic chemistry. The protecting group of the amino group is formyl group, acetyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2 —Jib mouth methoxycarbonyl, vinyloxycarbonyl, benzyloxycarbonyl, (1-phenyl) benzyloxycarbonyl, 9-anthrylmethyloxycarbonyl, P-methoxybenzyl In the case of a oxycarbonyl group or a p-nitro-2-benzyloxycarbonyl group, it can be removed by treating with an acid in an inert solvent or an aqueous solvent. In this case, the target compound can be obtained as a salt. The acid used can be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic carbons such as hexane, heptane, lignin, and petroleum ether. Hydrogens; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; getyl ether, diisopropyl Ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; meta Alcohols such as ethanol, ethanol, propanol, 2-propanol or butanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or a mixed solvent of water and the above-mentioned solvent can be mentioned. , Ethers, alcohols, fatty acids or a mixed solvent of water and the above solvent, more preferably halogenated hydrocarbons (particularly dichloromethane), ethers (particularly tetrahydrofuran or dioxane), fatty acids (particularly Acetic acid), alcohols (especially methanol or ethanol), or water or water and the above solvents A mixed solvent of. The reaction temperature varies depending on the starting compound, the solvent and the acid used, but is usually from 10 ° C to 15O :, preferably from 0 ° C to 10 °. The reaction time varies depending on the starting compound, solvent or acid used, but is usually 5 minutes to 48 hours, preferably 10 minutes to 15 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the ability to filter out the target compound precipitated in the reaction solution, if necessary, neutralize as appropriate, evaporate the solvent and dry, or pour the reaction solution into water, or Neutralize and add a solvent that is immiscible with water (eg, benzene, ether, ethyl acetate, etc.), extract, wash the organic layer containing the target compound with water, dry using anhydrous magnesium sulfate, etc., and evaporate the solvent Thereby, the target compound is obtained. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the protecting group of the amino group is an alkanol, arylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aryldicarbonyl, aralkyl or aralkyloxycarbonyl, in an inert solvent. Alternatively, it can be removed by treating with a base in an aqueous solvent. Bases used are, for example, alkali metal bicarbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride or lithium hydride; sodium hydroxide, alkaline metal hydroxides such as sodium hydroxide, lithium hydroxide or lithium hydroxide; sodium methoxide; Alkali metal alcohols such as sodium methoxide, potassium t-butoxide or lithium methoxide; alkali metals such as hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4 -(N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane ( DABCO) or organic bases such as 1,8-diazabicyclo [5.4.0] dex-7-ene (DBU), preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate). Alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or potassium methoxide) or organic bases (especially hydrazine or methylamine). . The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.For example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene; getyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N —Dimethyl acetate § such as bromide or to Kisamechirurin acid triamide The solvent may be a mixed solvent with a solvent, preferably a halogenated hydrocarbon, an ether, an alcohol, or a mixed solvent of water and the above solvent, and more preferably an ether (particularly tetrahydrofuran). Or dioxane), alcohols (particularly methanol and ethanol), or a mixed solvent of water and the above solvent. The reaction temperature varies depending on the starting compound, the solvent or the base used, but is usually from 11 ° C. to 50 ° C., preferably from 15 ° C. to 10 ° C. The reaction time varies depending on the starting compound, solvent or base used, but is usually 5 minutes to 20 hours, preferably 10 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or, if necessary, neutralized with an acid and then the solvent is distilled off, or water is poured into the reaction solution to adjust the pH of the aqueous layer. The resulting precipitate is collected by filtration, or a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added for extraction. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the like. The target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the protecting group of the amino group is t-butoxycarbonyl group, it can also be removed by treating with a silyl compound or a Lewis acid, particularly in an inert solvent. Examples of the silyl compound used include trimethylsilyl chloride, trimethylsilyl iodide and trimethylsilyl trifluoromethanesulfonate. Examples of the Lewis acid used include aluminum chloride. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Ethers such as tyl ether, tetrahydrofuran or dioxane; or nitriles such as acetonitrile, preferably halogenated hydrocarbons (especially dichloromethane or chloroform) or nitriles (especially acetone). Toril). The reaction temperature varies depending on the starting compound, reagent, solvent and the like, but is usually from 120 to 100 ° C, preferably from 0 ° C to 5 Ot. The reaction time varies depending on the starting compound, the reagent, the solvent, the reaction temperature and the like, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the protecting group of the amino group is an aryloxycarbonyl group, it can be particularly removed in the same manner as the removal method by the corrosion reduction reaction in the case of an aralkyl group or the like. That is, it can be removed using palladium, and triphenylphosphine or nickel tetracarbonyl. When the protecting group of the amino group is an aralkyl group or C₇— C_uWhen it is an aralkyloxycarbonyl group, it is usually removed by contacting with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent or by using an oxidizing agent. There are methods to remove You. In the case of the reaction for removing the protecting group by catalytic reduction, the solvent to be used is not particularly limited as long as it does not participate in this reaction.For example, aliphatic solvents such as hexane and cyclohexane Hydrocarbons; aromatic hydrocarbons such as toluene, benzene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; methanol, ethanol or 2-propanol Alcohols such as formic acid; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, Esters, alcohols, fatty acids, or a mixed solvent of these organic solvents and water. Methanol or ethanol), fatty acids (especially formic acid or acetic acid), or a mixed solvent of these organic solvents and water. The catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction. Examples thereof include palladium-carbon, Raney nickel, rhodium-aluminum aluminum and palladium-barium sulfate. However, it is preferably palladium-carbon or Raney nickel. The pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm. The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like, but is usually from 0 ° C to 100 ° C, and preferably from 10 ° C to 50 ° C. The reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature, and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after removing the catalyst by filtration, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is removed. Either filter or add a solvent that is immiscible with water (for example, benzene, ether, ethyl acetate, etc.), extract, wash the organic layer containing the target compound with water, dry over anhydrous magnesium sulfate, etc., and evaporate the solvent Thereby, the target compound is obtained. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction. Examples thereof include ketones such as acetone; halogenated carbons such as dichloromethane, chloroform, and carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as getyl ether, tetrahydrofuran or dioxane; such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethyl phosphorotriamide Amides; sulfoxides such as dimethyl sulfoxide; or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitriles, ethers, amides, Sulfoxides or mixed solvents of these organic solvents and water, more preferably keto (Especially acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethyl phosphorotriamide), sulfoxides (especially dimethyl sulfoxide), and organic solvents of these It is a mixed solvent with water. The oxidizing agent used can be, for example, potassium persulphate, sodium persulphate, ammonium cerium nitrate (CAN) or 2,3-dichroic-5,6-dicyano-p-benzoquinone (DDQ). , Preferably CAN or DDQ. The reaction temperature varies depending on the starting compound, the solvent, the oxidizing agent used, and the like, but is usually from 0 to 150, preferably from 10 to 50 ° C. The reaction time varies depending on the compound, the solvent, the oxidizing agent used, and the like, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 12 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (eg, benzene, ether, ethyl acetate) ), And the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. In the desired reaction (c), the “reaction for introducing a desired substituent into an amino group”, the starting compound is reacted in an inert solvent with or without a base (preferably in the presence of a base),

Reagent R ⁶ -X a (X a is achieved by reacting a halogen atom (especially a fluorine atom or a chlorine atom) and an alkoxy group (especially a methoxy group or an ethoxy group). Solvent used in reaction (c) Is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin, and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene, etc .; such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroether, diisopropylether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether Ethers; ketones such as acetone or methyl ethyl ketone; nitrometa Nitro compounds such as acetonitrile or isopyronitrile; nitriles such as acetonitrile or isobutyronitrile; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N— Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably alcohols (particularly ethanol) The base used in the reaction (c) is, for example, sodium carbonate, potassium carbonate or lithium carbonate. Alkali metal carbonates such as lithium; sodium bicarbonate, aluminum bicarbonate or lithium bicarbonate; Alkali metal bicarbonates such as sodium hydroxide, lithium hydroxide or lithium hydroxide Alkali metal hydroxides; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N -Jetylaniline, 1,5-diazabicyclo [4.3.0] Nona-5-ene, 1,4_diazabicyclo [2.2.2] octane (DABCO) or 1,8 diazabicyclo [5. 4. 0] Organic bases such as dex-7-ene (DBU), preferably alkali metal carbonates (sodium or potassium carbonate) or organic bases (especially triethyla). Min). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -1 to 100 ° C, preferably 0 to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 1 hour to 48 hours, preferably from 5 hours to 15 hours. 'After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or after completion of the reaction, water is added to the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound. After extraction, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. The desired reaction (d), “ester hydrolysis reaction”, is generally carried out according to a method well known in the art of organic synthetic chemistry, by reacting a starting compound in an inert solvent or in the absence of a solvent, in the presence of an acid or a base, This is achieved by hydrolysis, but hydrolysis with an acid is more preferred. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include methanol, ethanol, propanol, 2-propanol, butanol and isobutanol. It may be a mixed solvent of alcohols and water, and is preferably aqueous methanol or aqueous ethanol. Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid and phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid. Acid or a sulfonic acid such as p-toluenesulfonic acid; or a carboxylic acid salt such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably a mineral acid (particularly hydrochloric acid). ). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alternatively, it can be an alkali metal hydroxide such as sodium hydroxide, sodium oxidizing lithium or lithium hydroxide, preferably sodium hydroxide. The reaction temperature varies depending on the starting compound, the reagent, and the like.In the case of a reaction using an acid, the reaction temperature is usually o: to 150 ° C (preferably 50 ° C to 100 ° C). The reaction used is usually at −10 ° C. (to 50 ° C. (preferably −50 ° C. to 10 ° C.). The reaction time varies depending on the starting material, the reagent and the reaction temperature. The reaction is usually 30 minutes to 48 hours (preferably 3 hours to 10 hours), and the reaction using a base is usually 5 minutes to 10 hours (preferably 10 minutes to 10 hours). After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method, for example, by distilling off the solvent after completion of the reaction, or after completion of the reaction, by adding an acid (eg, hydrochloric acid). ) To make the reaction solution acidic, and precipitate the target compound by filtration or use a solvent that is immiscible with water. (Example For example, benzene, ether, ethyl acetate, etc.) are added to extract the target compound, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate, etc., and then the solvent is distilled off. can get. After completion of the reaction, the carbonate of the target compound can also be obtained by passing carbon dioxide gas through an aqueous solvent or by adding sodium carbonate or carbonated lime. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. The desired reaction (e), the “reaction to remove the protected hydroxyl group” is described, for example, in Protective Groups in Organic Synthesis, 3rd Edition, T.W. Green'and · GM Watts, John 'Ili-I' and 'Sands', Inc. [Protective Groups in Organic Synthesis, 3rd edition, TWGreene &PGMWuts; John Wiley & Sons, Inc.]. Hydroxyl protecting groups are formyl, acetyl, benzoyl, tetrahydropyran-12-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-14-yl, tetrahydrothio Pyran-1-yl group, 4-methoxytetrahydrothiopyran-4-yl group, tetrahydrofuran-1-yl group, tetrahydrothiofuran-2-yl group, methoxymethyl group, 1,1-dimethyl-1-yl group —Methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2 —Cross-mouth ethoxy) methyl group, 1-ethoxyhexyl group, 1- (isopropoxy) ethyl group, methoxycarbonyl , Ethoxycarbonyl group, t-boxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-promo t-butoxycarbonyl group, 2,2-dibutanol, t-butoxycarbonyl group, vinyloxycarbonyl group, benzylo When it is a xycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 91-anthrylmethyloxycarbonyl, p-methoxybenzyloxycarbonyl or P-nitrobenzyloxycarbonyl Can be removed by treating with an acid in an inert solvent or an aqueous solvent. The acid used can be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.For example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene; getyl ether, dizopropyl Ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol. And formamide, N, N Amides such as dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or water and The solvent may be a mixed solvent with the solvent described above, preferably a mixed solvent of halogenated hydrocarbons, ethers, esters, alcohols, fatty acids or water with the above solvent, and more preferably a halogenated hydrocarbon. Hydrocarbons (especially dichloromethane), ethers (especially tetrahydrofuran or dioxane), esters (especially ethyl acetate), fatty acids (especially acetic acid), or water or a mixed solvent of water and the above solvent. The reaction temperature varies depending on the starting compound, the solvent or the acid used, but is usually from 1 to 15 ° C., preferably from 0 ° C. to 60 ° C. The reaction time varies depending on the starting compound, solvent or acid used, but is usually 5 minutes to 20 hours, preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, After completion of the reaction, the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted. The organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the hydroxyl-protecting group is an alkanol, alkoxylated alkanoyl, halogenoalkanol, alkoxyalkanol, unsaturated alkanoyl, arylcarbonyl, halogenoarylcarbonyl, alkylated arylcarbonyl, In the case of a carboxylated arylcarbonyl, arylcarbonylcarbonyl, alkoxycarbonylarylaryl or arylalkylcarbonyl, in an inert solvent or an aqueous solvent Can be removed by treating with a base. Bases used are, for example, alkali metal bicarbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride or hydrogen hydride; 7K sodium hydroxide, alkaline metal hydroxides such as hydroxide hydride or lithium hydroxide; sodium methoxide Alkali metal alcohols such as sodium methoxide, potassium t-butoxide or lithium methoxide; alkali metal alcohols; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, pyridine , 4-(N, N-dimethylamino) pyridine, N, N-dimethylylaniline, N, N-getylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] Organic bases such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] dex-7-ene (DBU), preferably alkali metal carbonates (especially sodium carbonate or Potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal Alkoxides (especially sodium methoxide, sodium ethoxide or potassium tert-oxide) or organic bases (especially hydrazine or methylamine). The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.For example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene; getyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N , N—Dimethylacetoa And a mixed solvent with an organic solvent such as hexamethylphosphoric acid triamide, preferably a halogenated hydrocarbon, an ether, an alcohol, or a mixed solvent of water and the above solvent. Preferable are ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol and ethanol), or a mixed solvent of water and the above solvent. The reaction temperature varies depending on the starting compound, the solvent and the base used, but it is usually from 100 to 150 ° C, preferably from Ot to 50 ° C. The reaction time varies depending on the starting compound, the solvent or the base used, but is usually 50 minutes to 20 hours, preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added for extraction, and the organic layer containing the target compound is washed with water. After drying with anhydrous magnesium sulfate etc., the target compound is obtained by evaporating the solvent. can get. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contact with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent. Or a method of removing using an oxidizing agent. In the case of the reaction of removing the protecting group by catalytic reduction, the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, aliphatic hydrocarbons such as hexane or cyclohexane; Aromatic hydrocarbons such as toluene, benzene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; such as methanol, ethanol or 2-propanol Alcohols; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, Alcohols, fatty acids or a mixed solvent of these organic solvents and water, more preferably, alcohols ( Particularly, methanol or ethanol), fatty acids (especially formic acid or acetic acid), or a mixed solvent of these organic solvents and water. The catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction. For example, palladium-carbon, Raney nickel, rhodium aluminum monoxide or palladium-barium sulfate can be used. Is palladium monocarbon or Raney nickel. The pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm. The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like, but is usually 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature and the like, but is usually from 15 minutes to 10 hours, preferably from 30 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after removing the catalyst by filtration, the solvent is distilled off, a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted, and the organic layer containing the target compound is washed with water, and dried over anhydrous magnesium sulfate. The target compound is obtained by drying using a solvent or the like and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction. Examples thereof include ketones such as acetone; halogenated carbons such as dichloromethane, chloroform, and carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as getyl ether, tetrahydrofuran or dioxane; such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphorotriamide Amides; sulfoxides such as dimethyl sulfoxide; or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitrils, ethers, amides , Sulfoxides, or a mixed solvent of these organic solvents and water, more preferably a ketone (Especially acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetate nitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide), or an organic solvent thereof and water And a mixed solvent. The oxidizing agent used can be, for example, potassium persulphate, sodium persulphate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Is CAN or DDQ. The reaction temperature varies depending on the starting compound, solvent, oxidizing agent used, etc. To 150 ° C, and preferably from 10 ° C to 50 ° C. The reaction time varies depending on the compound, the solvent, the oxidizing agent used, and the like, but is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted, and the organic layer containing the target compound is washed with water, and then anhydrous magnesium sulfate. And the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. When the hydroxyl-protecting group is a silyl, it is usually preferable to remove the protecting group by reacting it with a compound producing fluorine anion in an inert solvent. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.Examples include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, polyester, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxybenzene Or ethers such as diethylene dalicol dimethyl ether, preferably ethers (preferably tetrahydrofuran). The compound forming the fluoroanion used can be, for example, tetrabutylammonium fluoride, hydrofluoric acid, monopyridine hydrofluoride or potassium fluoride, preferably tetrabutylammonium fluoride. It is. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 150 to 100 ° C, preferably from -10 to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 12 hours, preferably 10 minutes to 1 hour. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and sulfuric anhydride is added. After drying using magnesium or the like, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

Method B is a method for producing a compound having the general formula (4). 3rd step

This step is a step for producing a compound having the general formula (6). The compound having the general formula (2) is prepared by reacting the compound having the general formula (2) in an inert solvent in the presence of a phosphine or an azo compound. Is achieved by condensation with a compound having the formula

This step can be performed in the same manner as in the first step. 4th step

This step

(a) removing a hydroxyl-protecting group of compound (6), and

(b) The compound obtained in the step (a) and a compound represented by the general formula (7)

(7)

[Wherein, R ^6a , R ⁷ , R ⁸ and n are as defined above. And condensing the compound represented by the general formula (4) to produce a compound having the general formula (4). The former (a) can be performed in the same manner as in the second step (e), and the latter (b) can be performed in the same manner as in the first step.

Method C is a method for producing a compound having the general formula (2). Fifth step,

This step is a step for producing a compound represented by the general formula (9),

Formula (Ph) ₃ PCR ² CHO [In the formula, Ph represents a phenyl group, and R ² has the same meaning as described above. And the compound having the general formula (8) in an inert solvent. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as ethylene glycol dimethyl ether; or nitriles such as acetonitrile, propionitrile or ptyronitrile, preferably aromatic Hydrocarbons (particularly benzene or toluene). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 0 ° C to 150 ° C, and preferably from 30 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. Step 6

This step is a step of producing compound (2), and is accomplished by reducing compound (9) in an inert solvent in the presence of a reducing agent. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.Examples include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene or xylene ジクロロメタン; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorodiisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or an ether such as diethylene glycol dimethyl ether; an alcohol such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent of the above solvents, wherein the reducing agent is aluminum hydride or In the case of dipolane, aliphatic hydrocarbons (Hexane hexane or cycloheteroalkyl particular), aromatic hydrocarbons Motorui (particularly benzene, toluene or xylene) or ethers (particularly Jefferies chill ether, Tetrahydrofuran or dioxane), and when the reducing agent is sodium borohydride, an alcohol (especially methanol or ethanol) or a mixed solvent of halogenated hydrocarbons and alcohols (especially a mixed solvent of dichloromethane and ethanol). . The reducing agent used can be an aluminum hydride compound such as lithium aluminum hydride or diisobutyl aluminum hydride, sodium borohydride or diporane, and is preferably sodium borohydride. When sodium borohydride is used as the reducing agent, cerium chloride can be used as a catalyst. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 178 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is added to the obtained residue, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, The extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. Steps 7 and 8

This step is a step for producing a compound having the general formula (11),

A compound having the formula HCCCH ₂ PPro (wherein Pro has the same meaning as described above) can be obtained by reacting a compound having the (seventh) inert solvent or in the absence of a solvent (preferably in the absence of a solvent), After reacting with catechol pollan,

(Eighth) The obtained intermediate compound was dissolved in an inert solvent in the presence of a palladium catalyst and a base. It is achieved by reacting with a compound having the general formula (10). The solvent used in the seventh step is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.For example, hexane, cyclohexane, heptane, lignin or petroleum ether Aliphatic hydrocarbons such as benzene, toluene, or xylene; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethyl ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl It can be an ether such as toxicethane or dimethylene glycol dimethyl ether, preferably an aliphatic hydrocarbon (especially hexane or petroleum ether) or an aromatic hydrocarbon (especially toluene). The reaction temperature of the seventh step varies depending on the raw material compounds, reagents and the like, but is usually from 110 to 100 ° C, preferably from 30 to 80 ° C. The reaction time of the seventh step varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the target compound is obtained by distilling off the solvent. In addition, it can be used in the eighth step without particular purification. The solvent used in the eighth step is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.For example, hexane, cyclohexane, heptane, lignin or petroleum ether Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroether, diisopropyl ether, tetrahydrofuran, dioxane; .Dimethoxy Ethers such as ethane or dimethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent of the above organic solvents. Preferably, they are aromatic hydrocarbons (particularly toluene). The palladium catalyst used in the eighth step includes, for example, tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex, palladium bis (diphenylphosphine phenol) complex or palladium bis (acetate) complex A palladium phosphine complex such as triphenylphosphine); or a tris (dibenzylideneaceton) dipalladium chromate form complex, bis (dibenzylideneacetone) palladium, palladium acetate or diaryl palladium chloride, which is preferable. Are tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex or palladium bis (diphenylphosphinophene) complex, more preferably tetrakis (triphenylphosphine) complex. It is (triphenyl phosphine) palladium. The base used in the eighth step is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal carbonate such as sodium bicarbonate, hydrogen bicarbonate or lithium hydrogen carbonate. Metal bicarbonates; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide or lithium methoxide; or, triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4 — (N, N-Dimethylamino) pyridine, N, N-Dimethylaniline, N, N-Jetylaniline, 1,5-Diazabicyclo [4.3.0] Noner 5-ene, 1,4-Diazabicyclo [2. 2.2] octane (DABC0) or 1,8-diazabicyclo [5.4.0] decane 7-ene (DBU) And preferably an alkali metal alkoxide (particularly sodium ethoxide). The reaction temperature of the eighth step varies depending on the starting compounds, reagents, etc., but is usually 0 ° C to 150 And preferably 5 Ot to 120 ° C. The reaction time of this step varies depending on the starting compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours. After completion of the reaction, the target compound of the eighth step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and dried over anhydrous magnesium sulfate. After drying using, for example, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, recrystallization, precipitation, or chromatography. 9th step

The ninth step is a step of producing the compound (2), which is achieved by removing the hydroxyl-protecting group of the compound (11), and can be carried out under the same conditions as in the reaction (e) of the second step. it can. Step 10

The tenth step is a step of producing a compound having the general formula (14). In the compound having the general formula (12), when X represents a leaving group,

(a) a compound represented by the general formula (13)

(13) [Wherein, R ^6b , R ⁷ , R ⁸ and n are as defined above. Is reacted with compound (12) in an inert solvent in the presence of a base, or

Or, in the compound (12), when X represents a hydroxyl group,

(b) This is achieved by subjecting the above general formula (13) to dehydration condensation with the compound (12) in the presence of a phosphine and an azo compound in an inert solvent.

This step can be performed in the same manner as in the first step.

(a) Law:

The solvent used in this step is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.For example, hexane, cyclohexane, heptane, rigoin or petroleum ether Aliphatic hydrocarbons such as benzene; toluene or xylene; aromatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroether, diisopropylether, tetrahydrofuran, dioxane, and dimethoxybenzene. Or ethers such as dimethylene glycol dimethyl ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isoptyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide Or an amino such as N-methyl-2-pyrrolidinone Or sulphoxides such as dimethylsulphoxide or sulfolane, preferably amides (especially N, N-dimethylformamide or N, N-dimethylacetamide). The base used in this step is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Bicarbonates; Alkali metal acetates, such as sodium acetate; Alkali metal hydrides, such as lithium hydride, sodium hydride or potassium hydride; 7_ sodium oxide, such as sodium hydroxide, lithium hydroxide or lithium hydroxide Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine; Triptyluamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-dimethylaniline, 1,5-diazabicyclo [4. 3.0] Nonar 5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8 diazabicyclo [5.4.0] pendeku 7-den (DBU) Organic bases; lithium alkylamides such as methyllithium, ethyl pyramide or lithium dicyclohexylamide, preferably alkali metal hydrides (especially lithium hydride or sodium hydride), metals Alkoxides (especially sodium methoxide) or alkyllithiums (especially butyllithium). The reaction temperature in this step varies depending on the starting compound, the reagent, and the like, but is usually −IO to 100 ° C., and preferably 15 to 50 ° C. The reaction time of this step varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and sulfuric anhydride is added. After drying over magnesium or the like, the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, or chromatography. 11th step

This step is a method for producing a compound having the general formula (15), and is performed when R ^6b is a substituent different from R ^6a in the general formula (17). Deprotection of the protecting group for the amino group can be carried out according to the above-mentioned second step (b). Note that this step, when R ^6b is the same substituent as R ^6a in the general formula (17) is Ru are omitted. 12th step

This step is a method for producing a compound having the general formula (16).

(1) In an inert solvent, a reagent R ⁶ -Xa (Xa is a halogen atom (especially a chlorine or bromine atom), an alkoxy group (especially a methoxy or ethoxy group) is reacted in the presence of a base,

(2) React reagent R ⁶ — Xa (Xa is a halogen atom (especially chlorine or bromine atom), trifluoromethanesulfonyloxy group) in an inert solvent in the presence of a palladium catalyst, phosphines and a base Or or

(3) In an inert solvent, a chain ketone having 1 to 6 carbon atoms or a cyclic ketone having 3 to 8 carbon atoms is subjected to acetic acid and sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of , React,

It is performed by any of the methods. This step is omitted if the first step is omitted.

'Reaction (1) can be carried out according to the above-mentioned second step (c). The solvent used in the reaction (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as benzene, toluene or xylene; Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as cyetane or methylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, propanol or isobutanol; or a mixed solvent of the above organic solvents. Are aromatic hydrocarbons (particularly toluene). The palladium catalyst to be used is, for example, tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex, palladium chloride bis (diphenylphosphinophenephenic acid) complex or palladium bis (triphenylphosphine) complex. Palladium phosphine complex such as fin); or dimer of tris (dibenzylideneacetone) diparadium, bis (dibenzylideneacetone) palladium, palladium acetate or dipyrrolid palladium chloride, preferably palladium acetate or tris (Dibenzylideneacetone) Dipalladium. Phosphines used are, for example, trimethylphosphine, tri E chill phosphine, Bok Li propyl phosphine, tributyl phosphine, tri t one-butylphosphine, tri C j such hexyl phosphine to ladle down chill phosphine or tri - C ₆ alkyl phosphine Tri C ₆ -C ₁₀ aryl phosphines such as triphenyl phosphine, triindenyl phosphine or trinaphthyl phosphine; tolyl diphenyl phosphine, tritolyl phosphine, trimesityl phosphine, tributyl phenyl phosphine or tri-6-ethyl 2 —Tri C ₆ —C ₁₀ arylphosphine which may have C “C ₄ alkyl as a substituent, such as naphthylphosphine; or 2- (di-tert-butylphosphino) biphenyl, 2- (di

2, — (N, N-dimethylamino) biphenyl and the like, preferably tri-t_butylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) piphenyl or 2-(Dicyclohexylphosphino)-2,-(N, N-dimethylamino) biphenyl. The base used is, for example, sodium carbonate, potassium carbonate or lithium carbonate. Alkali metal bicarbonates such as sodium bicarbonate, hydrogen bicarbonate or lithium bicarbonate; sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or lithium methoxide Alkali metal alkoxides such as: triadilamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-Jetylaniline, 1,5-Diazabicyclo [4.3.0] Nona-5-ene, 1,4-Diazabicyclo [2.2.2] octane (DABCO) or 1,8-Diazabicyclo [5.4. 0] organic amines such as dex-1-7-ene (DBU), preferably alkali metal alkoxy (Especially sodium t-butoxide). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 0 ° C to 150 ° C, preferably from 50 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 1 hour to 5 hours. -After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. The chain ketone having 1 to 6 carbon atoms used in the reaction (3) includes formaldehyde, acetoaldehyde, propane-one-one, propane-2-one (acetone), butane-one-one, pentane- 2-one, hexane-2-one, etc., preferably, acetone, and examples of the cyclic ketone having 3 to 8 carbon atoms include cyclopropanone, cyclobutanone, cyclopentanone, and cyclopentane. Hexanone, cycloheptanone, and cyclooctanone are preferred, and cyclopentanone is preferred. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chloroisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethoxy Ethers such as ethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Like N-methyl-2-pyrrolidinone Amides; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above organic solvents, preferably, halogenated hydrocarbons (particularly dichloromethane), alcohols (methanol or ethanol) or These are mixed solvents (especially mixed solvents of dichloromethane and methanol). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 ° C to 150 ° C, preferably from 0 ° C to 100 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 1 hour to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and anhydrous sulfuric acid. After drying with GN, etc., the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. This step is omitted if the first step is omitted. Step 13

This step is a step for producing a compound (17), wherein the compound (14) or the compound (16) is

(1) In an inert solvent under a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm), using a catalytic reduction catalyst, or

(2) It is usually achieved by applying a method of reducing a nitro group known to organic chemistry to an amino group by stirring in acetic acid in the presence of metal powder. The solvent used in the catalytic reduction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.Examples include hexane, cyclohexane, heptane, ligwin or petroleum Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxetane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent thereof, preferably Alcohols (especially methanol) or ethers And a mixed solvent of alcohols (in particular a mixed solvent of tetrahydrofuran and methanol or ethanol). The catalytic reduction catalyst used is not particularly limited as long as it is used in a usual catalytic reduction reaction.For example, palladium black, palladium monocarbon, palladium hydroxide, palladium heptaoxide monocarbon, and It may be mono-nickel, rhodium-aluminum oxide, palladium barium monosulfate, platinum oxide or platinum black, preferably palladium-carbon. The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from 10 ° C to 100 ° C. The temperature is preferably from 50 ° C. to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 6 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is removed by filtration, and the filtrate is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. The solvent used in the reduction using the metal powder may be acetic acid, aqueous hydrochloric acid, water, an alcohol or a mixture with an organic solvent soluble in water, and is preferably acetic acid. The metal powder used can be, for example, zinc powder, tin powder or iron powder, preferably zinc powder or tin powder. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from 10 ° C to 10 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the insolubles are removed by filtration, and the filtrate is distilled off to obtain the desired compound. If necessary, the desired compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

Can be further purified. Step 14 This step is a step for producing a compound having the general formula (3). The compound (17) is prepared by reacting the compound (17) in an inert solvent in the presence or absence of a base (preferably in the presence of a base), ^This is achieved by reacting with a compound having the formula: ^3a — Xa (wherein, R3a has the same meaning as described above, and Xa represents a leaving group). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include hexane, cyclohexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorodiisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or ethers such as diethylenedaricol dimethyl ether; ketones such as acetone or methylethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide; N, N-dimethylform Amide, N, N-dimethylacetamide or Amides such as N-methyl-2-pyrrolidinone. Preference is given to halogenated hydrocarbons (especially dichloromethane), ethers (getyl ether or tetrahydrofuran) or amides (especially N, N-dimethylformamide). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or hydrogen hydride; aluminum metal hydroxides such as sodium hydroxide, hydroxide hydride or lithium hydroxide; sodium methoxy Alkali metal alkoxides such as sodium, sodium methoxide, potassium t-butoxide or lithium methoxide; methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, disopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo [4.3.0] nona-1-ene, 1, .4-diazabicyclo [2.2] 2] octane (DABCO) or organic bases such as 1,8-diazabicyclo [5.4.0] dex-7-ene (DBU), preferably alkali metal carbonates ( In particular, sodium carbonate or potassium carbonate, alkali metal bicarbonates (especially sodium bicarbonate or potassium bicarbonate) or alkali metal hydrides (especially lithium hydride or sodium hydride). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 1 ot: to 100 ° C, preferably 0 to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 1 hour to 12 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and dried. After drying with magnesium sulfate or the like, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography. 'The starting compounds (5), (7), (8) and (12) of the present invention are known or are easily produced according to known methods. {For example, Bioorganic and Medicinal 'Chemistry' Letters, Vol. 8, p. 277 (1998) [Bioorg. Med. Chem. Lett ... 8, 277 (1998)], Tetrahedron ' Letters, Vol. 37, p. 6439 (1996) [Tetrahedron Letters, 37, 6439 (1996) 1 et al.]. [Brief description of drawings]

FIG. 1 is a diagram showing an experimental device for evaluating iontophoresis skin permeability from a liquid preparation for transdermal administration, and FIG. 2 is a diagram showing a preparation from a 5 mg / ml liquid preparation of Production Example 98. FIG. 3 is a view showing an iontophoresis skin permeation profile (current density of 131 A / cm ² ) in Ales rat skin.

[Best mode for carrying out the invention]

Hereinafter, the present invention will be described more specifically with reference to Examples, Comparative Examples, Test Examples, Production Examples, and Reference Examples, but the present invention is not limited thereto. Example 1

Each compound of Production Example was dissolved in purified water at a concentration of 5 mg / ml, and the pH was adjusted to 5 with sodium hydroxide to obtain a liquid preparation for transdermal administration. Example 2

100 mg of each compound of Production Example and 50 mg of citric acid were dissolved in 6.25 g of purified water to obtain one solution. Next, 100 mg of aluminum glycinate and 0.5 g of polyvinylacetamide were dispersed in 3 g of concentrated glycerin in a local area to obtain two liquids.

1 solution was added to 2 solutions little by little, and after uniformly stirring, poured into a glass petri dish having a diameter of 9 cm, and allowed to stand at room temperature for 1 day to obtain a transdermal gel preparation. .

An electrode in which a silver lead wire was welded to a silver thin film was lightly pressed to adhere to the gel formulation. On the other hand, a silver electrode was immersed in silver salt heated and melted, pulled up, allowed to cool, and solidified to form an electrode on the cathode side. Similarly to the gel preparation for transdermal administration described above, a gel containing no compound was prepared, and a cathode electrode was adhered thereto. By bonding a silver electrode to a transdermal gel formulation containing a compound and a silver chloride-coated silver wire electrode to a gel not containing a compound, the gel is bonded to the anode and cathode of the power supply, respectively. The tophoresis administration system was completed. Comparative Example 1

The following two compounds (Compound A and Eich Compound B) were dissolved in purified water at a concentration of 5 mg / ml, and the pH was adjusted to 5 with sodium hydroxide to obtain a liquid preparation for transdermal administration.

Compound A

Compound B Compound A is disclosed in WO 01/02356, and compound B is disclosed in WO 96/16940. Test example 1

Skin permeability

Using the experimental device shown in FIG. 1, iontophoresis skin permeability from the transdermal solution prepared in Example 1 was evaluated.

The cell is made up of three chambers: the + pole chamber, the one pole chamber, and the receptor chamber. The receptor chamber was worn so that it was behind the skin. The receptor chamber of the cell was _c- recept kept at 37 by refluxing constant-temperature water. The 33 mM isotonic phosphate buffer (pH 7.2, 0.13M (NaCl added) was injected with a Verizon lute pump, and the liquid coming out of the outlet was sent to a fraction collector. The interior of the receptor chamber was constantly stirred with a magnetic stirrer.

In the device having such a configuration, the transdermal administration solution is placed in the positive electrode chamber, the same isotonic phosphate buffer solution as in the receptor chamber is placed in the negative electrode chamber, and the silver wire is placed in the positive electrode chamber. an electrode, the pole chamber in one fitted with a silver wire electrodes one coating silver chloride copolymers, by connecting the electrodes to a constant current power supply unit, so that the current flowing through the skin is 131 a / cm ² DC current was applied. With the time of the start of current supply as time zero, the liquid flowing out of the reception chamber at the end of 1.5 hours was sampled into test tubes, and the drug concentration in each sample was quantified by HPLC. Using the quantitative value Ct at the time t, the volume Vr of the receptor chamber and the flow rate q of the receptor liquid, the cumulative skin permeation Qt every 1.5 hours was calculated by the equation (1).

When Qt is plotted against time, it becomes a straight line after a certain time as shown in Fig. 2. The skin permeation velocity (flux) was calculated from the slope of this linear part, and the lag time (lag time) was calculated from the intercept obtained by extrapolating the linear part to the time axis. Table 1 shows the obtained results.

[table 1]

flux (g / hr / cm ") lag ume (hr)

54 47 ± 9 5 ± 1

60 86 + 11 4 ± 1

66 46 ± 7 4 ± 0.5

72 87 ± 16 4 ± 1

94 52 + 10 4 ± 1

98 67 ± 9 5 ± 1

102 37 ± 1 6 ± 1

103 65 + 11 4 ± 1

105 65 + 24 6 ± 4

110 78 ± 10 4 ± 1

131 84 ± 8 5 ± 1

132 74 + 11 6 ± 0.4

143 85 ± 16 5 ± 1

147 73 ± 11 5 ± 1

151 76 + 21 3 ± 3

Comparative example l "2 ± 0.4 7 ± 1

Comparative Example 2 22 ± 6 6 ± 0.03 Test Example 2

Skin permeability.

As in Test Example 1, iontophoresis skin permeability from the transdermal solution prepared in Example 1 was evaluated using the experimental apparatus shown in FIG. A DC current was applied so that the current flowing through the skin was 100 A / cm ² . Table 2 shows the obtained results. 2]

Production example flux (g / r / cm ² ) lag time (hr)

157 68 ± 4 6 ± 0.4

159 57 ± 2 6 ± 1

161 77 ± 5 5 ± 1

163 90 ± 76 ± 1 The compound of the Preparation Example showed higher skin permeability under the same iontophoretic conditions than the compound of the Comparative Example. Production Example 1

N- [3- (3-Amidinophenyl) -1-2- (E) -propenyl] —N— [3-Chloro4_ (1-methylpiperidine-14-yloxy) phenyl] ethyl sulfamoyl acetate dihydrochloride

N— [3-—Mouth —4- (1-methylpiperidine—1-yloxy) phenyl) obtained in Reference Example 7—N— [3- (3-cyanophenyl) -2- (E) —probenyl ] Ethyl sulfamoyl acetate (938 mg) is dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride is passed under ice-cooling, and the mixture is sealed and stirred at room temperature for 5 hours. did. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (189 mg dissolved in 10 ml of water) and 28% ammonia water (0.35 ml) were added. After the addition, the mixture was stirred at room temperature overnight. After adding 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in 1 N hydrochloric acid, and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 841 mg (yield 77%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.90-2.08 (2H, m), 2.14-2.26 (2H, m), 2.74 (3H, m), 3.00-3.10 (2H, m), 3.32 (1H, m), 3.40-3.50 (1H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.62 and 4.87 (total 1H, m each), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (1H, t, J = 9.0), 7.41 (1H, m), 7.55 (IH, t, J = 8.0), 7.60 (1H, m), 7.69 (IH, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (IH , s);

IR (KBr, cm ¹ ): 1737, 1675, 1352, 1156. Production Example 2

N— [3- (3-Amidinophenyl) —2— (E) 1-Propenyl] 1-N— [3-Chloro 4 -— (1-Methyllepiperidine-14-yloxy) phenyl] sulfamoylacetic acid _ 2 Production Example N— [3- (3-amidinofenyl) -1-2- (E) -propidenyl] obtained in 1 -N- [3-chloro- 4- (1-methylpiperidine-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride (435 mg) is dissolved in 3N hydrochloric acid (20 ml), and the solution is dissolved at 60 ° C at 6. Stir for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 13% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.00 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 243 mg (yield 59%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.94 and 2.03 (total 2H, m each), 2.19 (2H, m), 2.74 (3H, m), 3.00-3.10 (2H, m), 3.30- 3.50 (2H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.61 and 4.87 (total IH, m each), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.31 (1H, m), 7.41 (1H, m), 7.55 (IH, t, J = 8.0), 7.60 (IH, m), 7.69 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1732, 1676, 1348, 1155. Production Example 3

N- [3 -— (3-Amidinophenyl) -1-2- (E) —Probenyl] -1-N_ [3-Chloro 4- (1-ethylpyperidin-1-yloxy) phenyl] sulfamoyl acetate dihydrochloride

N- [3-chloro-1,4- (1-ethyloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -pro obtained in Reference Example 13 [Benyl] sulfamoyl acetate ethyl (1240 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml). After passing through hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride solution (243 mg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.41 ml) were added. Stirred. After adding 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. Dissolve this in water and freeze-dry to obtain The compound (807 mg, yield 56%) was obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.22 (3H, t, J = 7.0), 1.26 (3H, t, J = 7.0), 1.92-2.08 (2H, m), 2.21 (2H, m ), 2.99 (2H, m), 3.09 (2H, m), 3.36 and 3.50 (total 2H, each m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d , J = 6.0), 4.64 and 4.90 (total IH, m each), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (1H, m), 7.41 ( IH, m), 7.55 (IH, t, J = 8.0), 7.60 (1H, m), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s );

IR (KBr, cm- ¹ ): 1738, 1675, 1353, 1155. Production Example 4

N- [3- (3-Amidinophenyl) -2-(E) -probenyl] -N- [3-chloro- 4-(1-Ethylbiperidine-1_4_yloxy) phenyl] sulfamoylacetic acid 2 Preparation Example N— [3- (3-Amidinophenyl) -1-2- (E) —probenyl] -N- [3-—Mouth _4- (1-Ethylpiperidine-1-4-yloxy) phenyl obtained in Step 3 Ethyl sulfamoyl acetate dihydrochloride (40 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 6 O for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative separation-PLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 1 N hydrochloric acid (1.0 Oml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 324 mg (yield 85%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.5), 1.98 (2H, m), 2.18 (2H, m), 3.05 (2H, m), 3.00-3.50 ( 4H, m), 4.15 (2H, s), 4.48 (2H, d, J = 6.0), 4.75 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.29 (1H, d, J = 9.0), 7.43 (1H, dd, J = 9.0, 2.5), 7.54 (IH, t, J = 8.0), 7.62 (1H, d, J = 2.5), 7.68 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm— ¹ ): 1731, 1676, 1348, 1154. Production Example 5

N- [3- (3-Amidinophenyl) -l2- (E) -l-probenyl] -l N- [3-chloro-4- (1-l-isopropylpyridine-l- 4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride salt

N— [3-Chloro-4-((1-isopropylpyridine-4-yloxy) phenyl) obtained in Reference Example 17—N— [3- (3-Cyanophenyl) -12— (E) 1-probenyl Ethyl sulfamoyl acetate (1 171 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride solution (224 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.42 ml) were added. Stirred overnight. The reaction mixture was added with 4 N hydrogen chloride in dioxane, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile // water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 904 mg (yield 67%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.28 (6H, m), 2.00-2.12 (2H, m), 2.18-2.36 (2H, m), 3.07 (2H, m), 3.22-3.52 (3H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, m), 4.47 (2H, d, J = 6.0), 4.66 and 4.95 (total 1H, m each), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (1H, m), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (1H, m), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm ¹ ): 1738, 1675, 1353, 1156. Production Example 6

N— [3 -— (3-Amidinophenyl) —2— (E) —Probenyl] —N— [3-Chlorol 4- (1-isopropylpiperidine—4-yloxy) phenyl] sulfamoyl acetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-probenyl] -N- [3--chloro- 4- (l-isopropylpiperidine-l-yloxy) phenyl obtained in Production Example 5 ] Ethyl sulfamoyl acetate dihydrochloride (615 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 60 ° C for 4 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 17% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.00 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 433 mg (yield 74%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (6H, d, J = 6.5), 1.97 (2H, m), 2.18 (2H, m), 2.90-3.40 (5H, m), 3.99 ( 2H, s), 4.48 (2H, d, J = 6.0), 4.75 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.27 (1H , D, J = 9.0), 7.46 (1H, dd, J = 9.0, 2.5), 7.54 (1H, t, J = 8.0), 7.65 (IH, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.87 (1H, s);

IR (KBr, cur ¹ ): 1677, 1344, 1151. Production Example 7

N— [3 -— (3-Amidinophenyl) —2 -— (E) 1-probenyl] 1 N— [4- (1-butylpiperidin-1-4-yloxy) —3-cloclophenyl] Sulfamoyl acetate 2 Hydrochloride

N- [4- (1-Phtylpyridinine_4-I-yloxy) -13-chlorophenyl] -N- [3- (3-cyanophenyl) 1-2- (E) -probenyl obtained in Reference Example 21 Ethyl sulfamoyl acetate (1177 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml). After passing through hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonia chloride solution (219 mg dissolved in water 10 ml) and 28% ammonia water (0.41 ml) were added, and the mixture was stirred at room temperature overnight. did. After adding 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 27% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 742 mg (yield 55%) of the title compound as a colorless amorphous solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 0.93 (3H, t, J = 7.5), 1.23 (3H, t, J = 7.0), 1.32 (2H, m), 1.67 (2H, m), 1.90-2.08 (2H, m), 2.15-2.28 (2H, m), 2.95-3.10 (4H, m), 3.35-3.58 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H , s), 4.47 (2H, d, J = 6.0), 4.63 and 4.88 (total IH, each m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (IH, m), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (1H, m), 7.67 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.87 (IH, s);

IR (KBr, cur ¹ ): 1738, 1675, 1353, 1156. Production Example 8

N— [3- (3-Amidinophenyl) -2 -— (E) —Probenyl] —N— [4- (1-Phtylpiperidine—4-yloxy) —3-Clo-phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) _2- (E) -probenyl] obtained in Production Example 7 N- [4- (1-butylpiperidine-4-yloxy) -3-cyclophenyl Ethyl sulfamoyl acetate dihydrochloride (600 mg) was dissolved in 3 N hydrochloric acid (20 ml), and the mixture was stirred at 60 ° C for 4.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in 1 N hydrochloric acid (1.00 ml), and concentrated under reduced pressure to dryness. This was dissolved in water and freeze-dried to obtain 45 O mg (yield: 78%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 0.90 (3H, t, J = 7.5), 1.31 (2H, m), 1.61 (2H, m), 1.92 (2H, m), 2.13 (2H, m), 2.87 (2H, m), 2.90-3.20 (4H, m), 4.03 (2H, s), 4.48 (2H, d, J = 6.0), 4.70 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.56 (IH, d, J = 16.0), 7.27 (1H, d, J = 9.0), 7.45 (IH, dd, J = 9.0, 2.5), 7.54 (1H, t, J = 8.0), 7.64 (1H, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cm- ¹ ): 1676, 1347, 1153. Production Example 9 N- [3- (3-Amidinophenyl) —2- (E) —Probenyl] — N_ C4-(1-Benzylpiperidine—4-yloxy) -13-Chlorophenyl Phenyl] sulfamoylacetate Diethyl hydrochloride

N— [4- (1-Benzylpiperidine-14-yloxy) —3 monochlorophenyl) —N— [3- (3-Cyanophenyl) —2 -— (E) monopro obtained in Reference Example 25 [Benyl] sulfamoyl acetate ethyl (1531 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml). After passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonia chloride (233 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.40 ml) were added. Stirred. After adding a 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 931 mg (yield 53%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.94-2.05 (2H, m), 2.16-2.28 (2H, m), 3.01 (2H, m), 3.24-3.44 (2H, m), 4.18 (2H, q, J = 7.0), 4.31 (2H, m), 4.40 (2H, s), 4.46 (2H, d, J = 6.0), 4.59 and 4.88 (total 1H, m each), 6.42 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.27 (1H, d, J = 9.0), 7.31 (1H, d, J = 9.0) ), 7.38 (1H, m), 7.43-7.51 (3H, m), 7.52-7.59 (2H, m), 7.60-7.66 (2H, m), 7.67 (1H, d, J = 8.0), 7.72 (1H , D, J = 8.0), 7.87 (1H, s);

IR (KBr, cm ' ¹ ): 1738, 1675, 1353, 1155. Production Example 10

N— [3 -— (3-Amidinophenyl) -1-2- (E) -Propenyl] —N— [4 -— (1-Benzylpiperidine-1.4-^-peroxy) -13-Cl-Phenylphenyl] sulfamoylacetic acid salt

N- [3- (3-amidinofenyl) -1-2_ (E) -probenyl] -N- [4-((1-benzylpiperidine-14-yloxy) -13-clophenyl) obtained in Production Example 9 S Rufamoyl acetate ethyl dihydrochloride (731 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 60 ° C for 6.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in IN hydrochloric acid (1.00 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 547 mg (yield 87%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.90-2.08 (2H, m), 2.12-2.26 (2H, m), 2.92-3.02 (2H, m), 3.20-3.50 (2H, m), 4.20-4.38 (2H, m), 4.25 (2H, s), 4.46 (2H, d, J = 6.0), 4.61 and 4.83 (total 1H, each m), 6.42 (1H, dt, J = 16.0, 6.0) , 6.56 (1H, d, J = 16.0), 7.27 (1H, d, J = 9.0), 7.39 (1H, dd, J = 9.0, 2.5), 7.40-7.50 (3H, m), 7.54 (1H, t , J = 8.0), 7.55-7.65 (3H, m), 7.66 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.85 (1H, s);

IR (KBr, cur ¹ ): 1732, 1675, 1349, 1154. Production Example 11

N— [3- (3-Amidinophenyl) 1 2- (E) 1-Propenyl] 1 N— [3-Chloro 4- (1 _phenethylbiperidine 1-4 _yloxy) phenyl] Sulfamoyl acetic acid ethyl ester Dihydrochloride

N- [3-Chloro-4- (1-phenethylpiperidine-1-4-yloxy) phenyl] obtained in Reference Example 29—N— [3- (3-Cyanophenyl) 1-2- (E) -pro Nyl] Sulfamoyl acetate ethyl (1013 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through under ice-cooling. The mixture was sealed and stirred at room temperature for 6 hours. did. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride solution (174 mg dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.33 ml) were added. Stirred overnight. After adding a 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% aqueous acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. By dissolving this in water and subjecting it to lyophilization, The title compound (788 mg, yield 68%) was obtained as a colorless amorphous solid.

Video R (500 MHz, DMSO-d ₆ ) d ppm: 1.22 (3H, t, J = 7.0), 1.96-2.12 (2H, m), 2.19-2.32 (2H, m), 3.02-3.18 (4H, m), 3.24-3.40 (2H, m), 3.49 and 3.62 (total 2H, each m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0 ), 4.65 and 4.91 (total IH, m each), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.22-7.38 (6H, m), 7.41 (1H, m), 7.55 (IH, t, J = 8.0), 7.60 (IH, m), 7.68 (IH, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm. ¹ ): 1738, 1675, 1353, 1156. Production Example 12

N- [3 -— (3-Amidinophenyl) —2— (E) —Probenyl] —N— [3-Chlorol 4_ (1-phenethylpiperidine—4-yloxy) phenyl] sulfamoyl acetic acid dihydrochloride

N— [3 -— (3-amidinofenyl) _2— (E) —probenyl] -N- [3-chloro-4-1 (1-phenethylpiperidine-1-4-yloxy) phen obtained in Production Example 11 Nile] Sulfamoyl acetate ethyl dihydrochloride (588 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 60 ° C for 6.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.00 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 405 mg (72% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 2.02 (2H, m), 2.18-2.28 (2H, m), 3.07 (4H, m), 3.20-3.50 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.22-7.39 (6H , M), 7.42 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.60 (IH, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.87 (IH, s);

IR (KBr, ¹ ): 1732, 1675, 1349, 1154. Production Example 13

N- [3 -— (3-Amidinophenyl) 1-2— (E) —probenyl] — N— [3-chloro 4- (1-phenylpiperidine-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride salt

N- [3-Chloro-41- (1-phenylpiperidine-4-yloxy) phenyl] obtained in Reference Example 33—N— [3- (3-Cyanophenyl) —2 -— (E) —probe Nyl] sulfamoyl acetate (1440 mg) was dissolved in a mixed solvent of dichloromethane (18 ml) and ethanol (18 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of ammonium chloride (233 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.49 ml) were added. Stirred. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 60% acetonitrile Z water) to obtain 924 mg of an amorphous solid. 254 mg of this solid was dissolved in ethanol (6 ml), 4N hydrogen chloride dioxane solution (0.31 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 78 mg (yield 61%) of the title compound as a colorless amorphous solid.

^X H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.93-2.14 (2H, m), 2.16-2.37 (2H, m), 3.17-3.94 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.48 (2H, d, J = 6.0), 4.85 (IH, m), 6.45 (1H, dt, J = 16.0, 6.0 ), 6.59 (1H, d, J = 16.0), 7.21 (1H, m), 7.28-7.64 (4H, m), 7.34 (1H, d, J = 9.0), 7.42 (IH, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.61 (1H, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.74 (IH, d, J = 8.0), 7.89 (IH , s);

IR (KBr, cm- ¹ ): 1738, 1675, 1353, 1156. Production Example 14

N- [3- (3-Amidinophenyl) —2— (E) —Probenyl] — N— [3-Crawol 4- (1 -phenylpiperidine-1 -4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-amidinofenyl) —2 -— (E) —probene obtained in Production Example 13 ] —N— [3-Clot-41- (1-phenylpiperidine-1-4-yloxy) phenyl] sulfamoyl acetate (676 mg) was dissolved in a mixed solvent of 3N hydrochloric acid (9 ml) and dioxane (3 ml). And stirred at 80 for 6 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 40% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (10 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 385 mg (yield 53%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.88-2.08 (2H, m), 2.10-2.32 (2H, m), 3.04-3.91 (4H, m), 4.28 (2H, s), 4.47 ( 2H, d, J = 6.0), 4.82 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.11 (1H, m), 7.26-7.49 (4H, m), 7.32 (1H, d, J = 9.0), 7.42 (IH, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.60 (1H, d, J = 2.5) ), 7.68 (1H, d, J = 8.0), 7.74 (IH, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1676, 1349, 1155. Production Example 15

N— [3 -— (3-amidinofenyl) —2— (E) monopropenyl] —N— [3-chloro-4_ (1-methoxycarbonylmethylpiperidine-1-41-yloxy) phenyl] ethyl ethyl sulfamoyl acetate salt

N— [3-—Mouth—4— (1-Methoxycarbonylmethylpyridine- 14-yloxy) phenyl) obtained in Reference Example 37—N— [3- (3-Cyanophenyl) —2 -— (E) —pro Benil] Sulfamoyl acetate ethyl (1700mg) in dichloromethane (30m

The mixture was dissolved in a mixed solvent of 1) and ethanol (15 ml), passed through with hydrogen chloride under ice cooling, sealed, and stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was ethanol (2

0ml), aqueous ammonium chloride solution (227mg dissolved in 10ml water) and 2

After addition of 8% aqueous ammonia (0.42 ml), the mixture was stirred at room temperature. After adding 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 35% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. Dissolve this in water and freeze-dry This gave 950 mg (yield 48%) of the title compound as a colorless amorphous solid. 1H NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.22 (3H, t, J = 7.0), 1.84-2.32 (4H, m), 2.90-3.68 (4H, m), 3.76 (3H, s), 4.19 (2H, q, J = 7.0), 4.30 (2H, m), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.63 and 4.84 (total 1H, each m), 6.43 (IH , dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.30 (1H, m), 7.40 (1H, m), 7.55 (1H, t, J = 8.0), 7.59 (1H, m), 7.68 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.87 (IH, s);

IR (KBr, cm " ¹ ): 1742, 1675, 1353, 1156. Production Example 16

N- [3--(3-Amidinophenyl) -2- (E) -probenyl] -N- [4- (1 l-loxymethylpiperidine-4_yloxy) -3- 3-chlorophenyl] sulfamoyl Acetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -probenyl] -l-N- [3--clo- 4-(1-methoxycarbonylmethylpiperidine-l-) obtained in Production Example 15 [Yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (810 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 60 ° C for 15 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile Z). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 581 mg (yield 76%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.91-2.07 (2H, m), 2.14-2.28 (2H, m), 3.00-3.90 (4H, m), 4.16 (2H, s), 4.28 ( 2H, s), 4.47 (2H, d, J = 6.0), 4.65 and 4.84 (total 1H, m each), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0) , 7.32 (1H, m), 7.42 (1H, dd, J = 9.0, 2.5), 7.54 (1H, t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.72 (2H, m), 7.91 (1H, s);

IR (KBr, cur ¹ ): 1737, 1676, 1348, 1155. Production Example 17 N— [4- (1-Acetylbiperidine-1 4-yloxy) —3-cyclochlorophenyl] 1-N- [3- (3-Amidinophenyl) 1-2— (E) —Probenyl] Sulfamoyl acetate Hydrochloride

N- [4- (1-acetylpiperidine-1-4-yloxy) -13-chlorophenyl] obtained in Reference Example 39—N— [3- (3-cyanophenyl) -2- (E) -probe [2] Ethyl sulfamoyl acetate (733 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (175 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.1%).

And then stirred at room temperature overnight. After adding a 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by preparative HP LC (YMC-PackODS-A; YMC, elution solvent:

Purified with 35% acetonitrile Z water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 488 mg (yield 64%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.55 (1H, m), 1.65 (1H, m), 1.84 (IH, m), 1.93 (1H, m), 2.01 (3H, s), 3.28-3.44 (2H, m), 3.56-3.72 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.46 (2H, d, J = 6.0), 4.75 (1H, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.29 (1H, d, J = 9.0), 7.38 (IH, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.57 (IH, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.73 (1H, d , J = 8.0), 7.86 (IH, s);

IR (KBr, cm " ¹ ): 1739, 1677, 1354, 1157. Production Example 18

N— [4- (1-Acetylpiperidin-4-yloxy) —3-chlorophenyl] —N— [3- (3-Amidinophenyl) 1-2— (E) —Propenyl] Sulfamoylacetic acid Production Example 17 N— [4 -— (1-Acetylpiperidine-1-4-yloxy) —3 monochlorophenyl] —N— [3— (3-Amidinophenyl) 1-2— (E) 1-probenyl] Ethyl sulfamoyl acetate hydrochloride (352 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 60 ° C for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.50 ml) and concentrated to dryness under reduced pressure to give 109 mg (yield 32%) of the title compound as a colorless amorphous solid.

^{X H NMR (500 MHz, DMSO} -d 6) δ ppm: 1.54 (IH, m), 1.65 (IH, m), 1.83 (IH, m), 1.92 (IH, m), 2.00 (3H, s), 3.30-3.70 (4H, m), 3.83 (2H, s), 4.48 (2H, d, J = 6.0), 4.71 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.53 (IH , d, J = 16.0), 7.26 (IH, d, J = 9.0), 7.48 (IH, dd, J = 9.0, 2.5), 7.52 (IH, t, J = 8.0), 7.66 (1H, d, J = 8.0), 7.68 (IH, d, J = 2.5), 7.71 (IH, d, J = 8.0), 7.85 (IH, s);

IR (KBr, cm- ¹ ): 1682, 1345, 1152. Production Example 19

N— [3 -— (3-Amidinophenyl) -1-2- (E) -Propenyl] —N— [4- (1-Rubamoylbiperidine-1-4-yloxy) —3-Methyl-phenyl] sulfamoyl acetic acid Ethyl hydrochloride

N- [4- (4- (1-hydroxylrubamoylbiperidine-1-4-yloxy) -1-3-chlorophenyl) -1 N- [3- (3-cyanophenyl) -2- (E) obtained in Reference Example 43 [Propylene] Ethyl sulfamoyl acetate (1015 mg) is dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol '(15 ml), hydrogen chloride is passed through under ice-cooling, and the container is capped and sealed at room temperature for 6 hours. Stirred. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride solution (194 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.36 ml) were added. Stirred. After adding a 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to obtain 737 mg (yield 66%) of the title compound as a colorless amorphous solid.

Plan R 00 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.46-1.58 (2H, m), 1.80-1.89 (2H, m), 3.15-3.24 (2H, m), 3.49-3.60 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.46 (2H, d , J = 6.0), 4.68 (IH, m), 6.43 (IH, dt, J = 16.0, 6,0), 6.58 (IH, d, J = 16.0), 7.28 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.57 (1H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.87 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1675, 1352, 1156. Production Example 20

N— [3 -— (3-amidinofenyl) -1-2- (E) 1-probenyl] —N— [4- (1-rubamoylpiperidine-1-4-yloxy) -3-cyclo-phenyl] sulfamoyl acetic acid hydrochloride

N— [3- (3-amidinofenyl) -12— (E) 1-probe] obtained in Production Example 19—N— [4- (1-l-rubamoylpiperidine-14-yloxy) -1 3— [Phenyl phenyl] sulfamoyl acetate ethyl hydrochloride (600 mg) was dissolved in 3N hydrochloric acid (20 ml), and the mixture was stirred at 60 for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was suspended in water and dioxane (1 drop) and lyophilized to give 66 mg (81% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.48-1.58 (2H, m), 1.80-1.90 (2H, m), 3.14-3.24 (2H, m), 3.50-3.60 (2H, m), 4.27 (2H, s), 4.46 (2H, d, J = 6.0), 4.67 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.27 (IH, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.57 (IH, d, J = 2.5), 7.67 (IH, d , J = 8.0), 7.73 (IH, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cur ¹ ): 1676, 1348, 1155. Production Example 21

N— [3 -— (3-amidinofenyl) —2— (E) —probenyl] —N— “3-chloro-4-1- (1-methanesulfonyl-biperidine-4-1-yloxy) phenyl] sulfamo Ethyl acetate hydrochloride

N- [3-Chloro-41- (1-methanesulfonylpiperidine-4-yloxy) phenyl] obtained in Reference Example 47 N- [3- (3-Cyanophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate (835 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and the solution was stirred under ice-cooling, filtered, sealed, and stirred at room temperature for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonia chloride (15 Omg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.19 ml) were added, and the mixture was added at room temperature.ー晚After adding a 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 40% aqueous acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 685 mg (yield 75%) of the title compound as a colorless amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.72-1.82 (2H, m), 1.93-2.03 (2H, m), 2.89 (3H, s) , 3.12-3.22 (2H, m), 3.24-3.40 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.70 ( IH, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.28 (1H, d, J = 9.0), 7.39 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.58 (1H, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.85 (1H , S);

IR (KBr, cm- ¹ ): 1739, 1677, 1346, 1156. Production Example 22

N— [3 -— (3-Amidinophenyl) —2 -— (E) —Probenyl] -1-N— [3-chloro-41- (1-methanesulfonylbiperidine-1-4-yloxy) phenyl] sulfamoylacetic acid hydrochloride

N- [3- (3-amidinofenyl) —2- (E) -probenyl] -N- [3-chloro-4-((1-methanesulfonylpiperidine-1-4-yloxy) phenyl) obtained in Production Example 21 Ethyl sulfamoyl acetate hydrochloride (502 mg) was dissolved in a mixed solvent of 3N hydrochloric acid (20 ml) and dioxane (5 ml), and the mixture was stirred at 60 ° C for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was collected by preparative HP LC (YMC-Pack ODS-A; YC, Elution solvent: 25-50% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated under reduced pressure to dryness to obtain 346 mg (yield: 72%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.72-1.82 (2H, m), 1.93-2.03 (2H, m), 2.89 (3H, s), 3.12-3.20 (2H, m), 3.23- 3.40 (2H, m), 4.04 (2H, s), 4.48 (2H, d, J = 6.0), 4.68 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d , J = 16.0), 7.26 (1H, d, J = 9.0), 7.44 (1H, dd, J = 9.0, 2.5), 7.54 (IH, t, J = 8.0), 7.63 (1H, d, J = 2.5) ), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cm- ¹ ): 1679, 1344, 1155. Production Example 23

N- [3 -— (3-amidinofenyl) -1-2- (E) -propenyl] —N— [3-chloro-4-1- [1- (2-pyridyl) piperidine-4-1yloxy] phenyl] sulfamo Ethyl acetate dihydrochloride

N- [3-Chloro-4- [1- (2-pyridyl) piperidine-1-41-yloxy] phenyl] -N- [3- (3-cyanophenyl) -2- (E) obtained in Reference Example 51 —Propenyl] Ethyl sulfamoylacetate (1095mg) is dissolved in a mixed solvent of dichloromethane (30ml) and ethanol (15ml), hydrogen chloride is passed through under ice-cooling, and the cap is sealed and stirred at room temperature for 6 hours. did. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonia chloride (197 mg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.37 ml) were added, and the mixture was added at room temperature. Stirred. After adding a 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 50% aqueous acetonitrile). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 533 mg (42% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.72-1.84 (2H, m), 2.01-2.13 (2H, m), 3.68-3.79 (2H, m ), 3.88-3.99 (2H, m), 4.20 (2H, q, J = 7.0), 4.43 (2H, s), 4.48 (2H, d, J = 6.0), 4.85 (IH, m), 6.45 (IH , dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 6.92 (1H, m), 7.35 (IH, d, J = 9.0), 7.32-7.44 (1H, m), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.70 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.90 (1H, s) , 7.96 (1H, m), 8.02 (IH, d, J = 4.5);

IR (KBr, cm- ¹ ): 1738, 1674, 1353, 1155. Production Example 24

N— [3 -— (3-Amidinophenyl) -1-2- (E) diprobenyl] -1-N— [3-Chlorol 4- [1-1- (2-pyridyl) piperidine-1-4-yloxy] phenyl] Sulfamo Acetic acid dihydrochloride

N— [3- (3-amidinofenyl) -12_ (E) —probenyl] 1-N— [3-chloro-4— [1— (2-pyridyl) piperidine—4 obtained in Production Example 23 [Iroxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (533 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 60 for 6 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 30 to 50% acetonitrile water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 427 mg (yield 84%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.71-1.82 (2H, m), 2.01-2.12 (2H, m), 3.63-3.75 (2H, m), 3.85-3.97 (2H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 6.89 (1H, m), 7.33 (1H, d, J = 9.0), 7.30-7.40 (1H, m), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (IH, s), 7.93 (1H, m), 8.02 (1H , J = 6.0);

IR (KBr, cm: ¹ ): 1733, 1676, 1349, 1155. Production Example 25

N— [3-(3-Amidinophenyl) _2— (E) 1-probenyl] 1 N— [3—Chlorol 4- 1 [1-(3-pyridyl) piperidine-1 4-yloxy] phenyl] —Sulfamo Ethyl acetate dihydrochloride

N- [3-Chloro-41- (1- (3-pyridyl) piperidine-41-yloxy] phenyl] obtained in Reference Example 55-N- [3- (3-cyanophenyl) -2- (E) [1Provenyl] sulfamoyl acetate ethyl (490 mg) was dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (9 ml), aqueous ammonium chloride solution (79 mg dissolved in 3 ml of water) and 28% aqueous ammonia.

(0.17 ml), and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 40% acetonitrile / water) to obtain 306 mg of an amorphous solid. 44 mg of this solid in ethanol

(4 ml), 4N hydrogen chloride in dioxane (0.05 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 47 mg (yield 58%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.23 (3H, t, J = 7.0), 1.69-1.82 (2H, m), 1.96-2.08 (2H, m), 3.42 (2H, m), 3.66 (2H, m), 4.19 (2H, q, J = 7.0), 4.43 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.33 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0) ), 7.59 (1H, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.75 (1H, dd, J = 9.0, 5.0), 7.89 ( IH, s), 8.03 (1H, dd, J = 9.0, 2.5), 8.15 (1H, d, J = 5.0), 8.48 (1H, d, J = 2.5);

IR (KBr, cm ¹ ): 1737, 1675, 1352, 1155. Production Example 26

N- [3--(3-Amidinophenyl) -2-(E) 1-Propenyl] 1 N- [3 -Chloro 1-4-[1-(3-pyridyl) piperidine-4-yloxy] phenyl] Sulfamo Acetic acid dihydrochloride

N— [3- (3-Amidinophenyl) -2- (E) —probel] obtained in Production Example 25—N— [3-Chloro-41- [1- (3-pyridyl) piperidine— 4- [yloxy] phenyl] sulfamoylethyl acetate (247mg) dissolved in 3N hydrochloric acid (12ml) Then, the mixture was stirred at 60 for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 27% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1 Oml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 427 mg (yield 84%) of the title compound as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) d ppm: 1.69-1.81 (2H, m), 1.97-2.08 (2H, m), 3.42 (2H, m), 3.67 (2H, m), 4.29 (2H, m s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.33 (IH, d , J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.69 (1H, d, J = 8.0) ), 7.74 (1H, d, J = 8.0), 7.77 (1H, dd, J = 9.0, 5.5), 7.89 (1H, s), 8.04 (IH, dd, J = 9.0, 2.0), 8.15 (1H, d, J = 5.5), 8.48 (IH, d, J = 2.0);

IR (KBr, cm- ¹ ): 1731, 1675, 1348, 1154. Production example 27 '

N— [3- (3-Amidinophenyl) —2— (E) —Probenyl] —N— [3-Chlorol 4- [1— (4-Pyridyl) piperidine-1 4-yloxy] phenyl] Sulfamo Ethyl acetate dihydrochloride

N— [3-—Mouth—4-1 (1- (4-pyridyl) piperidine-1 4-yloxy) phenyl) obtained in Reference Example 59—N— [3- (3-Cyanophenyl) 1-2— ( E) [Propenyl] sulfamoyl acetate ethyl ester (637 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through with hydrogen chloride under ice-cooling, sealed and sealed for 5.5 hours at room temperature. Stirred. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium salt (115 mg dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.21 ml) were added. Thereafter, the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 27% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 456 mg (yield 62%) of the title compound as a colorless amorphous solid. ¾ NMR (500 MHz, DMSO-d ₆ ) <5 ppm: 1.23 (3H, t, J = 7.0), 1.72-1.82 (2H, m), 2.00-2.10 (2H, m), 3.71 (2H, m) , 3.86 (2H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.48 (2H, d, J = 6.0), 4.87 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.23 (2H, J = 7.5), 7.34 (1H, d, J = 9.0), 7.41 (IH, dd, J = 9.0, 2.5) , 7.55 (IH, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (1H, s ), 8.24 (2H, d, J = 7.5);

IR (KBr, cm- ¹ ): 1738, 1675, 1352, 1155. Production Example 2 8

N— [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] —N— [3-chloro-open 4- [1-('4-Pyridyl) piperidine-1-4-yloxy] phenyl] sulfamo Acetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -probenyl] -N- [3-chloro- 4- [1- (4-pyridyl) piperidine obtained in Production Example 27] [141] [yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (315 mg) was dissolved in 3N hydrochloric acid (2Om1) and stirred at 6O for 8 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in 1 N hydrochloric acid (0.50 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 2886 mg (yield 95%) of the title compound as a colorless amorphous solid. '

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.70-1.80 (2H, m), 1.99-2.09 (2H, m), 3.69 (2H, m), 3.85 (2H, m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.22 (2H, d , J = 7.5), 7.33 (1H, d, J = 9.0), 7.42 (IH, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.59 (1H, d, J = 2.5) ), 7.69 (IH, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s), 8.24 (2H, d, J = 7.5);

IR (KBr, cm- ¹ ): 1731, 1675, 1347, 1154. Production Example 2 9 N- [3- (3-Amidinophenyl) -1-2- (E) -probenyl] —N— [3-Chloro4-1- [1- (2-Pyrimidyl) piperidine-1-4-yloxy] phenyl] Sulfa Moethyl acetate dihydrochloride

N— [3-—Mouth—4— [1— (2-Pyrimidyl) piperidine-1-4-yloxy-3-phenyl) obtained in Reference Example 63—N— [3- (3-Cyanophenyl) 1-2— ( E) Propenyl] Ethyl sulfamoyl acetate (1 590 mg) is dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride is passed through under ice-cooling, and the container is sealed at room temperature. Stir for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (285 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.53 ml) were added, and the mixture was added at room temperature. Stirred overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 27% acetonitrile // water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1280 mg (yield 70%) of the title compound as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.23 (3H, t, J = 7.0), 1.58-1.68 (2H, m), 1.89-1.99 (2H, m), 3.68 (2H, m), 4.04 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 6.63 (1H, t, J = 4.5), 7.31 (1H, d, J = 9.0), 7.39 (IH, dd, J = 9.0, 2.5 ), 7.55 (1H, t, J = 8.0), 7.57 (IH, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.86 (1H, s), 8.36 (2H, d, J = 4.5);

IR (KBr, cm- ¹ ): 1740, 1676, 1348, 1151. Production Example 30

N— [3 -— (3-Amidinophenyl) 1 2- (E) 1-probenyl] 1 N— [3-Chloro 4-—1-1- (2-pyrimidyl) piperidine-1 4-yloxy] phenyl Sulfamoyl acetic acid dihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] -N— [3-chloro-4-1 [1- (2-pyrimidyl) piperidine—4— obtained in Production Example 29 Iloxy] [Phenyl] sulfamoyl acetate ethyl dihydrochloride (80 Omg) was dissolved in 3N hydrochloric acid (40 ml) and stirred at 60 ° C for 9 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 35 to 50% aqueous acetonitrile). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 673 mg (yield 88%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.60-1.70 (2H, m), 1.90-2.00 (2H, m), 3.60-3.80 (2H, m), 4.00-4.10 (2H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.81 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 6.68 (IH, t, J = 5.0), 7.31 (1H, d, J = 9.0), 7.40 (IH, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.58 (IH, d , J = 2.5), 7.69 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.89 (1H, s), 8.40 (2H, J = 5.0);

IR (KBr, cm- ¹ ): 1732, 1675, 1345, 1154. Production Example 31

N— [3- (3-Amidinophenyl) -1-2- (E) -Propenyl] —N— [3-—Cross—4-1— [1- (3-Pyridylmethyl) piperidine-1—4-yloxy] phenyl] Famoyl acetate ethyl trihydrochloride

N- [3-Chloro-41- (1- (3-pyridylmethyl) piperidine-1-4-yloxy] phenyl] obtained in Reference Example 67 N- [3- (3-Cyanophenyl) -2- (E) —Provenyl] sulfamoyl acetate (945 mg) is dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 6.5 hours. did. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (2 Oml), aqueous ammonium chloride solution (1661118 dissolved in 1 Oml of water) and 28% aqueous ammonia (0.31 ml) were added. And stirred overnight. The reaction solution was added with a 4N hydrogen chloride dioxane solution, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 25% acetonitrile Z water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 328 mg (yield 29%) of the title compound as a colorless amorphous solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.96-2.09 (2H, m), 2.18-2.31 (2H, m), 3.07 (2H, m), 3.33 and 3.46 (total 2H, m each), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.42-4.52 (2H, m), 4.46 (2H, d, J = 6.0), 4.62 And 4.89 (total 1H, m each), 6.43 (IH, dt, J = 1 * 6.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.40 (1H, m), 7.55 (IH, t, J = 8.0), 7.58 (IH, s), 7.68 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.75 (1H, m), 7.87 (1H , S), 8.36-8.48 (IH, m), 8.79 (IH, d, J = 4.5), 8.96 (IH, m);

IR (KBr, cm): 1736, 1674, 1350, 1154. Production Example 3 2

N— [3-— (3-amidinofenyl) —2 -— (E) -Iprobenyl] — N— [3-—Mouth—4— [1— (3-Pyridylmethyl) piperidine-1-4-yloxy] Phenyl] sulfamoylacetic acid trihydrochloride

Production Example 31 N— [3- (3-amidinofenyl) —2 -— (E) —probenyl] -N— [3-chloro-4_ [1- (3-pyridylmethyl) pi) obtained in 1 Lysine-41-yloxy] phenyl] sulfamoyl acetate ethyl trihydrochloride (175 mg) was dissolved in 3 N hydrochloric acid (1 O ml) and stirred at 6 Ot for 8 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15 to 20% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1 N hydrochloric acid, and then concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 74 mg (yield 44%) of the title compound as a colorless amorphous solid.

