JP2002363159A - Benzamidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a benzamidine derivative having excellent inhibiting action against activated blood coagulation factor X and useful as an agent for the treatment or prevention of blood coagulation diseases, its pharmacologically permissible salt and a drug containing the same. SOLUTION: The benzamidine derivative is expressed by general formula (1) [R<1> is H, a halogen atom, an alkyl group or OH; R<2> is H or a halogen atom; R<3> is H, a (substituted) alkyl, an aralkyl, a (substituted) alkylcarbonyl, a (substituted) alkylsulfonyl or the like; R<4> and R<5> are each H, a halogen atom, a (substituted) alkyl, carbamoyl or the like; R<6> is a heterocyclic group or the like; R<7> and R<8> are each H, an alkyl or the like; and (n) is 0, 1 or 2].

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD OF THE INVENTION

The present invention provides a benzamidine derivative which has an excellent activated blood coagulation factor X inhibitory activity and is useful as a therapeutic or prophylactic agent for blood coagulation diseases, their pharmacologically acceptable salts, and It relates to the medicine contained.

[0002]

2. Description of the Related Art In recent years, the aging of the population has led to a noticeable increase in cardiovascular diseases associated with aging. Among them, thrombotic diseases such as cerebral infarction, myocardial infarction and peripheral circulatory disorders not only directly lead to the cause of death, but also impose many personal and social burdens such as poor prognosis of patients and restrictions on their lives. Anticoagulant therapy is expected to become increasingly important as a treatment for these thrombosis.

[0003] Blood coagulation goes through a multi-step amplification process of an enzymatic reaction activated by some stimulus, and finally activated thrombin degrades fibrinogen, which is a soluble plasma protein, to a limited extent. Is generated. Fibrin forms a clot with insoluble proteins. This process is known as the blood clotting cascade, and has two pathways, intrinsic and extrinsic, each of which activates blood coagulation factor X and merges. As described above, the activated blood coagulation factor X thus produced is an enzyme occupying an important position in the blood coagulation cascade.
Valvalent calcium ions, phospholipids and activated blood coagulation V
Creates a complex with factors and the like, efficiently converts prothrombin to thrombin, and promotes the blood coagulation reaction [for example, Principles of Biochemistry: Marmarian Biochemistry, 7th edition (1983)]
[EL Smith, A. White et al 'Principles of Bioch
emistry: Mammalian Biochemistry 7th edition 'McGra
w-Hill, Inc. (1983)].

At present, warfarin and antithrombin are known and used as anticoagulants. However, although warfarin is commonly used as an oral antithrombotic,
It is a vitamin K antagonist, and it is known that it is difficult to control the anticoagulant ability due to frequent interactions with the diet and concomitant drugs [for example, Clinical Pharmacokinetics, Vol. 30, Vol. 416 pages (19
1996) [ Clin. Pharmacokinet. , 30 , 416 (1996)]
etc]. In addition, with the current antithrombin agents, a bleeding tendency of side effects associated with the drug effect is observed, so that development of a new anticoagulant is desired. Activated blood coagulation factor X is directly involved in the generation of thrombin, and its inhibitor is known to exhibit an anticoagulant effect, suggesting its potential as a novel anticoagulant [eg, Drugs , Vol. 49, No. 8
56 (1995) [ Drugs , 49 , 856 (1995)].

As a competitive antagonist type activated blood coagulation factor X inhibitor, JP-A-5-208946 (EP
540051), WO 96/16940 (EP7982)
95) or WO 00/47553 describes aromatic amidine derivatives or amidinonaphthyl derivatives.
WO 98/31661 (EP97722) describes, for example, N- [4- [1-acetimidoyl-4-
Benzamidine derivatives such as piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) ethyl] sulfamoylacetic acid trifluoroacetate are described.

[0006]

DISCLOSURE OF THE INVENTION The inventors of the present invention aimed at the development of a compound having an excellent inhibitory effect on activated blood coagulation factor X, and over the years, have intensively studied the pharmacological activity of various benzamidine derivatives. As a result, since the benzamidine derivative having a specific structure has an excellent activated blood coagulation factor X inhibitory action and does not exhibit a trypsin inhibitory action, there is no side effect caused thereby, and a preventive drug for blood coagulation disease. Alternatively, they have found that they are useful as therapeutic agents (particularly therapeutic agents), and have completed the present invention.

The present invention relates to a benzamidine derivative having an excellent activated blood coagulation factor X inhibitory activity, a pharmacologically acceptable salt thereof, a production method thereof, an intermediate useful for their synthesis, and a blood coagulation disease. And a medicament containing the benzamidine derivative, which is useful as a prophylactic or therapeutic agent for the above.

[0008]

The compound of the present invention has the general formula (1)

[0009]

Embedded image Or a pharmacologically acceptable salt thereof and a prodrug thereof. In the above formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group having 1 to 6 carbon atoms, R ² represents a hydrogen atom or a halogen atom, and R ³ represents a hydrogen atom, a carbon atom having 1 carbon atom. To 6 alkyl groups, hydroxyl-substituted alkyl group having 1 to 6 carbon atoms, carboxyalkyl group having 2 to 7 carbon atoms, alkoxycarbonylalkyl group having 3 to 13 carbon atoms, alkyl having 1 to 6 carbon atoms A sulfonyl 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, wherein R ⁴ and R ⁵ are the same Or differently, 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 , Carboxyl group, having 2 to 7 alkoxycarbonyl group having a carbon indicates a carbamoyl group, a 2 to 7 carbon atoms mono-alkylcarbamoyl group, or having 3 to 13 amino dialkylcarbamoyl group having a carbon, 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, and 7 carbon atoms
To 16 aralkyl groups, an alkyl group having 1 to 6 carbon atoms substituted with a heterocycle, a carboxyalkyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms, 7 aliphatic acyl groups, aromatic acyl groups having 7 to 11 carbon atoms, carbamoyl groups, alkylsulfonyl groups having 1 to 6 carbon atoms, aryl groups having 6 to 10 carbon atoms, heterocycles, formimidoyl A 1-iminoalkyl group having 3 to 7 carbon atoms, an N-alkylformimidoyl group having 2 to 7 carbon atoms or an iminoarylmethyl group having 7 to 11 carbon atoms,
R ⁷ and R ^{8 each} represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ⁶ and R ⁷ together or R ⁷
And R ⁸ together represent an alkylene group having 2 to 5 carbon atoms, and n represents 0, 1 or 2.

[0010] As the "halogen atom" of R ^1, 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, bromine An atom, a chlorine atom or a fluorine atom, particularly preferably a fluorine atom, and R ² is preferably a bromine atom, a fluorine atom or a chlorine atom, particularly preferably a fluorine atom, R ⁴ and R ⁵ are a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.

Examples of the “alkyl group having 1 to 6 carbon atoms” for R ¹ , 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 group and the like, R ¹ is preferably a methyl group, and R ³ is preferably a methyl, ethyl or isopropyl group. Particularly preferred is an isopropyl group, for R ⁴ and R ⁵ , preferably a methyl group, and for R ⁶ , preferably a methyl, ethyl, isopropyl or butyl group, particularly preferably , A methyl, ethyl or isopropyl group, for R ⁷ is preferably a methyl group, and for R ⁸ it is preferably a methyl group.

The alkyl moiety of the “C 1 to C 6 hydroxyl-substituted alkyl group” for R ³ is the same as the above-mentioned “C 1 to C 6 alkyl group”. Is a group in which the alkyl moiety has 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 It is.

The alkyl portion of the “C2 to C7 carboxyalkyl group” for R ³ is the same as that described above for the “C1 to C6 alkyl group”. The alkyl moiety is one to three, more preferably a methyl group, and a preferable “carboxyalkyl group having 2 to 7 carbon atoms” 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” for R ³ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. The same may be mentioned, and the alkyl moiety preferably has 1 to 4 carbon atoms, and the preferred "alkoxycarbonylalkyl group having 3 to 13 carbon atoms" includes a methoxycarbonylmethyl group and an ethoxy group. They are a carbonylmethyl group, a propoxycarbonylmethyl group and a butoxycarbonylmethyl group, more preferably a methoxycarbonylmethyl group and an ethoxycarbonylmethyl group, and particularly preferably an ethoxycarbonylmethyl group.

The alkyl moiety of the “C 2-7 carboxyalkylsulfonyl group” for R ³ is the above “C 1 -C 1 carboxyalkylsulfonyl group”.
And the same as those described in the section "6 to 6 alkyl groups". Preferably, the alkyl moiety is a group having 1 to 4 carbon atoms, more preferably a methyl group, The “carboxyalkylsulfonyl group having 2 to 7 carbon atoms” is a carboxymethanesulfonyl group.

The alkyl portion of the “alkylsulfonyl group having 1 to 6 carbon atoms” for R ³ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. The alkyl moiety has 1 to 4 carbon atoms, more preferably an ethyl group, and a preferable "alkylsulfonyl group having 1 to 6 carbon atoms" 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” for R ³ is the same as the above “1 carbon atom”.
And the same as those described in "1 to 6 alkyl groups". Preferably, the alkyl moiety has 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms. The preferred “alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms” is an ethoxycarbonylmethanesulfonyl group.

The alkyl moiety of the “C ³ -C 8 carboxyalkylcarbonyl group” for R ³ is the above “C 1 -C 1 carboxyalkylcarbonyl group”.
And alkyl groups having 1 to 4 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 alkyl group. A preferred "carboxyalkylcarbonyl group having 3 to 8 carbon atoms" is a carboxyacetyl group.

The alkyl moiety of the “halogen-substituted alkyl group having 1 to 6 carbon atoms” for R ⁴ and R ⁵ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. Preferably, 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 portion of the “alkoxy group having 1 to 6 carbon atoms” for R ⁴ and R ⁵ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. Has an alkyl moiety having 1 to 4 carbon atoms, more preferably having 1 carbon atom, and a preferable “alkoxy group having 1 to 6 carbon atoms” includes a methoxy group It is.

The alkyl portion of the “alkoxycarbonyl group having 2 to 7 carbon atoms” for R ⁴ and R ⁵ includes the same as those described above for the “alkyl group having 1 to 6 carbon atoms”. Preferably, the alkyl moiety has 1 to 2 carbon atoms, and a preferred "alkoxycarbonyl group having 2 to 7 carbon atoms" is an ethoxycarbonyl group.

The alkyl moiety of the “C 2 to C 7 monoalkylcarbamoyl group” for R ⁴ and R ⁵ is the same as the above-mentioned “C 1 to C 6 alkyl group”. Preferably, the alkyl moiety has 1 to 2 carbon atoms.
The preferred “monoalkylcarbamoyl group having 2 to 7 carbon atoms” is an N-methylcarbamoyl group.

Examples of the alkyl portion of the “dialkylcarbamoyl group having 3 to 13 carbon atoms” for R ⁴ and R ⁵ are the same as those described above for the “alkyl group having 1 to 6 carbon atoms”. Preferably, the alkyl moiety has 1 to 2 carbon atoms.
The preferred “dialkylcarbamoyl group having 3 to 13 carbon atoms” is an N, N-dimethylcarbamoyl group.

The "cyclic alkyl group having 3 to 8 carbon atoms" for R ⁶ includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. is there.

The "aralkyl group having 7 to 16 carbon atoms" for R ⁶ includes, for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl group and the like.
Preferably, it is a benzyl or phenethyl group.

The alkyl part of the “heterocyclic-substituted alkyl group having 1 to 6 carbon atoms” for R ⁶ is the above-mentioned “C 1 -C 1 alkyl group”.
And the same as the ones mentioned in the above “6 to 6 alkyl groups”. Preferably, the alkyl moiety has 1 to 2 carbon atoms, and the heterocyclic moiety has a sulfur atom, an oxygen atom or / And a 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3
Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, aromatic heterocyclic groups such as pyrazinyl and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidyl And a partially or completely reduced group corresponding to the group of. Preferably, the group contains at least one nitrogen atom and may contain an oxygen atom or a sulfur atom.
To 7-membered heterocyclic groups, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
Aromatic heterocyclic groups such as pyrazinyl and morpholinyl,
Partial or fully reduced groups corresponding to these groups such as thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl (for example,
4,5-dihydro-3H-pyrrol-2-yl, 2,
3,4,5-tetrahydropyridin-6-yl, 4,5
-Dihydrooxazol-2-yl, 5,6-dihydro-2H- [1,4] thiazin-3-yl);
The “5- to 7-membered heterocyclic group” may be condensed with another cyclic group, for example, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, indolyl, Indazolyl,
Purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl,
Examples include groups such as isoindolinyl, and preferably,
A pyridyl group, and a preferable “alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic ring” is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl group or 2- (2-pyridyl) Ethyl, 2- (3-pyridyl)
An ethyl or 2- (4-pyridyl) ethyl group.

The alkyl moiety of the “C2 to C7 carboxyalkyl group” for R ⁶ includes the same as those described above for the “C1 to C6 alkyl group”. The alkyl moiety has 1 to 2 carbon atoms, and a preferable "carboxyalkyl group having 2 to 7 carbon atoms" is a carboxymethyl group.

The alkyl moiety of the “alkoxycarbonylalkyl group having 3 to 13 carbon atoms” for R ⁶ is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. Represents an alkyl moiety having 1 to 2 carbon atoms
The preferred “alkoxycarbonylalkyl group having 3 to 13 carbon atoms” is a methoxycarbonylmethyl group.

As the "aliphatic acyl group having 2 to 7 carbon atoms" for R ⁶ , for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl and the like can be mentioned. Is an acetyl group.

The "aromatic acyl group having 7 to 11 carbon atoms" for R ⁶ includes, for example, benzoyl, 1-naphthylcarbonyl, 2-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 is the same as the above-mentioned “alkyl group having 1 to 6 carbon atoms”. The alkyl moiety has 1 to 2 carbon atoms, and a preferable "alkylsulfonyl group having 1 to 6 carbon atoms" is a methanesulfonyl group.

R ⁶ "Aryl group having 6 to 10 carbon atoms"
Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl and the like, and a phenyl group is preferable.

As the "heterocycle" for R ⁶ , those similar to the above-mentioned "heterocycle-substituted alkyl group having 1 to 6 carbon atoms" can be mentioned. Ie, 4,5-dihydro-3H-pyrrole-
2-yl (A), 2,3,4,5-tetrahydropyridin-6-yl (B), 4,5-dihydrooxazole-
2-yl (C), 5,6-dihydro-2H- [1,4]
Thiazin-3-yl (D) or 4-pyridyl group.

[0034]

Embedded image The alkyl portion of the “1-iminoalkyl group having 3 to 7 carbon atoms” of R ⁶ is the above “alkyl group having 1 to 6 carbon atoms”
The alkyl moiety is preferably one having 3 carbon atoms, and a preferable "1-iminoalkyl group having 3 to 7 carbon atoms" is 1- It is an iminopropyl group.

The alkyl part of the “N-alkylformimidoyl group having 2 to 7 carbon atoms” for R ⁶ is the above “C 1 -C 1 -alkylformimidyl group”.
And alkyl groups having 1 to 2 carbon atoms. Preferably, the alkyl moiety has 1 to 2 carbon atoms, and preferably an N-alkyl group having 2 to 7 carbon atoms. The “alkylformimidoyl group” is an N-ethylformimidoyl group.

The "iminoarylmethyl group having 7 to 11 carbon atoms" for R ⁶ includes, for example, iminophenylmethyl, iminonaphthylmethyl and the like.
It is an iminophenylmethyl group.

The “alkylene group having 2 to 5 carbon atoms” formed by combining R ⁶ and R ⁷ or combining R ⁷ and R ⁸ includes, for example, ethylene, trimethylene, Tetramethylene, pentamethylene group and the like, preferably,
An ethylene or trimethylene group.

N is preferably 1.

[0039]

Among the compounds of the present invention, preferred compounds include the following. (1) a compound wherein R ¹ is a hydrogen atom or a hydroxyl group,

(2) a compound wherein R ² is a hydrogen atom,

(3) a compound wherein R ³ is an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms or a carboxyalkylsulfonyl group having 2 to 7 carbon atoms;

(4) a compound wherein R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group;

(5) R ⁴ and R ⁵ are the same or different,
A compound which is 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 carbamoyl group;

(6) R ⁴ and R ⁵ are the same or different,
A compound which is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group,

(7) 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 carbon atom substituted with a heterocyclic ring. 6 to 6 alkyl groups, 6 to 10 carbon atom aryl groups, heterocyclic ring, formimidoyl group, 3 to 7 carbon atoms
A 1-iminoalkyl group, an iminoarylmethyl group having 7 to 11 carbon atoms or a N-alkylformimidoyl group having 2 to 7 carbon atoms,

(8) R ⁶ is methyl, ethyl or isopropyl, cyclopentyl, benzyl or phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, -(3
-Pyridyl) ethyl or 2- (4-pyridyl) ethyl group, phenyl group, 4,5-dihydro-3H-pyrrole-
2-yl, 2,3,4,5-tetrahydropyridine-6
-Yl, 4,5-dihydrooxazol-2-yl,
Compounds which are 5,6-dihydro-2H- [1,4] thiazin-3-yl or 4-pyridyl groups, formimidoyl groups, 1-iminopropyl groups, iminophenylmethyl groups or N-ethylformimidoyl groups ,

(9) compounds wherein R ⁷ and R ⁸ are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

(10) R ⁶ and R ⁷ are taken together, or
A compound wherein R ⁷ and R ⁸ together are an alkylene group having 2 to 5 carbon atoms,

(11) R ⁶ and R ⁷ are taken together, or
A compound wherein R ⁷ and R ⁸ together are an ethylene or trimethylene group,

(12) Compounds wherein n is 1 can be mentioned, and combinations thereof, for example, (1)
(2), (3), (5), (7), (9) and (12)
, (1), (2), (4), (6),
Combinations of (8), (9) and (12), etc.
It is suitable.

"Pharmacologically acceptable salt" means the compound (1) of the present invention, which can be converted into a salt, and the salt is preferred. Alkali metal salts such as potassium salts, lithium salts,
Metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts; Dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, Amine salts such as chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, organic salts such as tris (hydroxymethyl) aminomethane salts; hydrofluoric acid salts, hydrochloride salts , Hydrobromide, hydrogen iodide Hydrohalides, such as acid salts
Inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; methanesulfonate, trifluoromethanesulfonate,
Lower alkane sulfonates such as ethane sulfonate, benzene sulfonates, aryl sulfonates such as p-toluene sulfonate, acetic acid, malic acid, fumarate, succinate, citrate And organic acid salts such as tartrate, oxalate, maleic acid and trifluoroacetate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate and aspartate. .

When the compound (1) of the present invention is left in the air, it may absorb water and may absorb adsorbed water or form hydrates. Included in the invention.

Further, the compound (1) of the present invention may absorb some other solvent to form a solvate, and such salts are also included in the present invention.

The “prodrug” means that the compound (1) of the present invention may have a hydroxyl group, an amino group, an amidino group or a carboxyl group, in which case the group is chemically or in vivo. A group protected by a group that can be biochemically cleaved. As a group forming a prodrug, in the case of a hydroxyl group, an amino group or an amidino group, a “protecting group in a reaction” that can be cleaved by a chemical method. And "a protecting group that can be cleaved in vivo by a biological method such as hydrolysis". Examples of the "protecting group in the reaction" include formyl, acetyl, propionyl, butyryl, isobutyryl, and pentanoyl. , Pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyl Kutanoiru, 3,7-dimethyl octanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methyl pentadecanoyl, 14-
Alkylcarbonyl groups such as methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and henicosanoyl, succinoyl,
Glutaroyl, carboxylated alkylcarbonyl groups such as adipoyl, chloroacetyl, dichloroacetyl,
Trichloroacetyl, a halogeno lower alkylcarbonyl group such as trifluoroacetyl, a lower alkoxy lower alkylcarbonyl group such as methoxyacetyl,
(E) an “aliphatic acyl group” such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl; an arylcarbonyl group such as benzoyl, α-naphthoyl and β-naphthoyl; 2-bromobenzoyl; A halogenoarylcarbonyl group such as chlorobenzoyl, 2,
Lower-alkylated arylcarbonyl groups such as 4,6-trimethylbenzoyl and 4-toluoyl; lower-alkoxylated arylcarbonyl groups such as 4-anisoyl;
-Carboxybenzoyl, 3-carboxybenzoyl,
Carboxylated arylcarbonyl groups such as 4-carboxybenzoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, 2-
“Aromatic acyl groups” such as lower alkoxycarbonylated arylcarbonyl groups such as (methoxycarbonyl) benzoyl and arylated arylcarbonyl groups such as 4-phenylbenzoyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran- "Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2
“Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as -yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, "Silyl groups such as tri-lower alkylsilyl groups such as isopropylsilyl, and tri-lower alkylsilyl groups substituted with one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl. ";
Lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylation such as 2-methoxyethoxymethyl Lower alkoxymethyl group,
"Alkoxymethyl group" such as halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; lower alkoxy such as 1-ethoxyethyl and 1- (isopropoxy) ethyl "Substituted ethyl group" such as ethyl halide, ethyl halide such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenyl Methyl, lower alkyl group substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,
5-trimethylbenzyl, 4-methoxybenzyl, 4-
Lower alkyl such as methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, piperonyl, lower alkoxy, halogen,
An “aralkyl group” such as a lower alkyl group substituted with one to three aryl groups in which an aryl ring is substituted with a cyano group; methoxycarbonyl, ethoxycarbonyl, t-
A lower alkoxycarbonyl group such as butoxycarbonyl and isobutoxycarbonyl, and a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl. "Alkoxycarbonyl group";"alkenyloxycarbonylgroup" such as vinyloxycarbonyl and allyloxycarbonyl; phenoxycarbonyl, 4-methoxyphenoxycarbonyl, 3,4-dimethoxyphenoxycarbonyl, 2-nitrophenoxycarbonyl, 4-nitrophenoxycarbonyl , An aryl ring in which the aryl ring may be substituted with one or two lower alkoxy, nitro group or halogen atom such as 4-fluorophenoxycarbonyl Carbonyl group "; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,
An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Can be mentioned,

On the other hand, examples of the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" include, for example, ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl, 1-acetoxy. Acyloxyalkyl groups such as ethyl; 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl,
1- (t-butoxycarbonyloxy) ethyl, 1-
1- such as (ethoxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) ethyl
(Alkoxycarbonyloxy) alkyl group; phthalidyl group; 4-methyl-oxodioxolenylmethyl, 4-
A "carbonyloxyalkyl group" such as an oxodioxorenylmethyl group such as phenyl-oxodioxorenylmethyl and oxodioxorenylmethyl; the above "aliphatic acyl group"; the above "aromatic acyl group";"Half ester salt residue of succinic acid";"phosphateresidue";"ester forming residue such as amino acid"; carbamoyl group; carbamoyl group substituted by one or two lower alkyl groups; Examples include "carbonyloxyalkyloxycarbonyl group" such as baroyloxymethyloxycarbonyl. Whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice, and Can be determined by examining the bodily fluid of the original compound or a pharmacologically acceptable salt thereof can be detected, preferably acetyl It is in,

In the case of an amino group or an amidino group, they can be used without any particular limitation, but are preferably, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, Alkylcarbonyl groups such as palmitoyl and stearoyl; halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl; (E) -2-methyl Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as -2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl; 2-bromobenzoyl;
A halogenoarylcarbonyl group such as 4-chlorobenzoyl, a lower alkylated arylcarbonyl group such as 2,4,6-trimethylbenzoyl, 4-toluoyl,
A lower alkoxylated arylcarbonyl group such as 4-anisoyl, a nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl, a lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, 4 Aromatic acyl groups such as arylated arylcarbonyl groups such as -phenylbenzoyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, An alkoxycarbonyl group such as a halogen or a lower alkoxycarbonyl group substituted with a tri-lower alkylsilyl group such as 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl,
An alkenyloxycarbonyl group such as allyloxycarbonyl or 1 such as phenoxycarbonyl, 4-methoxyphenoxycarbonyl, 3,4-dimethoxyphenoxycarbonyl, 2-nitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-fluorophenoxycarbonyl And two or more aryloxycarbonyl groups in which the aryl ring may be substituted with a lower alkoxy, nitro group or a halogen atom, preferably an ethoxycarbonyl group or a 1- (propionyloxy) ethoxycarbonyl group A 4-methoxyphenoxycarbonyl group or a 4-fluorophenoxycarbonyl group,

In the case of a carboxyl group, "a protecting group which can be cleaved in vivo by a biological method such as hydrolysis"
And "protecting group in the reaction" that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
And such "protecting group in the reaction" is preferably methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, s-butyl, tert-butyl,
n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,
-Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl "Lower alkyl groups", such as, 2-ethylbutyl; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1
-Methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-
2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1- Ethyl-3-butenyl, 1-pentenyl,
2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-
3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-
4-pentenyl, 1-hexenyl, 2-hexenyl, 3
"Alkenyl groups" such as -hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-
Methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-
Methyl-2-butynyl, 2-methyl-2-butynyl, 1
-Ethyl-2-butynyl, 3-butynyl, 1-methyl-
3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3- Pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3
"Alkynyl groups" such as -hexynyl, 4-hexynyl, 5-hexynyl; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2 , 2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl,
"Halogeno lower alkyl group" such as 6-iodohexyl, 2,2-dibromoethyl; 2-hydroxyethyl,
Hydroxy "lower alkyl group" such as 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl; "aliphatic acyl" such as acetylmethyl- "lower alkyl group";
Benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-
"Lower alkyl group" substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-
Nitrophenyl) methyl, piperonyl, lower alkyl such as 4-methoxycarbonylbenzyl, lower alkoxy, nitro, halogen, cyano, lower alkyl substituted with one to three aryl groups substituted with an aryl ring with an alkoxycarbonyl group "Aralkyl group" such as a group; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropyl "Silyl group" such as silyl,

The “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” refers to an ester that is hydrolyzed or the like in a human body to form a free acid or a salt thereof.

Examples of the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” include methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl , 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1
-Dimethyl-1-methoxymethyl, ethoxymethyl, n
-Propoxymethyl, isopropoxymethyl, n-butoxymethyl, lower alkoxy lower alkyl groups such as tert-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl,
“Aryl” oxy “lower alkyl” such as phenoxymethyl, 2,2,2-trichloroethoxymethyl,
“Alkoxy lower alkyl group” such as halogenated lower alkoxy lower alkyl group such as bis (2-chloroethoxy) methyl: “lower alkoxy” carbonyl “lower alkyl group” such as methoxycarbonylmethyl; cyanomethyl, 2-cyanoethyl "Lower alkyl" thiomethyl groups such as cyano "lower alkyl groups"; methylthiomethyl, ethylthiomethyl; phenylthiomethyl;
An "aryl" thiomethyl group such as naphthylthiomethyl; a "lower alkyl" sulfonyl "lower alkyl group" which may be substituted with halogen such as 2-methanesulfonylethyl, 2-trifluoromethanesulfonylethyl;
"Aryl" sulfonyl "lower alkyl group" such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl; formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl , Isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1
-Pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryl Oxyethyl, 2-pivaloyloxyethyl, 2-
Valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-
Pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-
Pivaloyloxybutyl, 1-acetoxypentyl, 1
-"Aliphatic acyl" oxy "lower alkyl group" such as propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl, cyclopentanoyloxymethyl, cyclohexa Noyloxymethyl, 1-cyclopentanoyloxyethyl, 1-cyclohexanoyloxyethyl, 1-cyclopentanoyloxypropyl, 1-cyclohexanoyloxypropyl, 1-cyclopentanoyloxybutyl, 1-cyclohexanoyloxy Acyloxy "lower alkyl group" such as "cycloalkyl" carbonyloxy "lower alkyl group" such as butyl, "aromatic acyl" oxy "lower alkyl group" such as benzoyloxymethyl; methoxycarbonyloxymethyl, ethoxycarbonyl Xymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl , 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-propoxycarbonyloxyethyl, 1- (isopropoxycarbonyloxy) ethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl , 1- (tert-butoxycarbonyloxy) ethyl,
1-pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxypropyl, 1-cyclohexyloxycarbonyloxypropyl, 1-cyclopentyloxycarbonyloxybutyl, Cyclohexyloxycarbonyloxybutyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl, 2-propoxycarbonyloxyethyl, 2-isopropoxy Carbonyloxyethyl, 2-butoxycarbonyloxyethyl, 2-isobutoxycarbonyloxyethyl,
2-pentyloxycarbonyloxyethyl, 2-hexyloxycarbonyloxyethyl, 1-methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl,
1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl, 1-pentyloxycarbonyloxypropyl, 1-hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl,
-Ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl, 1-butoxycarbonyloxybutyl,
(Alkoxycarbonyloxy) alkyl groups such as 1-isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl, 1-ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl, 1-ethoxycarbonyloxyhexyl; (5-phenyl -2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5-
(4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [ 5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-
Oxo-1,3-dioxolen-4-yl) methyl,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl, (5-ethyl-2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-propyl-2)
-Oxo-1,3-dioxolen-4-yl) methyl,
(5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-)
"Carbonyloxyalkyl group" such as oxodioxorenylmethyl group such as 1,3-dioxolen-4-yl) methyl: "phthalidyl group" such as phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl: phenyl, indanyl "Aryl group" such as: "alkyl group": "carboxyalkyl group" such as carboxymethyl; and "amide-forming residue of amino acid" such as phenylalanine. Whether or not can be administered by intravenous injection to an experimental animal such as a rat or a mouse, and then examine the body fluid of the animal, and determine whether the original compound or a pharmacologically acceptable salt thereof can be detected. Is an ethyl group.

Table 1 shows specific examples of the compounds of the present invention. In ellipsis points in Table 1, Et represents an ethyl group, -MS represents the -CH ₂ SO ₂ group, Ph represents phenyl group, Pyr represents a pyridyl group, Pyrm is pyrimidinyl Represents a group, cPn represents a cyclopentyl group, and-(CH ₂ ) ₃
-(5) indicates that R ⁶ and R ⁷ together form a trimethylene group, and the ring containing them is a 5-membered ring,
C ₃ H ₄ NO represents a 4,5-dihydrooxazol-2-yl group, and C ₄ H ₆ N represents 4,5-dihydro-3H-pyrrole-
It indicates 2-yl group, C ₃ H ₄ NS denotes the 4,5-dihydro-2-yl group, a C ₅ H ₈ N is 2,3,4,5-tetrahydropyridin-6-yl group And C ₆ H ₁₀ N is 3,
Represents a 4,5,6-tetrahydro-2H-azepin-7-yl group, and C ₄ H ₆ NS represents 5,6-dihydro-2H- [1,
4] represents a thiazin-3-yl group, and C ₅ F ₄ N represents 2,3,
Represents a 5,6-tetrafluoropyridin-4-yl group,
H (CH ₃ CH ₂ N) C indicates an N-ethylformimidoyl group, and-(CH ₂ ) ₂ -indicates that the 2-position R ⁷ and 6-position R ⁸ together form an ethylene group. And C ₈ H ₁₄ N is 3, 4, 5,
It represents a 6,7,8-hexahydro-2H-azonin-9-yl group.

[0062]

[Table 1]

[0063]