Plan R (500 MHz, DMSO-d ₆ ) δ ppm: 1.97-2.12 (2H, m), 2.17-2.34 (2H, m), 3.00-3.17 (2H, m), 3.33 and 3.46 (2H, each m), 4.27 (2H, s), 4.47 (2H, d, J = 6.0), 4.48-4.56 (2H, m), 4.62 and 4.90 (total IH, m each), 6.44 (IH, dt, J = 16.0 , 6.0), 6.57 (1H, d, J = 16.0), 7.30 (IH, m), 7.36-7.45 (1H, m), 7.54 (1H, t, J = 8.0), 7.58 (1H, s), 7.69 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.83-7.93 (2H, m), 8.60 (1H, m), 8.86 (1H, d, J = 5.0), 9.06 ( 1H, m);

IR (KBr; cm— ¹ ): 1731, 1675, 1347, 1155. Production Example 33

N- [3 -— (3-amidinofenyl) -1-2- (E) -probenyl] — N— [3-chloro-open—4— [1- (4-pyridylmethyl) piperidine-1-4-yloxy] phenyl ] Sulfamoyl acetate ethyl trihydrochloride,

N- [3-Chloro-41- (1- (4-pyridylmethyl) piperidine-1 4-yloxy] phenyl] -N- [3- (3-cyanophenyl) 1-2- (E) obtained in Reference Example 72 [Propenyl] ethyl sulfamoylacetate (97 lmg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (17 lmg dissolved in 10 ml of water) and 28% aqueous ammonia (0.32 ml) were added. The mixture was stirred at room temperature. After adding 4N salt solution of hydrogen dioxane to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10 to 35% aqueous acetonitrile Z). did. The obtained amorphous solid was dissolved in a 1N aqueous hydrochloric acid solution and then concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 580 mg (yield 49%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.98-2.16 (2H, m), 2.16-2.40 (2H, m), 3.07 (2H, m), 3.32 and 3.44 (total 2H, m each), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.46 (2H, d, J = 6.0), 4.44-4.56 (2H, m), 4.62 And 4.90 (total 1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.40 (IH, m), 7.54 (IH , t, J = 8.0), 7.58 (IH, s), 7.68 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (IH, s), 8.00 (2H, m) , 8.82 (2H, m);

IR (KBr, cm- ¹ ): 1737, 1675, 1351, 1155. Production Example 34

N- [3- (3-amidinofenyl) -2- (E) 1-probenyl] 1 N— [3-chloro 4- 4- [1- (4-pyridylmethyl) piperidine-1 4-yloxy] phenyl] Sur

Shelf 3 hydrochloride, N— [3- (3-amidinofenyl) -12- (E) -one-probe] obtained in Production Example 33—N— [3-chloro-41- [1- (4-pyridylmethyl) piperidine [141-yloxy] phenyl] sulfamoyl acetate ethyl trihydrochloride (440 mg) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 10 to 20% acetonitrile Z water). The obtained amorphous solid was dissolved in a 1N aqueous hydrochloric acid solution and then concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 55 mg (yield 37%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.97-2.16 (2H, m), 2.16-2.40 (2H, m), 3.10 (2H, m), 3.32 and 3.44 (total 2H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.56 (2H, m), 4.61 and 4.90 (total 1H, each m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (IH, d,. J = 16.0), 7.31 (IH, m), 7.41 (1H, m), 7.54 (1H, t, J = 8.0), 7.59 (IH, s), 7.71 (2H, m), 7.90 (1H, s), 8.18 (2H, m), 8.91 (2H, m);

IR (KBr, cm- ¹ ): 1731, 1675, 1347, 1154. Production Example 35

N— [3— (3-Amidinophenyl) 1 2— (E) 1probenyl] 1 N— [3—Chloro—4 1 [1— [2— (2-Pyridyl) ethyl] piperidine 1 [Yloxy] phenyl] sulfamoyl acetate ethyl trihydrochloride

N— [3-Chloro-41- [1-[2- (2-pyridyl) ethyl] piperidine-1-41-yloxy] obtained in Reference Example 77-N- [3- (3-cyanophenyl) —2— (E) -Propenyl] Ethyl sulfamoylacetate (1727mg) was dissolved in a mixed solvent of dichloromethane (30ml) and ethanol (15ml), passed through hydrogen chloride under ice-cooling, sealed and sealed at room temperature. Stir for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium salt (296 mg dissolved in 1 Om 1 of water) and 28% aqueous ammonia (0.72 ml) were added. The mixture was stirred at room temperature for 1 B. The reaction solution was added with a 4N hydrogen chloride dioxane solution, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25 to 30% aqueous acetonitrile). Obtained nothing After dissolving the fixed solid in IN hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 944 mg (yield 45%) of the title compound as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 2.00-2.12 (2H, m), 2.21-2.33 (2H, m), 3.10-3.70 (4H, m ), 3.48-3.60 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.48 (2H, d, J = 6.0), 4.82 (1H, m), 6.44 (1H , Dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.33 (1H, d, J = 9.0), 7.42 (IH, dd, J = 9.0, 2.5), 7.55 (1H, t , J = 8.0), 7.60 (IH, d, J = 2.5), 7.67-7.75 (IH, m), 7.70 (IH, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.80 ( 1H, m), 7.90 (1H, s), 8.26 (1H, m), 8.73 (1H, d, J = 5.0);

IR (KBr, crrr ¹ ): 1736, 1674, 1350, 1154. Production Example 36

N— [3-(3-Amidinophenyl) —2— (E) 1-Propenyl] _N_ [3—Black Mouth— 4— [1—1 [2- (2-Pyridyl) ethyl] piperidine-1 4-yloxy ] Phenyl] sulfamoylacetic acid trihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] obtained in Production Example 35—N— [3-—Mouth—41— [1— [2— (2-pyridyl) ) [Ethyl] piperidine-1-4- (yloxy) phenyl] sulfamoylacetate triethyl hydrochloride (400 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 60 for 4.5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 20 lmg (yield 52%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 2.00-2.12 (2H, m), 2.20-2.32 (2H, m), 3.20-3.60 (4H, m), 3.39-3.48 (2H, m), 3.50-3.59 (2H, m), 4.28 (2H, s), 4.47 (2H, d, J-6.0), 4.81 (IH, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (1H , D, J = 16.0), 7.32 (IH, d, J = 9.0) _} 7.42 (IH, dd, J = 9.0, 2.5), 7.50-7.58 (IH, m), 7.55 (1H, t, J = 8.0) ), 7.58- 7.66 (1H, m), 7.60 (IH, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.89 (1H, s), 8.07 (IH, m), 8.65 (1H, d, J = 4.5);

IR (KBr, cm " ¹ ): 1730, 1675, 1347, 1154. Production Example 37

N— [3 -— (3-Amidinophenyl) —2 -— (E) 1-Propenyl) 1-N— [3-Chloro 4- (1-cyclopentylpiperidine-1 4-yloxy) phenyl] Sulfamoyl acetate ethyl dihydrochloride

N- [3-chloro-41- (1-cyclopentylpiperidine_4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -12- (E) -probenyl] sulfamoylacetic acid obtained in Reference Example 81 Ethyl (1.30 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through with hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (0.24 g dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.45 ml) were added. Stirred overnight at room temperature. The reaction mixture was added with 4 N hydrogen chloride in dioxane, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and subjected to lyophilization to give 1.20 g (yield 80%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.47-1.60 (2H, m), 1.64-1.76 (2H, m), 1.76-1.90 (2H, m ), 1.94-2.12 (4H, m), 2.16-2.36 (2H, m), 3.02 (2H, m), 3.32-3.55 (3H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H , S), 4.48 (2H, d, J = 6.0), 4.68 and 4.92 (total 1H, each m), 6.45 (1H, dt, J = 16,0, 6.0), 6.58 (1H, d, J = 16.0) ), 7.32 (1H, m), 7.42 (IH, m), 7.55 (1H, t, J = 8.0), 7.60 (IH, m), 7.68-7.76 (2H, m), 7.92 (IH, s);

IR (KBr, cm " ¹ ): 1739, 1674, 1354, 1156. Production Example 38

N —— [3 —— (3-Amidinophenyl) 1 2—— (E) —Probenyl] — N—— [3-chloro Mouth—41- (1-cyclopentylpiperidine-1-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-propyl] -N- [3--chloro-l- (l-cyclopentylbiperidine-l-yloxy) obtained in Production Example 37 [Phenyl] sulfamoyl acetate ethyl dihydrochloride (790 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 60 for 4.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 522 mg (yield 69%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.48-1.63 (2H, m), 1.63-1.76 (2H, m), 1.76-1.88 (2H, m), 1.93-2.10 (4H, m), 2.15-2.35 (2H, m), 2.91-3.13 (2H, m), 3.20-3.59 (3H, m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.66 and 4.91 (total 1H, each m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (1H, d, J = 9.0), 7.42 (1H, dd, J = 9.0) , 2.5), 7.55 (1H, t, J = 8.0), 7.61 (1H, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.90 ( 1H, s);

IR (KBr, cm ' ¹ ): 1732, 1676, 1348, 1155. Production Example 39

N— [3 -— (3-Amidinophenyl) -1-2- (E) —Probenyl] —N— [3-Chloro-4 -— (1,2-dimethylbiperidine—1-yloxy) phenyl] sulfamoyl acetate Dihydrochloride

N— [3-—Mouth—4— (1,2-dimethylpiperidine—41-yloxy) phenyl) -1-N— [3- (3-cyanophenyl) -2- (E) —pro obtained in Reference Example 89 Benzyl] Sulfamoyl acetate ethyl (llO Omg) is dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), hydrogen chloride is passed through under ice-cooling, sealed and sealed for 4 hours at room temperature Stirred. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (25 ml), aqueous ammonium chloride solution (24 Omg dissolved in 5 ml of water) and 28% ammonia After adding water (0.54 ml), the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N sodium chloride dioxane solution (0.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 42 Omg of the title compound (yield). 33%) as a colorless amorphous solid.

¾ NMR (500MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.33 (3H, d, J = 6.5), 1.70-1.85 (1H, m), 1.85-2.00 (1H, m), 2.20-2.35 (2H, m), 2.75 (3H, s), 3.05-3.15 (IH, m), 3.25-3.35 (1H, m), 3.45-3.55 (1H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.65 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d , J = 16.0), 7.33 (IH, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t J = 8.0), 7.59 (1H, d, J = 2.5) , 7.68 (IH, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.87 (1H, s);

IR (KBr, cm " ¹ ): 1738, 1675. Production example 40

N— [3- (3-Amidinophenyl) —2— (E) 1-probenyl] —N— [3-Chloro4-1 (1,2-dimethylpiperidine-4-yloxy) phenyl] sulfamoyl acetic acid dihydrochloride

N— [3 -— (3-amidinofenyl) -12— (E) —probenyl] —N— [3—clomouth—4— (1,2-dimethylpiperidine-14—) obtained in Production Example 39 [Yloxy) phenyl] sulfamoyl acetate dihydrochloride (26 Omg) was dissolved in 3 N hydrochloric acid (20 ml) and stirred at 60 ° C for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated under reduced pressure to dryness to obtain 22 Omg of the title compound (89% yield) as a colorless amorphous solid.

Video R (500MHz, DMSO-d ₆ ) δ ppm: 1.33 (3H, d, J = 6.5), 1.70-1.80 (IH, m), 1.85-1.95 (IH, m), 2.20-2.35 (2H, m ), 2.76 (3H, s), 3.05-3.15 (IH, m), 3.20-3.35 (1H, m), 3.45-3.60 (IH, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.64 (IH, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.33 (1H, d, J = 9.0), 7.41 (IH, dd, J = 9.0, 2.5), 7.55 (1H, t, J-8.0), 7.59 (1H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0) , 7.86 (IH, s);

IR (KBr, cm ' ¹ ): 1733, 1676. Production Example 41

N- [3- (3-Amidinophenyl) —2— (E) —Probenyl] -1-N— [3-Chloro 4 -— (Indolizine-1-7-yloxy) phenyl] sulfamoyl acetate-ethyl-2 Obtained N- [3-cloguchi_4- (indolizine-7-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propionyl] sulfamoylacetic acid Echirile (600 mg) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and after passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml), and an aqueous solution of ammonium chloride (13 Omg dissolved in 5 ml of water) and 28% aqueous ammonia (0.29 ml) were added. Stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride in dioxane (0.2 Oml) was added, and the mixture was concentrated to dryness under reduced pressure to give 140 mg of the title compound (20% yield). ) Was obtained as a yellow amorphous solid.

¾ NMR (500MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.60-2.35 (8H, m), 3.00-3.10 (2H, m), 3.25-3.35 (1H, m) , 3.45-3.55 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.98 (IH, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.30-7.35 (IH, m), 7.40-7.45 (IH, m), 7.55 (1H, t, J = 8.0), 7.55 -7.65 (IH, m), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.87 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1675. Production example 42

N- [3-(3-Amidinophenyl) 1 2-(E)-probenyl, 1 N-[3- Rho 4- (indridine-1 7-yloxy) phenyl] sulfamoylacetic acid dihydrochloride N— [3- (3-amidinofenyl) —2 -— (E) 1-probe] obtained in Production Example 41—N— [ 3-Chloro-41- (indolizine-7-yloxy) phenyl] sulfamoyl acetate diethyl hydrochloride (13 Omg) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 60 for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated to dryness under reduced pressure to give the title compound II Omg (yield 88%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.60-2.35 (8H, m), 2.95-3.10 (2H, m), 3.15-3.50 (3H, m), 4.28 (2H, s), 4.47 (2H , D, J = 6.0), 4.99 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.30-7.35 (IH, m), 7.40- 7.45 (1H, m), 7.55 (1H, t, J = 8.0), 7.55-7.65 (1H, m), 7.69 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s); IR (KBr, cm ¹ ): 1734, 1675. Production Example 43.

N- [3- (3-amidinofenyl) -1- (E) -propenyl] —N— [4- (1-methylbiperidine-4-yloxy) phenyl] sulfamoyl acetate ethyl ester dihydrochloride

例 — [3- (3-Cyanophenyl) -2— (Ε) 1-probenyl] -Ν- [4- (1-Methylpiperidine-1-41-yloxy) phenyl) obtained in Reference Example 99 Ethyl sulfamoyl acetate (57 Omg) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and after passing hydrogen chloride under ice-cooling, the mixture was capped and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (14 Omg dissolved in 5 ml of water) and 28% aqueous ammonia (0.3 lm 1) were added. Stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was collected by preparative HP LC

(YMC-Pack ODS-A; YMC, elution solvent: 17.5% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (0.22 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound 150. mg (22% yield) as a pale yellow amorphous solid.

Video R (500MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85-2.05 (2H, m), 2.05-2.25 (2H, m), 2.73 (3H, s), 3.00-3.15 (2H, m), 3.20-3.30 (IH, m), 3.40-3.50 (IH, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d , J = 6.0), 4.50-4.60 and 4.70-4.80 (total IH, m each), 6.43 (IH, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.00-7.10 (2H , M), 7.35-7.45 (2H, m), 7.54 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.71 (IH, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm. ¹ ): 1738, 1674. Production Example 44

N- [3- (3-Amidinophenyl) 1 2- (E) 1-probenyl] 1 N— [4- (1-Methylpiperidine-1 4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-Amidinophenyl) —2 -— (E) monopropyl) obtained in Production Example 43—N— [4- (1-Methylpiperidine—4-yloxy) phenyl] sulfamoylacetic acid Ethyl dihydrochloride (250 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 60 for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 10% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated under reduced pressure to dryness to obtain 160 mg (yield 58%) of the title compound as a colorless amorphous solid.

Marauder R (500MHz, DMSO-d ₆ ) d ppm: 1.80-1.95 (1H, m), 1.95-2.05 (IH, m), 2.05-2.25 (2H, m), 2.70-2.80 (3H, m), 3.00-3.15 (2H, m), 3.20-3.30 (1H, m), 3.40-3.50 (1H, m), 4.20 (2H, s), 4.45 (2H, d, J = 6.0), 4.53 and 4.74 (total 1H, each m), 6.44 (IH, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.02 (1H, d, J = 9.0), 7.05 (1H, d, J = 9.0 ), 7.39 (1H, d, J = 9.0), 7.41 (1H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.87 (1H, s);

IR (KBr, cm- ¹ ) 1733, 1676. Production example 45 N- [3- (3-Amidinophenyl) —2- (E) —Probenyl] — N—C4- (1-Methylpiperidine-14-yloxy) -1-3-trifluoromethylphenyl] Sulfamoyl acetate Dihydrochloride

N— [3- (3-cyanophenyl) -12- (E) -propenyl] -N- [4- (1-methylbiperidine-14-yloxy) obtained in Reference Example 104 [Trifluoromethylphenyl] sulfamoylethyl acetate (1298 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml). After passing through hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 6.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (246 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.32 ml) were added, and the mixture was stirred at room temperature. And stirred overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated under reduced pressure to dryness, thereby obtaining the title compound (111 mg, yield 74%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.91 and 2.06 (2H, m in each), 2.17-2.27 (2H, m), 2.73 (3H, m), 2.87 and 3.50 (total 2H, each m), 3.37 and 3.44 (total 2H, each m), 4.19 (2H, q, J = 7.0), 4.45 (2H, m), 4.50 (2H, d, J = 6.0), 4.74 and 5.00 (total 1H, m each), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.39 and 7.45 (total 1H, each d, J = 10.0), 7.55 (1H, t, J = 8.0), 7.65-7.74 (4H, m), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1739, 1676, 1353, 1155. Production Example 46

N— [3- (3-amidinofenyl) —2- (E) —probenyl] -1-N— [4- (1-Methylpiperidine—4-yloxy) -1-3-trifluoromethylphenyl] sulfamoylacetic acid Dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) 1-probe] obtained in Production Example 45 N- [4- (1-Methylpiperidine- 14-yloxy) -13-Trifluoromethylphenyl ] Ethyl sulfamoyl acetate dihydrochloride (803mg) was added to 3N hydrochloric acid (20 ml) and stirred at 60 ° C for 8 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 607 mg (79% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, CD ₃ OD) d ppm: 1.93 and 2.17 (2H, m each), 2.28 and 2.39 (2H, m each), 2.90 (3H, m), 3.10-3.25 (2H, m) , 3.47 and 3.60 (total 2H, m each), 4.12 (2H, s), 4.55 (2H, d, J = 6.5), 5.00 (1H, m), 6.43 (1H, dt, J = 16.0, 6.5) , 6.57 (1H, d, J = 16.0), 7.30 and 7.36 (1H, m each), 7.54 (1H, t, J = 8.0), 7.65 (1H, d, J = 8.0) 7.71 (1H, d, J = 8.0) 7.72-7.80 (2H, m), 7.80 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1676, 1350, 1154. Production Example 47

N— [3- (3-Amidinophenyl) 1 2- (E) 1-probenyl] 1 N— [3-Chloro 4- (1-formimidoylpiperidine-1 4-yloxy) phenyl] Sulfamoyl acetate Dihydrochloride

(a) N— [3 -— (3-Amidinophenyl) —2 -— (E) —probenyl] —N— [3-chloro-1- (piperidine—4-yloxy) phenyl] sulfamoyl acetate ethyl hydrochloride

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-cyclobutenyl obtained in Reference Example 70—N- [3- (3-cyanophenyl) -2- (E) —Provenyl] Sulfamoyl acetate ethyl (1200 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml), passed through hydrogen chloride under ice-cooling, sealed and stirred at room temperature for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (2 Oml), and an aqueous solution of sodium chloride (208 mg dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.40 ml) were added. For one minute. After adding 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile water). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 662 mg (yield 56%) of the title compound as a pale yellow amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.88 (2H, m), 2.10 (2H, m), 3.08 (2H, m), 3.17 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.5), 4.78 (1H, m), 6.44 (1H, dt, J = 16.0, 6.5 ), 6.57 (1H, d, J = 16.0), 7.30 (1H, d, J = 9.5), 7.41 (1H, dd, J = 9.5, 2.5), 7.55 (1H, t, J = 8.0), 7.59 ( 1H, d, J = 2.5), 7.69 (IH, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm- ¹ ): 1737, 1675.

(b) N— [3- (3_ (amidinophenyl) —2 -— (E) —probenyl] —N— [3—chloro-4 -— (1-formimidoylpiperidine-1-41-yloxy) phenyl] sulf Famoyl acetate ethyl dihydrochloride

N— [3 -— (3-Amidinophenyl) -1-2- (E) propenyl) obtained in Production Example 47 (a) N— [3-—Mouth—4-1 (piperidine-1-yloxy) phenyl Ethyl sulfamoyl acetate dihydrochloride (0.79 g) was dissolved in ethanol (25 ml), and ethyl ethylformimidate hydrochloride (0.29 g) and triethylamine (0.72 ml) were added at room temperature. It was left at the same temperature for 16 hours. Add 4 N hydrogen chloride dioxane solution to the reaction solution

(10 ml), the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid is ethanol

(10 ml), 4N hydrogen dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.50 g (yield 61%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.73-1.87 (2H, m), 1.99-2.10 (2H, m), 3.57-3.68 (2H, m ), 3.71-3.78 (2H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.81-4.86 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.33 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (1H , T, J = 8.0), 7.60 (IH, d, J = 2.5), 7.69-7.75 (2H, m), 7.90 (1H, s), 7.99 (IH, dd, J = 15.0, 7.0);

IR (KBr, cm ' ¹ ): 1737, 1702, 1675, 1351, 1155. Production Example 48

N- [3 -— (3-amidinofenyl) —2- (E) -propenyl] —N— [3-chloro-41- (1-formimidoylpiperidine-1_4-yloxy) phenyl] sulfamoyl Acetic acid dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) propionyl] 1-N- [3-chloro-1,4- (1-formimidoylpi) obtained in Production Example 47 (b) [Dilysine-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (0.35 g) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 60 ° C for 4.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetate nitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water, and then freeze-dried to obtain 0.17 g (yield 52%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.73-1.87 (2H, m), 1.98-2.11 (2H, m), 3.57-3.79 (4H, m), 4.28 (2H, s), 4.47 ( 2H, d, J = 6.0), 4.79-4.86 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.42 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.70 (IH, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (IH, s), 7.99 (1H, dd, J = 15.0, 7.0);

IR (KBr, cm- ¹ ): 1731, 1703, 1675, 1347, 1154. Production Example 49

N— [3 -— (3-amidinofenyl) -1-2- (E) -propenyl] — N— [3-chloro-4— [1- (1-iminopropyl) pyridin-1-41-yloxy] phenyl] sulf Famoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -1- (E) -loop obtained in Production Example 47 (a) [Rhodinyl] -N- [3-Chloro-4_ (piperidine- 4-yloxy) phenyl] sulfamoylacetate dihydrochloride (0.77 g) was dissolved in ethanol (25 ml), and the mixture was stirred at room temperature. Ethylpropionimid synthesized from propionitrile according to the method described in Bu American Chemical Society, Vol. 98, p. 567 (1976) [J. Amer. Chem. Soc., 567 (1976)]. After adding date hydrochloride (0.54 g) and triethylamine (0.88 ml), the mixture was allowed to stand at the same temperature for 22 hours. Since the progress of the reaction was slow, ethyl propionimidate hydrochloride (0.18 g) and triethylamine (0.35 ml) were added, and the mixture was further stirred at room temperature for 4.5 hours. After adding 4 N hydrogen chloride dioxane solution (10 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 25% aqueous acetonitrile Z). . The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.57 g (yield 67%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.15 (3H, t, J = 7.5), 1.23 (3H, t, J = 7.0), 1.74-1.83 (2H, m), 2.01-2.10 (2H , m), 2.61 (2H, q, J = 7.5), 3.58-3.77 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 5.5), 4.80-4.89 (1H, m), 6.45 (1H, dt, J = 15.5, 5.5), 6.58 (1H, d, J = 15.5), 7.33 (1H, d, J = 9.0), 7.41 (1H , Dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.69-7.74 (2H, m), 7.90 (1H, s);

IR (KBr, crrr ¹ ): 1738, 1671, 1619, 1352, 1157. Production Example 50

N— [3 -— (3-Amidinophenyl) —2- (E) —probenyl] —N— [3-chloroau 4-1 [1- (1-iminopropyl) pyridin-1-41-yloxy] phenyl] sulf Famoyl acetic acid dihydrochloride

N— [3 -— (3-amidinofenyl) obtained in Production Example 49. 1—2_ (E) —one probel——N— [3-chloro—41— [1— (1-iminopropyl) pi Lysine-41-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.42 g) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 60 ° C. for 6.5 hours. After cooling the reaction solution to room temperature, It was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetate nitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.37 g (yield 93%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.15 (3H, t, J = 7.5), 1.71-1.87 (2H, m), 2.00-2.12 (2H, m), 2.63 (2H, q, J = 7.5), 3.59-3.81 (4H, m), 4.30 (2H, s), 4.48 (2H, d, J = 5.5), 4.81-4.88 (IH, m), 6.46 (IH, dt, J = 16.0, 5.5), 6.58 (IH, d, J = 16.0), 7.34 (1H, d, J = 9.0), 7.43 (1H, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.70-7.76 (2H, m), 7.94 (1H, s);

IR (KBr, cm- ¹ ): 1734, 1671, 1620, 1349, 1156. Production Example 51

N- [3- (3-Amidinophenyl) —2— (E) —Probenyl] -1-N— [4 -— (1-Iminophenylmethylpiperidine-1-4-yloxy) -3-cyclophenyl) sulfamoylacetic acid Ethyl dihydrochloride

N— [3- (3-Amidinophenyl) -1-2-E) —Propenyl] -N- [3-—Mouth—41- (piperidine-14-yloxy) phenyl obtained in Production Example 47 (a) Ethyl sulfamoyl acetate dihydrochloride (0.69 g) was dissolved in ethanol (20 ml), and at room temperature, ethyl ethyl benzimidate hydrochloride (0.63 g) and triethylamine (0.94 ml) were added. After stirring at 60 ° C for 2.5 hours, the mixture was left at room temperature for 16.5 hours. After stirring at 60 ° C for 11.5 hours, the mixture was left at room temperature for 60.5 hours. After adding 4 N hydrogen chloride dioxane solution (5 ml) to the reaction mixture, the mixture was concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.36 g of the title compound (yield: 4.5%). ) Was obtained as a colorless amorphous solid. '

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.73-1.81 (1H, m), 1.90-2.03 (2H, m), 2.17-2.24 (1H, m ), 3.30-3.51 (2H, m), 3.78-3.86 (IH, m), 3.89-3.95 (1H, m), 4.18 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (IH, d, J = 6.0), 4.83-4.88 (IH, m), 6.43 (1H , Dt, J = 16.0, 6,0), 6.58 (IH, d, J-16.0), 7.33 (IH, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.53-7.73 (9H, m), 7.88 (IH, s);

IR (KBr, cm ' ¹ ): 1738, 1671, 1605, 1353, 1156. Production example 52 —.

N— [3 -— (3-Amidinophenyl) -1-2- (E) —Probenyl] -1-N— [4- (1-Iminophenylmethylpiperidine-14-yloxy) -13-clophenyl) sulfamoylacetic acid Dihydrochloride

N— [3- (3-amidinofenyl) —2 -— (E) —probenyl] -N- [4- (1-iminophenylmethylpiperidine-1-4-yloxy) obtained in Production Example 51 3 —Chlorophenyl] Sulfamoyl acetate ethyl dihydrochloride (0.25 g) was dissolved in 3N hydrochloric acid (12 ml) and stirred at 60 ° C. for 3 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.21 g (89% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.70-1.78 (1H, m), 1.88-2.02 (2H, m), 2.14-2.22 (1H, m), 3.28-3.50 (2H, m), 3.83-3.90 (IH, m), 3.91-4.01 (IH, m), 4.27 (2H, s), 4.45 (2H, d, J = 5.0), 4.82-4.89 (1H, m), 6.44 (IH, dt) , J = 16.0, 5.0), 6.56 (IH, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.51-7.71 (9H, m ), 7.90 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1673, 1605, 1349, 1155. Production Example 53

N- [3 -— (3-amidinofenyl) _2— (E) monoprodenyl] —N— [3-chloro-mouth—4— [1— (4,5-dihydro-3H—pyrrole-one—2) Piperidine—4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride N— [3- (3_amidinofenyl) —2 -— (E) prodenyl] obtained in Production Example 47 (a) —N— [3-chloromouth—41- (piperidine-141-yloxy) Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.75 g) is dissolved in ethanol (25 ml), and at room temperature, the organic preparation and procedurals are prepared at room temperature. Page 147 (1992) [Org. Prep. Proced. Int .. 24.147 (1992)] 5-methoxy-3,4-dihydro-2H-pyrrol (0.25) synthesized from 2-pyrrolidinone according to the method described in g) and triethylamine (0.69 ml) were added, the mixture was stirred at the same temperature for 10 hours, and then left for 84 hours. After adding 4N hydrogen chloride dioxane solution ⁽ 10 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC> elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N sodium chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. Drying afforded 0.52 g (62% yield) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.75-1.86 (2H, m), 2.02-2.14 (4H, m), 2.97 (2H, t, J = 8.0), 3.50-3.91 (6H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.81-4.87 (IH, m) , 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.34 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (IH, d, J = 2.5), 7.70-7.74 (2H, m), 7.91 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1672, 1352, 1156. Production Example 54

N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] —N— [3-chloro 4-—1— (4,5-dihydro—3H—pyrroyl-2-yl) ) Pyridine-4-4-ylphenyl] sulfamoylacetic acid _2 hydrochloride

Production Example 53 N— [3 -— (3-amidinofenyl) —2- (E) -propenyl] obtained in 3—N— [3-—Mouth—4— [1- (4,5-dihydro) Dissolve 3H-pyrroyl-2-yl) piperidine-4'-yloxy] phenyl] sulfamoylacetate diethyl hydrochloride (0.36 g) in 3N hydrochloric acid (15 ml) and heat at 60 ° C for 6 hours Stirred. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15 to 18% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1 N hydrochloric acid (3 ml), and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.32 g (yield 90%) of the title compound as a colorless amorphous solid.

^J H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.73-1.88 (2H, m), 2.00-2.14 (4H, m), 2.97 (2H, t, J = 8.0), 3.50-3.88 (6H, m), 4.30 (2H, s), 4.47 (2H, d, J = 5.5), 4.81-4.88 (1H, m), 6.46 (1H, dt, J = 16.0, 5.5), 6.58 (1H, d, J = 16.0), 7.34 (1H, d, J = 9.0), 7.42 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (1H, d, J = 2.5), 7.71-7.76 (2H, m), 7.93 (1H, s);

IR (KBr, cm— ¹ ): 1734, 1672, 1350, 1155. Production Example 5 5

N— [3 -— (3-amidinofenyl) -2- (E) 1-prodenyl] 1 N— [3-chloro 4-4-1 [1- (2, 3, 4, 5, 5-tetrahydropyridine 1-yl) ) Piperidine-4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) propionyl] -N- [3-clo-mouth-41- (piperidine-1-4-yloxy) obtained in Production Example 47 (a) Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.81 g) was dissolved in ethanol (20 ml), At room temperature, described in Organic Preparation and Procedures International, Vol. 24, pp. 147 (1992) [Org. Prep. Proced. Int..24.147 (1992)] Calorie 6-ethoxy 2,3,4,5-tetrahydropyridine (0.333 g) and triethylamine (0.74 ml) synthesized from piperidin-2-one according to the method After stirring at 3.5 ° C for 3.5 hours, the mixture was left at room temperature for 11 hours, and further stirred at 45 ° C for 24 hours. After adding 4 N hydrogen chloride dioxane solution (5 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected. Was purified. The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.21 g (yield 23%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.65-1.80 (6H, m), 2.00-2.09 (2H, m), 2.66-2.72 (2H, m ), 3.30-3.36 (2H, m), 3.49-3.75 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 5.5), 4.81 -4.87 (1H, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.58 (IH, d, J = 16.0), 7.33 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.53-7.59 (2H, m), 7.69-7.74 (2H, m), 7.90 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1674, 1637, 1354, 1155. Production Example 5 6

N- [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] -N— [3-chloro-4— [1 -— (2,3,4,5-tetrahydropyridine-1-6-yl) ) Piperidine-1 4 -yloxy] phenyl] 'sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -2- (E) -one-probe] obtained in Production Example 5-5—N- [3--Cross-mouth 4 -— [1- (2,3,4 , 5-Tetrahydropyridine-16-yl) piperidine-14-yloxy] phenyl] sulfamoylacetate diethyl hydrochloride (0.28 g) was dissolved in 3N hydrochloric acid (12 ml), and the mixture was dissolved at 60 for 5 hours. Stirred. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid is diluted with 1N hydrochloric acid. (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.19 g (yield 71%) of the title compound as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.64-1.81 (6H, m), 1.99-2.08 (2H, m),

2.67- 2.72 (2H, m), 3.30-3.37 (2H, m), 3.55-3.78 (4H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.80-4.87 (1H , m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5 ), 7.53-7.59 (2H, m), 7.67-7.74 (2H, m), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1734, 1675, 1637, 1352, 1156. Production Example 57

N- [3 -— (3-amidinofenyl) —2- (E) -l-prodenyl] —N— [3-chloro-4— [1 -— (3,4,5,6-tetrahydro- 1H-azepine) —Yl) piperidine—4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) propenyl] -N- [3-Cromouth—4- (piperidine-1 4-fluorooxy) obtained in Production Example 47 (a) [Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.75 g) was dissolved in ethanol (25 ml), and at room temperature, 7-methoxy-1,3,4,5,6-tetrahydro-1H-azepine (0.39 g) was dissolved. And triethylamine (0.85 ml) were added, and the mixture was stirred at the same temperature for 7 hours and left to stand for 15 hours. Due to the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-1H-azepine (0.22 g) and triethylamine (0.51 ml) were added, and the mixture was stirred at 45 ° C for 12 hours. The mixture was left at room temperature for 11 hours and further stirred at 45 ° C for 10 hours. After adding 4N hydrogen chloride dioxane solution (5 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). . The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. After dissolving this in water and subjecting to lyophilization, 0.30 g (yield 35%) of the title compound was obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.21 (3H, t, J = 7.0), 1.52-1.63 (4H, m),

1.68- 1.81 (4H, m), 2.04-2.10 (2H, m), 2.84-2.88 (2H, m), 3.36-3.42 (2H, m), 3.62-3.91 (4H, m), 4.18 (2H, q, J = 7.0), 4 / ", (2H, s), 4.46 (2H, d, J = 6.0), 4.81-4.87 (IH, m), 6.44 (1H, dt, J = 16.0, · 57 (1H, d, J = 16.0), 7.32 (IH, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.52- 7.59 (2H, m), 7.66-7.74 (2H, m), 7.88 (IH, s); IR (KBr, cm '1): 1738, 1674, 1628, 1353, 1156. production example 58

N- [3- (3-amidinofenyl) -2- (E) 1-probenyl] — N— [3-chloro 4 -— [1— (3,4,5,6-tetrahydro-2H-azepine-1— Yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -12- (E) -one-probe] obtained in Production Example 57—N- [3--Mouth-one 4 -— [1- (3, 4, 5, 6-Tetrahydro-2H-azepin-7-yl) piperidine- [4-yloxy] phenyl] sulfamoylethyl acetate dihydrochloride (0.24 g) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 for 6 hours. . After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, eluent: 18% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give 0.18 g (76% yield) of the title compound as a colorless amorphous solid.

^X H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.52-1.62 (4H, m), 1.67-1.82 (4H, m), 2.00-2.09 (2H, m), 2.84-2.88 (2H, m) , 3.43-3.49 (2H, m), 3.63-3.91 (4H, m), 4.27 (2H, s), 4.46 (2H, d, J = 5.5), 4.80-4.86 (1H, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.57 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.40 (IH, dd, J = 9.0, 2.5), 7.51-7.61 (2H, m), 7.68-7.75 (2H, m), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1734, 1675, 1628, 1351, 1156. Production Example 59

N- [3 -— (3-amidinofenyl) -1- (E) —probenyl] —N— [4-1- (1- (4,5-dihydro-1-3H-pyrroyl-2-1-r) piぺ Lysine 1 4-yloxy] Enyl] sulfamoyl acetate ethyl dihydrochloride

(a) N— [3- (3-Amidinophenyl) 1-2— (E) —probenyl] 1-N— [4- (piperidine-14-yloxy) phenyl] sulfamoylacetic acid diethyl hydrochloride obtained in Reference Example 108 N- [4- (1- (t-butoxycarbonylpiperidine-14-yloxy) phenyl)] — N— [3- (3-cyanophenyl) 1-2- (E) -probenyl ethylethyl sulfamoyl acetate (1 46 g) was dissolved in a mixed solvent of dichloromethane (50 ml) and ethanol (25 ml), hydrogen chloride was passed through the mixture for 1 hour under ice-cooling, the mixture was sealed, and the mixture was stirred at room temperature for 8 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (40 ml), and an aqueous solution of ammonium chloride (0.30 g dissolved in 15 ml of water) and 28.% aqueous ammonia (0.58 ml) were added. It was left at room temperature for 12 hours. The reaction solution is added with a 4 N salt / hydrogen dioxane solution, concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). As a result, 0.98 g (yield 68%) of the title compound was obtained as a pale yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.83 (2H, m), 2.10 (2H, m), 3.05 (2H, m), 3.19 (2H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 6.0), 4.66 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0 ), 6.55 (1H, d, J = 16.0), 7.04 (2H, d, J = 8.5), 7.39 (2H, d, J = 8.5), 7.55 (IH, t, J = 8.0), 7.69 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1737, 1675.

(b) N— [3 -— (3-amidinofenyl) 1 2- (E) 1-probenyl] N— [4—1— (4,5-dihydro-3H—pyrroyl-2-yl) [Lysine-1 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) propionyl] -N- [4- (piperidine-l-l-^-hydroxy) phenyl) sulfamoyl obtained in Production Example 59 (a) Ethyl acetate dihydrochloride (0.52 g) is dissolved in ethanol (5 ml) and at room temperature, Organic Preparation 'and Procedures International, No. 24 Vol., P. 147 (1992) 5-Methoxy-3,4-dihydromono synthesized from 2-pyrrolidinone according to the method described in [Org. Prep. Proced. Int., 24, 147 (1992)]. 2H-Pyrrol (0.26 g) and triethylamine (0.60 ml) were added, and the mixture was stirred at the same temperature for 29 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid is ethanol

(40 ml), 4 N hydrogen chloride dioxane solution (0.75 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.43 g (yield 77%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.68-1.80 (2H, m), 2.00-2.14 (4H, m), 2.96 (2H, t, J = 8.0), 3.46-3.87 (6H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 6.0), 4.67-4.73 (1H, m) , 6.44 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.55 (1H , T, J = 8.0), 7.68-7.73 (2H, m), 7.88 (1H, s);

1R (KBr, cm ¹ ): 1738, 1671, 1349, 1157. Production Example 60

N— [3— (3-Amidinophenyl) — 2— (E) ^ probenyl] — N— [4-1-1 (4,5-dihydro-3 H-pyrroyl-2-yl) piperidine — 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

■ 2HCI

N- [3- (3-amidinofenyl) -l- (E) propynyl] -lN- [4- [1- (4,5-dihydro-3H-pyro) obtained in Production Example 59 (b) 1--2) Lysine-4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.38 g) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C. for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.21 g (yield 59%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.68-1.80 (2H, m), 2.00-2.13 (4H, m), 2.96 (2H, t, J = 8.0), 3.46-3.72 (5H, m ), 3.83-3.92 (1H, m), 4.20 (2H, s), 4.45 (2H, d, J = 5.5), 4.67-4.73 (1H, m), 6.45 (1H, dt, J = 16.0, 5.5) , 6.54 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.71 (2H, d , J = 8.0), 7.90 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1672, 1347, 1155. Production Example 61

N— [3- (3-Amidinophenyl) -1-2- (E) -probenyl] —N— [4- [1- (1,2,3,4,5-tetrahydropyridine-1-6-yl) piperidine-1 4-1-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -1-2- (E) propionyl] -N- [4- (piperidine- 4-yloxy) phenyl] sulfamoylacetic acid obtained in Production Example 59 (a) Ethyl dihydrochloride (0.50 g) was dissolved in ethanol (5 ml) and, at room temperature, Organic Preparation and 'Procedures' International, 24, 147 (1992) [Org Prep. Proced. Tnt..24.147 (1992)], 6-ethoxy 2,3,4,5-tetrahydropyridine synthesized from piperidine-1-one (0.31 g). And triethylamine (0.60 ml) were added, and the mixture was stirred at the same temperature for 4 days. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack'ODS-A; YMC, eluting solvent: 25% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (25 ml), 4N hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. After dissolving this in water and subjecting it to lyophilization, 0.27 g (yield 47%) of the product was obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.65-1.78 (6H, m), 1.99-2.07 (2H, m), 2.68-2.72 (2H, m ), 3.29-3.36 (2H, m), 3.44-3.55 (2H, m), 3.70-3.90 (2H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H , D, J = 5.5), 4.68-4.74 (IH, m), 6.44 (IH, dt, J = 16.0, 5.5), 6.55 (1H, d, J = 16.0), 7.03 (2H, d, J = 9.0) ), 7.39 (2H, d, J = 9.0), 7.55 (IH, t, J = 7.7Hz), 7.68-7.73 (2H, m), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1674, 1637, 1351, 1157. Production Example 62

N— [3 -— (3-Amidinophenyl) -1-2- (E) —probenyl] —N— [4- [1-1— (2,3,4,5-tetrahydropyridine-1 6— ^ f) piぺ lysine-1 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3- (amidinophenyl) -12- (E) -one-probe] -N- [4-[1- (2,3,4,5-tetrahydropyridine) obtained in Production Example 61 (6-yl) piperidin- 14-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.76 g) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 6 for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (5 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.60 g (yield 83%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.65-1.78 (6H, m), 2.00-2.07 (2H, m), 2.68-2.71 (2H, m), 3.30-3.55 (4H, m), 3.70-3.87 (2H, m), 4.21 (2H, s), 4.45 (2H, d, J = 5.5), 4.67-4.73 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.03 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.67-7.73 (2H, m ), 7.87 (IH, s);

IR (KBr, cm " ¹ ): 1734, 1674, 1637, 1348, 1156. Production Example 63 N- [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] —N— [4- [1- [3,4,5,6-tetrahydro- 1H-azepine] Le) piperidine-1 4-ethoxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3 -— (3-Amidinophenyl) —2 -— (E) propionyl] -1-N— [4- (piperidine-1-4-yloxy) phenyl) sulfamoylacetic acid obtained in Production Example 59 (a) Ethyl dihydrochloride (0.51 g) was dissolved in ethanol (5 ml), and at room temperature, 7-methoxy 3,4,5,6-tetrahydro-2H-azepine (0.34 g) and triethylamine (0.60 ml) were dissolved. ) And stirred at the same temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.14 g (yield 24%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.46-1.76 (8H, m), 2.01-2.10 (2H, m), 2.86-2.89 (2H, m ), 3.45-3.50 (2H, m), 3.57-3.70 (2H, m), 3.85-3.97 (2H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H , D, J = 6.0), 4.70- 4.76 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.39 (2H, d, J = 9.0) ), 7.54 (2H, d, J = 9.0), 7.54 (IH, t, J = 8.0Hz), 7.69-7.73 (2H, m), 7.90 (1H, s);

IR (KBr, cm ¹ ): 1737, 1674, 1629, 1351, 1158. Production Example 64

N— [3 -— (3_amidinofenyl) —2 -— (E) —probenyl] —N— [4- [1— (3,4,5,6-tetrahydro-2H—azepin-17-yl) 4-Pyridine-1-phenyloxy] phenyl] sulfamoylacetic acid dihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] one N— [4- [1 -— (3,4,5,6-tetrahydro-2H—) obtained in Production Example 63 Azepin-7-yl) piperidine-4- [yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.96 g) was dissolved in 3N hydrochloric acid (25 ml) and stirred at 60 for 6 hours. Reaction solution at room temperature After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (5 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.54 g (yield 59%) of the title compound as a colorless amorphous solid.

^X H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.53-1.64 (4H, m), 1.68-1.77 (4H, m), 2.02-2.10 (2H, m), 2.86-2.88 (2H, m) , 3.45-3.50 (2H, m), 3.56-3.70 (2H, m), 3.78-3.97 (2H, m), 4.21 (2H, s), 4.45 (2H, d, J = 6.0), 4.69-4.75 ( 1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.40 (2H, d, J = 9.0) , 7.54 (1H, t, J = 7.5), 7.69-7.72 (2H, m), 7.90 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1677, 1629, 13,44, 1154. Production Example 65

N- [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] -N—C4- [1- (4,5-dihydro-3H-pyrrole—2-yl) piperidine—4 —Iroxy] 1-3-Methylphenyl] sulfamoyl acetate ethyl dihydrochloride

(a) N- [3 -— (3-amidinofenyl) _2— (E) 1-propidinyl] 1-N— [3-Methyl-41- (piperidine-1-4-yloxy) phenyl] sulfamoylacetate diethyl hydrochloride

N— [4- (1-t-butoxycarbonylpiperidine—4-yloxy) -1-3-methylphenyl] -N- [3- (3-cyanophenyl) 1-2— (E) 1-pro obtained in Reference Example 112 Nyl] sulfamoyl acetate (1.90 g) was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (40 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), and an aqueous solution of ammonium salt (0.34 g was dissolved in 15 ml of water) and 28% aqueous ammonia (0.64 ml) were added. It was left at room temperature for 13 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 20% acetonitrile Z water). The obtained amorphous solid The title compound was dissolved in methanol (20 ml), 4N hydrogen chloride in ethyl acetate (lml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.36 g (yield 73%) of the title compound in the form of a colorless amorphous Obtained as a solid.

^X H NMR (400 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.87 (2H, m), 2.10 (2H, m), 2.17 (3H, s), 3.07 (2H , m), 3.17 (2H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.65 (1H, m), 6.44 (IH , dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.05 (1H, d, J = 9.0), 7.24 (IH, dd, J = 9.0, 2.5), 7.29 (IH, d , J = 2.5), 7.54 (1H, t, J = 8.0), 7.71 (2H, m), 7.90 (1H, s);

IR (KBr, crrf ¹ ): 1738, 1675.

(b) N— [3 -— (3-amidinofenyl) 1-2— (E) —probenyl] one N— [4-1— (4,5-dihydro-3H—pyrrol-2-yl) Piperidine—4-yloxy] -1-3-methylphenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) 1-2- (E) propionyl] -N- [3-Methyl-41- (piperidine-4-yloxy) phenyl] obtained in Production Example 65 (a) Ethyl sulfamoyl acetate (700 mg) is dissolved in ethanol (15 ml), and at room temperature, o-Ganical Preparation 'and' Procedures International, Vol. 24, p. 147 (1992) [Org. Prep. Proced. Int..24.147 (1992)], 5-methoxy-3,4-dihydro-1H-pyrrole (405 mg) and triethylamine (0.57 ml), which were synthesized from 2-pyrrolidinone, were added at the same temperature.ー晚 Stirred. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, eluent: 22% acetonitrile Z water) to obtain 565 mg of an amorphous solid. 15 lmg of this solid was dissolved in ethanol (4 ml), 4N hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 157 mg (yield 66%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.72-1.85 (2H, m), 1.98-2.14 (4H, m), 2.16 (3H, s), 2.96 (2H, t, J = 8.0), 3.46-3.81 (6H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.57 (1H, d , J = 16.0), 7.07 (1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0, 2.5), 7.29 (IH, d, J = 2.5), 7.55 (m, t, J = 8.0) ), 7.69 (1H, d, J-8.0), 7.72 (1H, d, J = 8.0), 7.89 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1671, 1350, 1157. Production Example 66

N— [3 -— (3-amidinofenyl) 2- (E) —probenyl] —N— [4- [1

-(4,5-Dihydro-3H-pyrrol-2-yl) piperidine-1-4-yloxy] -13-methylphenyl] sulfamoylacetic acid _ dihydrochloride

N_ [3— (3_amidinofenyl) -1-2- (E) propionyl] —N— [4--1- [1— (4,5-dihydro_3H—pyrrole) obtained in Production Example 65 (b) —2-yl) piperidine— [4-yloxy] -3-methylphenyl] sulfamoyl acetate ethyl (409 mg) was dissolved in 4N hydrochloric acid (12 ml) and stirred at 70 ° C. for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1 Oml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 266 mg (yield 60%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) <5 ppm: 1.72-1.86 (2H, m), 1.97-2.14 (4H, m), 2.16 (3H, s), 2.96 (2H, m), 3.47-3.80 (5H, m), 3.72-3.82 (1H, m), 4.19 (2H, s), 4.44 (2H, d, J = 6.0), 4.72 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.06 (IH, d, J = 8.5), 7.25 (IH, dd, J = 8.5, 2.5), 7.29 (1H, d, J = 2.5), 7.55 (IH, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.89 (IH, s);

IR (KBr, cnr ¹ ): 1733, 1672, 1347, 1155. Production Example 67

N— [3- (3-Amidinophenyl) _2— (E) 1-Propenyl] 1-N— [3-Methyl 4- (1— (2,3,4,5-tetrahydropyridine-1-yl) Piperidine-1 4 -yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -1-2- (E) propionyl] -N- [3-methyl-41- (piperidine-4-yloxy) phenyl obtained in Production Example 65 (a) Ethyl sulfamoyl acetate (730 mg) is dissolved in ethanol (15 ml), and at room temperature, oganic preparation and procedures in Yuichi National, Vol. 24, pp. 147 (1992) [ Org. Prep. Proced. Int..24.147 (1992)] 6-ethoxy 2,3,4,5 tetrahydropyridine (482 mg) and triethyl synthesized from piperidin-2-one according to the method described in (0.59 ml) was added and the mixture was stirred at the same temperature for 2 days. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 28% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (6 ml), 4N hydrogen chloride dioxane solution (0.39 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 331 mg (yield 36%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.64-1.70 (6H, m), 1.96-2.08 (2H, m), 2.16 (3H, s), 2.70 (2H, t, J = 6.0), 3.25-3.37 (2H, m), 3.46-3.83 (4H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H , d, J = 6.0), 4.73 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0), 7.06 (1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0, 2.5), 7.29 (IH, d, J = 2.5), 7.55 (IH, t, J = 8.0), 7.70 (IH, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.90 (IH, s);

IR (KBr, cm " ¹ ): 1738, 1674, 1637, 1351, 1157. Production example 68

N— [3 -— (3-Amidinophenyl) —2 -— (E) —Probenyl] —N— [3-Methyl 4 -— [1 -— (2,3,4,5-tetrahydropyridine-6-yl) ) Piperidine-1-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -probenyl] obtained in Production Example 67 N- [3-methyl-41- [1- (2,3,4,5-) Tetrahydropyridine-16-yl) piperidine-14-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (265 mg) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (8 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 236 g (yield 93%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.64-1.82 (6H, m), 1.96-2.08 (2H, m), 2.16 (3H, s), 2.70 (2H, m), 3.33 (2H, m m), 3.46-3.83 (4H, m), 4.21 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (IH, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.56 (IH, d, J = 16.0), 7.05 (1H, d, J = 8.5), 7.25 (1H, dd, J = 8.5, 2.5), 7.29 (1H, d, J = 2.5), 7.55 (1H, t, J = 8.0), 7.69 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1733, 1676, 1637, 1347, 1156. Production Example 69

N— [3 -— (3-amidinofenyl) -1-2 -— (E) -probenyl] —N— [3-methyl-41- [1 -— (3,4,5,6-tetrahydro-2H-azepine) Yl) piperidine—4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) propenyl] obtained in Production Example 65 (a) N- [3-Methyl-41- (piperidine-141-yloxy) phenyl] Ethyl sulfamoyl acetate (640 mg) was dissolved in ethanol (12 ml), and 7-methoxy-3,4; 5,6-tetrahydro-2H-azepine (348 mg) and triethylamine (0.26 ml) were added at room temperature. 2. Stirred for 5 days. The reaction solution was concentrated under reduced pressure. After condensing, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetate nitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4 N hydrogen chloride dioxane solution (0.42 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (336 mg, yield 40%) as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.52-1.64 (4H, m), 1.68-1.82 (4H, m), 1.98-2.09 (2H, m ), 2.17 (3H, s), 2.87 (2H, m), 3.48 (2H, m), 3.65-3.75 (2H, m), 3.77-3.88 (2H, m), 4.19 (2H, q, J = 7.0 ), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.74 (IH, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0) , 7.06 (1H, d, J = 8.5), 7.25 (1H, dd, J = 8.5, 2.5), 7.28 (1H, d, J = 2.5), 7.55 (IH, t, J = 8.0), 7.69 (IH , d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.89 (1H, s);

IR (KBr, cm ¹ ): 1738, 1675, 1628, 1351, 1157. Production Example 70

N— [3— (3-Amidinophenyl) -1-2 (E) -propenyl] —N— [3-Methyl-1-4-1 [1-(3,4,5,6-tetrahydro-2H-azepine-1-7— Yl) piperidin-1- 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-amidinofenyl) 1-2— (E) —probenyl] —N— [3_methyl—4-1— [1— (3,4,5,6) obtained in Production Example 69 —Tetrahydro-2H-azepin-17-yl) piperidine—4-yloxy] phenyl] sulfamoylacetic acid ethyl dihydrochloride (335 mg) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C. for 5 hours. . After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (10 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give 258 mg (yield 80%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.53-1.65 (4H, m), 1.68-1.84 (4H, m), 1.98-2.10 (2H, m), 2.16 (3H, s), 2.88 ( 2H, m), 3.44-3.53 (2H, m), 3.62-3.93 (4H, m), 4.19 (2H, s), 4.40 (2H, d, J = 6.0), 4.74 (IH, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.56 (IH, d, J = 16.0 ), 7.05 (1H, d, J = 9.0), 7.26 (IH, dd, J = 9.0, 2.5), 7.29 (1H, d, J = 2.5), 7.55 (IH, t, J = 8.0), 7.69 ( IH, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.89 (IH, s);

IR (KBr, cm- ¹ ): 1732, 1676, 1628, 1348, 1156. Production example Ί 1

Ν— [3 -— (3-amidinofenyl) —2— (Ε) 1-probenyl] — Ν— [3-carbamoyl 4-1 [1 -— (4,5-dihydro-3 Η—pyrrole—2-yl) ) Piperidine-1-yloxy] phenyl] sulfamoylacetate diethyl hydrochloride

(a) N- [3- (3- (amidinophenyl) -1-2- (E) -probenyl] —N— [3-ylrubamoyl-41- (piperidine-14-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

Reference Example 1 N— [4- (1-t-butoxycarbonylpiperidine—4-yloxy) -13-butyrubamoylphenyl] 1-N— [3- (3-cyanophenyl) —2-1 (E ) 1-Propenyl] sulfamoylethyl acetate (2.40 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through under ice-cooling for 2.5 hours. And stirred at room temperature for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (0.50 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.10 ml) were added, and the mixture was added at room temperature. Left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 15% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride acetate solution (0.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.60 g (yield) of the title compound. 25%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85-2.00 (2H, m), 2.05-2.20 (2H, m), 3.00-3.10 (2H, m ), 3.15-3.25 (2H, m), 4.20 (2H, q, J = 7.0), 4.38 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (IH, m), 6.45 (IH , dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0), 7.24 (1H, m), 7.50 (1H, m), 7.54 (1H, m), 7.65-7.75 (3H, m), 7.90 (IH, m);

IR (KBr, cur ¹ ): 1736, 1671, 1658.

(b) N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] 1-N— [3 rubumoylu 4-1-1- (4,5-dihydro-3H-pyrrol—2 —Yl) piperidin-1- 4-yloxy] phenyl] sulfamoyl acetate ethyl hydrochloride

N- [3- (3-amidinofenyl) -l- (E) propronyl] -N- [3-l-r-bamoyl-4-1 (piperidine-l-yloxy) phenyl obtained in Production Example 71 (a) Ethyl sulfamoyl acetate (500 mg) is dissolved in ethanol (15 ml) and, at room temperature, Organic Preparation 'and' Procedures in Yuichi National, 24, 147 (1992) [Org. Prep. Proced. Int..24.147 (1992)], 5-methoxy-3,4-dihydro-2H-pyrrole (340 mg) and triethylamine (0.77 ml) synthesized from 2-pyrrolidinone, and the same temperature was added. It was stirred. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid is ethanol

(5 ml), 4N hydrogen chloride in dioxane (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 420 mg (yield 67%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.00-2.15 (4H, m), 2.96 (2H, m), 3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 3.61 (2H, m), 3.65-3.75 (IH, m), 3.75-3.85 (1H, m), 4.20 (2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.28 (IH, d, J = 9.0), 7.51 (IH, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.68 (1H, d, J-8.0), 7.72 (IH, d, J = 8.0), 7.77 (IH, d, J = 2.5), 7.87 (1H, s);

IR (KBr, cm ' ¹ ): 1737, 1670. Production Example 72 N- [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] —N— [3-carbamoyl-4-1 [1- (4,5-dihydro-1H-pyrroyl-2-i) Le) piperidine-41-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l2- (E) propionyl] -N- [3--l-bamoyl-4-1 obtained from Production Example 71 (b) [1- (4,5- Dihydro-3H-pyrroyl-2- ^ ryl) piperidine- [4-yloxy] phenyl] sulfamoylacetic acid ethyl 2-hydrochloride (38 Omg) was dissolved in 3N hydrochloric acid (12 ml) and stirred at 60 ° C for 3 hours. . The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 13% aqueous acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.2 ml) and water (5 ml), and concentrated to dryness under reduced pressure to obtain 24 Omg (yield 65%) of the title compound as a colorless amorphous solid. Was.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.80-1.95 (2H, m), 2.00-2.15 (4H, m), 2.96 (2H, m), 3.45-3.55 (IH, m), 3.55 -3.65 (IH, m), 3.61 (2H, m), 3.65-3.75 (1H, m), 3.75-3.85 (1H, m), 4.24 (2H, s), 4.47 (2H, d, J = 6.0) , 4.85 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J, = 16.0), 7.28 (1H, d, J = 9.0), 7.52 (IH, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.77 (IH, d, J = 2.5) , 7.86 (1H, s);

IR (KBr, cm— ¹ ): 1731, 1670. Production example 73

N- [3- (3-amidinofenyl) -1- (E) -probenyl] -N- [3-cal Pamoyl 4- [1— (2,3,4,5-tetrahydropyridine-6-yl) piberidine—4-yloxy] phenyl] s> refamoyl acetate ethyl dihydrochloride

Production Example 7 N— [3 -— (3-Amidinophenyl) -1-2— (E) —Propenyl] obtained in 1 (a) —N— [3-Hyrbamoyl-4-1- (piperidine-1-4-yloxy) phenyl ] Ethyl sulfamoyl acetate (500 mg) is dissolved in ethanol (15 ml), and at room temperature, organic preparation 'and' procedures' In Yuichi National, Vol. 24, p. 147 (1992) [Org. Prep Int. 24.147 (1992)], 6-ethoxy 2,3,4,5-tetrahydropyridine (36 Omg) and triethylamine (0%) synthesized from piperidin-2-one. .77 ml) and stirred at the same temperature. Due to the slow progress of the reaction, 6-ethoxy-2,3,4,5-tetrahydropyridine (63 Omg) and triethylamine (0.77 ml) were added, and the mixture was stirred at the same temperature for 1 day. 3,4,5-Tetrahydropyridine (32 Omg) and trieduramine (0.35 ml) were added, and the mixture was further stirred at the same temperature for 1 day. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (6 ml), 4N dihydrogen dioxane solution (0.25 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 20 Omg (yield) of the title compound. (31%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.65-1.90 (6H, m), 2.00-2.10 (2H, m), 2.70 (2H, m), 3.34 (2H, m), 3.40-3.60 (2H, m), 3.70-3.85 (2H, m), 4.21 (2H, q, J = 7.0), 4.37 (2H, s), 4.48 (2H, d, J = 6.0), 4.87 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.28 (1H, d, J = 9.0), 7.52 (1H, dd, J = 9.0, 3.0), 7.56 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.78 (1H, d, J- 3.0), 7.86 (1H, s);

IR (KBr, cm ¹ ): 1737, 1673. Production example 74

N— [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] —N— [3-carbaziru 4 -— [1 —— (2._3, —4,5-tetrahydropyridine 1-6-) Piberisi 4-N-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -probe] obtained in Production Example 73-N- [3--l-bamoyl-4-1- (2,3,4,5 —Tetrahydropyridine-16-yl) piperidine-14-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (200 mg) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 60 ° C. for 3 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 13% aqueous acetonitrile). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.9 ml) and concentrated to dryness under reduced pressure to obtain 137 g (yield 71%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.65-1.90 (6H, m), 2.00-2.10 (2H, m), 2.69 (2H, m), 3.34 (2H, m), 3.40-3.60 ( 2H, m), 3.70-3.85 (2H, m), 4.24 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0 ), 6.57 (IH, d, J = 16.0), 7.27 (1H, d, J = 9.0), 7.52 (IH, dd, J = 9.0, 3.0), 7.55 (1H, t, J = 8.0), 7.67 ( 1H, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.77 (IH, d, J = 3.0), 7.86 (IH, s);

IR (KBr, cm- ¹ ): 1731, 1674. Production example 75

N- [3 -— (3-amidinofenyl) -1 2_ (E) —probenyl] -1-N— [3-carbamoyl-4-1 [1 -— (3,4,5,6-tetrahydro-1H-azepine-1 7— Yl) piperidine-1 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -l2- (E) -Propenyl] -N- [3--l-bamoyl-41- (piperidine-41-yloxy) phenyl obtained in Production Example 71 (a) Ethyl sulfamoyl acetate (400 mg) was dissolved in ethanol (10 ml), and at room temperature, 7-methoxy 3,4,5,6-tetrahydro-2H-azepine (280 mg) and triethylamine (0.31 ml) were added. The mixture was stirred at the same temperature. Due to the slow progress of the reaction, 7-methoxy 3,4,5,6-tetrahydro-2H-azepine (28 Omg) and triethylamine (0.31 ml) were added, and the mixture was further stirred at 40 ° C for 12 hours. Leave at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride dioxane solution (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 140 mg (yield 26%) of the title compound. Obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.50-1.65 (4H, m), 1.70-1.75 (2H, m), 1.80-1.90 (2H, m ), 2.05-2.15 (2H, m), 2.85-2.90 (2H, m), 3.45-3.50 (2H, m), 3.55-3.65 (1H, m), 3.65-3.75 (IH, m), 3.75-3.85 (IH, m), 3.85-3.95 (1H, m), 4.20 (2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m) , 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.28 (1H, d, J = 9.0), 7.51 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.78 (1H, d, J = 2.5), 7.86 (IH, s);

IR (KBr, cm- ¹ ): 1737, 1672. Production Example 76

N— [3 -— (3-amidinofenyl) -1-2- (E) -propenyl] —N— [3-carbamoyl—4-1—1 -— (3,4,5,6-tetrahydro-2H-azepine) 7-yl) piperidine-4-1-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-amidinofenyl) —2 -— (E) -propenyl] obtained in Production Example 75—N— [3-—Rubamoyl 4-—1— (3, 4, 5, 6 —Tetrahydro—2H—azepine-17-yl) piperidine-14-yloxy] phenyl] sulfamoylacetate dihydrochloride (130 mg) is dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C for 2 hours. did. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 12% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.25 ml) and water (5 ml) and concentrated to dryness under reduced pressure to give 50 mg (yield 40%) of the title compound as a colorless amorphous solid. Obtained.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.55-1.65 (4H, m), 1.70-1.75 (2H, m), 1.80-1.90 (2H, m), 2.05-2.15 (2H, m), 2.85-2.90 (2H, m), 3.45-3.50 (2H, m), 3.55-3.65 (1H, m), 3.65-3.75 (IH, m), 3.80-3.90 (IH, m), 3.90-4.00 (1H , M), 4.24 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.27 ( 1H, d, J = 9.0), 7.51 (1H, dd, J = 9.0, 2.5), 7.54 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.77 (1H, d, J = 2.5), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1732, 1674. Production example 77

N— [3 -— (3-Amidinophenyl) —2_ (E) 1-probenyl] —N—C4— [1 -— (4,5-dihydro—3H—pyrrole-1-2-yl) piperidine-1 4 —Yloxy] ― 3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride

(a) N- [3- (3-amidinofenyl) -1-2- (E) -propenyl] — N— [4-1- (piperidine-4-yloxy) —3-trifluoromethylphenylsulfamoylacetic acid Ethyl dihydrochloride

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-trifluoromethylphenyl] -N- [3- (3-cyanophenyl) 1-2— (obtained in Reference Example 122) E) 1-Propenyl] ethyl sulfamoylacetate (2.06 g) was dissolved in a mixed solvent of dichloromethane (50 ml) and ethanol (25 ml), passed through hydrogen chloride under ice-cooling, and sealed. Stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (45 ml), and an aqueous solution of ammonium chloride (0.34 g dissolved in 15 ml of water) and 28% aqueous ammonia (0.63 ml) were added. It was left at room temperature for 12 hours. After adding 4N hydrogen chloride dioxane solution (2.5 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). Purified. The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride in dioxane (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 1.21 g (yield) of the title compound. (60%) as a colorless amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.87 (2H, m), 2.08 (2H, m), 3.11 (2H, m), 3.33 (2H , M), 4.18 (2H, q, J = 7.0), 4.44 (2H, s), 4.50 (2H, d, J = 6.5), 4.89 (1H, m), 6.44 (1H, dt, J = 16.0, 6.5), 6.57 (1H, d, J = 16.0), 7.39 (1H, d, J = 9.0), 7.55 (IH, t, J = 8.0), 7.66-7.73 (4H, m), 7.85 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1676.