Embedded image -------------------------------------------------- --------------------- No. R ¹ R ^Two R ^Three R ^Four R ^Five R ⁶ R ⁷ R ⁸ n ------------------------------------------------- ---------------------- 1 HH EtOOC-MS 3-Cl H CH _Three HH 1 2 HH EtOOC-MS 3-Cl H CH _Three CH _Two HH 1 3 HH EtOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 1 4 HH EtOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 15 HH EtOOC-MS 3-Cl H PhCH _Two HH 16 HH EtOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 17 HH EtOOC-MS 3-Cl H Ph HH 18 HH EtOOC-MS 3-Cl H CH _Three OCOCH _Two HH 19 HH EtOOC-MS 3-Cl H CH _Three CO HH 1 10 HH EtOOC-MS 3-Cl HH _Two NCO HH 1 11 HH EtOOC-MS 3-Cl H CH _Three SO _Two HH 1 12 HH EtOOC-MS 3-Cl H 2-Pyr HH 1 13 HH EtOOC-MS 3-Cl H 3-Pyr HH 1 14 HH EtOOC-MS 3-Cl H 4-Pyr HH 1 15 HH EtOOC-MS 3 -Cl H 2-Pyrm HH 1 16 HH EtOOC-MS 3-Cl H Pyr-3-CH _Two HH 117 HH EtOOC-MS 3-Cl H Pyr-4-CH _Two HH 1 18 HH EtOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 1 19 HH EtOOC-MS 3-Cl H cPn HH 1 20 HH EtOOC-MS 3-Cl H CH _Three 2-CH _Three H 1 21 HH EtOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 122 HH EtOOC-MS 3-Cl HH (NH) CHH 123 HH EtOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 1 24 HH EtOOC-MS 3-Cl H Ph (NH) CHH 1 25 HH EtOOC-MS 3-Cl HC _Four H ₆ NHH 1 26 HH EtOOC-MS 3-Cl HC _Five H ₈ NHH 1 27 HH EtOOC-MS 3-Cl HC ₆ H _Ten NHH 1 28 HH EtOOC-MS 3-Cl HC _Four H ₆ NS HH 1 29 HH EtOOC-MS 3-CH _Three H CH _Three HH 1 30 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two HH 1 31 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 1 32 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 133 HH EtOOC-MS 3-CH _Three H PhCH _Two HH 1 34 HH EtOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 1 35 HH EtOOC-MS 3-CH _Three H Ph HH 1 36 HH EtOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 1 37 HH EtOOC-MS 3-CH _Three H CH _Three CO HH 1 38 HH EtOOC-MS 3-CH _Three HH _Two NCO HH 1 39 HH EtOOC-MS 3-CH _Three H CH _Three SO _Two HH 1 40 HH EtOOC-MS 3-CH _Three H 2-Pyr HH 1 41 HH EtOOC-MS 3-CH _Three H 3-Pyr HH 1 42 HH EtOOC-MS 3-CH _Three H 4-Pyr HH 1 43 HH EtOOC-MS 3-CH _Three H 2-Pyrm HH 144 HH EtOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 1 45 HH EtOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 1 46 HH EtOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 1 47 HH EtOOC-MS 3-CH _Three H cPn HH 1 48 HH EtOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 1 49 HH EtOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 1 50 HH EtOOC-MS 3-CH _Three HH (NH) CHH 1 51 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 1 52 HH EtOOC-MS 3-CH _Three H Ph (NH) CHH 1 53 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NHH 1 54 HH EtOOC-MS 3-CH _Three HC _Five H ₈ NHH 1 55 HH EtOOC-MS 3-CH _Three HC ₆ H _Ten NHH 1 56 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NS HH 1 57 HH EtOOC-MS HH CH _Three HH 1 58 HH EtOOC-MS HH CH _Three CH _Two HH 1 59 HH EtOOC-MS HH CH _Three (CH _Three ) CH HH 1 60 HH EtOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 1 61 HH EtOOC-MS HH PhCH _Two HH 1 62 HH EtOOC-MS HH Ph (CH _Two ) _Two HH 163 HH EtOOC-MS HH Ph HH 164 HH EtOOC-MS HH CH _Three OCOCH _Two HH 1 65 HH EtOOC-MS HH CH _Three CO HH 1 66 HH EtOOC-MS HHH _Two NCO HH 1 67 HH EtOOC-MS HH CH _Three SO _Two HH 168 HH EtOOC-MS HH 2-Pyr HH 169 HH EtOOC-MS HH 3-Pyr HH 170 HH EtOOC-MS HH 4-Pyr HH 171 HH EtOOC-MS HH 2-Pyrm HH 172 HH EtOOC- MS HH Pyr-3-CH _Two HH 1 73 HH EtOOC-MS HH Pyr-4-CH _Two HH 1 74 HH EtOOC-MS HH Pyr-2- (CH _Two ) _Two HH 1 75 HH EtOOC-MS HH cPn HH 1 76 HH EtOOC-MS HH CH _Three 2-CH _Three H 1 77 HH EtOOC-MS HH-(CH _Two ) _Three -(5)-H 1 78 HH EtOOC-MS HHH (NH) CHH 1 79 HH EtOOC-MS HH CH _Three CH _Two (NH) CHH 1 80 HH EtOOC-MS HH Ph (NH) CHH 1 81 HH EtOOC-MS HHC _Four H ₆ NHH 1 82 HH EtOOC-MS HHC _Five H ₈ NHH 183 HH EtOOC-MS HHC ₆ H _Ten NHH 1 84 HH EtOOC-MS HHC _Four H ₆ NS HH 1 85 HH EtOOC-MS 3-CF _Three H CH _Three HH 186 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two HH 1 87 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 1 88 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 1 89 HH EtOOC-MS 3-CF _Three H PhCH _Two HH 1 90 HH EtOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 191 HH EtOOC-MS 3-CF _Three H Ph HH 1 92 HH EtOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 1 93 HH EtOOC-MS 3-CF _Three H CH _Three CO HH 1 94 HH EtOOC-MS 3-CF _Three HH _Two NCO HH 1 95 HH EtOOC-MS 3-CF _Three H CH _Three SO _Two HH 1 96 HH EtOOC-MS 3-CF _Three H 2-Pyr HH 1 97 HH EtOOC-MS 3-CF _Three H 3-Pyr HH 1 98 HH EtOOC-MS 3-CF _Three H 4-Pyr HH 1 99 HH EtOOC-MS 3-CF _Three H 2-Pyrm HH 1 100 HH EtOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 1 101 HH EtOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 1 102 HH EtOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 1 103 HH EtOOC-MS 3-CF _Three H cPn HH 1 104 HH EtOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 1 105 HH EtOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 1 106 HH EtOOC-MS 3-CF _Three HH (NH) CHH 1 107 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 1 108 HH EtOOC-MS 3-CF _Three H Ph (NH) CHH 1 109 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NHH 1 110 HH EtOOC-MS 3-CF _Three HC _Five H ₈ NHH 1 111 HH EtOOC-MS 3-CF _Three HC ₆ H _Ten NHH 1 112 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NS HH 1 113 HH EtOOC-MS 3-H _Two NCO H CH _Three HH 1 114 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 1 115 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 1 116 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 1 117 HH EtOOC-MS 3-H _Two NCO H PhCH _Two HH 1 118 HH EtOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 1 119 HH EtOOC-MS 3-H _Two NCO H Ph HH 1 120 HH EtOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 1 121 HH EtOOC-MS 3-H _Two NCO H CH _Three CO HH 1 122 HH EtOOC-MS 3-H _Two NCO HH _Two NCO HH 1 123 HH EtOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 1 124 HH EtOOC-MS 3-H _Two NCO H 2-Pyr HH 1 125 HH EtOOC-MS 3-H _Two NCO H 3-Pyr HH 1 126 HH EtOOC-MS 3-H _Two NCO H 4-Pyr HH 1 127 HH EtOOC-MS 3-H _Two NCO H 2-Pyrm HH 1 128 HH EtOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 1 129 HH EtOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 1 130 HH EtOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 1 131 HH EtOOC-MS 3-H _Two NCO H cPn HH 1 132 HH EtOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 1 133 HH EtOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 1 134 HH EtOOC-MS 3-H _Two NCO HH (NH) CHH 1 135 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 1 136 HH EtOOC-MS 3-H _Two NCO H Ph (NH) CHH 1 137 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 1 138 HH EtOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 1 139 HH EtOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 1 140 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 1 141 HH EtOOC-MS 3-FH CH _Three HH 1 142 HH EtOOC-MS 3-FH CH _Three CH _Two HH 1 143 HH EtOOC-MS 3-FH CH _Three (CH _Three ) CH HH 1 144 HH EtOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 1 145 HH EtOOC-MS 3-FH PhCH _Two HH 1 146 HH EtOOC-MS 3-FH Ph (CH _Two ) _Two HH 1 147 HH EtOOC-MS 3-FH Ph HH 1 148 HH EtOOC-MS 3-FH CH _Three OCOCH _Two HH 1 149 HH EtOOC-MS 3-FH CH _Three CO HH 1 150 HH EtOOC-MS 3-FHH _Two NCO HH 1 151 HH EtOOC-MS 3-FH CH _Three SO _Two HH 1 152 HH EtOOC-MS 3-FH 2-Pyr HH 1 153 HH EtOOC-MS 3-FH 3-Pyr HH 1 154 HH EtOOC-MS 3-FH 4-Pyr HH 1 155 HH EtOOC-MS 3-FH 2 -Pyrm HH 1 156 HH EtOOC-MS 3-FH Pyr-3-CH _Two HH 1 157 HH EtOOC-MS 3-FH Pyr-4-CH _Two HH 1 158 HH EtOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 1 159 HH EtOOC-MS 3-FH cPn HH 1 160 HH EtOOC-MS 3-FH CH _Three 2-CH _Three H 1 161 HH EtOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 1 162 HH EtOOC-MS 3-FHH (NH) CHH 1 163 HH EtOOC-MS 3-FH CH _Three CH _Two (NH) CHH 1 164 HH EtOOC-MS 3-FH Ph (NH) CHH 1 165 HH EtOOC-MS 3-FHC _Four H ₆ NHH 1 166 HH EtOOC-MS 3-FHC _Five H ₈ NHH 1 167 HH EtOOC-MS 3-FHC ₆ H _Ten NHH 1 168 HH EtOOC-MS 3-FHC _Four H ₆ NS HH 1 169 HH EtOOC-MS 3-Cl H CH _Three HH 0 170 HH EtOOC-MS 3-Cl H CH _Three CH _Two HH 0 171 HH EtOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 0 172 HH EtOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 0 173 HH EtOOC-MS 3-Cl H PhCH _Two HH 0 174 HH EtOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 0 175 HH EtOOC-MS 3-Cl H Ph HH 0 176 HH EtOOC-MS 3-Cl H CH _Three OCOCH _Two HH 0 177 HH EtOOC-MS 3-Cl H CH _Three CO HH 0 178 HH EtOOC-MS 3-Cl HH _Two NCO HH 0 179 HH EtOOC-MS 3-Cl H CH _Three SO _Two HH 0 180 HH EtOOC-MS 3-Cl H 2-Pyr HH 0 181 HH EtOOC-MS 3-Cl H 3-Pyr HH 0 182 HH EtOOC-MS 3-Cl H 4-Pyr HH 0 183 HH EtOOC-MS 3 -Cl H 2-Pyrm HH 0 184 HH EtOOC-MS 3-Cl H Pyr-3-CH _Two HH 0 185 HH EtOOC-MS 3-Cl H Pyr-4-CH _Two HH 0 186 HH EtOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 0 187 HH EtOOC-MS 3-Cl H cPn HH 0 188 HH EtOOC-MS 3-Cl H CH _Three 2-CH _Three H 0 189 HH EtOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 0 190 HH EtOOC-MS 3-Cl HH (NH) CHH 0 191 HH EtOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 0 192 HH EtOOC-MS 3-Cl H Ph (NH) CHH 0 193 HH EtOOC-MS 3-Cl HC _Four H ₆ NHH 0 194 HH EtOOC-MS 3-Cl HC _Five H ₈ NHH 0 195 HH EtOOC-MS 3-Cl HC ₆ H _Ten NHH 0 196 HH EtOOC-MS 3-Cl HC _Four H ₆ NS HH 0 197 HH EtOOC-MS 3-CH _Three H CH _Three HH 0 198 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two HH 0 199 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 0 200 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 0 201 HH EtOOC-MS 3-CH _Three H PhCH _Two HH 0 202 HH EtOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 0 203 HH EtOOC-MS 3-CH _Three H Ph HH 0 204 HH EtOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 0 205 HH EtOOC-MS 3-CH _Three H CH _Three CO HH 0 206 HH EtOOC-MS 3-CH _Three HH _Two NCO HH 0 207 HH EtOOC-MS 3-CH _Three H CH _Three SO _Two HH 0 208 HH EtOOC-MS 3-CH _Three H 2-Pyr HH 0 209 HH EtOOC-MS 3-CH _Three H 3-Pyr HH 0 210 HH EtOOC-MS 3-CH _Three H 4-Pyr HH 0 211 HH EtOOC-MS 3-CH _Three H 2-Pyrm HH 0 212 HH EtOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 0 213 HH EtOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 0 214 HH EtOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 0 215 HH EtOOC-MS 3-CH _Three H cPn HH 0 216 HH EtOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 0 217 HH EtOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 0 218 HH EtOOC-MS 3-CH _Three HH (NH) CHH 0 219 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 0 220 HH EtOOC-MS 3-CH _Three H Ph (NH) CHH 0 221 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NHH 0 222 HH EtOOC-MS 3-CH _Three HC _Five H ₈ NHH 0 223 HH EtOOC-MS 3-CH _Three HC ₆ H _Ten NHH 0 224 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NS HH 0 225 HH EtOOC-MS HH CH _Three HH 0 226 HH EtOOC-MS HH CH _Three CH _Two HH 0 227 HH EtOOC-MS HH CH _Three (CH _Three ) CH HH 0 228 HH EtOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 0 229 HH EtOOC-MS HH PhCH _Two HH 0 230 HH EtOOC-MS HH Ph (CH _Two ) _Two HH 0 231 HH EtOOC-MS HH Ph HH 0 232 HH EtOOC-MS HH CH _Three OCOCH _Two HH 0 233 HH EtOOC-MS HH CH _Three CO HH 0 234 HH EtOOC-MS HHH _Two NCO HH 0 235 HH EtOOC-MS HH CH _Three SO _Two HH 0 236 HH EtOOC-MS HH 2-Pyr HH 0 237 HH EtOOC-MS HH 3-Pyr HH 0 238 HH EtOOC-MS HH 4-Pyr HH 0 239 HH EtOOC-MS HH 2-Pyrm HH 0 240 HH EtOOC- MS HH Pyr-3-CH _Two HH 0 241 HH EtOOC-MS HH Pyr-4-CH _Two HH 0 242 HH EtOOC-MS HH Pyr-2- (CH _Two ) _Two HH 0 243 HH EtOOC-MS HH cPn HH 0 244 HH EtOOC-MS HH CH _Three 2-CH _Three H 0 245 HH EtOOC-MS HH-(CH _Two ) _Three -(5)-H 0 246 HH EtOOC-MS HHH (NH) CHH 0 247 HH EtOOC-MS HH CH _Three CH _Two (NH) CHH 0 248 HH EtOOC-MS HH Ph (NH) CHH 0 249 HH EtOOC-MS HHC _Four H ₆ NHH 0 250 HH EtOOC-MS HHC _Five H ₈ NHH 0 251 HH EtOOC-MS HHC ₆ H _Ten NHH 0 252 HH EtOOC-MS HHC _Four H ₆ NS HH 0 253 HH EtOOC-MS 3-CF _Three H CH _Three HH 0 254 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two HH 0 255 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 0 256 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 0 257 HH EtOOC-MS 3-CF _Three H PhCH _Two HH 0 258 HH EtOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 0 259 HH EtOOC-MS 3-CF _Three H Ph HH 0 260 HH EtOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 0 261 HH EtOOC-MS 3-CF _Three H CH _Three CO HH 0 262 HH EtOOC-MS 3-CF _Three HH _Two NCO HH 0 263 HH EtOOC-MS 3-CF _Three H CH _Three SO _Two HH 0 264 HH EtOOC-MS 3-CF _Three H 2-Pyr HH 0 265 HH EtOOC-MS 3-CF _Three H 3-Pyr HH 0 266 HH EtOOC-MS 3-CF _Three H 4-Pyr HH 0 267 HH EtOOC-MS 3-CF _Three H 2-Pyrm HH 0 268 HH EtOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 0 269 HH EtOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 0 270 HH EtOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 0 271 HH EtOOC-MS 3-CF _Three H cPn HH 0 272 HH EtOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 0 273 HH EtOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 0 274 HH EtOOC-MS 3-CF _Three HH (NH) CHH 0 275 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 0 276 HH EtOOC-MS 3-CF _Three H Ph (NH) CHH 0 277 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NHH 0 278 HH EtOOC-MS 3-CF _Three HC _Five H ₈ NHH 0 279 HH EtOOC-MS 3-CF _Three HC ₆ H _Ten NHH 0 280 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NS HH 0 281 HH EtOOC-MS 3-H _Two NCO H CH _Three HH 0 282 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 0 283 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 0 284 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 0 285 HH EtOOC-MS 3-H _Two NCO H PhCH _Two HH 0 286 HH EtOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 0 287 HH EtOOC-MS 3-H _Two NCO H Ph HH 0 288 HH EtOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 0 289 HH EtOOC-MS 3-H _Two NCO H CH _Three CO HH 0 290 HH EtOOC-MS 3-H _Two NCO HH _Two NCO HH 0 291 HH EtOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 0 292 HH EtOOC-MS 3-H _Two NCO H 2-Pyr HH 0 293 HH EtOOC-MS 3-H _Two NCO H 3-Pyr HH 0 294 HH EtOOC-MS 3-H _Two NCO H 4-Pyr HH 0 295 HH EtOOC-MS 3-H _Two NCO H 2-Pyrm HH 0 296 HH EtOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 0 297 HH EtOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 0 298 HH EtOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 0 299 HH EtOOC-MS 3-H _Two NCO H cPn HH 0 300 HH EtOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 0 301 HH EtOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 0 302 HH EtOOC-MS 3-H _Two NCO HH (NH) CHH 0 303 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 0 304 HH EtOOC-MS 3-H _Two NCO H Ph (NH) CHH 0 305 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 0 306 HH EtOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 0 307 HH EtOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 0 308 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 0 309 HH EtOOC-MS 3-FH CH _Three HH 0 310 HH EtOOC-MS 3-FH CH _Three CH _Two HH 0 311 HH EtOOC-MS 3-FH CH _Three (CH _Three ) CH HH 0 312 HH EtOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 0 313 HH EtOOC-MS 3-FH PhCH _Two HH 0 314 HH EtOOC-MS 3-FH Ph (CH _Two ) _Two HH 0 315 HH EtOOC-MS 3-FH Ph HH 0 316 HH EtOOC-MS 3-FH CH _Three OCOCH _Two HH 0 317 HH EtOOC-MS 3-FH CH _Three CO HH 0 318 HH EtOOC-MS 3-FHH _Two NCO HH 0 319 HH EtOOC-MS 3-FH CH _Three SO _Two HH 0 320 HH EtOOC-MS 3-FH 2-Pyr HH 0 321 HH EtOOC-MS 3-FH 3-Pyr HH 0 322 HH EtOOC-MS 3-FH 4-Pyr HH 0 323 HH EtOOC-MS 3-FH 2 -Pyrm HH 0 324 HH EtOOC-MS 3-FH Pyr-3-CH _Two HH 0 325 HH EtOOC-MS 3-FH Pyr-4-CH _Two HH 0 326 HH EtOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 0 327 HH EtOOC-MS 3-FH cPn HH 0 328 HH EtOOC-MS 3-FH CH _Three 2-CH _Three H 0 329 HH EtOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 0 330 HH EtOOC-MS 3-FHH (NH) CHH 0 331 HH EtOOC-MS 3-FH CH _Three CH _Two (NH) CHH 0 332 HH EtOOC-MS 3-FH Ph (NH) CHH 0 333 HH EtOOC-MS 3-FHC _Four H ₆ NHH 0 334 HH EtOOC-MS 3-FHC _Five H ₈ NHH 0 335 HH EtOOC-MS 3-FHC ₆ H _Ten NHH 0 336 HH EtOOC-MS 3-FHC _Four H ₆ NS HH 0 337 HH EtOOC-MS 3-Cl H CH _Three HH 2 338 HH EtOOC-MS 3-Cl H CH _Three CH _Two HH 2 339 HH EtOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 2 340 HH EtOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 2 341 HH EtOOC-MS 3-Cl H PhCH _Two HH 2 342 HH EtOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 2 343 HH EtOOC-MS 3-Cl H Ph HH 2 344 HH EtOOC-MS 3-Cl H CH _Three OCOCH _Two HH 2 345 HH EtOOC-MS 3-Cl H CH _Three CO HH 2 346 HH EtOOC-MS 3-Cl HH _Two NCO HH 2 347 HH EtOOC-MS 3-Cl H CH _Three SO _Two HH 2 348 HH EtOOC-MS 3-Cl H 2-Pyr HH 2 349 HH EtOOC-MS 3-Cl H 3-Pyr HH 2 350 HH EtOOC-MS 3-Cl H 4-Pyr HH 2 351 HH EtOOC-MS 3 -Cl H 2-Pyrm HH 2 352 HH EtOOC-MS 3-Cl H Pyr-3-CH _Two HH 2 353 HH EtOOC-MS 3-Cl H Pyr-4-CH _Two HH 2 354 HH EtOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 2 355 HH EtOOC-MS 3-Cl H cPn HH 2 356 HH EtOOC-MS 3-Cl H CH _Three 2-CH _Three H 2 357 HH EtOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 2 358 HH EtOOC-MS 3-Cl HH (NH) CHH 2 359 HH EtOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 2 360 HH EtOOC-MS 3-Cl H Ph (NH) CHH 2 361 HH EtOOC-MS 3-Cl HC _Four H ₆ NHH 2 362 HH EtOOC-MS 3-Cl HC _Five H ₈ NHH 2 363 HH EtOOC-MS 3-Cl HC ₆ H _Ten NHH 2 364 HH EtOOC-MS 3-Cl HC _Four H ₆ NS HH 2 365 HH EtOOC-MS 3-CH _Three H CH _Three HH 2 366 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two HH 2 367 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 2 368 HH EtOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 2 369 HH EtOOC-MS 3-CH _Three H PhCH _Two HH 2 370 HH EtOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 2 371 HH EtOOC-MS 3-CH _Three H Ph HH 2 372 HH EtOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 2 373 HH EtOOC-MS 3-CH _Three H CH _Three CO HH 2 374 HH EtOOC-MS 3-CH _Three HH _Two NCO HH 2 375 HH EtOOC-MS 3-CH _Three H CH _Three SO _Two HH 2 376 HH EtOOC-MS 3-CH _Three H 2-Pyr HH 2 377 HH EtOOC-MS 3-CH _Three H 3-Pyr HH 2 378 HH EtOOC-MS 3-CH _Three H 4-Pyr HH 2 379 HH EtOOC-MS 3-CH _Three H 2-Pyrm HH 2 380 HH EtOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 2 381 HH EtOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 2 382 HH EtOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 2 383 HH EtOOC-MS 3-CH _Three H cPn HH 2 384 HH EtOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 2 385 HH EtOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 2 386 HH EtOOC-MS 3-CH _Three HH (NH) CHH2 387 HH EtOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 2 388 HH EtOOC-MS 3-CH _Three H Ph (NH) CHH 2 389 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NHH 2 390 HH EtOOC-MS 3-CH _Three HC _Five H ₈ NHH 2 391 HH EtOOC-MS 3-CH _Three HC ₆ H _Ten NHH 2 392 HH EtOOC-MS 3-CH _Three HC _Four H ₆ NS HH 2 393 HH EtOOC-MS HH CH _Three HH 2 394 HH EtOOC-MS HH CH _Three CH _Two HH 2 395 HH EtOOC-MS HH CH _Three (CH _Three ) CH HH 2 396 HH EtOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 2 397 HH EtOOC-MS HH PhCH _Two HH 2 398 HH EtOOC-MS HH Ph (CH _Two ) _Two HH 2 399 HH EtOOC-MS HH Ph HH 2 400 HH EtOOC-MS HH CH _Three OCOCH _Two HH 2 401 HH EtOOC-MS HH CH _Three CO HH 2 402 HH EtOOC-MS HHH _Two NCO HH 2 403 HH EtOOC-MS HH CH _Three SO _Two HH 2 404 HH EtOOC-MS HH 2-Pyr HH 2 405 HH EtOOC-MS HH 3-Pyr HH 2 406 HH EtOOC-MS HH 4-Pyr HH 2 407 HH EtOOC-MS HH 2-Pyrm HH 2 408 HH EtOOC- MS HH Pyr-3-CH _Two HH 2 409 HH EtOOC-MS HH Pyr-4-CH _Two HH 2 410 HH EtOOC-MS HH Pyr-2- (CH _Two ) _Two HH 2 411 HH EtOOC-MS HH cPn HH 2 412 HH EtOOC-MS HH CH _Three 2-CH _Three H 2 413 HH EtOOC-MS HH-(CH _Two ) _Three -(5)-H 2 414 HH EtOOC-MS HHH (NH) CHH 2 415 HH EtOOC-MS HH CH _Three CH _Two (NH) CHH 2 416 HH EtOOC-MS HH Ph (NH) CHH 2 417 HH EtOOC-MS HHC _Four H ₆ NHH 2 418 HH EtOOC-MS HHC _Five H ₈ NHH 2 419 HH EtOOC-MS HHC ₆ H _Ten NHH 2 420 HH EtOOC-MS HHC _Four H ₆ NS HH 2 421 HH EtOOC-MS 3-CF _Three H CH _Three HH 2 422 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two HH 2 423 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 2 424 HH EtOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 2 425 HH EtOOC-MS 3-CF _Three H PhCH _Two HH 2 426 HH EtOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 2 427 HH EtOOC-MS 3-CF _Three H Ph HH 2 428 HH EtOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 2 429 HH EtOOC-MS 3-CF _Three H CH _Three CO HH 2 430 HH EtOOC-MS 3-CF _Three HH _Two NCO HH 2 431 HH EtOOC-MS 3-CF _Three H CH _Three SO _Two HH 2 432 HH EtOOC-MS 3-CF _Three H 2-Pyr HH 2 433 HH EtOOC-MS 3-CF _Three H 3-Pyr HH 2 434 HH EtOOC-MS 3-CF _Three H 4-Pyr HH 2 435 HH EtOOC-MS 3-CF _Three H 2-Pyrm HH 2 436 HH EtOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 2 437 HH EtOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 2 438 HH EtOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 2 439 HH EtOOC-MS 3-CF _Three H cPn HH 2 440 HH EtOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 2 441 HH EtOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 2 442 HH EtOOC-MS 3-CF _Three HH (NH) CHH 2 443 HH EtOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 2 444 HH EtOOC-MS 3-CF _Three H Ph (NH) CHH 2 445 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NHH 2 446 HH EtOOC-MS 3-CF _Three HC _Five H ₈ NHH 2 447 HH EtOOC-MS 3-CF _Three HC ₆ H _Ten NHH 2 448 HH EtOOC-MS 3-CF _Three HC _Four H ₆ NS HH 2 449 HH EtOOC-MS 3-H _Two NCO H CH _Three HH 2 450 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 2 451 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 2 452 HH EtOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 2 453 HH EtOOC-MS 3-H _Two NCO H PhCH _Two HH 2 454 HH EtOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 2 455 HH EtOOC-MS 3-H _Two NCO H Ph HH 2 456 HH EtOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 2 457 HH EtOOC-MS 3-H _Two NCO H CH _Three CO HH 2 458 HH EtOOC-MS 3-H _Two NCO HH _Two NCO HH 2 459 HH EtOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 2 460 HH EtOOC-MS 3-H _Two NCO H 2-Pyr HH 2 461 HH EtOOC-MS 3-H _Two NCO H 3-Pyr HH 2 462 HH EtOOC-MS 3-H _Two NCO H 4-Pyr HH 2 463 HH EtOOC-MS 3-H _Two NCO H 2-Pyrm HH 2 464 HH EtOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 2 465 HH EtOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 2 466 HH EtOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 2 467 HH EtOOC-MS 3-H _Two NCO H cPn HH 2 468 HH EtOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 2 469 HH EtOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 2 470 HH EtOOC-MS 3-H _Two NCO HH (NH) CHH 2 471 HH EtOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 2 472 HH EtOOC-MS 3-H _Two NCO H Ph (NH) CHH 2 473 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 2 474 HH EtOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 2 475 HH EtOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 2 476 HH EtOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 2 477 HH EtOOC-MS 3-FH CH _Three HH 2 478 HH EtOOC-MS 3-FH CH _Three CH _Two HH 2 479 HH EtOOC-MS 3-FH CH _Three (CH _Three ) CH HH 2 480 HH EtOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 2 481 HH EtOOC-MS 3-FH PhCH _Two HH 2 482 HH EtOOC-MS 3-FH Ph (CH _Two ) _Two HH 2 483 HH EtOOC-MS 3-FH Ph HH 2 484 HH EtOOC-MS 3-FH CH _Three OCOCH _Two HH 2 485 HH EtOOC-MS 3-FH CH _Three CO HH 2 486 HH EtOOC-MS 3-FHH _Two NCO HH 2 487 HH EtOOC-MS 3-FH CH _Three SO _Two HH 2 488 HH EtOOC-MS 3-FH 2-Pyr HH 2 489 HH EtOOC-MS 3-FH 3-Pyr HH 2 490 HH EtOOC-MS 3-FH 4-Pyr HH 2 491 HH EtOOC-MS 3-FH 2 -Pyrm HH 2 492 HH EtOOC-MS 3-FH Pyr-3-CH _Two HH 2 493 HH EtOOC-MS 3-FH Pyr-4-CH _Two HH 2 494 HH EtOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 2 495 HH EtOOC-MS 3-FH cPn HH 2 496 HH EtOOC-MS 3-FH CH _Three 2-CH _Three H 2 497 HH EtOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 2 498 HH EtOOC-MS 3-FHH (NH) CHH 2 499 HH EtOOC-MS 3-FH CH _Three CH _Two (NH) CHH 2 500 HH EtOOC-MS 3-FH Ph (NH) CHH 2 501 HH EtOOC-MS 3-FHC _Four H ₆ NHH 2 502 HH EtOOC-MS 3-FHC _Five H ₈ NHH 2 503 HH EtOOC-MS 3-FHC ₆ H _Ten NHH 2 504 HH EtOOC-MS 3-FHC _Four H ₆ NS HH 2 505 HH HOOC-MS 3-Cl H CH _Three HH 1 506 HH HOOC-MS 3-Cl H CH _Three CH _Two HH 1 507 HH HOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 1 508 HH HOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 1 509 HH HOOC-MS 3-Cl H PhCH _Two HH 1 510 HH HOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 1 511 HH HOOC-MS 3-Cl H Ph HH 1 512 HH HOOC-MS 3-Cl H CH _Three OCOCH _Two HH 1 513 HH HOOC-MS 3-Cl H CH _Three CO HH 1 514 HH HOOC-MS 3-Cl HH _Two NCO HH 1 515 HH HOOC-MS 3-Cl H CH _Three SO _Two HH 1 516 HH HOOC-MS 3-Cl H 2-Pyr HH 1 517 HH HOOC-MS 3-Cl H 3-Pyr HH 1 518 HH HOOC-MS 3-Cl H 4-Pyr HH 1 519 HH HOOC-MS 3 -Cl H 2-Pyrm HH 1 520 HH HOOC-MS 3-Cl H Pyr-3-CH _Two HH 1 521 HH HOOC-MS 3-Cl H Pyr-4-CH _Two HH 1 522 HH HOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 1 523 HH HOOC-MS 3-Cl H cPn HH 1 524 HH HOOC-MS 3-Cl H CH _Three 2-CH _Three H 1 525 HH HOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 1 526 HH HOOC-MS 3-Cl HH (NH) CHH 1 527 HH HOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 1 528 HH HOOC-MS 3-Cl H Ph (NH) CHH 1 529 HH HOOC-MS 3-Cl HC _Four H ₆ NHH 1 530 HH HOOC-MS 3-Cl HC _Five H ₈ NHH 1 531 HH HOOC-MS 3-Cl HC ₆ H _Ten NHH 1 532 HH HOOC-MS 3-Cl HC _Four H ₆ NS HH 1 533 HH HOOC-MS 3-CH _Three H CH _Three HH 1 534 HH HOOC-MS 3-CH _Three H CH _Three CH _Two HH 1 535 HH HOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 1 536 HH HOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 1 537 HH HOOC-MS 3-CH _Three H PhCH _Two HH 1 538 HH HOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 1 539 HH HOOC-MS 3-CH _Three H Ph HH 1 540 HH HOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 1 541 HH HOOC-MS 3-CH _Three H CH _Three CO HH 1 542 HH HOOC-MS 3-CH _Three HH _Two NCO HH 1 543 HH HOOC-MS 3-CH _Three H CH _Three SO _Two HH 1 544 HH HOOC-MS 3-CH _Three H 2-Pyr HH 1 545 HH HOOC-MS 3-CH _Three H 3-Pyr HH 1 546 HH HOOC-MS 3-CH _Three H 4-Pyr HH 1 547 HH HOOC-MS 3-CH _Three H 2-Pyrm HH 1 548 HH HOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 1 549 HH HOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 1 550 HH HOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 1 551 HH HOOC-MS 3-CH _Three H cPn HH 1 552 HH HOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 1 553 HH HOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 1 554 HH HOOC-MS 3-CH _Three HH (NH) CHH 1 555 HH HOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 1 556 HH HOOC-MS 3-CH _Three H Ph (NH) CHH 1 557 HH HOOC-MS 3-CH _Three HC _Four H ₆ NHH 1 558 HH HOOC-MS 3-CH _Three HC _Five H ₈ NHH 1 559 HH HOOC-MS 3-CH _Three HC ₆ H _Ten NHH 1 560 HH HOOC-MS 3-CH _Three HC _Four H ₆ NS HH 1 561 HH HOOC-MS HH CH _Three HH 1 562 HH HOOC-MS HH CH _Three CH _Two HH 1 563 HH HOOC-MS HH CH _Three (CH _Three ) CH HH 1 564 HH HOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 1 565 HH HOOC-MS HH PhCH _Two HH 1 566 HH HOOC-MS HH Ph (CH _Two ) _Two HH 1 567 HH HOOC-MS HH Ph HH 1 568 HH HOOC-MS HH CH _Three OCOCH _Two HH 1 569 HH HOOC-MS HH CH _Three CO HH 1 570 HH HOOC-MS HHH _Two NCO HH 1 571 HH HOOC-MS HH CH _Three SO _Two HH 1 572 HH HOOC-MS HH 2-Pyr HH 1 573 HH HOOC-MS HH 3-Pyr HH 1 574 HH HOOC-MS HH 4-Pyr HH 1 575 HH HOOC-MS HH 2-Pyrm HH 1 576 HH HOOC- MS HH Pyr-3-CH _Two HH 1 577 HH HOOC-MS HH Pyr-4-CH _Two HH 1 578 HH HOOC-MS HH Pyr-2- (CH _Two ) _Two HH 1 579 HH HOOC-MS HH cPn HH 1 580 HH HOOC-MS HH CH _Three 2-CH _Three H 1 581 HH HOOC-MS HH-(CH _Two ) _Three -(5)-H 1 582 HH HOOC-MS HHH (NH) CHH 1583 HH HOOC-MS HH CH _Three CH _Two (NH) CHH 1 584 HH HOOC-MS HH Ph (NH) CHH 1 585 HH HOOC-MS HHC _Four H ₆ NHH 1 586 HH HOOC-MS HHC _Five H ₈ NHH 1 587 HH HOOC-MS HHC ₆ H _Ten NHH 1 588 HH HOOC-MS HHC _Four H ₆ NS HH 1 589 HH HOOC-MS 3-CF _Three H CH _Three HH 1 590 HH HOOC-MS 3-CF _Three H CH _Three CH _Two HH 1 591 HH HOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 1 592 HH HOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 1 593 HH HOOC-MS 3-CF _Three H PhCH _Two HH 1 594 HH HOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 1 595 HH HOOC-MS 3-CF _Three H Ph HH 1 596 HH HOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 1 597 HH HOOC-MS 3-CF _Three H CH _Three CO HH 1 598 HH HOOC-MS 3-CF _Three HH _Two NCO HH 1 599 HH HOOC-MS 3-CF _Three H CH _Three SO _Two HH 1 600 HH HOOC-MS 3-CF _Three H 2-Pyr HH 1 601 HH HOOC-MS 3-CF _Three H 3-Pyr HH 1 602 HH HOOC-MS 3-CF _Three H 4-Pyr HH 1 603 HH HOOC-MS 3-CF _Three H 2-Pyrm HH 1 604 HH HOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 1 605 HH HOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 1 606 HH HOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 1 607 HH HOOC-MS 3-CF _Three H cPn HH 1 608 HH HOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 1 609 HH HOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 1 610 HH HOOC-MS 3-CF _Three HH (NH) CHH 1 611 HH HOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 1 612 HH HOOC-MS 3-CF _Three H Ph (NH) CHH 1 613 HH HOOC-MS 3-CF _Three HC _Four H ₆ NHH 1 614 HH HOOC-MS 3-CF _Three HC _Five H ₈ NHH 1 615 HH HOOC-MS 3-CF _Three HC ₆ H _Ten NHH 1 616 HH HOOC-MS 3-CF _Three HC _Four H ₆ NS HH 1 617 HH HOOC-MS 3-H _Two NCO H CH _Three HH 1 618 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 1619 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 1 620 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 1 621 HH HOOC-MS 3-H _Two NCO H PhCH _Two HH 1 622 HH HOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 1 623 HH HOOC-MS 3-H _Two NCO H Ph HH 1 624 HH HOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 1 625 HH HOOC-MS 3-H _Two NCO H CH _Three CO HH 1 626 HH HOOC-MS 3-H _Two NCO HH _Two NCO HH 1 627 HH HOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 1 628 HH HOOC-MS 3-H _Two NCO H 2-Pyr HH 1 629 HH HOOC-MS 3-H _Two NCO H 3-Pyr HH 1 630 HH HOOC-MS 3-H _Two NCO H 4-Pyr HH 1 631 HH HOOC-MS 3-H _Two NCO H 2-Pyrm HH 1 632 HH HOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 1 633 HH HOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 1 634 HH HOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 1 635 HH HOOC-MS 3-H _Two NCO H cPn HH 1 636 HH HOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 1 637 HH HOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 1 638 HH HOOC-MS 3-H _Two NCO HH (NH) CHH 1 639 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 1 640 HH HOOC-MS 3-H _Two NCO H Ph (NH) CHH 1641 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 1 642 HH HOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 1 643 HH HOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 1 644 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 1 645 HH HOOC-MS 3-FH CH _Three HH 1 646 HH HOOC-MS 3-FH CH _Three CH _Two HH 1 647 HH HOOC-MS 3-FH CH _Three (CH _Three ) CH HH 1 648 HH HOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 1 649 HH HOOC-MS 3-FH PhCH _Two HH 1 650 HH HOOC-MS 3-FH Ph (CH _Two ) _Two HH 1 651 HH HOOC-MS 3-FH Ph HH 1 652 HH HOOC-MS 3-FH CH _Three OCOCH _Two HH 1 653 HH HOOC-MS 3-FH CH _Three CO HH 1 654 HH HOOC-MS 3-FHH _Two NCO HH 1 655 HH HOOC-MS 3-FH CH _Three SO _Two HH 1 656 HH HOOC-MS 3-FH 2-Pyr HH 1 657 HH HOOC-MS 3-FH 3-Pyr HH 1 658 HH HOOC-MS 3-FH 4-Pyr HH 1 659 HH HOOC-MS 3-FH 2 -Pyrm HH 1 660 HH HOOC-MS 3-FH Pyr-3-CH _Two HH 1 661 HH HOOC-MS 3-FH Pyr-4-CH _Two HH 1 662 HH HOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 1 663 HH HOOC-MS 3-FH cPn HH 1 664 HH HOOC-MS 3-FH CH _Three 2-CH _Three H 1 665 HH HOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 1 666 HH HOOC-MS 3-FHH (NH) CHH 1 667 HH HOOC-MS 3-FH CH _Three CH _Two (NH) CHH 1 668 HH HOOC-MS 3-FH Ph (NH) CHH 1 669 HH HOOC-MS 3-FHC _Four H ₆ NHH 1 670 HH HOOC-MS 3-FHC _Five H ₈ NHH 1 671 HH HOOC-MS 3-FHC ₆ H _Ten NHH 1 672 HH HOOC-MS 3-FHC _Four H ₆ NS HH 1 673 HH HOOC-MS 3-Cl H CH _Three HH 0 674 HH HOOC-MS 3-Cl H CH _Three CH _Two HH 0 675 HH HOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 0 676 HH HOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 0 677 HH HOOC-MS 3-Cl H PhCH _Two HH 0 678 HH HOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 0 679 HH HOOC-MS 3-Cl H Ph HH 0 680 HH HOOC-MS 3-Cl H CH _Three OCOCH _Two HH 0 681 HH HOOC-MS 3-Cl H CH _Three CO HH 0 682 HH HOOC-MS 3-Cl HH _Two NCO HH 0 683 HH HOOC-MS 3-Cl H CH _Three SO _Two HH 0 684 HH HOOC-MS 3-Cl H 2-Pyr HH 0 685 HH HOOC-MS 3-Cl H 3-Pyr HH 0 686 HH HOOC-MS 3-Cl H 4-Pyr HH 0 687 HH HOOC-MS 3 -Cl H 2-Pyrm HH 0 688 HH HOOC-MS 3-Cl H Pyr-3-CH _Two HH 0 689 HH HOOC-MS 3-Cl H Pyr-4-CH _Two HH 0 690 HH HOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 0 691 HH HOOC-MS 3-Cl H cPn HH 0 692 HH HOOC-MS 3-Cl H CH _Three 2-CH _Three H 0 693 HH HOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 0 694 HH HOOC-MS 3-Cl HH (NH) CHH 0 695 HH HOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 0 696 HH HOOC-MS 3-Cl H Ph (NH) CHH 0 697 HH HOOC-MS 3-Cl HC _Four H ₆ NHH 0 698 HH HOOC-MS 3-Cl HC _Five H ₈ NHH 0 699 HH HOOC-MS 3-Cl HC ₆ H _Ten NHH 0 700 HH HOOC-MS 3-Cl HC _Four H ₆ NS HH 0 701 HH HOOC-MS 3-CH _Three H CH _Three HH 0 702 HH HOOC-MS 3-CH _Three H CH _Three CH _Two HH 0 703 HH HOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 0 704 HH HOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 0 705 HH HOOC-MS 3-CH _Three H PhCH _Two HH 0 706 HH HOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 0 707 HH HOOC-MS 3-CH _Three H Ph HH 0 708 HH HOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 0 709 HH HOOC-MS 3-CH _Three H CH _Three CO HH 0 710 HH HOOC-MS 3-CH _Three HH _Two NCO HH 0 711 HH HOOC-MS 3-CH _Three H CH _Three SO _Two HH 0 712 HH HOOC-MS 3-CH _Three H 2-Pyr HH 0 713 HH HOOC-MS 3-CH _Three H 3-Pyr HH 0 714 HH HOOC-MS 3-CH _Three H 4-Pyr HH 0 715 HH HOOC-MS 3-CH _Three H 2-Pyrm HH 0 716 HH HOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 0 717 HH HOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 0 718 HH HOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 0 719 HH HOOC-MS 3-CH _Three H cPn HH 0 720 HH HOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 0 721 HH HOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 0 722 HH HOOC-MS 3-CH _Three HH (NH) CHH 0 723 HH HOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 0 724 HH HOOC-MS 3-CH _Three H Ph (NH) CHH 0 725 HH HOOC-MS 3-CH _Three HC _Four H ₆ NHH 0 726 HH HOOC-MS 3-CH _Three HC _Five H ₈ NHH 0 727 HH HOOC-MS 3-CH _Three HC ₆ H _Ten NHH 0 728 HH HOOC-MS 3-CH _Three HC _Four H ₆ NS HH 0 729 HH HOOC-MS HH CH _Three HH 0 730 HH HOOC-MS HH CH _Three CH _Two HH 0 731 HH HOOC-MS HH CH _Three (CH _Three ) CH HH 0 732 HH HOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 0 733 HH HOOC-MS HH PhCH _Two HH 0 734 HH HOOC-MS HH Ph (CH _Two ) _Two HH 0 735 HH HOOC-MS HH Ph HH 0 736 HH HOOC-MS HH CH _Three OCOCH _Two HH 0 737 HH HOOC-MS HH CH _Three CO HH 0 738 HH HOOC-MS HHH _Two NCO HH 0 739 HH HOOC-MS HH CH _Three SO _Two HH 0 740 HH HOOC-MS HH 2-Pyr HH 0 741 HH HOOC-MS HH 3-Pyr HH 0 742 HH HOOC-MS HH 4-Pyr HH 0 743 HH HOOC-MS HH 2-Pyrm HH 0 744 HH HOOC- MS HH Pyr-3-CH _Two HH 0 745 HH HOOC-MS HH Pyr-4-CH _Two HH 0 746 HH HOOC-MS HH Pyr-2- (CH _Two ) _Two HH 0 747 HH HOOC-MS HH cPn HH 0 748 HH HOOC-MS HH CH _Three 2-CH _Three H 0 759 HH HOOC-MS HH-(CH _Two ) _Three -(5)-H 0 750 HH HOOC-MS HHH (NH) CHH 0 751 HH HOOC-MS HH CH _Three CH _Two (NH) CHH 0 752 HH HOOC-MS HH Ph (NH) CHH 0 753 HH HOOC-MS HHC _Four H ₆ NHH 0 754 HH HOOC-MS HHC _Five H ₈ NHH 0 755 HH HOOC-MS HHC ₆ H _Ten NHH 0 756 HH HOOC-MS HHC _Four H ₆ NS HH 0 757 HH HOOC-MS 3-CF _Three H CH _Three HH 0 758 HH HOOC-MS 3-CF _Three H CH _Three CH _Two HH 0 759 HH HOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 0 760 HH HOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 0 761 HH HOOC-MS 3-CF _Three H PhCH _Two HH 0 762 HH HOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 0 763 HH HOOC-MS 3-CF _Three H Ph HH 0 764 HH HOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 0 765 HH HOOC-MS 3-CF _Three H CH _Three CO HH 0 766 HH HOOC-MS 3-CF _Three HH _Two NCO HH 0 767 HH HOOC-MS 3-CF _Three H CH _Three SO _Two HH 0 768 HH HOOC-MS 3-CF _Three H 2-Pyr HH 0 769 HH HOOC-MS 3-CF _Three