(b) N— [3 -— (3-amidinofenyl) 1-2— (E) —probenyl] —N— [4— [1- (4,5-dihydro—3H—pyrrole—2-yl)ぺ lysine-1-4-yloxy] -13-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3 -— (3-amidinofenyl) -2- (E) propenyl) obtained in Production Example 77 (a) —N— [4- (piperidine—4-yloxy) _3-trifluoro [Romethylphenyl] sulfamoyl acetate dihydrochloride (80 Omg) is dissolved in ethanol (20 ml), and at room temperature, Organic Preparation 'and' Procedures International, Vol. 24, p. 147 (Org. Prep. Proced. Int., 24. 147 (1992)). 5-Methoxy-1,3,4-dihydro-1 2H-pyrrolyl synthesized from 2-pyrrolidinone according to the method described in [Org. Prep. 37 Omg) and triethylamine (0.87 ml) were added, and the mixture was stirred at the same temperature. Due to the slow progress of the reaction, 5-methoxy-3,4-dihydrido-2H-pyrrole (12 Omg) and triethylamine (0.26 ml) ′ were added, and the mixture was further stirred at room temperature for 4 hours. After adding 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 26% acetate. Nitrile Z water). . The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 622 mg (70% yield) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₅ ) δ ppm: 1.22 (3H, t, J = 7,0), 1.82 (2H, m), 2.00-2.15 (4H, m), 2.97 (2H, t, J = 8.0), 3.53-3.64 (4H, m), 3.72 (2H, m), 4.19 (2H, q, J = 7.0), 4.45 (2H, s), 4.50 (2H, d, J = 6.0), 4.96 (IH, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.58 (m, d, J = 16.0), 7.44 (IH, d, J = 10.0), 7.55 (1H, t, J = 8.0 ), 7.67-7.75 (4H, m), 7.90 (1H, s);

IR (KBr, cm ¹ ): 1739, 1672, 1353, 1144. Production Example 78 N- [3- (3-amidinofenyl) 1 2- (E) 1-probenyl] 1 N— [4— [1 1- (4,5-dihydro-3H-pyrroyl-2-yl) piperidine 1 4 1-yloxy] -1-3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-Amidinophenyl) -1-2- (E) propenyl) obtained in Production Example 77 (b) —N— [4- [1 -— (4,5-dihydro-3H— Pyrolyl-2-yl) pyridine—4-yloxy] -13-trifluoromethylphenyl] sulfamoyl acetate dihydrochloride (47 lmg) is dissolved in 3N hydrochloric acid (20m 1), and the solution is dissolved at 60 ° The mixture was stirred with C for 5.5 hours. After cooling the reaction solution to room temperature, it is concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 404 mg (89% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.82 (2H, m), 2.00-2.15 (4H, m), 2.96 (2H, t, J = 8.0), 3.49-3.64 (4H, m), 3.70 (2H, m), 4.19 (2H, s), 4.50 (2H, d, J = 6.0), 4.95 (IH, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d , J = 16.0), 7.43 (1H, d, J = 9.5), 7.54 (1H, t, J = 8.0), 7.66-7.77 (4H, m), 7.89 (IH, s);

IR (KBr, cm- ¹ ): 1739, 1672, 1353, 1144. Production Example 79

N— [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] —N— [4 -—— 1-1 (2,3,4,5-tetrahydropyridine-1-6-yl) piperidine— 4 -Yloxy] 1-3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride 'N- [3- (3-amidinofenyl) 1-2_ (E) -op-obenyl] obtained in Production Example 77 (a) -N- [4- (piperidine-1-4-yloxy) -13-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (90 Omg) is dissolved in ethanol (20 ml) and the organic prep. Proped. Int .. 24. 147 (1992)], and piperidine one-two according to the method described in Translation and Procedures International, Vol. 24, pp. 147 (1992). 6-methoxy-synthesized from ON 2, 3, 4, 5-tetrahydropyridine (48 mg) and triethylamine (0.98 ml) were added, and the mixture was stirred at the same temperature for 10 minutes. Due to the slow progress of the reaction, 6-ethoxy-2,3,4,5-tetrahydropyridine (48 Omg) and triethylamine (0.98 ml) were added, and the mixture was stirred at room temperature for 1 day. Stirred for days. After adding 4N hydrogen chloride dioxane solution (2.5 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). Purified. After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 429 mg (yield 42%) of the title compound as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.64-1.85 (6H, m), 1.99-2.10 (2H, m), 2.70 (2H, m), 3.27-3.39 (2H, m), 3.53-3.73 (4H, m), 4.19 (2H, q, J = 7.0), 4.45 (2H, s), 4.50 (2H, d, J = 6.0), 4.95 (1H , M), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.43 (1H, d, J = 10.0), 7.55 (1H, t, J = 8.0), 7.65-7.75 (4H, m), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1739, 1675, 1355, 1141. Production Example 80

N— [3 -— (3-Amidinophenyl) —2_ (E) 1-propidinyl] —N— [4- [1- (2,3,4,5-tetrahydropyridine-1-6-yl) piperidine-1 4-1-yloxy] -1-3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -probe] l obtained in Production Example 79 N- [4- [l- (2,3,4,5-tetrahydropyridine-l) 6-yl) piperidine-1 4-yloxy] -13-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride (291 mg) is dissolved in 3N hydrochloric acid (2 Qml), and the solution is dissolved at 60 ° C at 5. Stirred for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 22% acetonitrile Z water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. This was dissolved in water, and the dried product was subjected to drying with frozen thread i-mouth to give 240 mg (86% yield) of the title compound as a colorless amorphous solid. Obtained.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.63-1.85 (6H, m), 2.03 (2H, m), 2.70 (2H, m), 3.20-3.48 (2H, m), 3.52-3.76 ( 4H, m), 4.12 (2H, s), 4.50 (2H, d, J = 6.0), 4.94 (IH, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.42 (1H, d, J = 9.0), 7.54 (IH, t, J = 8.0), 7.69 (IH, d, J = 8.0), 7.71 (IH, d, J = 8.0), 7.73- 7.78 (2H, m), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1732, 1675, 1352, 1143. Production Example 81

N— [3 -— (3-Amidinophenyl) -1-2- (E) -propidinyl] —N— [4- [1- (3,4,5,6-tetrahydro-2H-azepine-17-yl) [Pyridine-1-4-yloxy] -13-trifluoromethylphenyl] sulfamoylethyl acetate dihydrochloride N- [3- (3-amidinofenyl) -2- (E) obtained in Production Example 77 (a) Propenyl] -N- [4- (piperidine-1-yloxy) -13-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (900 mg) was dissolved in ethanol (2 Oml) and the mixture was dissolved at room temperature. , 7-Methoxy-3,4,5,6-tetrahydro-2H-azepine (54 Omg) and triethylamine (0.98 ml) were added, and the mixture was stirred at the same temperature. Due to the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (54 Omg) and triethylamine (0.98 ml) were added, and the mixture was further stirred at room temperature for 5 hours. Stirred at C for 1 day. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 340 mg (yield 33%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ld ppm: 1.22 (3H, t, J-7.0), 1.52-1.67 (4H, m), 1.67-1.85 (4H, m), 2.06 (2H, m), 2.87 (2H, m), 3.48 (2H, m), 3.67-3.83 (4H, m), 4.19 (2H, q, J = 7.0), 4.46 (2H, s), 4.50 (2H, d, J = 6.0) , 4.97 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.44 (1H, d, J = 9.5), 7.55 (1H, t, J = 8.0), 7.67- 7.75 (4H, m), 7.90 (1H, s);

IR (KBr, cm " ¹ ): 1739, 1675, 1354, 1142. Production example 82 ·

N— [3 -— (3-Amidinophenyl) -1- (E) 1-probenyl] —N— [4- [1- (3,4,5,6-tetrahydro-2H-azepine-17-yl) {Lysine-1-4-yloxy] 13-trifluoromethylphenyl] sulfamoylacetate diethyl hydrochloride N— [3- (3-amidinophenyl) 1-2— (E) 1-probe obtained in Production Example 81 2-]-N- [4- [1-1- (3,4,5,6-tetrahydro-2H-azepin-17-yl) piperidine- 4-yloxy] -13-trifluoromethylphenyl] Ethyl sulfamoyl acetate dihydrochloride (307 mg) was dissolved in 3N hydrochloric acid (2 Oml), and the mixture was stirred at 60 ° C for 6.5 hours. After cooling the reaction solution to room temperature, it is concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 23% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (218 mg, yield 74%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.46-1.67 (4H, m), 1.67-1.87 (4H, m), 2.07 (2H, m), 2.87 (2H, m), 3.42-3.52 ( 2H, m), 3.64-3.85 (4H, m), 4.27 (2H, s), 4.50 (2H, d, J = 6.0), 4.96 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0 ), 6.58 (1H, d, J = 16.0), 7.43 (lH, d, J = 10.0), 7.55 (1H, t, J = 8.0), 7.66-7.76 (4H, m), 7.89 (1H, s) ;

IR (KBr, cm- ¹ ): 1733, 1676, 1351, 1144. Production Example 83

N— [3— (3-Amidinophenyl) -1 2_ (E) 1-probenyl] —N— [3-Chloro4-1—1— (5,6-Dihydro-2H— [1,4] thiazine-1— Yl) piberidin-4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3 '-(3-Amidinophenyl) -12- (E) propenyl] obtained in Production Example 47 (a) N- [3-Chloro-41- (piperidine-1-4-yloxy) phenyl] Sur Famoyl acetate ethyl dihydrochloride (0.25 g) was dissolved in ethanol (10 ml) and, at room temperature, Indian Journal of Chemistry, 10, 323 (1972) [Indian J. Chem., 10, .323 (1972)]. 5-ethoxy-3,6-dihydro-1H- [1,4] thiazine (0.24 g) and trie synthesized from 3-thiomorpholine. Luamine (0.23 ml) was added, and the mixture was stirred at the same temperature for 4 hours, then at 45 ° C for 3 hours, and left at room temperature for 11 hours. After further stirring at 45 ° C for 12 hours, the mixture was left at room temperature for 11 hours. After adding 4 N hydrogen chloride dioxane solution (2 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile) did. The obtained amorphous solid was dissolved in ethanol (4 ml), 4 N hydrogen dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.07 g, yield 24%). Was obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.73-1.82 (2H, m), 2.02-2.10 (2H, m), 2.91-2.96 (2H, m ), 3.59-3.91 (8H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.81-4.88 (1H, m), 6.44 (1H, dt, J = 15.5, 6.0), 6.58 (IH, d, J = 15.5), 7.33 (1H, d, J = 9.0), 7.41 (IH, dd, J = 9.0, 2.5), 7.51- 7.60 (2H, m), 7.64-7.75 (2H, m), 7.87 (IH, s);

IR (KBr, cu ¹ ): 1737, 1674, 1633, 1350, 1155. Production Example 84

N— [3- (3-Amidinophenyl) —2— (E) —Probenyl] -N— [3-Chloro4-1- [1— (2,3,5,6-Tetrafluoropyridine-1 4 1 ^ (peryl) piperidine-1-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-Amidinophenyl) —2 -— (E) propionyl] -1-N— [3-chloro-4 -— (pyridin-1-yloxy) obtained in Production Example 47 (a) [Phenyl] sulfamoyl acetate ethyl dihydrochloride (930 mg) is dissolved in ethanol (20 ml), and at room temperature, 2,3,5,6-tetrafluoropyridine (0.16 ml) and triethylamine (0.64 ml) are dissolved. Was added and stirred at the same temperature for 5 hours. After adding a 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was collected by preparative HP LC (YMC-Pack ODS-A; Elution solvent: 55% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 893 mg (yield 81%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.73-1.84 (2H, m), 2.01-2.12 (2H, m), 3.38-3.48 (2H, m ), 3.59-3.69 (2H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (IH, m), 6.43 (1H , Dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.31 (1H, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t , J = 8.0), 7.59 (IH, d, J = 2.5), 7.66 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cm- ¹ ); 1739, 1677, 1351, 1147. Production Example 85

N— [3 -— (3-amidinofenyl) -1-2- (E) -probenyl] —N— [3-chloro-1-4-1 [1- (2,3,5,6-tetrafluoropyridine) 14-yl) piperidine-14-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-amidinofenyl) -12- (E) -probenyl] obtained in Production Example 84—N— [3-chloro-4 -— [1- (2,3,5,6- Tetrafluoropyridine (4-yl) piperidine (4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (356 mg) in 3N hydrochloric acid (2 Om 1) and 4N hydrogen chloride in dioxane (2 Om 1) Dissolved in the mixed solvent and stirred at 60 for 8.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 40% acetonitrile / water to only acetonitrile). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 322 mg (yield 94%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.72-1.84 (2H, m), 2.00-2.12 (2H, m), 3.38-3.48 (2H, m), 3.59-3.69 (2H, m), 4.21 (2H, s), 4.47 (2H, d, J = 6.0), 4.79 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.31 (IH, d, J = 9.0), 7.42 (IH, dd, J = 9.0, 2.5), 7.55 (IH, t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.66 (1H, d , J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (IH, s); IR (KBr, cm " ¹ ): 1678, 1346, 1147. Production Example 86

N— [3 -— (3-Amidinophenyl) -2 -— (E) 1-probenyl] — N— [3-chloro 4 -— [1- (N-ethylformimidoyl) piperidine-1-4-yloxy ] Phenyl] Sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -2- (E) propionyl] -N- [3-clocloth-4-1 (piperidine-4-yloxy) obtained in Production Example 47 (a) [Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.38 g) was dissolved in ethanol (20 ml), and the mixture was dissolved at room temperature at room temperature in Angevante Chemie, Vol. 75, p. 790 (1963) [Angew. Chem "7S, 790 (1963)], add methyl N-ethylformimidate (0.09 g) and triethylamine (0.30 ml) synthesized from N-ethylformamide, and add 46 ml at the same temperature. To the reaction mixture was added 4N hydrogen chloride dioxane solution (2 ml.)-, And the mixture was concentrated under reduced pressure. The residue was collected by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 20). The obtained amorphous solid was dissolved in ethanol (5 ml), and 4N hydrogen chloride dioxane solution (1 ml) was added. Thereafter, by concentrating to dryness under reduced pressure, 0.14 g (yield 35%) of the title compound was obtained as a colorless amorphous solid.

Video R (400 MHz, DMSO-d ₆ ) δ ppm: 1.16-1.27 (6H, m), 1.72-1.88 (2H, m), 1.99-2.10 (2H, m), 3.40-3.48 (2H, m) , 3.51-3.73 (4H, m), 4.19 (2H, q, J = 7.5), 4.42 (2H, s), 4.47 (2H, d, J = 5.5), 4.79-4.85 (IH, m), 6.45 ( 1H, dt, J = 16.0, 5.5), 6.58 (1H, d, J = 16.0), 7.32 (IH, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.5), 7.52- 7.59 ( 2H, m), 7.65-7.75, (2H, m), 7.87 (1H, s), 8.11 (IH, d, J = 13.5);

IR (KBr, cm- ¹ ): 1738, 1697, 1675, 1350, 1156. Production Example 87

N- [3 -— (3-Amidinophenyl) -2- (E) —probenyl] -1-N— [3-chloro-4— [1-1- (N-ethylformimidoyl) piperidine-1-4-yloxy ] Phenyl] sulfamoylacetic acid _2 hydrochloride N- [3- (3-amidinofenyl) -l- (E) -l-pronyl] obtained in Production Example 86-N- [3- (l-chloro-)-4-[1- (N-ethylformimide) Il) piperidine- [1-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.38 g) was dissolved in 3N hydrochloric acid (14 ml) and stirred at 60 ° C for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.25 g (yield 67%) of the title compound as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.19 (3H, t, J = 7.0), 1.72-1.88 (2H, m), 1.98-2.09 (2H, m), 3.51-3.79 (6H, m ), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.80-4.87 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.0), 7.52-7.60 (2H, m), 7.68-7.75 (2H, m), 7.89 (1H, s ), 8.13 (1H, d, J = 13.5);

IR (KBr, cm ' ¹ ): 1731, 1698, 1677, 1347, 1155. Production Example 88

N—C3- (3-Amidinophenyl) —2— (E) 1-probenyl] —N— [3—Cro- mouth—4-1— (1,5- (4,5-dihydrooxazole-2-yl))ぺ lysine-1 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) propionyl] -N- [3-cloth-4- (piperidine-4-yloxy) phenyl obtained in Production Example 47 (a) ] Ethyl sulfamoyl acetate dihydrochloride (0.75 g) is dissolved in ethanol (25 ml), and at room temperature, 一口アンジャーナルジャーナル Journal ォ Ob 'オー Organic ケ Chemistry, Vol. 10, pp. 2645 (1999) [ Eur. J. Org. Chem ..] Ό.2645 (1999)], 2-ethoxy-4,5-dihydrooxazole synthesized from 2-oxazolidone

(0.28 g) and triethylamine (0.68 ml) were added, and the mixture was stirred at the same temperature for 22 hours. After adding 4 N hydrogen chloride dioxane solution (5 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected. HP LC (YMC-Pack ODS-A; YMC, elution solvent: 23% acetonitrile Z water) Was purified. The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in dioxane (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.56 g (yield 67%) of the title compound. Obtained as a colorless amorphous solid.

lK NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.22 (3H, t, J = 7.0), 1.75-1.86 (2H, m), 1.98-2.10 (2H, m), 3.51-3.78 (4H, m ), 3.85 (2H, t, J = 8.5), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.76-4.85 (3H, m) , 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.40 (IH, dd, J = 9.0, 2.5), 7.52 -7.60 (2H, m), 7.69 (1H, d, J = 7.5), 7.73 (1H, d, J = 7.5), 7.87 (IH, s);

MS (FAB, m / z): 604 (M + H-2HC1) ⁺ . Production Example 89

N— [3- (3-Amidinophenyl) —2 -— (E) —Probenyl] one N— [3-chloroau 4-1-1 (1,5- (4,5-dihydrooxazozol-2-yl) piperidine — 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-Amidinophenyl) —2— (E) 1-probe] obtained in Production Example 88—N— [3-chloro-4— [1 -— (4,5-dihydroxazozo) (Ru-2-yl) piperidine-1-4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.29 g) was dissolved in 3N hydrochloric acid (12 ml) and stirred at 60 for 10 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack.ODS-A; YMC, elution solvent: 17% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2 ml), and concentrated under reduced pressure to dryness to obtain 0.23 g (yield 82%) of the title compound as a colorless amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.76-1.87 (2H, m), 1.98-2.10 (2H, m), 3.51-3.78 (4H, m), 3.85 (2H, t, J = 8.5), 4.28 (2H, s), 4.47 (2H, d, J = 5.5), 4.77-4.84 (3H, m), 6.44 (IH, dt, J-16.0, 5.5), 6.58 (1H, d, J = 16.0), 7.31 (IH, d, J = 9.0), 7.41 (IH, dd, J = 9.0, 2.5), 7.52-7.61 (2H, m), 7.68 (IH, d, J = 7.5), 7.73 ( IH, d, J = 7.5), 7.88 (1H, s);

IR (KBr, cnr ¹ ): 1733, 1685, 1349, 1155. Manufacturing example 90

N- [3- (3-amidinofenyl) -1- (E) -probenyl] -1-N- [3-chloro-4-1 (tropane-1-yloxy) phenyl] sulfamoyl acetate ethyl 2-hydrochloride obtained in Reference Example 126 N— [3-—Mouth—41- (tropane-1-3-yloxy) phenyl] —N— [3- (3-cyanophenyl) 1-2— (E) 1-probenyl] ethyl ethyl sulfamyl acetate (1 30 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (35 ml), passed through with hydrogen chloride under ice cooling, sealed, and stirred at room temperature for 3.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml), and an aqueous solution of ammonium chloride (0.40 g was dissolved in 5 ml of water) and 28% aqueous ammonia (0.90 ml) were added. Stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile / water). 'The obtained amorphous solid was dissolved in ethanol (15 ml), 4N hydrogen dioxane solution (1.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.07 g (yield) of the title compound. 70%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 2.05-2.30 (8H, m), 2.66 (3H, s), 3.94 (2H, m), 4.19 ( 2H, q, J = 7.0), 4.40 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.43 (1H, dt, J = 6.0, 16.0), 6.57 (1H , D, J = 16.0), 7.35-7.45 (2H, m), 7.50-7.60 (2H, m), 7.69 (1H, m), 7.73 (1H, m), 7.88 (1H, m);

IR (KBr, cnr ¹ ): 1737, 1675. Production Example 91

N— [3 -— (3-Amidinophenyl) -1-2- (E) -Probenyl] —N— [3-Chloro 4- (tropane-1-3-yloxy) phenyl] sulfamoylacetic acid dihydrochloride

N— [3- (3-Amidinophenyl) —2— (E) 1-probenyl] obtained in Production Example 90—N— [3-Chloro-41- (tropane-3-yloxy) phenyl] sulfamoylacetic acid Ethyl dihydrochloride (70 Omg) was dissolved in 3N hydrochloric acid (20 ml), and Stir for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3.3 ml) and water (10 ml), and concentrated to dryness under reduced pressure to obtain 580 mg (yield 86%) of the title compound as a colorless amorphous solid. .

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 2.05-2.30 (8H, m), 2.66 (3H, s), 3.93 (2H, m), 4.27 (2H, s), 4.47 (2H, d, J = 6.0), 4.83 (1H, m), 6.44 (1H, dt, J = 6.0, 16.0), 6.57 (1H, d, J = 16.0), 7.35-7.45 (2H, m), 7.50-7.60 (2H , m), 7.68 (1H, m), 7.73 (1H, m), 7.87 (1H, m);

IR (KBr, cm- ¹ ): 1732, 1675. Production Example 92

N- [3- (3-amidinofenyl) 1 2- (E) 1-propenyl] 1 N— [3-chloro 4- 1 [1 (3, 4, 5, 6, 7, 8, 8-hexahydro-2H) —Azonin-1 9-yl) piperidine-1 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-Amidinophenyl) -1-2- (E) -O-Pop-Benyl] obtained in Production Example 47 (a) —N- [3--clo-mouth-4-1 (piperidine-141-yloxy) [Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.78 g) was dissolved in ethanol (20 ml), and the mixture was treated at room temperature with Organic Preparation and Procedures, Yuichi National, Vol. 24, Vol. Page 147 (1992) 9-methoxy-3,4,5,6,7,8- synthesized from azonan-1-one according to the method described in [Org. Prep. Proced. Int..24.147 (1992)] Hexahydro-2H-azonin (0.80 g) and triethylamine (0.7 lml) were added, and the mixture was stirred at the same temperature for 18 hours. Due to the slow progress of the reaction, 9-methoxy-1,3,4,5,6,7,8-hexahydro-2H-azonin (0.29 g) and triethylamine (0.53 ml) were added, and the mixture was further stirred for 72 hours. . After adding 4N hydrogen chloride dioxane solution (5 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile / water). . The obtained amorphous solid was dissolved in ethanol (5 ml), and 4N hydrogen chloride dioxane solution (2 ml) Was added, and the mixture was concentrated to dryness under reduced pressure. After dissolving this in water and subjecting it to lyophilization, N- [3- (3-amidinofenyl) -l- (E) -l-propenyl] -lN- [3-l-chloro-4-1 [1 — (3,4,5,6,7,8-Hexahydro-2H-azonin-1 9-yl) piperidine-1 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride and a mixture of impurities 0.28 g was obtained as a colorless amorphous solid.

Next, this mixture was dissolved in 3 N hydrochloric acid (10 ml), stirred at 5 Ot for 6 hours, left at room temperature for 61 hours, and further stirred at 50 ° C for 7 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 23% aqueous acetonitrile). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2 ml) and concentrated to dryness under reduced pressure to obtain 0.09 g (yield 58%) of the title compound as a colorless amorphous solid. '

Video R (400 MHz, DMSO-d ₆ ) d ppm: 1.38-1.81 (12H, m), 2.00-2.09 (2H, m), 2.78-2.85 (2H, m), 3.48-3.57 (2H, m) , 3.59-3.72 (2H, m), 3.73-3.86 (2H, m), 4.27 (2H, s), 4.46 (2H, d, J = 5.5), 4.80-4.88 (IH, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.57 (1H, d, J = 16.0), 7.31 (IH, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.51-7.60 (2H, m), 7.64-7.75 (2H, m), 7.87 (IH, s);

IR (KBr, cm- ¹ ): 1733, 1675, 1627, 1352, 1156. Production Example 93

N- [3 -— (3-Amidinophenyl) -1-2- (E) -propidinyl] — N— [4 -— [1- (4,5-dihydrooxazole-2-yl) piperidine-1 4 [1-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-Amidinophenyl) —2 -— (E) —Propenyl] -N- [4- (piperidin-1-41-yloxy) phenyl] sulfamoylacetic acid obtained in Production Example 59 (a) Ethyl dihydrochloride (533 mg) was dissolved in ethanol (10 ml), and at room temperature, you were able to obtain Pian 'Journal * Ob' Organic 'Chemistry, Vol. 10, p. 2645 (1999) [Eur. J. Org Chem..1 £>, 2645 (1999)], 2-ethoxy-4,5-dihydrooxazole (235 mg) synthesized from 2-oxazolidone. And trieduramine (0.43 ml) were added, and the mixture was stirred overnight at the same temperature. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride dioxane solution (0.36 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 278 mg (yield 47%) of the title compound. Obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.66-1.80 (2H, m), 1.94-2.10 (2H, m), 3.62-3.82 (4H, m ), 3.85 (2H, t, J = 8.5), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 6.0), 4.68 (1H, m), 4.79 (2H, t, J = 8.5), 6.44 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d , J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, m), 7.88 (1H, s);

MS (FAB, m / z): 570 (M + H-2HC1) ⁺ . Production Example 94

N- [3— (3 amidinophenyl) -2 (E) -l-propidinyl] —N —— [4 —— [1

-(4,5-dihydrooxazolyl-2-yl) piperidine-1-yloxy] phenyl] -sulfamoylacetic acid _2 hydrochloride

■ 2HCI

N— [3- (3-amidinofenyl) —2 -— (E) —probenyl] —N— [4- [1 -— (4,5-dihydrooxazole) obtained in Production Example 93 (Pyridine-1 4- [yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (272 mg) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 for 5 hours. After cooling the reaction solution to room temperature, it is concentrated under reduced pressure, and the residue is collected by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: The solution was purified with acetonitrile (water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (4 ml), and concentrated under reduced pressure to dryness to obtain 209 mg (yield 80%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.65-1.81 (2H, m), 1.97-2.10 (2H, m), 3.43-3.62 (4H, m), 3.85 (2H, t, J = 8.5 ), 4.21 (2H, s), 4.44 (2H, d, J = 6.0), 4.68 (1H, m), 4.79 (2H, t, J = 8.5), 6.44 (IH, dt, J = 16.0, 6.0) , 6.55 (IH, d, J = 16.0), 7.03 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.54 (IH, t, J = 8.0), 7.70 (2H, m ), 7.88 (1H, s);

IR (KBr, cm " ¹ ): 1687, 1346, 1156. Production example 95

N— [4 -— (1_acetoimidoylpiperidine-1_4_yloxy) phenyl] 1 N— — [3 —— (3-amidinofenyl) 1 2— _ (E) —probenyl] ethanesulfonamide — 2

(a) N- [3- (3-Amidinophenyl) -1-2- (E) -probenyl] -1-N— [4-(Piperidin-4-yloxy) phenyl] phosphoryl sulfonamide dihydrochloride

N— [4 -— (1-t-butoxycarbonylbiperidine-1-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) —2 -— (E) -probenyl obtained in Reference Example 129 Ethane sulfonamide (955 mg) was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (20 ml), and after passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 9 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of sodium chloride (193 mg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.375 ml) were added. Left for 12 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile Z water). The obtained amorphous solid is methanol

(10 ml), 4N hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 354 mg (44% yield) of the title compound as a colorless amorphous solid. 'Η NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.27 (3H, t, J = 7.0), 1.83 (2H, m), 2.09 (2H, m), 3.03 (2H, m), 3.17 (2H , q, J = 7.0), 3.19 (2H, m), 4.45 (2H, d, J = 6.0), 4.64 (IH, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16,0), 7.00 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, m), 7.89 (1H, s);

MS (FAB, m / z): 443 (M + H-2HC1) ⁺ .

(b) N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -N- [3- (3-amidinofenyl) —2 -— (E) 1-propionyl] ethanesulfonic acid De dihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) prodenyl] -N- [4- (piperidine-1-4-yloxy) phenyl] ethanesulfon obtained in Production Example 95 (a) Mido dihydrochloride (311 mg) was dissolved in ethanol (10 ml), and ethyl ethyl cetimidate hydrochloride (26 Omg) and triethylamine (0.50 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 243 mg (yield 62%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.27 (3H, t, J = 7.0), 1.72 (2H, m), 2.04 (2H, m), 2.30 (3H, s), 3.18 (2H, q, J = 7.0), 3.50-3.59 (2H, m), 3.72 (1H, m), 3.84 (1H, m), 4.45 (2H, d, J = 6.0), 4.70 (1H, m), 6.46 ( IH, dt, J = 15.5, 6.0), 6.55 (IH, d, J = 15.5), 7.01 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.71 (2H, m), 7.91 (1H, s);

IR (KBr, cm " ¹ ): 1674, 1625. Production Example 96

N- [4- (1-acetoimidoylpiperidine-1 4-yloxy) phenyl] N- [3 -— (3-Amidinophenyl) —2-methyl-2- (E) —probenyl] ethanesulfonamide dihydrochloride

(a) N— [3- (3-amidinofenyl) -1-methyl-2- (E) -propenyl] —N— [4 -— (piperidine-1-yloxy) phenyl] ethanesulfonamide monosalt N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] obtained in Reference Example 133—N— [3- (3-Cyanophenyl) 1-2—methyl 2- (E) 1 [Propenyl] ethanesulfonamide (839 mg) was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (20 ml). After passing through hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 8 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of ammonium chloride (166 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.32 ml) were added. Left for 12 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 514 mg (yield 63%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.27 (3H, t, J = 7.0), 1.84 (2H, m), 1.87 (3H, s), 2.09 (2H, m), 3.04 (2H, m), 3.16 (2H, q, J = 7.0), 3.20 (2H, m), 4.39 (2H, s), 4.64 (1H, m), 6.35 (1H, s), 7.01 (2H, d, J = 9.5), 7.39 (2H, d, J = 9.5), 7.47 (1H, d, J = 8.0), 7.55 (2H, m), 7.64 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1675.

(b) N— [4 -— (1-acetimidoylpiperidine—4-yloxy) phenyl] -N- [3- (3-amidinofenyl) -2-methyl-2- (E) -propenyl] etha Sulfonamide '' dihydrochloride

N_ [3- (3-amidinofenyl) -1-2-methyl-2 obtained in Production Example 96 (a) 1- (E) -Probenyl] 1-N- [4- (Piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride (303 mg) is dissolved in ethanol (10 ml), and ethyl acetate is added at room temperature. After adding imidate hydrochloride (246 mg) and triditylamine (0.46 ml), the mixture was stirred at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (0.90 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). Purified. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 17 Omg (yield 45%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.27 (3H, t, J = 7.0), 1.71 (2H, m), 1.87 (3H, s), 2.04 (2H, m), 2.30 (3H, s), 3.17 (2H, q, J = 7.0), 3.53 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.39 (2H, s), 4.70 (1H, m), 6.35 (1H, s), 7.01 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.47 (1H, d, J = 8.0), 7.55 (1H, s), 7.55 (1H, t, J = 8.0), 7.65 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1673, 1626. Production Example 97

N— [4 -— (1-Acetimidoylpiperidine—4-yloxy) phenyl] —N— [3- (3-Amidinophenyl) 1-2— (E) —Probenyl] ethyl sulfamoyl acetate 2 Hydrochloride

N- [3- (3-Amidinophenyl) -l- (E) -p-orbenyl] -N- [4- (piperidine-l- 4-yloxy) phenyl] sulfamoylacetic acid obtained in Production Example 59 (a) Ethyl dihydrochloride (109 Omg) was dissolved in ethanol (40 ml), and ethyl acetimidate hydrochloride (705 mg) and triethylamine (1.30 ml) were added at room temperature. Stirred for hours. After adding a 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). Dissolve the obtained amorphous solid in methanol (15 ml), add 4N hydrogen chloride dioxane solution (1 ml), and concentrate under reduced pressure to dryness. By the above, 812 mg (yield: 70%) of the title compound was obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.67-1.79 (2H, m), 2.04 (2H, m), 2.29 (3H, s), 3.50 ( 2H, m), 3.72 (1H, m), 3.81 (1H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 6.0), 4.70 ( 1H, m), 6.45 (1H, dt, J = 16.5, 6.0), 6.55 (1H, d, J = 16.5), 7.04 (2H, d, J = 9.5), 7.39 (2H, d, J = 9.5) , 7.54 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm " ¹ ): 1738, 1673, 1626. Production Example 98

N— [4- (1-acetimidoylpiperidine-1-41-yloxy) phenyl] — N—

[3- (3-Amidinophenyl) -111- (E) -Propenyl] sulfamoylacetic acid

■ 2HCI

N— [4- (1-acetimidoylpiperidin-1-yloxy) phenyl] -N- [3- (3-amidinofenyl) -2- (E) -probenyl obtained in Production Example 97 Ethyl sulfamoyl acetate dihydrochloride (440 mg) was dissolved in 3N hydrochloric acid (30 ml) and stirred at 80 for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4N hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to obtain 331 mg (yield 78%) of the title compound.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.73 (2H, m), 2.04 (2H, m), 2.29 (3H, s), 3.51 (2H, m), 3.72 (1H, m), 3.80 (IH, m), 4.18 (2H, s), 4.45 (2H, d, J = 6.0), 4.70 (1H, m), 6.44 (IH, m) dt, J = 16.5, 6.0), 6.55 (IH, d, J = 16.5), 7.03 (2H, d, J = 8.5), 7.40 (2H, d, J = 8.5), 7.54 (IH, t, J = 8.0), 7.68 (IH, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.87 (IH, s);

IR (KBr, cmf ¹ ): 1733, 1673, 1627. Production Example 99

N- [4_ (1-acetimidoylpiperidine-1 4-yloxy) phenyl] — N—

[3- (5-Amidino 2-fluorophenyl) -1- (E) -probenyl] ethanesulfonamide dihydrochloride

(a) N— [3- (5-Amidino-2-fluorophenyl) -2- (E) monopropyl] -N- [4-1 (piperidine-1-4-1yloxy) phenyl] ethanesulfonamide 2 Reference N- [4- (1-t-butoxycarbonylbiperidine-14-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -pro obtained in Example 236 [Benyl] ethanesulfonamide (2.00 g) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 7 hours. . After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (50 ml), and an aqueous solution of ammonium chloride (0.39 g dissolved in 25 ml of water) and 28% aqueous ammonia (0.76 ml) were added. And left for 12 hours. After adding 4 N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1.20 g (yield 61%) of the title compound as a pale brown amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.27 (3H, t, J = 7.0), 1.82 (2H, m), 2.09 (2H, m), 3.04 (2H, m), 3.17 (2H, q, J = 7.0), 3.18 (2H, m), 4.49 (2H, d, J = 6.0), 4.64 (1H, m), 6.55 (IH, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.01 (2H, d, J = 8.5), 7.37 (2H, d, J = 8.5) ), 7.45 (1H, m), 7.78 (1H, m), 8.11 (IH, m);

IR (KBr, cm " ¹ ): 3056, 1676.

(b) N- [4- (1-acetoimidoylpiperidin-4-yloxy) phenyl] -1-N— [3- (5-amidino-1-fluorophenyl) 1-2— (E) —probe2 Ethanesulfonic acid dihydrochloride

N_ [3- (5-amidino-l-fluorophenyl) -l- (E) -probenyl] -l-N- [4- (piperidine-l 4-peroxy) phenyl obtained in Production Example 99 (a) Dissolve ethanesulfonamide dihydrochloride (534 mg) in ethanol (20 ml), add ethyl acetimidate hydrochloride (371 mg) and triethylamine (0.7 Oml) at room temperature, and then add the same temperature. For 12 hours. After adding 4 N hydrogen chloride dioxane solution (2 m 1) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is fractionated. HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water) Was purified. The obtained amorphous solid is methanol

(10 ml), 4 N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 415 mg (yield 75%) of the title compound as a colorless amorphous solid.

Image R (500 MHz, DMSO-d ₆ ) δ ppm: 1.28 (3H, t, J = 7.0), 1.74 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.18 (2H, q, J = 7.0), 3.52 (2H, m), 3.72 (IH, m), 3.81 (IH, m), 4.50 (2H, d, J = 6.0), 4.70 (1H, m), 6.56 (1H, dt, J = 16.5, 6.0), 6.62 (1H, d, J = 16.5), 7.02 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.46 (1H, m), 7.78 (1H, m), 8.12 (1H, m); IR (KBr, cm- ¹ ): 3113, 1674, 1625. Production Example 100

, N— [4- (1-Acetimidoylpiperidine—4-yloxy) -1-2-methylphenyl] -1-N— [3- (3-Amidinophenyl) —2 -— (E) —Probenyl] Sulfamoyl Ethyl acetate-dihydrochloride (a) N- [3- (3-amidinofenyl) 1-2- (E) -probenyl] N- [2-methyl-4- (piperidine-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [4- (1-t-butoxycarbonylpiperidine-4-yloxy) -12-methylphenyl] -N- [3- (3-cyanophenyl) 1-2 (E) -probe obtained in Reference Example 137 [Nyl] sulfamoyl acetate (1.80 g) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), passed through with hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), and aqueous ammonium chloride solution (0.32 g was dissolved in 25 ml of water) and 28% aqueous ammonia (0.62 ml) were added. It was left at room temperature for 12 hours. The reaction solution was added with 4 N hydrogen chloride dioxane solution, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 20% acetonitrile water). 0.78 g (yield 45%) of the compound was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.73 (2H, m), 2.04 (2H, m), 2.27 (3H, s), 3.00 (2H, m), 3.18 (2H, m), 4.20 (2H, q, J = 7.0), 4.25 (1H, m), 4.33 (IH, d, J = 14.5), 4.45 (1H, m), 4.46 (1H, d, J = 14.5), 4.59 (IH, m), 6.46 (2H, s), 6.88 (1H, d, J = 9.0), 6.90 (1H, s), 7.39 (1H, d, J = 9.0), 7.55 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.71 (IH, d, J = 8.0), 7.81 (IH, s);

IR (KBr, cm- ¹ ): 1737, 1676.

(b) N— [4 -— (1-acetoimidoylpiperidine-1-4-yloxy) -1-2-methylphenyl] —N— [3- (3-amidinofenyl) 1-2— (E) Benyl] sulfamyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) _2- (E) -propionyl] -N- [2-methyl-41- (piperidine-1 4-yloxy) phenyl] sulphamoyl obtained in Production Example 100 (a) Ethyl acetate dihydrochloride (63 lmg) is dissolved in ethanol (30 ml), and ethylacetimidate hydrochloride (397 mg) and triethylamine (0.75 ml) are added at room temperature, and the mixture is stirred at the same temperature for 64 hours. did. Add 4 N hydrogen chloride dioxane to the reaction mixture After adding the solution (2 ml), the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 24% aqueous acetonitrile). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 423 mg (yield 60%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.24 (3H, t, J = 6.5), 1.65-1.79 (2H, m), 2.04 (2H, m), 2.28 (3H, s), 2.31 ( 3H, s), 3.48-3.59 (2H, m), 3.72 (1H, m), 3.85 (1H, m), 4.21 (2H, q, J = 6.5), 4.28 (IH, dd, J = 14.5, 6.0 ), 4.34 (1H, d, J = 15.0), 4.43 (IH, dd, J = 14.5, 4.5), 4.49 (IH, d, J = 15.0), 4.70 (IH, m), 6.46 (IH, d, J = 15.5), 6.49 (IH, m), 6.90 (IH, dd, J = 9.0, 3.0), 6.93 (IH, d, J = 3.0), 7.41 (IH, d, J = 9.0), 7.55 (IH , t, J = 8.0), 7.72 (2H, m), 7.88 (IH, s);

IR (KBr, cm " ¹ ): 1738, 1673, 1624. Production Example 101

N— [4- (1- (acetoimidoylpiperidine-1-4-yloxy) -1-3-methoxyphenyl) _N—C3- (3-amidinofenyl) 1-2 (E) —probenyl] ethyl ethyl sulfamoyl acetate 2 Hydrochloride

(a) N-C3- (3-amidinofenyl) — 2- (E) —probenyl] 1 N— [3-methoxy -4- 4- (piperidine-1 4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-methoxyphenyl] -N- [3- (3-cyanophenyl) -2- (E) -1 obtained in Reference Example 141 [Propenyl] sulfamoyl acetate ethyl (985 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous solution of ammonium chloride (172 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.33 ml) were added, and the mixture was added at room temperature. Left for hours. 4N salt in the reaction solution After addition of a dioxane hydride solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17% aqueous acetonitrile). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride dioxane solution (0.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (560 mg, yield). (58%) as a pale yellow amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.24 (3H, t, J = 7.0), 1.84 (2H, m), 2.05 (2H, m), 3.03 (2H, m), 3.19 (2H , m), 3.79 (3H, s), 4.21 (2H, q, J = 7.0), 4.38 (2H, s), 4.46 (2H, d, J = 6.0), 4.56 (IH, m), 6.46 (IH , dt, J = 15.5, 6.0), 6.57 (1H, d, J = 15.5), 6.98 (IH, dd, J = 9.0, 2.0), 7.08 (IH, d, J = 9.0), 7.11 (1H, d , J = 2.0), 7.55 (1H, t, J = 7.5), 7.69 (1H, d, J = 7.5), 7.73 (1H, d, J = 7.5), 7.90 (1H, s);

IR (KBr, cm " ¹ ): 1737, 1675.

(b) N- [4-((1_acetoimidoylpiperidine-1-4-yloxy))-3- (methoxyphenyl) _N_ [3- (3_ (amidinophenyl) 1-2 (E) pronenyl] Rufamoyl acetate ethyl dihydrochloride

N— [3- (3-Amidinophenyl) —2 -— (E) -propenyl) —N— [3-Methoxyxy 4- (piperidine-4-yloxy) obtained in Production Example 101 (a) Phenyl] sulfamoyl acetate dihydrochloride (392 mg) was dissolved in ethanol (20 ml), and at room temperature, ethyl acetimidate hydrochloride (24 lmg) and triethylamine (0.45 ml) were added. Then, the mixture was stirred at the same temperature for 38 hours. After adding 4 N hydrogen chloride dioxane solution (0.80 m 1) to the reaction mixture, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-PackODS-A; YMC, elution solvent: 20% acetonitrile Z water). did. The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride dioxane solution (0.30 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (317 mg, yield 76%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.66-1.80 (2H, m), 2.01 (2H, m), 2.30 (3H, s), 3.47- 3.59 (2H, m), 3.72 (1H, m), 3.78 (3H, s), 3.82 (1H, m), 4.21 (2H, q, J = 7.0), 4.39 (2H, s), 4.47 (2H, d, J = 5.5), 4.62 (1H, m), 6.47 (IH, dt, J = 15.5, 5.5), 6.57 (1H, d, J = 15.5), 6.99 (1H, dd, J = 9.0, 3.0), 7.11 (2H, m), 7.55 (1H, t, J = 8.0) , 7.71 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.91 (1H, s);

IR (KBr, cm " ¹ ): 1738, 1674, 1625. Production Example 102

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) —3-chlorophenyl] —N— [3- (3-amidinofenyl) 1-2— (E) —probenyl] Ethyl sulfamyl acetate dihydrochloride

N_ [3- (3-Amidinophenyl) -1-2- (E) propenyl] obtained in Production Example 47 (a) — N— [3-Crosin_4-1 (piperidine-14-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (387 mg) was dissolved in ethanol (10 ml). Ethyl acetimidate hydrochloride (232 mg) and triethylamine (0.44 ml) were added at room temperature, followed by 5 hours at the same temperature. Stirred. After adding 4N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile / water). Purified. The obtained amorphous solid is methanol

(20 ml), 4 N hydrogen chloride dioxane solution (0.25 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (268 mg, yield 66%) as a colorless amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.80 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.55-3.78 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.45 (1H, dt, J = 15.5, 6.0), 6.58 (1H, d, J = 15.5), 7.33 (IH, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 3.0), 7.55 (IH, t, J = 8.0), 7.59 (IH, d, J = 3.0), 7.70 (1H, d , J = 8.0), 7.73 (IH, d, J = 8.0), 7.90 (1H, s);

IR (KBr, cm ' ¹ ): 1738, 1673, 1623. Production Example 103

N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-chlorophenyl] — N— [3- (3-amidinofenyl) —2— (E) 1-propenyl] Sulfamoylacetic acid _2 hydrochloride

N— [4- (1-Acetimidoylpiperidine-4-yloxy) -3-3-chlorophenyl] -N- [3- (3-amidinofenyl) obtained in Production Example 102 E) -Propenyl] sulfamoyl acetate diethyl hydrochloride (187 mg) was dissolved in 3N hydrochloric acid (7 ml) and stirred at 80 for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride in dioxane (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 147 mg (82% yield) of the title compound.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.79 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.54-3.75 (4H, m), 4.23 (2H, s) , 4.47 (2H, d, J = 6.0), 4.83 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (IH, m), 7.68 (1H, d, J = 8.0), 7.73 (IH, d, J = 8.0) , 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1734, 1673, 1625. Production example 104

N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-fluorophenyl] -1-N— [3- (3-amidinofenyl) -12- (E) 1-probenyl] sulfa Moethyl acetate dihydrochloride

(a) N-C3- (3-amidinofenyl) 1-2- (E) 1-propenyl] 1-N- [3-fluoro-4- (piperidine-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-fluorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -1pro obtained in Reference Example 145 [Benyl] sulfamoyl acetate (121 Omg) was dissolved in a mixed solvent of dichloromethane (3 Om1) and ethanol (20 ml), and after passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). An aqueous ammonium chloride solution (215 mg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.41 ml) were added, and the mixture was added at room temperature for 17 hours. I left it. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 17% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (15 ml), 4N hydrogen chloride in dioxane (0.30 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 798 mg (yield 67%) of the title compound. Was obtained as a pale yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.23 (3H, t, J = 7.0), 1.85 (2H, m), 2.09 (2H, m), 3.06 (2H, m), 3.19 (2H, m), 4.19 (2H, q, J = 7.0), 4.40 (2H, s), 4.47 (2H, d, J = 7.0), 4.68 (1H, m), 6.43 (IH, m), 6.58 (1H, d, J = 16.0), 7.25 (1H, dd, J = 9.0, 2.5), 7.31 (IH, t, J = 9.0), 7.43 (IH, dd, J = 12.5, 2.5), 7.55 (1H, t, J = 8.0), 7.68 (IH, m), 7.73 (IH, d, J = 8.0), 7.88 (IH, bs);

IR (KBr, cm- ¹ ): 1737, 1675. (b) N— [4- (1-Acetimidoylpiperidine—4-yloxy) —3-fluorophenyl] 1-N— [3- (3-amidinofenyl) —2 -— (E) —Probenyl ] Sulfamoyl acetate ethyl dihydrochloride

N_ [3- (3-Amidinophenyl) -2- (E) 1-probenyl] obtained in Production Example 104 (a) — N— [3-Fluoro-41- (piperidine-4-yloxy) phenyl] sulfamoylacetic acid Ethyl dihydrochloride (467 mg) was dissolved in ethanol (25 ml), and ethyl acetimidate hydrochloride (293 mg) and triethylamine (0.55 ml) were added at room temperature, followed by stirring at the same temperature for 66 hours. After adding a 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (15 ml), 4N salted hydrogen oxane solution (0.30 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (284 mg, yield 57%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.68-1.82 (2H, m), 2.06 (2H, m), 2.31 (3H, s), 3.51 ( 1H, m), 3.59 (1H, m), 3.71 (1H, m), 3.86 (IH, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.76 (1H, m), 6.46 (IH, dt, J = 15.5, 6.0), 6.57 (1H, d, J = 15.5), 7.26 (1H, d, J = 9.0), 7.35 (1H , T, J = 9.0), 7.43 (IH, dd, J = 12.0, 2.5), 7.54 (1H, t, J = 8.0), 7.73 (2H, m), 7.95 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1673, 1623. Production example 105

N— [4- (1-Acetimidoylpiperidin-1-yloxy) -3-fluorophenyl] —N— [3- (3-Amidinophenyl) 1-2— (E) —Probenyl] Sulfa Moyl acetic acid dihydrochloride

N— [4- (1-acetimidoylpiperidine—4-yloxy) -13-fluorophenyl] —N— [3- (3-amidinofenyl) obtained in Production Example 104 (b) (E) One-Propenyl] sulfamoyl acetate ethyl dihydrochloride (199 mg) was dissolved in 3N hydrochloric acid (7 ml), and the mixture was stirred at 80 ° C. for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 15% acetate nitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to obtain 163 mg (yield 86%) of the title compound.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.77 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.52 (2H, m), 3.71 (1H, m), 3.80 (1H, m), 4.23 (2H, s), 4.47 (2H, d, J = 6.0), 4.73 (IH, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0), 7.26 (1H, m), 7.32 (IH, t, J = 8.5), 7.43 (1H, dd, J = 13.0, 2.0), 7.55 (IH, t, J = 8.0), 7.68 (1H , D, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 3295, 1733, 1673, 1624. Production example 106

N— [4- (1-Acetoimidoylpiperidine-1-4-yloxy) phenyl] —N—

[3- (5-Amidino-2-methylphenyl) -1- (E) -propenyl] sulfamoyl acetate ethyl dihydrochloride

(a) N- [3- (5-Amidino-2-methylphenyl) -1- (E) -probenyl] • N- [4-((piperidine-1-4-yloxy) phenyl] ethylamyl acetate 2] N— [4- (1-t-butoxycarponylpiperidine-14-yloxy) phenyl] obtained in Reference Example 234] —N— [ 3- (5-Cyano-2-methylphenyl) 1-2- (E) -Probenyl] Sulfamoylethyl acetate (2.03 g) is dissolved in a mixed solvent of dichloromethane (40m1) and ethanol (40ml). Then, the mixture was passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (45 ml), an aqueous ammonium chloride solution (0.36 g was dissolved in 15 ml of water) and 28% aqueous ammonia (0.68 ml) were added, and the mixture was stirred at room temperature. And left for 12 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride in ethyl acetate (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.49 g of the title compound (yield 75%). ) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.82 (2H, m), 2.09 (2H, m), 2.22 (3H, s), 3.05 (2H, m), 3.21 (2H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.46 (2H, d, J = 6.5), 4.66 (1H, m), 6.30 (IH, dt, J = 16.0, 6.5), 6.66 (IH, d, J = 16.0), 7.05 (2H, d, J = 9.5), 7.37 (1H, d, J = 7.5), 7.38 (2H, d, J = 9.5), 7.61 (1H, dd, J = 7.5, 2.0), 7.86 (1H, d, J = 2.0);

IR (KBr, cm- ¹ ): 1738, 1674.

(b) N— [4 -— (1-acetimidoylpiperidine-1-4-yloxy) phenyl]

[3- (5-amidino-2-methylphenyl) -1- (E) -probenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (5-Amidino-2-methylphenyl) -l- (E) -l-propenyl] -lN- [4- (piperidine-l-l-yloxy) phenyl] s obtained in Production Example 106 (a) Ethyl rufamoyl acetate dihydrochloride (1.43 g) was dissolved in ethanol (40 ml), and at room temperature, ethyl acetimidate hydrochloride (0.60 g) and triethylamine (1. (4 ml), and the mixture was stirred at the same temperature for 13 hours. After adding a 4 N solution of hydrogen chloride in ethyl acetate (2 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was collected by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water) ). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride in ethyl acetate (0.8 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.18 g of the title compound (yield 77%). %) Was obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.67-1.80 (2H, m), 2.05 (2H, m), 2.22 (3H, s), 2.30 ( 3H, s), 3.49-3.61 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.19 (2H, q, J = 7.0), 4.35 (2H, s), 4.46 (2H, m d, J = 6.0), 4.72 (1H, m), 6.32 (1H, dt, J = 16.0, 6.0), 6.66 (1H, d, J = 16.0), 7.06 (2H, d, J = 9.5), 7.38 (1H, d, J = 9.0), 7.39 (2H, d, J = 9.5), 7.64 (1H, dd, J = 9.0, 2.0), 7.88 (1H, d, J = 2.0);

IR (KBr, cm- ¹ ): 1738, 1675, 1626. Production example 107

N— [4- (1-Acetimidoylpiperidine—4-yloxy) _3-Trifluoromethylphenyl] N— [3- (3-Amidinophenyl) 1-2— (E) 1-probenyl] ethyl ethyl sulfamoyl acetate 2 Hydrochloride

N- [3- (3-amidinofenyl) -l- (E) propionyl] -lN- [4- (piperidine-l- 4-yloxy) -3- 3-trifluoro obtained in Production Example 77 (a) Romethylphenyl] sulfamoyl acetate diethyl hydrochloride (1.13 g) was dissolved in ethanol (2 Om 1), and at room temperature, ethyl acetimidate hydrochloride (0.65 g) and triethylamine (1 20 ml), and the mixture was stirred at the same temperature for 13 hours. The reaction mixture was added with 4N hydrogen chloride in dioxane, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile Z water). The amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride in ethyl acetate (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.04 g of the title compound (87% yield). Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.81 (2H, m), 2.07 (2H, m), 2.30 (3H, s), 3.59-3.73 (4H, m), 4.19 (2H, q, J = 7.0), 4.46 (2H, s), 4.50 (2H, d, = 6.5), 4.96 (1H, m), 6.47 (IH, dt, J = 16.5, 6.5), 6.58 (IH, d, J = 16.5), 7.44 (1H, d, J = 9.5), 7.56 (1H, t, J = 8.0), 7.71 (4H, m), 7.90 (1H, s);

IR (KBr, cm " ¹ ): 1739, 1673, 1618. Production Example 108

N— [4- (1-Acetimidoylpiperidine-1-4-yloxy) -1-3-trifluoromethylphenyl] —N— [3 -— (3-Amidinophenyl) 1-2— (E) 1-probenyl] sulfamoylacetic acid Dihydrochloride

N— [4- (1-acetoimidoylpiperidine-141-yloxy) _3-trifluoromethylphenyl] —N— [3- (3-amidinofenyl) obtained in Production Example 107 2- (E) -Probenyl] sulfamoyl acetate ethyl dihydrochloride (321 mg) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 80 ° C for 3 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 231 mg (yield 75%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.79 (2H, m), 2.05 (2H, m), 2.31 (3H, s), 3.40-3.75 (4H, m), 4.32 (2H, s) , 4.50 (2H, d, J = 6.5), 4.96 (1H, m), 6.47 (1H, dt, J = 17.0, 6.5), 6.57 (1H, d, J = 17.0), 7.43 (IH, d, J = 10.0), 7.54 (IH, d, J = 7.5), 7.71 (4H, m), 7.92 (IH, s);

IR (KBr, cm- ¹ ): 3102, 1734, 1675, 1617. Production Example 109

N— [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) —3-methylphenyl] 1-N— [3- (3-Amidinophenyl) —2 -— (E) 1-probenyl] sulfamo Ethyl acetate dihydrochloride N— [3 -— (3-amidinofenyl) —2 -— (E) prodenyl] obtained in Production Example 65 (a) —N— [3-Methyl-4- (piperidine-1-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (1.23 g) was dissolved in ethanol (40 ml), and at room temperature, ethyl acetimidate hydrochloride (0.52 g) and triethylamine (1.20 ml) were added. The mixture was stirred at the same temperature for 13 hours. After adding a 4 N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride in ethyl acetate (0.60 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.10 g (yield) of the title compound. (84%) as a colorless amorphous solid.

^X H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.77 (2H, m), 2.03 (2H, m), 2.16 (3H, s), 2.30 (3H , s), 3.60-3.80 (4H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (IH, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.06 (IH, d, J = 9.0), 7.25 (IH, dd, J = 9.0, 2.5), 7.29 (IH , d, J = 2.5), 7.55 (1H, t, J = 8.0), 7.71 (2H, m), 7.91 (1H, s);

IR (KBr, cm " ¹ ): 1738, 1672, 1624.

.Ten

N— [4 -— (1-acetimidoylpiperidine-4-yloxy) -1-methylphenyl] —N— [3- (3-amidinofenyl) —2 -— (E) —probenyl] sulfamoy Ruacetic acid-dihydrochloride

N— [4- (1-acetoimidoylpiperidine—4-yloxy) -1-3-methylphenyl] —N— [3- (3- (amidinophenyl) 1-2— (E) obtained in Production Example 109 —Probenyl] sulfamoyl acetate ethyl dihydrochloride (48 Omg) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 80 ° C. for 3 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 20% aceto nitritol water). The obtained amorphous solid was dissolved in methanol (15 ml), 4N hydrogen dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 315 mg (yield 69%) of the title compound. Obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.78 (2H, m), 2.02 (2H, m), 2.14 (3H, s), 2.29 (3H, s), 3.62 (4H, m), 3.71 (2H, s), 4.12 (1H, m), 4.46 (2H, d, J = 6.0), 4.70 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.50 (1H, d, J = 16.0), 7.02 (IH, d, J = 8.5), 7.36 (IH, s), 7.37 (1H, d, J = 8.5), 7.52 (IH, d, J = 8.0), 7.67 (1H, d , J = 7.5), 7.69 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cm- ¹ ): 3067, 1678, 1608, 1497. Production Example 111

N— [4 -— (1-acetoimidoylpiperidine—4-yloxy) phenyl] — N— [3 -— (3-amidino-5-methylphenyl) 1-2— (E) 1-probenyl] sulfamoyl Ethyl acetate dihydrochloride

(a) N— [3 -— (3-Amidino-5-methylphenyl) 1-2— (E) —probenyl] —N— [4- (piperidine-14-yloxy) phenyl] sulfamoyl acetate 2 Reference Example 148 Obtained N- [4- (1-t-butoxycarbonylpiperidine-14-yloxy) phenyl] —N— [3- (3-cyano-5-methylphenyl) 1-2- (E) -probenyl] sulfamoylacetic acid Ethyl (1.59 g) was dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was ethanol (20m The mixture was dissolved in 1), an aqueous solution of ammonium chloride (0.2 lg dissolved in 4 ml of water) and 28% ammonia water (0.53 ml) were added, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water) to give 1.10 g (yield) of the title compound. (80%) as a colorless amorphous solid.

¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85 (2H, m), 2.10 (2H, m), 2.36 (3H, s), 3.06 (2H , m), 3.18 (2H, m), 4.19 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 5.5), 4.66 (1H, m), 6.41 (1H , Dt, J = 16.0, 5.5), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.54 (1H, s), 7.58 (1H, s), 7.68 (1H, s);

IR (Br, cm- ¹ ): 1737, 1674.

(b) N— [4- (1-acetoimidoylpiperidine—4-yloxy) phenyl] —N— [3 -— (3-amidinol 5-methylphenyl) 1-2— (E) 1-probenyl] Ethyl sulfamoyl acetate dihydrochloride

N- [3- (3-Amidino-5-methylphenyl) -l- (E) -l-probenyl] -lN- [4- (piperidine-l-l-yloxy) phenyl] obtained in Production Example 111 (a) Ethyl rufamoyl acetate dihydrochloride (800 mg) is dissolved in ethanol (25 ml), and ethyl acetimidate hydrochloride (1400 mg) and triethylamine (2.2 ml) are added at room temperature, followed by stirring at the same temperature for 27 hours. did. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetate nitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride in ethyl acetate solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was suspended in ethyl acetate and collected by filtration to obtain 400 mg (yield 41%) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.70 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 3.45-3.65 (2H, m), 3.65-3.95 (2H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 5.5), 4.71 (1H, m), 6.41 (1H, dt, J = 16.0, 5.5), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.56 (Total 2H, each s), 7.70 (1H, s);

IR (KBr, cm ' ¹ ): 1738, 1672, 1625. Production example 112

N- [4-((1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -N- [3- (3-amidino-5-methylphenyl) 1-2- (E) -propionyl] sulfamoyl Acetic acid dihydrochloride

N— [4- (1-acetoimidoylpiperidine-1_4-yloxy) phenyl] -1-N— [3- (3-amidinol 5-methylphenyl) 1-2— (E) obtained in Production Example 111 [1 Probenyl] sulfamoyl acetate ethyl dihydrochloride (200 mg) was dissolved in IN hydrochloric acid (8 ml) and stirred at 80 ° C for 8 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in water, 4N hydrogen chloride acetate solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 11 Omg (57% yield) of the title compound. Obtained as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) 6 ppm: 1.60-1.85 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 3.40-3.65 (2H, m), 3.65-3.95 (2H, m), 4.20 (2H, s), 4.44 (2H, d, J = 5.0), 4.70 (1H, m), 6.41 (1H, dt, J = 16.0, 5.0), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.55 (total 2H, each s), 7.69 (1H, s);

MS (FAB, m / z): 528 (M + H-2HC1 production example 113

N- [4 -— (1-acetoimidoylpiperidin-1-41-yloxy) phenyl] —N— “3- (3- (amidino-4-fluorophenyl) -2- (E) -propionyl] sulfamoyl Ethyl acetate dihydrochloride

(a) N— [3 -— (3-Amidino 4-fluorophenyl) —2 -— (E) —probenyl] —N— [4-1- (piperidine—4-yloxy) phenyl] sulfamoyl acetate H Dihydrochloride

N- [4-((1-t-butoxycarbonylbiperidine-1-4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) 1-2- (E) -1 obtained in Reference Example 150 [Propenyl] sulfamoyl acetate ethyl (153 Omg) was dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (2 Oml), aqueous ammonium chloride solution (20 Omg dissolved in 4 ml of water) and 28% aqueous ammonia (0.50 ml) were added, and the mixture was added at room temperature. -I left it. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water) to give 55 Omg of the title compound (yield 41%). %) Was obtained as a colorless amorphous solid-1.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.75-1.95 (2H, m), 2.00-2.20 (2H, m), 2.95-3.15 (2H, m ), 3.15-3.30 (2H, m), 4.19 (2H, q, J = 7.0), 4.33 (2H, s), 4.42 (2H, d, J = 6.0), 4.65 (1H, m), 6.35 (IH , dt, J = 16.0, 6.0), 6.53 (1H, d, J = 16.0), 7.03 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.42 (IH, m), 7.73 (2H, m);

IR (KBr, cm- ¹ ): 1737, 1677.

(b) N— [4- (1-acetoimidoylpiperidine-1_4-yloxy) phenyl] -N- [3 -— (3-amidinol-4-fluorophenyl) —2 -— (E) monopropenyl ] Sulfamoyl acetate ethyl dihydrochloride

N- [3- (3- (amidino-4-fluorophenyl) -l- (E) -l-propenyl] -N- [4- (piperidine-l- 4-isoleoxy) phenyl) obtained in Production Example 113 (a) Ethyl sulfamoyl acetate dihydrochloride (35 Omg) was dissolved in ethanol (14 ml), ethyl acetimidate hydrochloride (16 Omg) and triethylamine (0.36 ml) were added at room temperature. Stirred for hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (8 ml), and 4N hydrogen chloride acetate was added. A chilled solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 279 mg (yield 65%) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.73 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.40-3.65 ( 2H, m), 3.65-3.90 (2H, m), 4.19 (2H, q, J = 7.0), 4.33 (2H, s), 4.42 (2H, d, J = 5.5), 4.71 (1H, m), 6.35 (1H, dt, J = 16.0, 5.5), 6.54 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.40 (1H, m), 7.73 (2H, m);

IR (KBr, cm- ¹ ): 1738, 1675, 1618. Production Example 1 14

N— [4 -— (1-acetoimidoylpiperidine—4-yloxy) phenyl] -1-N— [3- (3-amidinofenyl) —2 -— (E) -probenyl] acetamide dihydrochloride

(a) N— [3 -— (3-amidinofenyl) -1-2 -— (E) 1-probenyl] —N— [4-1— (piperidine-141-yloxy) phenyl] acetoamide dihydrochloride

Reference Example 1 N— [4- (1-t-butoxycarbonylbiperidine—4-yloxy) phenyl] —N— [3- (3-cyanophenyl) —2- (E) probe obtained from 56 Acetamide (1 + 203 mg) was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (3 Oml), passed through hydrogen chloride under ice cooling, sealed, and stirred at room temperature for 7 hours. . After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), and an aqueous solution of ammonium chloride (27 lmg dissolved in 25 ml of water) and 28% aqueous ammonia (0.5 1 ml) were added. Then, it was left at room temperature for 12 hours. A 4 N hydrogen chloride dioxane solution (1.5 Oml) was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was separated by HPLC (YMC-PackODS-A; YMC, elution solvent: 13% acetonitrile / water) Was purified. The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (1.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 8553 mg (yield 72%) of the title compound as a pale yellow amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.78 (3H, s), 1.83 (2H, m), 2.11 (2H, m), 2.90-3.30 (4H, m), 4.39 (2H, m), 4.50-4.80 (IH, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J = 9.0), 7.28 (2H, d , J = 9.0), 7.55 (1H, t, J = 7.5), 7.71 (IH, d, J = 7.5), 7.73 (IH, d, J = 7.5), 7.94 (IH, s);

I (KBr, cm ' ¹ ): 1675, 1626.

(b) N- [4- (1-acetimidoylpiperidin-1-41-yloxy) phenyl] -N- [3- (3-amidinophenyl) -12- (E) -probenyl] acetamide 2 hydrochloride salt

Production Example 1 N— [3 -— (3-amidinofenyl) —2 -— (E) —propenyl) —N— [4- (piperidine—4-yloxy) phenyl] acetamide obtained in 14 (a) 2 hydrochloride The salt (40 Omg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (32 Omg) and triethylamine (0.60 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, concentrate under reduced pressure, and concentrate the residue with preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile water). Purified. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 342 mg (yield 79%) of the title compound as a colorless amorphous solid.

^X H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.74 (2H, m), 1.78 (3H, s), 2.04 (2H, m), 2.31 (3H, s), 3.45-3.95 (4H, m ), 4.39 (2H, m), 4.60-4.80 (IH, m), 6.40-6.60 (2H, m), 7.05 (2H, d, J = 8.5), 7.28 (2H, d, J = 8.5), 7.55 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.95 (1H, s);

IR (KBr, cm- ¹ ): 1672, 1624. Production example 1 15

N— [4- (1-Acetimidoylpiperidine_4_yloxy) phenyl] 1 N— “3- (3-Amidinophenyl) -2- (E) —Probenyl] —2-Hydroxyacet Amide dihydrochloride (a) N- [3- (3-Amidinophenyl) -1-2- (E) -probenyl] -1-N- [4-1- (piperidine-4-yloxy) phenyl] -12-hydroxyacetamide dihydrochloride 簠

N— [4 -— (1-t-butoxycarbonylpiperidine-14-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) -2- (E) 1-probenyl obtained in Reference Example 157 12-Hydroxyacetoamide (977 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the mixture was capped, and the mixture was stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of sodium chloride (213 mg dissolved in 10 ml of water) and 28% aqueous ammonia (.0.40 ml) were added. And left for 12 hours. To the reaction mixture was added 4N Shiojiri hydrogen dioxane solution (1 ml), and the mixture was concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 11% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), and a 4N hydrogen chloride dioxane solution was added.

(0.5 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to obtain 685 mg (yield 72%) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) d ppm: 1.84 (2H, m), 2.10 (2H, m), 2.90-3.80 (6H, m), 4.36 (2H, m), 4.65 (1H, m) , 6.50 (2H, m), 7.03 (2H, d, J = 8.5), 7.28 (2H, d, J = 8.5), 7.55 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.92 (1H, s);

IR (Br, cm- ¹ ): 1673.

(b) N- [4 -— (1-acetimidoylpiperidine-1-4-yloxy) phenyl] -N- [3- (3-amidinofenyl) -1-2- (E) —probenyl] —2— Hydroxyacetamide dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) -propidinyl] -N- [4- (piperidine-141-yloxy) phenyl] -12-hydroxy obtained in Production Example 115 (a) Dissolve ciacetamide dihydrochloride (385 mg) in methanol (20 ml), After adding ethyl acetimidate hydrochloride (30 Omg) and triethylamine (0.56 ml), the mixture was stirred at the same temperature for 12 hours. After adding 4N hydrogen chloride dioxane solution (lm'1) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 14% acetonitrile water). Purified. The obtained amorphous solid was dissolved in methanol (1 Oml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 36 mg (yield 80%) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) <5 ppm: 1.73 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.30-3.90 (6H, m), 4.39 (2H, m) ), 4.69 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J = 9.0), 7.28 (2H, d, J = 9.0), 7.55 (IH, t, J = 8.0) , 7.65-7.80 (2H, m), 7.93 (IH, s);

IR (KBr, cm- ¹ ): 1671. Production example 116

3— [3— [N— [4- (1-acetoimidoylpiperidine-1 4-yloxy) phenyl] -1-N-benzylamino] 1-1-1 (E) —probenyl] benzamidine trihydrochloride

(a) 3— [3— [N—benzylyl N— [4- (piperidin-4-yloxy) phenyl] amino] -111 (E) —probenyl] benzamidine trihydrochloride

3- (3- [N-benzyl-N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] amino] 1-1- (E) obtained in Reference Example 155 Benzonitrile (916 mg) was dissolved in a mixed solvent of dichloromethane (3 Oml) and ethanol (15 ml), and after passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (187 mg dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.46 ml) were added, and the mixture was added at room temperature. Left for hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography [Cosmosil (registered trademark) 75C18-PREP; Nacalai Tesque, elution solvent: 5% acetonitrile / water) Was purified. The obtained amorphous solid was dissolved in methanol (10 ml), and 4 After addition of N hydrogen chloride dioxane solution (0.50 ml), the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 58 lmg (yield 60%) of the title compound as a pale brown amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.78 (2H, m), 2.03 (2H, m), 2.98 (2H, m), 3.15 (2H, m), 4.35 (2H, m), 4.50 (IH, m), 4.76 (2H, m), 6.61 (IH, dt, J = 16.0, 6.5), 6.70 (1H, d, J = 16.0), 6.93 (2H, m), 7.20-7.35 (3H, m), 7.35-7.50 (4H, m), 7.57 (IH, t, J = 8.0), 7.70 (1H, d, J = 8.0) _? 7.73 (1H, d, J = 8.0), 7.89 (1H, s );

IR (KBr, cm- ¹ ): 1675.

(b) 3— [3— [N- [4-1 (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -1-N-benzylamino] -1- (E) —pronenyl] benzamidine _3 salt

• 3— [3 -— [N—benzyl-N—L4- (piperidine-141-yloxy) phenyl] amino] -111 (E) -probenyl] benzamidine trihydrochloride obtained in 16 (a) 335 mg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (230 mg) and triethylamine (0.51 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. To the reaction solution was added 4N salt / hydrogen dioxane solution (1 ml), and the mixture was concentrated under reduced pressure, and the residue was collected by preparative separation. Was purified. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 252 mg (yield 70%) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.50-1.75 (2H, m), 1.96 (2H, m), 2.29 (3H, s), 3.40 -3.90 (4H, m), 4.40 (2H, m), 4.50-4.90 (3H, m), 6.63 (IH, dt, J = 16.0, 6.0), 6.74 (IH, d, J = 16.0), 6.97 (2H, d, J = 8.5), 7.15-7.30 (3H, m), 7.40-7.60 (4H, m), 7.56 (IH, t, J = 7.5), 7.66 (1Ή, d, J = 7.5), 7.77 (1H, d, J = 7.5), 7.92 ( 1H, s);

IR (KBr, cm- ¹ ): 1672, 1624. Production Example 117

3- [3- [N— [4- (1-Acetamimidoylpiperidine-4-1yloxy) phenyl] amino] 111 (E) —Probenyl] benzamidine trihydrochloride

(a) 3-C3-CN- [4- (piperidin-1-yloxy) phenyl] amino] — 1— (E) 1-propenyl] benzamidine trihydrochloride

3- [3- [N- [4-1- (1-t-butoxycarpenylpyridine-41-yloxy) phenyl] amino] -1-amino (-1-propenyl) benzonitryl obtained in Reference Example 151 (90 Omg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride solution (222 mg dissolved in 1 Om1 of water) and 28% aqueous ammonia (0.54 ml) were added, and the mixture was added at room temperature. Left for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, it is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water) did. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 735 mg (yield 77%) of the title compound. Obtained as a yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.82 (2H, m), 2.05 (2H, m), 3.03 (2H, m), 3.20 (2H, m), 3.95-4.10 (2H, m) , 4.50-4.65 (1H, m), 6.55 (1H, dt, J = 16.0, 6.5),

6.79 (1H, d, J = 16.0), 7.05 (2H, m), 7.20-7.45 (2H, m), 7.61 (1H, t, J = 8.0), 7.70-

7.80 (2H, m), 7.87 (1H, s);

IR (KBr, cm ' ¹ ): 1675.

(b) 3— [3— [N— [4- (1_acetoimidoylpiperidin-1-41-yloxy) phenyl] amino] -111 (E) —propenyl] benzamidine trihydrochloride

3- (3- [N- [4- (piperidine-14-yloxy) phenyl] amino] -111 (E) -probenyl] benzamidine trihydrochloride obtained in Production Example 117 (a) (34 5 mg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (185 mg) and triethylamine (0.52 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile aqueous solution). . The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 272 mg (yield 72%) of the title compound as a yellow amorphous solid. '

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.73 (2H, m), 2.05 (2H, m), 2.30 (S, 3H), 3.40-3.95 (4H, m), 4.06 (2H, d, J = 6.5), 4.69 (1H, m), 6.56 (IH, dt, J = 16.0, 6.5), 6.80 (IH, d, J = 16.0), 7.10 (2H, d, J = 9.0), 7.35-7.55 (2H, m), 7.60 (IH, t, J = 8.0), 7.70-7.80 (2H, m), 7.87 (IH, s);

IR (KBr, cm- ¹ ): 1672, 1625. Production example 118

3— [3— [N— [4- (1-Acetoimidoylpiperidine—4-yloxy) phenyl] -1-N-isopropylamino] 1-1— (E) —Probenyl] benzamidine trisalt

(a) 3- [3- [N-isopropyl-N- [4- (piperidine-4-yloxy) phenyl] amino] — 1- (E) -probenyl] benzamidine trihydrochloride

3- [3- [N-4-1 (11-t-butoxycarbylbiperidine) -4- (phenyloxy) phenyl-N-isopropylamino] -11 (E) -prodini obtained in Reference Example 154 ] Benzonitrile (705 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through with hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (159 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.39 ml) were added, followed by 12 hours at room temperature. I left it. Add 4 N hydrogen chloride dioxane to the reaction mixture After adding the solution (1 ml), the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 570 mg (yield 70%) of the title compound as a pale brown amorphous solid.

1H belly R (270 MHz, DMSO-d ₆ ) δ ppm: 1.16 (3H, m), 1.40 (3H, m), 1.82 (2H, m), 2.07 (2H, m), 3.03 (2H, m), 3.18 (2H, m), 3.98 (1H, m), 4.41 (2H, m), 4.68 (1H, m), 6.40 (1H, m), 6.72 (1H, d, J = 16.0), 7.13 (2H, m m), 7.50-7.65 (2H, m), 7.70-7.85 (4H, m);

IR (KBr, cm- ¹ ): 1675.

(b) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -probenyl] benzamidine 3 3- [3- [N-isopropyl-1-N- [4- (piperidin-41-yloxy) phenyl] amino] -111 (E) -probenyl] benzamidine obtained in Production Example 118 (a) Trihydrochloride (310 mg) was dissolved in methanol (20 ml), and ethyl acetate imidate hydrochloride (229 mg) and triethylamine (0.52 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water) . The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 259 mg (yield 77%) of the title compound as a pale brown amorphous solid.

Marauder R (270 MHz, DMSO-d ₆ ) 5 ppm: 1.17 (3H, d, J = 6.0), 1.43 (3H, d, J = 6.0), 1.70 (2H, m), 2.04 (2H, m), 2.31 (3H, s), 3.45-4.05 (5H, m), 4.41 (2H, m), 4.74 (1H, m), 6.42 (1H, dt, J = 16.0, 7.0), 6.73 (1H, d, J = 16.0), 7.15 (2H, d, J = 8.5), 7.50-7.65 (2H, m), 7.70-7.90 (4H, m); IR (KBr, cm " ¹ ): 1672, 1623. Production example 1 19

2— [N— [4- (1-acetoimidoylpiperidine—4-yloxy) phenyl] -1-N— [3- (3-amidinophenyl) -1-2- (E) -propionyl] amino Ethyl trihydrochloride

(a) 2— [N— [3 -— (3-amidinofenyl) -1-2- (E) —probenyl] -1-N— [4- (piperidine—4-yloxy) phenyl] amino] ethyl acetate trihydrochloride Reference 2- [N— [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) 1-2— (E) —P obtained from Example 158 [Nyl] amino] ethyl acetate (1305 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and the solution was stirred under ice-cooling, passed through hydrogen chloride, sealed, and stirred at room temperature for 7 hours. . After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (269 mg dissolved in 10 ml of water) and 28% ammonia water (0.66 ml) were added. I left it. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile water). . The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 652 mg (yield 48%) of the title compound as a pale yellow amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) d ppm: 1.18 (3H, t, J = 7.0), 1.80 (2H, m), 2.04 (2H, m), 3.00 (2H, m), 3.17 (2H, m), 4.11 (2H, q, J = 7.0), 4.10-4.20 (4H, m), 4.42 (IH, m), 6.55 (1H, dt, J = 16.0, 5.0), 6.65 (2H, d, = 9.0), 6.67 (IH, d, J = 16.0), 6.87 (2H, d, J = 9.0), 7.56 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.91 (1H, s );

IR (KBr, cm- ¹ ): 1747, 1675.

(b) 2- [N— [4 -— (1-acetimidoylpiperidine-1-yloxy) -phene Nyl] _N_ [3- (3-amidinofenyl) 1 2— (E) 1-propionyl] amino] ethyl ethyl acetate trihydrochloride

Production Example 1 2- [N- [3- (3-amidinofenyl) -l- (E) -l-propenyl] obtained in 19 (a) -N- [4- (piperidine-l-yloxy) phenyl] [Amino] Ethyl acetate trihydrochloride (40 Omg) was dissolved in methanol (20 ml), ethyl acetimidate hydrochloride (27 Omg) and triethylamine (0.61 ml) were added at room temperature, and then stirred at the same temperature for 12 hours. . After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 24% acetonitrile / water) did. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (35 Omg, yield 81%) as a pale-yellow amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.18 (3H, t, J = 7.0), 1.70 (2H, m), 1.99 (2H, m), 2.31 (3H, s), 3.45-3.85 ( 4H, m), 4.11 (2H, q, J = 7.0), 4.15-4.25 (4H, m), 4.48 (1H, m), 6.56 (1H, dt, J = 16.0, 4.5), 6.66 (2H, d , J = 9.0), 6.67 (1H, d, J = 16.0), 6.88 (2H, d, J = 9.0), 7.56 (1H, t, J = 8.0), 7.65-7.80 (2H, m), 7.92 ( 1H, s);

IR (KBr, cirr ¹ ): 1747, 1672, 1623. Production example 120

3— [3— [N— [4- (1-Acetimidoylpiperidine—4-yloxy) phenyl] -1-N-ethylamino] —1- (E) —Probenyl] benzamidine trihydrochloride

(a) 3- [3- [N-ethyl-N- [4- (piperidine- 4-yloxy) phenyl] amino] -111 (E) -probenil] benzamidine trihydrochloride

3- [3- [N- [4- (1-t-butoxycarpenylpyridin-1-4-yloxy) phenyl] -1-N-ethylamino] —1- (E) 1-propenyl obtained in Reference Example 153 ] Benzonitrile (77 Omg) was added to dichloromethane (30 ml) and ethanol (15 m

Dissolve in the mixed solvent of 1), pass hydrogen chloride under ice-cooling, stopper tightly and stir at room temperature for 7 hours did. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (178 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.44 ml) were added. Then, it was left at room temperature for 12 hours. Add 4 N hydrogen chloride dioxane solution to the reaction mixture

After adding (lm 1), the mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid is methanol

(10 ml), 4 N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 570 mg (70% yield) of the title compound as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.07 (3H, t, J = 7.0), 1.83 (2H, m), 2.10 (2H, m), 2.95-3.25 (4H, m), 3.60 ( 2H, m), 4.30 (2H, m), 4.69 (1H, m), 6.48 (1H, dt, J = 16.0, 7.0), 6.72 (1H, d, J = 16.0), 7.15 (2H, d, J = 8.5), 7.56 (1H, t, J = 7.5), 7.66 (1H, d, J = 7.5), 7.70-8.00 (4H, m);

IR (KBr, cm ¹ ): 1675.