H 3-Pyr HH 0 770 HH HOOC-MS 3-CF _Three H 4-Pyr HH 0 771 HH HOOC-MS 3-CF _Three H 2-Pyrm HH 0 772 HH HOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 0 773 HH HOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 0 774 HH HOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 0 775 HH HOOC-MS 3-CF _Three H cPn HH 0 716 HH HOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 0 777 HH HOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 0 778 HH HOOC-MS 3-CF _Three HH (NH) CHH 0 779 HH HOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 0 780 HH HOOC-MS 3-CF _Three H Ph (NH) CHH 0 781 HH HOOC-MS 3-CF _Three HC _Four H ₆ NHH 0 782 HH HOOC-MS 3-CF _Three HC _Five H ₈ NHH 0 783 HH HOOC-MS 3-CF _Three HC ₆ H _Ten NHH 0 784 HH HOOC-MS 3-CF _Three HC _Four H ₆ NS HH 0 785 HH HOOC-MS 3-H _Two NCO H CH _Three HH 0 786 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 0 787 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 0 788 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 0 789 HH HOOC-MS 3-H _Two NCO H PhCH _Two HH 0 790 HH HOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 0 791 HH HOOC-MS 3-H _Two NCO H Ph HH 0 792 HH HOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 0 793 HH HOOC-MS 3-H _Two NCO H CH _Three CO HH 0 794 HH HOOC-MS 3-H _Two NCO HH _Two NCO HH 0 795 HH HOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 0 796 HH HOOC-MS 3-H _Two NCO H 2-Pyr HH 0 797 HH HOOC-MS 3-H _Two NCO H 3-Pyr HH 0 798 HH HOOC-MS 3-H _Two NCO H 4-Pyr HH 0 799 HH HOOC-MS 3-H _Two NCO H 2-Pyrm HH 0 800 HH HOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 0 801 HH HOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 0 802 HH HOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 0 803 HH HOOC-MS 3-H _Two NCO H cPn HH 0 804 HH HOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 0 805 HH HOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 0 806 HH HOOC-MS 3-H _Two NCO HH (NH) CHH 0 807 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 0 808 HH HOOC-MS 3-H _Two NCO H Ph (NH) CHH 0 809 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 0 810 HH HOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 0 811 HH HOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 0 812 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 0 813 HH HOOC-MS 3-FH CH _Three HH 0 814 HH HOOC-MS 3-FH CH _Three CH _Two HH 0 815 HH HOOC-MS 3-FH CH _Three (CH _Three ) CH HH 0 816 HH HOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 0 817 HH HOOC-MS 3-FH PhCH _Two HH 0 818 HH HOOC-MS 3-FH Ph (CH _Two ) _Two HH 0 819 HH HOOC-MS 3-FH Ph HH 0 820 HH HOOC-MS 3-FH CH _Three OCOCH _Two HH 0 821 HH HOOC-MS 3-FH CH _Three CO HH 0 822 HH HOOC-MS 3-FHH _Two NCO HH 0 823 HH HOOC-MS 3-FH CH _Three SO _Two HH 0 824 HH HOOC-MS 3-FH 2-Pyr HH 0 825 HH HOOC-MS 3-FH 3-Pyr HH 0 826 HH HOOC-MS 3-FH 4-Pyr HH 0 827 HH HOOC-MS 3-FH 2 -Pyrm HH 0 828 HH HOOC-MS 3-FH Pyr-3-CH _Two HH 0 829 HH HOOC-MS 3-FH Pyr-4-CH _Two HH 0 830 HH HOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 0 831 HH HOOC-MS 3-FH cPn HH 0 832 HH HOOC-MS 3-FH CH _Three 2-CH _Three H 0 833 HH HOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 0 834 HH HOOC-MS 3-FHH (NH) CHH 0 835 HH HOOC-MS 3-FH CH _Three CH _Two (NH) CHH 0 836 HH HOOC-MS 3-FH Ph (NH) CHH 0 837 HH HOOC-MS 3-FHC _Four H ₆ NHH 0 838 HH HOOC-MS 3-FHC _Five H ₈ NHH 0 839 HH HOOC-MS 3-FHC ₆ H _Ten NHH 0 840 HH HOOC-MS 3-FHC _Four H ₆ NS HH 0 841 HH HOOC-MS 3-Cl H CH _Three HH 2 842 HH HOOC-MS 3-Cl H CH _Three CH _Two HH 2 843 HH HOOC-MS 3-Cl H CH _Three (CH _Three ) CH HH 2 844 HH HOOC-MS 3-Cl H CH _Three (CH _Two ) _Two CH _Two HH 2 845 HH HOOC-MS 3-Cl H PhCH _Two HH 2 846 HH HOOC-MS 3-Cl H Ph (CH _Two ) _Two HH 2 847 HH HOOC-MS 3-Cl H Ph HH 2 848 HH HOOC-MS 3-Cl H CH _Three OCOCH _Two HH 2 849 HH HOOC-MS 3-Cl H CH _Three CO HH 2 850 HH HOOC-MS 3-Cl HH _Two NCO HH 2 851 HH HOOC-MS 3-Cl H CH _Three SO _Two HH 2 852 HH HOOC-MS 3-Cl H 2-Pyr HH 2 853 HH HOOC-MS 3-Cl H 3-Pyr HH 2 854 HH HOOC-MS 3-Cl H 4-Pyr HH 2 855 HH HOOC-MS 3 -Cl H 2-Pyrm HH 2 856 HH HOOC-MS 3-Cl H Pyr-3-CH _Two HH 2 857 HH HOOC-MS 3-Cl H Pyr-4-CH _Two HH 2 858 HH HOOC-MS 3-Cl H Pyr-2- (CH _Two ) _Two HH 2 859 HH HOOC-MS 3-Cl H cPn HH 2 860 HH HOOC-MS 3-Cl H CH _Three 2-CH _Three H 2 861 HH HOOC-MS 3-Cl H-(CH _Two ) _Three -(5)-H 2 862 HH HOOC-MS 3-Cl HH (NH) CHH 2 863 HH HOOC-MS 3-Cl H CH _Three CH _Two (NH) CHH 2 864 HH HOOC-MS 3-Cl H Ph (NH) CHH 2 865 HH HOOC-MS 3-Cl HC _Four H ₆ NHH 2 866 HH HOOC-MS 3-Cl HC _Five H ₈ NHH 2 867 HH HOOC-MS 3-Cl HC ₆ H _Ten NHH 2 868 HH HOOC-MS 3-Cl HC _Four H ₆ NS HH 2 869 HH HOOC-MS 3-CH _Three H CH _Three HH 2 870 HH HOOC-MS 3-CH _Three H CH _Three CH _Two HH 2 871 HH HOOC-MS 3-CH _Three H CH _Three (CH _Three ) CH HH 2 872 HH HOOC-MS 3-CH _Three H CH _Three (CH _Two ) _Two CH _Two HH 2 873 HH HOOC-MS 3-CH _Three H PhCH _Two HH 2 874 HH HOOC-MS 3-CH _Three H Ph (CH _Two ) _Two HH 2 875 HH HOOC-MS 3-CH _Three H Ph HH 2 876 HH HOOC-MS 3-CH _Three H CH _Three OCOCH _Two HH 2 877 HH HOOC-MS 3-CH _Three H CH _Three CO HH 2 878 HH HOOC-MS 3-CH _Three HH _Two NCO HH 2 879 HH HOOC-MS 3-CH _Three H CH _Three SO _Two HH 2 880 HH HOOC-MS 3-CH _Three H 2-Pyr HH 2 881 HH HOOC-MS 3-CH _Three H 3-Pyr HH 2 882 HH HOOC-MS 3-CH _Three H 4-Pyr HH 2 883 HH HOOC-MS 3-CH _Three H 2-Pyrm HH 2 884 HH HOOC-MS 3-CH _Three H Pyr-3-CH _Two HH 2 885 HH HOOC-MS 3-CH _Three H Pyr-4-CH _Two HH 2 886 HH HOOC-MS 3-CH _Three H Pyr-2- (CH _Two ) _Two HH 2 887 HH HOOC-MS 3-CH _Three H cPn HH 2 888 HH HOOC-MS 3-CH _Three H CH _Three 2-CH _Three H 2 889 HH HOOC-MS 3-CH _Three H-(CH _Two ) _Three -(5)-H 2 890 HH HOOC-MS 3-CH _Three HH (NH) CHH 2 891 HH HOOC-MS 3-CH _Three H CH _Three CH _Two (NH) CHH 2 892 HH HOOC-MS 3-CH _Three H Ph (NH) CHH 2 893 HH HOOC-MS 3-CH _Three HC _Four H ₆ NHH 2 894 HH HOOC-MS 3-CH _Three HC _Five H ₈ NHH 2 895 HH HOOC-MS 3-CH _Three HC ₆ H _Ten NHH 2 896 HH HOOC-MS 3-CH _Three HC _Four H ₆ NS HH 2 897 HH HOOC-MS HH CH _Three HH 2 898 HH HOOC-MS HH CH _Three CH _Two HH 2 899 HH HOOC-MS HH CH _Three (CH _Three ) CH HH 2 900 HH HOOC-MS HH CH _Three (CH _Two ) _Two CH _Two HH 2 901 HH HOOC-MS HH PhCH _Two HH 2 902 HH HOOC-MS HH Ph (CH _Two ) _Two HH 2 903 HH HOOC-MS HH Ph HH 2 904 HH HOOC-MS HH CH _Three OCOCH _Two HH 2 905 HH HOOC-MS HH CH _Three CO HH 2 906 HH HOOC-MS HHH _Two NCO HH 2 907 HH HOOC-MS HH CH _Three SO _Two HH 2 908 HH HOOC-MS HH 2-Pyr HH 2 909 HH HOOC-MS HH 3-Pyr HH 2 910 HH HOOC-MS HH 4-Pyr HH 2 911 HH HOOC-MS HH 2-Pyrm HH 2 912 HH HOOC- MS HH Pyr-3-CH _Two HH 2 913 HH HOOC-MS HH Pyr-4-CH _Two HH 2 914 HH HOOC-MS HH Pyr-2- (CH _Two ) _Two HH 2 915 HH HOOC-MS HH cPn HH 2 916 HH HOOC-MS HH CH _Three 2-CH _Three H 2 917 HH HOOC-MS HH-(CH _Two ) _Three -(5)-H 2 918 HH HOOC-MS HHH (NH) CHH 2 919 HH HOOC-MS HH CH _Three CH _Two (NH) CHH 2 920 HH HOOC-MS HH Ph (NH) CHH 2 921 HH HOOC-MS HHC _Four H ₆ NHH 2 922 HH HOOC-MS HHC _Five H ₈ NHH 2 923 HH HOOC-MS HHC ₆ H _Ten NHH 2 924 HH HOOC-MS HHC _Four H ₆ NS HH 2 925 HH HOOC-MS 3-CF _Three H CH _Three HH 2 926 HH HOOC-MS 3-CF _Three H CH _Three CH _Two HH 2 927 HH HOOC-MS 3-CF _Three H CH _Three (CH _Three ) CH HH 2 928 HH HOOC-MS 3-CF _Three H CH _Three (CH _Two ) _Two CH _Two HH 2 929 HH HOOC-MS 3-CF _Three H PhCH _Two HH 2 930 HH HOOC-MS 3-CF _Three H Ph (CH _Two ) _Two HH 2 931 HH HOOC-MS 3-CF _Three H Ph HH 2 932 HH HOOC-MS 3-CF _Three H CH _Three OCOCH _Two HH 2 933 HH HOOC-MS 3-CF _Three H CH _Three CO HH 2 934 HH HOOC-MS 3-CF _Three HH _Two NCO HH 2 935 HH HOOC-MS 3-CF _Three H CH _Three SO _Two HH 2 936 HH HOOC-MS 3-CF _Three H 2-Pyr HH 2 937 HH HOOC-MS 3-CF _Three H 3-Pyr HH 2 938 HH HOOC-MS 3-CF _Three H 4-Pyr HH 2 939 HH HOOC-MS 3-CF _Three H 2-Pyrm HH 2 940 HH HOOC-MS 3-CF _Three H Pyr-3-CH _Two HH 2 941 HH HOOC-MS 3-CF _Three H Pyr-4-CH _Two HH 2 942 HH HOOC-MS 3-CF _Three H Pyr-2- (CH _Two ) _Two HH 2 943 HH HOOC-MS 3-CF _Three H cPn HH 2 944 HH HOOC-MS 3-CF _Three H CH _Three 2-CH _Three H 2 945 HH HOOC-MS 3-CF _Three H-(CH _Two ) _Three -(5)-H 2 946 HH HOOC-MS 3-CF _Three HH (NH) CHH 2 947 HH HOOC-MS 3-CF _Three H CH _Three CH _Two (NH) CHH 2 948 HH HOOC-MS 3-CF _Three H Ph (NH) CHH 2 949 HH HOOC-MS 3-CF _Three HC _Four H ₆ NHH 2 950 HH HOOC-MS 3-CF _Three HC _Five H ₈ NHH 2 951 HH HOOC-MS 3-CF _Three HC ₆ H _Ten NHH 2 952 HH HOOC-MS 3-CF _Three HC _Four H ₆ NS HH 2 953 HH HOOC-MS 3-H _Two NCO H CH _Three HH 2 954 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two HH 2 955 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Three ) CH HH 2 956 HH HOOC-MS 3-H _Two NCO H CH _Three (CH _Two ) _Two CH _Two HH 2 957 HH HOOC-MS 3-H _Two NCO H PhCH _Two HH 2 958 HH HOOC-MS 3-H _Two NCO H Ph (CH _Two ) _Two HH 2 959 HH HOOC-MS 3-H _Two NCO H Ph HH 2 960 HH HOOC-MS 3-H _Two NCO H CH _Three OCOCH _Two HH 2 961 HH HOOC-MS 3-H _Two NCO H CH _Three CO HH 2 962 HH HOOC-MS 3-H _Two NCO HH _Two NCO HH 2 963 HH HOOC-MS 3-H _Two NCO H CH _Three SO _Two HH 2 964 HH HOOC-MS 3-H _Two NCO H 2-Pyr HH 2 965 HH HOOC-MS 3-H _Two NCO H 3-Pyr HH 2 966 HH HOOC-MS 3-H _Two NCO H 4-Pyr HH 2 967 HH HOOC-MS 3-H _Two NCO H 2-Pyrm HH 2 968 HH HOOC-MS 3-H _Two NCO H Pyr-3-CH _Two HH 2 969 HH HOOC-MS 3-H _Two NCO H Pyr-4-CH _Two HH 2 970 HH HOOC-MS 3-H _Two NCO H Pyr-2- (CH _Two ) _Two HH 2 971 HH HOOC-MS 3-H _Two NCO H cPn HH 2 972 HH HOOC-MS 3-H _Two NCO H CH _Three 2-CH _Three H 2 973 HH HOOC-MS 3-H _Two NCO H-(CH _Two ) _Three -(5)-H 2 974 HH HOOC-MS 3-H _Two NCO HH (NH) CHH 2 975 HH HOOC-MS 3-H _Two NCO H CH _Three CH _Two (NH) CHH 2 976 HH HOOC-MS 3-H _Two NCO H Ph (NH) CHH 2 977 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 2 978 HH HOOC-MS 3-H _Two NCO HC _Five H ₈ NHH 2 979 HH HOOC-MS 3-H _Two NCO HC ₆ H _Ten NHH 2 980 HH HOOC-MS 3-H _Two NCO HC _Four H ₆ NS HH 2 981 HH HOOC-MS 3-FH CH _Three HH 2 982 HH HOOC-MS 3-FH CH _Three CH _Two HH 2 983 HH HOOC-MS 3-FH CH _Three (CH _Three ) CH HH 2 984 HH HOOC-MS 3-FH CH _Three (CH _Two ) _Two CH _Two HH 2 985 HH HOOC-MS 3-FH PhCH _Two HH 2 986 HH HOOC-MS 3-FH Ph (CH _Two ) _Two HH 2 987 HH HOOC-MS 3-FH Ph HH 2 988 HH HOOC-MS 3-FH CH _Three OCOCH _Two HH 2 989 HH HOOC-MS 3-FH CH _Three CO HH 2 990 HH HOOC-MS 3-FHH _Two NCO HH 2 991 HH HOOC-MS 3-FH CH _Three SO _Two HH 2 992 HH HOOC-MS 3-FH 2-Pyr HH 2 993 HH HOOC-MS 3-FH 3-Pyr HH 2 994 HH HOOC-MS 3-FH 4-Pyr HH 2 995 HH HOOC-MS 3-FH 2 -Pyrm HH 2 996 HH HOOC-MS 3-FH Pyr-3-CH _Two HH 2 997 HH HOOC-MS 3-FH Pyr-4-CH _Two HH 2 998 HH HOOC-MS 3-FH Pyr-2- (CH _Two ) _Two HH 2 999 HH HOOC-MS 3-FH cPn HH 2 1000 HH HOOC-MS 3-FH CH _Three 2-CH _Three H 2 1001 HH HOOC-MS 3-FH-(CH _Two ) _Three -(5)-H 2 1002 HH HOOC-MS 3-FHH (NH) CHH 2 1003 HH HOOC-MS 3-FH CH _Three CH _Two (NH) CHH 2 1004 HH HOOC-MS 3-FH Ph (NH) CHH 2 1005 HH HOOC-MS 3-FHC _Four H ₆ NHH 2 1006 HH HOOC-MS 3-FHC _Five H ₈ NHH 2 1007 HH HOOC-MS 3-FHC ₆ H _Ten NHH 2 1008 HH HOOC-MS 3-FHC _Four H ₆ NS HH 2 1009 HH EtOOC-MS 3-Cl HC _Three H _Four NO HH 1 1010 HH EtOOC-MS 3-CH _Three HC _Three H _Four NO HH 1 1011 HH EtOOC-MS HHC _Three H _Four NO HH 1 1012 HH EtOOC-MS 3-CF _Three HC _Three H _Four NO HH 1 1013 HH EtOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 1 1014 HH EtOOC-MS 3-FHC _Three H _Four NO HH 1 1015 HH EtOOC-MS 3-Cl HC _Three H _Four NO HH 0 1016 HH EtOOC-MS 3-CH _Three HC _Three H _Four NO HH 0 1017 HH EtOOC-MS HHC _Three H _Four NO HH 0 1018 HH EtOOC-MS 3-CF _Three HC _Three H _Four NO HH 0 1019 HH EtOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 0 1020 HH EtOOC-MS 3-FHC _Three H _Four NO HH 0 1021 HH EtOOC-MS 3-Cl HC _Three H _Four NO HH 2 1022 HH EtOOC-MS 3-CH _Three HC _Three H _Four NO HH 2 1023 HH EtOOC-MS HHC _Three H _Four NO HH 2 1024 HH EtOOC-MS 3-CF _Three HC _Three H _Four NO HH 2 1025 HH EtOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 2 1026 HH EtOOC-MS 3-FHC _Three H _Four NO HH 2 1027 HH HOOC-MS 3-Cl HC _Three H _Four NO HH 1 1028 HH HOOC-MS 3-CH _Three HC _Three H _Four NO HH 1 1029 HH HOOC-MS HHC _Three H _Four NO HH 1 1030 HH HOOC-MS 3-CF _Three HC _Three H _Four NO HH 1 1031 HH HOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 1 1032 HH HOOC-MS 3-FHC _Three H _Four NO HH 1 1033 HH HOOC-MS 3-Cl HC _Three H _Four NO HH 0 1034 HH HOOC-MS 3-CH _Three HC _Three H _Four NO HH 0 1035 HH HOOC-MS HHC _Three H _Four NO HH 0 1036 HH HOOC-MS 3-CF _Three HC _Three H _Four NO HH 0 1037 HH HOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 0 1038 HH HOOC-MS 3-FHC _Three H _Four NO HH 0 1039 HH HOOC-MS 3-Cl HC _Three H _Four NO HH 2 1040 HH HOOC-MS 3-CH _Three HC _Three H _Four NO HH 2 1041 HH HOOC-MS HHC _Three H _Four NO HH 2 1042 HH HOOC-MS 3-CF _Three HC _Three H _Four NO HH 2 1043 HH HOOC-MS 3-H _Two NCO HC _Three H _Four NO HH 2 1044 HH HOOC-MS 3-FHC _Three H _Four NO HH 2 1045 HH EtOOC-MS 3-Cl HC _Five F _Four NHH 1 1046 HH EtOOC-MS 3-CH _Three HC _Five F _Four NHH 1 1047 HH EtOOC-MS HHC _Five F _Four NHH 1 1048 HH EtOOC-MS 3-CF _Three HC _Five F _Four NHH 1 1049 HH EtOOC-MS 3-H _Two NCO HC _Five F _Four NHH 1 1050 HH EtOOC-MS 3-FHC _Five F _Four NHH 1 1051 HH EtOOC-MS 3-Cl HC _Five F _Four NHH 0 1052 HH EtOOC-MS 3-CH _Three HC _Five F _Four NHH 0 1053 HH EtOOC-MS HHC _Five F _Four NHH 0 1054 HH EtOOC-MS 3-CF _Three HC _Five F _Four NHH 0 1055 HH EtOOC-MS 3-H _Two NCO HC _Five F _Four NHH 0 1056 HH EtOOC-MS 3-FHC _Five F _Four NHH 0 1057 HH EtOOC-MS 3-Cl HC _Five F _Four NHH 2 1058 HH EtOOC-MS 3-CH _Three HC _Five F _Four NHH 2 1059 HH EtOOC-MS HHC _Five F _Four NHH 2 1060 HH EtOOC-MS 3-CF _Three HC _Five F _Four NHH 2 1061 HH EtOOC-MS 3-H _Two NCO HC _Five F _Four NHH 2 1062 HH EtOOC-MS 3-FHC _Five F _Four NHH 2 1063 HH HOOC-MS 3-Cl HC _Five F _Four NHH 1 1064 HH HOOC-MS 3-CH _Three HC _Five F _Four NHH 1 1065 HH HOOC-MS HHC _Five F _Four NHH 1 1066 HH HOOC-MS 3-CF _Three HC _Five F _Four NHH 1 1067 HH HOOC-MS 3-H _Two NCO HC _Five F _Four NHH 1 1068 HH HOOC-MS 3-FHC _Five F _Four NHH 1 1069 HH HOOC-MS 3-Cl HC _Five F _Four NHH 0 1070 HH HOOC-MS 3-CH _Three HC _Five F _Four NHH 0 1071 HH HOOC-MS HHC _Five F _Four NHH 0 1072 HH HOOC-MS 3-CF _Three HC _Five F _Four NHH 0 1073 HH HOOC-MS 3-H _Two NCO HC _Five F _Four NHH 0 1074 HH HOOC-MS 3-FHC _Five F _Four NHH 0 1075 HH HOOC-MS 3-Cl HC _Five F _Four NHH 2 1076 HH HOOC-MS 3-CH _Three HC _Five F _Four NHH 2 1077 HH HOOC-MS HHC _Five F _Four NHH 2 1078 HH HOOC-MS 3-CF _Three HC _Five F _Four NHH 2 1079 HH HOOC-MS 3-H _Two NCO HC _Five F _Four NHH 2 1080 HH HOOC-MS 3-FHC _Five F _Four NHH 2 1081 HH EtOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 1 1082 HH EtOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 1 1083 HH EtOOC-MS HHH (CH _Three CH _Two N) CHH 1 1084 HH EtOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 1 1085 HH EtOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 1 1086 HH EtOOC-MS 3-FHH (CH _Three CH _Two N) CHH 1 1087 HH EtOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 0 1088 HH EtOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 0 1089 HH EtOOC-MS HHH (CH _Three CH _Two N) CHH 0 1090 HH EtOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 0 1091 HH EtOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 0 1092 HH EtOOC-MS 3-FHH (CH _Three CH _Two N) CHH 0 1093 HH EtOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 2 1094 HH EtOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 2 1095 HH EtOOC-MS HHH (CH _Three CH _Two N) CHH 2 1096 HH EtOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 2 1097 HH EtOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 2 1098 HH EtOOC-MS 3-FHH (CH _Three CH _Two N) CHH 2 1099 HH HOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 1 1100 HH HOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 1 1101 HH HOOC-MS HHH (CH _Three CH _Two N) CHH 1 1102 HH HOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 1 1103 HH HOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 1 1104 HH HOOC-MS 3-FHH (CH _Three CH _Two N) CHH 1 1105 HH HOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 0 1106 HH HOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 0 1107 HH HOOC-MS HHH (CH _Three CH _Two N) CHH 0 1108 HH HOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 0 1109 HH HOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 0 1110 HH HOOC-MS 3-FHH (CH _Three CH _Two N) CHH 0 1111 HH HOOC-MS 3-Cl HH (CH _Three CH _Two N) CHH 2 1112 HH HOOC-MS 3-CH _Three HH (CH _Three CH _Two N) CHH 2 1113 HH HOOC-MS HHH (CH _Three CH _Two N) CHH 2 1114 HH HOOC-MS 3-CF _Three HH (CH _Three CH _Two N) CHH 2 1115 HH HOOC-MS 3-H _Two NCO HH (CH _Three CH _Two N) CHH 2 1116 HH HOOC-MS 3-FHH (CH _Three CH _Two N) CHH 2 1117 HH EtOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --1 1118 HH EtOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --1 1119 HH EtOOC-MS HH CH _Three -(CH _Two ) _Two --1 1120 HH EtOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --1 1121 HH EtOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --1 1122 HH EtOOC-MS 3-FH CH _Three -(CH _Two ) _Two --1 1123 HH EtOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --0 1124 HH EtOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --0 1125 HH EtOOC-MS HH CH _Three -(CH _Two ) _Two --0 1126 HH EtOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --0 1127 HH EtOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --0 1 128 HH EtOOC-MS 3-FH CH _Three -(CH _Two ) _Two --0 1129 HH EtOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --2 1130 HH EtOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --2 1131 HH EtOOC-MS HH CH _Three -(CH _Two ) _Two --2 1132 HH EtOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --2 1133 HH EtOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --2 1134 HH EtOOC-MS 3-FH CH _Three -(CH _Two ) _Two --2 1135 HH HOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --1 1136 HH HOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --1 1137 HH HOOC-MS HH CH _Three -(CH _Two ) _Two --1 1138 HH HOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --1 1139 HH HOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --1 1140 HH HOOC-MS 3-FH CH _Three -(CH _Two ) _Two --1 1141 HH HOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --0 1142 HH HOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --0 