(b) 3- [3- [N- [4-I- (1-acetoimidoylpiperidine- 14-yloxy) phenyl] -N-ethylamino] -111 (E) -probenyl] benzamidine 3HCl Son

Preparation Example 1 3- [3- [N-Ethyl-N- [4-((piperidine-1 4-yloxy) phenyl] amino]-1-(E) 1-probe] benzamidine obtained in 20 (a) 3 Hydrochloride (420 mg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (319 mg) and triethylamine (0.72 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (lm l) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 20% aqueous acetonitrile). Purified. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.5 Oml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 287 mg (yield 63%) of the title compound as a colorless amorphous solid. '

^X H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.09 (3H, t, J = 7.0), 1.71 (2H, m), 2.03 (2H, m), 2.32 (3H, s), 3.50-3.95 (6H, m), 4.30 (2H, m), 4.75 (1H, m), 6.49 (IH, dt, J = 16.0, 6.5), 6 , 73 (IH, d, J = 16.0), 7.00-7.30 (2H, m), 7.58 (1H, t, J = 7.5), 7.67 (IH, d, J = 7.5), 7.75-7.90 (4H, m );

IR (KBr, cm " ¹ ): 1673, 1623. Production Example 121

N- [4- (1-acetoimidoylpyrrolidine-1-3-yloxy) phenyl] — N_ [3- (3-amidinofenyl) —2- (E) monopropenyl] ethyl sulfamoyl acetate dihydrochloride

(a) N- [3- (3-amidinophenyl) -1- (E) -probenyl] — N— [4- (pyrrolidine-13-yloxy) phenyl] sulfamoylacetate diethyl hydrochloride obtained in Reference Example 160 N- [4- (1-t-butoxycarbonylpyrrolidine-3-yloxy) phenyl] -N- [3- (3-cyanophenyl) 1-2- (E) 1-probe] sulfamoyl acetate (2349mg ) Was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (30 ml), hydrogen chloride was passed under ice-cooling, and the mixture was sealed and stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (100 ml), and an aqueous solution of ammonium chloride (44 Omg dissolved in 5 Om1 of water) and 28% aqueous ammonia (0.83 ml) were added. It was left at room temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (2 ml) to the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by preparative HP LC

(YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), and 4N hydrogen chloride in dioxane was added.

(0.50 ml), and concentrated to dryness under reduced pressure to give the title compound (272 mg, yield 12%) as a colorless amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 2.05-2.25 (2H, m), 3.15-3.50 (4H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 5.5), 5.12 (1H, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.56 (1H, d, J = 16.0), 7.01 (2H, d, J = 9.0), 7.42 (2H, d, J = 9.0), 7.54 (IH, t, J = 8.0), 7.65-7.75 (2H, m), 7.90 (1H, s ); IR (KBr, cnr ¹ ): 1737, 1675.

(b) N— [4 -— (1-acetoimidoylpyrrolidine-1-3-yloxy) phenyl] -N- [3- (3-amidinofenyl) —2_ (E) 1-probenyl] ethyl ethyl sulfamoyl acetate salt

N- [3- (3-Amidinophenyl) -l- (E) -l-propenyl] obtained in Production Example 121 (a) -N- [4-((pyrrolidine-l-l ^^-fluoro) phenyl] sulfamoyl acetic acid Ethyl dihydrochloride (400 mg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (35 Omg) and triethylamine (0.50 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. . After adding 4 N hydrogen chloride dioxane solution (lm 1) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC solvent: 20% acetonitrile / water) did. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 55 mg (yield 59%) of the title compound 2 as a colorless amorphous solid.

NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 2.10-2.30 (2H, m), 2.26 and 2.29 (total 3H, each s), 3.40-4.05 (4H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 5.5), 5.10-5.30 (1H, m), 6.44 (1H, dt, J = 16.0 , 5.5), 6.56 (1H, d, J = 16.0), 7.01 and 7.02 (total 2H, d, J = 9.0), 7.42 and 7.43 (total 2H, d, J = 9.0), 7.54 (1H, t , J = 7.5), 7.65-7.75 (2H, m), 7.91 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1672, 1629. Production example 122

2— [N— [4 -— (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -N- [3 -— (3-amidinofenyl) -2 -— (E) 1-probenyl] amino Ethyl acid trihydrochloride

(a) 2 -— [N—— “3- (3-amidinofenyl)-2-(E) —probenyl] —— N [4- (Piperidine-4-yloxy) phenyl] _amino] _ethyl propionate 3 Reference example 1 2- [N- [4- (1-t-butoxycarbonylpiperidine 1-4-yloxy) obtained in 9) [Phenyl] -N- [3- (3-cyanophenyl) -2- (E) propionyl] amino] Ethyl propionate (88 2 mg) mixed with dichloromethane (30 ml) and ethanol (15 ml) After dissolving in a solvent and passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (177 mg was dissolved in 10 ml of water) and 28% aqueous ammonia (0.43 ml) were added. Then, it was left at room temperature for 12 hours. After adding 4N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was collected by HP LC

(YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), and 4N hydrogen chloride in dioxane was added.

(0.50 ml), and concentrated to dryness under reduced pressure to give 84 mg of the title compound and 20 Omg of the title compound of low purity (yield 41% or more) as brown amorphous solids, respectively. .

Video R (500 MHz, DMSO-d ₆ ) δ ppm: 1.16 (3H, t, J = 7.0), 1.44 (3H, d, J = 7.0), 1.78 (2H, m), 2.04 (2H, m) , 3.01 (2H, m), 3.18 (2H, m), 4.09 (2H, q, J = 7.0), 3.96-4.15 (2H, m), 4.42 (1H, m), 4.55 (1H, q, J = 7.0), 6.55 (1H, dt, J = 16.0, 4.5), 6.64 (1H, d, J = 16.0), 6.72 (2H, d, J = 8.5), 6.86 (2H, d, J = 8.5), 7.54 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, cm- ¹ ): 1745, 1681.

(b) 2— [N— [4 -— (1-acetimidoylpiperidine—4-yloxy) phenyl] —N— [3 -— (3-amidinofenyl) —2 -— (E) —probenyl ] Amino] ethyl propionate trihydrochloride

Production Example 1 2- [N- [3- (3-amidinofenyl) -l- (E) -l-propenyl] -l-N- [4- (piperidine-l-l-yloxy) phenyl] obtained in 22 (a) Dissolve the mixture (544 mg) containing ethyl ethyl propionate trihydrochloride in methanol (30 ml). After dissolving, at room temperature, ethyl acetimidate hydrochloride (360 mg) and triethylamine (0.81 ml) were added, and the mixture was stirred at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). Purified. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound (468 mg, yield 47% in two steps) as a pale-brown amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.15 (3H, t, J = 7.0), 1.45 (3H, d, J = 7.0), 1.68 (2H, m), 1.98 (2H, m), 2.29 (3H, s), 3.45-3.60 (2H, m), 3.65-3.85 (2H, m), 4.09 (2H, q, J = 7.0), 3.95-4.20 (2H, m), 4.49 (1H, m ), 4.56 (1H, q, J = 7.0), 6.56 (1H, dt, J = 16.0, 4.5), 6.64 (1H, d, J = 16.0), 6.76 (2H, d, J = 9.0), 6.87 ( 2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s);

IR (KBr, cm- ¹ ): 1745, 1673, 1623. Production Example 123

3— [3— [N— [4- (1-Acetoimidoylpiperidine-1-41-yloxy) phenyl] -1-N-methylamino] —1-1 (E) —Probenyl] benzamidine trihydrochloride

(a) 3- [3- [N-methyl-N- [4- (piperidine-141-yloxy) phenyl] amino] _1-1 (E) -probenyl] benzamidine trihydrochloride

3- [3- [N-4-((1-t-butoxycarbonylpiperidin-1-41-yloxy) phenyl) N-methylamino] -11- (E) -propionyl] obtained in Reference Example 152 Benzonitrile (76 lmg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed through under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride (18 lmg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.44 ml) were added. Left for 12 hours. Add 4 N hydrogen chloride dioxane solution (lm

After adding 1), concentrate under reduced pressure, and collect the residue by preparative HP LC (YMC-Pack ODS-A; YMC, Solvent: 8% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (1 Oml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (401 mg, yield 50%). Was obtained as a yellow amorphous solid.

1H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.83 (2H, m), 2.08 (2H, m), 2.95-3.25 (7H, m), 4.22 (2H, m), 4.60 (IH, m) , 6.49 (IH, dt, J = 16.0, 6.5), 6.71 (IH, d, J = 16.0), 6.90-7.90 (8H, m);

IR (KBr, cm- ¹ ): 1675.

(b) 3- [3- [N- [4- (1-acetoimidoylpiperidine-1-41-yloxy) phenyl] -1-N-methylamino] —1- (E) —probenyl] benzamidine 3HCl Son

3- [3- [N-Methyl-N- [4- (piperidine-141-yloxy) phenyl] amino] -111 (E) -probenyl] benzamidine 3-hydrochloride obtained in Production Example 123 (a) (368 mg) was dissolved in methanol (20 ml), and ethyl acetimidate hydrochloride (290 mg) and triethylamine (0.65 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, it is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% acetonitrile / water) did. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 288 mg (yield 72%) of the title compound as a pale brown amorphous solid.

¾ NMR (270 MHz, DMSO-d ₆ ) δ ppm: 1.71 (2H, m), 2.02 (2H, m), 2.31 (3H, s), 3.13 (3H, s), 3.40-3.70 (4H, m) , 4.29 (2H, d, J = 7.0), 4.75 (IH, m), 6.50 (1H, dt, J = 16.0, 7.0), 6.76 (IH, d, J-16.0), 7.15 (2H, d, J = 9.0), 7.58 (IH, t, J = 7.5), 7.69 (1H, d, J = 7.5), 7.70-7.85 (3H, m), 7.92 (IH, s);

IR (KBr, cnr ¹ ): 1672, 1625. Production Example 124

3 -— [3- [N- [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) phenyl] -1-N— (2-hydroxyethyl) amino] 1-11 (E) Nil] benzamidine trihydrochloride

(a) 3- [3-CN- (2-hydroxyethyl) -1-N- [4- (piperidine-1-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine 3HCl

3- [3- [N- [4- (1-t-butoxycarpenylpyridin-1-4-yloxy) phenyl] -1N- (2-hydroxyethyl) amino-1-1 obtained in Reference Example 161

(E) Propenyl] benzonitrile (1098 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 6 hours. . Reaction: After concentrating the solution under reduced pressure, the residue was ethanol (20m

The mixture was dissolved in 1), an aqueous solution of ammonium chloride (246 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.6 Oml) were added, and the mixture was left at room temperature for 12 hours. After adding 4 N hydrogen chloride dioxane solution (lml) to the reaction mixture, the mixture was concentrated under reduced pressure.

(YMC-Pack ODS-A; YMC, elution solvent: 12% aqueous acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), and 4N hydrogen chloride in dioxane was added.

(0.5 Oml) and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to obtain 555 mg (yield 48%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.82 (2H, m), 2.07 (2H, m), 3.03 (2H, m), 3.18 (2H, m), 3.54 (2H, m), 3.60 (2H, m), 4.31 (2H, m), 4.62 (IH, m), 6.48 (1H, dt, J = 16.0, 6.5), 6.69 (IH, d, J = 16.0), 7.08 (2H, m) , 7.50 (2H, m), 7.58 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s);

IR (KBr, crrr ¹ ): 1676.

(b) 3— [3— [N —— [4— (1-acetimidoylpiperidine-1_4-yloxy) [Phenyl] -N- (2-hydroxyethyl) amino] — 1- (E) -probenyl] benzamidine trihydrochloride

3- (3- [N- (2-hydroxyethyl) -1-N- [4- (piperidine-1 4-yloxy) phenyl] amino] 1-1-1 (E) obtained in Production Example 124 (a) Benzyl] benzamidine trihydrochloride (295 mg) was dissolved in methanol (20 ml), and ethylacetimidate hydrochloride (362 mg) and triethylamine (0.41 ml) were added at room temperature. Stirred for hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 16% acetonitrile Z water) did. The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 175 mg (yield 55%) of the title compound as a pale yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.71 (2H, m), 2.03 (2H, m), 2.31 (3H, s), 3.40-4.00 (8H, m), 4.32 (2H, m) , 4.67 (IH, m), 6.50 (1H, dt, J = 16.0, 6.5), 6.70 (1H, d, 16.0), 7.08 (2H, m), 7.50 (2H, m), 7.58 (IH, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.75 (IH, d, J = 8.0), 7.89 (1H, s);

IR (KBr, cm ¹ ): 1673, 1626. Production Example 125

N— [4 -— (1-Acetimidoylpiperidine—4-yloxy) —3-ethoxyethoxyponylphenyl] —N— [3- (3-Amidinophenyl) 1-2- (E) -propionyl] sulfamoylacetic acid Ethyl dihydrochloride

(a) N- [3- (3-amidinofenyl) —2- (E) 1-propenyl] 1-N— [3-ethoxycarbonyl-4-1 (piperidine-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [4- (1-t-butoxycarbonylbiperidine—41-yloxy) -13-ethoxycarboephenyl] —N— [3 -— (3-cyanophenyl) obtained in Reference Example 164 —2— (E) —Probenyl] Sulfamoyl acetate ethyl (2.45 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), and after passing through hydrogen chloride under ice-cooling. The mixture was sealed and stirred at room temperature for 4.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (0.44 g was dissolved in 5 ml of water) and 28% aqueous ammonia (1.00 ml) were added, and the mixture was added at room temperature for 30 minutes. After stirring, the mixture was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride acetate solution (1.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.41 g of the title compound (yield). 58%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.29 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H , m), 3.05-3.40 (4H, m), 4.19 (2H, q, = 7.0), 4.28 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0 ), 4.86 (IH, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.55 (IH, m), 7.61 (IH , m), 7.65-7.80 (3H, m), 7.89 (IH, m);

IR (KBr, cm " ¹ ): 1729, 1676.

(b) N— [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) —3-ethoxycarbonylphenyl] -1-N— [3- (3-Amidinophenyl) 1-2— (E) — Probenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) —propenyl) obtained in Production Example 125 (a) —N— [3-ethoxycarbinyl 4- (piperidine—4-yloxy) Phenyl] sulfamoyl acetate diethyl hydrochloride (1.24 g) in ethanol (20 m

1), ethylethylacetimidate hydrochloride (0.72 g) and triethylamine (1.70 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes and left to stand for 15 hours. After concentrating the reaction solution under reduced pressure, the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent:

(22% acetonitrile in water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (1.30 ml) was added, and the mixture was concentrated under reduced pressure to dryness. By solidification, 1.01 g (yield 76%) of the title compound was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.27 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 1.95-2.10 (2H , m), 2.31 (3H, s), 3.60-3.70 (3H, m), 3.70-3.80 (1H, m), 4.19 (2H, q, J = 7.0), 4.26 (2H, q, J = 7.0) , 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.90 (IH, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.32 (IH, m), 7.55 (1H, m), 7.62 (IH, m), 7.65-7.70 (3H, m), 7.90 (IH, m);

IR (KBr, cm- ¹ ): 1730, 1673, 1624. Production example 126 '

N— [4_ (1-acetoimidoylpiperidine—4-yloxy) -13-potoxyphenyl] N— [3- (3-amidinofenyl) -2- (E) probenyl] sulfamoylacetic acid 2 Hydrochloride

N_ [4 -— (1-acetoimidoylpiperidine—41-yloxy) -3-3-ethoxycarponylphenyl] —N— [3- (3-amidinofenyl) obtained in Production Example 125 (b) _2— (E) —probenil] Sulfamoyl acetate ethyl dihydrochloride (0.30 g) was dissolved in 3N hydrochloric acid (6 ml) and stirred at 8 Ot for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.1 Om 1) and concentrated to dryness under reduced pressure to give 0.22 g (yield 79%) of the title compound as a colorless amorphous solid. Was.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.75-1.90 (2H, m), 1.90-2.10 (2H, m), 2.29 (3H, s), 3.55-3.75 (4H, m), 4.26 ( 2H, s), 4.47 (2H, d, J = 6.0), 4.87 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (IH, d, J = 16.0), 7.28 (1H , M), 7.50-7.65 (2H, m), 7.65-7.80 (3H, m), 7.86 (IH, m);

IR (KBr, cm-: 1726, 1673, 1627. Production example 127 N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) —3-bromophenyl] —N— [3- (3-amidinofenyl) —2 -— (E) 1-propenyl] sulfamo Ethyl acetate dihydrochloride

(a) N— [3 -— (3-amidinofenyl) —2— (E) monoprodenyl] — N— [3-promo 4 _ (piperidine-4 _yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3-Bromo-4-1 (1-1t-butoxycarboxylpyridine-1-41-yloxy) phenyl] obtained in Reference Example 168—N— [3- (3-Cyanophenyl) 1-2- (E) [Propenyl] ethyl sulfamoylacetate (2.20 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 5 hours. did. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (0.40 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.90 ml) were added. After stirring for 30 minutes, the mixture was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 22% acetonitrile water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride in ethyl acetate (1.70 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (1.34 g, (61% yield) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.20 (4H, m ), 4.20 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.44 (IH, dt, J = 16.0, 6.0) , 6.58 (IH, d, J = 16.0), 7.27 (1H, m), 7.45 (1H, m), 7.55 (IH, m), 7.65-7.80 (3H, m), 7.90 (1H, m);

IR (KBr, cm ¹ ): 1737, 1675.

(b) N— [4 -— (1-Acetamimidoylpiperidine-1-4-yloxy) -1-3-promophenyl] —N— [3— (3-Amidinophenyl) —2 -— (E) —Probe Nyl] 'Sulfamoyl acetate ethyl 2-hydrochloride N- [3- (3-Amidinophenyl) -l- (E) -propenyl] -N- [3-bromo-41- (piperidine-l-yloxy) phenyl] obtained in Production Example 127 (a) Ethyl rufamoyl acetate dihydrochloride (1.17 g) was dissolved in ethanol (30 ml), and ethyl acetimidate hydrochloride (0.67 g) and triethylamine (1.50 ml) were added under ice-cooling. After stirring for 2 hours, the mixture was left for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (1.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.97 g (yield) of the title compound. 77%) as a colorless amorphous solid.

^J H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.70-1.90 (2H, m), 1.95-2.15 (2H, m), 2.30 (3H, s) , 3.55-3.75 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (IH, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (IH, d,

J = 16.0), 7.29 (1H, m), 7.45 (IH, m), 7.55 (1H, m), 7.65-7.80 (3H, m), 7.90 (1H, m);

IR (KBr, cm " ¹ ): 1738, 1674, 1625. Production Example 128

N- [4- (1-acetoimidoylpiperidine-4-1-yloxy) -1-3-bromophenyl] -1-N— [3- (3-amidinofenyl) —2 -— (E) —p-t3-dinyl sulfamo Acetic acid dihydrochloride

N- [4- (1-1-acetoimidoylpiperidine-4-yloxy) -13-bromophenyl] -N- [3- (3-amidinofenyl) -2-(-) obtained in Production Example 127 (b) E) —Probenil] Sulfamoyl acetate ethyl dihydrochloride (0.80 g) was dissolved in 3N hydrochloric acid (15 ml), and the mixture was stirred at 90 for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.37 g (yield) of the title compound. 48%) as a colorless amorphous solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.55-3.75 (4H, m), 4.26 ( 2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.29 (IH , m), 7.46 (1H, m), 7.55 (IH, m), 7.65-7.75 (3H, m), 7.89 (IH, m);

IR (KBr, cm ' ¹ ): 1732, 1672, 1626. Production Example 129

N— [4 -— (1-Acetimidoylpiperidin-1-4-yloxy) —3-Isopropylphenyl] N— [3- (3-Amidinophenyl) 1-2— (E) 1-Propenyl] sulfamoyl Ethyl acetate dihydrochloride

(a) N- [3- (3-Amidinophenyl) —2— (E) —Probenyl] 1 N— [3—Isopropyl 1- (piperidine 1-4-yloxy) phenyl] Sulfamoyl acetate ethyl dihydrochloride

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-isopropylphenyl] -N- [3- (3-cyanophenyl) —21 (E) obtained in Reference Example 173 [Probenyl] sulfamoyl acetate ethyl (1.82 g) was dissolved in a mixed solvent of dichloromethane (3 Oml) and ethanol (30 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 2 hours. did. After concentrating the reaction solution under reduced pressure, the residue was ethanol

(2 Oml), an aqueous ammonium chloride solution (0.35 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.80 ml) were added, and the mixture was stirred at room temperature for 30 minutes and left to stand for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% aqueous acetonitrile Z). The obtained amorphous solid is ethanol

(20 ml), 4N hydrogen chloride in ethyl acetate (1.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.92 g (yield 51%) of the title compound as a colorless amorphous solid. Obtained.

Video R (500 MHz, DMSO-d ₆ ) δ ppm: 1.15 (6H, d, J = 7.0), 1.24 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.05-2.20 ( 2H, m), 3.00-3.20 (4H, m), 3.21 (IH, m), 4.21 (2H, q, J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J = 6.0), 4.68 (IH, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.55 (1H, d , J = 16.0), 7.04 (1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 3.0), 7.29 (1H, d, J-3.0), 7.54 (IH, m), 7.65- 7.75 (2H, m), 7.89 (IH, m);

IR (Br, cm- ¹ ): 1738, 1676.

(b) N— [4- (1-Acetimidoylpiperidin-1-4-yloxy) -1-3-isopropylpropylphenyl] —N— [3- (3-Amidinophenyl) -1-2- (E) [Penil] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-propinyl] -l-N- [3-isopropyl-l-l (piperidine-l-l-yloxy) phne obtained in Production Example 129 (a) E) Sulfamoyl acetate ethyl dihydrochloride (0.78 g) was dissolved in ethanol (30 ml), and under ice cooling, ethyl acetimidate hydrochloride (0.50 g) and triethylamine (1.10 ml) were dissolved. In addition, the mixture was stirred at room temperature for 7 hours and then left for 12 hours. After the reaction solution was concentrated under reduced pressure, the remaining brew was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride acetate solution (0.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.67 g (yield) of the title compound. 80%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.14 (6H, d, J = 7.0), 1.24 (3H, t, J = 7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H , m), 2.30 (3H, s), 3.22 (1H, m), 3.50-3.60 (IH, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m), 4.21 (2H, q , J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J = 6.0), 4.74 (IH, m), 6.45 (IH, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.07 (IH, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 3.0), 7.28 (1H, d, J = 3.0), 7.55 (1H, m), 7.71 (2H , M), 7.90 (1H, m);

IR (KBr, cm- ¹ ): 1739, 1673, 1623. Production Example 130

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-isopropylpropyl] —N— [3- (3-amidinophenyl) 1-2— (E) _— probenyl] sulf Famoyl acetic acid dihydrochloride

N- [4- (1-acetoimidoylpiperidine-1-yloxy) -13-isopropylphenyl] one N— [3- (3-amidinophenyl) obtained in Production Example 12 9 (b) [1- 2- (E) monopropenyl] sulfamoyl acetate ethyl dihydrochloride (0.51 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 90 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluting solvent: 25% aqueous acetonitrile water). The obtained amorphous solid was dissolved in 1 N hydrochloric acid (1.70 ml) and concentrated to dryness under reduced pressure to obtain 0.33 g (yield 66%) of the title compound as a colorless amorphous solid. Obtained.

^J H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.14 (6H, d, J = 7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s) , 3.21 (IH, m), 3.50-3.60 (IH, m), 3.60-3.70 (2H, m), 3.70-3.80 (IH, m), 4.21 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (IH, m), 6.46 (IH, dt, J = 16.0, 6.0), 6.54 (1H, d, J = 16.0), 7.06 (1H, d, J = 9.0), 7.24 (1H, dd , J = 9.0, 3.0), 7.29 (1H, d, J = 3.0), 7.54 (IH, m), 7.71 (2H, m), 7.90 (IH, m);

IR (KBr, cm- ¹ ): 1733, 1673, 1625. Production Example 131

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) —3-—Rubamoyl ulfenyl] —N— [3 -— (3-Amidinophenyl) 1-2_ (E) 1-probenyl ] Sulfamoyl acetate ethyl dihydrochloride

Production Example 7 N— [3 -— (3-amidinofenyl) 1-2— (E) group obtained in 1 (a) Rhodinil] — N— [3-Carpamoyl 4 -— (piperidine-141-yloxy) phenyle] Sulfamoyl acetate ethyl dihydrochloride (0.44 g) is dissolved in ethanol (20 ml) and cooled under ice cooling. Acetimidate hydrochloride (0.27 g) and triethylamine (0.60 ml) were added, and the mixture was stirred at room temperature for 30 minutes and left to stand for 14 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetate ditriol Z water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.37 g of the title compound (yield). 78%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (3H, s), 3.45-3.65 (2H, m), 3.65-3.85 (2H, m), 4.20 (2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (IH , m), 6.44 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.28 (1H, m), 7.45-7.60 (2H, m), 7.70 (2H, m) , 7.78 (1H, m), 7.88 (IH, m);

IR (KBr, cm- ¹ ): 1737, 1672. Production Example 132

N— [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) 1-31 rubamoyl ulfenyl] — N— [3-(3-Amidinophenyl) 1-2- (E) 1-Propenyl ] Sulfamoylacetic acid dihydrochloride

N— [4- (1-acetoimidoylpiperidin-4-yloxy) -1-3-potassium phenyl) obtained in Production Example 131—N— [3- (3-amidinofenyl) —2_ (E ) [1Provenyl] sulfamoyl acetate ethyl dihydrochloride (0.20 g) was dissolved in 1.5 N hydrochloric acid (20 ml) and stirred at 6 Ot for 6 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetate nitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.75 ml) and concentrated to dryness under reduced pressure to obtain 0.14 g (yield 71%) of the title compound as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.75-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (3H, s), 3.45-3.65 (2H, m), 3.65- 3.85 (2H, m), 4.24 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (IH, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d , J = 16.0), 7.27 (IH, m), 7.45-7.60 (2H, m), 7.70 (2H, m), 7.77 (1H, m), 7.88 (1H, m);

IR (KBr, cm- ¹ ): 1729, 1672. Production Example 133

N— [4-((1-acetoimidoylpiperidine-1-4-yloxy)) 1-3- (Ν'-methylcarbamoyl) phenyl] -1 一 — [3- (3-amidinofenyl) _2— (Ε) -1 Propenyl] Sulfamoyl acetate ethyl dihydrochloride

(a) N— [3 -— (3-Amidinophenyl) -2— (E) —probenyl] —N— [3- (Ν′—methylcarbamoyl) —41- (piperidine—4-yloxy) phenyl] Rufamoyl acetate ethyl dihydrochloride

Ν— [4- (1-t-butoxycarbonylpiperidine-14-yloxy) -13- (Ν′-methylcarbamoyl) phenyl) obtained in Reference Example 177— 一 — [3- (3-cyanophenyl)- 2-(Ε) 1-Probenyl] ethyl sulfamoylacetate (1.50 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), passed through hydrogen chloride under ice-cooling, and sealed. The mixture was stirred at room temperature for 3.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (0.29 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.66 ml) were added, and the mixture was stirred at room temperature for 2 hours. After stirring, the mixture was left for 15 hours. After concentrating the reaction mixture under reduced pressure, the residue was fractionated by HP LC (YMC- Purified with Pack ODS-A; YMC, elution solvent: 15% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), and a 4N hydrogen chloride ethyl acetate solution (1.5

5ml) and concentrated to dryness under reduced pressure to give 1.14 g (yield) of the title compound.

73%) as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) 6 ppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.79 (3H, m), 2.95-3.10 (2H, m), 3.10-3.25 (2H, m), 4.20 (2H, q, J = 7.0), 4.38 (2H, s), 4.47 (2H, d, J = 6.0), 4.79 (IH , m), 6.45 (IH, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.24 (1H, m), 7.48 (1H, m), 7.54 (IH, m), 7.62 (1H, m), 7.12 (2H, m), 7.92 (IH, m);

IR (KBr, cm- ¹ ): 1737, 1676, 1641.

(b) N— [4- (1-acetoimidoylpiperidine-1-41-yloxy) -13- (N, -methylcarbamoyl) phenyl] -1-N— [3- (3-amidinofenyl) 1-2— ( E) Monopropionyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-probenyl] -lN- [3-((N, -methylcarbamoyl) -l 4-(piperidine-1) obtained in Production Example 133 (a) 4-yloxy) phenyl] Sulfamoyl acetate dihydrochloride (1.00 g) was dissolved in ethanol (30 ml), and the mixture was cooled under ice-cooling with ethyl acetate imidide hydrochloride (0.60 g) and triethyl. After addition of the amine (1.35 ml), the mixture was stirred at room temperature for 8 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.79 g (yield) of the title compound. 74%) as a colorless amorphous solid.

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ZZnO / ZOdT / lDd C08680 / Z0 OAV N- [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -13- (N ', N, 1-dimethylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) obtained in Reference Example 181 ) —2— (E) —Probenyl] Ethyl sulfamoylacetate (1.70 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), passed through hydrogen chloride under ice-cooling, and the stopper was sealed. And stirred at room temperature for 3.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (0.30 g was dissolved in 5 ml of water) and 28% aqueous ammonia (0.70 ml) were added, and the mixture was stirred at room temperature for 5 hours. After stirring, the mixture was left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% T-cetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride in ethyl acetate (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.75 g (yield) of the title compound. 44%) as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.75-1.95 (2H, m), 1.95-2.15 (2H, m), 2.69 (3H, s), 2.97 (3H, s), 2.95-3.15 (4H, m), 4.19 (2H, q, J = 7.0), 4.38 (2H, s), 4.35-4.55 (2H, m), 4.75 (IH, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.22 (1H, d, J = 9.0), 7.30 (1H, d, J = 3.0), 7.45 (IH, dd, J = 9.0, 3.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1676, 1618.

(b) N— [4 -— (1-Acetoimidoylpiperidin-1-41-yloxy) —3 -— (N ,, Ν'-dimethylcarbamoyl) phenyl] -1 一 — [3 -— (3-Amidinophenyl) 1-2 — (E) —Propenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-Amidinophenyl) —2- (E) -propidinyl] -N- [3-(N ,, N, 1-dimethylcarbamoyl) 1-41 obtained in Production Example 135 (a) (Piperidine-4-yloxy) phenyl] Sulfamoyl acetate ethyl dihydrochloride (0.60 g) was dissolved in ethanol (20 ml), and ethyl ethyl acetate hydrochloride (0.35 g) was added under ice cooling. Triethylamine (0.80 ml) was added, and the mixture was stirred at room temperature for 30 minutes and left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen chloride in ethyl acetate (0.60 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.47 g (yield) of the title compound. (73%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) d ppm: 1.22 (3H, t, J = 7.0), 1.60-1.85 (2H, m), 1.85-2.10 (2H, m), 2.29 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.19 (2H, q, J = 7.0), 4.35-4.55 (2H, m), 4.39 (2H, s), 4.79 (IH, m), 6.44 (IH, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.25 (1H, d, J = 9.0), 7.29 (1H, d, J = 3.0), 7.45 (IH, dd, J = 9.0, 3.0), 7.54 (IH, m), 7.65-7.75 (2H, m), 7.90 (IH, s);

IR (KBr, cm ¹ ): 1738, 1673, 1618. Production Example 136

N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) -13- (N ,, N, 1-dimethylcarbamoyl) phenyl] -1-N— [3- (3-amidinofenyl) —2— ( E) Monoprobenyl] sulfamoylacetic acid dihydrochloride

N- [4- (1- (acetoimidoylpiperidin-1-41-yloxy))-3- (N ', N, 1-dimethylcarbamoyl) phenyl) obtained in Production Example 135 (b) -(3-Amidinophenyl) -l2- (E) -l-probenyl] Sulfamoyl acetate ethyl dihydrochloride (0.30 g) is dissolved in 1.5 N hydrochloric acid (1 Oml), and 9.5 at 60 ° C. Stirred for hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.20 ml) and concentrated to dryness under reduced pressure to obtain 0.24 g (yield 83%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.65-1.85 (2H, m), 1.90-2.10 (2H, m), 2.28 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.25 (2H, s), 4.35-4.55 (2H, m), 4.78 (1H, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.55 ( 1H, d, J = 16.0), 7.24 (1H, d, J = 9.0), 7.29 (IH, d, J = 3.0), 7.46 (IH, dd, J = 9.0, 3.0), 7.54 (1H, m) , 7.65-7.75 (2H, m), 7.88 (1H, s); IR (KBr, cm " ¹ ): 1733, 1672, 1614. Production Example 137

N— [4- (1-acetoimidoylpiperidin-4-yloxy) —3-chlorophenyl] —N— [3— (5-amidino_2-hydroxyphenyl) 1-2— (E) —Provenyl] sulfamoyl acetate ethyl dihydrochloride,

(a) N- [3- (5-amidino-2-hydroxyphenyl) -12- (E) -probenyl] -1-N- [3-chloro-41- (piperidine-14-yloxy) phenyl] sulfamoylacetic acid Etil

N- [4- (1-t-butoxycarbylbiperidine-1 4-yloxy) -1 31-chlorophenyl] -N- [3- (5-cyano 2τmethoxymethoxyphenyl) obtained in Reference Example 185 2- (E) -Propenyl] ethyl sulfamoylacetate (1.4 g) is dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), passed through hydrogen chloride under ice-cooling, and sealed. And stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (40 ml), and aqueous ammonium chloride solution (0.2 g dissolved in 10 ml of water) and 28% aqueous ammonia (0.5 ml) were added. After stirring for 30 minutes, it was left for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water), and concentrated under reduced pressure to dryness to give the title. Compound 0.1g (4% yield) was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.15 (2H, m ), 3.15-3.25 (2H, m), 4.19 (2H, q, J = 7.0), 4.40 (2H, s), 4.45 (2H, d, J = 6.0), 4.78 (IH, m), 6.38 (IH , dt, J = 16.0, 6.0), 6.66 (1H, d, J = 16.0), 7.04 (1H, d, J = 9.0), 7.31 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 3.0), 7.56 (1H, d, J = 3.0), 7.62 (IH, dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.0).

(b) N— [4-((1-Acetimidoylpiperidine-1_4-yloxy) -1-3-chlorophenyl)] — N— [3— (5-Amidino-2-hydroxyphenyl) —2— _ (E) — Propenyl] Sulfamoyl acetate ethyl dihydrochloride

N- [3- (5-Amidino-2-hydroxyphenyl) —2 -— (E) —probenyl] obtained in Production Example 137 (a) —N— [3-cloguchi—41- (piperidine— (4-yloxy) phenyl] Sulfamoyl acetate ethyl ester (0.05 g) was dissolved in ethanol (10 ml), and under ice cooling, ethyl acetimidate hydrochloride (0.04 g) and triethylamine (0.08 ml) were added. After stirring at room temperature for 5 hours, the mixture was left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride in ethyl acetate (0.05 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.04 g, yield 59%). %) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 3.50-3.80 (4H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.45 (2H, d, J = 6.0), 4.84 (IH, m), 6.39 (IH, dt) , J = 16.0, 6.0), 6.65 (IH, d, J = 16.0), 7.08 (1H, d, J = 9.0), 7.33 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0) , 2.0), 7.56 (IH, d, J = 2.0), 7.63 (1H, dd, J = 9.0, 2.0), 7.95 (IH, d, J = 2.0);

IR (KBr, cm- ¹ ): 1738, 1671 . ^; Production Example 138

N— [4 -— (1-acetoimidoylpiperidine-1-4-yloxy) -1-5—potassium rubamoyl 3-cyclochlorophenyl] —N— [3— (3-amidinofenyl) —2— (E) — Probenyl] sulfamoyl acetate ethyl dihydrochloride

(a) N— [3- (3-amidinofenyl) -1 -— (E) —propenyl) —N— [5 rubamoyl-3—chloro—41 (piperidine-1.4.1-phenyloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride

N- [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -1-5-potassium rubamoyl-3-cyclophenyl obtained in Reference Example 193—N— [3- (3-cyanophenyl) -2 — (E) —Probenyl] ethyl sulfamyl acetate (1.50 g) After dissolving in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), passing hydrogen chloride under ice-cooling, stoppered, and stirred at room temperature for 4 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (0.26 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.60 ml) were added. After stirring for 4 hours, it was left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure to give 0.55 g (yield 37%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.95-3.05 (2H, m ), 3.20-3.30 (2H, m), 4.19 (2H, q, J = 7.0), 4.35 (1H, m), 4.48 (2H, s), 4.51 (2H, d, J = 6.0), 6.44 (1H , Dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.88 (1H, m);

IR (KBr, cm " ¹ ): 1737, 1672.

(b) N— [4- (1-Acetimidoylpiperidine—4-yloxy) -1-5-carbamoyl—3-chlorophenyl) —N— [3- (3-amidinofenyl) —2_ (E) —Pro Benyl] sulfamoyl acetate ethyl dihydrochloride

N_ [3- (3-amidinofenyl) -2- (E) -propidinyl] -N- [5 _caproluvamoyl-3-3-cloguchi-4-1 (piperidine-4) obtained in Production Example 138 (a) —Iryloxy) Phenyl] sulfamoyl acetate ethyl dihydrochloride (0.51 g) is dissolved in ethanol (25 ml), and ice-cooled ethyl acetimidate hydrochloride (0.30 g) and triethylamine (0.35 g). (0.70 ml) was added, and the mixture was stirred at room temperature for 1 hour and left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N sodium chloride solution in ethyl acetate (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.36 g of the title compound ( (Yield 66%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.23 H, t, J = 7.0), 1.75-1.90 (2H, m), 1.90-2.05 (2H, m), 2.29 (3H, s), 3.40-3.55 (2H, m), 3.75-3.90 (2H, m), 4.20 (2H, q, J = 7.0), 4.42 (1H, m ), 4.48 (2H, s), 4.52 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.89 (IH, m);

IR (KBr, cm- ¹ ): 1738, 1671, 1622. Production Example 139

N— [4- (1-acetoimidoylpiperidine—4-yloxy) —5-—Lubamoyl 3-3-chlorophenyl] —N— [3- (3-amidinofenyl) -1-2— (E) — [Propenyl] sulfamoylacetic acid dihydrochloride.

N- [4- (1-Acetimidoylpiperidine-1_4-yloxy) -5-butyrubamoyl 3-cyclobutenyl obtained in Production Example 138 (b) -N- [3--(3- Amidinophenyl) _2_ (E) —probenyl] sulfamoyl acetate ethyl dihydrochloride (0.20 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 70 ° C. for 1.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile 7). The obtained amorphous solid is diluted with 1N hydrochloric acid.

(0.80 ml), and concentrated to dryness under reduced pressure to give the title compound (0.16 g).

(83% yield) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.75-1.90 (2H, m), 1.90-2.05 (2H, m), 2.28 (3H, s), 3.40-3.55 (2H, m), 3.75- 3.90 (2H, m), 4.35 (2H, s), 4.42 (IH, m), 4.51 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.61 (IH, d , J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.87 (IH, m);

IR (KBr, cm- ¹ ): 1730, 1671, 1628. Production example 140

N— [4- (1-acetoimidoylpiperidine—4-yloxy) -13-forcebamoyl-1-5-methylphenyl] —N— [3- (3-amidinofenyl) -1 2 '— (E) -pro Nyl] sulfamoyl acetate ethyl dihydrochloride (a) N— [3 -— (3-amidinophenyl) —2 -— (E) —probenyl] 1-N— [3 rubamoyl-5-methyl—4- (piperidine—4-yloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride

Reference Example 2 N— [4- (1- (1-t-butoxycarbonylpiperidine-14-yloxy))-13-capillumyl-5-methylphenyl] -1-N— [3- (3-cyanophenyl) obtained in 2000 — (E) —Probenyl] Ethyl sulfamoyl acetate (3.20 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), and the solution was passed through hydrogen chloride under ice cooling. The mixture was stoppered and stirred at room temperature for 2.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of ammonium chloride (0.59 g dissolved in 8 ml of water) and 28% aqueous ammonia (1.34 ml) were added. After stirring at room temperature for 30 minutes, the mixture was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile). The obtained amorphous solid was dissolved in ethanol (10 ml), added with a 4N hydrogen chloride dioxane solution (3.0 ml), and concentrated to dryness under reduced pressure to give the title compound 2.85. g (90% yield) was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H,), 1.95-2.05 (2H, m), 2.26 (3H, s), 2.90 -3.00 (2H, m), 3.20-3.30 (2H, m), 4.15-4.20 (1H, m), 4.20 (2H, q, J = 7.0), 4.39 (2H, s), 4.47 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.54 (2H, m), 7.57 (1H, m), 7.68 (1H, m), 7,73 (1H, m), 7.87 (1H, m);

IR (KBr, cm- ¹ ): 1737, 1672.

(b) N— [4- (1-acetoimidoylpiperidin-4-yloxy) -1-3-carbamoyl-5-methylphenyl] —N— [3- (3-amidinofenyl) 1-2— (E) Benyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-probenyl] -l-N- [3--l-bamoyl-5-methyl-4_ (piperidine-l- 4-ylo) obtained in Production Example 140 (a) Xy) phenyl] sulfamoyl acetate ethyl dihydrochloride (2.68 g) in ethanol (4 0 ml), ethylethylacetimidate hydrochloride (1.58 g) and triethylamine (3.55 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and left to stand for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml), added with 4N hydrogen chloride dioxane solution (0.44 ml), and concentrated to dryness under reduced pressure to obtain 0.38 g of the title compound (yield 13%). %) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.23 (3H, t, J = 7.0), 1.70-1.90 (2H, m), 1.90-2.00 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 3.35-3.45 (2H, m), 3.75-3.95 (2H, m), 4.20 (2H, q, J = 7.0), 4.25 (IH, m), 4.40 (2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (IH, d, J = 16.0), 7.43 (2H, m), 7.55 (1H, m), 7.69 (1H, m), 7.73 (IH, m), 7.88 (IH, m);

IR (KBr, cm ¹ ): 1738, 1672, 1625. Production Example 141

N ~ [4- (1-Acetimidoylpiperidine-4-yloxy)-1-3-Lupamoyl-1-5-Methylphenyl]-N-[3- (3-amidinofenyl)-2-(E) Benyl] sulfamoylacetic acid dihydrochloride

N— [4- (1-Acetoimidoylpiperidine—4-yloxy) -13-rubbamoyl-5-methylphenyl] obtained in Production Example 140 (b) N— [3-(3-Amidinophenyl) 1)-(E) -Provenyl] sulfamoyl acetate ethyl dihydrochloride (0.24 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 70 ° C for 2.5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile Z water). The obtained amorphous solid is diluted with 1N hydrochloric acid.

(1.00 ml) and concentrated to dryness under reduced pressure to give the title compound (0.18 g).

(78% yield) was obtained as a colorless amorphous solid and ^1.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.70-1.85 (2H, m), 1.90-2.00 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 3.30-3.45 ( 2H, m), 3.75-3.90 (2H, m), 4.25 (IH, m), 4.27 (2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.43 (2H, m), 7.55 (IH, m), 7.67 (IH, m), 7.72 (1H, m), 7.86 (1H, m);

IR (KBr, cm- ¹ ): 1731, 1672. Production example 142

N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-difluorophenyl] — N—C 3-(3 _amidinophenyl) 1-2- (E) -propenyl Sulfamoyl acetate ethyl dihydrochloride

(a) N- [3 -— (3-Amidinophenyl) —2 -— (E) —probenyl] -1-N— [3,5-difluoro-41- (piperidine-41-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [4- (1-t-butoxycarbonylpiperidine—4-yloxy) -3,5-difluorophenyl] —N— [3- (3-cyanophenyl) 1-2— (E) obtained in Reference Example 205 1-Propenyl] ethyl sulfamoylacetate (1823 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed through under ice-cooling, and the solution was sealed at room temperature. Stir for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and aqueous ammonium chloride solution (315 mg dissolved in 1 Oml of water) and 28% aqueous ammonia (0.59 ml) were added. Left for hours. After adding 4 N hydrogen chloride dioxane solution (1 ml) to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is purified by HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water) did. The obtained amorphous solid was dissolved in ethanol (20 ml), 1N hydrochloric acid (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1214 mg (yield 68%) of the title compound as a colorless amorphous solid. Obtained.

¾ NMR (400 MHz, DMSO-d ₆ ) ppm: 1.21 (3H, t, J = 7.0), 1.85-1.91 (2H, m), 2.04-2.10 (2H, m), 2.99-3.05 (2H, m) , 3.18-3.24 (2H, m), 4.18 (2H, q, J = 7.0), 4.37 (1H, m), 4.50 (2H, s), 4.51 (2H, d, J = 6.0), 6.42 (1H, dt, J = 16.0, 6.0), 6.62 (IH, d, J = 16.0), 7.39 (2H, m), 7.55 (IH, t, J = 8.0), 7.68 (IH, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm- ¹ ): 1738, 1676.

(b) N— [4- (1-acetoimidoylpiperidine—4-yloxy) —3,5-difluorophenyl] —N— [3- (3-amidinofenyl) -1-2- (E) pro Benil] Sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-difluoro-4-1 (piperidine-1-yloxy) phene obtained in Production Example 142 (a) Nyl] Sulfamoyl acetate ethyl dihydrochloride (102 Omg) was dissolved in ethanol (30 ml), and ethyl acetimidate hydrochloride (62 Omg) and triethylamine (1.17 ml) were added, followed by stirring at room temperature for 15 hours. did. After adding 4 N hydrogen chloride dioxane solution (1.0 Oml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile Z water). Purified. The obtained amorphous solid was dissolved in ethanol (15 ml), 1N hydrochloric acid (1. Oml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give 851 mg (yield 78%) of the title compound as a colorless amorphous solid. '

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22 (3H, t, J = 7.0), 1.76-1.83 (2H, m), 1.98-2.03 (2H, m), 2.30 (3H, s), 3.52 (2H, m), 3.78 (2H, m), 4.18 (2H, q, J = 7.0), 4.46 (1H, m), 4.51 (2H, s), 4.52 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (IH, d, J = 16.0), 7.39 (2H, m), 7.55 (IH, t, J = 8.0), 7.70 (IH, d, J = 8.0), 7.73 (IH, d, J = 8.0), 7.91 (1H, s);

IR (KBr, cm- ¹ ): 1739, 1673, 1624. Production Example 143

N— [4-((1-acetoimidoylpiperidine-1-4 ^ -hydroxy) —3,5-difluorophenyl] -1-N— [3- (3-amidinophenyl) -2- (E) pro Nil] Sulfamoylacetic acid dihydrochloride

N— [4- (1-1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-difluorophenyl] 1-N— [3- (3-amidinofenyl)-obtained in Production Example 142 (b) 2- (E) -Propenyl] sulfamoyl acetate ethyl dihydrochloride (415 mg) was dissolved in 2 N hydrochloric acid (20 ml) and stirred at 60 for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 15% acetonitrile water (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 319 mg (yield 80%) of the title compound as a colorless amorphous solid.

Plan R (400 MHz, DMSO-d ₆ ) δ ppm: 1.70-1.90 (2H, m), 1.95-2.10 (2H, m), 2.29 (3H, s), 3.40-3.60 (2H, m), 3.78 (2H, m), 4.37 (2H, s), 4.46 (1H, m), 4.52 (2H, d, J = 6.0), 6.43 (IH, dt, J = 16.0, 6.0), 6.62 (IH, d, J = 16.0), 7.38 (2H, m), 7.55 (IH, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.74 (IH, d, J = 8.0), 7.89 (IH, s );

IR (Br, cm " ¹ ): 3123, 1733, 1674, 1626. Production Example 144

N— [4- (1-Acetimidoylpiperidine-1-4-yloxy) -1,3,5-dichloromouth phenyl] —N— [3-(3-Amidinophenyl) —2 -— (E) -Propenyl ] Sur

Ethyl acetate dihydrochloride

(a) N— [3- (3-amidinofenyl) -1-2- (E) -probenyl] -1-N— [3,5-dichloro-41- (piperidine-41-yloxy) phenyl] sulfamoyl acetate Chill dihydrochloride

N- [4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) -1,3,5-dichlorophenyl] obtained in Reference Example 209—N— [3- (3-cyanophenyl) 1-2 1 (E ) 1-Propenyl] ethyl sulfamylacetate (2057mg) dissolved in a mixed solvent of dichloromethane (30ml) and ethanol (15ml), passed through with hydrogen chloride under ice-cooling, sealed and stirred at room temperature for 6 hours did. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (40 ml), and aqueous ammonium chloride solution (337 mg dissolved in 20 ml of water) and 28% aqueous ammonia (0.663 ml) were added. For 15 hours. After adding 4N hydrogen chloride dioxane solution (2. Oml) to the reaction mixture, it is concentrated under reduced pressure, and the residue is purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 23% acetonitrile Z water). did. The obtained amorphous solid was dissolved in ethanol (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1002 mg (yield 49%) of the title compound as a colorless amorphous solid. As obtained.

¾ NMR (400 MHz, DMSO-d ₆ ) d ppm: 1.21 (3H, t, J = 7.0), 1.95-2.15 (4H, m), 2.95-3.10 (2H, m), 3.20-3.35 (2H, m ), 4.18 (2H, q, J = 7.0), 4.46 (IH, m), 4.53 (4H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0) , 7.55 (1H, t, J = 7.5), 7.67 (2H, s), 7.68 (IH, d, J = 7.5), 7.74 (IH, d, J = 7.5), 7.88 (1H, s);

IR (KBr, cm- ¹ ): 1738, 1676.

(b) N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-dichlorophenyl] —N— [3- (3-amidinofenyl) —2 -— (E) — Provenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-Amidinophenyl) -2- (E) -pronenyl] -N— [3,5-dichloro mouth obtained from Preparation Example 144 (a) 4- (piperidine-1-4-yloxy) [Fenyl] sulfamoyl acetate dihydrochloride (80 Omg) was dissolved in ethanol (30 ml), and ethyl acetimidate hydrochloride (462 mg) and triethylamine (0.87 ml) were added at room temperature. The mixture was stirred at the same temperature for 15 hours. After adding 4N hydrogen chloride in dioxane (1 ml) to the reaction mixture, it was concentrated under reduced pressure, and the residue was separated by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 722 mg (yield 85%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.22 (3H, t, J = 7.0), 1.80-2.00 (2H, m), 2.00-2.10 (2H, m), 2.29 (3H, s), 3.40-3.55 (2H, m), 3.80-4.00 (2H, m), 4.18 (2H, q, J = 7.0), 4.53 (5H, m), 6.43 (IH, dt, J = 16.0, 6.0), 6.63 (IH, d, J = 16.0), 7.56 (1H, t, J = 8.0), 7.67 (2H, s), 7.68 (IH, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (IH, s);

IR (KBr, cm " ¹ ): 1739, 1674, 1624. Production Example 145

N— [4- (1-Acetimidoylpiperidin-1-4-yloxy) _3,5-dichloromouth phenyl] N— [3- (3-Amidinophenyl) —2 -— (E) 1-propenyl] Sulfamoylacetic acid dihydrochloride

N— [4- (1-1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-dichloromouth phenyl] obtained in Production Example 144 (b) N— [3- (3-Amidinophenyl) -1 2- (E) -Propionyl] sulfamoyl acetate ethyl dihydrochloride (30 Omg) was dissolved in 2N hydrochloric acid (20 ml) and stirred at 60 ° C for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% aqueous acetonitrile (20 ml), 1N hydrochloric acid (1. Oml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 233 mg ′ (81% yield) of the title compound as a colorless amorphous solid. '

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.80-2.00 (2H, m), 2.00-2.10 (2H, m), 2.30 (3H, s), 3.40-3.55 (2H, m), 3.80- 4.00 (2H, m), 4.39 (2H, s), 4.53 (2H, d, J = 6.0), 4.53 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (IH, d , J = 16.0), 7.56 (IH, t, J = 8.0), 7.67 (2H, s), 7.70 (1H, d, J = 8.0), 7.74 (IH, d, J = 8.0), 7.90 (1H, s);

IR (KBr, cur ¹ ): 3127, 1733, 1673, 1625. Production Example 146

N- [4 -— (1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-dimethylmethylphenyl] N— [3- (3-amidinophenyl) 1-2— (E) monopropenyl] Sulfamoyl methyl sulfonate dihydrochloride

(a) N- [3- (3-Amidinophenyl) 1 2- (E) 1-Propenyl] 1 N— [3,5-Dimethyl 4- (piperidine-1 4-yloxy) phenyl] Sulfamoyl acetate 2HCl salt

Reference Example 213 N- [4- (1-t-butoxycarbonylpiperidine-4-yloxy) -3,5-dimethylphenyl] —N— [3- (3-cyanophenyl) -2-1 (E) —Provenyl] sulfamoyl acetate ethyl (1.75 g) is dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride under ice-cooling, sealed and sealed for 6 hours at room temperature. Stirred. After concentrating the reaction solution under reduced pressure, the residue was ethanol

(30 ml), an aqueous solution of ammonium chloride (0.31 g dissolved in 15 ml of water) and 28% aqueous ammonia (0.57 ml) were added, and the mixture was allowed to stand at room temperature for 14 hours. After adding 4N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). . The obtained amorphous solid was dissolved in ethanol (20 ml), 1N hydrochloric acid (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.21 g (yield 70%) of the title compound as a colorless amorphous Obtained as a solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.23 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.00-2.10 (2H, m), 2.22 (6H, s) , 2.94 (2H, m), 3.26 (2H, m), 4.12 (1H, m), 4.19 (2H, q, J = 7.0), 4.35 (2H, s), 4.44 (2H, d, J = 6.0) , 6.43 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.17 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm— ¹ ): 1738, 1676. (b) N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) —3,5-dimethylphenyl] —N— [3- (3-amidinofenyl) _2— (E) —pro Benyl] methyl sulfamoyl acetate dihydrochloride

N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-dimethyl- 4- (piperidine-1-yloxy) phen obtained in Production Example 146 (a) [2] Ethyl sulfamoyl acetate dihydrochloride (1.00 g) was dissolved in methanol (30 ml), and ethyl acetimidate hydrochloride (0.62 g) and triethylamine (1.16 ml) were dissolved at room temperature. After the addition, the mixture was stirred at the same temperature for 14 hours. After adding 4 N hydrogen chloride in dioxane (2 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water) did. The obtained amorphous solid was dissolved in methanol (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.81 g (yield 78%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H, s), 2.29 (3H, s), 3.25-3.35 (2H, m) , 3.73 (3H, s), 3.85 (IH, m), 4.02 (IH, m), 4.18 (IH, m), 4.38 (2H, s), 4.44 (2H, d, J = 6.0), 6.42 (1H , Dt, J = 16.0, 6.0), 6.59 (IH, d, J = 16.0), 7.16 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm ¹ ): 1743, 1673, 1626. Production Example 147

N— [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) —3,5-dimethylthiophene] — N— [3 -— (3-Amidinophenyl) —2 -— (E) —Probenyl] Sulfamoylacetic acid dihydrochloride:

N- [4- (1-1-acetoimidoylpiperidin-1-yloxy) -1,3,5-dimethylphenyl] -N- [3- (3-amidinofenyl) obtained in Production Example 146 (b) (2- (E) -Probenyl] methyl sulfamoylacetate dihydrochloride (62 Omg) was dissolved in 2N hydrochloric acid (2 Oml) and stirred at 60 ° C for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 18% acetonitrile Z water). The obtained amorphous solid was dissolved in 18% aqueous acetonitrile Z (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 22 Omg (yield 57%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H, s), 2.29 (3H, s), 3.25-3.40 (2H, m) , 3.85 (IH, m), 4.02 (1H, m), 4.17 (IH, m), 4.22 (2H, s), 4.44 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (IH, d, J = 16.0), 7.17 (2H, s), 7.55 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);

IR (KBr, cm " ¹ ): 3131, 1733, 1673, 1626. Production example 148

4- [N— [4 -— (1-acetoimidoylpiperidine-1-41-yloxy) phenyl] -N- [3- (3-amidinofenyl) —2_ (E) —probenyl] amino] butyric acid Thiol trihydrochloride

(a) 4- [N- [3 -— (3-amidinofenyl) 1-2— (E) —probenyl] -1- [N-1- [4- (piperidine-1-yloxy) phenyl] amino] ethylethyl butyrate trihydrochloride 4- [N- [4- (1-t-butoxycarbonylpiperidine-14-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) —2 -— (E) — obtained in Reference Example 214 [Benyl] amino] ethyl butyrate (2.19 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through with hydrogen chloride under ice-cooling, sealed, and sealed at room temperature. Stir for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous solution of ammonium chloride (0.43 g dissolved in 10 ml of water) and 28% aqueous ammonia (1.04 ml) were added. It was left at room temperature for 14 hours. After adding 4N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was collected by HP LC

(YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1N hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1.52 g (yield 66%) of the title compound as a pale yellow amorphous solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.19 (3H, t, J = 7.0), 1.70-1.95 (4H, m), 2.00-2.15 (2H, m), 2.39 (2H, m) , 3.00-3.15 (2H, m), 3.15-3.30 (2H, m), 3.30-3.40 (2H, m), 4.07 (2H, q, J = 7.0), 4.00-4.20 (2H, m), 4.43 ( 1H, m), 6.52 (1H, dt, J = 16.0, 5.5), 6.55-7.00 (5H, m), 7.59 (1H, t, J = 8.0), 7.65-7.80 (2H, m), 7.88 (1H , s);

IR (KBr, cm- ¹ ): 1728, 1674.

(b) 4— [N— [4 -— (1-acetoimidoylpiperidin-1-41-yloxy) phenyl] -1-N— [3 -— (3-amidinofenyl) —2 -— (E) 1-probenyl ] Amino] Ethyl butyrate trihydrochloride

Preparation Example 148 [N- [3- (3-amidinofenyl) -12- (E) -probenyl] obtained in 148 (a) [N- [4-1 (piperidine-14-yloxy) phenyl] Amino] ethyl butyrate trihydrochloride (1378 mg) was dissolved in ethanol (2 Oml), and ethyl acetimidate hydrochloride (89 Omg) and triethylamine (2.01 ml) were added at room temperature. For 4 hours. A 4N hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 25% acetonitrile Z water). . The obtained amorphous solid was dissolved in ethanol (20 ml), IN hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1072 mg (yield 73%) of the title compound as a pale yellow amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.16 (3H, t, J = 7.0), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.29 (3H, s), 2.30-2.40 (2H, m), 3.20-3.40 (2H, m), 3.45-3.60 (2H, m), 3.70-3.85 (2H, m), 4.04 (2H, q, J = 7.0), 4.00-4.10 (2H, m), 4.40-4.55 (1H, m), 6.49 (IH, dt, J = 16.0, 6.0), 6.55-6.95 (5H, m), 7.57 (1H, t, J = 7.5), 7.65- 7.75 (2H, m), 7.85 (1H, s);

IR (KBr, cm- ¹ ): 1727, 1673, 1624. Production Example 149

4- [N- [4- (1-acetoimidoylpiperidine-1-41-yloxy) phenyl] -1-N— [3- (3-amidinofenyl) -1-2- (E) -propionyl] amino] butyric acid 3 Production Example 148 [b] [N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] obtained in (b) —N— [3- (3-amidinofenyl) 1-2— (E ) [1Provenyl] amino] ethyl ethyl butyrate trihydrochloride (572 mg) was dissolved in 2N hydrochloric acid (2 Oml). The mixture was stirred at room temperature for 2 hours and then at 50 ° C for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% aqueous acetonitrile Z (20 ml), 1N hydrochloric acid (1. Oml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 333 mg (yield 61%) of the title compound as a pale brown amorphous solid.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.40-1.95 (4H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 2.25-2.35 (2H, m), 3.45-4.40 (8H, ra), 4.65-4.80 (IH, m), 6.50 (1H, dt, J = 15.5, 6.5), 6.55-7.30 (5H, m), 7.58 (IH, t, J = 7.5), 7.65- 7.75 (2H, m), 7.85 (IH, s);

IR (KBr, cm ¹ ): 3119, 1726, 1673, 1625. Production example 150

N- [4- (1-acetoimidoylpiperidine-1 4-yloxy) phenyl] -1-N— [3- (3-amidinofenyl) —2-fluoro-2- (Z) —probenyl] sulfamoyl Ethyl dihydrochloride

(a) N— [3 -— (3-Amidinophenyl) —2-fluoro-2 -— (Z) —probenyl] —N— [4- (piperidine-141-yloxy) phenyl] ethyl sulfamoyl acetate dihydrochloride salt

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) -12-fluoro-2- (Z) —probe obtained in Reference Example 216 Nyl] sulfamoyl acetate ethyl (1.41 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 10 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of ammonium chloride (0.25 g dissolved in 10 ml of water) and 28% aqueous ammonia (0.47 ml) were added. For 8 hours. After adding 4N hydrogen chloride dioxane solution (1 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is collected by HP LC

(YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile Z water). The obtained amorphous solid was dissolved in methanol (15 ml), and 4N hydrogen chloride in dioxane was added.

(0.50 ml), and concentrated to dryness under reduced pressure to give 1.00 g (yield 75%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.81 (2H, m), 2.08 (2H, m), 3.06 (2H, m), 3.22 (2H, m), 4.20 (2H, q, J = 7.0), 4.36 (2H, s), 4.56 (2H, d, J-16.5), 4.65 (IH, m), 5.94 (1H, d, J = 39.0), 7.05 (2H, d, J = 9.5), 7.40 (2H, d, J = 9.5), 7.56 (1H, d, J-8.0), 7.74 (2H, m), 7.81 (1H, s);

IR (KBr, cnr ¹ ): 3061, 2985, 1737, 1676, 1507.

(b) N- “4- (1-acetimidoylpiperidine—4-yloxy) phenyl] —N— [3- (3-amidinophenyl) -1-fluoro-2- (Z) -propidinyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-amidinofenyl) —2-fluoro-2--2- (Z) -propenyl) -1-N— [4- (piperidine-1-4-yloxy) phenyl] obtained in Production Example 150 (a) Ethyl sulfamoyl acetate dihydrochloride (800 mg) was dissolved in ethanol (20 ml), and at room temperature, ethyl ethyl acetate hydrochloride (515 mg) and triethylamine (0.97 ml) were added, followed by stirring at the same temperature for 4 hours. did. After adding 4N hydrogen chloride dioxane solution (2 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile Z water). Purified. The obtained amorphous solid is methanol

(15 ml), 4N hydrogen chloride in dioxane (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 458 mg (yield 54%) of the title compound as a pale yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.24 (3H, t, J = 7.0), 1.74 (2H, m), 2.05 (2H, m), 2.28 (3H, s), 3.52 (2H, m), 3.72 (IH, m), 3.78 (1H, m), 4.20 (2H, q, J = 7.0), 4.36 (2H, s), 4.59 (2H, d, J = 15.5), 4.71 (IH, m), 5.96 (IH, d, J = 39.0), 7.05 (2H, d, J = 9.5), 7.41 (2H, d, J = 9.5), 7.59 (1H, t, J = 7.5), 7.67 (1H , D, J = 7.5), 7.76 (1H, d, J = 7.5), 7.80 (1H, s);

IR (KBr, cm- ¹ ): 3103, 1738, 1673, 1627, 1606. Production Example 151

N— [4- (1-acetoimidoylpiperidine-1-yloxy) phenyl] — N—

[3- (3-Amidinophenyl) -2-fluoro-2- (Z) -probenyl] sulfamoylacetic acid dihydrochloride

• 2HCI N— [4- (1-acetoimidoylpiperidine—4-yloxy) phenyl] obtained in Production Example 150 (b) —N— [3- (3-amidinofenyl) 1-2-fluoro-2-—

(Z) Iprobenzyl] Sulfamoyl acetate ethyl dihydrochloride (265 mg) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 80 ° C for 2 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile water). The obtained amorphous solid was dissolved in methanol (10 ml), 4N hydrogen dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 218 mg (86% yield) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.74 (2H, m), 2.05 (2H, m), 2.29. (3H, s), 3.52 (2H, m), 3.72 (1H, m), 3.82 (1H, m), 4.20 (2H, s), 4.59 (2H, d, J = 15.5), 4.71 (IH, m), 5.95 (IH, d, J = 38.0), 7.06 (2H, d, J = 9.0), 7.42 (2H, d, J = 9.0), 7.59 (1H, t, J = 8.0), 7.68 (IH, d, J = 8.0), 7.76 (IH, d, J = 8.0), 7.81 ( IH, s);

IR (Br, cm ¹ ): 1734, 1673, 1627. Production example 152,

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1,3,5-dicafrebamoylphenyl] N— [3- (3-Amidinophenyl) 1-2— (E) —probenyl] Ethyl sulfamoyl acetate dihydrochloride

(a) N— [3- (3-Amidinophenyl) -1-2- (E) -probenyl] -1-N— [3,5-Dicarbamoyl-4-1 (piperidine-4-1yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [4- (1-t-butoxycarbonylpiperidine-14-yloxy) -1,3,5-dicarbamoylphenyl] -N- [3- (3-cyanophenyl) -2- () obtained in Reference Example 225 E) 1-Propenyl] ethyl sulfamoylacetate (0.84 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), and hydrogen chloride was added under ice-cooling. After passing through, the container was sealed and stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (25 ml), and aqueous ammonium chloride solution (0.15 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.35 nil) were added. After stirring for 2.5 hours, the mixture was left for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 17.5% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.17 g of the title compound. (20% yield) was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.85-2.00 (4H, m), 2.95-3.05 (2H, m), 3.20-3.30 (2H, m ), 4.20 (2H, q, J = 7.0), 4.25-4.35 (1H, m), 4.45 (2H, s), 4.50 (2H, d, J = 6.0), 6.45 (1H, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.55 (1H, t, J = 8.0), 7.61 (2H, s), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);

MS (FAB, m / z): 587 (M + H-2HC1) ⁺ .

(b) N— [4- (1-acetoimidoylpiperidine—4-yloxy) -1,3,5-dicarpamoylphenyl] —N— [3- (3-amidinofenyl) —1 2_ (E ) -Propenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -l- (E) -l-probenyl] -N- [3,5-dicarbamoyl-l- (piperidine-l-yloxy) phenyl) obtained in Production Example 152 (a) Ethyl sulfamoyl acetate dihydrochloride (0.17 g) was dissolved in ethanol (20 ml), and ethylacetimidate hydrochloride (1.67 g) and triethylamine (1.68 ml) were added at room temperature. Then, the mixture was stirred at the same temperature for 5.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17.5% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride in dioxane (0.10 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.08 g of the title compound (yield 43). %) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.24 H, t, J = 7.0), 1.75-2.00 {4}, m), 2.28 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.20 (2H, q, J = 7.0), 4.30-4.40 (1H, m), 4.45 (2H, s ), 4.51 (2H, d, J = 6.0), 6.44 (IH, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.55 (1H, t, J = 8.0), 7.64 ( 2H, s), 7.68 (1H, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7.88 (1H, s);

MS (FAB, m / z): 628 (M + H-2HC1 production example 153

N— [4 -— (1-acetimidoylpiperidine—4-yloxy) -1,3,5-dicar pamoylphenyl] _ 'N— [3 -— (3-amidinofenyl) 1-2— (E) —probenyl ] Sulfamoylacetic acid dihydrochloride

N- [4- (1-acetoimidoylpiperidine-4-1yloxy) -1,3,5-dicarbamoylphenyl] -N- [3- (3-amidinofue) obtained in Production Example 152 (b) (12) 12- (E) -Provenyl] sulfamoyl acetate ethyl dihydrochloride (0.07 g) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 70 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.30 ml) and concentrated to dryness under reduced pressure to obtain 0.05 g (yield 69%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.75-2.00 (4H, m), 2.27 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.32 ( 2H, s), 4.35-4.40 (1H, m), 4.51 (2H, d, J = 6.0), 6.45 (IH, dt, J = 16.0, 6.0), 6.60 (IH, d, J = 16.0), 7.55 (IH, t, J = 8.0), 7.63 (2H, s), 7.67 (IH, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.87 (1H, s);

IR (KBr, cm- ¹ ): 1729, 1668. Production example 154

N— [4 -— (1-Acetimidoylpiperidine-1-4-yloxy) -1-5-Lubamoyl 2-Methylphenyl] —N— [3- (3-Amidinophenyl) —2 -— (E) —Pro ぺLe] Sulfamoyl acetate ethyl dihydrochloride (a) N— [3- (3-Amidinophenyl) -2- (E) —probenyl] —N— [5 rubamoyl-2-methyl-41- (piperidine-1-4-yloxy) phenyl] sulfamoyl acetate ethyl Dihydrochloride

N- [4- (1-t-butoxycarbonylpiperidine-4-1yloxy) -1.5-force rubamoyl-2-methylphenyl] -N- [3- (3-cyanophenyl) -2- () obtained in Reference Example 232 E) 1-Propenyl] ethyl sulfoyl acetate (2.10 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml). The mixture was passed through hydrogen chloride under ice-cooling, sealed, and sealed. For 3 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (25 ml), and aqueous ammonium chloride solution (0.59 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.34 ml) were added. After stirring for 7 hours, it was left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 17.5% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (20 ml), 4N hydrogen dioxane solution (1.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.18 g of the title compound (yield). (57%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.10-2.20 (2H, m), 2.33 (3H, s), 3.05-3.15 (2H, m), 3.20-3.30 (2H, m), 4.21 (2H, q, J = 7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J = 14.0), 4.45 -4.50 (1H, m), 4.51 (1H, d, J = 14.0), 4.80 (1H, m), 6.40-6.55 (2H, m), 6.48 (1H, s), 7.55 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7,77 (1H, s), 7.83 (1H, s);

IR (KBr, cm-1): 1737, 1673, 1657.

(b) N— [4 -— (1-acetimidoylpiperidine-1-41-yloxy) -1-5-kalebamoyl_2-methylphenyl] —N— [3- (3-amidinofenyl) 1-2— (E ) One probenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3 -— (3-amidinofenyl) —2 -— (E) -propenyl) obtained in Production Example 154 (a) —N— [5-carboxyl-2-methyl-4 -— (piperidine_4-1 Illu Xy) phenyl] sulfamoyl acetate dihydrochloride (1.00 g) was dissolved in ethanol (50 ml), and at room temperature, ethyl acetimidate hydrochloride (0.59 g) and triethylamine (1.33 ml) were dissolved. ), Stirred at the same temperature for 1 hour, and left for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound 0.988 (yield 92%). %) Was obtained as a colorless amorphous solid. '

Video R (500 MHz, DMSO-d ₆ ) d ppm: 1.24 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s) , 2.34 (3H, s), 3.50-3.60 (2H, m), 3.70-3.80 (1H, m), 3.80-3.90 (IH, m), 4.21 (2H, q, J = 7.0), 4.25-4.30 ( 1H, m), 4.36 (1H, d,

J = 14.0), 4.45-4.50 (IH, m), 4.51 (IH, d, J = 14.0), 4.87 (IH, m), 6.40-6.55 (2H, m), 7.19 (IH, s), 7.56 ( IH, t, J = 8.0), 7.70 (IH, d, J = 8.0), 7.72 (IH, d, J = 8.0), 7,82 (IH, s), 7.84 (IH, s);

IR (KBr, cm ¹ ): 1737, 1672, 1622. Production Example 155

N— [4_ (1-acetoimidoylpiperidine-1 4-yloxy) -1-5-potassium 2-methylphenyl] N— [3- (3_ (amidinophenyl) 1-2— (E) —probenyl] Sulfamoyl acetic acid dihydrochloride

N— [4 -— (1-acetoimidoylpiperidine—4-yloxy) -1.5-force rubamoyl—2-methylphenyl) obtained in Production Example 154 (b) —N— [3 -— (3-amidinophenyl) 1)-(E) -Ipronenyl] sulfamoyl acetate ethyl dihydrochloride (0.880 g) was dissolved in 3N hydrochloric acid (40 ml) and stirred at 70 for 1.5 hours. After the reaction solution was cooled to nitrogen temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 12.5% acetonitrile water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3.00 ml) and concentrated to dryness under reduced pressure to give 0.71 g (yield 92%) of the title compound as a colorless amorphous solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.75-1.90 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 3.45-3.55 ( 1H, m), 3.55-3.65 (1H, m), 3.65-3.80 (IH, m), 3.80-3.95 (IH, m), 4.20-4.30 (1H, m), 4.22 (IH, d, J = 15.0 ), 4.41 (1H, d,

J = 15.0), 4.45-4.55 (1H, m), 4.86 (1H, m), 6.40-6.55 (2H, m), 7.18 (1H, s), 7.55 (1H, t, J = 7.0), 7.70 ( 1H, d, J = 7.0), 7.72 (1H, d, J = 7.0), 7,83 (IH, s), 7.84 (IH, s);

IR (KBr, cm- ¹ ): 1730, 1672. Production Example 156

N- [4 -— (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -1-N— [3- (3-amidinofenyl) -1-2-methyl-2- (E) —probenyl] sulfamoy Ethyl acetate dihydrochloride

(a) N— [3- (3-Amidinophenyl) -1-2-methyl-2- (E) —probenyl] —N— [4 -— (piperidine—4-yloxy) phenyl] sulfamoylacetic acid Reference Example 237 N— [4- (1-t-Butoxycarbonylpiperidine-1-4-yloxy) phenyl] obtained in the above step—N— [3- (3-Cyanophenyl) —2-methyl-2- (E) —probenyl] sulfamoyl Ethyl acetate (4.92 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), hydrogen chloride was passed under ice-cooling, the solution was sealed, and the mixture was stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (60 ml), and an aqueous solution of ammonium chloride (0.79 g dissolved in 2 Om1 of water) and 28% aqueous ammonia (1.65 ml) were added. Left overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water) to give 3.52 g of the title compound (83% yield). Was obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.78-1.92 (2H, m), 1.87 (3H, s), 2.05-2.16 (2H, m), 2.98-3.10 (2H, m), 3.14-3.25 (2H, m), 4.20 (2H, q, J = 7.0), 4.32 (2H, s), 4.37 (2H, s), 4.66 (IH, m), 6.34 (1H, s), 7.04 (2H, d, J = 9.0), 7.40 (2H, d, J = 9.0), 7.48 (1H, d, J = 8.0), 7.52-7.59 (2H, m), 7.66 (1H, d, J = 8.0). (b) N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] -N- [3- (3-amidinofenyl) 1-2-methyl-2- (E) —probenyl] Ethyl sulfamoyl acetate dihydrochloride

N- [3- (3-Amidinophenyl) -12-methyl-2- (E) -probenyl] -N- [4- (piperidine-4-yloxy) phenyl] sulfamoyl obtained in Production Example 156 (a) Ethyl acetate (2.48 g) was dissolved in ethanol (45 ml), and ethyl cetimidate hydrochloride (1.31 g) and triethylamine (2.22 ml) were added, followed by stirring at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile water) to obtain 2.55 g of an amorphous solid. 0.20 g of this solid was dissolved in ethanol (4 ml), 4N hydrogen dioxane solution (0.28 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.2,0 g (yield 80%) of the title compound as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.64-1.81 (2H, m), 1.87 (3H, s), 1.98-2.11 (2H, m), 2.30 (3H, s), 3.47-3.62 (2H, m), 3.66-3.89 (2H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.37 (2H, s), 4.71 (1H, m), 6.34 (1H, s), 7.05 (2H, d, J = 9.0), 7.40 (2H, d, J = 9.0), 7.48 (1H, d, J = 8.0), 7.52-7.58 (2H, m), 7.66 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1738, 1672, 1349, 1158. Production Example 157

N— [4- (1-acetimidoylpiperidin-1-41-yloxy) phenyl] —N— [3- (3-amidinophenyl) —2-methyl-2- (E) —probenyl] sulfamoylacetic acid 2 Hydrochloride

N- [4- (1- (acetoimidoylpiperidine-14-yloxy) phenyl] —N— [3- (3-amidinofenyl) -12-methyl-2- () obtained in Production Example 156 (b) E) 1-Propenyl] ethyl sulfyl acetate (1.97 g) in 3N hydrochloric acid (35 ml) Dissolved and stirred at 60 ° C for 3 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 11% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in water (30 ml), 4N hydrogen chloride dioxane solution (2.59 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1.86 g (yield 87%) of the title compound as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.64-1.82 (2H, m), 1.88 (3H, s), 1.98-2.11 (2H, m), 2.30 (3H, s), 3.46-3.90 ( 4H, m), 4.19 (2H, s), 4.37 (2H, s), 4.71 (1H, m), 6.33 (1H, s), 7.04 (2H, d, J = 9.0), 7.41 (2H, d, J = 9.0), 7.48 (1H, d, J = 8.0), 7.52-7.58 (2H, m), 7.67 (1H, d, J = 8.0);

IR (KBr, cm ¹ ): 1672, 1345, 1156. Production Example 158

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) phenyl] —N— [3- (3-amidinofenyl) -1-2-ethyl-2- (E) -propenyl] sulfamoyl Ethyl acetate dihydrochloride

(a) N— [3- (3-Amidinophenyl) —2-ethyl-2— (E) monopropyl] N— [4- (piperidine-4-yloxy) phenyl] ethyl sulfamoyl acetate 2HCl salt

N- [4- (1-t-butoxycarbonylbiperidine-14-yloxy) phenyl] -N- [3- (3-cyanophenyl) -1-2-ethyl- 2- (E) obtained in Reference Example 240 [Pinyl] sulfamoyl acetate (2.04 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), passed through hydrogen chloride under ice-cooling, sealed, and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (40 ml), and an aqueous solution of ammonium chloride (0.36 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.61 ml) were added. Thereafter, the mixture was stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (20 ml), and a 4N hydrogen chloride dioxane solution (8 m 1) was added. This was again concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid is ethanol

(20 ml), 4N hydrogen chloride in dioxane (8 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.49 g (yield 74%) of the title compound as a colorless amorphous solid. Was.

1H NMR (500 MHz, DMSO-d ₆ ) <5 ppm: 1.17 (3H, t, J = 7.0), 1.23 (3H, t, J = 7.0), 1.79-1.88 (2H, m), 2.08-2.13 ( 2H, m), 2.22 (2H, q, J = 7.0), 3.01-3.09 (2H, m), 3.18-3.24 (2H, m), 4.20 (2H, q, J = 7.0), 4.31 (2H, s ), 4.41 (2H, s), 4.66 (1H, m), 6.32 (1H, s), 7.05 (2H, d, J = 8.5), 7.38-7.43 (3H, m), 7.47 (1H, s), 7.56 (1H, t, J = 7.5), 7.65 (1H, d, J = 7.5);

IR (KBr, cm " ¹ ): 1740, 1674, 1350, 1157.

(b) N— [4- (1-Acetimidoylpiperidine-1-4-yloxy) phenyl] -1-N— [3- (3-Amidinophenyl) -1-2-ethyl-2- (E) -propenyl] Ethyl sulfamoyl acetate dihydrochloride

N- [3- (3-Amidinophenyl) -l- 2-ethyrelay 2- (E) -l-propenyl] -l-N- [4-1- (piperidine-l 4-yloxy) phenyl] s obtained in Production Example 158 (a) Ethyl rufamoyl acetate dihydrochloride (2.53 g) was dissolved in ethanol (40 ml), and ethyl acetimidate hydrochloride (1.30 g) and triethylamine (2.90 ml) were added. Left for days. After adding 4 N hydrogen chloride dioxane solution (10 ml) to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is separated by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 20% acetonitrile / water). Purified. The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (3 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 2.13 g of the title compound (yield 79%) Was obtained as a colorless amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.06 (3H, t, J = 7.5), 1.24 (3H, t, J = 7.0), 1.65-1.82 (2H, m), 1.99-2.11 (2H , m), 2.22 (2H, q, J = 7.5), 2.31 (3H, s), 3.48-3.61 (2H, m), 3.68-3.84 (2H, m), 4.20 (2H, q, J = 7.0) , 4.32 (2H, s), 4.41 (2H, s), 4.72 (IH, m), 6.31 (IH, s), 7.05 (2H, d, J-9.0), 7.38-7.44 (3H, m), 7.46 (IH, s), 7.56 (m, t, J = 8.0) , 7.66 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1733, 1672, 1345, 1156. Production Example 159

N— [4- (1-acetoimidoylpiperidine—4-yloxy) phenyl] N—

[3- (3-Amidinophenyl) -1-ethyl-2- (E) -probenyl] sulfamoylacetic acid dihydrochloride

N- [4- (1-Acetoimidoylpiperidine-1-4-yloxy) phenyl] —N— [3- (3-amidinofenyl) -12-ethyl-2- () obtained in Production Example 158 (b) E) were dissolved one-propenyl] sulfamoyl acetic Echiru 2 hydrochloride (1. 72 g) in 3N hydrochloric acid (4 0 ml), and stirred for 4 h at 60 ^D C. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 13% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (10 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1.34 g (yield 81%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.06 (3H, t, J = 7.5), 1.68-1.80 (2H, m), 2.01-2.10 (2H, m), 2.23 (2H, q, J = 7.5), 2.31 (3H, s), 3.49-3.78 (4H, m), 4.19 (2H, s), 4.41 (2H, s), 4.71 (1H, m), 6.31 (1H, s), 7.05 ( 2H, d, J = 9.0), 7.37-7.43 (3H, m), 7.47 (IH, s), 7.56 (IH, t, J = 8.0), 7.66 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1733, 1672, 1345, 1156. Production example 160

N— [4- (1-Acetimidoylpiperidine-1-4-yloxy) —3-caprolubyl ulfenyl] —N— [3— (3-Amidinophenyl) 1-2-fluoro-2- (Z) —P Benyl] sulfamoyl acetate ethyl dihydrochloride

(a) N— [3 -— (3-amidinophenyl) -1-fluoro-2 -— (Z) probe Nyl] — N— [3-—Lumbamoyl—41- (piperidine-41-yloxy) phenyl] sulfupmoylethyl acetate

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -13-capillubaylphenyl] -1 N- [3- (3-cyanophenyl) -2-2-fluoro-2- obtained in Reference Example 241 (Z) 1-Propenyl] Ethyl sulfamoyl acetate (4.30 g) was dissolved in a mixed solvent of dichloromethane (35 ml) and ethanol (35 ml), passed through hydrogen chloride under ice-cooling, and sealed. The mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (30 ml), and aqueous ammonium chloride solution (0.80 g was dissolved in 5 ml of water) and 28% aqueous ammonia (1.80 ml) were added. And left overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water) to give 2.20 g of the title compound (yield 58%) as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.88-1.96 (2H, m), 2.09-2.17 (2H, m), 3.02-3.09 (2H, m ), 3.17-3.24 (2H, m), 4.21 (2H, q, J = 7.0), 4.40 (2H, s), 4.62 (2H, d, J = 16.0), 4.81 (1H, m), 5.98 (1H , D, J = 38.0), 7.26 (1H, d, J = 9.0), 7.51 (1H, dd, J = 9.0, 3.0), 7.57-7.71 (2H, m), 7.73-7.78 (2H, m), 7.81 (1H, s).

(b) N— [4- (1-Acetamimidoylpiperidine-1-4-yloxy) 13-force rubamoylphenyl] —N— [3— (3-amidinofenyl) -2-fluoro-2-(Z ) 1-Propenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3- (3-amidinofenyl) -12-fluoro-1-2- (Z) -probenyl] obtained in Production Example 160 (a) —N— [3-carpamoyl-4-1 (piperidine-1— Ethyl sulfymoyl acetate (2.20 g) was dissolved in ethanol (50 ml), and ethyl acetimidate hydrochloride (1.00 g) and triethylamine (2.20 ml) were added. After stirring for 2 hours, the mixture was left overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (5.6 Oml), and then reduced. By concentrating to dryness under reduced pressure, 2.20 g (yield 93%) of the title compound was obtained as a colorless amorphous solid. '

¾ NMR (500 MHz, DMSO-d ₆ + D _a O) δ ppm: 1.24 (3H, t, J = 7.0), 1.79-1.92 (2H, m), 2.02-2.13 (2H, m), 2.30 (3H , S), 3.50-3.58 (2H, m), 3.69-3.77 (1H, m), 3.78-3.85 (1H, m), 4,21 (2H, q, J = 7.0), 4.39 (2H, s) , 4.62 (2H, d, J = 16.0), 4.88 (1H, m), 5.98 (IH, d, J = 38.5), 7.31 (IH, d, J = 9.0), 7.53 (IH, dd, J = 9.0) , 2.5), 7.59 (IH, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.76 (IH, d, J = 8.0), 7.79-7.82 (2H, m);

IR (KBr, cm " ¹ ): 1671, 1353, 1157. Production Example 161

N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1—3-rubamoylphenyl] —N— [3- (3-amidinofenyl) —2-fluoro-2- (Z) pro [Pinyl] sulfamoylacetic acid dihydrochloride

N— [4- (1-acetoimidoylpiperidine-1-41-yloxy) obtained in Production Example 160 (b) -1—3-basic rubamoylphenyl] -N- [3 -— (3-amidinofenyl) -1 2-Fluoro-2- (Z) monoprobenyl] sulfamoyl acetate ethyl dihydrochloride (2.20 g) was dissolved in 3N hydrochloric acid (40 ml) and stirred at 70 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% acetate nitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (7.0 ml) and concentrated to dryness under reduced pressure to give 1.70 g (yield 72%) of the title compound as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.80-1.92 (2H, m), 2.02-2.12 (2H, m), 2.30 (3H, s), 3.49-3.64 (2H, m), 3.68- 3.76 (IH, m), 3.78-3.84 (IH, m), 4.27 (2H, s), 4.62 (2H, d, J = 16.0), 4.87 (1H, m), 5.98 (IH, d, J = 39.0 ), 7.30 (1H, d, J = 9.0), 7.51-7.71 (3H, m), 7.73-7.83 (3H, m);

IR (KBr, cm " ¹ ): 1672, 1352, 1158. Production Example 162 N- [4 -— (1-acetimidoylpiperidin-4-peroxy) -l-3-rubbamoylphenyl] -N- [3- (3-amidinofenyl) -l2-methyl-2- (E) -pro- Nyl] sulfamoyl acetate ethyl dihydrochloride

(a) N- [3- (3- (amidinophenyl) -1-2-methyl-12- (E) -probenyl] -1-N- [3-carbamyl-41- (piperidine-14-yloxy) phenyl] sulfamoyl Ethyl acetate

N— [4- (1-t-butoxycarbonylpiperidine-14-yloxy) -13-force-rubamoylphenyl] -N- [3- (3-cyanophenyl) 1-2-methyl-2- obtained in Reference Example 242 (E) —Probenyl] Sulfamoyl acetate ethyl (3.20 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml). After passing through hydrogen chloride under ice-cooling, stoppered. The mixture was stirred at room temperature for 0.75 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous solution of ammonium chloride (0.60 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.40 ml) were added. I left it. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, eluent: 15% acetonitrile Z water) to give 0.87 g of the title compound (yield 31%). %) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.87 (3H, s), 1.87-1.96 (2H, m), 2.08-2.16 (2H, m), 3.02-3.09 (2H, m), 3.17-3.24 (2H, m), 4.21 (2H, q, J = 7.0), 4.36 (2H, s), 4.39 (2H, s), 4.81 (1H, m), 6.37 (1H, s), 7.24 (1H, d, J = 9.0), 7.47-7.59 (3H, m), 7.63-7.68 (2H, m), 7.75 (1H, d, J = 3.0).

(b) N— [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-force rubamoylphenyl] —N— [3— (3-amidinofenyl) 1-2-methyl-2-— (E) monoprobenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-Amidinophenyl) -1-2-methyl-2- (E) -provenyl] obtained in Production Example 162 (a) —N— [3-Rybamoyl—4 -— (piperidine-1 4 —Yloxy) phenyl] sulfamoyl acetate (0.87 g) in ethanol (20 ml) Then, ethyl acetimidate hydrochloride (0.39 g) and triethylamine (0.87 ml) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 18% acetonitrile Z water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (4.7 ml) and concentrated to dryness under reduced pressure to obtain 0.79 g (yield 75%) of the title compound as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ + D ₂₀ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.80-1.92 (2H, m), 1.87 (3H, s), 2.02-2.13 (2H , m), 2.29 (3H, s), 3.50-3.62 (2H, m), 3.70-3.82 (2H, m), 4.21 (2H, q, J = 7.0), 4.35 (2H, s), 4.39 (2H , s), 4.87 (IH, m), 6.38 (IH, s), 7.29 (1H, d, J = 9.0), 7.48-7.58 (4H, m), 7.64 (1H, d, J = 8.0), 7.80 (IH, d, J = 3.0);

IR (KBr, cnr ¹ ): 1671, 1349, 1156. Production Example 163

N- [4- (1-Acetimidoylpiperidine—4-yloxy) —3-—Rubamoyl ulfenyl] N— [3- (3-Amidinophenyl) —2-Methyl_2_ (E) —Pro [Pinyl] sulfamoylacetic acid dihydrochloride

N— [4- (1-Acetimidoylpiperidine—4-yloxy) -1 obtained in Production Example 162 (b) 1-3 1-Rubamoylphenyl] -N- [3- (3-Amidinophenyl) -1 2-Methyl-2- (E) -probenyl] sulfamoyl acetate ethyl dihydrochloride (0.64 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 80 for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 10% acetonitril / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (3.0 ml) and concentrated to dryness under reduced pressure to obtain 0.28 g (yield 46%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.79-1.92 (2H, m), 1.87 (3H, s), 2.02- 2.12 (2H, m), 2.30 (3H, s), 3.50-3.63 ( 2H, m), 3.68-3.77 (IH, m), 3.79-3.86 (IH, m), 4.23 (2H, s), 4.39 (2H, s), 4.86 (1H, m), 6.36 (IH, s) , 7.28 (1H, d, J = 9.0), 7.49 (IH, d, J = 8.0), 7.52-7.68 (4H, m), 7.79 (IH, d, J = 2.5);

IR (KBr, cm— ¹ ): 1671, 1348, 1156. Production Example 1 64

N— [3 -— (3-amidinofenyl) _ 2-methyl-2- (E) —probenyl] 1 N-[4 1 [1— (4,5-dihydro _ 3 H—pyrroyl-2-i] Le) piperidine-1-4-yl] phenyl] sulfamoyl acetate ethyl dihydrochloride

N- [3- (3-amidinofenyl)-2-methyl- 2- (E) -probenyl] obtained in Production Example 1 56 (a)-N- [4- (piperidine- 1-4-yloxy) phenyl Ethyl sulfamoyl acetate (1.15 g) is dissolved in ethanol (50 ml), and the mixture is cooled with ice, and the organic preparation and procedures' International, Vol. 24, pp. 147 ( 1992) 5-Methoxy-3,4-dihydro-1H-pyrrolyl synthesized from 2-pyrrolidinone according to the method described in [Org. Prep. Proced. Int., .24, 147 992)] (0.67 g) and triethylamine (1.90 ml) were added and stirred at room temperature for 4 hours. Then, 5-methoxy-3,4-dihydro-2H-pyrrole (0.67 g) and triethylamine (1.90 ml) were added. 90 ml) was added, and the mixture was further allowed to stand. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20 to 22% acetate nitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4 N hydrogen chloride dioxane solution (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.72 g of the title compound. (Yield 49%) was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.24 (3H, t, J = 7.0), 1.68-1.81 (2H, m), 1.87 (3H, s), 2.01-2.14 (4H, m), 2.97 (2H, t, J = 8.0), 3.44-3.52 (IH, m), 3.57-3.62 (3H, m), 3.66-3.72 (1H, m), 3.82-3.90 (1H, m), 4.20 (2H , q, J = 7.0), 4.32 (2H, s), 4.37 (2H, s), 4.71 (IH, m), 6.34 (IH, s), 7.05 (2H, d, J = 9.0), 7.40 (2H , d, J = 9.0), 7.48 (IH, d, J = 8.0), 7.53-7.58 (2H, m), 7.66 (1H, d, J = 8.0);

IR (KBr, cm- ¹ ): 1671, 1350, 1158. Production example 1 6 5

N— [3_ (3-amidinofenyl) —2-methyl-2- (E) 1-probenyl] 1 N— [4 —— [1— (4,5-dihydro-3H—pyrroyl-2-yl) 4) Roxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinophenyl) -2-methyl-2- (E) -l-propenyl] obtained in Production Example 164 -N- [4- [1- (4,5-dihydro-3H-pyrro-L-) 2_ (yl) piperidine-1_4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (0.59 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 70 for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetate nitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2.7 ml) and concentrated to dryness under reduced pressure to give 0.51 g (yield 90%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.68-1.80 (2H, m), 1.88 (3H, s), 2.01- 2.13 (4H, m), 2.97 (2H, t, J = 8.0), 3.47-3.89 (6H, m), 4.19 (2H, s), 4.37 (2H, s), 4.70 (IH, m), 6.33 (IH, s), 7.04 (2H, d, J = 9.0), 7.41 ( 2H, d, J = 9.0), 7.48 (IH, d, J = 8.0), 7.52-7.58 (2H, m), 7.66 (IH, d, J = 8.0);

IR (KBr, cm- ¹ ): 1671, 1347, 1156. Production Example 166

N— [3 -— (3-amidinofenyl) -1-fluoro-2 -— (Z) -probenyl] —N— [4- [1 -— (4,5-dihydro-3H—pyrrole-1-yl)ぺ lysine-1 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N_ [3- (3-amidinofenyl) -2_fluoro-1- (Z) -probenyl] -N- [4- (piperidine-1-4-yloxy) phenyl] sulfamoyl obtained in Production Example 150 (a) Ethyl acetate (1.27 g) is dissolved in ethanol (50 ml) and the mixture is organically prepared at room temperature. Organic Preparation and 'Procedures in Yuichi National, Vol. 24, pp. 147 (1992) [Org. Prep Proced. Int..24.147 (1QQ2)] 5-Methoxy-3,4-dihydro_2H-pyrrolyl (0.73 g) and triethylamine (2. After stirring at the same temperature for 4 hours, 5-methoxy-3,4-dihydro-2H-pyrrole (0.73 g) and triethylamine (2.10 ml) were added, and the mixture was further left overnight. Concentrate the reaction mixture under reduced pressure After that, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 20% aqueous acetonitrile water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N sodium chloride dioxane solution (0.80 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound 0. 60 g (37% yield) were obtained as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.24 (3H, t, J = 7.0), 1.68-1.82 (2H, m), 2.02-2.13 (4H, m), 2.97 (2H, t, J = 8.0), 3.47-3.53 (1H, m), 3.58-3.73 (4H, m), 3.85-3.92 (IH, m), 4.21 (2H, q, J = 7.0), 4.37 (2H, s), 4.60 (2H, d, J = 16.0), 4.71 (1H, m), 5.95 (1H, d, J = 39.0), 7.07 (2H, d, J = 9.0), 7.41 (2H, d, J = 9.0), 7.59 (IH, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.76 (IH, d, J = 8.0), 7.82 (IH, s);

IR (KBr, cm- ¹ ): 1672, 1354, 1161. Production Example 167

N— [3 -— (3-Amidinophenyl) —2-fluoro-2 -— (Z) —propidinyl] N— [4- [1-1 (4,5-dihydro-3H—pyrroyl-2-yl)ぺ lysine-1 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -1-fluoro-2- (Z) -propidinyl] obtained in Production Example 166—N— [4- [1-(4,5-dihydro-3H-pyrro) 21-yl) piperidine 4-yloxy] phenyl] sulfamoylethyl acetate dihydrochloride

(0.47 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 70 ° C for 2.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% aqueous acetonitrile). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2.5 m 1) and concentrated to dryness under reduced pressure to obtain 0.39 g (yield 86%) of the title compound as a colorless amorphous solid. .

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.68-1.81 (2H, m), 2.02-2.14 (4H, m), 2.96 (2H, t, J = 8.0), 3.44-3.74 (6H, m ), 4.23 (2H, s), 4.59 (2H, d, J = 16.0), 4.71 (IH, m), 5.95 (1H, d, J = 39.0), 7.06 (2H, d, J = 9.0), 7.42 (2H, d, J = 9.0), 7.59 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.76 (1H, d, J = 8.0), 7.81 (1H, s);

IR (KBr, cm— ¹ ): 1672, 1352, 1158. Production Example 168

N— [3 -— (3-amidinofenyl) —2-fluoro-2- (Z) —probenyl] —N— [3-carbamoyl-4-1 [1- (4,5-dihydro-3H-pyrrolyl) — 2-—yl) Piperidine-1- 4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride

N— [3 -— (3-amidinofenyl) —2-fluoro-1-2- (Z) -propidinyl) —N— [3-—pyrubamoyl-4-1 (piperidine-1-4-yl) obtained in Production Example 160 (a) Phenyl) sulfamoyl acetate (1.20 g) dissolved in ethanol (40 ml) and organic preparation at room temperature 'and' procedures' International, Vol. 24, p. 147 (1992) Prep. Proced. Int., 24, 147 (1992)]. 5-Methoxy-3,4-dihydro-2H-pyrrole synthesized from 2-pyrrolidinone (0.64 g). And triethylamine (1.80 ml) were added, and the mixture was stirred at the same temperature for 1 hour and left overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (5 ml), 4N hydrogen chloride dioxane solution (1.60 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.40 g of the title compound (yield 26%). ) Was obtained as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) ppm: 1.24 (3H, t, J = 7.0), 1.81-1.92 (2H, m), 2.02-2.14 (4H, m), 2.96 (2H, t, J = 8.0), 3.48-3.88 (6H, m), 4.21 (2H, q, J = 7.0), 4.40 (2H, s), 4.62 (2H, d, J = 16.0), 4.87 (1H, m), 5.98 ( IH, d, J = 39.0), 7.30 (IH, d, J = 9.0), 7.49-7.63 (2H, m), 7.68 (1H, d, J = 8.0), 7.74-7.82 (3H, m);

IR (KBr, cm- ¹ ): 1669, 1354, 1156. Production example 169 '

N— [3 -— (3-amidinofenyl) -1-2-fluoro-2 -— (Z) -probenyl] —N— [3-carbamoyl—4-1— (1- (4,5-dihydro—3H—pyrroyl) 2 —Yl) piperidine-1 4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride

N- [3- (3-amidinofenyl) -2-fluoro-2- obtained in Production Example 168 (Z) —Provenyl] — N— [3-Ferubamoyl 4-1 [1-(4,5-dihydro-3H-pyrroyl-2-yl) piperidine-1 4-yloxy] phenyl] sulfamoyl Ethyl acetate (0.27 g) was dissolved in 3N hydrochloric acid (20 ml) and stirred at 70 ° C for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.2 ml) and concentrated to dryness under reduced pressure to obtain 0.20 g (yield 77%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) 6 ppm: 1.82-1.93 (2H, m), 2.02-2.15 (4H, m), 2.96 (2H, t, J = 8.0), 3.48-3.73 (5H, m ), 3.78-3.88 (IH, m), 4.27 (2H, s), 4.62 (2H, d, J = 16.0), 4.87 (IH, m), 5.98 (IH, d, J = 39.0), 7.30 (1H , D, J = 9.0), 7.49-7.71 (3H, m), 7.73-7.83 (3H, m);

IR (KBr, cm- ¹ ): 1670, 1352, 1156. Production example 170

N- [3- (3-Amidinophenyl) -2- (E) —probenyl] — N— [3-Carbamoyl-4-1C 1-(4,5-dihydro-3H-pyrroyl-2-i) Le) piperidine-1.4-yloxy] phenyl] methanesulfonamide dihydrochloride

(a) N— [3— (3_amidinofenyl) -1-2- (E) —probenyl] —N— [3—pothamamoyl-4- (piperidine-1-4-yloxy) phenyl] methanesulfonamide dihydrochloride salt

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) obtained in Reference Example 244—3-Ferubamoylphenyl] —N— [3- (3-Cyanophenyl) —2-1 (E) [Propenyl]] methanesulfonamide (1.01 g) was dissolved in a mixed solvent of dichloromethane (7.5 ml) and ethanol (7.5 ml), passed through hydrogen chloride under ice-cooling, sealed and sealed. For 4 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethanol (15 ml), and aqueous ammonium chloride solution (0.24 g dissolved in 3 ml of water) and 28% aqueous ammonia (0.43 ml) were added. It was left at room temperature. Reduce reaction volume After concentration under reduced pressure, the residue was dissolved in ethanol (10 ml), and 4N hydrogen chloride dioxane solution (2 ml) was added. This was again concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% acetonitrile Z water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.95 g (yield 98%) of the title compound as a pale yellow amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.87-1.97 (2H, m), 2.08-2.18 (2H, m), 3.06 (3H, s), 3.14-3.25 (2H, m), 3.65- 3.74 (2H, m), 4.45 (2H, d, J = 6.0), 4.80 (IH, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.23 (IH, d, J = 9.0), 7.48-7.59 (2H, m), 7.68-7.75 (3H, m), 7.90 (1H, s);

(t N— [3— (3-amidinofenyl) —2— (E) —probenyl] — N— [3 rubumoylu 4 _ [1— (4,5-dihydro-3 H—pyrroyl 2— Yl) piperidin-1 4-yloxy] phenyl] methanesulfonamide dihydrochloride

N— [3- (3-Amidinophenyl) -12_ (E) -1-propenyl] -1-N— [3-Carpamoyl-4-((piperidine-14-yloxy) phenyl) obtained in Production Example 170 (a) Dissolve methanesulfonamide dihydrochloride (0.95 g) in ethanol (15 ml) and, at room temperature, Organic Preparation 'and' Procedures International, Vol. 24, p. 147 (1992) [ Org. Prep. Proced. Int..24.147 (1992)] and synthesized from 2-pyrrolidinone. 5-Methoxy-3,4-dihydro-2H-pyrrol (0.52 g) and triethylamine (1.20 ml) was added, and the mixture was allowed to stand at the same temperature for 1 hour. Then, 5-methoxy-3,4-dihydro-2H-pyrrole (0.17 g) and triethylamine (0.24 ml) were added, and the mixture was further stirred for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (10 ml), and 4N hydrogen chloride dioxane solution (4 ml) was added. This was again concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A YMC, elution solvent: 10% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (5 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give 0.67 g (yield 63%) of the title compound as a colorless amorphous solid Obtained as body.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.79-1.92 (2H, m), 2.02-2.14 (4H, m), 2.99 (2H, t, J = 8.0), 3.37 (3H, s), 3.41 -3.58 (4H, m), 3.82-3.90 (2H, m), 4.46 (2H, d, J = 6.0), 4.86 (1H, m), 6.47 (1H, dt, J = 16.0, 6.0), 6.59 ( 1H, d, J = 16.0), 7.26 (1H, d, J = 9.0), 7.49-7.58 (2H, m), 7.67-7.77 (3H, m), 7.91 (1H, s);

IR (KBr, cm- ¹ ): 1669, 1334, 1151. Production Example 17 1

N— [3 -— (3-Amidinophenyl) -2 -— (E) —Probenyl] -1-N— [3-Carbamoyl—4-1— (1,5- (4,5-dihydro-3H—pyrroyl-2-yl) ) Piperidine-4-yloxy] phenyl] ethanesulfonamide dihydrochloride

(a) N- [3 -— (3-amidinofenyl) —2— (E) 1-probenyl] — N— [3 1-rubamoyl-41- (piperidine-1-4-yloxy) phenyl] ethanesulfonamide dihydrochloride

N- [4- (11-t-butoxycarbonylbiperidine-14-yloxy) -13-forcerubamoylphenyl] -N- [3- (3-cyanophenyl) 1-2 (E) obtained in Reference Example 245 ) 1-Propenyl] ethanesulfonamide (1.08 g) was dissolved in a mixed solvent of dichloromethane (8 ml) and ethanol (8 ml), passed through with hydrogen chloride under ice-cooling, stoppered, and sealed at room temperature. Stir for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (16 ml), and an aqueous solution of ammonium chloride (0.26 g was dissolved in 3 ml of water) and 28% aqueous ammonia (0.46 ml) were added. And left overnight. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (10 ml), and 4N hydrogen chloride dioxane solution (2 ml) was added. This was again concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-PackODS-A; YMC, elution solvent: 10% aqueous acetonitrile water). The obtained amorphous solid was dissolved in ethanol (10 ml), 4N hydrogen dioxane solution (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.68 g of the title compound (yield 64%). Was obtained as a pale yellow amorphous solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.26 (3H, t, J = 7.5), 1.86-1.94 (2H, m), 2.07-2.14 (2H, m), 3.01-3.09 (2H, m ), 3.13-3.23 (4H, m), 4.45 (2H, d, J = 6.0), 4.77 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.55 (IH, d, J = 16.0), 7.20 (1H, d, J = 9.0), 7.46-7.75 (5H, m), 7.87 (IH, s).

(b) N— [3 -— (3-amidinofenyl) -1-2 -— (E) -probenyl] —N— [3 rubumoylu 4-1-1 [1- (4,5-dihydro-3H—pyrroyl-2) —Yl) piperidine-1- 4-yloxy] phenyl] ethanesulfonamide dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-propenyl] obtained in Production Example 171 (a) -N- [3-l-l-bamoyl-4-1- (piperidine-41-yloxy) phenyl Ethanesulfonamide dihydrochloride (0.68 g) is dissolved in ethanol (15 ml), and at room temperature, the organic 'preparation' and procedures' International, Vol. 24, p. 147 (1992 Int., 24.147 (1992)], 5-methoxy-3,4-dihydro-2H-pyrrole (0.36 g) synthesized from 2-pyrrolidinone and triethylamine ( 0.85 ml), and allowed to stand at the same temperature. Then, 5-methoxy-3,4-dihydro 2H-pyrrole (0.19 g) and triethylamine (0.34 ml) were added, and the mixture was further stirred for 5 hours. . After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (10 ml), and 4N hydrogen chloride dioxane solution (4 ml) was added. This was again concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC, elution solvent: 10% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (8 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.56 g (yield 73%) of the title compound as a pale brown amorphous solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.27 (3H, t, J = 7.5), 1.79-1.91 (2H, m), 2.02-2.14 (4H, m), 2.97 (2H, t, J = 7.0), 3.21 (2H, q, J = 7.5), 3.47-3.73 (5H, m), 3.90 (IH, m), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.26 (1H, d, J = 9.0), 7.49-7.58 (2H, m), 7.69-7.76 (3H, m ), 7.92 (1H, s); IR (KBr, cm- ¹ ): 1671, 1331, 1146. Production Example 172

N- [3 -— (3-amidinofenyl) —2 -— (E) —probenyl] —N— [3-carbamoyl-1-4- (1- (4,5-dihydrooxazole-2-yl) ) Piperidine-1-yloxy] phenyl] methanesulfonamide dihydrochloride

N- [3- (3-amidinofenyl) -l- (E) -l-propenyl] -N- [3--l-bamoyl-4-1 (piperidine-l-yloxy) pheny obtained in Production Example 170 (a) ] Methanesulfonamide (0.32 g) is dissolved in methanol (15 ml), and the mixture is dissolved at room temperature at room temperature. The Journal of Biochemical Chemistry, Ob Organic Chemistry, Vol. 10, pp. 2645 (1999) [Eur J. Org. Chem ... 10, 2645, 2-ethoxy-4,5-dihydrooxazol (0.21 g) synthesized from 2-oxazolidone and triethylamine ( 0.56 ml), and the mixture was stirred at the same temperature for 2 hours and left overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HP LC (YMC-PackODS-A; YMC, elution solvent: 12% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2.0 ml), and concentrated to dryness under reduced pressure to obtain 0.11 g (yield 26%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.78-1.92 (2H, m), 1.98-2.11 (2H, m), 3.06 (3H, s), 3.47-3.88 (6H, m), 4.45 ( 2H, d, J = 5.5), 4.76-4.85 (3H, m), 6.47 (IH, dt, J = 16.0, 5.5), 6.59 (IH, d, J = 16.0), 7.25 (1H, d, J = 9.0), 7.49-7.58 (2H, m), 7.67-7.76 (3H, m), 7.91 (1H, s);

IR (KBr, cm ¹ ): 1686, 1334, 1151. Production Example 173

N— [3 -— (3-amidinofenyl) -1-2- (E) -propidinyl] —N— [3-carbaziru 4-—1 -— (4,5-dihydro-thiazol-2-yl) Piperidine—4-yloxy] phenyl] methanesulfonamide dihydrochloride

N- [3- (3-amidinofenyl) -2- (E) -I obtained in Production Example 170 (a) [Propenyl] -N- [3-Ferubamoyl-4-1 (piperidine-1-yloxy) phenyl] methanesulfonamide (0.32 g) in tetrahydrofuran (3 ml), 1,4-dioxane (3 ml) and water ( 3 ml), 2-isobutyl isothiocyanate (0.05 ml) and tritylamine (0.07 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours and left overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HP LC (YMC-Pack ODS-A; YMC elution solvent: 12% aqueous acetonitrile Z). The obtained amorphous solid was dissolved in 1N hydrochloric acid (1.2 ml) and concentrated to dryness under reduced pressure to give 0.15 g (yield 59%) of the title compound as a colorless amorphous solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.82-1.93 (2H, m), 2.02-2.12 (2H, m), 3.06 (3H, s), 3.52-3.63 (3H, m), 3.68- 3.82 (2H, m), 3.91-4.02 (3H, m), 4.45 (2H, d, J = 6.0), 4.85 (IH, m), 6.47 (1H, dt, J = 16.0, 6.0), 6.59 (1H , D, J = 16.0), 7.25 (1H, d, J = 9.0), 7.49-7.58 (2H, m), 7.68-7.76 (3H, m), 7.91 (1H, s);

IR (KBr, cm ¹ ): 1673, 1632, 1333, 1151. Reference Example 1

3—cyanocinnamic aldehyde

3-Cyanobenzaldehyde (4.5 g) was dissolved in toluene (200 ml), and triphenylphosphoranilideneacetaldehyde (13.6 g) was added, followed by stirring at 70 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane), and further recrystallized from toluene and hexane to give 3.09 g of the title compound (yield 57%). %) Was obtained as pale yellow needles.

_{¾ NMR (500MHz, CDC1 3)} d ppm: 6.76 (1H, dd, J = 16.0, 7.5), 7.46 (IH, d, J = 16.0), 7.58 (1H, t, J = 8.0), 7.73 (1H, d, J = 8.0), 7.80 (1H, d, J = 8.0), 7.84 (IH, s), 9.75 (1H, d, J-7.5).

3-(3-Cyanophenyl) 1 2-(E) 1-propene 1-1-ol

The 3-cyanocinnamic aldehyde (3.00 g) obtained in Reference Example 1 was added to dichloromethane (3 0 ml) and ethanol (70 ml), add sodium borohydride (1.32 g) and cerium chloride (2.49 g) under ice-cooling, and add Γ.5 hours at the same temperature. Stirred. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted three times with dichloromethane, the extract was washed with saturated saline, and the organic layer was dried using anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 3Z2) to obtain 3.27 g (yield quantitative) of the title compound as a pale yellow oil Obtained as material.

_{¾ NMR (500MHz, CDC1 3)} δ ppm: 4.37 (2H, m), 6.43 (1H, dt, J = 16.0, 5.0), 6.62 (IH, d, J = 16.0), 7.43 (IH, t, J = 8.0), 7.52 (1H, d, J = 8.0), 7.60 (1H, d, J = 8.0), 7.65 (lH, s).

4- (1-t-butoxycarbonylpiperidine-4-yloxy) 1-3-chloronitrate Benzene

1-t-butoxycarbone 4-hydroxypiperidine (3.32 g), 2-chloro-4-nitrophenyl (2.36 g) and triphenylphosphine (5.1 1 g) were added to dichloromethane (6 Om 1 ), And under ice-cooling, azodiphenol getyl ruptonate (3.1 Oml) was added dropwise, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/2) to give 3.90 g (yield 76%) of the title compound as a pale yellow color Obtained as a solid.

_{¾ NMR (500MHz, CDC1 3)} 6 ppm: 1.48 (9H, s), 1.84-1.98 (4H, m) 3.54 (2H, m), 3.62 (2H, m), 4.73 (1H, m), 7.00 (1H , D, J = 9.0), 8.14 (1H, dd, J = 9.0, 3.0), 8.31 (1H, d, J = 3.0). Reference Example 4

3-chloro-1-4- (1-methylpiperidine-1-yloxy) nitrobenzene

The 4- (1-t-butoxycarbonylpiperidine-1-yloxy) _3-chloronitrobenzene (1.50 g) obtained in Reference Example 3 was suspended in 90% formic acid (4.00 g). 37% Formalin (2.50 g) was added, and the mixture was stirred at 100 for 2 hours. The reaction solution was cooled to room temperature, neutralized with an aqueous potassium carbonate solution, extracted with ethyl acetate, and the extract was washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (1.12 g, yield 98%) as a yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.90-2.10 (4H, m), 2.33 (3H, s), 2.35-2.45 (2H, m), 2.60-2.70 (2H, m), 4.58 (1H, m), 6.98 (1H, d, J = 9.0), 8.13 (1H, dd, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0). Reference Example 5

3—Black mouth—41- (1-methylpiperidine—41-yloxy) anilin

Dissolve the 3-chloro-1- (1-methylpiperidine-4-yloxy) nitrobenzene (8.48 g) obtained in Reference Example 4 in acetic acid (200 ml), and powder at room temperature (18.59 g). ) And stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous potassium carbonate solution, and extracted five times with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 3/1) to give 6.95 g (yield 92%) of the title compound as a red-brown solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.82-2.02 (4H, m), 2.20-2.30 (2H, m), 2.30 (3H, s), 2.68-2.78 (2H, m), 4.12 (1H, m), 6.51 (1H, dd, J = 8.5, 3.0), 6.72 (1H, d, J = 3.0), 6.81 (1H, d, J = 8.5). Reference example β

N— [3-Chloro-41- (1-methylbiperidine-1-yloxy) phenyl] sulfamoyl acetate

3-Chloro-41- (1-methylpiperidine-14-yloxy) aline (6.95 g) obtained in Reference Example 5 was dissolved in dichloromethane (150 ml), and ethyl chlorosulfonyl acetate (3 88 ml) and pyridine (4.67 ml) were added dropwise, followed by stirring at room temperature for 5 hours. Water was added to the reaction solution, and extracted three times with ethyl acetate. Dried over magnesium acid. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 4/1 to 1/1) to give 9.12 g of the title compound (yield 81%). %) Was obtained as a brown amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.37 (3H, s), 2.40- 2.50 (2H, m), 2.70-2.80 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.41 (1H, m), 6.93 (1H, d, J = 9.0 ), 7.21 (1H, dd, J = 9.0, 2.5), 7.40 (1H, d, J = 2.5).

N- [3-—Mouth—4 -— (1-Methylpiperidine-1-41-yloxy) phenyl] —N- [3- (3-Cyanophenyl) -1-2- (E) -propionyl] sulfamoyl acetate ik

3- (3-Cyanophenyl) -l- (E) -propene-l-l-ol (3.30 g) obtained in Reference Example 2, N- [3-chloro-opening obtained in Reference Example 6 4- (1-Methylbiberidine-1 4-yloxy) phenyl] Ethyl sulfamoylacetate (7.37 g) and triphenylphosphine (5.93 g) are dissolved in dichloromethane (200 ml), and cooled under ice-cooling to give azodicarboxylic acid. After getyl (3.49 ml) was added dropwise, the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate = 1 / 3-2 / 1) to give 7.29 g of the title compound (73% yield). ) Was obtained as an orange amorphous solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.36 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 2.31 (3H, s), 2.30 -2.40 (2H, m), 2.60-2.70 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.40 (1H, m), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.92 (1H, d, J = 9.0), 7.31 (1H, dd, J = 9.0, 2.5) , 7.40 (1H, t, J = 8.0), 7.46-7.58 (4H, m). Reference Example 8

3-chloro-4-1 (piperidine-1 reoxy) nitrobenzene 4- (1-t-butoxycarbonylpiperidine-1-yloxy) obtained in Reference Example 3 — 3-chloronitrobenzene (7.91 g) was dissolved in dioxane (80 ml), and 4N hydrogen chloride dioxane was added at room temperature. After the solution (70 ml) was added, the mixture was stirred overnight at the same temperature. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water, neutralized with sodium hydrogen carbonate, and the precipitated crystals were collected by filtration to give 8.06 g (quantitative yield) of the title compound. Obtained as pale yellow needle-like crystals.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.50-1.60 (2H, m), 1.90-2.00 (2H, m), 2.57-2.68 (2H, m), 2.90-3.00 (2H, m), 3.96 (IH, m), 7.45 (IH, d, J = 9.0), 8.18 (1H, dd, J = 9.0, 3.0), 8.31 (IH, d, J = 3.0). Reference Example 9

4- (1_Acetylpiperidine-1-4 ^^ fluoroxy) -13-chloronitrobenzene 3.-Chloro-4- (piperidine-14-yloxy) nitrobenzene (1.00 g) obtained in Reference Example 8 The residue was dissolved in pyridine (20 ml), acetic anhydride (0.55 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with aqueous sodium hydrogen carbonate solution and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.05 g (yield 90%) of the title compound as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.88-2.03 (4H, m), 2.14 (3H, s), 3.50-3.63 (2H, m), 3.71 (1H, m), 3.94 (1H, m) , 4.81 (IH, m), 7.01 (IH, d, J = 9.0), 8.15 (1H, dd, J = 9.0, 2.5), 8.32 (IH, d, J = 2.5). Reference example 10

4- (1-Acetylpiperidine-1 4-yloxy) —3-chloroaniline

4- (1-Acetylpiperidine-4-yloxy) -13-chloro nitrobenzene (1.05 g) obtained in Reference Example 9 was dissolved in acetic acid (30 ml) and powdered at room temperature (2.09 g). Was added and stirred at the same temperature for 10 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of potassium carbonate, and extracted five times with ethyl acetate. The organic layer is After drying with magnesium, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z methanol = 15/1) to give 0.82 g (yield 86%) of the title compound as an orange oily substance.

^{: H NMR (500 MHz, CDC1} 3) d ppm: 1.78-1.94 (4H, m), 2.11 (3H, s), 3.33-3.43 (IH, m), 3.60-3.70 (1H, m), 3.70-3.82 (2H, m), 4.35 (1H, m), 6.53 (1H, dd, J = 8.5, 3.0), 6.74 (IH, d, J = 3.0), 6.81 (1H, d, J = 8.5). Reference example 11

3—Black mouth—41- (1-ethylpiperidine-1 4-yloxy) aniline

Lithium aluminum hydride (23 Omg) was suspended in tetrahydrofuran (5 ml) under a nitrogen atmosphere, and 4- (1-acetylpiperidine-4-yloxy) -13-chloroa obtained in Reference Example 10 was suspended under ice cooling. After dropwise adding a solution of diphosphorus in tetrahydrofuran (10 ml), the mixture was heated under reflux for 3.5 hours. Due to the slow progress of the reaction, lithium aluminum hydride (115 mg) was added, and the mixture was further heated under reflux for 2 hours. After cooling the reaction solution, sodium sulfate · 107 hydrate was added, and the mixture was further stirred at room temperature. After removing the insoluble matter by filtration, the filtrate is concentrated under reduced pressure.

Purification by ZI I / Z) gave 448 mg (58% yield) of the title compound as a brown oil.

^{X H NMR (500 MHz, CDC1} 3) 6 ppm: 1.11 (3H, t, J = 7.0), 1.82-1.93 (2H, m), 1.93-2.04 (2H, m), 2.29 (2H, m), 2.45 (2H, q, J = 7.0), 2.78 (2H, m), 4.15 (1H, m), 6.51 (IH, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.81 ( IH, d, J = 8.5). Reference Example 12

N- [3-Chloro-41- (1-ethylpiperidine-1-yloxy) phenyl 1 Sulfamoyl acetate

3-Chloro-4- (1-ethylpiperidine-4-yloxy) aniline (853 mg) obtained in Reference Example 11 was dissolved in dichloromethane (, 20 ml), and ethyl chlorosulfonyl acetate (0.45 ml) was dissolved under ice-cooling. And pyridine (0.54 ml) were added dropwise. For 4 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / Z methanol = 3 ：:! ~ 11) to obtain 113 mg of the title compound (82% yield). ) Was obtained as a tan amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.15 (3H, t, J = 7.0), 1.34 (3H, t, J = 7.0), 1.87-2.00 (2H, m), 2.00-2.13 (2H, m ), 2.40-2.60 (4H, m), 2.70-2.83 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.43 (1H, m), 6.93 (1H, d , J = 9.0), 7.21 (1H, dd, J = 9.0, 2.5), 7.40 (1H, d, J = 2.5).

N- [3-Chloro-41- (1-ethylpiperidine-41-yloxy) phenyl] -N- [3- (3-Cyanophenyl) -l2- (E) -probenyl] ethyl sulfamoyl acetate)

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 1-year-old (0.48 g), [3-chloroopening 4 obtained in Reference Example 12 1- (1-ethylpiperidine-1-4-yloxy) phenyl] Ethyl sulfamoylacetate (1.11 g) and triphenylphosphine (0.87 g) are dissolved in dichloromethane (20 ml), and azodicarboxylic acid is added under ice cooling. After getyl (0.5 1 ml) was added dropwise, the mixture was stirred at room temperature for 1 B. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/3 to 1Z1) to give 1.24 g of the target compound (83% yield). Was obtained as an orange amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) (5 ppm: 1.12 (3H, t, J = 7.0), 1.36 (3H, t, J = 7,0), 1.86-1.98 (2H, m), 1.98-2.10 ( 2H, m), 2.35-2.50 (2H, m), 2.48 (2H, q, J = 7.0), 2.73 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.43 (1H, m), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.93 (1H, d, J = 9.0), 7.31 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 7.5), 7.48-7.58 (4H, m). Reference Example 14 3-Clot mouth 4- (1-Isopropylpiperidine-4-yloxy) nitrobenzene 3-Clot mouth-4- (piperidine-4-yloxy) nitrobenzene obtained in Reference Example 8 (1.50 g) Was suspended in acetone (20 ml), acetic acid (0.33 ml) and sodium cyanoborohydride (0.18 g) were added under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. Due to the slow progress of the reaction, sodium cyanoborohydride (0.18 g) was added, and after stirring for 3 hours, acetic acid (0.33 ml) and sodium cyanoborohydride (0.18 g) were added. Thereafter, the mixture was further stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of potassium carbonate, and extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.36 g (yield 78%) of the title compound as a yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.09 (6H, d, J = 6.5), 1.90-2.00 (2H, m), 2.00-2.15 (2H, m), 2.45-2.60 (2H, m), 2.75-2.90 (3H, m), 4.59 (IH, m), 6.98 (1H, d, J = 9.0), 8.13 (1H, dd, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0) Reference example 15

3—Black mouth— 4— (1-Isopropylpiperidine—41-yloxy) aniline

3-Chloro-41- (1-isopropylpyridine-4-yloxy) nitrobenzene (1.36 g) obtained in Reference Example 14 was dissolved in acetic acid (30 ml), and the powder (2.70 g) was added at room temperature. ) And stirred at the same temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of potassium carbonate, extracted three times with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 5 to 1Z1) to obtain 0.99 g (yield 81%) of the title compound as a brown oily substance As obtained.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.15 (6H, d, J = 6,5), 1.80-2.20 (4H, m), 2.66 (2H, m), 2.97 (2H, m), 3.03 (1H, m), 4.27 (1H, m), 6.52 (IH, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.80 (IH, d, J = 8.5). Reference example 16 N- [3-Chloro-4 (1-isopropylpiperidine-1-yloxy) phenyl] sulfamoyl acetate

3-Chloro-41- (1-isopropylpiperidine-141-yloxy) aniline (985 mg) obtained in Reference Example 15 was dissolved in dichloromethane (20 ml), and ethyl chlorosulfonyl acetate (0. After dropwise adding 49 ml) and pyridine (0.59 ml), the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and extracted twice with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10/1 to 31) to give 1094 mg (yield 71%) of the title compound as an orange amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.10 (6H, d, J = 6.5), 1.33 (3H, t, J = 7.0), 1.84-1.98 (2H, m), 1.98-2.12 (2H, m ), 2.50 (2H, m), 2.76-2.90 (3H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.39 (1H, m), 6.93 (IH, d, J = 9.0), 7.20 (IH, dd, J = 9.0, 2.5), 7.39 (1H, d, J = 2.5). Reference Example 17

N- [3-Chloro-41- (4-yloxy) phenyl] -N- [3- (3-Cyanophenyl) -2- (E) -probenyl] ethyl ethyl sulfamoylacetate

3- (3-Cyanophenyl) 1-2- (E) -propene-11-all obtained in Reference Example 2 (0.46 g), N- [3-chloro-41- (4-chloro-4-) obtained in Reference Example 16 1-Isopropylpiperidine-141-yloxy) phenyl] Sulfamoyl acetate ethyl (1.09 g) and triphenylphosphine (0.82 g) are dissolved in dichloromethane (30 ml), and acetyl dicarboxylate (0. (48 ml) was added dropwise, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate = 1/2 to 1Z1) to give 1.17 g (yield 80%) of the title compound. Obtained as a yellow oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.08 (6H, d, J = 6.5), 1.36 (3H, t, J = 7.0), 1.84-1.95 (2H, m), 1.95-2.09 (2H, m ), 2.47 (2H, m), 2.72-2.88 (3H, m), 3.99 (2H, m) s), 4.31 (2H, q, J = 7.0), 4.41 (1H, m), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d , J = 16.0), 6.92 (1H, d, J = 9.0), 7.31 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.48-7.58 (4H, m). Reference Example 1 8

4- (1-butylpiperidine-4-yloxy) -1-3-chloronitrobenzene

3-Chloro-41- (piperidine-1-yloxy) nitrobenzene (1.50 g) and butyraldehyde (1.04 ml) obtained in Reference Example 8 were dissolved in dichloromethane (30 ml) and cooled on ice. Acetic acid (0.333 ml) and sodium cyanoborohydride (0.18 g) were added thereto, and the mixture was stirred at room temperature for 3 hours. Due to the slow progress of the reaction, sodium cyanoborohydride (0.18 g) was added, and the mixture was further stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with water, an aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1/20) to give 0.88 g (yield 48%) of the title compound as a yellow oil. Obtained as material.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 0.94 (3H, t, J = 7.5), 1.35 (2H, m), 1.53 (2H, m), 1.92-2.04 (2H, m), 2.04-2.15 ( 2H, m), 2.44 (2H, m), 2.53 (2H, m), 2.75 (2H, m), 4.62 (1H, m), 6.99 (1H, d, J = 9.0), 8.13 (1H, dd, J = 9.0, 2.5), 8.30 (1H, d, J = 2.5).

4- (1-butylpiperidine-1-yloxy) — 3-chloroaniline

Reference Example 18 The 4- (1-butylpyperidine-14-yloxy) -13-chloro mouth nitrobenzene (1.48 g) obtained in Example 8 was dissolved in acetic acid (3 Oml) and powdered at room temperature (2.8 1 g), and the mixture was stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was neutralized with an aqueous solution of sodium hydrogen carbonate, extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography. Purification by chromatography (elution solvent: dichloromethane / methanol = 5/1 to 3/1) gave 1.09 g (82% yield) of the title compound as a brown oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 0.93 (3H, t, J = 7.5), 1.34 (2H, m), 1.60 (2H, m), 1.92-2.02 (2H, m), 2.08-2.18 ( 2H, m), 2.62 (2H, m), 2.79 (2H, m), 2.94 (2H, m), 4.31 (1H, m), 6.52 (1H, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.79 (1H, d, J = 8.5). Reference example 20

N- [4- (1-butylbiperidine-1 4-yloxy) —3-chlorophenyl] sulfamoyl acetate

The 4- (1-butylpiperidine-4-yloxy) -3-chloroaniline (1.09 g) obtained in Reference Example 19 was dissolved in dichloromethane (20 ml), and the mixture was dissolved in ice-cooled ethyl chlorosulfonyl acetate (1.0 ml). 0.52 m 1) and pyridine (0.62 m O) were added dropwise, and the mixture was stirred overnight at room temperature.The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and concentrated. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / zinc solvent = 20 / :! ~ 9Z1). 1.41 g (yield 84%) of the title compound were obtained as a brown amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 0.93 (3H, t, J = 7.5), 1.34 (3H, t, J = 7.0), 1.28-1.38 (2H, m), 1.54 (2H, m), 1.86-1.99 (2H, m), 2.02-2.15 (2H, m), 2.40-2.60 (4H, m), 2.79 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0 ), 4.41 (1H, m), 6.93 (1H, d, J = 9.0), 7.21 (1H, dd, J = 9.0, 2.5), 7.40 (1H, d, J = 2.5).

N— [4 -— (1-Phtylpiperidine—4-yloxy) -1-3-chlorophenyl) -1-N- [3- (3-Cyanophenyl) —2 -— (E) -probenyl] sulfamoyl acetate JV

3- (3-Cyanophenyl) —2— (E) —propene obtained in Reference Example 2 (0.57 g), N- [4- (1-butylpyperidine-4 ^-(roxy) -3-chlorophenyl] sulfamoylacetate (1.41 g) obtained in Reference Example 20 and triethylamine Phenylphosphine (1.02 g) was dissolved in dichloromethane (30 ml), and azodiphenol geronate (0.60 ml) was added dropwise under ice-cooling, followed by stirring at room temperature overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/20 to 1/10) to give 1.17 g of the title compound (63% yield). %) As a tan oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 0.93 (3H, t, J = 7.5), 1.36 (3H, t, J = 7.0), 1.28-1.40 (2H, m), 1.48-1.60 (2H, m ), 1.85-2.00 (2H, m), 2.00-2.15 (2H, m), 2.38-2.58 (4H, m), 2.77 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.38-4.52 (IH, m), 4.46 (2H, d, J-6.5), 6.22 (IH, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.93 ( IH, d, J = 9.0), 7.31 (1H, dd, J = 9.0, 2.5), 7.40 (IH, t, J = 8.0), 7.48-7.58 (4H, m).

4- (1-Benzylpiperidine-4-yloxy) -1-3-chloronitrobenzene The 3-chloro-4- (piperidine-14-yloxy) nitrobenzen (1.00 g) obtained in Reference Example 8 was added to N, N —Dissolved in dimethylformamide (20 ml), benzylpromamide (0.56 ml) and potassium carbonate (0.81 g) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate == 2Z only with 5-ethyl acetate) to obtain 1.02 g of the title compound (yield 75%). %) As a yellow oil.

_{¾ NMR (400 MHz, CDC1 3} ) d ppm: 1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 2.42 (2H, m), 2.72 (2H, m), 3.55 (2H, s) , 4.58 (IH, m), 6.97 (1H, d, = 9.0), 7.23-7.37 (5H, m), 8.12 (1H, dd, J = 9.0, 2.5), 8.30 (1H, d, J = 2.5) . Reference Example 23

4-((1-benzylpiperidine-1 4-yloxy) 3-1-chloroaniline Dissolve 4- (1-benzylpiperidine-1-yloxy) -13-chloronitrobenzene (1.02 g) obtained in Reference Example 22 in acetic acid (40 ml), and powder at room temperature (1.75 g). Was added and stirred at the same temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extract was washed sequentially with an aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate Z methanol = 10Z1) to obtain 0.78 g (yield 84%) of the title compound as a brown oil. Obtained.

_{1H NMR (400 MHz, CDC1 3} ) d ppm: 1.80-1.90 (2H, m), 1.90-2.00 (2H, m), 2.26 (2H, m), 2.76 (2H, m), 3.52 (2H, s) , 4.12 (1H, m), 6.50 (1H, dd, J = 8.5, 3.0), 6.72 (1H, d, J = 3.0), 6.80 (1H, d, J = 8.5), 7.25 (1H, m), 7.28-7.36 (4H, m). Reference example 24

N— [4- (1-benzylpiperidine-1-4-yloxy) -1-3-chlorophenyl] sulfamoyl acetate

The 4- (1-benzylpiperidine-14-yloxy) -13-chloroaniline (780 mg) obtained in Reference Example 23 was dissolved in dichloromethane (20 ml), and the mixture was cooled with ice and chlorosulfonyl acetate ethyl (0.35 ml). ) And pyridine (0.40 ml) were added dropwise, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate Z methanol = 25 Z2) to give 1018 mg (89% yield) of the title compound as a tan amorphous solid. Obtained.

^{X H NMR (400 MHz, CDC1} 3) δ ppm: 1.33 (3H, t, J = 7.0), 1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.36 (2H, m), 2.73 (2H, m), 3.54 (2H, s), 3.91 (2H, s), 4.29 (2H, q, J = 7.0), 4.37 (1H, m), 6.92 (1H, d, J-9.0), 7.19 (1H, dd, J = 9.0, 2.5), 7.27 (1H, m), 7.29-7.37 (4H, m), 7.38 (1H, d, J = 2.5). Reference Example 25

N- [4 -— (1-Benzylpiperidine-1-4-yloxy) -1-3-chlorophenyl] -N— [3- (3-Cyanophenyl) 1-2— (E) —Probenyl] Sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (0.36 g), N- [4- (1-1-1) obtained in Reference Example 24 Benzylpiperidine-14-yloxy-13-chlorophenyl) ethyl sulphamoylacetate (1.02 g) and triphenylphosphine (0.69 g) were dissolved in dichloromethane (20 ml), and the mixture was dissolved in ice-cooled getyl azodicarboxylate. (0.40 ml) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1.53 g (quantitative yield) of the title compound as a yellow-brown oily substance. .

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.35 (3H, t, J = 7.0), 1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.36 (2H, m), 2.71 ( 2H, m), 3.53 (2H, s), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.40 (1H, m), 4.46 (2H, d, J = 6.5), 6.22 ( 1H, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.91 (IH, d, J = 9.0), 7.23-7.37 (6H, m), 7.40 (1H, t, J = 8.0), 7.44-7.58 (4H, m). Reference Example 26

3-Chloro-41- (1-phenethylpiperidine-1-yloxy) nitrobenzene 3-chloro-4- (piperidine-1_4-yloxy) nitrobenzen (957 mg) obtained in Reference Example 8 was converted to N, N-dimethyl After dissolving in formamide (20 ml), phenethyl bromide (0.61 ml) and potassium carbonate (770 mg) were added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane_ethyl acetate = 1/5-only ethyl acetate) to give 936 mg of the title compound (70% yield). ) Was obtained as a pale yellow solid.

¾ image _{R (400 MHz, CDC1 3)} δ ppm: 1.93-2.03 (2H, m), 2.03-2.13 (2H, m), 2.46-2.59 (2H, m), 2.61-2.71 (2H, m), 2.73-2.88 (4H, m), 4.61 (1H, m), 6.99 (1H, d, J = 9.0), 7.17-7.24 (3H , M), 7.24-7.34 (2H, m), 8.13 (1H, dd, J = 9.0, 3.0), 8.31 (1H, d, J = 3.0). Reference Example 27

3-chloro-4- (1-phenethylpiperidine-1-yloxy) aniline

Dissolve nitrobenzene (936 mg) in acetic acid (40 ml) in 3-acetic acid (4-1 mg) obtained in Reference Example 26, and add tin powder (154 mg) at room temperature. The mixture was stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed sequentially with an aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10: 1) to give 72 Omg (84% yield) of the title compound. Obtained as a yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.83-1.95 (2H, m), 1: 95-2.06 (2H, m), 2.37 (2H, m), 2.58-2.67 (2H, m), 2.77- 2.91 (4H, m), 4.16 (1H, m), 6.52 (1H, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.82 (1H, d, J = 8.5), 7.17 -7.24 (3H, m), 7.24-7.32 (2H, m).

N— [3-Chloro-4- (1-phenethylpiperidine-1 4-yloxy) phenyl] sulfamoyl acetate

3-Chloro-41- (1-phenethylpiperidine-14-yloxy) aniline (72 Omg) obtained in Reference Example 27 was dissolved in dichloromethane (20 ml), and the solution was cooled under ice-cooling. After dropwise addition of 31 ml) and pyridine (0.35 ml), the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with aqueous sodium hydrogen carbonate solution and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: Purification by ethyl acetate (methyl acetate = 25/2) gave 936 mg (89% yield) of the title compound as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 2.48 (2H, m), 2.60- 2.70 (2H, m), 2.76-2.89 (4H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.41 (IH, m), 6.93 (IH, d, J = 9.0 ), 7.18-7.24 (4H, m), 7.24-7.33 (2H, m), 7.39 (IH, d, J = 2.5).

N- [3-—Mouth—41- (1-phenethylbiperidine-1-4-yloxy) phenyl] -N- [3 -— (3-Cyanophenyl) 1-2— (E) 1-probenyl] ethyl ethyl sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene-1-ol obtained in Reference Example 2 (325 mg), N- [3-Cro mouth 1-4- obtained in Reference Example 28 1-Phenethylbiperidine- (1-yloxy) phenyl] Sulfamoyl acetate (936 mg) and triphenylphosphine (610 mg) were dissolved in dichloromethane (20 ml), and acetyl dipyrogenate (0.36 ml) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 1Z2-ethyl acetate only) to give 1013 mg (84% yield) of the title compound as a pale yellow amorphous Obtained as a solid.

^{1 H NMR (500 MHz, CDC1} 3) δ ppm: 1.36 (3H, t, J = 7.0), 1.87-1.98 (2H, m), 1.98-2.09 (2H, m), 2.47 (2H, m), 2.60 -2.68 (2H, m), 2.76-2.87 (4H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.43 (IH, m), 4.46 (2H, d, J = 6.5), 6.22 (IH, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.93 (IH, d, J = 9.0), 7.17-7.23 (3H, m), 7.23-7.34 (3H, m), 7.40 (1H, t, J = 8.0), 7.48-7.58 (4H, m). Reference example 30

3-Chloro-41- (1-phenylbiperidine-1 4-fluoro) nitrobenzene 3-Chloro-41- (piperidine-1-41 ^ T-loxy) nitrobenzene obtained in Reference Example 8 (2.68'g), bromobenzene (1.97 g), 2- (di-t-butylphosphino) piphenyl (0.62 g), tris (dibenzylideneacetone) dipalladium (0.95 g) , And sodium t-butoxide (1.20 g) were suspended in toluene (30 ml), and the mixture was stirred at 80 ° C for 2 hours. After the reaction solution was cooled to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. After the residue was diluted with ethyl acetate, the residue was washed with an aqueous solution of sodium hydrogencarbonate and a saturated saline solution in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: hexane Z: ethyl acetate = 4/1) to give 1.86 g of the title compound (54% yield). ) Was obtained as a yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 2.00-2.10 (2H, m), 2.11-2.21 (2H, m), 3.24 (2H, m), 3.48 (2H, m), 4.73 (1H, m) , 6.88 (1H, t, J = 7.5), 6.95-7.00 (2H, m), 7.03 (1H, d, J = 9.0), 7.25-7.32 (2H, m), 8.15 (1H, dd, J = 9.0) , 3.0), 8.31 (1H, d, J = 3.0).

3—black mouth— 4_ (1-phenylpiperidine—4-yloxy) aniline

Dissolve nitrobenzene (1.86 g) nitrobenzene (1.86 g) obtained in Reference Example 30 in acetic acid (35 ml), and add tin powder (3.32 g) at room temperature. In addition, the mixture was stirred at the same temperature for 1 hour. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate solution and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.69 g (quantitative yield) of the title compound as a pale yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.90-2.01 (2H, m), 2.03-2.12 (2H, m), 3.07 (2H, m), 3.55 (2H, m), 4.27 (1H, m) , 6.53 (1H, dd, J = 8.5, 3.0), 6.74 (1H, d, J = 3.0), 6.81-6.87 (1H, m), 6.84 (1H, d, J = 8.5), 6.96 (2H, d , J = 8.0) 7.23-7.29 (2H, m).

N— [3—black mouth—4— (1-phenylbiperidine-1-4-yloxy) phenyl] sulfamoyl acetate

3-cyclomouth-4- (1-phenylpiperidine-4-yloxy obtained in Reference Example 31) B) Dissolve aniline (1.69 g) in dichloromethane (25 ml) and add a solution of ethyl sulfonyl acetate (1.15 g) in dichloromethane (5 ml) and pyridine (0.50 ml) under ice-cooling. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous solution of sodium salt to the reaction mixture, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate Z hexane = 2/3) to obtain 2.23 g of the title compound (88% yield). Was obtained as a colorless oil.

_{¾ NMR (400 MHz, CDC1 3} ) d ppm: 1.34 (3H, t, J = 7.0), 1.95-2.05 (2H, m), 2.06-2.15 (2H, m), 3.17 (2H, m), 3.50 ( 2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.52 (1H, m), 6.86 (1H, t, J = 7.5), 6.94-7.00 (2H, m), 6.97 (1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 2.5), 7.25-7.30 (2H, m), 7.40 (IH, d, J = 2.5). Reference Example 33

N— [3-Chloro-41- (1-phenylbiperidine-14-yloxy) phenyl] -1-N— [3- (3-Cyanophenyl) —2 -— (E) —Probenyl] ethyl sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene 1-1-4 (0.41 g) obtained in Reference Example 2, N- [3-chloro-4-1-1 (1-Phenylpyridine-l-4T oxy) phenyl] Ethyl sulfamoylacetate (1.16 g) and triphenylphosphine (0.87 g) were dissolved in dichloromethane (25 ml), and azodicarboxylic acid was added under ice-cooling. After getyl (0.52 ml) was added dropwise, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / dichloromethane = 1/12) to give 1.45 g of the title compound.

(95% yield) as a colorless amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) d ppm: 1.36 (3H, t, J = 7.0), 1.95-2.05 (2H, m), 2.06-2.16 (2H, m), 3.18 (2H, m), 3.49 ( 2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.0), 4.55 (1H, m), 6.23 (IH, dt, J = 16.0 , 6.0), 6.42 (1H, d, J = 16,0), 6.86 (IH, t, J = 7.5), 6.93-6.99 (2H, m), 6.97 (IH, d, J = 9.0), 7.24- 7.30 (2H, m), 7.33 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 7.5), 7.49-7.58 (4H, m). Reference Example 34

3—Mouth—4— (1-Methoxycarbonylmethylpiperidine-1 4-yloxy)

Dissolve 3- (cloper) -4- (piperidine-141-yloxy) nitrobenzene (1.00 g) obtained in Reference Example 8 in N, N-dimethylformamide (20 ml), and cool under ice-cooling. After adding methyl lomoacetate (0.43 ml) and potassium carbonate (0.81 g), the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 1.16 g (yield 90%) of the title compound as a yellow oily substance.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.93-2.04 (2H, m), 2.04-2.15 (2H, m), 2.59-2.69 (2H, m), 2.73-2.83 (2H, m), 3.29 ( 2H, s), 3.74 (3H, s), 4.62 (1H, m), 6.98 (1H, d, J = 9.0), 8.13 (1H, dd, J = 9.0, 2.5), 8.31 (1H, d, J = 2.5). Reference Example 35

3-chloro-4- (1-methoxycarbonylmethylbiperidine-4-yloxy) aniline

3-Chloro-4- (1-methoxycarbonylmethylpiperidine-4-yloxy) nitrobenzene (1.16 g) obtained in Reference Example 34 was dissolved in acetic acid (30 ml), and tin powder (2.09 g) was added at room temperature. Was added and stirred at the same temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate = 25/1) to give 0.79 g of the title compound. (75% yield) as a yellow oil.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.87-1.95 (2H, m), 1.95-2.03 (2H, m), 2.43-2.53 (2H, m), 2.77-2.86 (2H, m), 3.25 (2H, s), 3.73 (3H, s), 4.17 (1H, m), 6.51 (1H, dd, J = 8.5, 3.0 ), 6.73 (1H, d, J = 3.0), 6.80 (1H, d, J = 8.5).

N— [3-Chloro-41- (1-methoxycarbonylmethylbiperidine-1 4-yloxy) phenyl] sulfamoyl acetate

Dissolve 3-chloro-1- (1-methoxycarbonylmethylpiperidine_4-yloxy) aniline (0.79 g) obtained in Reference Example 35 in dichloromethane (20 ml), and add ethyl chlorosulfonyl acetate (20 ml) under ice-cooling. 0.37 ml) and pyridine (0.43 ml) were added dropwise, and the mixture was stirred at room temperature. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 1.06 g (yield 89%) of the title compound as a yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 1.34 (3H, t, J = 7.0), 1.90-1.99 (2H, m), 1.99-2.08 (2H, m), 2.53-2.62 (2H, m) , 2.75-2.84 (2H, m), 3.27 (2H, s), 3.74 (3H, s), 3.91 (2H, s), 4.30 (2H, q, J = 7.0), 4.41 (1H, m), 6.92 (1H, d, J = 9.0), 7.20 (1H, dd, J = 9.0, 2.5), 7.39 (1H, d, J = 2.5). Reference Example 37

N-[3-Chloro-4 _ (1-methoxycarbonylmethylpiperidine-1-yloxy) phenyl] 1-N-[3-(3-Cyanophenyl) 1-2-(E) 1-propenyl] ethyl sulfamyl acetate.

3- (3-Cyanophenyl) -1- (E) -propene obtained in Reference Example 2 (0.39 g), N- [3--black-mouth obtained in Reference Example 36 4- (1-Methoxycarbonylmethylpiperidine-1-4-yloxy) phenyl] Sulfamoylethyl acetate (1.06 g) and triphenylphosphine (0.74 g) are dissolved in dichloromethane (30 ml), and the mixture is dissolved in ice (30 ml). After dropwise addition of getyl acid (0.44 ml), 晚 Stirred. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1.70 g (quantitative yield) of the title compound as a yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.90-1.99 (2H, m), 1.99-2.08 (2H, m), 2.54-2.63 (2H, m), 2.75-2.84 (2H, m), 3.27 (2H, s), 3.73 (3H, s), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.45 (1H, m), 4.46 ( 2H, d, J = 6.5), 6.22 (IH, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.92 (1H, d, = 9.0), 7.31 (IH, dd, J = 9.0, 2.5), 7.40 (IH, t, J = 8.0), 7.44-7.58 (4H, m).