1143 HH HOOC-MS HH CH _Three -(CH _Two ) _Two --0 1144 HH HOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --0 1145 HH HOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --0 1146 HH HOOC-MS 3-FH CH _Three -(CH _Two ) _Two --0 1147 HH HOOC-MS 3-Cl H CH _Three -(CH _Two ) _Two --2 1148 HH HOOC-MS 3-CH _Three H CH _Three -(CH _Two ) _Two --2 1149 HH HOOC-MS HH CH _Three -(CH _Two ) _Two --2 1150 HH HOOC-MS 3-CF _Three H CH _Three -(CH _Two ) _Two --2 1151 HH HOOC-MS 3-H _Two NCO H CH _Three -(CH _Two ) _Two --2 1152 HH HOOC-MS 3-FH CH _Three -(CH _Two ) _Two --2 1153 HH EtOOC-MS 3-Cl HC ₈ H ₁₄ NHH 1 1154 HH EtOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 1 1155 HH EtOOC-MS HHC ₈ H ₁₄ NHH 1 1156 HH EtOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 1 1157 HH EtOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 1 1158 HH EtOOC-MS 3-FHC ₈ H ₁₄ NHH 1 1159 HH EtOOC-MS 3-Cl HC ₈ H ₁₄ NHH 0 1160 HH EtOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 0 1161 HH EtOOC-MS HHC ₈ H ₁₄ NHH 0 1162 HH EtOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 0 1163 HH EtOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 0 1164 HH EtOOC-MS 3-FHC ₈ H ₁₄ NHH 0 1165 HH EtOOC-MS 3-Cl HC ₈ H ₁₄ NHH 2 1166 HH EtOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 2 1167 HH EtOOC-MS HHC ₈ H ₁₄ NHH 2 1168 HH EtOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 2 1169 HH EtOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 2 1170 HH EtOOC-MS 3-FHC ₈ H ₁₄ NHH 2 1171 HH HOOC-MS 3-Cl HC ₈ H ₁₄ NHH 1 1172 HH HOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 1 1173 HH HOOC-MS HHC ₈ H ₁₄ NHH 1 1174 HH HOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 1 1175 HH HOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 1 1176 HH HOOC-MS 3-FHC ₈ H ₁₄ NHH 1 1177 HH HOOC-MS 3-Cl HC ₈ H ₁₄ NHH 0 1178 HH HOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 0 1179 HH HOOC-MS HHC ₈ H ₁₄ NHH 0 1180 HH HOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 0 1181 HH HOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 0 1182 HH HOOC-MS 3-FHC ₈ H ₁₄ NHH 0 1183 HH HOOC-MS 3-Cl HC ₈ H ₁₄ NHH 2 1184 HH HOOC-MS 3-CH _Three HC ₈ H ₁₄ NHH 2 1185 HH HOOC-MS HHC ₈ H ₁₄ NHH 2 1186 HH HOOC-MS 3-CF _Three HC ₈ H ₁₄ NHH 2 1187 HH HOOC-MS 3-H _Two NCO HC ₈ H ₁₄ NHH 2 1188 HH HOOC-MS 3-FHC ₈ H ₁₄ NHH 2 1189 HHH _Three CSO _Two HHC _Three H _Four NO HH 0 1190 HHH _Three CSO _Two 3-FHC _Three H _Four NO HH 0 1191 HHH _Three CSO _Two 3-Cl HC _Three H _Four NO HH 0 1192 HHH _Three CSO _Two 3-CH _Three HC _Three H _Four NO HH 0 1193 HHH _Three CSO _Two 3-CF _Three HC _Three H _Four NO HH 0 1194 HHH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NO HH 0 1195 HFH _Three CSO _Two HHC _Three H _Four NO HH 0 1196 HFH _Three CSO _Two 3-FHC _Three H _Four NO HH 0 1197 HFH _Three CSO _Two 3-Cl HC _Three H _Four NO HH 0 1198 HFH _Three CSO _Two 3-CH _Three HC _Three H _Four NO HH 0 1199 HFH _Three CSO _Two 3-CF _Three HC _Three H _Four NO HH 0 1200 HFH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NO HH 0 1201 HHH _Three CSO _Two HHC _Three H _Four NO HH 1 1202 HHH _Three CSO _Two 2-FHC _Three H _Four NO HH 1 1203 HHH _Three CSO _Two 2-Cl HC _Three H _Four NO HH 1 1204 HHH _Three CSO _Two 2-CH _Three HC _Three H _Four NO HH 1 1205 HHH _Three CSO _Two 2-CF _Three HC _Three H _Four NO HH 1 1206 HHH _Three CSO _Two 2-H _Two NCO HC _Three H _Four NO HH 1 1207 HHH _Three CSO _Two 3-FHC _Three H _Four NO HH 1 1208 HHH _Three CSO _Two 3-Cl HC _Three H _Four NO HH 1 1209 HHH _Three CSO _Two 3-CH _Three HC _Three H _Four NO HH 1 1210 HHH _Three CSO _Two 3-CF _Three HC _Three H _Four NO HH 1 1211 HHH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NO HH 1 1212 HFH _Three CSO _Two HHC _Three H _Four NO HH 1 1213 HFH _Three CSO _Two 3-FHC _Three H _Four NO HH 1 1214 HFH _Three CSO _Two 3-Cl HC _Three H _Four NO HH 1 1215 HFH _Three CSO _Two 3-CH _Three HC _Three H _Four NO HH 1 1216 HFH _Three CSO _Two 3-CF _Three HC _Three H _Four NO HH 1 1217 HFH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NO HH 1 1218 HH EtSO _Two HHC _Three H _Four NO HH 0 1219 HH EtSO _Two 3-FHC _Three H _Four NO HH 0 1220 HH EtSO _Two 3-Cl HC _Three H _Four NO HH 0 1221 HH EtSO _Two 3-CH _Three HC _Three H _Four NO HH 0 1222 HH EtSO _Two 3-CF _Three HC _Three H _Four NO HH 0 1223 HH EtSO _Two 3-H _Two NCO HC _Three H _Four NO HH 0 1224 HF EtSO _Two HHC _Three H _Four NO HH 0 1225 HF EtSO _Two 3-FHC _Three H _Four NO HH 0 1226 HF EtSO _Two 3-Cl HC _Three H _Four NO HH 0 1227 HF EtSO _Two 3-CH _Three HC _Three H _Four NO HH 0 1228 HF EtSO _Two 3-CF _Three HC _Three H _Four NO HH 0 1229 HF EtSO _Two 3-H _Two NCO HC _Three H _Four NO HH 0 1230 HH EtSO _Two HHC _Three H _Four NO HH 1 1231 HH EtSO _Two 2-FHC _Three H _Four NO HH 1 1232 HH EtSO _Two 2-Cl HC _Three H _Four NO HH 1 1233 HH EtSO _Two 2-CH _Three HC _Three H _Four NO HH 1 1234 HH EtSO _Two 2-CF _Three HC _Three H _Four NO HH 1 1235 HH EtSO _Two 2-H _Two NCO HC _Three H _Four NO HH 1 1236 HH EtSO _Two 3-FHC _Three H _Four NO HH 1 1237 HH EtSO _Two 3-Cl HC _Three H _Four NO HH 1 1238 HH EtSO _Two 3-CH _Three HC _Three H _Four NO HH 1 1239 HH EtSO _Two 3-CF _Three HC _Three H _Four NO HH 1 1240 HH EtSO _Two 3-H _Two NCO HC _Three H _Four NO HH 1 1241 HF EtSO _Two HHC _Three H _Four NO HH 1 1242 HF EtSO _Two 3-FHC _Three H _Four NO HH 1 1243 HF EtSO _Two 3-Cl HC _Three H _Four NO HH 1 1244 HF EtSO _Two 3-CH _Three HC _Three H _Four NO HH 1 1245 HF EtSO _Two 3-CF _Three HC _Three H _Four NO HH 1 1246 HF EtSO _Two 3-H _Two NCO HC _Three H _Four NO HH 1 1247 HHH _Three CSO _Two HHC _Three H _Four NS HH 0 1248 HHH _Three CSO _Two 3-FHC _Three H _Four NS HH 0 1249 HHH _Three CSO _Two 3-Cl HC _Three H _Four NS HH 0 1250 HHH _Three CSO _Two 3-CH _Three HC _Three H _Four NS HH 0 1251 HHH _Three CSO _Two 3-CF _Three HC _Three H _Four NS HH 0 1252 HHH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NS HH 0 1253 HFH _Three CSO _Two HHC _Three H _Four NS HH 0 1254 HFH _Three CSO _Two 3-FHC _Three H _Four NS HH 0 1255 HFH _Three CSO _Two 3-Cl HC _Three H _Four NS HH 0 1256 HFH _Three CSO _Two 3-CH _Three HC _Three H _Four NS HH 0 1257 HFH _Three CSO _Two 3-CF _Three HC _Three H _Four NS HH 0 1258 HFH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NS HH 0 1259 HHH _Three CSO _Two HHC _Three H _Four NS HH 1 1260 HHH _Three CSO _Two 2-FHC _Three H _Four NS HH 1 1261 HHH _Three CSO _Two 2-Cl HC _Three H _Four NS HH 1 1262 HHH _Three CSO _Two 2-CH _Three HC _Three H _Four NS HH 1 1263 HHH _Three CSO _Two 2-CF _Three HC _Three H _Four NS HH 1 1264 HHH _Three CSO _Two 2-H _Two NCO HC _Three H _Four NS HH 1 1265 HHH _Three CSO _Two 3-FHC _Three H _Four NS HH 1 1266 HHH _Three CSO _Two 3-Cl HC _Three H _Four NS HH 1 1267 HHH _Three CSO _Two 3-CH _Three HC _Three H _Four NS HH 1 1268 HHH _Three CSO _Two 3-CF _Three HC _Three H _Four NS HH 1 1269 HHH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NS HH 1 1270 HFH _Three CSO _Two HHC _Three H _Four NS HH 1 1271 HFH _Three CSO _Two 3-FHC _Three H _Four NS HH 1 1272 HFH _Three CSO _Two 3-Cl HC _Three H _Four NS HH 1 1273 HFH _Three CSO _Two 3-CH _Three HC _Three H _Four NS HH 1 1274 HFH _Three CSO _Two 3-CF _Three HC _Three H _Four NS HH 1 1275 HFH _Three CSO _Two 3-H _Two NCO HC _Three H _Four NS HH 1 1276 HH EtSO _Two HHC _Three H _Four NS HH 0 1277 HH EtSO _Two 3-FHC _Three H _Four NS HH 0 1278 HH EtSO _Two 3-Cl HC _Three H _Four NS HH 0 1279 HH EtSO _Two 3-CH _Three HC _Three H _Four NS HH 0 1280 HH EtSO _Two 3-CF _Three HC _Three H _Four NS HH 0 1281 HH EtSO _Two 3-H _Two NCO HC _Three H _Four NS HH 0 1282 HF EtSO _Two HHC _Three H _Four NS HH 0 1283 HF EtSO _Two 3-FHC _Three H _Four NS HH 0 1284 HF EtSO _Two 3-Cl HC _Three H _Four NS HH 0 1285 HF EtSO _Two 3-CH _Three HC _Three H _Four NS HH 0 1286 HF EtSO _Two 3-CF _Three HC _Three H _Four NS HH 0 1287 HF EtSO _Two 3-H _Two NCO HC _Three H _Four NS HH 0 1288 HH EtSO _Two HHC _Three H _Four NS HH 1 1289 HH EtSO _Two 2-FHC _Three H _Four NS HH 1 1290 HH EtSO _Two 2-Cl HC _Three H _Four NS HH 1 1291 HH EtSO _Two 2-CH _Three HC _Three H _Four NS HH 1 1292 HH EtSO _Two 2-CF _Three HC _Three H _Four NS HH 1 1293 HH EtSO _Two 2-H _Two NCO HC _Three H _Four NS HH 1 1294 HH EtSO _Two 3-FHC _Three H _Four NS HH 1 1295 HH EtSO _Two 3-Cl HC _Three H _Four NS HH 1 1296 HH EtSO _Two 3-CH _Three HC _Three H _Four NS HH 1 1297 HH EtSO _Two 3-CF _Three HC _Three H _Four NS HH 1 1298 HH EtSO _Two 3-H _Two NCO HC _Three H _Four NS HH 1 1299 HF EtSO _Two HHC _Three H _Four NS HH 1 1300 HF EtSO _Two 3-FHC _Three H _Four NS HH 1 1301 HF EtSO _Two 3-Cl HC _Three H _Four NS HH 1 1302 HF EtSO _Two 3-CH _Three HC _Three H _Four NS HH 1 1303 HF EtSO _Two 3-CF _Three HC _Three H _Four NS HH 1 1304 HF EtSO _Two 3-H _Two NCO HC _Three H _Four NS HH 1 1305 HH EtOOC-MS HHC _Three H _Four NS HH 0 1306 HH EtOOC-MS 3-FHC _Three H _Four NS HH 0 1307 HH EtOOC-MS 3-Cl HC _Three H _Four NS HH 0 1308 HH EtOOC-MS 3-CH _Three HC _Three H _Four NS HH 0 1309 HH EtOOC-MS 3-CF _Three HC _Three H _Four NS HH 0 1310 HH EtOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 0 1311 HF EtOOC-MS HHC _Three H _Four NS HH 0 1312 HF EtOOC-MS 3-FHC _Three H _Four NS HH 0 1313 HF EtOOC-MS 3-Cl HC _Three H _Four NS HH 0 1314 HF EtOOC-MS 3-CH _Three HC _Three H _Four NS HH 0 1315 HF EtOOC-MS 3-CF _Three HC _Three H _Four NS HH 0 1316 HF EtOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 0 1317 HH EtOOC-MS HHC _Three H _Four NS HH 1 1318 HH EtOOC-MS 2-FHC _Three H _Four NS HH 1 1319 HH EtOOC-MS 2-Cl HC _Three H _Four NS HH 1 1320 HH EtOOC-MS 2-CH _Three HC _Three H _Four NS HH 1 1321 HH EtOOC-MS 2-CF _Three HC _Three H _Four NS HH 1 1322 HH EtOOC-MS 2-H _Two NCO HC _Three H _Four NS HH 1 1323 HH EtOOC-MS 3-FHC _Three H _Four NS HH 1 1324 HH EtOOC-MS 3-Cl HC _Three H _Four NS HH 1 1325 HH EtOOC-MS 3-CH _Three HC _Three H _Four NS HH 1 1326 HH EtOOC-MS 3-CF _Three HC _Three H _Four NS HH 1 1327 HH EtOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 1 1328 HF EtOOC-MS HHC _Three H _Four NS HH 1 1329 HF EtOOC-MS 3-FHC _Three H _Four NS HH 1 1330 HF EtOOC-MS 3-Cl HC _Three H _Four NS HH 1 1331 HF EtOOC-MS 3-CH _Three HC _Three H _Four NS HH 1 1332 HF EtOOC-MS 3-CF _Three HC _Three H _Four NS HH 1 1333 HF EtOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 1 1334 HH HOOC-MS HHC _Three H _Four NS HH 0 1335 HH HOOC-MS 3-FHC _Three H _Four NS HH 0 1336 HH HOOC-MS 3-Cl HC _Three H _Four NS HH 0 1337 HH HOOC-MS 3-CH _Three HC _Three H _Four NS HH 0 1338 HH HOOC-MS 3-CF _Three HC _Three H _Four NS HH 0 1339 HH HOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 0 1340 HF HOOC-MS HHC _Three H _Four NS HH 0 1341 HF HOOC-MS 3-FHC _Three H _Four NS HH 0 1342 HF HOOC-MS 3-Cl HC _Three H _Four NS HH 0 1343 HF HOOC-MS 3-CH _Three HC _Three H _Four NS HH 0 1344 HF HOOC-MS 3-CF _Three HC _Three H _Four NS HH 0 1345 HF HOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 0 1346 HH HOOC-MS HHC _Three H _Four NS HH 1 1347 HH HOOC-MS 2-FHC _Three H _Four NS HH 1 1348 HH HOOC-MS 2-Cl HC _Three H _Four NS HH 1 1349 HH HOOC-MS 2-CH _Three HC _Three H _Four NS HH 1 1350 HH HOOC-MS 2-CF _Three HC _Three H _Four NS HH 1 1351 HH HOOC-MS 2-H _Two NCO HC _Three H _Four NS HH 1 1352 HH HOOC-MS 3-FHC _Three H _Four NS HH 1 1353 HH HOOC-MS 3-Cl HC _Three H _Four NS HH 1 1354 HH HOOC-MS 3-CH _Three HC _Three H _Four NS HH 1 1355 HH HOOC-MS 3-CF _Three HC _Three H _Four NS HH 1 1356 HH HOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 1 1357 HF HOOC-MS HHC _Three H _Four NS HH 1 1358 HF HOOC-MS 3-FHC _Three H _Four NS HH 1 1359 HF HOOC-MS 3-Cl HC _Three H _Four NS HH 1 1360 HF HOOC-MS 3-CH _Three HC _Three H _Four NS HH 1 1361 HF HOOC-MS 3-CF _Three HC _Three H _Four NS HH 1 1362 HF HOOC-MS 3-H _Two NCO HC _Three H _Four NS HH 1 1363 HHH _Three CSO _Two HHC _Four H ₆ NHH 0 1364 HHH _Three CSO _Two 2-FHC _Four H ₆ NHH 0 1365 HHH _Three CSO _Two 2-Cl HC _Four H ₆ NHH 0 1366 HHH _Three CSO _Two 2-CH _Three HC _Four H ₆ NHH 0 1367 HHH _Three CSO _Two 2-CF _Three HC _Four H ₆ NHH 0 1368 HHH _Three CSO _Two 2-H _Two NCO HC _Four H ₆ NHH 0 1369 HHH _Three CSO _Two 3-FHC _Four H ₆ NHH 0 1370 HHH _Three CSO _Two 3-Cl HC _Four H ₆ NHH 0 1371 HHH _Three CSO _Two 3-CH _Three HC _Four H ₆ NHH 0 1372 HHH _Three CSO _Two 3-CF _Three HC _Four H ₆ NHH 0 1373 HHH _Three CSO _Two 3-H _Two NCO HC _Four H ₆ NHH 0 1374 HHH _Three CSO _Two HHC _Four H ₆ NHH 1 1375 HHH _Three CSO _Two 2-FHC _Four H ₆ NHH 1 1376 HHH _Three CSO _Two 2-Cl HC _Four H ₆ NHH 1 1377 HHH _Three CSO _Two 2-CH _Three HC _Four H ₆ NHH 1 1378 HHH _Three CSO _Two 2-CF _Three HC _Four H ₆ NHH 1 1379 HHH _Three CSO _Two 2-H _Two NCO HC _Four H ₆ NHH 1 1380 HHH _Three CSO _Two 3-FHC _Four H ₆ NHH 1 1381 HHH _Three CSO _Two 3-Cl HC _Four H ₆ NHH 1 1382 HHH _Three CSO _Two 3-CH _Three HC _Four H ₆ NHH 1 1383 HHH _Three CSO _Two 3-CF _Three HC _Four H ₆ NHH 1 1384 HHH _Three CSO _Two 3-H _Two NCO HC _Four H ₆ NHH 1 1385 HH EtSO _Two HHC _Four H ₆ NHH 0 1386 HH EtSO _Two 2-FHC _Four H ₆ NHH 0 1387 HH EtSO _Two 2-Cl HC _Four H ₆ NHH 0 1388 HH EtSO _Two 2-CH _Three HC _Four H ₆ NHH 0 1389 HH EtSO _Two 2-CF _Three HC _Four H ₆ NHH 0 1390 HH EtSO _Two 2-H _Two NCO HC _Four H ₆ NHH 0 1391 HH EtSO _Two 3-FHC _Four H ₆ NHH 0 1392 HH EtSO _Two 3-Cl HC _Four H ₆ NHH 0 1393 HH EtSO _Two 3-CH _Three HC _Four H ₆ NHH 0 1394 HH EtSO _Two 3-CF _Three HC _Four H ₆ NHH 0 1395 HH EtSO _Two 3-H _Two NCO HC _Four H ₆ NHH 0 1396 HH EtSO _Two HHC _Four H ₆ NHH 1 1397 HH EtSO _Two 2-FHC _Four H ₆ NHH 1 1398 HH EtSO _Two 2-Cl HC _Four H ₆ NHH 1 1399 HH EtSO _Two 2-CH _Three HC _Four H ₆ NHH 1 1400 HH EtSO _Two 2-CF _Three HC _Four H ₆ NHH 1 1401 HH EtSO _Two 2-H _Two NCO HC _Four H ₆ NHH 1 1402 HH EtSO _Two 3-FHC _Four H ₆ NHH 1 1403 HH EtSO _Two 3-Cl HC _Four H ₆ NHH 1 1404 HH EtSO _Two 3-CH _Three HC _Four H ₆ NHH 1 1405 HH EtSO _Two 3-CF _Three HC _Four H ₆ NHH 1 1406 HH EtSO _Two 3-H _Two NCO HC _Four H ₆ NHH 1 1407 HFH _Three CSO _Two HHC _Four H ₆ NHH 0 1408 HFH _Three CSO _Two 2-FHC _Four H ₆ NHH 0 1409 HFH _Three CSO _Two 2-Cl HC _Four H ₆ NHH 0 1410 HFH _Three CSO _Two 2-CH _Three HC _Four H ₆ NHH 0 1411 HFH _Three CSO _Two 2-CF _Three HC _Four H ₆ NHH 0 1412 HFH _Three CSO _Two 2-H _Two NCO HC _Four H ₆ NHH 0 1413 HFH _Three CSO _Two 3-FHC _Four H ₆ NHH 0 1414 HFH _Three CSO _Two 3-Cl HC _Four H ₆ NHH 0 1415 HFH _Three CSO _Two 3-CH _Three HC _Four H ₆ NHH 0 1416 HFH _Three CSO _Two 3-CF _Three HC _Four H ₆ NHH 0 1417 HFH _Three CSO _Two 3-H _Two NCO HC _Four H ₆ NHH 0 1418 HFH _Three CSO _Two HHC _Four H ₆ NHH 1 1419 HFH _Three CSO _Two 2-FHC _Four H ₆ NHH 1 1420 HFH _Three CSO _Two 2-Cl HC _Four H ₆ NHH 1 1421 HFH _Three CSO _Two 2-CH _Three HC _Four H ₆ NHH 1 1422 HFH _Three CSO _Two 2-CF _Three HC _Four H ₆ NHH 1 1423 HFH _Three CSO _Two 2-H _Two NCO HC _Four H ₆ NHH 1 1424 HFH _Three CSO _Two 3-FHC _Four H ₆ NHH 1 1425 HFH _Three CSO _Two 3-Cl HC _Four H ₆ NHH 1 1426 HFH _Three CSO _Two 3-CH _Three HC _Four H ₆ NHH 1 1427 HFH _Three CSO _Two 3-CF _Three HC _Four H ₆ NHH 1 1428 HFH _Three CSO _Two 3-H _Two NCO HC _Four H ₆ NHH 1 1429 HF EtSO _Two HHC _Four H ₆ NHH 0 1430 HF EtSO _Two 2-FHC _Four H ₆ NHH 0 1431 HF EtSO _Two 2-Cl HC _Four H ₆ NHH 0 1432 HF EtSO _Two 2-CH _Three HC _Four H ₆ NHH 0 1433 HF EtSO _Two 2-CF _Three HC _Four H ₆ NHH 0 1434 HF EtSO _Two 2-H _Two NCO HC _Four H ₆ NHH 0 1435 HF EtSO _Two 3-FHC _Four H ₆ NHH 0 1436 HF EtSO _Two 3-Cl HC _Four H ₆ NHH 0 1437 HF EtSO _Two 3-CH _Three HC _Four H ₆ NHH 0 1438 HF EtSO _Two 3-CF _Three HC _Four H ₆ NHH 0 1439 HF EtSO _Two 3-H _Two NCO HC _Four H ₆ NHH 0 1440 HF EtSO _Two HHC _Four H ₆ NHH 1 1441 HF EtSO _Two 2-FHC _Four H ₆ NHH 1 1442 HF EtSO _Two 2-Cl HC _Four H ₆ NHH 1 1443 HF EtSO _Two 2-CH _Three HC _Four H ₆ NHH 1 1444 HF EtSO _Two 2-CF _Three HC _Four H ₆ NHH 1 1445 HF EtSO _Two 2-H _Two NCO HC _Four H ₆ NHH 1 1446 HF EtSO _Two 3-FHC _Four H ₆ NHH 1 1447 HF EtSO _Two 3-Cl HC _Four H ₆ NHH 1 1448 HF EtSO _Two 3-CH _Three HC _Four H ₆ NHH 1 1449 HF EtSO _Two 3-CF _Three HC _Four H ₆ NHH 1 1450 HF EtSO _Two 3-H _Two NCO HC _Four H ₆ NHH 1 1451 HF EtOOC-MS HHC _Four H ₆ NHH 0 1452 HF EtOOC-MS 2-FHC _Four H ₆ NHH 0 1453 HF EtOOC-MS 2-Cl HC _Four H ₆ NHH 0 1454 HF EtOOC-MS 2-CH _Three HC _Four H ₆ NHH 0 1455 HF EtOOC-MS 2-CF _Three HC _Four H ₆ NHH 0 1456 HF EtOOC-MS 2-H _Two NCO HC _Four H ₆ NHH 0 1457 HF EtOOC-MS 3-FHC _Four H ₆ NHH 0 1458 HF EtOOC-MS 3-Cl HC _Four H ₆ NHH 0 1459 HF EtOOC-MS 3-CH _Three HC _Four H ₆ NHH 0 1460 HF EtOOC-MS 3-CF _Three HC _Four H ₆ NHH 0 1461 HF EtOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 0 1462 HF EtOOC-MS HHC _Four H ₆ NHH 1 1463 HF EtOOC-MS 2-FHC _Four H ₆ NHH 1 1464 HF EtOOC-MS 2-Cl HC _Four H ₆ NHH 1 1465 HF EtOOC-MS 2-CH _Three HC _Four H ₆ NHH 1 1466 HF EtOOC-MS 2-CF _Three HC _Four H ₆ NHH 1 1467 HF EtOOC-MS 2-H _Two NCO HC _Four H ₆ NHH 1 1468 HF EtOOC-MS 3-FHC _Four H ₆ NHH 1 1469 HF EtOOC-MS 3-Cl HC _Four H ₆ NHH 1 1470 HF EtOOC-MS 3-CH _Three HC _Four H ₆ NHH 1 1471 HF EtOOC-MS 3-CF _Three HC _Four H ₆ NHH 1 1472 HF EtOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 1 1473 HF HOOC-MS HHC _Four H ₆ NHH 0 1474 HF HOOC-MS 2-FHC _Four H ₆ NHH 0 1475 HF HOOC-MS 2-Cl HC _Four H ₆ NHH 0 1476 HF HOOC-MS 2-CH _Three HC _Four H ₆ NHH 0 1477 HF HOOC-MS 2-CF _Three HC _Four H ₆ NHH 0 1478 HF HOOC-MS 2-H _Two NCO HC _Four H ₆ NHH 0 1479 HF HOOC-MS 3-FHC _Four H ₆ NHH 0 1480 HF HOOC-MS 3-Cl HC _Four H ₆ NHH 0 1481 HF HOOC-MS 3-CH _Three HC _Four H ₆ NHH 0 1482 HF HOOC-MS 3-CF _Three HC _Four H ₆ NHH 0 1483 HF HOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 0 1484 HF HOOC-MS HHC _Four H ₆ NHH 1 1485 HF HOOC-MS 2-FHC _Four H ₆ NHH 1 1486 HF HOOC-MS 2-Cl HC _Four H ₆ NHH 1 1487 HF HOOC-MS 2-CH _Three HC _Four H ₆ NHH 1 1488 HF HOOC-MS 2-CF _Three HC _Four H ₆ NHH 1 1489 HF HOOC-MS 2-H _Two NCO HC _Four H ₆ NHH 1 1490 HF HOOC-MS 3-FHC _Four H ₆ NHH 1 1491 HF HOOC-MS 3-Cl HC _Four H ₆ NHH 1 1492 HF HOOC-MS 3-CH _Three HC _Four H ₆ NHH 1 1493 HF HOOC-MS 3-CF _Three HC _Four H ₆ NHH 1 1494 HF HOOC-MS 3-H _Two NCO HC _Four H ₆ NHH 1 ------------------------------------------------ -----------------------