N— [4— (1-Acetylpiperidine—4-yloxy) 1-3 _black phenyl] Sulfamoyl acetate

4- (1-Acetylpiperidine-1 4-yloxy) _3-chloroaniline (65 Omg) obtained in Reference Example 10 was dissolved in dichloromethane (20 ml), and the mixture was dissolved in ice-cooled ethyl chlorosulfonyl acetate (0. After dropwise addition of 33 ml) and pyridine (0.39 ml), the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate only to ethyl acetate Z methanol = 10/1) to give 773 mg (yield 76%) of the title compound as an orange oily substance.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.82-1.98 (4H, m), 2.13 (3H, s), 3.47 (1H, m), 3.63 (IH, m), 3.72 (1H, m), 3.84 (1H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.60 (1H, m), 6.94 (IH, d, J = 9.0), 7.23 (IH, dd, J = 9.0, 2.5), 7.41 (IH, d, J = 2.5) .Reference example 39

N- [4- (1-Acetylpiperidine-1-4-yloxy)-3-chlorophenyl] -N- [3--(3-Cyanophenyl) -2- (E) -Prodionyl sulfamoyl acetate Chill

3- (3-Cyanophenyl) -12- (E) monopropene-1-ol (323 mg) obtained in Reference Example 2, N- [4- (1-acetylpiperidine) obtained in Reference Example 38 — 4-yloxy) 1-3-chlorophenyl] ethyl ethyl sulfamylacetate (773 mg) and triphenylphosphine (581 mg) are dissolved in dichloromethane (20 ml), and acetyl diazotyl ruponate (0.34 ml) is dissolved under ice-cooling. After the dropwise addition, the mixture was stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate only to ethyl acetate Z methanol = 9/1) to give 33 mg of the title compound (71% yield). Obtained as a pale yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.82-1.98 (4H, m), 2.12 (3H, s), 3.48 (1H, m), 3.61 (IH, m), 3.70 (1H, m), 3.85 (1H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.63 (1H, m), 6.22 (1H, dt, J = 16.0, 6.5), 6.42 (IH, d, J = 16.0), 6.94 (IH, d, J = 9.0), 7.34 (1H, dd, J = 9.0, 2.5) , 7.41 (1H, t, J = 8.0), 7.48-7.58 (4H, m). Reference example 40

4- (1-Lumbamoylbiperidine-4-yloxy) -1-3-chloronitrobenzene The 3-chloro-41- (piperidine-4-yloxy) nitrobenzene (500 mg) obtained in Reference Example 8 was converted to N, The residue was dissolved in N-dimethylacetamide (10 ml), and potassium cyanate (790 mg) was added thereto under ice cooling, followed by stirring at room temperature. Since the progress of the reaction was slow, potassium cyanate (790 mg) was added, the mixture was stirred at −40 ° C., and 4N hydrogen chloride dioxane solution (1.0 ml) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed sequentially with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the solvent was distilled off under reduced pressure to obtain 523 mg (yield: 88%) of the title compound as a pale yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) 6 ppm: 1.53-1.67 (2H, m), 1.86-2.00 (2H, m), 3.18-3.31 (2H, m), 3.51-3.64 (2H, m), 4.92 ( 1H, m), 7.49 (IH, d, J = 9.0), 8.20 (1H, dd, J = 9.0, 2.5), 8.33 (IH, d, J = 2.5). Reference Example 41

4- (1 rubamoyl piperidine 1-4-yloxy) 1-3-chloroaniline

4- (1-Rubamoylbiperidine-14-yloxy) -13-chloronitrobenzene (1.25 g) obtained in Reference Example 40 was dissolved in acetic acid (30 ml), and powdered tin (2. 47 g) was added thereto, followed by stirring at the same temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 201) to give 0.91 g (81% yield) of the title compound as a pale orange color Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.80-1.96 (4H, m), 3.30-3.40 (2H, m), 3.62-3.72 (2H, m), 4.33 (1H, m), 6.52 (1H, dd, J = 8.5, 3.0), 6.74 (1H, d, J = 3.0), 6.81 (1H, d, J = 8.5). Reference example 42

N— [4- (1-Lumbamoylpiperidine-1 4-yloxy) -3-cyclophenyl] sulfamoyl acetate

4- (1-l-rubamoylpiperidine-14-yloxy) -13-, chloroaniline (907 mg) obtained in Reference Example 41 was dissolved in dichloromethane (20 ml), and chlorosulfonyl acetate ethyl chloride (20 ml) was dissolved under ice-cooling. (0.45 ml) and diisopropylethylamine (0.88 ml) were added dropwise, followed by stirring at room temperature overnight. Since the progress of the reaction was slow, chlorosulfonyl ethyl acetate (0.05 ml) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30Z1 to 20Z1) to obtain 809 mg (57% yield) of the title compound as a pale yellow amorphous solid As obtained.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.83-1.99 (4H, m), 3.47 (2H, m), 3.61 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.58 (1H, m), 6.94 (1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 2,5), 7.41 (1H, d, J = 2.5). Reference Example 43, N— [4— (1—Lubamoylpiperidine-1 4— Iloxy) i 3—black mouth phenyl]

-N- [3- (3-Cyanophenyl) -1-2- (E) -probenyl] sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (322 mg), N- [4- (1-Ichiriki Lubamoyl) obtained in Reference Example 42 Piperidine-14-yloxy-1-3-cyclophenyl] ethyl sulphamoylacetate (809 mg) and triphenylphosphine (61 mg) are dissolved in dichloromethane (20 ml), and chilled ice-cooled getyl azolate (0.36 ml) under ice-cooling. ) Was added dropwise, followed by stirring at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1) to give 1015 mg (yield 94%) of the title compound as a pale yellow amorphous solid. Was.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.36 (3H, t, J = 7.0), 1.84-1.99 (4H, m), 3.48 (2H, m), 3.59 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.62 (1H, m), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d , J = 16.0), 6.94 (1H, d, J = 9.0), 7.33 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.49-7.57 (4H, m). Reference example 44

3-Chloro-41- (1-methanesulfonylbiperidine-14-yloxy) nitrobenzene

3-Chloro-41- (piperidine-4-yloxy) nitrobenzene (1.00 g) obtained in Reference Example 8 was suspended in dichloromethane (20 ml), and methanesulfonyl chloride (0.33 ml) and triethylamine were cooled under ice-cooling. (1.09 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 11), 0.96 g (yield 73%) of the title compound was obtained as a colorless amorphous solid.

_{1H NMR (500 MHz, CDC1 3} ) d ppm: 2.06-2.14 (4H, m), 2.84 (3H, s), 3.29 (2H, m), 3.55 (2H, m), 4.82 (1H, m), 7.00 (1H, d, J = 9.0), 8.16 (1H, dd, J = 9.0, 2.5), 8.33 (1H, d, J = 2.5). Reference example 45

3-Chloro-41- (1-methanesulfonylpiperidine-1-4-yloxy) aniline 3-Chloro-4- (1-methanesulfonylbiperidine-1-4-yloxy) nitrobenzene (955 mg) obtained in Reference Example 44 was converted to acetic acid (955 mg). 30 ml), tin powder (169 Omg) was added at room temperature, and the mixture was stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 5Z3) to give 737 mg (85% yield) of the title compound as a yellow amorphous solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.92-2.08 (4H, m), 2.81 (3H, s), 3.33-3.45 (4H, m), 4.38 (1H, m), 6.54 (1H, dd, J = 8.5, 3.0), 6.74 (1H, d, J = 3.0), 6.80 (1H, d, J = 8.5).

N— [3-Chloro-4 -— (1-methanesulfonylpiperidine—4-yloxy) phenyl] sulfamoylacetyl acetate-3-chloro mouth obtained in Reference Example 45—4— (1-methanesulfonylpiperidine-1--4-) (Iroxy) aniline (737 mg) was dissolved in dichloromethane (20 ml), chlorosulfonyl acetate ethyl (0.33 ml) and pyridine (0.39 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and then the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z hexane = 32) to obtain 805 mg of the title compound (yield 7). 3%) was obtained as a pink amorphous solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.26 (3H, t, J = 7.0), 1.96-2.10 (4H, m), 2.82 (3H, s), 3.31 (2H, m), 3.47 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.62 (1H, m), 6.93 (1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 2.5 ), 7.42 (1H, d, J = 2.5).

N— [4— (1 _ Power-l-bamoylpiperidine- 1 _ 4-yloxy) 1-3-Clo-phenyl) 1 N— [3 -— (3-Cyanophenyl) —2— (E) —Probenyl] Sulfamoyl acetate

3- (3-Cyanophenyl) _2- (E) 1-propene-1-ol obtained in Reference Example 2 (296 mg), N- [3-Cro mouth 1-4- (1 Ethyl monomethanesulfonylpiperidine-14-yloxy) phenyl] sulfamoylacetate (805 mg) and triphenylphosphine (560 mg) were dissolved in dichloromethane (20 ml), and under ice-cooling, azodicarboxylic acid geronate (0.33 ml) was added dropwise. Thereafter, the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 20Z1-10 / 1) to give 835 mg of the title compound (79% yield) as a colorless solid Obtained as a shaped solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.96-2.09 (4H, m), 2.82 (3H, s), 3.30 (2H, m), 3.48 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.65 (1H, m), 6.22 (1H, dt, J = 16.0, 6.5 ), 6.42 (1H, d, J = 16.0), 6.94 (1H, d, J = 9.0), 7.35 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 7.5), 7.50- 7.55 (2H, m), 7.56 (IH, s), 7.56 (1H, d, J = 2.5).

3—Black mouth— 4— [1- (2-pyridyl) piperidine-1 4-yloxy] nitrobenzene

3-Chloro-41- (piperidine-41-yloxy) nitrobenzene (3.00 g) obtained in Reference Example 8 was suspended in pyridine (30 ml), and 2-bromopyridine (1. Was added and stirred at 150 ° C. for 16 hours. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/2) to obtain 0.80 g (yield 20%) of the title compound. Obtained as a yellow solid.

_{1H NMR (500 MHz, CDC1 3} ) <5 ppm: 1.93-2.06 (2H, m), 2.06-2.17 (2H, m), 3.60-3.72 (2H, m), 3.79-3.90 (2H, m), 4.79 (1H, m), 6.64 (1H, dd, J = 7.0, 5.0), 6.71 (1H, d, J = 8.5), 7.04 (1H, d, J = 9.0), 7.50 (1H, m), 8.16 ( 1H, dd, J = 9.0, 3.0), 8.20 (1H, dd, J = 5.0, 2.0), 8.32 (1H, d, J = 3.0).

3-Chloro-41- [1- (2-pyridyl) piperidine-41-yloxy] aniline 3-Chloro mouth obtained in Reference Example 48-4-1 [1-(2-Pyridyl) piperidine- 4-— [Iroxy] nitrobenzene (796 mg) was dissolved in acetic acid (40 ml), tin powder (1420 mg) was added at room temperature, and the mixture was stirred at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate Z hexane = 1Z1) to give 680 mg (94% yield) of the title compound as a pale red-violet oil Obtained as material.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.83-1.95 (2H, m), 1.97-2.07 (2H, m), 3.41 (2H, m), 3.95 (2H, m), 4.34 (1H, m) , 6.53 (1H, dd, J = 8.5, 3.0), 6.59 (1H, dd, J = 7.0, 5.5), 6.69 (1H, d, J = 8.5), 6.74 (1H, d, J = 3.0), 6.85 (1H, d, J = 8.5), 7.47 (1H, m), 8.19 (1H, m). Reference example 50

N- [3-—Mouth-one 4 -— [1- (2-Pyridyl) piperidine—4-yloxy] phenyl] sulfamoyl acetate

3-Chloro-4- [1- (2-pyridyl) piperidine-1-4- obtained in Reference Example 49 [Roxy] aniline (680 mg) was dissolved in dichloromethane (20 ml), chlorosulfonyl acetate ethyl (0.32 ml) and pyridine (0.36 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate, it was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl ethyl hexane = 1/1) to obtain 858 mg (yield 85%) of the title compound as a pale yellow amorphous solid As obtained.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 3.56 (2H, m), 3.86 ( 2H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.58 (1H, m), 6.61 (1H, m), 6.70 (1H, d, J = 8.5), 6.97 ( 1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 2.5), 7.40 (1H, d, J = 2.5), 7.48 (1H, m), 8.19 (1H, m).

N— [3-—Mouth— 4 -— [1- (2-Pyridyl) piperidine—4-yloxy] phenyl] N— [3 -— (3-Cyanophenyl) 1-2— (E) 1-Propenyl] sulfamoi Ethyl acetate

3- (3-Cyanophenyl) -2- (E) -propene-1-ol obtained in Reference Example 2 (316 mg), N- [3-Crosin mouth—4-— obtained in Reference Example 50 1- (2-Pyridyl) piperidine- [4-yloxy] phenyl] Sulfamoyl acetate ethyl ester (858 mg) and triphenylphosphine (59 Omg) are dissolved in dichloromethane (20 ml), and ice-cooled ezodipyrrugonic acid ethyl ester is dissolved. (0.35 ml) was added dropwise, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10: 1) to give 110 Omg (98% yield) of the title compound as a colorless solid. Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.36 (3H, t, J = 7.0), 1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 3.57 (2H, m), 3.84 ( 2H, m), 4.00 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.61 (1H, m), 6.23 (1H, dt, J = 16.0 , 6.5), 6.42 (1H, d, J = 16.0), 6.61 (1H, dd, J = 7.0, 5.0), 6.69 (1H, d, J = 8.5), 6.97 (1H, d, J = 9.0), 7.33 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.48 (1H, m), 7.50-7.58 (4H, m), 8.19 (1H, m).

3-black mouth-4-1 [1-1 (3-pyridyl) piperidine 1-4-yloxy] nitrobenzene

3-chloro-41- (piperidine-1-yloxy) nitrobenzene obtained in Reference Example 8 (2.72 g), 3-bromopyridine (2.01 g), 2- (di-tert-butylphosphino) After suspending pifenyl (0.32 g), tris (dibenzylideneacetone) dipalladium (0.49 g), and sodium t-butoxide (1.22 g) in toluene (30 ml), the suspension was heated to 70 ° C. For 2 hours. After the reaction solution was cooled to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed successively with an aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel gel chromatography (elution solvent: dichloromethane, Z methanol = 9/1) to obtain 1.56 g (yield 44%) of the title compound as a yellow color Obtained as a solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ? ppm: 2.03-2.22 (4H, m), 3.31 (2H, m), 3.49 (2H, m), 4.77 (1H, m), 7.03 (1H, d, J = 9.0), 7.18 (1H, dd, J = 8.5, 4.5), 7.24 (1H, m), 8.12 (1H, dd, J = 4.5, 1.5), 8.16 (1H, dd, J = 9.0, 3.0), 8.32 (1H, d, J = 3.0), 8.36 (1H, d, J = 3.0). Reference Example 53

3-Chloro-4- [1- (3-pyridyl) piperidine-4-4-yloxy] aniline 3-Chloro-4-1 [1- (3-pyridyl) piperidine-4-yloxy obtained in Reference Example 52 Nitrobenzene (1.54 g) was dissolved in acetic acid (3 Oml), tin powder (2.74 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, elute (eluent: dichloromethane / methanol = 9/1) to give 1.39 g (yield 99%) of the title compound as a yellow oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.92-2.11 (4H, m), 3.14 (2H, m), 3.56 (2H, m), 4.31 (1H, m), 6.53 (1H, dd, J = 9.0, 2.0), 6.74 (IH, d, J = 2.0), 6.84 (IH, d, J = 9.0), 7.16 (1H, dd, J = 8.5, 4.5), 7.21 (1H, m), 8.08 (1H , D, J = 4.5), 8.34 (1H, d, J = 2.5).

N- [3-Chloro-41- [1- (3-pyridyl) piperidine-4-yloxy] phenyl] sulfamoyl acetate

3-Chloro-41- [1- (3-pyridyl) piperidine-1-4-yloxy] aniline (1.38 g) obtained in Reference Example 53 was dissolved in dichloromethane (20 ml), and the solution was dissolved in chloroform under ice-cooling. After a solution of ethyl sulfonyl acetate (0.93 g) in dichloromethane (5 ml) and pyridine (0.37 ml) were added dropwise, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / z-methanol = 9/1) to give 1.61 g (yield 78%) of the title compound as a pale brown color Obtained as an amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.97-2.15 (4H, m), 3.24 (2H, m), 3.51 (2H, m), 3.93 (2H, s), 4.29 (2H, q, J = 7.0), 4.56 (1H, m), 6.97 (1H, d, J = 9.0), 7.18 (1H, dd, J = 8.5, 4.0), 7.21-7.28 (2H , m), 7.42 (IH, d, J = 2.5), 8.10 (IH, d, J = 4.0), 8.35 (lH, s).

N- [3-Chloro-4-[1- (3-pyridyl) piperidine-4-yloxy] phenyl] -N- [3- (3-Cyanophenyl) -1-2- (E) -probenyl] Sulfamoi Ethyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (294 mg), N- [3-chloro-4-1 [1-] obtained in Reference Example 54 (3—Pirizi G) Piperidine- [4-yloxy] phenyl] sulfamoyl acetate (840 mg) and triphenylphosphine (630 mg) are dissolved in dichloromethane (20 ml), and under ice-cooling, azodicarboxylic acid getyl (0.38 ml) is added dropwise. After that, the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97Z3) to obtain 206 Omg (yield quantitative) of the title compound as a yellow amorphous solid. Was.

_{1H NMR (400 MHz, CDC1 3} ) 6 ppm: 1.36 (3H, t, J = 7.0), 1.97-2.16 (4H, m), 3.25 (2H, m), 3.49 (2H, m), 4.00 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.60 (IH, m), 6.23 (1H, dt, J = 16.0, 6.5), 6.42 (1H, d , J = 16.0), 6.97 (1H, d, J = 9.0), 7.34 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.44-7.71 (6H, m), 8.10 (IH, m), 8.35 (IH, m). Reference Example 56

3-Chloro-4-1 [1-1 (4-pyridyl) piperidine-1 4-yloxy] nitrobenzene

Dissolve 3-chloro-41- (piperidine-1-yloxy) nitrobenzen (3.00 g) obtained in Reference Example 8 in N, N-dimethylformamide (30 ml) and add 41-bromopyridine at room temperature. (2.50 g) and N-methylmorpholine (5.14 ml) were added, and the mixture was stirred at 150 ° C for 7 hours. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol = 30Z1 to 10Z1) to obtain 1.27 g (yield 33) of the title compound as a dark yellow amorphous Obtained as a solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.98-2.14 (4H, m), 3.46-3.55 (2H, m), 3.58-3.67 (2H, m), 4.83 (1H, m), 6.72 (2H, d, J = 6.5), 7.03 (1H, d, J = 9.0), 8.16 (1H, dd, J = 9.0, 3.0), 8.28 (2H, d, J = 6.5), 8.32 (1H, d, J = 3.0). Reference Example 57 3-Chloro-41- [1- (4-pyridyl) piperidine-1-4-yloxy] aniline 3-Chloro-4-1 [1- (4-pyridyl) piperidine-1 4-f-roxy] obtained in Reference Example 56 Nitrobenzene (1.26 g) was dissolved in acetic acid (50 ml), tin powder (2.24 g) was added at room temperature, and the mixture was stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of potassium carbonate, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/1 to 1/1) to obtain a residue. 0.85 g (yield 74%) of the title compound was obtained as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.85-2.05 (4H, m), 3.30-3.38 (2H, m), 3.65-3.73 (2H, m), 4.37 (1H, m), 6.54 (1H, dd, J = 8.5, 3.0), 6.69 (2H, dd, J = 5.0, 1.5), 6.74 (1H, d, J = 3.0), 6.83 (1H, d, J = 8.5), 8.25 (2H, dd, J = 5.0, 1.5). Reference Example 58

N— [3-chloro-41- [1- (4-pyridyl) piperidine-1 4-yloxy] phenyl] sulfamoyl acetate

3-Chloro-41- [1- (4-pyridyl) piperidine-1-4-yloxy] aniline (854 mg) obtained in Reference Example 57 was dissolved in dichloromethane (20 ml), and ethyl chlorosulfonyl acetate was dissolved under ice-cooling. (0.40 ml) and pyridine (0.45 ml) were added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous potassium carbonate solution, extracted twice with ethyl acetate, and the extract was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane MeOH = 5Z1-2 to 1) to give 888 mg of the title compound (yield (70%) as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.33 (3H, t, J = 7.0), 1.94-2.07 (4H, m), 3.47 (2H, m), 3.65 (2H, m), 3.93 (2H, s), 4.29 (2H, q, J = 7.0), 4.63 (1H, m), 6.72 (2H, dd, J = 5.0, 1.5), 6.96 (1H, d, J = 9.0), 7.25 (1H, dd) , J = 9.0, 2.5), 7.43 (1H, d, J = 2.5), 8.26 (2H, dd, J = 5.0, 1.5). One: # 圑 ^ ¥ (% 6 £ ^ m SQZ-τ Q:

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Γ08680 / Ζ0 ΟΛ ^X H image _{R (500 MHz, CDC1 3)} δ ppm: 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 3.92-4.00 (2H, m), 4.00-4.08 (2H, m), 4.82 (IH, m), 6.51 (1H, t, J = 5.0), 7.04 (1H, d, J = 9.0), 8.16 (1H, dd, J = 9.0, 3.0), 8.32 (IH, d, J = 3.0), 8.33 (2H, d, J = 5.0). Reference Example 61

3-Chloro-4- [1- (2-pyrimidyl) piperidine-41-yloxy] aniline 3-Chloro-4- [1- (2-pyrimidyl) piperidine-1-4-yloxy] obtained in Reference Example 60 Nitrobenzene (1.29 g) was dissolved in acetic acid (40 ml), tin powder (2.28 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. After the extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 2Z1) to obtain 1.01 g (yield 86%) of the title compound as a brown oily substance. .

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.80-1.90 (2H, m), 1.92-2.02 (2H, m), 3.67 (2H, m), 4.20 (2H, m), 4.37 (1H, m) , 6.46 (IH, t, J = 4.5), 6.53 (IH, dd, J-8.5, 3.0), 6.74 (1H, d, J = 3.0), 6.85 (1H, d, J = 8.5), 8.30 (2H , d, J = 4.5). Reference example 62

N— [3-Chloro-41 CI- (2-pyrimidyl) piperidine-41-yloxy] phenyl] ethyl ethyl sulfamoylacetate

3-Chloro-41- [1- (2-pyrimidyl) piperidine-41-yloxy] aniline (1.01 g) obtained in Reference Example 61 was dissolved in dichloromethane (30 ml) and chlorosulfonyl under ice-cooling. After ethyl acetate (0.47 ml) and pyridine (0.53 ml) were added dropwise, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (elution solvent: ethyl hexanoacetate = 2 to 1 to 11). Thus, 1.29 g (yield 85%) of the title compound was obtained as a pale brown amorphous solid.

_{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.85 (2H, m), 3.93 ( 2H, s), 4.09 (2H, m), 4.30 (2H, q, J = 7.0), 4.61 (IH, m), 6.48 (1H, t, J = 4.5), 6.98 (IH, d, J = 9.0 ), 7.23 (1H, dd, J = 9.0, 2.5), 7.41 (1H, d, J = 2.5), 8.32 (2H, d, J = 4.5).

N— [3-Chloro-4-1 [1- (2-pyrimidyl) piperidine-1-41-yloxy] phenyl] -1-N— [3 -— (3-Cyanophenyl) -1-2- (E) —Probenyl] Sulfamo Ethyl acetate

3- (3-Cyanophenyl) obtained in Reference Example 2 — 2- (E) 1-propene-one-year-old (0.47 g), N- [3-chloro-4 obtained in Reference Example 6 2 I [1- (2-Pyrimidyl) piperidine-1-4-yloxy] phenyl] ethyl sulphamoyl acetate (1.29 g) and triphenylphosphine (0.89 g) were dissolved in dichloromethane (30 ml). Under ice cooling, acetyl azodicarboxylate (0.52 ml) was added dropwise, and the mixture was stirred at room temperature with stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 91) to give 1.59 g (94% yield) of the title compound as a colorless amorphous Obtained as a solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.36 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.87 (2H, m), 4.00 ( 2H, s), 4.06 (2H, m), 4.31 (2H, q, J = 7.0),

4.47 (2H, d, J = 6.5), 4.64 (1H, m), 6.23 (1H, dt, J = 16.0, 6.5), 6.43 (IH, d, J = 16.0),

6.48 (1H, t, J = 4.5), 6.98 (IH, d, J = 9.0), 7.34 (IH, dd, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.50-7.55 ( 2H, m), 7.55 (1H, d, J = 2.5), 7.57 (1H, s), 8.31 (2H, d, J = 4.5). Reference example 64 '

3-Chloro-4-1 [1- (3-pyridylmethyl) piperidine-4-yloxy] nitro mouth benzene

3-Cross mouth—4— (piperidine—41-yloxy) nitrobenze obtained in Reference Example 8. (1.OO g) was dissolved in N, N-dimethylformamide (20 ml), and 3- (bromomethyl) pyridine hydrobromide (1.08 g) and potassium carbonate (1.08 g) were dissolved at room temperature. After the addition, the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / Z methanol = 25/1) to obtain 0.98 g (yield 72%) of the title compound as a yellow oil. As obtained.

_{1H NMR (500 MHz, CDC1 3} ) d ppm: 1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 2.39-2.49 (2H, m), 2.65-2.75 (2H, m), 3.56 ( 2H, s), 4.60 (1H, m), 6.97 (1H, d, J = 9.0), 7.27 (1H, dd, J = 8.0, 5.0), 7.68 (1H, d, J = 8.0), 8.12 (1H , Dd, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0), 8.52 (1H, dd, J = 5.0, 1.5), 8.56 (1H, d, J = 1.5).

3-Chloro-4- [1- (3-pyridylmethyl) piperidine-1 4-yloxy] ani U>

3-Chloro-41- [1- (3-pyridylmethyl) piperidin-4-yloxy] nitrobenzene (980 mg) obtained in Reference Example 64 was dissolved in acetic acid (50 ml), and tin powder (1670 mg) was added at room temperature. In addition, the mixture was stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the remaining brew was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. After the extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel gel chromatography (elution solvent: dichloromethane / methanol = 10 / l to 5Zl) to give 874 mg (yield 98%) of the title compound as a pale yellow color Obtained as an oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.80-1.90 (2H, m), 1.90-2.00 (2H, m), 2.32 (2H, m), 2.76 (2H, m), 3.55 (2H, s) , 4.16 (1H, m), 6.51 (1H, dd, J = 8.5, 3.0), 6.72 (1H, d, J = 3.0), 6.80 (1H, d, J = 8.5), 7.27 (1H, m), 7.70 (1H, d, J = 7.5), 8.51 (1H, d, J = 6.5), 8.55 (1H, s). Reference Example 66

N- [3-Chloro-41- [1- (3-pyridylmethyl) piperidine-41-yloxy] phenyl] sulfamoyl acetate

3-chloro-mouth 4--4- [1- (3-pyridylmethyl) piperidine-1-yloxy] aniline (874 mg) obtained in Reference Example 65 was dissolved in dichloromethane (20 ml), and chlorosulfonyl was cooled under ice-cooling. After dropwise addition of ethyl acetate (0.39 ml) and pyridine (0.44 ml), the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, the extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / methanol = 20Z1-10Z1) to give 770 mg (yield 60%) of the title compound as a yellow amorphous solid. I got it.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.33 (3H, t, J = 7.0), 1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.38 (2H, m), 2.72 ( 2H, m), 3.55 (2H, s), 3.91 (2H, s), 4.29 (2H, q, J = 7.0), 4.39 (1H, m), 6.92 (1H, d, J = 9.0), 7.20 ( 1H, dd, J = 9.0, 2.5), 7.27 (1H, m), 7.39 (1H, d, J = 2.5), 7.69 (1H, d, J = 7.5), 8.51 (1H, d, J = 3.5) , 8.56 (1H, s). Reference example 67

N— [3_Cro mouth—41- [1- (3-pyridylmethyl) piperidine-1_4-yloxy] phenyl] 1-N— [3- (3-Cyanophenyl) —2— (E) 1-probenyl ] Sulfamoyl ethyl ester

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2-11-year-old (275 mg), N- [3-chloro-4-1-1 obtained in Reference Example 66 (3-pyridylmethyl) piperidin-4-peroxy] phenyl] sulfamoylethyl acetate (77 Omg) and triphenylphosphine (52 Omg) are dissolved in dichloromethane (20 ml), and the mixture is dissolved in ice-cooled ezodipyrrugonic acid dimethyl ester (20 ml). (0.30 ml) was added dropwise, followed by stirring at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z methanol = 10Z1 to 5/1) to give the target. The title compound (949 mg, yield 95%) was obtained as a pale-yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) 6 ppm: 1.36 (3H, t, J = 7.0), 1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.38 (2H, m), 2.70 ( 2H, m), 3.54 (2H, s), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.42 (IH, m), 4.46 (2H, d, J = 6.5), 6.22 ( IH, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.92 (IH, d, J = 9.0), 7.26 (IH, dd, J = 7.5, 5.0), 7.30 (IH, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 7.5), 7.48-7.54 (3H, m), 7.55 (IH, s), 7.68 (1H, d, J = 7.5), 8.51 (1H , Dd, J = 5.0, 1.5), 8.55 (1H, d, J = 1.5).

4-1- (1_t_butoxycarbonylpiperidine-1-4-yloxy) -1-3-chloroaniline

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -1-3-chloronitrobenzene (2.40 g) obtained in Reference Example 3 was dissolved in acetic acid (50 ml), and zinc powder (5.60) was added at room temperature. g) was added in four portions, and the mixture was stirred at the same temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z-ethyl acetate = 11) to give 1.99 g (yield) of the title compound. 87%) as an orange oil.

¾ image _{R (500MHz, CDC1 3) δ} ppm: 1.47 (9H, s), 1.77 (2H, m), 1.87 (2H, m), 3.31 (2H, m), 3.72 (2H, m), 4.26 (1H , M), 6.52 (1H, dd, J = 9.0, 3.0), 6.73 (1H, d, J = 3.0), 6.80 (IH, d, J = 9.0).

N— [4- (1-t-butoxycarbonylbiperidine-1-41-yloxy) -1-3-chlorophenyl] ethyl ethyl sulfamoyl acetate

4- (11-t-butoxycarbonylpiperidine-14-yloxy) -13-chloroaniline (1.50 g) obtained in Reference Example 68 was dissolved in dichloromethane (20 ml) and chlorosulfonylacetic acid was added under ice cooling. After dropwise addition of ethyl (0.74 ml) and pyridine (0.56 ml), the mixture was stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is Purification by chromatography (elution solvent: hexane Z ethyl acetate = 3/2) gave 1.19 g (54% yield) of the title compound as a pale red oil.

_{1H NMR (500MHz, CDC1 3)} 6 ppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3,46 (2H, m), 3.64 (2H , M), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.52 (1H, m), 6.94 (1H, d, J = 9.0), 7.22 (1H, dd, J = 9.0, 2.5), 7.40 (1H, d, J = 2.5). Reference example 70

N— [4 -— (1-t-butoxycarbonylpiperidine-1_4-yloxy) —3-chlorochlorophenyl) —N— [3 -— (3_cyanophenyl) —2 -— (E) 1-probenyl] sulfamoylacetic acid Etil

3_ (3-Cyanofutiryl) _2_ (E) -propene_1-all (0.40 g;) obtained in Reference Example 2 and N— [4— (1-1 t-Butoxycarbonylpiperidine-4-yloxy) -3-phenylphenyl] Sulfamoylethyl acetate (1.19 g) and triphenylphosphine (0.79 g) were dissolved in dichloromethane (2 Oml) and cooled on ice. After dropwise addition of azodiphenol geronate (0.50 ml), the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 10Z1) to give 1.20 g (yield 78%) of the title compound as a pale red Obtained as an amorphous solid.

_{¾ NMR (500MHz, CDC1 3)} δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.47 (2H, m), 3.62 (2H, m ), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.55 (1H, m), 6.23 (1H, dt, J = 16.0, 6.5) , 6.41 (1H, d, J = 16.0), 6.94 (1H, d, J = 9.0), 7.32 (1H, dd, J = 9.0, 3.0), 7.41 (1H, t, J = 7.5), 7.50-7.58 (4H, m). Reference example 71

N- [4 -— (piperidine-1-4-yloxy) -1-3-chlorophenyl) —N— [3- (3-cyanophenyl) —2- (E) —probenyl] ethyl ethyl sulfamoylacetate

N- [4- (1-t-butoxycarbylbiperidine-14-yloxy) -1-3-cyclopentenyl] -N- [3- (3-cyanophenyl) 1-2 (E) obtained in Reference Example 70 ) [Proponyl] sulfamoyl acetate ethyl (1.25 g) was dissolved in ethanol (15 ml), 4N hydrogen chloride dioxane solution (15 ml) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.10 g (quantitative yield) of the title compound as a pale yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.76-1.88 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m), 3.20 ( 2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5), 4.50 (1H, m), 6.22 (1H, dt, J = 16.0 , 6.5), 6.41 (1H, d, J = 16.0), 6.93 (1H, d, J = 9.0), 7.32 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.49-7.59 (4H, m).

'Reference example 72'

N— [3-Crosin-one 4-one [1-(4-Pyridylmethyl) piperidine-1-peroxy] phenyl] N— [3 -— (3-Cyanophenyl) one 2 -— (E) -Propenyl] sulfa Moethyl acetate

N— [4- (piperidine-1 4-yloxy) —3-chloromethylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl) sulfamoi obtained in Reference Example 71 Ethyl acetate (1.10 g) was dissolved in N, N-dimethylformamide (30 ml) and dissolved at room temperature in 41- (bromomethyl) pyridine hydrobromide (0.59 g) and potassium carbonate (0.59 g). After g) was added, the mixture was stirred overnight at the same temperature. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10: 1) to obtain 0.97 g (yield 75%) of the title compound. Obtained as a yellow amorphous solid.

NMR (500 MHz, CDCl ₃ ) 5 _PP m: 1.36 (3H, t, J = 7.0), 1.86-1.95 (2H, m), 1.95-2.04 (2H, m), 2.38 (2H, m), 2.70 ( 2H, m), 3.53 (2H, s), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.43 (1H, m), 4.46 (2H, d, J = 6.5), 6.22 ( 1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.92 (1H, d, J = 9.0), 7.28 (2H, d, J = 6.0), 7.31 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.49-7.54 (2H, m), 7.53 (1H, d, J = 2.5), 7.55 (1H, s), 8.54 (2H, d, J = 6.0). Reference example Ί 3

2- (2-bromoethyl) pyridine

Dissolve 2-pyridineethanol (1.0 Oml) in tetrahydrofuran (2 Oml), add trifenylphosphine (3.51 g) and carbon tetrabromide (4.44 g) at room temperature, and add And stirred overnight. Ether was added to the reaction solution, and the insolubles were removed by filtration. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography.

Purification with (elution solvent: hexane / ethyl acetate = 1/3) gave 1.30 g (yield 78%) of the title compound as a yellow oily substance.

_{1H NMR (400 MHz, CDC1 3} ) d ppm: 3.34 (2H, t, J = 7.0), 3.78 (2H, t, J = 7.0), 7.15-7.23 (2H, m), 7.64 (1H, m), 8.57 (1H, m). Reference example 74

3—Black mouth _4— [1— [2- (2-Pyridyl) ethyl] piperidine-1-4-yloxy] nitrobenzene

3-Chloro-41- (piperidine-1-yloxy) nitrobenzene (1.50 g) obtained in Reference Example 8 was dissolved in N, N-dimethylformamide (30 ml), and the mixture was heated at room temperature. After adding 2- (2-bromoethyl) pyridine (1.30 g) obtained in the above and lithium carbonate (1.21 g), the mixture was stirred overnight at the same temperature. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane Z methanol = 10Z1 to 5/1) to obtain 1.57 g (yield 74%) of the title compound. Obtained as a yellow solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.89-2.00 (2H, m), 2.00-2,11 (2H, m), 2.52 (2H, m), 2.75-2.85 (2H, m), 2.83 (2H, m), 3.01 (2H, m), 4.59 (1H, m), 6.99 (1H, d, J = 9.0), 7.13 (m , Dd, J = 7.5, 5.0), 7.20 (1H, d, J = 8.0), 7.61 (1H, m), 8.13 (1H, dd, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0) ), 8.53 (1H, d, J = 5.0).

3-chloro-4- [1- [2- (2-pyridyl) ethyl] piperidine-1 4-yloxy] anilin

The 3-chloro-4-1- [1- [2- (2-pyridyl) ethyl] piperidine-1-41-yloxy] nitrobenzene (1.57 g) obtained in Reference Example 74 was dissolved in acetic acid (50 ml). Tin powder (2.58 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted five times with ethyl acetate. After the extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 5Z1-1Z1) to obtain 1.26 g (yield 87%) of the title compound as a pale yellow solid Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.82-1.94 (2H, m), 1.94-2.06 (2H, m), 2.40 (2H, m), 2.81 (2H, m), 2.89 (2H, m) , 3.02 (2H, m), 4.15 (1H, m), 6.51 (1H, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.81 (1H, d, J = 8.5), 7.12 (1H, dd, J = 7.5, 5.0), 7.20 (1H, d, J = 8.0), 7.60 (1H, m), 8.52 (1H, d, J = 5.0). Reference Example 76

N— [3-Chloro-41- [1-1- [2- (2-pyridyl) ethyl] piperidine-1-4-yloxy] phenyl] Sulfamoyl acetate

The 3-chloro-4- [1- [2- (2-pyridyl) ethyl] piperidine-1-41-yloxy] aniline (1.26 g) obtained in Reference Example 75 was dissolved in dichloromethane (30 ml). Under ice-cooling, chlorosulfonyl acetate ethyl (0.54 ml) and pyridine (0.61 ml) were added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, extracted three times with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Dried with Nesium. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / l to 5Zl) to elute 1.5 Og (82% yield) of the title compound. Obtained as a yellow amorphous solid.

_{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.86-1.97 (2H, m),

1.97- 2.08 (2H, m), 2.50 (2H, m), 2.77-2.92 (4H, m), 3.03 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.40 (IH, m), 6.93 (IH, d, J = 9.0), 7.13 (IH, m), 7.21 (IH, dd, J = 9.0, 2.5), 7.17-7.24 (IH, m), 7.40 (1H , D, J = 2.5), 7.61 (1H, m), 8.53 (IH, d, J = 5.0).

N— [3-Chloro-4-1 [1 -— [2- (2-pyridyl) ethyl] piperidine—4-pyroxy] phenyl] —N— [3-(3-Cyanophenyl) -1-2 -— (E) — Probenyl] sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2-11 (0.52 g), N- [3-chloro-4-1-1 obtained in Reference Example 76 [1- [2- (2-pyridyl) ethyl] piperidine-1-yloxy] phenyl] Sulfamoyl acetate (1.50 g) and triphenylphosphine (0.98 g) in dichloromethane (40 ml) Then, under ice-cooling, azodiphenol geronate (0.57 ml) was added dropwise, and the mixture was stirred at room temperature for 10 minutes. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane Z methanol = 30Z1 to 10/1) to give 1.73 g (89% yield) of the title compound as a pale yellow color Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) 6 ppm: 1.36 (3H, t, J = 7.0), 1.86-1.98 (2H, m),

1.98- 2.10 (2H, m), 2.51 (2H, m), 2.78-2.92 (4H, m), 3.03 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.43 (IH, m), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.93 (IH, d, J = 9.0), 7.12 (IH, m), 7.20 (IH, d, J = 8.0), 7.31 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.49-7.55 (3H , M), 7.56 (1H, s), 7.60 (IH, m), 8.53 (1H, d, J = 4.5). Reference 78

3-chloro-1-41- (1-cyclopentylbiperidine-1-yloxy) nitrobenzen 3-chloro-41- (piperidine-14-yloxy) nitrobenzene obtained in Reference Example 8 (4.00 g) ) Was dissolved in N, N-dimethylformamide (70 ml), cyclopentyl bromide (1.96 ml) and potassium carbonate (3.23 g) were added at room temperature, and the mixture was stirred at 100 ° C for 7 hours. Due to the slow progress of the reaction, cyclopentyl bromide (0.70 ml) was added, and the mixture was further stirred at 100 ° C for 2 hours and at 120 at 5 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1-10 / 1) to obtain 2.35 g of the title compound (46% yield). Was obtained as a brown oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.37-1.48 (2H, m), 1.50-1.61 (2H, m), 1.65-1.76 (2H, m), 1.85-2.00 (4H, m), 2.00- 2.10 (2H, m), 2.50 (2H, m), 2.57 (1H, m), 2.75 (2H, m), 4.59 (IH, m), 6.98 (IH, d, J = 9.0), 8.13 (IH, dd, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0).

3-Chloro-41- (1-cyclopentylpiperidine-1-4-yloxy) aniline 3-Chloro-41- (1-cyclopentylpiperidine-1-4-yloxy) nitrobenzene (2.35 g) obtained in Reference Example 78 was added to acetic acid (50 ml). And tin powder (4.29 g) was added at room temperature, followed by stirring at the same temperature. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted five times with ethyl acetate. After the extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethanonomethanol 5-1-1 / 1) to obtain 1.97 g (yield 92%) of the title compound. Obtained as a light brown amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.48-1.61 (2H, m), 1.61-1.78 (4H, m), 1.86-2.02 (4H, m), 2.06-2.19 (2H, m), 2.76 (2H, m), 2.85 (1H, m), 2.94 (2H, m), 4.29 (1H, m), 6.52 (1H, m dd, J = 8.5, 2.5), 6.73 (1H, d, J = 2.5), 6.79 (1H, d, J = 8.5). Reference Example 80

N- [3-—Mouth—41- (1-cyclopentylpiperidine-1 4-yloxy) phenyl] Sulfamoyl acetate

3-Chloro-4- (1-cyclopentylpiperidine-14-yloxy) aniline (1.97 g) obtained in Reference Example 79 was dissolved in dichloromethane (40 ml), and ethyl chlorosulfonyl acetate (0 ml) was dissolved under ice-cooling. 94 ml) and pyridine (1.08 ml) were added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / Z methanol = 25 / 1-10 / 1) to obtain 1.09 g of the title compound (37% yield). Was obtained as a light brown amorphous solid.

^{: H NMR (400 MHz, CDC1} 3) δ ppm: 1.33 (3H, t, J = 7.0), 1.38-1.62 (4H, m), 1.62-1.77 (2H, m), 1.80-1.96 (4H, m) , 1.96-2.09 (2H, m), 2.47 (2H, m), 2.59 (1H, m), 2.79 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.39 (1H, m), 6.92 (1H, d, J = 9.0), 7.20 (1H, dd, J = 9.0, 2.5), 7.39 (1H, d, J = 2.5). Reference Example 81

N— [3—Cro-1- (1-cyclopentylpiperidine-14-yloxy) phenyl] —N— [3- (3-Cyanophenyl) -12- (E) -Propenyl] sulfamoyl ethyl acetate

3- (3-Cyanophenyl) —2- (E) —propene-11-all obtained in Reference Example 2 (0.39 g), N— [3-chloro-4-1) obtained in Reference Example 80 (1-cyclopentylbiperidine-1-yloxy) phenyl] Ethyl sulfamoylacetate (1.09 g) and triphenylphosphine (0.77 g) are dissolved in dichloromethane (3 Om 1), and the mixture is dissolved in ice-cooled getyl azodipyruponate. (0.45 ml) was added dropwise, and the mixture was stirred at room temperature overnight. Was. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethylethyl methanol acetate = 10Z1-5Z1) to give 1.30 g (yield 91%) of the title compound. Obtained as a tan amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) 6 ppm: 1.36 (3H, t, J = 7.0), 1.40-1.61 (4H, m), 1.64-1.80 (2H, m), 1.83-1.99 (4H, m), 1.99-2.14 (2H, m), 2.40-2.68 (3H, m), 2.68-2.87 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (IH, m ), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.92 (IH, d, J = 9.0), 7.31 ( IH, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.48-7.55 (3H, m), 7.56 (IH, s).

1-t-butoxycarbonyl-2-methyl-4-piperidone ethylene ketal

4-Piperidone ethylene ketone (9.6 g) was dissolved in acetone (10 Oml), and di-tert-butyl dicarbonate (16.0 g) was added under ice-cooling, followed by stirring at room temperature for 1 hour. . After the reaction solution was concentrated under reduced pressure, the residue was diluted with ether, and washed sequentially with water and saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give

1-t-butoxycarbonyl 4-piperidone ethylene ketal (17.4 g) was obtained as a pale yellow solid.

This was then dissolved in ether (200 ml) and, at 1 78, N, N, N, N, -tetramethylethylenediamine (1 3. Oml) and 1 Ns-butyl lithium (Six-mouth hexane and hexane mixed solution) (88. Oml) was added dropwise, and the mixture was stirred at 130 ° C for 30 minutes. After the reaction solution was cooled again to 178 ° C, methyl iodide was added, and the mixture was stirred at room temperature for 3 hours. After pouring water into the reaction mixture, the mixture was extracted with ether. The extract was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 9 /

Purification by 1) gave 6.0 g (yield 34%) of the title compound as a colorless oil.

^{X H NMR (500 MHz, CDC1} 3) d ppm: 1.23 (3H, d, J = 7.0), 1.46 (9H, s), 1.55-1.70 (4H, m), 1.85-1.90 (IH, m), 3.05 -3.15 (1H, m), 3.90-4.05 (4H, m), 4.47 (1H, m). Reference Example 8 3

1-t-butoxycarpine 2- 2-methyl-4-piperidone

Reference Example 8 1-t-butoxycarbonyl 2-methyl-4-piperidone ethylene ketal (6.00 g) obtained in 2 was dissolved in acetone (15 O ml), and p-toluene was added under ice-cooling. Sulfonic acid monohydrate (4.40 g) was added, and the mixture was stirred at room temperature. After the reaction solution was diluted with ethyl acetate, it was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (2.40 g, yield 48%) as a yellow oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.18 (3H, d, J = 7.0), 1.49 (9H, s), 2.20-2.30 (IH, m), 2.30-2.40 (IH, m), 2.45- 2.55 (IH, m), 2.65-2.70 (IH, m), 3.25-3.35 (IH, m), 3.90-4.05 (IH, m), 4.20-4.30 (1H, m).

1-t-butoxycarbonyl-4-hydroxy-2-methylpiperidine

In a nitrogen atmosphere, lithium aluminum hydride (1.30 g) was suspended in tetrahydrofuran (5 O ml), and the mixture was cooled with ice to obtain 111 t-butoxycarbonyl-2-methyl-4- obtained in Reference Example 83. After dropwise addition of piperidone (2.40 g), the mixture was stirred at room temperature for 1 hour. Sodium sulfate • 10-hydrate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 0.95 g of the title compound (yield 39) and 1.02 g of the highly polar compound (yield 39). (Yield 42%) as yellow oily substances.

^{1 H NMR (500 MHz, CDC1} 3) δ ppm highly polar compound: 1.14 (3H, d, J = 7.0), 1.30-1.40 (1H, m), 1.45-1.55 (1H, m), 1.46 (9H, s), 1.80-1.85 (1H, m), 1.90-1.95 (IH, m), 2.85-2.95 (1H, m), 3.90-4.00 (1H, m), 4.00-4.10 (IH, m), 4.45- . 4.55 (1H, m) ¾ NMR (500 MHz, CDC1 3) of the low polar compound δ ppm: 1.33 (3H, d , J = 7.0), 1.46 (9H, s), 1.60-1.75 (3H, m), 1.80-1.90 (IH, m), 3.20-3.30 (IH, m), 3.80-3.85 (1H, m), 4.15-4.20 (1H, m), 4.25-4.35 (1H, m). Reference Example 85

4- (1-t-butoxycarboxyl 2-methylpiperidine-1 4-yloxy) -3

Highly polar compound of 1,1-t-butoxycarbonyl 4-hydroxy-2-methylpiperidine obtained in Reference Example 84 (1.02 g), 2-chloro-412-trophenol (0.83 g) and triflic acid Enylphosphine (1.62 g) was dissolved in dichloromethane (60 ml). Under ice cooling, azodicarboxylic acid getyl (0.97 ml) was added dropwise, followed by stirring at room temperature for 8 hours. Because the reaction progressed slowly, triphenylphosphine (1.62 g) and getyl azodicarbonate (0.97 ml) were added, and the mixture was further stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 4/1) to give 1.15 g (yield 76%) of the title compound as yellow. Obtained as an oil.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.35 (3H, d, J = 7.0), 1.48 (9H, s), 1.75-1.85 (1H, m), 1.95-2.05 (3H, m), 3.25 -3.35 (1H, m), 3.90-4.00 (1H, m), 4.35-4.45 (1H, m), 4.87 (1H, m), 6.97 (1H, d, J = 9.0), 8.15 (1H, dd, J = 9.0, 2.5), 8.32 (1H, d, J = 2.5). Reference Example 86

3-Chloro-41- (1,2-dimethylpiperidine-1-4-yloxy) nitrobenzene 4- (1-t-butoxycarboxyl 2-methylpiperidine-1-4-yloxy) obtained in Reference Example 85-1,3-chloronitrobenzene ( 1.15 g) was suspended in 90% formic acid (3.10 g), 37% formalin (2.50 g) was added, and the mixture was stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature, neutralized with an aqueous potassium carbonate solution, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 9/1) to obtain 0.80 g of the title compound (yield 90%). Was obtained as a yellow oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.18 (3H, d, J = 6.0), 1.64 (IH, m), 1.85-1.95 (1H, m), 2.05-2.25 (4H, m), 2.32 ( 3H, s), 3.00 (1H, m), 4.39 (1H, m), 6.99 (IH, d, J = 9.0), 8.12 (IH, dd, J = 9.0, 2.5), 8.30 (IH, d, J = 2.5). Reference Example 87

3-chloro-41- (1,2-dimethylpiperidine-1-yloxy) anilin

3-Chloro-4- (1,2-dimethylpiperidine-14-yloxy) nitrobenzene (80 Omg) obtained in Reference Example 86 was dissolved in acetic acid (20 ml), and tin powder (170 Omg) was added at room temperature. The mixture was stirred at the same temperature for 4 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, a saturated aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 69 Omg (yield: 96%) of the title compound as a red-brown oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.13 (3H, d, J = 6.0), 1.52 (1H, m), 1.75-1.85 (1H, m), 1.90-2.15 (4H, m), 2.27 ( 3H, s), 2.93 (1H, m), 3.95 (1H, m), 6.50 (1H, dd, J = 8.5, 3.0), 6.72 (IH, d, J = 3.0), 6.83 (IH, d, J = 8.5). Reference Example 88

N— [3-Chloro-41- (1,2-dimethylpiperidine-14-yloxy) phenyl]

Etoxyl

3-Chloro-41- (1,2-dimethylpiperidine-4-yloxy) aniline (69 Omg) obtained in Reference Example 87 was dissolved in dichloromethane (2 Om 1), and ethyl chlorosulfonyl acetate was dissolved under ice-cooling. (0.40 ml) and pyridine (0.25 ml) were added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 9Z1-3Z1) to give 80 Omg (yield 73%) of the title compound as a yellow amorphous solid. As obtained.

^{1 H NMR (500 MHz, CDC1} 3) δ ppm: 1.18 (3H, t, J = 7.0), 1.26 (3H, m), 1.55-1.70 (1H, m), 1.75-1.90 (IH, m), 2.15 -2.30 (2H, m), 2.55-2.75 (3H, m), 2.80-3.30 (3H, m m), 4.11 (2H, q, J = 7.0), 4.20 (2H, s), 4.45-4.55 (IH, m), 7.17 (1H, dd, J = 9.0, 2.5), 7.27 (1H, d, J = 9.0), 7.29 (1H, d, J = 2.5). Reference example 89

N- [3-Chloro-41- (1,2-dimethylbiperidine-14-yloxy) phen J J] -N- [3- (3-Cyanophenyl) -1- 2- (E) -probenyl] sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) 1-2- (E) -propene-1-1-all obtained in Reference Example 2 (320 mg), N- [3-chloro-4-1- (1,2--) obtained in Reference Example 88 [Dimethylpiperidine-141-yloxy] phenyl] sulfamoyl acetate (800 mg) and triphenylphosphine (680 mg) were dissolved in dichloromethane (20 ml), and acetyl dicarboxylate (0. '40 ml) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 4/1 to dichloromethane / methanol = 9Z1) to give the title compound II O Omg (yield determination). Was obtained as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.14 (3H, d, J = 6.0), 1.36 (3H, t, J = 7.0), 1.50-1.65 (IH, m), 1.75-1.90 (IH, m ), 1.95-2.20 (4H, m), 2.29 (3H, s), 2.95 (IH, m), 3.98 (2H, s), 4.21 (IH, m), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5), 6.22 (IH, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.94 (IH, m), 7.31 (1H, m), 7.40 (IH, m), 7.45-7.50 (IH, m), 7.50-7.60 (2H, m), 7.65-7.70 (IH, m).

Indolizine—7—All

Lithium aluminum hydride (2.30 g) was suspended in tetrahydrofuran (5 Oml) under a nitrogen atmosphere, and the mixture was cooled under ice-cooling. Heterocycles, 43, 1391 (1996) [Heterocycles, 43, 1391 ( 1996)], and indolidine synthesized from 4,4-diethoxybutylamine and getyl 1,3-acetone dicarboxylate. After the dropwise addition of —7—one (2.8 O g), the mixture was stirred at the same temperature for 1 hour. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by reduced pressure (4/1) to give 1.70 g (yield 59%) of the title compound as a yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 1.24 (1H, m), 1.40-1.50 (1H, m), 1.55-1.80 (2H, m), 1.80-2.00 (4H, m), 2.00-2.15 (3H, m), 3.00-3.15 (2H, m), 3.65 (1H, m).

3-chloro-4-methoxymethoxyaniline

Dissolve 2-trophenol (5.2 g) in N, N-dimethylformamdo (5 Oml) and cool with ice-cold methoxyoxime chloride (2.7 ml) and triethylamine (2.5 ml). Oml) was added dropwise, followed by stirring at room temperature for 1 hour. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated saline in this order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3-chloro-4-methoxymethoxynitrobenzene (8.1 g) as a yellow oily substance.

Then, this was dissolved in a mixed solvent of acetone (100 ml) and water (100 ml), zinc dust (9.8 g) and ammonium chloride (8.0 g) were added at room temperature, and the mixture was added at 60 for 40 minutes. Stirred. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the extract was washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.4 g (yield 96%) of the title compound as a yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 3.53 (3H, s), 5.11 (2H, s), 6.52 (1H, dd, J = 8.5, 3.0), 6.73 (1H, d, J = 3.0), 6.98 (1H, d, J = 8.5). Reference example 92

N- (3-chloro mouth_4-methoxymethoxyphenyl) sulfamoyl acetate ethyl The 3-methoxy-4-methoxymethoxyaniline (5.4 g) obtained in Reference Example 91 was di-substituted. The residue was dissolved in chloromethane (50 ml), ethyl chlorosulfonylacetate (4.7 ml) and pyridine (2.9 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethanomethanol = 19Z1) to obtain 8.0 g (yield 82%) of the title compound as a red-brown oily substance Was.

_{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 3.52 (3H, s), 3.92 (2H, s),

4.30 (2H, q, J = 7.0), 5.24 (2H, s), 7.15-7.25 (2H, m), 7.41 (1H, m).

N- [3-Chloro-4-methoxymethoxyphenyl] — N— [3- (3-Cyanophenyl) —2- (E) -propenyl] ethyl ethyl sulfamoylacetate

3- (3-Cyanophenyl) -12- (E) -propene-11-ol (1.6 g) obtained in Reference Example 2, N- (3-Cro- mouth-1-4) obtained in Reference Example 92 -Methoxymethoxyphenyl) Ethyl sulfamoylacetate (3.4 g) and triphenylphosphine (3.2 g) were dissolved in dichloromethane (50 ml), and under ice-cooling, dimethyl diethyl azodicarboxylate (1.9 ml) was added. After the dropwise addition, the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19Z1) to give 3.9 g (yield 81%) of the title compound as a yellow oil. As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 3.51 (3H, s), 3.99 (2H, s),

4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 5.25 (2H, s), 6.22 (1H, dt, J = 15.5, 6.5), 6.42 (1H, d, J = 15.5), 7.20 (1H, m), 7.34 (1H, m), 7.41 (1H, m), 7.50-7.60 (4H, m).

N- [3-Chloro-4-hydroxyphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] ethyl ethyl sulfamoylacetate

N— [3-chloromouth-4-methoxymethoxyphenyl] -1-N— [3 obtained in Reference Example 93 1- (3-Cyanophenyl) -2- (E) -probenyl] Sulfamoylethyl acetate (3.9 g) was dissolved in a mixed solvent of ethyl acetate (50 ml) and dioxane (50 ml), and cooled with ice. After adding 4 N hydrogen chloride dioxane solution (25 ml), the mixture was stirred at room temperature overnight. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the extract was washed successively with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (3.6 g, quantitative yield) as a yellow oily substance.

_{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5 ), 6.22 (1H, dt, J = 16.0, 6.5), 6.40 (1H, d, J = 16.0), 7.03 (1H, m), 7.32 (1H, m), 7.41 (1H, m), 7.50-7.60 (4H, m). Reference example 95

N— [3-Chloro-4-1 (indolizine-1-7-yloxy) phenyl] -1-N— [3- (3-Siasophenyl) -1-2- (E) -probenyl] ethyl ethyl sulfamoyl acetate

N- [3-chloro- 4-hydroxyphenyl] -N- [3- (3-cyanophenyl) -l- (E) -probenyl] obtained in Reference Example 94 Ethyl sulfamoyl acetate (2.0 g) and indolizin-7-ol (l. '7 g) and triphenylphosphine (3.2 g) obtained in Reference Example 90 were dissolved in dichloromethane (60 ml), and the mixture was cooled under ice-cooling to obtain getyl azodicarboxylate. (1.9 ml) was added dropwise, followed by stirring at room temperature for 6 hours. Due to the slow progress of the reaction, trifenylphosphine (3.2 g) and getyl azodicarbonate (1.9 ml) were added, and the mixture was further stirred at the same temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Zmethanol = 2Z1) to give 0.6 g of the title compound as an impurity in orange oil. Reference Example 96

N- (4-methoxymethoxyphenyl) sulfamoyl acetate

4-Methoxymethoxyaniline (20.9 g) is dissolved in dichloromethane (400 ml), and cooled with ice, chlorosulfonyl acetate ethyl (18.0 ml) and pyridine (33 ml). Was added dropwise, and the mixture was stirred at room temperature overnight. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3Z2) to give 28.0 g (yield 67%) of the title compound as a brown oil. Obtained as material.

^X H image _{R (270 MHz, CDC1 3)} d ppm: 1.33 (3H, t, J = 7.0), 3.48 (3H, s), 3.90 (2H, s), 4.29 (2H, q, J = 7.0), 5.16 (2H, s), 7.03 (2H, d, J = 9.0), 7.28 (2H, d, J = 9.0).

N— [3- (3-Cyanophenyl) -1-2- (E) -probenyl] —N— (4-Methoxymethoxyphenyl) ethyl ethyl sulfamoylacetate

3- (3-Cyanophenyl) -12- (E) -propene-11-ol (0.53 g) obtained in Reference Example 2, N_ (4-methoxymethoxyphenyl) obtained in Reference Example 96 Ethyl sulfamoyl sulphate (1.00 g) and triphenylphosphine (1.12 g) were dissolved in dichloromethane (30 ml), and under ice-cooling, azodiphenol geronate (0.66 m1) was added dropwise. Thereafter, the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 1.38 g (yield 94%) of the title compound. Obtained as a yellow oil.

^{1 H NMR (270 MHz, CDC1} 3) δ ppm: 1.37 (3H, t, J = 7.0), 3.48 (3H, s), 3.99 (2H, s), 4.32 (2H, q, J = 7.0), 4.49 (2H, d, J = 6.0), 5.18 (2H, s), 6.25 (1H, dt, J = 16.0, 6.0), 6.42 (1H, d, J = 16.0), 7.06 (2H, d, J = 9.0) ), 7.40 (1H, t, J = 7.0), 7.41 (2H, d, J = 9.0), 7.52 (1H, d, J = 7.0), 7.54 (1H, d, J = 7.0), 7.56 (1H, s). Reference example 98

N- [3- (3-cyanophenyl) -1- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoylethyl acetate

N- [3- (3-cyanophenyl) -2- (E) -probenyl] -N- (4-methoxymethoxyphenyl) sulfamoylacetate (10.7 g) obtained in Reference Example 97 was added. The residue was dissolved in ethyl acetate (120 ml), a 4N hydrogen chloride-ethyl acetate solution (80 ml) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed sequentially with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 9.1 g (yield 95%) of the title compound as a yellow solid. Obtained as an oil.

_{1H NMR (270 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.0 ), 6.23 (IH, dt, J = 16.0, 6.0), 6.39 (1H, d, J = 16.0), 6.84 (2H, d, J = 9.0), 7.34 (2H, d, J = 9.0), 7.39 ( IH, t, J = 7.5), 7.50 (2H, m), 7.54 (1H, s).

N— [3- (3-Cyanophenyl) -1-2_ (E) —Probenyl] -1-N— [4 -— (1-Methylpiperidine-1-4-yloxy) phenyl] ethyl ethyl sulfamoylacetate

N- [3- (3-Cyanophenyl) 1-2- (E) -probenyl] -N- (4-hydroxyphenyl) sulfamoylacetate ethyl (700 mg) obtained in Reference Example 98, 4-hydroxyl 1 —Methylpiperidine (41 Omg) and triphenylphosphine (920 mg) were dissolved in dichloromethane (20 ml), and under ice-cooling, azodicarboxylic acid getyl (0.55 ml) was added dropwise, followed by stirring at room temperature overnight. . Due to the slow progress of the reaction, add 4-hydroxy-1-methylpiperidine (41 Omg), trifenylphosphine (92 Omg) and getyl azodiphenol (0.55 ml), and then stir at the same temperature for 4 hours. did. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Zmethanol = 2 / l to 1Zl) to give 69 Omg (yield 79%) of the title compound as yellow. Obtained as an oil.

^{1 H NMR (400 MHz, CDC1} 3) δ ppm: 1.35 (3H, t, J = 7.0), 1.70-1.90 (2H, m), 1.95-2.05 (2H, m), 2.31 (3H, s), 2.65 -2.75 (2H, m), 2.85-2.95 (2H, m), 3.98 (2H, s), 4.25-4.35 (IH, m), 4.30 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 6.23 (IH, dt, J = 16.0, 6.5), 6.40 (IH, d, J = 16.0), 6.90 (2H, d, J = 9.0), 7.35-7.45 (1H, m), 7.38 (2H, d, J = 9.0), 7.45-7.55 (3H, m). Reference Example 1 00

4- (11-t-butoxycarbonylpiperidine-14-yloxy) -1-3-trifluoromethylnitrobenzene

1-t-butoxycarbone 4-hydroxypiperidine (1.45 g), Journal of 'Ob' Organic Chemistry, 63, 4199 (1998) [J. Org. Chem] 3, 4199 (1998)], 2-trifluoromethyl-4,2-trophenol (1.38 g) and triphenylphenylphosphine (2 27 g) was dissolved in dichloromethane (65 ml), and azodiphenol geronate (1.4 ml) was added dropwise under ice-cooling, followed by stirring overnight at room temperature. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to obtain 2.28 g (yield 88%) of the title compound as a pale yellow oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.49 (9H, s), 1.88-1.99 (4H, m), 3.51 (2H, m), 3.64 (2H, m), 4.83 (1H, m), 7.09 (1H, d, J = 9.0), 8.41 (1H, dd, J = 9.0, 3.0), 8.53 (1H, d, J = 3.0).

4- (1-Methylpiperidine-4-1-yloxy) -1-3-trifluoromethylnitrobenzene ''

Reference Example 100 4- (1-t-butoxycarbonylpiperidine-1-yloxy) —3-trifluoromethylnitrobenzene (2.45 g) obtained in 100 was added to 90% formic acid (8.80 g). The suspension was suspended, 37% formalin (5.50 g) was added, and the mixture was stirred at 100 ° C for 6 hours. The reaction solution was cooled to room temperature, neutralized with an aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10/1) to obtain 1.82 g (yield 95%) of the title compound as a yellow oil. Obtained as material. _{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.94-2.02 (2H, m), 2.02-2.10 (2H, m), 2.33 (3H, s), 2.40-2.53 (2H, m), 2.53-2.65 ( 2H, m), 4.68 (1H, m), 7.07 (1H, d, J = 9.0), 8.39 (1H, dd, J = 9.0, 3.0), 8.51 (1H, d, J = 3.0).

4- (1-Methylbiperidine-1_4_yloxy) _3-Trifluoromethyladiline 4- (1-methylpiperidine-4_yloxy) _3—Trifluoromethylnitohate benzene obtained in Reference Example 101 (1.82 g) was dissolved in ethanol (30 ml), a palladium-carbon catalyst (0.18 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4.5 hours. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane Z methanol = 10Z1 to 1Z1) to give 1.55 g of the title compound (yield 95%). %) Was obtained as a light brown solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.85-2.00 (4H, m), 2.29 (3H, s), 2.25-2.40 (2H, m), 2.55-2.70 (2H, m), 4.31 (1H, m), 6.78 (1H, dd, J = 8.5, 3.0), 6.83 (1H, d, J = 8.5), 6.91 (1H, d, J = 3.0).

N— [4 -— (1-Methylpiperidine—4-yloxy) 13-trifluoromethylphenyl] ethyl sulfamyl acetate

4- (1-Methylpiperidine-1-4-yloxy) -3- (trifluoromethylaniline) (1.55 g) obtained in Reference Example 102 was dissolved in dichloromethane (30 ml) and chlorosulfonyl under ice-cooling. After dropwise addition of ethyl acetate (0.76 ml) and pyridine (0.91 ml), the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10Z1 to 5Z1) to give 2.39 g (yield quantitative) of the title compound as a pale brown color Obtained as an amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) d ppm: 1.34 (3H, t, J = 7.0), 2.00-2.15 (2H, m), 2.35-2.50 (2H, m), 2.62 (3H, s), 2.80-3.15 (4H, m), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.72 (IH, m), 6.98 (1H, d, J = 9.0), 7.55 (1H, dd, J = 9.0, 2.5), 7.62 (1H, d, J = 2.5). Reference example 104

N— [3- (3-Cyanophenyl) -1-2- (E) -Propenyl] —N— [4- (1-Methylpiperidine-14-yloxy) -1-3-trifluoromethylphenyl] sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene-11-ole (500 mg) obtained in Reference Example 2, N- [4- (1-methylpiperidine-4-1) obtained in Reference Example 103 (Iroxy) 13-Trifluoromethylphenyl] Sulfamoyl acetate ethyl (133 3 mg) and triphenylphosphine (99 Omg) were dissolved in dichloromethane (30 ml), and acetyl dicarboxylate (0.58 ml) was dissolved under ice-cooling. After the dropwise addition, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / Z-methanol = 15/1) to give the title compound (755 mg, yield 43%) as a pale-yellow amorphous solid. Was.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.90-2.10 (4H, m), 2.33 (3H, m), 2.40-2.50 (2H, m), 2.55- 2.65 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.53 (IH, m), 6.23 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.98 (1H, d, J = 9.0), 7.41 (1H, t, J = 7.5), 7.50-7.60 (4H, m), 7.71 ( IH, d, J = 2.5). Reference example 105

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) nitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (50.1 g) is dissolved in N, N-dimethylacetamide (550 ml), and iced. Under cooling, sodium hydride (10.5 g) was added, and the mixture was stirred at the same temperature for 30 minutes. A solution of 4-fluoronitrobenzene (42.2 g) in N, N-dimethylacetamide (100 ml) was added. The mixture was added dropwise and further stirred at room temperature overnight. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 13/7) to give 75.1 g (93% yield) of the title compound as a pale yellow color Obtained as a solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.43 (9H, s), 1.76 (2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.65 (2H, m), 4.56 (1H , m), 6.91 (2H, d, J = 9.0), 8.15 (2H, d, J = 9.0).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) anilin

The 4- (11-t-butoxycarbonylpiperidine-14-yloxy) nitrobenzene (11.9 g) obtained in Reference Example 105 was dissolved in methanol (100 ml), and the mixture was dissolved in methanol (100 ml). Then, the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 10.7 g (yield) of the title compound. 99%) as a pale red solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H , M), 6.63 (2H, d, J = 8.5), 6.76 (2H, d, J = 8.5).

N— [4- (1-t-butoxycarbonylbiperidine-1 4-yloxy) phenyl]

Ethyl acetate ''

The 4- (1-t-butoxycarbonylpiperidine-14-yloxy) aniline (4.39 g) obtained in Reference Example 106 was dissolved in dichloromethane (30 ml), and chlorosulfonyl acetate (2 .4 ml) and pyridine (2.4 ml) were added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl hexanenoacetate = 3 Z2) to give 4.96 g (yield 75%) of the title compound as a pale red color Obtained as an oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34 (2H, m) , 3.69 (2H, m), 3.89 (2H, s), 4.29 (2H, q, J = 7.0), 4.44 (1H, m), 6.89 (2H, d, J = 8.5), 7.27 (2H, d, J = 8.5).

N— [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] —N— [3- (3-cyanophenyl) —2- (E) -probenyl] ethyl ethyl sulfamoylacetate

3- (3-Cyanophenyl) 1-2 (E) -propene-11-ol (0.80 g) obtained in Reference Example 2, N- [4-1-1 (1 1-t-Butoxycarbonyl piperidine—4-yloxy) phenyl] Sulfamoyl acetate ethyl (2.21 g) and triphenylphosphine (1.70 g) are dissolved in dichloromethane (40 ml), and the azozic force under ice-cooling is obtained. After dropwise addition of getyl ruponate (1.0 ml), the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethanone Z-ethyl acetate = 1/1) to give 2.15 g (yield 74%) of the title compound. Obtained as a colorless oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34 (2H, m) , 3.68 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.45 (1H, m), 4.47 (2H, d, J = 6.0), 6.24 (1H, dt, J = 15.5, 6.0), 6.40 (1H, d, J = 15.5), 6.90 (2H, d, J = 8.5), 7.39 (3H, m), 7.51 (2H,

m), 7.55 (1H, s).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1 3-methylnitole Benzene

1 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-12-trophenol (2.55 g) and triphenylphosphine (5.25 g) were added to dichloromethane (1 00ml), and azodiphenol geronate (3.2 ml) was added dropwise under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue is purified by silica gel column chromatography (elution solvent: dichloromethane) to give a residue. 4.07 g of the title compound were obtained as a light yellow oily impurity.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1,48 (9H, s), 1.84 (2H, m), 1.95 (2H, m), 2.29 (3H, s), 3.49 (2H, m), 3.62 (2H, m), 4.66 (1H, m), 6.86 (1H, d, J = 8.5), 8.07 (2H, m). Reference Example 1 1 0

4— (1-t-butoxycarbonylbiperidine-1 4-yloxy) — 3-methylaniline

Reference Example 1 4- (1-t-butoxycarbonylpiperidine-4-yloxy) -13-methylnitrobenzene (4.07 g) obtained in 09 was dissolved in methanol (40 ml), and the mixture was dissolved in palladium-carbon catalyst. (0.41 g), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: hexane ethyl acetate = 3Z2) to give 2.73 g of the title compound ( Yield Reference Example 109 (53% in two steps) was obtained as a pale red oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.74 (2H, m), 1.87 (2H, m), 2.17 (3H, s), 3.30 (2H, m), 3.68 (2H , m), 4.25 (1H, m), 6.47 (1H, dd, J = 8.5, 2.5), 6.53 (1H, d, J = 2.5), 6.68 (1H, d, J = 8.5). Reference Example 1 1 1

N— [4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) —3-methylphenyl] ethyl ethyl sulfamoylacetate

Reference Example 11 4- (1-t-butoxycarbonylpiperidine-141-yloxy) _3-methylaniline (1.63 g) obtained in 10 was dissolved in dichloromethane (30 ml) and cooled on ice. Then, chlorosulfonyl acetate ethyl (0.86 ml) and pyridine (0.81 ml) were added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl hexanenoacetate = 3/2) to give 1.84 g (yield 76%) of the title compound as a pale solid. Obtained as a brown amorphous solid.

^{1 H NMR (500 MHz, CDC1} 3) d pom: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.22 (3H, s), 3.43 (2H, m), 3.62 (2H, m), 3.90 (2H, s), 4.29 (2H, q, J = 7.0), 4.48 (1H, m), 6.79 (1H, d, J = 8.0), 7.12 (2H, m).

N— [4 -— (1-t-butoxycarbonylbiperidine-1-4-yloxy) —3-methylphenyl] N— [3- (3-cyanophenyl) 1-2— (E) 1-probenyl] sulfamoyl Ethyl acetate

3- (3-cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (0.64 g), N- [4- (1-1-1) obtained in Reference Example 111 t-Butoxycarbonylpiperidine-1-yloxy-1-3-methylphenyl] sulfamoyl acetate ethyl (1.884 g) and triphenylphosphine (1.26 g) were dissolved in dichloromethane (40 ml), and the mixture was cooled under ice-cooling. After dropwise addition of azodiphenol getyl ruponate (0.76 ml), the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 12/1) to give 1.90 g (yield 79%) of the title compound as a colorless amorphous Obtained as a solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.21 (3H, s) , 3.44 (2H, m), 3.60 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5), 4.50 (IH, m) , 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (IH, d, J = 16.0), 6.80 (IH, d, J = 8.0), 7.24 (2H, m), 7.40 (1H, t, J = 8.0), 7.50 (IH, d, J = 7.5), 7.52 (1H, d, J = 8.0), 7.56 (1H, s). Reference Example 113

5 Ethyl torosalicylate

5-Nitrosalicylic acid (10.8 g) was dissolved in ethanol (100 ml), concentrated sulfuric acid (92. Og) was added at room temperature, and the mixture was refluxed for 7.5 hours. The reaction solution was cooled to room temperature, neutralized by adding an aqueous sodium hydroxide solution, extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate, 0.5 N hydrochloric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (10.7 g, yield 85%) as a pale yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (3H, t, J = 7.0), 4.49 (2H, q, J = 7.0), 7.09 (1H, d, J = 9.0), 8.33 (1H, dd , J = 9.0, 3.0), 8.79 (1H, d, J = 3.0).