Among the above exemplified compounds, preferred compounds include 14 (Example 27), 21 (Example 41) and 22 (Example 41).
(Example 47), 23 (Example 49), 25 (Example 5)
3), 26 (Example 55), 53 (Example 65), 54
(Example 67), 81 (Example 59), 82 (Example 6)
1), 85 (Example 45), 109 (Example 77), 1
10 (Example 79), 137 (Example 71), 138
(Example 73), 507 (Example 6), 518 (Example 28), 523 (Example 38), 525 (Example 4)
2), 526 (Example 48), 527 (Example 50),
529 (Example 54), 530 (Example 56), 557
(Example 66), 558 (Example 68), 585 (Example 60), 586 (Example 62), 589 (Example 4)
6), 613 (Example 78), 614 (Example 80),
641 (Example 72), 642 (Example 74), 102
7 (Example 89), 1029 (Example 94), 1081
(Example 86) and 1099 (Example 87). Particularly preferred compounds include

N- [3- (3-amidinophenyl) -2
-(E) -propenyl] -N- [3-chloro-4- [1
-(4-Pyridyl) piperidin-4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 14, Example 27), N- [3- (3-amidinophenyl) -2- (E) -propenyl ] -N- [3-chloro-4- (1-formimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (Exemplified Compound No. 22, Example 47), N- [3-
(3-amidinophenyl) -2- (E) -propenyl]
-N- [3-chloro-4- [1- (1-iminopropyl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid ethyl dihydrochloride (Exemplified Compound No. 23, Example 49), N- [3- ( 3-amidinophenyl) -2
-(E) -propenyl] -N- [3-chloro-4- [1
-(4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplified Compound No. 25, Example 5
3), N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-
Yloxy] -3-methylphenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplified Compound No. 53, Example 6
5), N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-
Yloxy] -3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplified Compound No. 10
9, Example 77), N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-
4- (1-isopropylpiperidin-4-yloxy)
Phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 507, Example 6), N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1 -(4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 518, Example 28), N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] -N-
[3-chloro-4- (1-cyclopentylpiperidine-
4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 523, Example 38), N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (indolizin-7-yloxy) phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 525, Example 42) ), N- [3-
(3-amidinophenyl) -2- (E) -propenyl]
-N- [3-chloro-4- (1-formimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 526, Example 48),
N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (1-iminopropyl) piperidin-4-yloxy] phenyl]
Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 52
7, Example 50), N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-
4- [1- (4,5-dihydro-3H-pyrrole-2-
Il) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 529, Example 54), N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-
Iloxy] -3-methylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 557, Example 66),
N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 585, Example 60), N- [3- (3-amidinophenyl) -2- (E)- Propenyl] -N- [4
-(1-Methylpiperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 589, Example 46), N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] -3
-Trifluoromethylphenyl] sulfamoylacetic acid
Dihydrochloride (Exemplary Compound No. 613, Example 78), N-
[3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4,5
-Dihydro-3H-pyrrol-2-yl) piperidine-
4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplified Compound No. 641, Example 72), N- [3
-(3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoyl Acetic acid dihydrochloride (Exemplified Compound No. 1027, Example 89), N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N-
[4- [1- (4,5-Dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1029, Example 94) and N- [3- (3- Amidinophenyl) -2
-(E) -propenyl] -N- [3-chloro-4- [1
-(N-ethylformimidoyl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1099, Example 87).