4- (1-t-butoxycarbonylpiperidine-1_4-yloxy) -1-3-ethoxycalponylnitrobenzene

1-t-butoxycarbonyl 4-hydroxypiperidine (10.2 g), 5-ethyl-2-ethylsalicylate (10.7 g) obtained in Reference Example 13 and triphenylphosphine (17.3 g) Was dissolved in dichloromethane (200 ml), and getyl azodicarboxylate (10.4 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue is purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 3/1), and hexane is added to the obtained yellow solid, followed by filtration. The title compound (12.3 g, yield 61%) was obtained as a white solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.40 (3H, t, J = 7.0), 1.47 (9H, s), 1.91 (4H, m), 3.58 (4H, m), 4.39 (2H, q, J = 7.0), 4.79 (1H, m), 7.04 (1H, d, J = 9.0), 8.32 (1H, dd, J = 9.0, 3.0), 8.69 (1H, d, J = 3.0). Reference example 115

4- (1-t-butoxycarbonylpiperidine—4-yloxy) -1-3-hydroxyl-nitrobenzene

4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -13-ethoxycarbonylnitrobenzene (1.0 g) obtained in Reference Example 114 was dissolved in ethanol (10 ml), and potassium heptaoxide was added at room temperature. after addition of an aqueous solution (0. dissolving 2 ^ in water 0.5 5 ml), for 2 hours _b reaction solution was heated to reflux and cooled to room temperature, was neutralized with 1N hydrochloric acid, and extracted with acetic acid Echiru, extracted The liquid was washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.9 g (yield: 96%) of the title compound as a pale yellow solid. _{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 2.00-2.10 (2H, m), 3.45-3.55 (2H, m), 3.65-3.75 ( 2H, m), 4.87 (IH, m), 7.13 (1H, d, J = 9.0), 8.39 (IH, dd, J = 9.0, 3.0), 8.93 (IH, d, J = 3.0).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-hydroxylvamoylnitrobenzene

The 4- (1-t-butoxycarbonylpiperidine_4-yloxy) -13-carbonyloxybenzene (0.9 g) obtained in Reference Example 115 was dissolved in dichloromethane (20 ml), and chloroform was added thereto. Isoptyl acid (0.3 ml) and triethylamine (0.4 ml) were added, the mixture was stirred at the same temperature for 1 hour, 28% aqueous ammonia (0.2 ml) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 19/1) to give 0.9 g (yield 98%) of the title compound. Obtained as a yellow amorphous solid. _{tHNMR (500 MHz, CDC1 3)} δ ppm: 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.20 (2H, m), 3.30-3.40 (2H, m), 3.75-3.90 (2H , M), 4.81 (1H, m), 7.11 (IH, d, J = 9.0), 8.33 (IH, dd, J = 9.0, 3.0), 9.09 (1H, d, J = 3.0).

4— (1 t-butoxycarbonylbiperidine-1 4_yloxy) 1-3

4- (1-t-Butoxycarbylbiperidine-14-yloxy) -13-caprolbumoylnitrobenzene (5.7 g) obtained in Reference Example 116 was dissolved in methanol (80 ml), and palladium-carbon was dissolved. A catalyst (0.6 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / Z methanol = 19/1) to give 4.8 g (yield) of the title compound. 91%) as a pale yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 3.19 (2H, m), 3.75-3.85 (2H, m), 4.44 (1H, m), 6.78 (1H, dd, J = 9.0, 3.0), 6.84 (1H, d, J = 9.0), 7.50 (1H, d, J = 3.0).

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-carbamoylphenyl] sulfamoylacetyl acetate 'The 4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) obtained in Reference Example 117 1) -Rubamoylaniline (4.8 g) was dissolved in dichloromethane (80 ml), and chlorosulfonyl acetate ethyl (2.5 ml) and pyridine (2.3 ml) were added dropwise under ice-cooling. For 6 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 19/1), ether was added to the obtained orange solid, and the mixture was filtered to give the title compound 3. .7 g (53% yield) were obtained as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.32 (3H, t, J = 7.0), 1.47 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.27 ( 2H, m), 3.75-3.85 (2H, m), 3.94 (2H, s), 4.28 (2H, q, J = 7.0), 4.65 (1H, m), 7.02 (1H, d, J = 9.0), 7.59 (1H, dd, J = 9.0, 3.0), 8.12 (1H, d, J = 3.0).

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-carbamoylphenyl] —N— [3- (3-cyanophenyl) 1-2- (E) -probenyl] sulfamoylacetic acid Etil

3- (3-Cyanophenyl) 1-2- (E) -propene-11-all (0.7 g) obtained in Reference Example 2, N- [4- (1-1-1) obtained in Reference Example 118 t-Butoxycarboxylbiperidine (14-yloxy) -13 rubamoylphenyl] Sulfamoyl acetate ethyl (2.0 g) and triphenylphosphine (1.5 g) are dissolved in dichloromethane (30 ml) and cooled on ice. After dropwise addition of azodiphenol geronate (0.9 ml), the mixture was stirred at room temperature for 8 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography. Purification with a single solvent (eluent: hexane / ethyl acetate = 1/2) gave 2.5 g (yield 94%) of the title compound as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.27 (2H, m), 3.75-3.85 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.53 (2H, d, J = 7.0), 4.66 (1H, m) , 6.22 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 7.01 (1H, m), 7.39 (1H, m), 7.45-7.60 (2H, m), 7.65- 7.75 (2H, m), 8.32 (1H, m). Reference example 120

4- (1-t-butoxycarpylbiperidine—4-yloxy) —3-trifluoromethylaniline

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -13-trifluoromethylnitrobenzene (2.28 g) obtained in Reference Example 100 was dissolved in methanol (50 ml), and palladium-carbon After adding a catalyst (0.20 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z-ethyl acetate = 3 Z2) to give 1.69 g (yield) of the title compound. (80%) as a pale red oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.76-1.88 (4H, m), 3.43 (2H, m), 3.59 (2H, m), 4.46 (1H, m), 6.78 (1H, dd, J = 9.0, 3.0), 6.83 (1H, d, J = 9.0), 6.91 (1H, d, J = 3.0).

N— [4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) —3-trifluoromethylphenyl] ethyl ethyl sulfamoylacetate

4- (1-t-butoxycarbonylpiperidine-14-yloxy) -13-trifluoromethylaniline (1.69 g) obtained in Reference Example 120 was dissolved in dichloromethane (20 ml). Chlorosulfonyl ethyl ester (0.76 ml) and pyridine (0.49 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure, the residue was removed. The residue was purified by silica gel column chromatography (elution solvent: hexane Z-ethyl acetate = 3/2) to obtain 1.74 g (yield 73%) of the title compound as a pale red oily substance.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.48 (9H, s), 1.83-1.94 (4H, m), 3.48-3.60 (4H, m), 3.91 ( 2H, s), 4.31 (2H, q, J = 7.0), 4.65 (1H, m), 6.99 (1H, d, J = 9.0), 7.52 (1H, dd, J = 9.0, 2.5), 7.56 (1H , D, J = 2.5). Reference example 122

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-trifluoromethylphenyl] —N— [3- (3-cyanophenyl) 1-2— (E) 1-probenyl ] Sulfamoyl acetate

3- (3-cyanophenyl) 1-2- (E) 1-propene / 1-all (0.57 g) obtained in Reference Example 2 and N— [4 -— (1-t-1) obtained in Reference Example 121 Butoxycarbonyl piperidine (4-yloxy) -1,3-trifluoromethylphenyl] sulfamoyl acetate (1.74 g) and triphenylphosphine (1.07 g) were dissolved in dichloromethane (27 ml) and cooled on ice. Under the solution, acetyl dicarboxylate (0.65 ml) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 12/1) to give 2.06 g (yield 93%) of the title compound. Obtained as a colorless amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J-7.0), 1.47 (9H, s), 1.82-1.92 (4H, m), 3.46-3.62 (4H, m), 3.98 ( 2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2H, d, J = 6.5), 4.66 (IH, m), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (IH , d, J = 16.0), 6.98 (1H, d, J = 7.5), 7.41 (1H, dd, J = 8.0, 7.5), 7.52 (2H, m), 7.57 flH, s), 7.58 (1H, dd) , J = 9.0, 2.0), 7.72 (1H, d, J = 2.0).

3—Black mouth 4— (Tropane-1—yloxy) Nitrobenzene

3-tropanol (6.7 g), 2-chloro-4-nitrophenol (8.2 g) and And triphenylphosphine (16.1 g) were dissolved in a mixed solvent of dichloromethane (200 ml) and tetrahydrofuran (50 ml), and under ice-cooling, azodicarboxylic acid getyl (9.7 ml) was added dropwise. Stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 19/1) to give 8.5 g (yield 60%) of the title compound as a pale yellow color Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.65-1.75 (2H, m), 2.00-2.10 (4H, m), 2.15-2.25 (2H, m), 2.46 (3H, s), 3.35-3.45 ( 2H, m), 4.68 (1H, m), 6.98 (1H, d, J = 9.0), 8.11 (1H, dd, J = 3.0, 9.0), 8.28 (1H, d, J = 3.0). '

3—Black mouth 41-1 (Tropane _ 3—Iroxy) Aniline

Dissolve 3-chloro-41- (tropan-1-yloxy) nitrobenzene (8.5 g) obtained in Reference Example 123 in acetic acid (500 ml) and add tin powder (17.0 g) at room temperature. Then, the mixture was stirred overnight at the same temperature. After the reaction solution was filtered, the filtrate was neutralized with an aqueous solution of potassium carbonate, and extracted with ethyl acetate. After the extract was washed with a saturated saline solution, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 3Z1) to give 2.5 g (yield 32%) of the title compound as a colorless solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.50-1.60 (2H, m), 1.85-1.95 (4H, m), 2.00-2.10 (2H, m), 2.38 (3H, s), 3.20-3.30 ( 2H, m), 4.23 (1H, m), 6.49 (1H, dd, J = 3.0, 8.5), 6.71 (1H, d, J = 3.0) 6.81 (1H, d, J = 8.5).

N— [3—Black 1—4— (Tropan-1—3-yloxy) phenyl] Sulfamoyl acetate

3-Chloro-4- (tropan-1-yloxy) aniline (2.5 g) obtained in Reference Example 124 was dissolved in dichloromethane (50 ml), and the solution was cooled with ice to give ethyl chlorosulfonyl acetate. (1.5 ml) and pyridine (0.9 ml) were added dropwise, followed by stirring at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 4/1) to give 3.5 g (yield 89%) of the title compound as a pale brown solid. Obtained as a shaped solid.

_{1H NMR (500 MHz, CDC1 3} ) d ppm: 1.32 (3H, t, J = 7.0), 1.95-2.05 (2H, m), 2.20-2.25 (2H, m), 2.30-2.75 (4H, m), 2.84 (3H, s), 3.89 (2H, m), 3.98 (2H, s), 4.28 (2H, q, J = 7.0), 4.49 (IH, m), 6.95 (IH, d, J = 8.5), 7.25 (IH, dd, J = 2.5, 8.5), 7.45 (IH, d, J = 2.5). Reference example 1 2 6

• N— [3-Chloro-41- (tropane-3-yloxy) phenyl] -1-N— [3- (3-Cyanophenyl) -1-2- (E) -probenyl] ethyl ethyl sulfamoyl acetate

3- (3-Cyanophenyl) -2- (E) -propene obtained in Reference Example 2 (1.4 g), N- [3-chloro-one obtained in Reference Example 125 41 (Tropane-3-yloxy) phenyl] Ethyl sulfamoylacetate (3.5 g) and triphenylphosphine (2.9 g) are dissolved in dichloromethane (50 ml), and the mixture is dissolved in ice-cooled getyl azodicarboxylate (1). .8 ml) was added dropwise, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 1971-91) to give 1.3 g of the title compound (yield 27%). Was obtained as a yellow amorphous solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.36 (3H, t, J = 7.0), 1.55-1.65 (2H, m), 1.90-2.00 (4H, m), 2.05-2.15 (2H, m) , 2.37 (3H, s), 3.27 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.5), 4.50 (IH, m) , 6.21 (IH, dt, J = 6.5, 16.0), 6.41 (1H, d, J = 16.0), 6.94 (1H, m), 7.29 (1H, m), 7.40 (IH, m), 7.50-7.60 ( 4H, m). Reference example 1 27

Carbonic acid [3 -— (3-Cyanophenyl) —2— (E) 1-probenyl] ethyl

3- (3-cyanophenyl) -1-2- (E) -propene obtained from Reference Example 2 (403 mg) was dissolved in dichloromethane (6 ml), ethylethyl chloroformate (0.38 ml) and pyridine (1.00 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours. An aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to obtain 492 mg (84% yield) of the title compound as a colorless oil As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 4.24 (2H, q, J = 7.0), 4.80 (2H, d, J = 5.5), 6.36 (1H, dt , J = 16.0, 5.5), 6.67 (1H, d, J = 16.0), 7.44 (1H, t, J = 8.0), 7.55 (1H, d, J = 8.0), 7.61 (1H, d, J = 8.0) ), 7.66 (1H, s). Reference Example 128

N- [4 -— (1-t-butoxycarbonylbiperidine-1 4-yloxy) phenyl] ethanesulfonamide

The 4- (1-t-butoxycarbonylpiperidine-14-yloxy) aniline (10.6 g) obtained in Reference Example 106 was dissolved in dichloromethane (75 ml), and ethanesulfonyl chloride (4.1 ml) was dissolved under ice-cooling. ) And pyridine (8 ml) were added dropwise, followed by stirring at room temperature for 5 hours. After adding methanol (1 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3Z2) to obtain 11.7 g of the title compound. (84% yield) as a pale pink solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.38 (3H, t, J = 8.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.07 (2H, q, J = 8.0), 3.34 (2H, m), 3.69 (2H, m), 4.42 (1H, m), 6.88 (2H, d, J = 9.0), 7.17 (2H, d, J = 9.0). Reference example 129

N— [4- (1-t-butoxycarbonylbiperidine—4-yloxy) phenyl] -N- [3- (3-cyanophenyl) 1-2— (E) 1-propenyl] ethanesulfonamide [3- (3-Cyanophenyl) carbonate-2- (E) -probenyl] ethyl carbonate (1.04 g) obtained in Reference Example 127 and N— [4-1- (1 — T-butoxy-l-ponylpiperidine— 4-yloxy) phenyl] ethanesulfonamide (1.15 g) is suspended in tetrahydrofuran (9 ml), and tris (dibenzylideneacetone) paradium chromate form complex (0.08 g) ) And triphenylphosphine (0.04 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 8/1) to give 1.57 g (quantitative yield) of the title compound as a pale yellow color Obtained as an oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.42 (3H, t, J = 7.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.06 (2H, q, J = 7.0), 3.34 (2H, m), 3.68 (2H, m), 4.42 (2H, d, J = 7.0), 4.44 (IH, m), 6.28 (1H, dt, J = 15.5, 7.0), 6.42 (IH, d, J = 15.5), 6.89 (2H, d, J = 9.0), 7.26 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.5), 7.52 (2H, m) , 7.56 (IH, s).

3— (3-Cyanophenyl) —2-methyl-2- (E) monopropenal

3-Cyanobenzaldehyde (2.62 g) was dissolved in toluene (90 ml), and 2-triphenylphosphoranylidenepropionaldehyde (8.28 g) was added, followed by stirring at 70 ° C for 11 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to give the title compound (2.61 g, yield 76%) as pale-yellow needles.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 2.07 (3H, s), 7.25 (1H, bs), 7.59 (1H, t, J = 8.0), 7.68 (IH, d, J = 8.0), 7.74 ( 1H, d, J = 8.0), 7.79 (IH, s), 9.63 (IH, s). Reference Example 131

3- (3-Cyanophenyl) -l-Methyl-2- (E) -propene-l-ol 3-(3-Cyanophenyl) -l-methyl-2- obtained from Reference Example 130 (E) One liter (2.00 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (60 ml), and sodium borohydride (0.83 g) and cerium chloride were added under ice-cooling. Then, the mixture was stirred at the same temperature for 3 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted three times with dichloromethane. The extract was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 2.05 g (yield quantitative) of the title compound as a pale yellow color Obtained as an oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm:. 1.87 (3H, s), 4.22 (2H, m), 6.52 (1H, bs), 7.42 - 7.52 (3H, m), 7.55 (1H, s) Reference Example 1 32

Reference Example 13 3- (3-Cyanophenyl) carbonate [2- (3-Cyanophenyl) -1- (E) -propenyl] ethyl 3- (3-cyanophenyl) —2-methyl-2- (E) ー obtained in 1 Dissolve pentanol (2.00 g) in dichloromethane (20 ml), add ethyl chloroformate (1.30 ml) and pyridine (3.00 ml) dropwise under ice-cooling, and allow to stand at room temperature for 12 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 2.46 g (yield 87%) of the title compound. Obtained as a colorless oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, = 7.0), 1.90 (3H, s), 4.25 (2H, q, J = 7.0), 4.70 (2H, s), 6.53 (1H , bs), 7.43-7.55 (4H, m).

N- [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -1-2-methyl-2- (E) -probenyl] ethane sulfonamide

[3- (3-Cyanophenyl) carbonate-2-methyl-2 -_ (E) -l-propenyl] ethyl carbonate obtained in Reference Example 132 and N— [4— () obtained in Reference Example 128 1-t-butoxycarbonylpiperidine-1 4-yloxy) phenyl] ethanesulfonamide (1150 mg) was suspended in tetrahydrofuran (9 ml), and tris (dibenzylide) was added. After addition of (acetone) palladium chromate form complex (78 mg) and triphenylphosphine (39 mg), the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12/1) to give 0.58 g (yield 36%) of the title compound as a colorless solid Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.42 (3H, t, J-7.5), 1.47 (9H, s), 1.75 (2H, m), 1.89 (3H, s), 1.91 (2H, m) , 3.07 (2H, q, J = 7.5), 3.34 (2H, m), 3.69 (2H, m), 4.37 (2H, s), 4.45 (1H, m), 6.21 (1H, s), 6.89 (2H , d, J = 9.0), 7.26 (2H, d, J = 9.0), 7.32 (1H, d, J = 8.0), 7.35 (1H, s), 7.38 (1H, t, J = 8.0), 7.48 ( 1H, d, J = 8.0). Reference example 134

4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) 2-methylnitole Mouth benzene

1-t-butoxycarbonyl 4-hydroxypiperidine (6.04 g), 3-methyl 4-212-trophenol (4.59 g) and triphenylphosphine (10.20 g) were added to dichloromethane (100 ml). After dissolving, ice-cooled getyl azolate (6.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give 6.04 g (yield 60%) of the title compound. Obtained as a yellow solid.

_{NMR (400 MHz, CDC1 3)} 6 ppm: 1.48 (9H, s), 1.78 (2H, m), 1.94 (2H, m), 2.62 (3H, s), 3.38 (2H, m), 3.69 (2H, m), 4.58 (1H, m), 6.80 (2H, m), 8.08 (1H, d, J = 9.5). Reference example 135

4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -1-2-methylaniline

The 4- (1-t-butoxycarbonylpiperidine-14-yloxy) -1-2-methylnitrobenzene (3.23 g) obtained in Reference Example 134 was dissolved in methanol (30 ml). After adding a palladium-carbon catalyst (0.21 g), the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 171) to give 3.02 g of the title compound (yield). 99%) as a pale red oil.

^{1 H NMR (400 MHz, CDC1} 3) δ ppm: 1.47 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 2.12 (3H, s), 3.27 (2H, m), 3.71 ( 2H, m), 4.26 (1H, m), 6.59-6.69 (3H, m).

N— [4— (1—t—butoxycarbonyl piperidine—4-yloxy) —2-methylphenyl] sulfamoyl acetate

Reference Example 1 4- (1-t-Butoxycarbonylpiperidine-4-yloxy) 1-2-methylaniline (3.00 g) obtained in 35 was dissolved in dichloromethane (20 ml), and chloroform was added under ice cooling. After dropwise addition of ethyl sulfonyl acetate (1.6 ml) and pyridine (1.6 ml), the mixture was stirred at room temperature for 13 hours. After adding methanol (1.0 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 32) to give the title compound 2.35. g (yield 53%) was obtained as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 2.38 (3H, s) , 3.34 (2H, m), 3.68 (2H, m), 4.01 (2H, s), 4.29 (2H, q, J = 7.0), 4.43 (1H, m), 6.73 (1H, dd, J = 8.5, 3.0), 6.80 (1H, d, J = 3.0), 7.34 (1H, d, J = 8.0).

N— [4- (1—t—Butoxycarbonylbiperidine—4-yloxy) -1-2-methylphenyl) N— [3 -— (3-Cyanophenyl) —2 -— (E) —Probenyl sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene-11-ol (0 · 48 g) obtained in Reference Example 2 and N— [4- (1-1-1) obtained in Reference Example 136 t-butoxycarbonyl [Piperidine-1-4-yloxy] -2-methylphenyl] Sulfamoyl acetate ethyl ester (1.37 g) and triphenylphosphine (0.94 g) were dissolved in dichloromethane (20 ml), and the mixture was dissolved in ice-cooled ice-cooled getyl azolate. (0.57 ml) was added dropwise, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography-(elution solvent: dichloromethane / ethyl acetate = 11/1) to give 1.80 g (quantitative yield) of the title compound as a pale yellow amorphous Obtained as a solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 2.35 (3H, s) , 3.34 (2H, m), 3.68 (2H, m), 3.99 (1H, d, J = 15.0), 4.12 (1H, d, J = 15.0), 4.27 (IH, dd, J = 15.0, 6.0), 4.31 (2H, m), 4.44 (IH, m), 4.50 (1H, dd, J = 15.0, 6.0), 6.28 (IH, dt, J = 16.5, 6.0), 6.32 (1H, d, J = 16.5) , 6.76 (IH, dd, J = 9.0, 3.0), 6.79 (1H, d, J = 3.0), 7.39 (IH, d, J = 9.0), 7.41 (IH, d, J = 7.5), 7.52 (3H , M). Reference Example 138

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -1-methoxynitrobenzene

1-t-butoxycarbone 4-hydroxypiperidine (3.02 g), 2-methoxy-14-nitrophenol (2.54 g) and triphenylphosphine (10.20 g) are dissolved in dichloromethane (60 ml). Then, under ice-cooling, acetyl dicarboxylate (3.1 ml) was added dropwise, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 5Z 2) to give 4.36 g (yield 82%) of the title compound as a pale yellow oil Obtained as a substance.

^{1 H NMR (500 MHz, CDC1} 3) δ ppm: 1.47 (9H, s), 1.83 (2H, m), 1.96 (2H, m), 3.33 (2H, m), 3.77 (2H, m), 3.94 ( 3H, s), 4.61 (IH, m), 6.94 (1H, d, J = 9.0), 7.76 (IH, d, J = 2.0), 7.87 (1H, dd, J = 9.0, 2.0). Reference Example 139 4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) -3-methoxydiline

4- (1-t-butoxycarbonylpiperidine- 4-yloxy) -13-methoxynitrobenzene (4.36 g) obtained in Reference Example 138 was dissolved in methanol (60 ml), and palladium-carbon catalyst (0. After stirring for 25 hours at room temperature under a hydrogen atmosphere. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane Z ethyl acetate = 1Z1) to give the title compound (2.03 g, yield). 51%) as a pale red oil.

_{1H NMR (500 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.18 (2H, m), 3.78 (2H, m), 3.80 (3H , s), 4.15 (IH, m), 6.19 (IH, dd, J = 8.5, 3.0), 6.29 (IH, d, J = 3.0), 6.76 (1H, d, J = 8.5).

N- [4- (1-t-butoxycarbonylbiperidine-1 4-yloxy) -1-3-methoxyphenyl] ethyl ethyl sulfamoylacetate

4- (1-t-butoxycarbonylbiperidine-14-yloxy) -13-methoxyaniline (2.00 g) obtained in Reference Example 139 was dissolved in dichloromethane (40 ml), and ethyl chlorosulfonyl acetate was dissolved under ice-cooling. After dropping (1. Oml) and pyridine (1. Oml), the mixture was stirred at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2 Z 1) to give 2.56 g (yield 87%) of the title compound as a pale red color Obtained as an oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.32 (3H, t, J = 7.0), 1.47 (9H, s), 1.76 (2H, m), 1.90 (2H, m), 3.25 (2H, m) , 3.78 (2H, m), 3.85 (3H, s), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.36 (IH, m), 6.82 (1H, dd, J = 9.0, 2.5), 6.88 (1H, d, J = 9.0), 6.96 (IH, d, J = 2.5). N- [4- (1-1 !!: butoxycarbonylbiperidine-1-4-yloxy) —3-Methoxyphenyl] —N— [3- (3-Cyanophenyl) -1-2- (E) -probenyl] sulfamoylacetic acid Etil

3- (3-Cyanophenyl) -2- (E) 1-propene / 1-all (338 mg) obtained in Reference Example 2, N- [4- (1-t-butoxycarbonylpi) obtained in Reference Example 140 was obtained. Ethyl (4-lyloxy) -3-methoxyphenyl] sulfamoylacetate (823 mg) and triphenylphosphine (100 Omg) were dissolved in dichloromethane (20 ml) and dissolved in ice-cooled ice-cooled getyl azolate. 43 ml), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 121) to give 985 mg (yield 76%) of the title compound as a colorless amorphous solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.37 (3H, t, J = 7.0), 1.48 (9H, s), 1.78 (2H, m), 1.93 (2H, m), 3.27 (2H, m) , 3.80 (2H, m), 3.84 (3H, s), 4.02 (2H, s), 4.32 (2H, q, J = 7.0), 4.43 (IH, m), 4.50 (2H, d, J = 7.0) , 6.27 (IH, dt, J = 15.5, 7.0), 6.42 (IH, d, J = 15.5), 6.92 (IH, d, J = 8.0), 7.03 (IH, dd, J = 8.0, 3.0), 7.05 (IH, d, J = 3.0), 7.42 (IH, t, J = 8.0), 7.53 (2H, m), 7.58 (1H, s). Reference example 142

4-1-1 (1-t-butoxycarbonylpiperidine-1 4-yloxy) 1-3-Fluoronitrile benzene

1-t-butoxycarbone 4-hydroxypiperidine (3.02 g), 2-furylfluoro-4-nitrophenol (2.36 g) and triphenylphosphine (5.11) were added to dichloromethane (60 ml). After dissolving, ice-cooled getyl argonate (3.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/2) to give 3.71 g (yield 73%) of the title compound. Obtained as a yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.84 (2H, m), 1.97 (2H, m), 3.41 (2H, m), 3.71 (2H, m), 4.66 (1H , M), 7.05 (1H, m), 8.04 (2H, m). Reference Example 143

4- (1-t-butoxycarbonylpiperidine-4-1-yloxy) 1-3-fluoroa diphosphate

The 4- (1-t-butoxycarbonylpiperidine-14-yloxy) —3-fluoronitrobenzene (3.71 g) obtained in Reference Example 142 was dissolved in methanol (50 ml), and the palladium-carbon catalyst ( After adding 0.30 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 1Z1) to give 3.27 g of the title compound (yield 97 %) Was obtained as a pale red solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.46 (9H, s), 1.72 (2H, m), 1.86 (2H, m), 3,23 (2H, m), 3.75 (2H, m), 4.17 (IH, m), 6.35 (1H, dd, J = 8.5, 3.0), 6.44 (1H, dd, J = 12.5, 3.0), 6.82 (1H, dd, J = 9.0, 8.5). Reference example 144

N— [4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) -1-3-fluorophenyl] ethyl ethyl sulfamoyl acetate

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -13-fluoroaniline (1.49 g) obtained in Reference Example 143 was dissolved in dichloromethane (30 ml), and chlorosulfonyl under ice-cooling. After dropwise addition of ethyl acetate (0.77 ml) and pyridine (0.77 ml), the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.58 g (yield 71%) of the title compound as a pale red color Obtained as an oil.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.47 (9H,), 1.77 (2H, m), 1.90 (2H, m), 3.32 (2H, m), 3.72 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.42 (1H, m), 6.97 (1H, dd, J = 9.0, 8.5), 7.04 (1H, dd) , J = 9.0, 3.0), 7.17 (IH, dd, J = l 1.5, 3.0). Reference Example 145

N- [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-phenyloxyphenyl] — N— [3-(3-cyanophenyl) -1-2- (E) -probenyl] sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) -2- (E) -propene-11-ol (0.40 g) obtained in Reference Example 2, N- [4- (1-1 Dissolve t-butoxycarbonylpiperidine-1- (4-yloxy) -3-fluorophenyl] sulfamoylethyl acetate (1.15 g) and triphenylphosphine (0.85 g) in dichloromethane (20 ml) and cool under ice-cooling. After dropwise addition of azodiphenol geronate (0.5 1 ml), the mixture was stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10Z1) to give 1.21 g (yield 81%) of the title compound as a pale yellow amorphous solid As obtained.

_{NMR (500 MHz, CDC1 3)} δ ppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.77 (2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.70 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (1H,), 4.47 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.41 (1H, d, J = 16.0), 6.98 (1H, dd, J = 9.0, 8.5), 7.20 (1H, dd, J = 8.5, 2.0), 7.27 (1H, m), 7.40 (1H, dd, J-8.0, 7.0), 7.52 (1H, d, J = 7.0), 7.53 (1H, d, J = 8.0), 7.56 (1H, s). Reference example 146 ''

3 One Promo 5—Cyanotoluene

3,5-Dibromotoluene (10.00 g) was dissolved in 1-methyl-2-pyrrolidone (7 Om 1), copper (I) cyanide (5.20 g) was added, and then 200 °. For 1.5 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water, and saturated saline in this order, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was suspended in a mixed solvent of hexane and ethyl acetate (9/1), and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane Z ethyl acetate = 9/1) to give 1.70 g (yield 21%) of the title compound. Was. _{¾ NMR (270 MHz, CDC1 3} ) δ ppm:. 2.39 (3H, s), 7.40 (1H, s), 7.57 (1H, s), 7.60 (1H, s) Reference Example 147

3- (3-cyano 5-methylphenyl) 1 2- (E) 1-propene 1-l

To 1-t-butyldimethylcyclohexyl-2-propyne (1.70 g) was added acetic alcohol (1.07 ml), and the mixture was stirred at 60 for 3 hours. After the reaction solution was cooled to room temperature, it was diluted with toluene (20 ml), and 3-bromo-5-cyanotoluene (1.40 g) obtained in Reference Example 146, tetrakis (triphenylphosphine) palladium complex (0. After adding 42 g) and 20% ethanol solution of sodium ethoxide (3.40 ml), the mixture was stirred at 100 ° C for 3 hours. After water was added to the reaction mixture, the mixture was extracted with ether. The extract was washed successively with a 1N aqueous solution of sodium hydroxide, water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 19-1) to obtain 1.50 g of a silyl ether compound.

Then, the obtained silyl ether compound was dissolved in tetrahydrofuran (30 ml), a 1 N tetrabutylammonium fluoride / tetrahydrofuran solution (7 ml) was added under ice cooling, and the mixture was heated at the same temperature for 1 hour. Stirred. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 32) to obtain 0.54 g of the title compound (yield 43% in two steps). Obtained as an oil.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 2.38 (3H, s), 4.35 (2H, d, J = 5.0), 6.40 (1H, dt, J = 16.0, 5.0), 6.58 (1H, d, J = 16.0), 7.33 (1H, s), 7.40 (1H, s), 7.46 (1H, s). Reference Example 148

N— [4 -— (1-t-butoxycarbonylbiperidine-1-4-yloxy) phenyl] -N- [3- (3-cyano-5-methylphenyl) _- 1-2- (E) —probenyl] sulf Amoyl acetate

3- (3-cyano-5-methylphenyl) 1-2- (E) -pu-pen-111-ol (0.54 g) obtained in Reference Example 147, N- [4- (1-t-butoxycarbonylpiperidine-4-yloxy) phenyl] Ethyl sulfamoylacetate (1.50 g) and triphenylphosphine (1.10 g) were dissolved in dichloromethane (30 ml) and dissolved in ice. After dropwise addition of azodiphenol geronate (0.66 ml), the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19Z1) to give 1.7 g of the title compound (91% yield) in amorphous form. Obtained as a solid.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 2.36 ( 3H, s), 3.25-3.40 (2H, m), 3.60-3.75 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.40-4.50 (3H, m), 6.21 (1H, dt, J = 16.0, 6.0), 6.36 (1H, d, J = 16.0), 6.90 (2H, m), 7.30-7.45 (5H, m).

3- (3-Cyanol 4-fluorophenyl) _2- (E) 1-propene-1-ol 1-t-butyldimethylcyclohexyl 2-propyne (1.70 g) and catecholporan (1.07 ml) The mixture was stirred at 60 ° C for 4 hours. After cooling the reaction solution to room temperature, it was diluted with toluene (20 ml), and 5-bromo-2-fluorobenzonitrile (1.43 g), tetrakis (triphenylphosphine) palladium complex (0.42 g) and sodium After adding a 20% ethanol solution of ethoxide (3.4 ml), the mixture was stirred at 100 ° C for 4 hours. After water was added to the reaction solution, the mixture was extracted with ether. The extract was washed successively with a 1N aqueous solution of sodium hydroxide, water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 191) to obtain 1.33 g of a silyl ether compound.

Then, the obtained silyl ether compound was dissolved in tetrahydrofuran (20 ml), and 1N tetrabutylammonium fluoride Z tetrahydrofuran solution (6 ml) was added under ice cooling. After the addition, the mixture was stirred at the same temperature for 1 hour. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: ethyl hexanoacetate = 3 to 2 to 1/1) to obtain 0.48 g of the title compound (yield: 2 steps). (37%) as a yellow oil.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 4.30-4.40 (2H, m), 6.35 (1H, dt, J = 16.0, 5.0), 6.59 (1H, d, J = 16.0), 7.18 (1H, m ), 7.55-7.65 (2H, m). Reference example 150

N- [4 -— (1-t-butoxycarbonirubiperidine_4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) 1-2- (E) -probenyl] sulfamoylacetic acid Etil

3- (3-cyano 4-fluorophenyl) -2- (E) -propene-1-1-ol obtained in Reference Example 149 (0.48 g), N— [4 -— ( 11-t-Butoxycarbonylpiperidine-14-yloxy) phenyl] Sulfamoyl acetate (1.30 g) and triphenylphosphine (1.00 g) are dissolved in dichloromethane (30 ml), and cooled under ice-cooling. After dropping getyl ketone (0.60 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 1.53 g (yield 93%) of the title compound. Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.30- 3.40 (2H, m), 3.65-3.75 (2H, m), 3.97 (2H, s), 4.30 (2H, q, J = 7.0), 4.40-4.50 (3H, m), 6.16 (1H, dt, J = 16.0, 6.0), 6.37 (1H, d, J = 16.0), 6.91 (2H, d, J = 9.0), 7.14 (1H, m), 7.38 (2H, d, J = 9.0), 7.45-7.55 ( 2H, m). Reference example 151

3-C3-"N- [4- (1-t-butoxycarbonylpiperidine_4-yloxy) phenyl] -amino]-1- (E) -probenyl] benzonitrile 3-cyanocinnamic aldehyde (6.0 g) obtained in Reference Example 1, 4- (1-t-butoxycarbonylpiperidine-4-peroxy) aniline (11.3 g) obtained in Reference Example 106, and Powdered molecular sieves 5A (15.0 g) was suspended in toluene (30 ml) and heated under reflux for 2 hours. The reaction solution was cooled to room temperature, filtered using celite, the filtrate was concentrated under reduced pressure, and the residue was recrystallized using dichloromethane and ether to obtain an imine compound (12.9 g). .

Next, the obtained imine compound was suspended in ethanol (200 ml), and sodium borohydride (1.1 g) and a catalytic amount of cerium chloride were added thereto under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by silica gel gel chromatography (elution solvent: hexane Z ethyl acetate = 3/2), and the obtained yellow solid is washed with diisopropyl ether. 10.0 g (yield 60%) of the title compound was obtained as pale yellow crystals.

_{¾ NMR (270 MHz, CDC1 3} ) d ppm: 1.46 (9H, s), 1.60 - 1.80 (2H, m), 1.80-1.95 (2H, m), 3.20 - 3.35 (2H, m), 3.65 - 3.80 ( 2H, m), 3.93 (2H, dd, J = 5.5, 1.0), 4.28 (IH, m), 6.39 (IH, dt, J = 16.0, 5.5), 6.61 (IH, d, J = 16.0), 6.61 (2H, d, J = 9.0), 6.81 (2H, d, J = 9.0), 7.41 (IH, t, J = 7.5), 7.51 (IH, d, J = 7.5), 7.57 (IH, d, J = 7.5), 7.63 (IH, s). Reference example 152

3- [3— [N— [4 -— (1-t-butoxycarbonylpiperidine_4_yloxy) phenyl] —N—methylylamino] _1- (E) —probenyl] benzonitrile

3- [3- [N- [4-1- (1-t-butoxycarpenylpyridin-1-4-yloxy) phenyl] amino] -11- (E) -pronenyl] benzonitryl obtained in Reference Example 151 (100 mg) and paraformaldehyde (138 mg) were suspended in dichloromethane (2 ml). Acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) were added under ice-cooling. It was stirred. After methanol (20 ml) was added to the reaction solution, the mixture was further stirred at 30 ° C for 5 hours. After adding water, extract with ethyl acetate The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate = 32) to obtain 761 mg (yield 74%) of the title compound as a yellow oil. Was.

_{1H NMR (270 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.72 (2H, m), 1.87 (2H, m), 2.92 (3H, s), 3.28 (2H, m), 3.71 (2H , m), 4.02 (2H, d, J = 5.0), 4.29 (1H, m), 6.32 (1H, dt, J = 16.0, 5.0), 6.51 (1H, d, J = 16.0), 6.72 (2H, d, J = 9.0), 6.86 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.49 (1H, d, J = 7.5), 7.56 (1H, d, J = 7.5) , 7.62 (1H, s). Reference example 153 '

3— [3— [N— [4-1- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] —N—ethylamino] 1-1_ (E) —probenyl] benzonitrile

3_ [3— [N— [4- (1-t-butoxycarboxylruberidine-4-yloxy) phenyl] amino] _1_ (E) —probenyl] benzonitryl (100 Omg) obtained in Reference Example 151 ) And acetoaldehyde (0.52 ml) were dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml). Under ice cooling, acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) were added. After stirring at the same temperature for 2 hours, the mixture was stirred at room temperature overnight. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 4 / 1-2 / 1) to obtain 661 mg of the title compound (62% yield). ) Was obtained as a yellow oil.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.16 (3H, t, J = 7.0), 1.46 (9H, s), 1.72 (2H, m), 1.87 (2H, m), 3.25 (2H, m) , 3.36 (2H, q, J = 7.0), 3.71 (2H, m), 4.01 (2H, d, J = 5.0), 4.26 (1H, m), 6.31 (1H, dt, J = 16.0, 5.0), 6.50 (1H, d, J = 16.0), 6.69 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.49 (1H, d, J = 7.5), 7.55 (1H, d, J = 7.5), 7.61 (1H, s). Reference Example 154

3— [3— [N— [4— (1-t-butoxycarbonylpiperidine—4-yloxy) phenyl] —N-isopropylamino] —1- (E) —probenyl] benzonitrile Reference example 3- [3— [N— [4 -— (1-t-butoxycarboxylpyridine-41-yloxy) phenyl] amino] 1-1- (E) -propionyl] benzonitryl (150 Omg) was dissolved in acetone (20 ml), acetic acid (0.20 ml) and sodium cyanoborohydride (214 mg) were added under ice-cooling, and the mixture was stirred at room temperature overnight, and then heated and refluxed for 8 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl hexane-acetate = 4: 1) to obtain 583 mg (yield 35%) of the title compound as a pale yellow oil. Was.

_{H NMR (270 MHz, CDC1 3} ) δ ppm: 1.18 (6H, d, J = 6.5), 1.46 (9H, s), 1.60-1.80 (2H, m), 1.80-1.95 (2H, m), 3.26 ( 2H, m), 3.71 (2H, m), 3.91 (2H, d, J = 4.5), 4.00 (1H, m), 4.26 (1H, m), 6.33 (1H, dt, J = 16.0, 4.5), 6.53 (1H, d, J = 16.0), 6.73 (2H, d, J = 9.0), 6.82 (2H, d, J = 9.0), 7.38 (1H, t, J = 7.5), 7.47 (1H, d, J = 7.5), 7.53 (1H, d, J = 7.5), 7.60 (1H, s). Reference example 155

3- [3- [N-benzyl-N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] amino] -11- (E) -probenyl] benzonitrile

3- [3- [N- [4- (1-t-butoxycarbonylpyridine-l-4-yloxy) phenyl] amino] -1-1 (E) -l-propenyl] benzonit obtained in Reference Example 151 Ril (100 Omg) and benzaldehyde (0.52 ml) are dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (20 ml.), And acetic acid (0.26 ml) and cyanogen triborohydride are added under ice-cooling. After adding sodium (144 mg), the mixture was heated under reflux for 10 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was silica gel Purification by column chromatography (elution solvent: ethyl hexane acetate = 471 to 21) gave 924 mg (yield 76%) of the title compound as a yellow oily substance.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 3.26 (2H, m), 3.69 (2H, m), 4.11 (2H , d, J = 5.0), 4.26 (1H, m), 4.52 (2H, s), 6.32 (1H, dt, J = 16.0, 5.0), 6.48 (1H, d, J = 16.0), 6.71 (2H, d, J = 9.0), 6.81 (2H, d, J = 9.0), 7.20-7.60 (9H, m). Reference example 156

N— [4- (1-t-butoxycarbonylpiperidine—4-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) -2- (E) -probenyl] acetamide

3- [3- [N- [4- (1-t-butoxycarbonylpyridine-1-4-yloxy) phenyl] amino] -11- (E) -probenyl] benzonitite obtained in Reference Example 151 Lil (503 mg) was dissolved in dichloromethane (10 ml), acetic anhydride (0.13 ml) and pyridine (0.14 ml) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (elution solvent: hexane Z-ethyl acetate = 1Z1-ethyl acetate), and the obtained yellow crystals are washed with diisopropyl ether. 403 mg (yield 50%) of the title compound were obtained as pale yellow crystals.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.88 (3H, s), 1.70-1.95 (4H, m), 3.33 (2H, m), 3.70 (2H, m), 4.41 (2H, d, J = 5.5), 4.47 (1H, m), 6.32 (1H, dt, J = 16.0, 5.5), 6.38 (1H, d, J = 16.0), 6.91 (2H, d, J = 9.0) ), 7.07 (2H, d, J = 9.0), 7.40 (1H, t, J = 8.0), 7.51 (1H, d, J = 8.0), 7.55 (1H, d, J = 8.0), 7.58 (1H, s). Reference example 157

N- [4- (1-t-butoxycarbonylbiperidine-4-1-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) —probenyl] -2-hydroxyacetamide 3- [3- (N- [4- (1-t-butoxycarpenylpyridin-1-4-yloxy) phenyl] amino] —11 (E) -probenyl] benzonitryl obtained in Reference Example 151 (100 mg) was dissolved in dichloromethane (20 ml), and acetoxacetyl chloride (0.27 ml) and pyridine (0.28 ml) were added under ice-cooling, followed by stirring at the same temperature for 1 hour. After water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z: ethyl acetate = 2/3) to obtain 1232 mg of an intermediate compound as a colorless amorphous solid .

Next, the obtained intermediate compound was dissolved in methanol (20 ml), potassium carbonate (64 mg) was added, and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1Z2) to obtain 977 mg (yield 86%) of the title compound as a colorless amorphous solid. Was. '

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.76 (2H, m), 1.93 (2H, m), 3.28 - 3.40 (2H, m), 3.60 - 3.80 (2H, m) , 3.81 (2H, d, J = 4.5), 4.46 (2H, d, J = 6.5), 4.47 (1H, m), 6.30 (1H, dt, J = 16.0, 6.5), 6.44 (1H, d, J = 16.0), 6.93 (2H, d, J = 9.0), 7.07 (2H, d, J = 9.0), 7.42 (1H, t, J = 7.5), 7.53 (1H, d, J = 7.5), 7.56 ( 1H, d, J = 7.5), 7.59 (1H, s). Reference example 158

2— [N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] —N— [3 -— (3-cyanophenyl) 1-2— (E) —probenyl] amino

3- [3- [N- [4-1- (1-t-butoxycarbonylpyridine-41-yloxy) phenyl] amino] obtained in Reference Example 151] —1- (E) —Probenyl] benzoni Triol (1.OO g) was dissolved in N, N-dimethylformamide (20 ml), and ethyl bromoacetate (0.62 ml) and potassium carbonate (0.96 g) were added. Time While stirring. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain 1.31 g of the title compound (quantitative yield). Obtained as a yellow oil.

_{1H NMR (270 MHz, CDC1 3} ) d ppm: 1.26 (3H, t, J = 7.0), 1.46 (9H, s), 1.71 (2H, m), 1.88 (2H, m), 3.27 (2H, m) , 3.71 (2H, m), 4.03 (2H, m), 4.15-4.35 (5H, m), 6.36 (IH, dt, J = 16.0, 5.0), 6.57 (IH, d, J = 16.0), 6.65 ( 2H, d, J = 9.0), 6.83 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.5), 7.50 (1H, d, J = 7.5), 7.57 (1H, d, J = 7.5), 7.63 (IH, s). Reference example 159

2-[N— [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) -1-2_ (E) —probenyl] amino dipropionic acid Etil

3- [3- [N- [4- (1-t-butoxycarpenylpyridine) -4-1 (E) -propionyl] benzonitryl obtained in Reference Example 151 (120 Omg) was dissolved in N, N-dimethylformamide (20 ml), ethyl 2-ethylpropionate (1.5 ml) and potassium carbonate (171 Omg) were added, and the mixture was stirred at 100 ° C for 12 hours. . After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2Z1) to obtain 882 mg (yield 60%) of the title compound as a yellow oily substance. Was.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.24 (3H, t, J = 7.0), 1.46 (9H, s), 1.50 (3H, d, J = 7.0), 1.71 (2H, m), 1.87 ( 2H, m), 3.27 (2H, m), 3.70 (2H, m), 4.17 (2H, q, J = 7.0), 4.01-4.32 (3H, m), 4.38 (IH, q, J = 7.0), 6.36 (IH, dt, J = 16.0, 4.5), 6.57 (1H, d, J = 16.0), 6.73 (2H, d, J = 9.0), 6.82 (2H, d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.55 (1H, d, J = 8.0), 7.61 (1H, s). Reference Example 160

N— [4- (1-t-butoxycarbonylpyrrolidine-3-yloxy) phenyl] -1-N— [3- (3-cyanophenyl) —2 -— (E) 1-probenyl] ethyl ethyl sulfamoyl acetate

N- [3- (3-Cyanophenyl) -1-2- (E) -probenyl] -N- (4-hydroxyphenyl) sulfamoyl acetate ethyl (800 mg :) obtained in Reference Example 98, 1-t-1 Butoxycarbone 3-hydroxypyrrolidine (450 mg) and triphenylphosphine (680 mg) were dissolved in tetrahydrofuran (20 ml), and under ice-cooling, azodicarboxylic acid getyl (0.68 ml) was added, followed by stirring at room temperature. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethan Z-ethyl ester = 10/1) to give 900 mg (yield 79%) of the title compound as a colorless amorphous Obtained as a solid.

_{¾ NMR (270 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 2.00-2.25 (2H, m), 3.40-3.70 (4H, m), 3.98 ( 2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2H, d, J = 6.5), 4.85 (IH, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (IH , d, J = 16.0), 6.87 (2H, d, J = 9.0), 7.35-7.45 (3H, m), 7.45-7.60 (3H, m). Reference Example 161

3— [3— [N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] -1-N— (2-hydroxyethyl) amino] _1_ (E) —probenyl] benzonit Lil

3- [3- (N- [4- (1-t-butoxycarbonylpyridine-1-41-yloxy) phenyl] amino] 1-111 (E) -probenyl] benzonit obtained in Reference Example 151 Dissolve ril (100 mg) and dalicholaldehyde dimer (277 mg) in dichloromethane (20 ml) and add acetic acid (0.13 ml) and sodium cyanoborohydride (72 mg) under ice-cooling. In addition, after stirring at the same temperature for 5 hours, the mixture was stirred at room temperature for 4 hours. After adding water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was silica gel Purification by column chromatography (elution solvent: ethyl hexanoacetate = 4/3) gave the title compound II O Omg (yield 50%) as a yellow oil.

^{X H NMR (500 MHz, CDC1} 3) 6 ppm: 1.46 (9H, s), 1.72 (2H, m), 1.89 (2H, m), 3.28 (2H, m), 3.45 (2H, t, J = 5.5 ), 3.71 (2H, m), 3.79 (2H, m), 4.07 (2H, m), 4.30 (IH, m), 6.31 (1H, dt, J = 16.0, 5.5), 6.48 (1H, d, J = 16.0), 6.80 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.54 ( 1H, d, J = 8.0), 7.60 (IH, s).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) _ 3-ethoxyethoxyponylaniline

Reference Example 1 4- (11-t-butoxycarbonylpiperidine-4-yloxy) -13-ethoxycarbonyl nitrate benzene (5.0 g) obtained in 14 was dissolved in methanol (75 ml). After adding a carbon catalyst (0.5 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to give the title compound (4.6 g, yield 99%) as a gray oil.

^{1 H NMR (400 MHz, CDC1} 3) δ ppm: 1.37 (3H, t, J = 7.0), 1.46 (9H, s), 1.70-1.95 (4H, m), 3.25-3.40 (2H, m), 3.60 -3.75 (2H, m), 4.30-4.40 (IH, m), 4.34 (2H, q, J = 7.0), 6.77 (1H, dd, J = 9.0, 3.0), 6.83 (1H, d, J = 9.0 ), 7.12 (1H, d, J = 3.0). Reference Example 1 63

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1 3-ethoxycarbonylphenyl] ethyl ethyl sulfamoylacetate

Reference Example 1 4- (1-t-butoxycarbonylpiperidine-141-yloxy) -13-ethoxycarponylaniline (4.6 g) obtained in 62 was dissolved in dichloromethane (70 ml) and cooled under ice-cooling. , Chlorosulfonyl acetate ethyl (2.5 ml) and pyridine (2.0 ml) were added dropwise, followed by stirring at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure, and the insolubles are filtered (ethyl hexanoacetate = 1 Z 1). The filtrate is purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1). 5.9 g of the title compound (90% yield) was obtained as an orange amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2H, m), 3.55-3.65 (2H, m), 3.91 (2H, s), 4.30 (2H, q, J = 7.0), 4.35 (2H, q, J = 7.0), 4.59 (IH , m), 6.97 (1H, d, J = 9.0), 7.47 (1H, dd, J = 9.0, 3.0), 7.70 (1H, d, J = 3.0). Reference Example 1 64

N— [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-ethoxycarbonylphenyl] —N— [3- (3-cyanophenyl) 1-2— (E) —probenyl] sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) -1- (E) -propene-1-all (1.7 g) obtained in Reference Example 2, N- [4- ( 1-t-Butoxycarbonylpiperidine-1-4-yloxy-1-3-ethoxycarbonylphenyl] sulfamoylethyl acetate (5.9 g) and triphenylphosphine (4.5 g) were added to dichloromethane (10 Oml). After melting, ice-cooled getyl azodicarbonate (2.7 ml) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 2/1) to give 5.7 g (yield 81%) of the title compound. Obtained as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.35 (2H, q, J = 7.0), 4.49 (2H, d, J = 7.0), 4.62 (1H, m), 6.23 (1H, dt, J = 16.0, 7.0), 6.41 (IH, d, J = 16.0), 6.97 (IH, m), 7.40 (1H, m), 7.45-7.60 (4H, m), 7.89 (1H, m). Reference example 1 6 5

3-Promote 4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) Nito Mouth Benzene

1-t-butoxycarbone 4-hydroxypiperidine (2.7 g), Journal of Organic 'Chemistry., 63, 4199 (1998) [J. Org. Chem., 4199 (1998)], 3-bromo-4-hydroxynitrobenzene (1.9 g) and triphenylphosphine (4.4 g) synthesized from 3-bromoditobenzene. Was dissolved in dichloromethane (50 ml), and azodicarboxylic acid diethyl (2.7 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 11.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2Z1) to give 3.1 g (yield 91%) of the title compound as a yellow solid. Obtained as an oil.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.91 (4H, m), 3.59 (4H, m), 4.75 (1H, m), 6.96 (1H, d, J = 9.0) , 8.19 (1H, dd, J = 9.0, 3.0), .8.48 (1H, d, J = 3.0). Reference Example 1 66

3-bromo-4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) aniline

Reference Example 16 3-promo 4_ (1-t-butoxycarbonylpiperidine-14-yloxy) nitrobenzene (3.1 g) obtained in 65 was dissolved in acetic acid (40 ml), and zinc powder (10%) was dissolved in acetic acid (40 ml). Og) was added in 10 portions, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was diluted with ethyl acetate, washed successively with a saturated aqueous solution of potassium carbonate, water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 2.O g of the title compound (69% yield). Was obtained as a brown amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.70-1.90 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.30 (1H, m), 6.57 (1H, dd, J = 9.0, 3.0), 6.78 (1H, d, J = 9.0), 6.91 (1H, d, J = 3.0).

N— [3-Promote 4- (1-t-butoxycarbonylpiperidine-1-41-yloxy) phenyl] sulfamoyl acetate

Reference Example 1 3-promo 4- (1-t-butoxycarbonylbiperidine obtained in 66) 1-41-yloxy) aniline (2.0 g) was dissolved in dichloromethane (60 ml), and chlorosulfonyl acetate ethyl (0.9 ml) and pyridine (0.9 ml) were added dropwise under ice-cooling, followed by 2 hours at room temperature. Stirred. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl hexanoacetate = 1/1) to give 2.1 g (yield 74%) of the title compound in yellow. Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2H, m), 3.55- 3.65 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.55 (IH, m), 6.85-6.95 (2H, m), 7.56 (IH, m). 168

N- [3-Promo 4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] — N— [3 -— (3-Cyanophenyl) —2_ (E) 1-probenyl] ethyl ethyl sulfamoyl acetate

3 _ (3-Cyanophenyl) —2— (E) 1-propene — 1-year-old (0.7 g) obtained in Reference Example 2; N— [3-bromo-4-1—1 obtained in Reference Example 167 (1-t-butoxy-l-ponyl-piperidine-1-yloxy) phenyl] Sulfamoyl acetate ethyl (2.1 g) and triphenylphosphine (1.4 g) were dissolved in dichloromethane (30 ml), and the azozol force was added under ice cooling. After dropwise addition of getyl ruponate (0.9 ml), the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 2.2 g (82% yield) of the title compound as a colorless solid Obtained as a shaped solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4H, m), 3.99 ( 2H, s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.0), 4.58 (1H, m), 6.22 (1H, dt, J = 16.0, 6.0), 6.42 (IH , d, J = 16.0), 6.90 (IH, m), 7.37 (1H, m), 7.42 (IH, m), 7.45-7.60 (3H, m), 7.71 (IH, m). Reference Example 169

2-Isopropyl-1-trophenol 2-Isopropylphenol (4.1 ml) was dissolved in acetic acid (30 ml), and 69% nitric acid (4 ml) was added under ice-cooling, followed by stirring at the same temperature for 30 minutes. The reaction solution was poured into ice water, extracted with t-butyl methyl ether, and the extract was washed with water and saturated saline sequentially, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4Z1) to give 2.66 g (yield 49%) of the title compound as a yellow solid. Obtained.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.30 (6H, d, J-7.0), 3.25 (IH, m), 6.82 (1H, d, J = 9.0), 8.01 (IH, dd, J = 9.0 , 2.5), 8.13 (1H, d, J = 2.5).

4- (11-t-butoxycarbylbiperidine-14-yloxy) 13-isopropylisopropylnitrobenzene

1-t-butoxycarbone 4-hydroxypiperidine (2.96 g), 2-isopropyl-14-nitrophenol obtained in Reference Example 169 (2.66 g) and triphenylphosphine (5.00 g) Was dissolved in dichloromethane (80 ml). Under ice cooling, acetyl dicarboxylate (3. Oml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane) to give the title compound (4.07 g, yield 76%) as a brown solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.26 (6H, d, J = 7.0), 1.48 (9H, s), 1.80-1.90 (2H, m), 1.90-2.05 (2H, m), 3.33 ( IH, m), 352 (2H, m), 3.62 (2H, m), 4.67 (1H, m), 6.87 (1H, d, J = 9.0), 8.08 (1H, dd, J = 9.0, 3.0), 8.12 (IH, d, J = 3.0).

.71

4- (1-t-butoxycarbonylpiperidine-1_4-yloxy) —3-isopropylaniline

4- (1-t-Butoxycarbonylpiperidine-14-yloxy) -13-isopropylnitrobenzene (4.1 g) obtained in Reference Example 170 was dissolved in methanol (70 ml). Then, after adding a palladium-carbon catalyst (0.4 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 3Z2) to obtain 2.8 g of the title compound (74% yield). ) Was obtained as a red oil.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.18 (6H, d, J = 7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.20- 3.40 (3H, m), 3.60-3.75 (2H, m), 4.29 (1H, m), 6.47 (1H, dd, J = 9.0, 3.0), 6.60 (1H, d, J = 3.0), 6.68 (1H , D, J = 9.0). Reference example 1 7 2 '

N— [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) _3-isopropylphenyl] sulfamoyl acetate

Reference Example 17 4- (1-t-Butoxycarbonylbiperidine-14 roxy) -13 f-sopropylaniline (2.8 g) obtained in 71 was dissolved in dichloromethane (80 ml) and cooled with ice. Thereafter, ethyl chlorosulfonylacetate (1.5 ml) and pyridine (1.4 ml) were added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19/1) to give 3.3 g (yield: 80%) of the title compound. Obtained as a yellow amorphous solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.20 (6H, d, J = 7.0), 1.37 (3H, t, J = 7.0), 1.48 (9H, s), 1.75-1.85 (2H, m) , 1.85-1.95 (2H, m), 3.30 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.90 (2H, s), 4.30 (2H, q, J = 7.0), 4.50 (1H, m), 6.80 (1H, d, J = 9.0), 7.13 (1H, dd, J = 9.0, 3.0), 7.17 (1H, d, J = 3.0).

N— [4 -— (1-t-butoxycarbonylbiperidine-1-4-yloxy) -1,3-isopropylpropylphenyl] N— [3- (3-cyanophenyl) 1-2— (E) 1-probenyl] sulfamoylacetic acid Etil

3- (3-Cyanophenyl) 1-2 (E) -propene-11-ole (0.5 g) obtained in Reference Example 2, N- [4- (1-1-1) obtained in Reference Example 1 72 t—butoxycarbonyl Peridine-1-4-yloxy-1-3-isopropylphenyl] sulfamoyl acetate

(1.5 g) and triphenylphosphine (1.1 g) were dissolved in dichloromethane (50 ml), and under ice-cooling, azodicarboxylic acid getyl (0.7 ml) was added dropwise, followed by stirring at room temperature for 4 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19Z1) to give 1.8 g (yield 96%) of the title compound as a yellow amorphous solid. Obtained.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.18 (6H, d, J = 7.0), 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.29 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0 ), 4.46 (2H, d, J = 6.0), 4.52 (1H, m), 6.25 (1H, dt, J = 16.0, 6.0), 6.40 (IH, d, J = 16.0), 6.81 (IH, d, J = 9.0), 7.22 (IH, dd, J = 9.0, 3.0), 7.31 (IH, d, J = 3.0), 7.40 (IH, m), 7.45-7.60 (3H, m).

4— (1—t—butoxycarbonylpiperidine—4-yloxy) —3— (N-methylcarbamoyl) nitrobenzene

Reference Example 11 4- (1-t-butoxycarbonylpiperidine-14-yloxy) -13-potoxynitrobenzene (3.3 g) obtained in 5 was dissolved in dichloromethane (50 ml) and cooled on ice. , Isobutyl chloroformate (1.4 ml) and triethylamine (1.4 ml) were added, and the mixture was stirred at the same temperature for 30 minutes. Then, a 40% aqueous solution of methylamine (1.1 ml) was added, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane Z methanol = 19Z1.) To give 3.5 g (quantitative yield) of the title compound as a yellow amorphous solid. As obtained.

_{H NMR (500 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.15 (2H, m), 3.04 (3H, m), 3.30-3.40 (2H, m), 3.75-3.85 (2H, m), 4.79 (IH, m), 7.08 (1H, d, J = 9.0), 8.29 (1H, dd, J = 9.0, 3.0), 9.07 (1H, d, J = 3.0). Reference example 175

4- (1-t-butoxycarbonylpiperidine- 4-yloxy) _3— (N-methyl Lukalpamoyl) Anilin

4- (11-t-butoxycarbonylpiperidine-14-yloxy) -13- (N-methylcarbamoyl) nitrobenzene (3.5 g) obtained in Reference Example 174 was dissolved in methanol (50 ml), and palladium was dissolved. —After adding carbon catalyst (0.4 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane Z methanol = 19-1) to give 2.9 g of the title compound (yield 92%). %) Was obtained as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) 6 ppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.99 (3H, m), 3.20 (2H, m) , 3.75-3.85 (2H, m), 4.40 (1H, m), 6.74 (1H, dd, J = 9.0, 3.0), 6.81 (1H, d, J = 9.0), 7.50 (1H, d, J = 3.0 ). Reference Example 176

N—C4-(1-t-butoxycarbonylpiperidine-14-yloxy) -1-3- (Ν'-methylcarbamoyl) phenyl] sulfamoyl acetate

The 4- (1-t-butoxycarbonylpiperidine-1_4-yloxy) -3- (N-methylcarbamoyl) aniline (2.9 g) obtained in Reference Example 175 was dissolved in dichloromethane (5 Oml), Under cooling, ethyl chlorosulfonylacetate (1.3 ml) and pyridine (0.8 ml) were added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 2/1) to give 3.0 g (yield 72%) of the title compound as a pale yellow color Obtained as a solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.28 (3H, t, J = 7.0), 1.48 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.05 ( 3H, m), 3.29 (2H, m), 3.70-3.85 (2H, m), 3.95 (2H, s), 4.22 (2H, q, J = 7.0), 4.63 (1H, m), 7.00 (1H, m) d, J = 9.0), 7.61 (1H, dd, J = 9.0, 3.0), 8.27 (1H, d, J = 3.0). Reference Example 177

N-Γ4- (1—t—butoxycarbonylpiperidine-1 4-yloxy) 1 3—— (N, -Methylcarbamoyl) phenyl] -1-N- [3- (3-cyanophenyl) -1-2- (E) -propenyl] ethyl ethyl sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene-11-all (0.5 g) obtained in Reference Example 2, N- [4- (1-t-butoxycarpo) obtained in Reference Example 176 Nylbiperidine-1-4-yloxy) -3- (Ν'-methylcarbamoyl) phenyl] Ethyl sulfamoylacetate (1.5 g) and triphenylphosphine (1.0 g) are dissolved in dichloromethane (40 ml) and cooled on ice. Under the solution, azodi-pyrogenic acid getyl (0.6 ml) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1Z2) to give 1.5 g (yield 77%) of the title compound as a colorless solid Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.01 ( 3H, m), 3.30 (2H, m), 3.70-3.80 (2H, m), 3.99 (2H, s), 4.32 (2H, q, J = 7.0), 4.53 (2H, d, J = 7.0), 4.64 (1H, m), 6.22 (IH, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 6.98 (1H, m), 7.35-7.45 (IH, m), 7.45-7.55 (4H, m), 8.33 (IH, m). Reference Example 178

4- (1-t-butoxycarbonylpiperidine-l-yloxy) -l3- (N, N-dimethylcarbamoyl) nitrobenzene

4- (1-t-butoxycarbonylbiperidine-14-yloxy) -13-carboxynitrile benzene (3.4 g) obtained in Reference Example 115 was dissolved in dichloromethane (60 ml), and cooled under ice-cooling. After adding isobutyl chloroformate (1.4 ml) and triethylamine (1.5 ml), stirring at the same temperature for 30 minutes, adding a 50% aqueous dimethylamine solution (1.1 ml), and further stirring at room temperature for 2 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 19/1) to give 3.1 g (83% yield) of the title compound as a pale yellow color Obtained as an amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.75-2.10 (4H, m), 2.89 (3H, s), 3.14 (3H, s), 3.35-3.65 (4H, m), 4.69 (1H, m), 7.00 (1H, d, J = 9.0), 8.20 (IH, d, J = 3.0), 8.25 (IH, dd , J = 9.0, 3.0).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -3- (N, N-dimethylcarbamoyl) aniline

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -3- (N, N-dimethylcarbamoyl) nitrobenzene (3.1 g) obtained in Reference Example 178 was dissolved in methanol (30 ml). After adding a palladium-carbon catalyst (0.3 g), the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue and residue were purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 2.8 g of the title compound ( (99% yield) as a yellow amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.45 (9H, s), 1.55-1.95 (4H, m), 2.89 (3H, s), 3.09 (3H, s), 3.25-3.40 (2H, m) , 3.50-3.65 (2H, m), 4.20-4.30 (IH, m), 6.61 (1H, d, J = 3.0), 6.64 (1H, dd, J = 9.0, 3.0), 6.76 (1H, d, J = 9.0) .Reference example 180

N— [4- (11-t-butoxycarbonylpiperidine—4-yloxy) -1-3- (Ν ', N'-dimethylcarbamoyl) phenyl] ethyl ethyl sulfamoyl acetate

The 4- (1-t-butoxycarbonylpiperidine- 4-yloxy) -3- (N, N-dimethylcarbamoyl) aniline (2.8 g) obtained in Reference Example 179 was dissolved in dichloromethane (30 ml). Then, chlorosulfonyl acetate ethyl (1.2 ml) and pyridine (0.7 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: dichloromethane / ethyl acetate = 1Ζ1) to give 3.3 g (yield 79%) of the title compound as a yellow amorphous. Obtained as a solid.

_{¾ NMR (400 MHz, CDC1 3} ) d ppm: 1.32 (3H, t, J = 7.0), 1.46 (9H, s), 1.70-2.00 (4H, m), 2.87 (3H, s), 3.10 (3H, s), 3.30-3.50 (2H, m), 3.50-3.60 (2H, m), 3.93 (2H, s), 4.28 (2H, q , J = 7.0), 4.48 (1H, m), 6.91 (1H, d, J = 9.0), 7.22 (1H, d, J = 3.0), 7.34 (1H, dd, J = 9.0, 3.0). 181

N- [4- (1-t-butoxycarbonylbiperidine-1 4-yloxy) -1-3- (N ', N'-dimethylcarbamoyl) phenyl] — N— [3-(3-Cyanophenyl) -2- (E ) 1-Propenyl] sulfamoyl acetate

3- (3-Cyanophenyl) —2— (E) —propene-11-ol (0.5 g) obtained in Reference Example 2, N— [4— (1 _) obtained in Reference Example 180 t-Butoxycarbonylpiperidine-4-1-yloxy-13- (N ', N, 1-dimethylcarbamoyl) phenyl] sulfamoylethyl acetate (1.5 g) and triphenylphosphine (1.Og) in dichloromethane 30 ml), and under ice-cooling, azodiphenol getyl sulfonate (0.6 ml) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1Z2) to give 1.7 g (yield 88%) of the title compound as a colorless amorphous Obtained as a solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.46 (9H, s), 1.75-2.00 (4H, m), 2.83 (3H, s), 3.10 (3H, s), 3.30-3.60 (4H, m), 3.95-4.05 (2H, m), 4.30 (2H,, q, J = 7.0), 4.47 (2H, d, J = 7.0), 4.52 (1H, m) , 6.23 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 6.92 (1H, m), 7.35-7.55 (6H, m).

5—Ciano 2—Hee

4-Cyanophanol (25.0 g) was dissolved in trifluoroacetic acid (150 ml), hexamethylenetetramine (50. Og) was added, and the mixture was stirred at 100 ° C for 9 hours. After cooling the anti-jfe solution to room temperature, sulfuric acid (50 ml) and water (300 ml) were added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane, and the extract was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, The residue was analyzed by gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1 z)

Purification by 19) yielded 4.3 g (13% yield) of the title compound as a colorless solid. '

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 7.11 (1H, d, J = 9.0), 7.78 (1H, dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.0), 9.93 (1H , S). Reference Example 183

5-cyano 2-hydroxycinnamic aldehyde

The 5-cyano 2-hydroxybenzaldehyde (4.3 g) and triphenylphosphoranilideneacetaldehyde (9.4 g) obtained in Reference Example 182 were dissolved in toluene (150 ml), and the solution was dissolved at 70 ° C. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z dichloromethane = 1Z3) to obtain 2.3 g (44% yield) of the title compound as a colorless solid. Was.

_{aH NMR (400 MHz, CDC1 3} ) d ppm: 6.98 (IH, dd, J = 16.0, 8.0), 7.08 (IH, d, J = 9.0), 7.73 (IH, d, J = 9.0), 7.83 (IH , d, J = 16.0), 8.22 (IH, s), 9.67 (1H, d, J = 8.0). Reference Example 184

5-cyano 2-methoxymethoxycinnamic aldehyde

5-Cyanol 2-hydroxycinnamic aldehyde (2.3 g) obtained in Reference Example 183 was dissolved in N, N-dimethylformamide (25 ml), and methoxymethoxy chloride (1.5 ml) and triethylamine were cooled under ice-cooling. (2.8 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (2.8 g) (yield 98%) as a colorless solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 3.52 (3H, s), 5.36 (2H, s), 6.80 (IH, dd, J = 16.0, 8.0), 7.30 (IH, d, J = 9.0), 7.66 (1H, dd, J = 9.0, 2.0), 7.75 (1H, d, J = 16.0), 7.84 (IH, d, J = 2.0), 9.74 (1H, d, J = 8.0). Reference Example 185

3- (5-cyano 2-methoxymethoxyphenyl) 1- (E) -propene 1-ol

5-Cyano-2-methoxymethoxycinnamic aldehyde (2.8 g) obtained in Reference Example 184 was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (40 ml), and the mixture was stirred under ice-cooling. .7 g), and the mixture was stirred at the same temperature for 0.5 hour. Then, sodium borohydride (0.9 g) was added, and the mixture was further stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed sequentially with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent hexane / ethyl acetate = 1zo 1) to obtain 2.6 g (yield 93%) of the title compound as a yellow oil. As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 3.49 (3H, s), 4.37 (2H, d, J = 5.0), 5.27 (2H, s), 6.41 (1H, dt, J = 16.0, 5.0) , 6.90 (1H, d, J = 16.0), 7.18 (1H, d, J = 9.0), 7.49 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.0). Reference Example 186

N— [4 -— (1-t-butoxycarbonylpiperidine—4-yloxy) —3-chlorophenyl) —N— [3- (5-cyano1-2-methoxymethoxyphenyl) —2 -— (E) 1-probenyl] sulfamoyl acetate

3- (5-cyano-2-methoxymethoxyphenyl) 1-2- (E) -propen-1-ol obtained in Reference Example 185 (0.6 g), N_ [4 — (1-t-butoxycarbonylpiperidine—4-yloxy) -13-chlorophenyl) Sulfamoylethyl acetate (1.3 g) and triphenylphosphine (0.9 g) are dissolved in dichloromethane (40 ml), and ice is added. Under cooling, acetyl azodicarboxylate (0.6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 9/1) to give 1.4 g (yield 74%) of the title compound as a yellow solid. Obtained as a shaped solid. _{1H NMR (500 MHz, CDC1 3} ) 6 ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75 - 1.85 (2H, m), 1.85-1.95 (2H, m), 3.40- 3.50 (2H, m), 3.44 (3H, s), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2H, d, J = 7.0 ), 4.55 (1H, m), 5.23 (2H, s), 6.17 (1H, dt, J = 16.0, 7.0), 6.70 (1H, d, J = 16.0), 6.94 (1H, d, J = 9.0) , 7.13 (1H, d, J = 9.0), 7.34 (1H, dd, J = 9.0, 3.0), 7.47 (1H, dd, J = 9.0, 2.0), 7.55 (1H, d, J = 3.0), 7.61 (1H, d, J = 2.0). Reference Example 187

3-chloro-5-methyl methyl salicylate

Dissolve 3-cloth salicylic acid (4.5 g) in a mixed solvent of methanol (1 Om 1) and benzene (4 Om 1), and add 2N trimethylsilyldiazomethane / hexane solution (20 ml) under ice-cooling. After the addition, the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was added to a mixture of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was poured into ice water and extracted with ethyl acetate, the extract was washed successively with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the obtained yellow solid, and this was collected by filtration to obtain 2.4 g (yield 39%) of the title compound as a yellow solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm:. 4.07 (3H, s), 8.47 (1H, d, J = 3.0), 8.72 (1H, d, J = 3.0) Reference Example 188

4- (1-t-butoxycarbonylpiperidine-4-yloxy) -3-chloro-5-methoxycarbonylnitrobenzene

1-t-butoxycarbonyl 2-hydroxypiperidine (6.3 g), methyl 3-chloro-5-nitrosalicylate (2.4 g) obtained in Reference Example 187, and triphenylphosphine (10.8 g) were added to dichloromethane. (100 ml), and getyl azodicarboxylate (6.6 ml) was added, followed by stirring at room temperature for 4 hours. After the reaction solution is concentrated under reduced pressure, the residue is subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate). = 4/1) to give 3.4 g (79% yield) of the title compound as a pink solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.11 (2H, m), 3.85-3.95 (2H, m), 3.97 (3H, s), 4.44 (1H, m), 8.43 (1H, d, J = 3.0), 8.56 (IH, d, J = 3.0). Reference Example 189

4- (1_t-butoxycarbonylbiperidine _4-yloxy) -5-hydroxypropyl-3-chloronitrobenzene

4- (1-t-Butoxycarbonylpiperidine-14-yloxy) -13-chloro-5-methoxycarbonylnitrobenzene (3.4 g) obtained in Reference Example 188 was dissolved in concentrated hydrochloric acid (30 mL), and dissolved in concentrated hydrochloric acid (30 mL). Stirred at ° C for 16 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in a mixed solvent of water (15 ml) and acetone (15 ml), and di-t-butyl dicarbonate (2.2 g) and sodium hydrogen carbonate (1 After adding 6 g), the mixture was stirred at 40 for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed sequentially with 0.5N hydrochloric acid, water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the obtained pale yellow solid, and the solid was collected by filtration to obtain 2.6 g (yield 79%) of the title compound as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.16 (2H, m), 3.90-4.00 (2H, m), 4.54 (1H, m), 8.45 (IH, d, J = 3.0), 8.70 (IH, d, J = 3.0).

4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-5-potassium rubamoyl 3-chloronitrobenzene

Reference Example 4-1 4- (1-t-butoxycarbonylbiperidine-14-yloxy) -1,5-carboxy-13-chloronitrobenzene (2.6 g) obtained in 189 was dissolved in dichloromethane (8 Oml), and cooled with ice. Below, isobutyl chloroformate (1. Oml) and triethylamine (1.1 ml) was added, and the mixture was stirred at the same temperature for 30 minutes. Then, 28% aqueous ammonia (0.5 ml) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19X1) to give 2.2 g (yield 84%) of the title compound as a pale yellow amorphous solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m), 4.05-4.15 (2H, m), 4.51 (1H, m), 8.42 (1H, d, J = 3.0), 8.79 (1H, d, J = 3.0).

4- (1-t-butoxycarbonylpiperidine- 4-yloxy) 1-5-Lubamoyl 3- 3-chloroaniline

Reference Example 4- (11-t-butoxycarbonylpiperidine-14-yloxy) -1-5-rubbamoyl-3-chloronitrobenzene (2.2 g) obtained in 190 was dissolved in acetic acid (100m1) at room temperature. After adding powder (9.9 g), the mixture was stirred at the same temperature for 11 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of potassium carbonate, extracted with ethyl acetate, and the extract was washed with water and saturated saline in this order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.7 g (yield: 83%) of the title compound as a yellow amorphous solid.

_{H NMR (500 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.77 (2H, m), 3.70-3.80 (2H, m), 4.17 (1H, m), 6.84 (1H, d, J = 3.0), 7.19 (1H, d, J = 3.0). Reference Example 192

N— [4- (1-t-butoxycarbylbiperidine—41-yloxy) -1-5-carbamoyl 3-cyclophenyl] sulfamoyl acetate

The 4- (11-t-butoxycarbonylbiperidine-4-yloxy) -1-5-rubbermoyl-13-chloroaniline (1.7 g) obtained in Reference Example 191 was added to dichloromethane (30 chlorosulfonyl acetate (0.7 ml) and pyridine (0.7 ml) were added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 1: 1) to give 1.2 g (yield 48%) of the title compound as a pale yellow solid. As obtained.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.17 (3H, t, J = 7.0), 1.40 (9H, s), 1.55- 1.65 (2H, m), 1.80-1.90 (2H, m), 2.95-3.05 (2H, m), 3.70-3.80 (2H, m), 4.10 (2H, q, J = 7.0), 4.21 (1H, m), 4.27 (2H, s), 7.28 (1H, d, J = 3.0), 7.36 (IH, d, J = 3.0). Reference Example 193

N— [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -1-5-carbamoyl-1-3-chlorophenyl] —N— [3- (3-cyanophenyl) —2 -— (E) Propenyl] Sulfamoyl acetate

3- (3-Cyanophenyl) 1-2- (E) -propene-11-ol (0.4 g) obtained in Reference Example 2, N- [4- (1-1-1) obtained in Reference Example 192 t-Butoxycarbonylpiperidine—4-yloxy) 1.5-l-rubamoyl-3-chlorophenyl] ethyl sulfyl acetate (1.2 g) and triphenylphosphine (0.8 g) in dichloromethane (50 ml) and tetrahydrofuran (20 ml), and acetyldicarboxylate (0.5 ml) was added under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3/2) to give 1.5 g (yield quantitative) of the title compound as a yellow amorphous. Obtained as a solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 2.79 ( 2H, m), 4.00 (2H, s), 4.00-4.15 (2H, m), 4.31 (2H, q, J = 7.0), 4.38 (IH, m), 4.53 (2H, d, J = 7.0), 6.21 (IH, dt, J = 16.0, 7.0), 6.46 (1H, d, J = 16.0), 7.23 (1H, m), 7.41 (1H, m), 7.50-7.60 (3H, m), 8.03 (1H , M). Reference Example 194

3-methyl-5-methyl ditrosalicylate 3-Methylsalicylic acid (5.1 g) was dissolved in a mixed solvent of methanol (10 ml) and benzene (40 ml), and 2N trimethylsilyldiazomethane Z hexane solution (25 ml) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was added to a mixture of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was poured into ice water and extracted with ethyl acetate, the extract was washed successively with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (eluent: hexane Z ethyl acetate = 2Z1), and hexane is added to the obtained yellow solid, which is then filtered. As a result, 1.8 g (yield 25%) of the title compound was obtained as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm:. 2.35 (3H, s), 4.03 (3H, s), 8.21 (1H, d, J = 3.0), 8.66 (1H, d, J = 3.0) Reference Example 195

4- (1-t-Butoxycarponylpiperidine _ 4-yloxy) -3-Methoxycarbonyl 5-methylnitrobenzene

1-t-butoxycarporinyl 4-hydroxypiperidine (4.2 g), methyl 3-methyl-5-ditrosalicylate (1.8 g) obtained in Reference Example 194, and triphenylphosphine (6.8 g) were obtained. After dissolving in dichloromethane (100 ml) and adding ice-cooled getyl ruponate (4.1 ml) under ice-cooling, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 4/1) to give 3.1 g (yield 91%) of the title compound as a pink oil Obtained as a solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.39 (3H, s), 2.97 (2H, m) , 3.90-4.00 (2H, m), 3.95 (3H, s), 4.16 (1H, m), 8.22 (1H, d, J = 3.0), 8.52 (1H, d, J = 3.0).

4-1-1 (1-t-butoxycarbonylpiperidine-1 4-yloxy) 1-3-capilloxy One 5-methylnitrobenzene

4- (1-t-butoxycarbonylbiperidine-14-yloxy) -13-methoxycarbonyl-5-methylnitrobenzene (4.0 g) obtained in Reference Example 195 was dissolved in concentrated hydrochloric acid (4 Oml). The mixture was stirred at Ί5 for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in a mixed solvent of water (2 Oml) and acetone (20 ml), and cooled under ice-cooling. After adding sodium (1.9 g), the mixture was further stirred at 40 ° C for 2 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed sequentially with 0.5N hydrochloric acid, water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the obtained pale yellow solid, and this was collected by filtration to obtain 3.6 g (yield 79%) of the title compound as a pale yellow solid.

_{¾ MR (400 MHz, CDC1 3} ) <5 ppm: 1.47 (9H, s), 1.70-1.85 (2H, m), 1.90-2.05 (2H, m), 2.43 (3H, s), 2.95 (2H, m ), 4.00-4.10 (2H, m), 4.26 (1H, m), 8.26 (1H, d, J = 3.0), 8.69 (1H, d, J = 3.0).

4- (1-t-butoxycarbonylpiperidine- 4-yloxy)-3-caproluvyl 5-5-methylnitrobenzene

Reference Example 196 4- (1-t-butoxycarbonylpiperidine—4-yloxy) -13-hydroxypropyl-5-methylnitrobenzene (3.6 g) was dissolved in dichloromethane (6 Oml), and the mixture was ice-cooled. Under cooling, add isobutyl chloroformate (1.4 ml) and triethylamine (1.6 ml), stir at the same temperature for 30 minutes, add 28% aqueous ammonia (0.7 ml), and add 1.5% at room temperature. Stirred for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / Z methanol = 19/1) to give 3,9 g (quantitative yield) of the title compound as a yellow oily substance. As obtained.

¾ NMR (500 MHz, CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.43 (3H, s), 2.79 (2H, m) , 4.05-4.15 (2H, m), 4.17 (1H, m), 8.20 (1H, d, J = 3.0), 8.66 (1H, d, J = 3.0). Reference Example 198

4-1 (11-t-butoxycarboxylbiperidine-1 4-1yloxy) -1-3-Lubamoyl-5-methylaniline

The 4- (11-t-butoxycarbonylpiperidine-14-yloxy) -13-capillobyl-5-methylnitrobenzene (3.9 g) obtained in Reference Example 197 was dissolved in methanol (100 ml), and After adding a carbon catalyst (0.5 g), the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to give the title compound (3.5 g, yield 97%) as a black-green amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.60-1.70 (2H, m), 1.90-2.00 (2H, m), 2.23 (3H, s), 2.71 (2H, m) , 3.62 (2H, m), 3.80-3.90 (IH, m), 6.65 (1H, d, J = 3.0), 7.11 (1H, d, J = 3.0). Reference Example 199

N— [4- (1-t-butoxycarbonylpiperidine-1_4-yloxy) —3-carbamoyl-5-methylphenyl] ethyl ethyl sulfamoylacetate

4- (1-t-Butoxycarbylbiperidine-14-yloxy) -13-potumbamoyl-5-methylaniline (3.5 g) obtained in Reference Example 198 was dissolved in dichloromethane (80 m 1), and iced. After cooling, ethyl ketone rosulfonyl acetate (1.6 ml) and pyridine (1.0 ml) were added dropwise, followed by stirring at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, the residue was removed.

/ 1) to give 2.6 g (yield 51%) of the title compound as a pale yellow solid.

^{1 H NMR (500 MHz, CDC1} 3) δ ppm: 1.31 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.90-2.00 (2H, m), 2.33 (3H, s), 2.74 (2H, m), 3.90-4.00 (IH, m), 3.97 (2H, s), 4.00-4.15 (2H, m), 4.27 (2H, q, J = 7.0), 7.44 (1H, d, J = 3.0), 7.72 (1H, d, J = 3.0). Reference example 200

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-force levamoyl-5-methylphenyl] -1-N— [3- (3-cyanophenyl) —2 -— (E) -1-prodenyl] Ethyl sulfamoyl acetate

3- (3-Cyanophenyl) -2- (E) monopropene-1-ole obtained in Reference Example 2 (0.8 g), N— [4 -— (1-t—) obtained in Reference Example 199 Mixture of butoxycarbonylpiperidine-1-4-yloxy) 13-forcerubamoyl-5-methylphenyl] sulfamoylacetate (2.6 g) and triphenylphosphine (1.7 g) in dichloromethane (50 ml) and tetrahydrofuran (50 ml) After dissolving in a solvent, ice-cooled getyl azodicarbonate (1.0 ml) was added, followed by stirring at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 1/2) to give 3.2 g (yield 96%) of the title compound as a yellow solid. Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.35 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.32 ( 3H, s), 2.73 (2H, m), 3.95-4.05 (1H, m), 4.00 (2H, s), 4.05-4.15 (2H, m), 4.31 (2H, q, J = 7.0), 4.52 ( 2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.44 (1H, d, J = 16.0), 7.22 (1H, m), 7.40 (1H, m), 7.50-7.60 (3H, m), 7.91 (1H, m).

2,6-difluoro-4-nitrophenol

2,6-Difluorophenol (2.00 g) was dissolved in acetic acid (20 ml), 60% nitric acid (1.20 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl hexanoacetate = 3 to 1-2Z1) to obtain 1.37 g of the title compound (yield 51%). ) Was obtained as a pale yellow solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 7.95 ί2Η, m). Reference Example 202

4- (1-t-butoxycarbonylpiperidine-1-4 ^ f-loxy) -3,5-difluoronitrobenzene

1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), 2,6-difluoro-4-12-trophenol obtained in Reference Example 201 (1.37 g) and triphenylphosphine (2.67 g) g) was dissolved in dichloromethane (30 ml), and while cooling with ice, getyl azodicarbonate (1.57 ml) was added dropwise, followed by stirring at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give 2.13 g (yield 76%) of the title compound as a pale solid. Obtained as a yellow solid.

_{NMR (400 MHz, CDC1 3)} d ppm: 1.47 (9H, s), 1.77-1.85 (2H, m), 1.89-1.96 (2H, m), 3.35 (2H, m), 3.72 (2H, m), 4.62 (1H, m), 7.87 (2H, m). Reference Example 203

4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) 1,3,5-difluoroaniline

The 4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -3,5-difluoronitrobenzene (2.13 g) obtained in Reference Example 202 was dissolved in ethanol (40 ml). After adding a carbon catalyst (0.20 g), the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 2Z1) to give 1.70 g (yield) of the title compound. 87%) as a colorless solid.

^{2 H NMR (400 MHz, CDC1} 3) ppm: 1.46 (9H, s), 1.72-1.78 (2Ή, m), 1.83-1.89 (2H, m), 3.23 (2H, m), 3.77 (2H, m) , 4.11 (1H, m), 6.21 (2H, m).

N— [4— (1—t—butoxycarbonylbiperidine _ 4-—yloxy) 1 3, 5_-: Difluorophenyl] sulfamoyl acetate

4- (1_t-butoxycarbonylpiperidine-14-yloxy) -13,5-difluoroaline (1.70 g) obtained in Reference Example 203 was dissolved in dichloromethane (30 ml), and the solution was cooled under ice-cooling. After chlorosulfonyl acetate ethyl (0.76 ml) and pyridine (0.84 ml) were added dropwise, the mixture was stirred at room temperature for 1.5 hours. After adding water to the reaction solution and extracting with ethyl acetate, the extract was washed with saturated saline and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 2.48 g (quantitative) of the title compound as a yellow oil. Obtained.

^{X H NMR (400 MHz, CDC1} 3) δ ppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.28 (2H, m), 3.75 (2H, m), 3.95 (2H, s), 4.30 (2H, q, J = 7.0), 4.31 (1H, m), 6.95 (2H, m).

N— [4 -— (1 t-butoxycarbonylbiperidine-4_yloxy) 1,3,5-difluorophenyl] N— [3— (3-cyanophenyl) _2— (E) 1-propenyl] ethyl ethyl sulfamoyl acetate

3- (3-Cyanophenyl) —2- (E) —propene-11-all obtained in Reference Example 2 (0.52 g), N_ [4- (1-1 t) obtained in Reference Example 204 Dissolve 1-butoxycarbonylpiperidine-14-yloxy-1-3,5-difluorophenyl] sulfamoylacetate (1.55 g) and triphenylphosphine (1.02 g) in dichloromethane (3 Oml) and ice. After cooling, acetyl dicarboxylate (0.60 ml) was added dropwise, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2 Z1) to give 1.82 g (yield 91%) of the title compound as a colorless amorphous Obtained as a solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.29 ( 2H, m), 3.73 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.37 (1H, m), 4.47 (2H, d, J = 6.5), 6.20 ( 1H, dt, J = 16.0, 6.5), 6.43 (1H, d, J = 16.0), 7.12 (2H, m), 7.41 (1H, t, J = 7.5), 7.53 (1H, d, J = 7.5), 7.54 (1H, d, J = 7.5), 7.57 (1H, s ). Reference Example 2 0 6

4- (1_t-butoxycarbonylbiperidine-1-4-yloxy) -1,3,5-dichloronitrobenzene

1-t-butoxycarbone 4-hydroxypiperidine (667 mg;), 2,6-dichloro-141-trophenol (70 mg) and triphenylphosphine (115 mg) were added to dichloromethane (40 ml). After dissolution, ice-cooled getyl azodicarboxylate (0.67 ml) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 6Z1) to give 95 Omg (yield 72%) of the title compound as a colorless solid. Obtained. '

^{X H NMR (400 MHz, CDC1} 3) δ ppm: 1.48 (9H, s), 1.85-2.00 (4H, m), 3.20 (2H, m), 3.91 (2H, m), 4.59 (1H, m), 8.23 (2H, s). Reference example 2 0 7

4- (1-t-butoxycarbonylbiperidine-1-4-yloxy) -1,3,5-dichloroaniline

Reference Example 210 4- (1-t-butoxycarbonylbiperidine-4-yloxy) -1,3,5-dichloronitrobenzene (1.95 g) obtained in Reference Example 206 was dissolved in acetic acid (50 ml), and the solution was stirred at room temperature. Then, zinc powder (1.1.10 g) was added in five portions, followed by stirring at 50 ° C for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate and water were added to the residue for extraction. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane ethyl acetate = 3Z1) to give 1.40 g (yield 78%) of the title compound as a colorless solid Obtained.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm ,: 1.47 (9H, s), 1.80-1.95 (4H, m), 3.09 (2H, m), 3.92 (2H, m), 4.22 (1H, m), 6.61 (2H, s).

N— [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1,3,5-dichlorophenyl] sulfamoyl acetate

The 4- (1-t-butoxycarbonylpiperidine-1-yloxy) -3,5-dichloroaniline (1.40 g) obtained in Reference Example 207 was dissolved in dichloromethane (30 ml) and cooled on ice. Then, ethyl chlorosulfonylacetate (0.57 ml) and pyridine (0.63 ml) were added dropwise, followed by stirring at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution for extraction. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: ethyl hexanoacetate = 2/1) to obtain 1.89 g (yield 95%) of the title compound as a pale yellow color Obtained as an amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.14 (2H, m), 3.92 (2H, m), 3.96 (2H, s), 4.30 (2H, q, J = 7.0), 4.37 (1H, m), 7.33 (2H, s). Reference Example 209

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1,3,5-dichlorophenyl] -1-N— [3- (3-cyanophenyl) 1-2— (E) —probenyl] sulfamoyl Ethyl acetate

3_ (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (0.59 g), N- [4- (1-1-1) obtained in Reference Example 208 t-Butoxycarbonylpiperidine-1-yloxy-1-3,5-dichlorophenyl) sulfamoylacetate (1.89 g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml). Then, under ice-cooling, azodiphenol geronate getyl (0.68 ml) was added dropwise, followed by stirring at the same temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 31) to give the title. 2.06 g (yield 86%) of the compound was obtained as a colorless amorphous solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.15 (2H, m), 3.90 (2H, m), 4.00 (2H, s), 4.31 (2H, q, J = 7.0), 4.41 (1H, m), 4.47 (2H, d, J = 6.5), 6.20 (IH, dt, J = 16.0, 6.5 ), 6.44 (IH, d, J = 16.0), 7.42 (IH, t, J = 8.0), 7.47 (2H, s), 7.53 (2H, m), 7.58 (IH, s).

4- (1-t-butoxycarbonylpiperidine—4-yloxy) -1,3,5-dimethylnitrobenzene

1-t-butoxycarbone 4-hydroxypiperidine (2.40 g), 2,6-dimethyl-412-trophenol (1.50 g) and triphenylphosphine (3.06 g) were added to dichloromethane (60 ml). , And acetyldicarboxylate (1.80 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 5: 1) to give 2.25 g (yield 71%) of the title compound as a colorless solid. Obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.73 (2H, m), 1.93 (2H, m), 2.35 (6H, s), 2.93 (2H, m), 4.00-4.10 (3H, m), 7.92 (2H, s). Reference Example 21 1

4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) -3,5-dimethyldianiline

Reference Example A mixed solvent of 4- (11-t-butoxycarbonylpiperidine-14-yloxy) —3,5-dimethylnitrobenzene (2.24 g) obtained in 210 and a mixture of ethanol (30 ml) and tetrahydrofuran (10 ml) After adding a palladium-carbon catalyst (0.20 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2Z1) to give 1.94 g (yield 95%) of the title compound. Was obtained as a pale pink solid. _{1H NMR (500 MHz, CDC1 3} ) d ppm: 1.47 (9H, s), 1.66 (2H, m), 1.92 (2H, m), 2.19 (6H, s), 2.86 (2H, m), 3.79 (1H , m), 4.02 (2H, m), 6.36 (2H, s).

N— [4— (1—t-butoxycarbonylbiperidine-1-4yloxy) -1,3,5-dimethylphenyl] sulfamoyl acetate

The 4- (1-t-butoxycarbonylbiperidine_4-yloxy) -3,5-dimethylaniline (1.94 g) obtained in Reference Example 211 was dissolved in dichloromethane (30 ml), and the mixture was cooled under ice-cooling. Ethyl chlorosulfonyl acetate (0.9, 7 ml) and pyridine (0.98 ml) were added dropwise, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate and water were added to the reaction solution to extract it. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 2Z1) to give 2.0 Og (70% yield) of the title compound as a pale yellow solid As obtained.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.69 (2H, m), 1.91 (2H, m), 2.26 (6H, s) , 2.89 (2H, m), 3.90 (1H, m), 3.93 (2H, s), 4.03 (2H, m), 4.29 (2H, q, J = 7.0), 6.98 (2H, s). Reference Example 213

N— [4- (1-t-butoxycarbonylpiperidine-1-4f-roxy) -1,3,5-dimethylphenyl] -1-N— [3- (3-cyanophenyl) 1-2— (E) -1-propenyl]

z-ethyl acetate

3- (3-Cyanophenyl) 1-2- (E) 1-propene obtained in Reference Example 2 (0.55 g), N- [4- (1- t-Butoxycarbonyl piperidine (1-yloxy) -1,3-dimethylphenyl] sulfamoyl acetate (1.50 g) and triphenylphosphine (1.08 g) are dissolved in dichloromethane (20 ml) Then, under ice-cooling, acetyl dicarboxylate (0.63 ml) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. After concentrating the reaction mixture under reduced pressure, the residue is purified by silica gel column chromatography. Purification by chromatography (elution solvent: hexane Z ethyl acetate = 2/1) gave 1.75 g (yield 90%) of the title compound as a colorless amorphous solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.70 (2H, m), 1.91 (2H, m), 2.26 (6H, s) , 2.90 (2H, m), 3.93 (1H, m), 3.99 (2H, s), 4.00 (2H, m), 4.30 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5) , 6.23 (1H, dt, J = 16.0, 6.5), 6.42 (1H, d, J = 16.0), 7.11 (2H, s), 7.40 (IH, t, J = 8.0), 7.52 (2H, m), 7.56 (IH, s). Reference example 214

4- [N— [4 -— (1-t-butoxycarboxylbiperidine-1-4-yloxy) phenyl] -1-N— [3 -— (3-cyanophenyl) —2 -— (E) —probenyl] amino] ethyl ethyl butyrate

3- [3- [N- [4- (1-t-butoxycarpenylpyridine-41-yloxy) phenylamino] obtained in Reference Example 151—1- (E) -propionyl] benzonitrile (2 .00 g) was dissolved in N, N-dimethylformamide (40 ml). Ethyl bromobutyrate (5.00 ml) and potassium carbonate (6.50 g) were added in five portions at room temperature. Stirred for 16 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to obtain 1.20 g (yield 48%) of the title compound as a yellow oil. Obtained as a solid.

^{1 H NMR (400 MHz, CDC1} 3) δ ppm: 1.25 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.80-2.00 (4H, m), 2.36 (2H, t, J = 7.0), 3.20-3.35 (4H, m), 3.65-3.75 (2H, m), 4.02 (2H, d, J = 5.0), 4.13 (2H, q, J = 7.0), 4.27 (1H, m), 6.29 (IH, dt, J = 16.0, 5.0), 6.47 (1H, d, J = 16.0), 6.70 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (IH, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.54 (IH, d, J = 8.0), 7.61 (1H, s). Reference Example 215

3- (3-Cyanophenyl) 1-fluoro-2- (Z) 1-propene-1-ol 2-Obetylphosphono synthesized according to the method described in Journal of Organometallic Chemistry, Vol. 332, p. 1 (1987) [J. Organomet. Chem. _? 332, 1 (1987)]. Dissolve 2-fluoroacetic acid (4.35 g) in tetrahydrofuran (90 ml), add -1.6 N butyllithium hexane solution (28 ml) dropwise at 78 ° C, stir at the same temperature for 1 hour, and add —A solution of cyanobenzaldehyde (2.66 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 3 hours. After the temperature of the reaction solution was raised to 0 ° C., water was added thereto, the aqueous layer was separated, and the organic layer was extracted twice with a saturated aqueous sodium hydrogen carbonate solution. After all the aqueous layers were combined, the pH of the solution was adjusted to 4 with concentrated hydrochloric acid, extracted five times with t-butyl methyl ether, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an intermediate compound (3.47 g) as a white solid. Then, the obtained intermediate compound (1.15 g) and triethylamine (0.92 ml) were dissolved in dichloromethane (10 ml), and ethyl ethyl carbonate (0.63 ml) was added under ice-cooling. Stir for 15 minutes. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the insoluble matter was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 m 1), and an aqueous sodium borohydride solution (0.45 g was dissolved in 5 ml of water) was added under ice-cooling. For 18 hours. After a saturated aqueous solution of ammonium chloride was added to the reaction solution, the mixture was extracted three times with t-butyl methyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z: ethyl acetate = 3/2) to obtain 0.33 g (yield 31%) of the title compound. Obtained as a colorless solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 4.32 (2H, dd, J = 12.5, 5.5), 5.82 (1H, d, J-37.5), 7.45 (1H, t, J = 8.0), 7.53 (1H , D, J = 8.0), 7.70 (IH, d, J = 8.0), 7.81 (IH, s).

N- [4- (1-t-butoxycarbonylpiperidine—4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl 1-Sulfamoyl acetate

3- (3-Cyanophenyl) -1-2-fluoro-2- (Z) -1 obtained in Reference Example 215 Propene-1-ol (0.45 g), N- [4- (1-t-butoxycarbonylbiperidine-14-yloxy) phenyl] obtained in Reference Example 107 ethyl sulfamoyl acetate (1.12 g) Then, triphenylphosphine (0.80 g) was dissolved in dichloromethane (20 ml), and acetyldipropionate getyl (0.48 ml) was added dropwise under ice-cooling, followed by stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 15Z1) to give 1.40 g (yield 92%) of the title compound. Obtained as a colorless oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.34 (2H, m) , 3.68 (2H, m), 4.00 (2H, s), 4.30 (2H, q, J = 7.0), 4.46 (IH, m), 4.54 (2H, d, J = 15.0), 5.62 (IH, d, J = 36.5), 6.92 (2H, d, J = 9.5), 7.42 (3H, m), 7.51 (1H, d, J = 7.0), 7.63 (IH, d, J = 8.0), 7.71 (1H, s ). Reference Example 217

2-hydroxyisophthalic acid

2-Methoxyisophthalic acid (1.0 g) was dissolved in 55% hydroiodic acid (10 ml) and stirred at 80 for 1 hour. The reaction solution was added to ice water, and the deposited precipitate was collected by filtration to obtain 0.9 g (yield 95%) of the title compound as a pale yellow solid.

¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm: 6.93 (IH, t, J = 8.0), 7.96 (2H, d, J = 8.0). Reference Example 218

Dimethyl 2-hydroxyisophthalate

2-Hydroxyisophthalic acid (1.9 g) obtained in Reference Example 217 was dissolved in methanol (2 Oml), and thionyl chloride (1.5 ml) was added under ice-cooling. Stir for 4 hours. The reaction solution was concentrated under reduced pressure to obtain 1.5 g (68%) of the title compound as a white solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 3.96 (6H, s), 6.94 (1H, t, J = 8.0), 8.06 (2H, d, J = 8.0). Reference Example 219

Dimethyl 2-hydroxy-5-nitroisophthalate

The dimethyl 2-hydroxyisophthalate (1.5 g) obtained in Reference Example 218 was added to a mixed solvent of 69% nitric acid (5 ml) and concentrated sulfuric acid (5 ml), and the mixture was stirred under ice-cooling for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and the extract was washed with water and saturated saline sequentially, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained yellow solid was added with hexane, and then filtered to give 1.6 g (yield 89%) of the title compound as a yellow solid.

_{NMR (500 MHz, CDC1 3)} δ ppm:. 4.03 (6H, s), 8.94 (2H, s) Reference Example 220

2- (1-t-butoxycarbonylbiperidine-1-4-yloxy) -1-5-dimethyl nitroisophthalate

11-t-butoxycarbone 4-hydroxypiperidine (2.6 g), dimethyl 2-hydroxy-5-nitroisophthalate (1.6 g) obtained in Reference Example 219, and triphenylphosphine (4. 4 g) was dissolved in a mixed solvent of dichloromethane (40 ml) and tetrahydrofuran (20 ml), and under ice-cooling, azodicarboxylic acid getyl (2.6 ml) was added, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19/1), and the obtained yellow solid was purified with hexane and ethyl acetate (4/1). After addition, the residue was collected by filtration to give 2.2 g (yield 78%) of the title compound as a white solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.46 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.05 (2H, m), 3.80-3.95 (2H, m), 3:97 (6H, s), 4.29 (1H, m), 8.74 (2H, s). Reference Example 221

2- (1-t-butoxycarbonylpiperidine-1 4-yloxy) 1-5-nitroisophthalic acid

2- (1-t-butoxycarbonylpiperidine obtained in Reference Example 220-4-ylo Xy) Dimethyl 5-nitroisophthalate (10.7 g) was dissolved in concentrated hydrochloric acid (100 ml) and stirred at 80 ° C for 10 hours. The reaction solution was concentrated under reduced pressure, hexane was added to the residue, and a white solid was collected by filtration.

Next, the obtained solid was dissolved in a mixed solvent of water (50 ml) and acetone (50 ml), and di-tert-butyl dicarbonate (5.9 g) and sodium hydrogen carbonate (4.6 g) were added at room temperature. Thereafter, the mixture was stirred at 40 C for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and this was collected by filtration to obtain 4.1 g (yield: 40%) of the title compound as a pale yellow solid.

¾ NMR (500 MHz, DMSO-d ₆ ) d ppm: 1.40 (9H, s), 1.55-1.65 (2H, m), 1.75- 1.85 (2H, m), 3.05-3.15 (2H, m), 3.55- 3.65 (2H, m), 4.40 (1H, m), 8.54 (2H, s). Reference Example 222

4- (1-t-butoxycarbonylpiperidine- 4-yloxy) -1,3-dicarbamoylnitrobenzene

2- (1-t-Butoxycarbonylpiperidine-4-yloxy) -1-5-nitroisophthalic acid (4.6 g) obtained in Reference Example 221 was dissolved in dichloromethane (150 ml), and chloroform was added thereto. After isobutyl acid (4.3 ml) and triethylamine (4.8 ml) were added, the mixture was stirred at the same temperature for 30 minutes, 28% aqueous ammonia (1.9 ml) was added, and the mixture was further stirred at room temperature for 1 hour. The precipitated precipitate was collected by filtration to give the title compound (3.0 g, yield 64%) as a pale-yellow solid.

¾ NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.40 (9H, s), 1.60-1.70 (2H, m), 1.75- 1.85 (2H, m), 3.05-3.15 (2H, m), 3.55- 3.65 (2H, m), 4.48 (1H, m), 8.31 (2H, s). Reference Example 223

4- (1-t-butoxycarbonylbibiperidine-1-4-yloxy) -1,3,5-dical pamoylaniline

4- (11-t-butoxycarbonylpiperidine-1-4-yl obtained in Reference Example 222 Xy) Dissolve 3,5-dicarbamoylnitrobenzene (3.0 g) in methanol (60 ml), add palladium-carbon catalyst (0.3 g), and stir at room temperature under a hydrogen atmosphere for 1 hour did. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 2.8 g (yield quantitative) of the title compound as a yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.45 (9H, s), 1.55-1.70 (2H, m), 1.85-2.00 (2H, m), 2.67 (2H, m), 3.80-3.90 (2H, m), 4.02 (1H, m), 7.34 (2H, s).

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1,3,5-dicarbamoylphenyl] sulfamoyl acetate

4- (1-t-Butoxycarbonylpiperidine-14-yloxy) -1,3,5-dicarbamoylaniline (2.8 g) obtained in Reference Example 223 was dissolved in dichloromethane (80 ml), and cooled with ice. Then, chlorosulfonyl acetate ethyl (2.4 ml) and pyridine (1.4 ml) were added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica to give 0.9 g (yield 23%) of the title compound as a pale yellow solid.

Marauder R (500 MHz, DMSO-d ₆ ) δ ppm: 1.18 (3H, t, J = 7.0), 1.40 (9H, s), 1.50-1.60 (2H, m), 1.75-1.85 (2H, m) , 2.90-3.00 (2H, m), 3.30 (2H, s), 3.65-3.75 (2H, m), 4.10 (2H, q, J = 7.0), 4.15-4.20 (1H, m), 7.43 (2H, s). Reference example 225

N- [4- (1-t-butoxycarbonylpiperidine-1 4-yloxy) —3,5-dicarbamoylphenyl] -1-N— [3- (3-cyanophenyl) 1-2— (E) —probenyl] Ethyl sulfamoyl acetate

3- (3-Cyanophenyl) -2- (E) monopropene-1-ol obtained in Reference Example 2 (0.9 g), N- [4- (1-I) obtained in Reference Example 224 t-butoxycarbonylperidine—4-yloxy) -3,5-dicarbamoylphenyl] sulfamoyl acetate (0.9 g) and triphenylphosphine (1.8 g) were added to dichloromethane (30 g). ml) and tetrahydrofuran (30 ml), and after adding ice-cooled getyl azodicarbonate (1.1 ml) under ice cooling, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 1/2) to give 0.8 g of the title compound (yield 73%) in yellow. Obtained as an amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.26 (3H, t, J = 7.0), 1.45 (9H, s), 1.60-1.75 (2H, m), 1.85-2.00 (2H, m), 2.60- 2.75 (2H, m), 4.00-4.15 (2H, m), 4.03 (2H, s), 4.15-4.25 (lH, m), 4.31 (2H, q, J = 7.0), 4.55 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.46 (1H, d, J = 16.0), 7.35-7.45 (2H, m), 7.50-7.60 (3H, m), 8.16 (1H, m). Reference Example 226

4-methyl-5-methylnitrosalicylate,

(4) Dissolve monomethylsalicylic acid (3.5 g) in a mixed solvent of methanol (8m1) and benzene (32ml), and add under ice-cooling. 2. Add ON-trimethylsilyldiazomethanehexane solution (15ml). The mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the obtained yellow oil was added to 69% nitric acid (20 ml) under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the extract was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 4Z 1) to give 1.3 g (yield 21%) of the title compound as a pale-yellow solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm:. 2.66 (3H, s), 4.01 (3H, s), 6.92 (1H, s), 8.66 (1H, s) Reference Example 227

4- (1-t-butoxycarbonylbiperidine-4-yloxy) -5-methoxycarbonyl-2-methylnitrate benzene

1-t-butoxycarbone 4-hydroxypiperidine (5.4 g), methyl 4-methyl-5-ditrosalicylate (2.8 g) obtained in Reference Example 226, and triphenyl Phosphine (9.0 g) was dissolved in dichloromethane (100 ml). Under ice-cooling, azodi force getyl ruponate (5.4 ml) was added, followed by stirring at room temperature for 9 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 4.9 g (yield 93%) of the title compound as a yellow oil. Obtained as a solid.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.85-1.95 (4H, m), 2.68 (3H, s), 3.50-3.65 (4H, m), 3.91 (3H, s) , 4.78 (1H, m), 6.84 (1H, s), 8.63 (1H, s).

4- (1-t-butoxycarponylpiperidine-1-4-yloxy) -1-5-potoxyloxy 2-methylnitrobenzene

4- (11-t-butoxycarbonylbiperidine-4-1 ^ r-roxy) -1-5-methoxycarbonyl 2-methylnitrobenzene (4.9 g) obtained in Reference Example 227 was concentrated hydrochloric acid (10 Oml). And stirred at 80 ° C for 5 hours. After the reaction solution was concentrated under reduced pressure, the obtained white solid was dissolved in a mixed solvent of water (30 ml) and acetone (30 ml), and the mixture was dissolved at room temperature at room temperature. After adding (2.3 g), the mixture was further stirred at 4 Ot: for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.8 g (quantitative yield) of the title compound as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) d ppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.71 (3H, s), 3.35-3.45 (2H, m), 3.70-3.80 (2H, m), 4.85 (1H, m), 6.93 (1H, s), 8.84 (1H, s). Reference example 229 '

4-1- (1-t-butoxycarbonylpiperidine-4-1-yloxy) -1-5-l-rubamoyl 2-methylnitrobenzene

The 4- (11-t-butoxycarbonylpiperidine-14-yloxy) -15-carboxy-2-methylnitrobenzene (4.8 g) obtained in Reference Example 228 was treated with dichloromethane (1 Under ice-cooling, add isobutyl chloroformate (1.7 ml) and triethyleamine (1.8 ml), stir at the same temperature for 1 hour, and add 28% aqueous ammonia (0.8 ml). The mixture was further stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane Z methanol = 19Z1) to give 4.7 g (yield 97%) of the title compound as a white solid. .

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.41 (9H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 2.61 (3H, s), 3.20-3.30 ( 2H, m), 3.60-3.70 (2H, m), 4.93 (IH, m), 7.35 (1H, s), 8.42 (IH, s).

4- (1-t-butoxycarboxylbiperidine-4-yloxy) 1-5 _rubamoyl-2-methylaniline

4- (1-t-Butoxycarbonylpiperidine-1 4-yloxy) -1-5-caproluvamoyl-2-methylnitrobenzene (4.7 g) obtained in Reference Example 229 was dissolved in methanol (120 mL), and palladium oxide After adding a carbon catalyst (0.5 g), the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 4.0 g (yield 93%) of the title compound as a yellow amorphous solid.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.20 (3H, s), 3.18 (2H, m ), 3.75-3.85 (2H, m), 4.45 (IH, m), 6.74 (1H, s), 7.47 (1H, s).

N- [4- (11-t-butoxycarbonylbiperidine-4-1-yloxy) -5-carpamoyl-1-methylphenyl] sulfamoyl acetate

The 4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-5-rubbamoyl-2-methylaniline (4.0 g) obtained in Reference Example 230 was dissolved in dichloromethane (60 ml), and dissolved in ice (60 ml). Under cooling, ethyl chlorosulfonylacetate (1.9 ml) and pyridine (1.2 ml) were added dropwise, followed by stirring at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, the residue was removed. Purification by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) gave 2.8 g (yield 48%) of the title compound as a pale yellow solid.

_{¾ NMR (500 MHz, CDC1 3} ) δ ppm: 1.35 (3H, t, J = 7.0), 1.48 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.49 ( 3H, s), 3.29 (2H, m), 3.75-3.85 (2H, m), 4.06 (2H, s), 4.33 (2H, q, J = 7.0), 4.66 (1H, m), 6.90 (1H, s), 8.16 (1H, s).

N— [4- (1-t-butoxycarbonylpiperidine-1_4-yloxy) _ 5-carbamoyl-2-methylphenyl] —N— [3- (3-cyanophenyl) — 2 -— (E) -propionyl sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) 1-2 (E) -propene-11-all obtained in Reference Example 2 (0.9 g), N- [4-1-1 ( 1-t-butoxycarbonylpiperidine-1 4-yloxy) — 5-potassium rubamoyl-2-methylphenyl] sulfamoyl acetate ethyl (2.8 g) and triphenylphosphine (2.0 g) in dichloromethane (100 ml) ), And thereto was added, under ice-cooling, azodicarboxylic acid getyl chloride (Cl. 2 ml), followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 1Z4) to give 2.1 g (yield 58%) of the title compound as a yellow solid. Obtained as a shaped solid.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.41 (3H, s), 3.25-3.35 (2H, m), 3.75-3.85 (2H, m), 4.02 (IH, d, J = 14.0), 4.16 (1H, d, J = 14.0), 4.20-4.25 ( 1H, m), 4.30-4.40 (2H, m), 4.65-4.75 (2H, m), 6.20-6.30 (1H, m), 6.35 (1H, d, J = 16.0), 6.88 (IH, s), 7.41 (1H, m), 7.50-7.55 (3H, m), 8.30 (1H, s).

3- (5-cyano 2-methylphenyl) — 2- (E) 1-propene

1-t-butyl dimethyl xylate 2-propyne (2.45 g) and catechol borane (1.5 ml) and stirred at 60 for 4 hours. After the reaction solution was cooled to room temperature, it was diluted with toluene (40 ml), and 3-bromo-4-monomethylbenzonitrile (2.02 g), tetrakis (triphenylphosphine) palladium complex (0.58 g) and After adding 20% sodium ethoxide ethanol solution (5.0 ml), the mixture was stirred with 9 O: for 4 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed successively with a 1N aqueous sodium hydroxide solution, water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane ethyl acetate = 8/1) to obtain 2.23 g of a silyl ether compound. Next, the obtained silyl ether compound was dissolved in tetrahydrofuran (60 ml), a 1N tetrabutylammonium fluoride Z tetrahydrofuran solution (12 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After water was added to the reaction mixture, the mixture was extracted with t-butyl methyl ether. The extract was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z-ethyl acetate = 3Z2) to give 0.64 g (yield 2%, 36%) of the title compound as a colorless solid As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) <5 ppm: 2.41 (3H, s), 4.39 (2H, bs), 6.30 (1H, dt, J = 16.0, 5.5), 6.80 (1H, d, J = 16.0) , 7.25 (1H, d, J = 8.0), 7.43 (1H, dd, J = 8.0, 2.0), 7.70 (1H, d, J = 2.0).

N— [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) phenyl] -N- [3 -— (5-cyano-2-methylphenyl) —2 -— (E) 1-probenyl] sulfamoyl acetate ethyl

3- (5-Cyano-2-methylphenyl) -2- (E) -pu-pen-1-ol (0.64 g) obtained in Reference Example 233, N- [4-I (1-t-butoxycarbonylpiperidine-4-yloxy) phenyl] Ethyl sulfamoylacetate (1.62 g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml), and azodicarbon was added under ice cooling. After dropping getyl acid (0.70 ml), add The mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 12/1) to give 2.03 g (yield 92%) of the title compound as a colorless amorphous solid. Obtained.

_{NMR (500 MHz, CDC1 3)} δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75 (2H, m), 1.91 (2H, m), 2.25 (3H, s), 3.43 (2H, m), 3.69 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (1H, m), 4.49 (2H, d, J = 6.5), 6.05 (1H, dt, J = 15.5, 6.5), 6.56 (1H, d, J = 15.5), 6.92 (2H, d, J = 10.0), 7.19 (1H, d, J = 7.5), 7.40 (3H, m), 7.55 (1H, s). Reference Example 235

3- (5-cyano 2-fluorophenyl) -1- (E) -propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (1.70 g) and catecholporan (1.07 ml) The mixture was stirred at 60 for 3 hours. After the reaction solution was cooled to room temperature, it was diluted with toluene (20 ml), and 3-bromo-4-fluorobenzonitrile (1.40 g), tetrakis (triphenylphosphine) palladium complex (0.41 g) and After adding a 20% ethanol solution of sodium ethoxide (3.4 ml), the mixture was stirred at 100 ° C for 6 hours. After adding a 1N aqueous solution of sodium hydroxide to the reaction solution, the mixture was extracted with ether. The extract was washed with a 1N aqueous solution of sodium hydroxide, water and saturated brine in that order, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 10/1) to obtain 1.9 g of a silyl ether compound.

Then, the obtained silyl ether compound is dissolved in tetrahydrofuran (10 ml), a 1N tetrabutylammonium fluoride / tetrahydrofuran solution (5.3 ml) is added under ice cooling, and the mixture is stirred at the same temperature for 1.5 hours. did. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with water and brine sequentially, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane Z ethyl acetate = 1Z1) to give 0.46 g (yield 37% of two steps) of the title compound as a colorless solid As obtained. _{NMR (400 MHz, CDC1 3)} δ ppm: 4.40 (2H, m), 6.52 (1H, dt, J = 16.5, 5.0), 6.75 (1H, d, J = 16.5), 7.16 (1H, dd, J = 10.0, 8.5), 7.53 (IH, ddd, J = 8.5, 5.0, 2.0), 7.70 (IH, dd, J = 7.0, 2.0). Reference Example 236

N- [4- (1-t-butoxycarbonylpiperidine-4-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -propionyl] ethanesulfonamide

3- (5-cyano 2-fluorophenyl) 1-2- (E) -propene-111-ol obtained in Reference Example 235 (0.72 g), N- [4 -— (4- ( 1-t-Butoxycarbonylpiperidine- (1-yloxy) phenyl] ethanesulfonamide (1.63 g) and triphenylphosphine (1.37 g) are dissolved in dichloromethane (40 ml), and azodicarboxylic acid is added under ice cooling. After getyl (0.83 ml) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10: 1) to give 2.00 g (yield 91%) of the title compound as a colorless oil. It is profitable.

_{¾ NMR (400 MHz, CDC1 3} ) <5 ppm: 1.42 (3H, t, J = 7.5), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.06 (2H, q , J = 7.5), 3.33 (2H, m), 3.68 (2H, m), 4.45 (3H, m), 6.34 (IH, dt, J = 16.0, 6.0), 6.54 (IH, d, J = 16.0) , 6.90 (2H, d, J = 9.0), 7.12 (IH, dd, J = 10.5, 9.0), 7.27 (2H, d, J = 9.0), 7.51 (IH, ddd, J = 9.0, 5.0, 2.0) , 7.68 (1H, dd, J = 6.5, 2.0). Reference Example 237

N— [4 -— (1-t-Butoxycarbonylpiperidine-1-4-yloxy) phenyl] -1-N— [3- (3-Cyanophenyl) -1-methyl-1--2- (E) -probenyl] ethyl ethyl sulfamoylacetate

3_ (3-Cyanophenyl) -12-methyl-2- (E) -pu-pen-1-ol (1.50 g) obtained in Reference Example 131, N— [4— (11-butoxycarbonylpiperidine-1-4-yloxy) phenyl] Sulfamoylethyl acetate (3.83 g) and triphenylphosphine (2.95 g) were added to dichloromethane (70 m The mixture was dissolved in 1), and under ice-cooling, azodiphenol geronate (1.77 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1/10) to give the title compound (4.98 g, yield 96). %) Was obtained as a yellow amorphous solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.69-1.79 (2H, m), 1.84-1.96 (2H, m), 1.88 ( 3H, s), 3.34 (2H, m), 3.69 (2H, m), 3.98 (2H, s), 4.32 (2H, q, J = 7.0), 4.40 (2H, s), 4.46 (1H, m) , 6.20 (1H, s), 6.91 (2H, d, J = 9.0), 7.28-7.34 (5H, m), 7.47 (1H, d, J = 7.5). Reference Example 238

3-(3-Cyanophenyl)-2-ethyl-2- (E)-propenal

Dissolve 3-cyanobenzaldehyde (3.71) in toluene (100 ml), add 2- (triphenylphosphoranylidene) butyraldehyde (10.06 g), and then add 60 ° The mixture was stirred at C for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 19Z1-4Z1) to give 1.86 g (yield 35%) of the title compound. Obtained as a white solid.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.15 (3H, t, J = 7.5), 2.53 (2H, q, J = 7.5), 7.18 (1H, s), 7.59 (1H, t, J = 8.0 ), 7.66-7.77 (3H, m), 9.59 (1H, s).

3- (3-Cyanophenyl) -2-ethyl 2- (E) 1-propene-1-ol Reference Example 2 3- (3-cyanophenyl) 1-2-ethyl 2- (E) obtained from Example 38 (1.86 g) was dissolved in a mixed solvent of dichloromethane (17 ml) and ethanol (33 ml). Under ice cooling, cerium chloride (1.30 g) and sodium borohydride (0.68 g) were dissolved. ) And stirred at the same temperature for 25 minutes. After a saturated aqueous ammonium chloride solution was added to the reaction solution, water was added, and the mixture was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9Z1 to 3/2) to obtain the target compound. The title compound (1.75 g, yield 94%) was obtained as a colorless oil.

_{1H NMR (400 MHz, CDC1 3} ) δ ppm: 1.11 (3H, t, J = 7.5), 2.28 (2H, q, J = 7.5), 4.27 (2H, d, J = 4.5), 6.50 (1H, s ), 7.49-7.53 (4H, m). Reference example 240

N- [4- (1-t-Butoxycarboxylbiperidine-1-4-yloxy) phenyl] -N- [3- (3-Cyanophenyl) -1-2-ethyl-2- (E) -probenyl] ethyl ethyl sulfamoylacetate

3- (3-Cyanophenyl) — 2-ethyl _2 — (E) -opening pen-1-1-ol (0.69 g) obtained in Reference Example 239, N— [4 -Dissolve (1-t-butoxycarbonylbiperidine- (1-yloxy) phenyl) sulfamoylacetate (1.63 g) and triphenylphosphine (1.15 g) in dichloromethane (30 ml) and cool on ice. After dropwise addition of azodiphenol geronate (0.70 ml), the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10 / 0-9Zl) to give 2.04 g (91%) of the title compound as a colorless oil As obtained.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.10 (3H, t, J = 7.5), 1.38 (3H, t, J = 7.0), 1.48 (9H, s), 1.72-1.81 (2H, m), 1.89-1.98 (2H, m), 2.22 (2H, q, J = 7.5), 3.31-3.39 (2H, m), 3.67-3.75 (2H, m), 3.99 (2H, s), 4.24 (2H, q , J = 7.0), 4.43-4.51 (3H, m), 6.18 (1H, s), 6.95 (2H, d, J = 9.0), 7.25-7.31 (2H, m), 7.36-7.51 (4H, m) Reference Example 241

N— [4- (1-t-butoxycarbonylpiperidine-1-4 f-roxy) -1-3-carbamoylphenyl] -1-N— [3- (3-cyanophenyl) —2-fluoro-2- (Z) 1-propenyl) sulfamoyl Ethyl acetate

3- (3-Cyanophenyl) 1-2-fluoro-2- (Z) -propen-1-ol obtained in Reference Example 215 (0.80 g), N- [4-1-1 (1 -t-Butoxycarbonylpiperidine—4-yloxy) —3—pothambylphenyl] sulf Ethyl famoyl acetate (2.20 g) and triphenylphosphine (1.50 g) were dissolved in dichloromethane (50 ml), and cooled under ice-cooling.

After 1) was added dropwise, the mixture was stirred at room temperature for 2.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 Z 4-1Z)

Purification in 2) gave 3.40 g (quantitative yield) of the title compound as a pale yellow amorphous solid.

^{X H NMR (500 MHz, CDC1} 3) δ ppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.84 (2H, m), 2.02-2.10 (2H, m), 3.23 -3.30 (2H, m), 3.76-3.84 (2H, m), 4.01 (2H, s), 4.31 (2H, q, J = 7.0), 4.57-4.70 (3H, m), 5.65 (1H, d, J = 36.5), 7.03 (1H, d, J = 9.0), 7.38-7.74 (5H, m), 8.35 (IH, d, J = 3.0). Reference example 242 '

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) —3-force J-le-bamoylphenyl] -1-N— [3- (3-cyanophenyl) -1-2-methyl-2- (E) -pro Benil] sulfamoyl acetate

3- (3-Cyanophenyl) 1-2-methyl-2- (E) -penten-1-ol (0.88 g) obtained in Reference Example 131, N- [4-1-1 (1-t-Butoxycarbonylpiperidine-1-4-yloxy) — 3-caprolbumoylphenyl] Ethyl sulfamoyl acetate (2.50 g) and triphenylphosphine (1.60 g) dissolved in dichloromethane (50 ml) Then, under ice-cooling, azodicarboxylic acid geronate (1.00 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 2Z1) to give 4.50 g (quantitative yield) of the title compound as a yellow amorphous solid. As obtained.

_{¾ NMR (500 MHz, CDC1 3} ) 6 ppm: 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.84 (2H, m), 1.88 (3H, s), 2.03-2.11 ( 2H, m), 3.23-3.31 (2H, m), 3.76-3.85 (2H, m), 3.99 (2H, s), 4.32 (2H, q, J = 7.0), 4.46 (2H, s), 4.68 ( IH, m), 6.24 (1H, s), 7.01 (1H, d, J = 9.0), 7.32-7.71 (5H, m), 8.34 (IH, d, J = 3.0). Reference Example 243

3- [3- [N— [4- (1-t-Butoxycarbonylpiperidine-1 4-yloxy) -3-3-Rubamoylphenyl] amino] -1-11 (E) —Propenyl] benzonitrile Reference Example The 3-cyanocinnamic aldehyde (0.64 g) obtained in 1 and the 4- (1-t-butoxycarbonylpiperidine-14-yloxy) -13-potassium lipamoylaniline obtained in Reference Example 117 (1. 36 g) and powdered molecular sieves 5A (5.06 g) were suspended in toluene (30 ml) and heated under reflux for 2.5 hours. After the reaction solution was cooled to room temperature, it was filtered using celite, and the filtrate was concentrated under reduced pressure to obtain an imine compound.

Then, the obtained imine form was suspended in ethanol (30 ml), and sodium borohydride (0.31 g) and cerium chloride (0.32 g) were added thereto under ice-cooling, followed by stirring at room temperature overnight. And sodium borohydride (0.16 g) were added, and the mixture was further stirred at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with water, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane Z ethyl acetate = 7 Z 3-0 / 10) to give 1.77 g of the title compound (yield 92 %) Was obtained as a colorless oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.47 (9H, s), 1.68-1.79 (2H, m), 1.98-2.17 (2H, m), 3.14-3.22 (2H, m), 3.78-3.88 ( 2H, m), 3.99 (2H, d, J = 5.5), 4.45 (1H, m), 6.38 (1H, dt, J = 16.0, 5.5), 6.60 (IH, d, J = 16.0), 6.75 (IH , dd, J = 9.0, 3.0), 6.89 (IH, d, J = 9.0), 7.41 (IH, t, J = 8.0), 7.49-7.53 (2H, m), 7.58 (IH, d, J = 8.0 ), 7.63 (1H, s). Reference Example 244

N- [4- (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-carbamoylphenyl] — N— [3- (3-cyanophenyl) —2- (E) 1-probenyl] methanesulfonamide

3- [3- [N- [4- (1-t-butoxycarpenylpyridine-41-yloxy)] obtained in Reference Example 243—3- (Rubamoylphenyl) amino] —1— (E) — Professional [Penyl] benzonitrile (0.85 g) was dissolved in dichloromethane (15 ml), methanesulfonyl chloride (0.17 ml) and pyridine (0.29 ml) were added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. . After adding methanol (3 ml) to the reaction mixture, it was concentrated under reduced pressure.

The resulting compound was purified by 10-0-9 / 1) to give the title compound 1: 01 g (yield quantitative) as a colorless oil.

_{¾ NMR (400 MHz, CDC1 3} ) δ ppm: 1.48 (9H, s), 1.74-1.85 (2H, m), 2.03-2.12 (2H, m), 2.96 (3H, s), 3.23-3.32 (2H, m), 3.75-3.85 (2H, m), 4.46 (2H, d, J = 6.5), 4.68 (1H, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.48 (1H, d, J = 16.0), 7.02 (1H, d, J = 9.0), 7.41 (IH, t, J = 7.5), 7.49-7.57 (4H, m), 8.18 (1H, d, J = 3.0). Reference example 245

N- [4 -— (1-t-butoxycarbonylpiperidine-1-4-yloxy) -1-3-carbamoylphenyl] 1-N— [3- (3-cyanophenyl) 1-2- (E) 1-probenyl] ethanesulfone Amide

3- [3- [N- [4- (1-t-butoxycarpylpyridin-1-4_yloxy) -1-3-force rubamoyl fuel] amino obtained in Reference Example 243] —11 (E) —Propenyl] benzonitrile (0.92 g) was dissolved in dichloromethane (15 ml), and ethanesulfonyl chloride (0.22 ml) and pyridine (0.31 ml) were added dropwise under ice-cooling. After stirring, ethanesulfonyl chloride (0.04 ml) and pyridine (0.16 ml) were added dropwise under ice cooling, and the mixture was further stirred at room temperature for 5 hours. After adding methanol (3 ml) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10/0 to 9Ζ1) to give the title compound 1.08. g (90%) was obtained as a yellow oil.

_{1H NMR (400 MHz, CDC1 3} ) <5 ppm: 1.42 (3H, t, J = 7.5), 1.47 (9H, s), 1.72-1.82 (2H, m), 2.03-2.10 (2H, m), 3.08 (2H, q, J = 7.5), 3.22-3.31 (2H, m), 3.74-3.83 (2H, m), 4.48 (2H, d, J = 6.5), 4.66 (IH, m), 6.24 (IH, dt, J = 16.0, 6.5), 6.44 (1H, d, J-16.0), 7.00 (1H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.48-7.55 (4H, m) , 8.16 (IH, d, J = 3.0).

[Industrial applicability]

Since the composition for iontophoresis of the present inventor is efficiently absorbed from the skin by forming an iontophoresis preparation, it is useful for treating or preventing thrombus or emboli in warm-blooded animals (particularly humans). It is useful as a percutaneous absorption preparation. The composition for iontophoresis of the present invention is a composition containing a benzamidine derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof. There is no particular limitation as long as it is absorbed and produces a pharmacological effect by the effect of tophoresis, and examples thereof include a liquid, a plaster, an ointment, a liniment, and a lotion. The plaster. The composition for iontophoresis of the present invention is obtained by adding a surfactant to an oily base, a water-soluble base, a pressure-sensitive adhesive, a gel base or an oil-based base, and a water-soluble base, which are commonly used for external preparations. Or an emulsion base. Examples of the oil base include vegetable oils such as cottonseed oil, sesame oil and olive oil; waxes such as carnaubax or beeswax; higher hydrocarbons such as white petrolatum, liquid paraffin or plastibase; stearic acid or palmitic acid; Fatty acids and esters thereof; higher alcohols such as seanol; and silicones such as silicon fluid or silicone rubber. As the water-soluble base, for example, a solution of polyvinyl alcohol, carboxyvinyl polymer or cellulose derivative, or polymer hydrogel; polyethylene glycol

(MacPorl Gap) or polyethylene glycol-polypropylene glycol copolymer; or propylene glycol, 1,3-butylene glycol, ethanol or glycerin, etc., and preferably propylene glycol or glycerin. Ah Examples of the pressure-sensitive adhesive _c include a methacrylate copolymer, a natural rubber-based pressure-sensitive adhesive, a synthetic rubber-based pressure-sensitive adhesive such as synthetic isoprene; and a silicone polymer-based pressure-sensitive adhesive. Gel bases include, for example, polyacrylic acid, force popole, polyaspartic acid, polyglutamic acid, hyaluronic acid, polybier alcohol, polyvinylpyrrolidone, polyvinylacetamide, hydroxypropyl methylcellulose, chitosan, Poly-L-lysine, polyallylamine, gelatin, carboxymethylcellulose, carrageenan, tragacanth gum, agarose, aluminum heptaoxide, or citric acid, and the like. Can be subjected to a crosslinking treatment by ultraviolet irradiation, gamma irradiation or addition of a crosslinking agent, and examples of the crosslinking agent include aluminum glycinate and dartalaldehyde. Examples of the surfactant used in the emulsion base include anionic surfactants such as fatty acids, saponins, fatty acid salcosides, alcohol sulfates and alcohol phosphates, and cations such as quaternary ammonium salts and heterocyclic amines. Surfactant; amphoteric surfactant such as alkyl betaine or lysolecithin; or non-ionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester, etc. Can be. The composition for iontophoresis of the present invention contains, if necessary, commonly used additives such as a surfactant, a thickener, a stabilizer, a pH adjuster, and a preservative or the like. But you can. Surfactants include fatty acids, saponins, fatty acid sarcosides, alcohol sulfate esters Anionic surfactants such as phenyl or alcoholic phosphates; cationic surfactants such as quaternary ammonium salts or heterocyclic amines; or amphoteric surfactants such as alkyl betaines or lysolecithins; polyoxyethylene alkyl ethers; Non-ionic surfactants such as polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester can be exemplified. Examples of the thickener include cellulose derivatives such as carboxymethylcellulose; polycarboxylic acids such as polyacrylic acid or methoxymethylene maleic anhydride copolymer; and nonionic water-soluble polymers such as polyvinylpyrrolidone or polyvinyl alcohol. Can be mentioned. The stabilizer is not particularly limited as long as it is commonly used, but is preferably an antioxidant such as ascorbic acid or sodium pyrosulfite; or a chelating agent such as EDTA. .

The pH adjuster is not particularly limited as long as it is commonly used, and is preferably a phosphate buffer or a citrate buffer. The preservative is not particularly limited as long as it is a commonly used preservative, but is preferably an alkyl quaternary ammonium salt such as parabens, benzalkonium chloride or benzethonium chloride. When the composition for iontophoresis of the present invention is used in an iontophoresis device, any electrode may be used as long as it is a conductive substance, for example, platinum, carbon, and silver. A silver chloride electrode or a conductive polymer such as polyacetylene or polypyrrole may be used, but a silver silver chloride electrode is preferred. When the composition for iontophoresis of the present invention is used in an iontophoresis device, There is no particular limitation on the power supply used in this case, and any of a DC type, a pulse type, a pulse depolarization type, etc. can be used.The current value may be fixed in advance or may change with time. May be. The composition for iontophoresis of the present invention can be prepared by a conventional method using the above-mentioned various bases, pressure-sensitive adhesives and other additives added as necessary. When preparing a preparation and lotion, the benzamidine derivative can be obtained by simply dissolving or dispersing the benzamidine derivative in water and a solvent containing propylene glycol, 1,3-butylene glycol, ethanol or glycerin. The above additives can be added accordingly. When preparing an ointment, the benzamidine derivative is mixed with the above-mentioned water-soluble base, the above-mentioned oleaginous base and a solvent commonly used in the art such as Z or water, vegetable oil, etc., and if necessary, a surfactant. To obtain an emulsification treatment, and if necessary, the above-mentioned additives can be added. For plasters,

(1) A solution containing a benzamidine derivative and a desired additive described above, together with the above-mentioned adhesive, is coated on a film base commonly used for skin patches such as polyethylene, polyester, boria acrylonitrile, and polyvinyl chloride. By or

(2) A solution containing a benzamidine derivative and the above gel base (which may contain the above-mentioned additives if necessary) is poured into a mold, and crosslinked as required. it can. Also, the gel can be dried and stored, and impregnated before use. The upper limit of the benzamidine derivative contained in the composition for iontophoresis of the present invention per adult is 1,000 mg (preferably 500 mg, more preferably 100 mg), and the lower limit is 0.01 mg (preferably l mg, more preferably 10 mg) once daily Administered topically for up to 10 times with varying duration. When the composition for iontophoresis of the present invention is used as a liquid, lotion, or ointment, it may be directly administered to the skin, or may be impregnated with lint cloth or gauze and administered to the skin. When used as a plaster, it may be applied as it is or may be applied to the skin using a backing film such as lint cloth, gauze, adhesive tape or the like. When a drug is administered by iontophoresis using the composition for iontophoresis of the present invention, the iontophoresis device including the power supply device and the electrode, etc. For use. The administration site of the composition for iontophoresis of the present invention is not particularly limited, and can be appropriately selected depending on the indication disease and the pharmacological or pharmacokinetic properties of the active ingredient. Abdominal, back, arm skin and the like.

Claims

The scope of the claims

General formula

Inside

R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxyl group, R ² represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,

R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl-substituted alkyl group having 1 to 6 carbon atoms, a carboxyalkyl group having 2 to 7 carbon atoms, or an alkoxy group having 3 to 13 carbon atoms. Cicarponylalkyl group, aralkyl group having 7 to 16 carbon atoms, aliphatic acryl group having 2 to 7 carbon atoms, hydroxyl-substituted aliphatic acryl group having 2 to 7 carbon atoms, 1 to 6 carbon atoms An alkylsulfonyl group, an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms, a carboxyalkylsulfonyl group having 2 to 7 carbon atoms or a carboxyalkylcarbonyl group having 3 to 8 carbon atoms,

R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms A carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, a monoalkyl carbamoyl group having 2 to 7 carbon atoms, or a dialkylcarbamoyl group having 3 to 13 carbon atoms,

R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or a carbon atom having 1 to 6 carbon atoms substituted by a heterocyclic ring. Alkyl groups, carboxyalkyl groups having 2 to 7 carbon atoms, alkoxycarbonyl groups having 3 to 13 carbon atoms, aliphatic acyl groups having 2 to 7 carbon atoms, 7 to 11 carbon atoms of Aromatic acyl group, carbamoyl group, alkylsulfonyl group having 1 to 6 carbon atoms, aryle group having 6 to 10 carbon atoms, heterocycle, formimidyl group, 11-iminoalkyl group having 2 to 7 carbon atoms Represents an N-alkylformimidoyl group having 2 to 7 carbon atoms or an iminoarylmethyl group having 7 to 11 carbon atoms;

R ⁷ and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

n represents 0, 1 or 2. ] Or a pharmacologically acceptable salt thereof, for iontophoresis.

2. The composition for iontophoresis according to claim ¹ , wherein R1 contains a benzamidine derivative or a pharmacologically acceptable salt thereof, which is a hydrogen atom or a hydroxyl group.

3. The composition for iontophoresis according to claim ¹ , wherein R ¹ comprises a benzamidine derivative or a pharmaceutically acceptable salt thereof, which is a hydrogen atom.

4. The claim 1 wherein R ² contains a benzamidine derivative which is a hydrogen atom, a bromine atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group or a pharmacologically acceptable salt thereof. The composition for iontophoresis according to claim 1, which is selected from claim 3.

5. The claim selected from claims 1 to 3, wherein R ² contains a benzamidine derivative or a pharmacologically acceptable salt thereof, which is a hydrogen atom, a fluorine atom or a methyl group. 3. The composition for iontophoresis according to item 1.

6. R ² has containing a certain base Nzuamijin derivative or salts acceptable pharmacologically a hydrogen atom, a Ionto Foreshisu to in one of claims selected from paragraphs 1 through claim 3 Composition.

7. A method according to claim 1, wherein R ² contains a benzamidine derivative or a pharmaceutically acceptable salt thereof, which is a fluorine atom or a methyl group. The composition for iontophoresis described above.

8. The composition for iontophoresis according to claim 1, wherein the composition comprises a benzamidine derivative or a pharmacologically acceptable salt thereof, which is a fluorine atom. .

9. A benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein R ³ is an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms or a carboxyalkylsulfonyl group having 2 to 7 carbon atoms, 9. The composition for iontophoresis according to claim 1, wherein the composition is selected from claims 1 to 8.

Contains a benzamidine derivative which is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group, or a pharmacologically acceptable salt thereof, in one of the claims 1 to 8. The composition for iontophoresis according to claim.

11. Benzamidine wherein R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms or a rubamoyl group The composition for iontophoresis according to any one of claims 1 to 10, comprising a derivative or a pharmacologically acceptable salt thereof.

1 2. Is R ⁴ and R ^5, same or different, a hydrogen atom, a chlorine atom, containing methyl group, triflate Ruoromechiru group or base is a force Rubamoiru group Nzuamijin derivative or salts acceptable pharmacologically, according The composition for iontophoresis according to claim 1, wherein the composition is selected from the range of items 1 to 10.

13. A benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group or a rubamoyl group; The composition for iontophoresis according to claim 1, wherein the composition is selected from claims 1 to 10.

14. The method according to claim 1, wherein 1 is a hydrogen atom, and R ⁵ contains a benzoamidine derivative or a pharmacologically acceptable salt thereof, wherein R ⁵ is a hydrogen atom or a rubamoyl group. The composition for iontophoresis according to claim 1, which is selected.

15. R ⁶ is an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, and 1 to 6 carbon atoms substituted with a heterocyclic ring. Alkyl groups, aryl groups having 6 to 10 carbon atoms, heterocycles, formimidoyl groups, 1-iminoalkyl groups having 2 to 7 carbon atoms, iminoarylmethyl having 7 to 11 carbon atoms A benzamidine derivative which is an N-alkylformimidyl group having 2 to 7 carbon atoms or a pharmacologically acceptable salt thereof, selected from the claims 1 to 14; The composition for iontophoresis according to Claim.

16. R ⁶ is methyl, ethyl or isopropyl, cyclopentyl, benzyl or phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 21- ( 3- (pyridyl) ethyl or 2- (4-pyridyl) ethyl group, phenyl group,, 5-dihydro-13H-pyrroyl-2-yl, 2,3,4,5-tetrahydropyridine-1-6- , 4,5-dihydrooxazole-2-yl, 5,

6-dihydro-2H- [1,4] thiazin-3-yl or 4-pyridyl group, formimidyl group, acetimidoyl group, 1-iminopropyl group, iminophenylmethyl group or N-ethylformimidoyl group The composition for iontophoresis according to any one of claims 1 to 14, comprising a benzamidine derivative or a pharmacologically acceptable salt thereof.

17. The claim 1 to claim 1, wherein R ⁶ contains a benzamidine derivative or a pharmacologically acceptable salt thereof, which is a 4,5-dihydro-3H-pyrrole-2-yl or acetimidoyl group. 15. The composition for iontophoresis according to claim 14, wherein the composition is selected from the item 14.

18. The ion according to claim 1, wherein R ⁶ contains a benzamidine derivative or a pharmaceutically acceptable salt thereof, which is an acetoimidoyl group. Composition for tophoresis.

19. The claim 1 wherein R ⁷ and R ⁸ are the same or different and contain a benzamidine derivative or a pharmacologically acceptable salt thereof, which is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The composition for iontophoresis according to claim 1, wherein the composition is selected from the group consisting of:

20. The method according to claims 1 to 18, wherein R ⁷ and R ⁸ are the same or different and contain a hydrogen atom or a methyl group, a benzamidine derivative or a pharmacologically acceptable salt thereof. The composition for iontophoresis according to claim 1, which is selected from the group consisting of:

21. The method according to claim 1, wherein R ⁷ and R ⁸ are a hydrogen atom or a benzamidine derivative or a pharmacologically acceptable salt thereof. The composition for iontophoresis described above.

2 2. R ⁶ and R ⁷ together such connexion, or, taken R ⁷ and R ⁸ gar緖, a benzamidine derivative or acceptable salts its pharmaceutically an alkylene group having 2 to 5 carbon atoms The composition for iontophoresis according to claim 1, wherein the composition is selected from the claims 1 to 14.

23. When R ⁶ and R ⁷ are joined together, or R ⁷ and R ⁸ are joined together, ethylene or tri The composition for iontophoresis according to any one of claims 1 to 14, comprising a benzamidine derivative which is a methylene group or a pharmacologically acceptable salt thereof.

24. The composition for iontophoresis according to claim 1, wherein the composition comprises a benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein n is 1. object.

25. The composition for iontophoresis according to claim 1, comprising a benzamidine derivative selected from the following group or a pharmacologically acceptable salt thereof:

N— [4- (1-acetoimidoylpiperidin-1-41-yloxy) phenyl] —N— [3- (3-amidinophenyl) -12- (E) -probenyl] sulfamoylacetic acid,

N— [4- (1-Acetimidoylpiperidine-1_4-yloxy) —3-chlorophenyl] —N— [3- (3-Amidinophenyl) —2_ (E) -Ipropionyl sulfamo Acetic acid,

N— [4- (1-Acetimidoylpiperidin-1-yloxy) -3_methylphenyl] —N— [3- (3-Amidinophenyl) -2- (E) 1-probenyl] Sulfamo Acetic acid,

N- [4- (1-acetoimidoylpiperidine-1-4-yloxy) -1-3-trifluoromethylphenyl] -N- [3- (3-amidinofenyl) -2- (E) 1-probenyl] sulfamoylacetic acid ,

N— [4 -— (1-acetoimidoylpiperidine-1_4-yloxy) —3—pothambyl ulfenyl] —N— [3— (3-amidinofenyl) -1-2— (E) 1-propenyl) sulf Famoyl acetic acid,

N— [4- (1-acetoimidoylpiperidin-1-41-yloxy) phenyl] -N- [3- (3-amidinophenyl) 1-2-fluoro-2- (Z) —probenyl] sulfamoylacetic acid ,

N— [4— (1-acetimidoylpiperidine—4-yloxy) phenyl] N— [3- (3-Amidinophenyl) -2-methyl-2- (E) -probenyl] sulfamoylacetic acid, and

N— [4- (1-Acetimidoylpiperidine—4-yloxy) -1-3-rubbamoylphenyl) -N- [3- (3-amidinofenyl) —2-fluoro-2 -— (Z) —pro [Pinyl] sulfamoyl acetic acid.

26. Claims defined in one claim selected from paragraphs 1 to 25

'A method for preventing or treating thrombus, comprising administering a composition for one cis to a warm-blooded animal.

27. A method for preventing or treating emboli, which comprises administering to a warm-blooded animal the composition for dialysis according to claim 1 selected from claims 1 to 25.