[0066]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (1) of the present invention can be produced, for example, by the following method.

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In the above process chart, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ and n indicate consent as described above, and R ^1a , R ^3a , R ^4a ,
R ^5a and R ^6a are each R ¹ , R ³ or R ³ in which the substituent on R ¹ or R ¹ is protected, and R ³ , R ⁴ or R ⁴ in which the substituent on R ³ or R ³ is protected.
R ⁴ substituents of the above protected, R ⁵ or R ⁵ substituents on R ⁵ are protected, and the substituents on R ⁶ or R ⁶ is a protected R ⁶
And R ^6b represents R ^6a or a protecting group for an amino group, and Pro
Represents a hydroxyl-protecting group, and X represents a halogen atom or a hydroxyl group.

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

(First Step) This step is a step for producing a compound having the general formula (4). The compound having the general formula (2) is prepared in an inert solvent in the presence of a phosphine and an azo compound. This is achieved by condensation with a compound having the general formula (3).

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 aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; , Toluene or xylene; aromatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or ethers such as diethylene glycol dimethyl ether, preferably halogenated hydrocarbons (dichloromethane) or ethers (particularly diethyl ether or tetrahydrofuran).

The phosphines used include, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexylphosphine, and other tri-C ₁ -C ₆ alkylphosphines; triphenylphosphine, triindenyl Tris such as phosphine or trinaphthylphosphine
C ₆ -C ₁₀ arylphosphine; or having a C ₁ -C ₄ alkyl as a substituent, such as tolyldiphenylphosphine, tolylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine. May be a tri-C ₆ -C ₁₀ arylphosphine, preferably tri-C ₁ -C ₆ alkyl phosphines (especially trimethylphosphine, triethylphosphine,
Tripropylphosphine or tributylphosphine,)
Or tri C ₆ -C ₁₀ aryl phosphine (particularly triphenyl phosphine, triindenyl phosphine or trinaphthyl phosphine), and more preferably tributyl phosphine or triphenyl phosphine.

The azo compound used is, for example, azodicarbonyldipiperidine or azodicarboxylic acid di-C ₁ -C ₄ such as dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate. It can be alkyl, preferably azodicarbonyl dipiperidine, dimethyl azodicarboxylate or diethyl 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 the completion of the reaction, if any insolubles are present, they are removed by filtration, and the solvent is distilled off. After adding an immiscible solvent (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 desired compound. . 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 for producing a compound having the general formula (1), wherein (a) a reaction for converting a cyano group into an amidino group, and if desired, (b)
Reaction for removing the protecting group of the protected amino group, (c)
The reaction can be achieved by combining a reaction for introducing a desired substituent into an amino group, (d) a hydrolysis reaction of an ester, and (e) a reaction for removing a protecting group of a protected hydroxyl group in an appropriate order.

The essential reaction (a), “reaction for converting a cyano group to an amidino group”, is generally carried out according to a method well known in the art, and (1) starting a compound in an inert solvent or In the absence of a solvent (preferably in an inert solvent)
Reacting with an alcohol in the presence of an acid to ammonolyse the imino ether compound generated as an intermediate, or (2) reacting the starting compound with hydroxylamine in an inert solvent in the presence or absence of a base, This is achieved by hydrogenolysis of an amide oxime compound produced as an intermediate.

Reaction (a) (1) is a two-step reaction. First, the first step is a reaction in which a nitrile 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 inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; esters such as methyl acetate or ethyl acetate; nitro compounds such as nitromethane; formamide, N, N-dimethylformamide; An amide such as N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; a sulfoxide such as dimethylsulfoxide or sulfolane; or a mixed solvent of the above organic solvents, preferably an aromatic hydrocarbon (Particularly benzene) or halogenated hydrocarbons (particularly dichloromethane), particularly preferably halogenated hydrocarbons (particularly dichloromethane).

In this reaction, the solvent may be used in excess alcohols (for example, methanol, ethanol, propanol, 2-propanol, butanol or isobutanol, etc., preferably methanol or ethanol). ), And the reaction is usually performed in alcohol unless there is a problem.

The acids used are, for example, mineral acids such as hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethane Sulfonic acids such as sulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or boron trifluoride, aluminum chloride, iron chloride (II
It can be a Lewis acid such as I), zinc chloride, mercury (II) chloride, 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 varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 48 hours.
Preferably, it is 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, a method of distilling off the solvent), but may be used for the next reaction without isolation and purification. it can.

The second step of the reaction (a) (1) is a reaction in which the imino ether compound produced in the first step is ammonolyzed. This reaction is usually carried out in an inert solvent,
Performed in the presence of ammonium ions.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, methanol, ethanol, propanol,
Alcohols such as 2-propanol, butanol or isobutanol; water; or a mixed solvent of alcohols and water, preferably methanol, ethanol,
It is water, hydrated methanol or hydrated ethanol, particularly preferably hydrated methanol or hydrated ethanol.

The ammonium source of the ammonium ion used can be, for example, aqueous ammonia, ammonium chloride, ammonium carbonate or a mixture thereof,
Preferably, it is ammonium chloride.

The pH in the reaction is neutral to weakly basic, and is preferably adjusted using aqueous ammonia and hydrochloric acid.
7 to 9.

The reaction temperature depends 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 varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 48 hours.
Preferably, it is 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 extract the target compound. After that, 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.

Reactions (a) and (2) are two-step reactions. First, the first step is a reaction in which a nitrile group is reacted with hydroxylamine in an inert solvent in the presence of a base, if desired, to obtain an amide oxime compound.

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 aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane 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- Alcohols such as propanol, butanol or isobutanol; formamide,
Amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethylsulfoxide or sulfolane; or water, preferably alcohols ( Especially methanol or ethanol).

The hydroxylamine source used may be an aqueous solution of hydroxylamine, a solution in an organic solvent or a salt with an acid.

The base to be used is not particularly limited as long as it can neutralize a salt of hydroxylamine with an acid (when a salt of hydroxylamine is used directly, Not necessarily required)), for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate;
Alkali metal bicarbonates such as potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal acetates such as sodium acetate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide , Sodium ethoxide, potassium t-
Alkali metal alkoxides such as butoxide or lithium methoxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N-diethylaniline, 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] undec-7-ene (DBU), preferably alkali metal carbonates (particularly carbonate). Sodium) or alkali metal alkoxides (particularly potassium t-butoxide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 50 ° C.
C. to 100.degree.

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, it is 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 particular isolation and purification. .

The second step of the reactions (a) and (2) is a reaction for subjecting the amide oxime compound produced in the first step to hydrogenolysis.

Usually, before the hydrogenolysis, the hydroxyl group is modified with an eliminable group, and an acetyl group is conveniently used.
Acetylation is usually performed using acetic anhydride in acetic acid, but may be performed in a solvent if necessary.

The solvent used for the acetylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples of the solvent include fatty acids such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl Ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; or acetonitrile or isobutyro Obtained a nitrile such as tolyl, preferably, a halogenated hydrocarbon (particularly dichloromethane) or an ether (particularly tetrahydrofuran).

The reaction temperature for acetylation varies depending on the starting compounds, reagents and the like, but is usually from 0 ° C. to 150 ° C.
Preferably it is 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.
Time, preferably 5 to 12 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture by a conventional method (for example, a method of distilling off the solvent after completion of the reaction). It can also be used.

The hydrogenolysis of the amide oxime compound (deacetoxylation when the hydroxyl group is acetylated) is usually performed successively without changing the reaction solvent. Also, if desired, the solvent is distilled off once, and the resulting residue is again
It can also be carried out by dissolving in an inert solvent.

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 aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane 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- Alcohols such as propanol, butanol or isobutanol; formamide,
Amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethylsulfoxide or sulfolane; carboxylic acids such as formic acid or acetic acid;
Water; or a mixed solvent of the above solvents,
Alcohols (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, and examples thereof include palladium black, palladium-carbon, palladium hydroxide, and hydroxide. It can be palladium-carbon, Raney nickel, rhodium-aluminum oxide, 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 100 ° 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, it is 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. Alternatively, after completion of the reaction, the catalyst is removed by filtration, and then water is added to the reaction solution, and a water-immiscible solvent (for example, benzene, Ether, ethyl acetate, etc.) to extract the desired compound, wash the extracted organic layer with water, dry using anhydrous magnesium sulfate, etc., and distill off the solvent 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 (b), “reaction for removing a protected amino group-protecting group”, is generally carried out as follows according to a method well known in the art of synthetic organic chemistry.

The protecting groups for the amino group are formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-bromo-t-butoxycarbonyl, 2,2-dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-type −
When it is a nitrobenzyloxycarbonyl 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 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 aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N- Amides such as methylformamide, 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 above solvent. Although a mixed solvent can be mentioned, a mixed solvent of halogenated hydrocarbons, ethers, alcohols, fatty acids or water and the above-mentioned solvent is preferable, and a halogenated hydrocarbon (especially Dichloromethane), ethers (especially tetrahydrofuran or dioxane), fatty acids (especially acetic acid), alcohols (especially methanol or ethanol), or
It is water or a mixed solvent of water and the above solvent.

The reaction temperature varies depending on the starting compound, the solvent and the acid used, but is usually from -10 ° C to 150 ° C.
And preferably from 0 ° C to 100 ° C.

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 target compound precipitated in the reaction solution is collected by filtration, or, if necessary, neutralized appropriately, the solvent is distilled off, and dried, or the reaction solution is poured into water, if necessary. Neutralize and extract by adding a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.), 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an alkanoyl, an arylcarbonyl, an alkoxycarbonyl, an alkenyloxycarbonyl, an aryldicarbonyl, an aralkyl or an aralkyloxycarbonyl, in an inert solvent or an aqueous solvent Can be removed by treating with a base.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Mercaptan alkali metals: hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic bases such as -diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates (especially sodium or potassium carbonate), alkali metal hydroxides (Especially sodium or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or potassium tert-butoxide) or organic bases (especially hydrazine or methylamine).

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 aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as 2-propanol or butanol; formamide, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons , Ethers, alcohols, or a mixed solvent of water and the above-mentioned solvent, more preferably ethers (particularly, tetrahydrofuran or dioxane), alcohols (particularly, methanol, ethanol), or a mixed solvent of water and the above-mentioned solvent It is.

The reaction temperature varies depending on the starting compound, the solvent or the base used, but is usually from -10 ° C to 50 ° C.
And preferably from -5 ° 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. Filter the resulting precipitate or
Or a solvent immiscible with water (eg, benzene, ether,
Ethyl acetate) is added, and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and 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.

When the amino-protecting group is a 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. For example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; Ethers such as ter, tetrahydrofuran or dioxane; or nitriles such as acetonitrile, preferably halogenated hydrocarbons (particularly dichloromethane or chloroform) or nitriles (particularly acetonitrile). .

The reaction temperature varies depending on the starting compound, reagent, solvent and the like, but is usually from -20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, reagent, solvent, 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 (eg, 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 and the like, and 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.

When the protecting group for the amino group is an allyloxycarbonyl group, it can be removed in the same manner as the removal method by catalytic reduction particularly 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 for the amino group is an aralkyl group or C ₇
In the case of a -C ₁₁ 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. Can be mentioned.

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 take part in this reaction. For example, an aliphatic hydrocarbon such as hexane or cyclohexane is used. Aromatic hydrocarbons such as toluene, benzene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or 2-propanol. 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), a mixed solvent of fatty acids (particularly formic acid or acetic acid), or 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.
Palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate can be mentioned, but palladium-carbon or Raney-nickel is preferred.

Although the pressure is not particularly limited, it is usually 1 to 1
It is carried out at 0 atm, preferably at 1 atm.

The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like.
° C, preferably from 10 ° C to 50 ° C.

The reaction time varies depending on the starting compound, solvent, reducing agent used, reaction temperature and the like.
Minutes to 24 hours, 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 collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) ), 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. 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; and halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; N, N-dimethylformamide, N, N
Amides such as dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; 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 with water, more preferably ketones (especially acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (Especially acetonitrile), amides (especially hexamethyl phosphorotriamide), sulfoxides (especially dimethyl sulfoxide), or a mixed solvent of these organic solvents and water.

The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Preferably, it is CAN or DDQ.

The reaction temperature varies depending on the starting compound, the solvent, the oxidizing agent used, and the like.
° C, 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 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 like, 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the desired reaction (c), “reaction to introduce a desired substituent into an amino group”, a starting compound is prepared by reacting a starting compound in an inert solvent in the presence or absence of a base (preferably in the presence of a base). ), Reagent R ⁶ -Xa (Xa is achieved by reacting a halogen atom (especially a fluorine atom or a chlorine atom) or an alkoxy group (especially a methoxy group or an ethoxy group).

The solvent used in the reaction (c) 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, ligroin and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; acetonitrile or isobutyronitrile Nitriles; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone Amides; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably alcohols (especially ethanol).

The base used in the reaction (c) is, 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; such as sodium hydroxide, potassium hydroxide or lithium hydroxide Alkali metal hydroxides; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4
-Diazabicyclo [2.2.2] octane (DABC
O) or organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU);
Preferably, they are alkali metal carbonates (sodium carbonate or potassium carbonate) or organic bases (particularly triethylamine).

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 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 that, 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 synthetic organic chemistry, by reacting a starting compound with an acid or base in an inert solvent or in the absence of a solvent. In the following, it 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 materials to some extent. For example, methanol, ethanol, propanol,
It may be a mixed solvent of alcohol and water such as 2-propanol, butanol or isobutanol, and is preferably hydrated methanol or hydrated 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, and the like. Sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid; or carboxylic acid salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, or maleic acid, and is preferably a mineral acid (particularly hydrochloric acid). )
It is.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alternatively, it can be an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.

The reaction temperature varies depending on the starting compounds, reagents, etc., but in the case of the reaction using an acid, it is usually 0 ° C. to 150 ° C.
° C (preferably 50 ° C to 100 ° C), and in a reaction using a base, usually -10 ° C to 50 ° C (preferably -5 ° C).
C. to 10 C.).

The reaction time varies depending on the starting compound, the reagent and the reaction temperature.
The reaction time is from 0 minute to 48 hours (preferably from 3 hours to 10 hours), and in the reaction using a base, it is usually from 5 minutes to 10 hours (preferably from 10 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 the completion of the reaction, by distilling off the solvent, or after the completion of the reaction,
The reaction solution is acidified with an acid (eg, hydrochloric acid), and the target compound precipitated is collected by filtration, or a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract and extract the target compound. The obtained organic layer is washed with water and dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the desired compound. After completion of the reaction, the carbonate of the target compound can be obtained by passing carbon dioxide gas through an aqueous solvent or adding sodium carbonate or potassium carbonate. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

The desired reaction (e), “reaction to remove a protected hydroxyl-protecting group” is described, for example, in Protective Groups in Organic Synthesis, Third Edition, T.W. W. Green and P. G. FIG. M. Watts, John Wiley and Sons, Inc. [Prot
ective Groups in Organic Synthesis, 3rd edition,
TW Greene & PGM Wuts; John Wiley & Sons, In
c.].

When the protecting group for a hydroxyl group is a formyl group, an acetyl group, a benzoyl group, a tetrahydropyran-2-yl group,
3-bromotetrahydropyran-2-yl group, 4-methoxytetrahydropyran-4-yl group, tetrahydrothiopyran-2-yl group, 4-methoxytetrahydrothiopyran-4-yl group, tetrahydrofuran-2-yl group, Tetrahydrothiofuran-2-yl group, methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group, t-butoxymethyl group,
2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, 1-ethoxyethyl group, 1- (isopropoxy)
Ethyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group Benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group in an inert solvent Alternatively, it can be removed by treating with an acid in 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. It is.

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 aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N- Amides such as methylformamide, 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 above solvent. Can be a mixed solvent,
Preferably, it is a mixed solvent of halogenated hydrocarbons, ethers, esters, alcohols, fatty acids or water and the above-mentioned solvent, and more preferably, halogenated hydrocarbons (particularly dichloromethane), ethers ( In particular, 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, solvent or acid used, but is usually from -10 ° C to 150 ° 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 water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added thereto, and the mixture is extracted. 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.

When the protecting group for the hydroxyl group is an alkanoyl, a carboxylated alkanoyl, a halogenoalkanoyl, an alkoxyalkanoyl, an unsaturated alkanoyl, an arylcarbonyl, a halogenoarylcarbonyl, an alkylated arylcarbonyl, a carboxylated arylcarbonyl, When it is a nitrated arylcarbonyl, an alkoxycarbonylated arylcarbonyl or an arylated arylcarbonyl, it can be removed by treating with a base in an inert solvent or an aqueous solvent.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Mercaptan alkali metals: hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic bases such as -diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates (especially sodium or potassium carbonate), alkali metal hydroxides (Especially sodium or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or potassium tert-butoxide) or organic bases (especially hydrazine or methylamine).

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 aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as 2-propanol or butanol; formamide, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons , Ethers, alcohols, or a mixed solvent of water and the above-mentioned solvent, more preferably ethers (particularly, tetrahydrofuran or dioxane), alcohols (particularly, methanol, ethanol), or a mixed solvent of water and the above-mentioned solvent It is.

The reaction temperature varies depending on the starting compound, solvent or base used, but is usually from -10 ° C to 150 ° C.
And preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, solvent or 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 completion of the reaction, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.)
After extracting and washing the organic layer containing the target compound with water,
The target compound is obtained by drying using anhydrous magnesium sulfate 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.

When the protecting group for a hydroxyl group is an aralkyl group or 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 a method of removing using an oxidizing agent.

In the case of the reaction for removing the protecting group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in this reaction. Examples thereof include aliphatic hydrocarbons such as hexane and cyclohexane; Aromatic hydrocarbons such as toluene, benzene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or 2-propanol; Fatty acids such as formic acid or acetic acid;
Alternatively, it may be 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,
It is an alcohol (especially methanol or ethanol), a fatty acid (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.
It can be palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferably palladium-carbon or Raney-nickel.

Although the pressure is not particularly limited, it is usually 1 to 1
It is carried out at 0 atm, preferably at 1 atm.

The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like.
° C, preferably from 10 ° C to 50 ° C.

The reaction time varies depending on the starting compound, solvent, reducing agent used, reaction temperature and the like.
Minutes to 10 hours, preferably 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, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted. After the organic layer containing the target compound is washed with water, anhydrous magnesium sulfate, etc. And the solvent is distilled off to obtain the desired compound. The resulting target compound is, if necessary,
It 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; and halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride. Hydrogens; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; N, N-dimethylformamide, N, N
Amides such as dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent of these organic solvents and water, preferably ketones and halogenated hydrocarbons. , Nitriles, ethers, amides, sulfoxides, or a mixed solvent of these organic solvents and water,
More preferably, ketones (especially acetone), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide) or a mixture thereof It is a mixed solvent of an organic solvent and water.

The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Preferably, it is 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 ° C. to 150 ° C.
And preferably 10 ° C to 50 ° C.

The reaction time varies depending on the compound, solvent or oxidizing agent used, 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, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted. The organic layer containing the target compound is washed with water, and then anhydrous magnesium sulfate, etc. 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 protecting group of the hydroxyl group is a silyl, a method of removing the protecting group by reacting it with a compound which generates a fluorine anion in an inert solvent is generally 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 aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ether. (Preferably tetrahydrofuran).

The compound forming the fluoride anion used can be, for example, tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride,
Preferably, it is tetrabutylammonium fluoride.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 100 ° C, preferably -50 ° C.
10 ° C. 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 anhydrous magnesium sulfate, etc. After drying using, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

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

(Third Step) This step is a step for producing a compound having the general formula (6). This is achieved by condensation with a compound having the general formula (5).

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

(Fourth Step) In this step, (a) the step of removing the hydroxyl-protecting group of compound (6), and (b)
A compound obtained in the step (a) and a compound represented by the general formula (7):

[0195]

Embedded image [Wherein, R ^6a , R ⁷ , R ⁸ and n are as defined above. And producing a compound having the general formula (4). The former (a) can be performed similarly to the second step (e), and the latter (b) can be performed similarly to the first step.

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

(Fifth Step) This step is a step of producing a compound represented by the general formula (9), and comprises the step of preparing a compound represented by the 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 inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or nitriles such as acetonitrile, propionitrile or butyronitrile, preferably aromatic hydrocarbons (particularly benzene or toluene).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 30 ° C.
To 100 ° 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 5 hours.

After the 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 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.

(Sixth Step) 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 inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol;
Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; or alcohols which can be a mixed solvent of the above solvents, and when the reducing agent is aluminum hydride or diborane, aliphatic hydrocarbons (particularly, Hexane or cyclohexane), aromatic hydrocarbons (particularly benzene, toluene or xylene) or ethers (particularly diethyl ether, tetrahydrofuran or dioxane), and alcohols (particularly methanol) when the reducing agent is sodium borohydride. Or a mixed solvent of halogenated hydrocarbons and alcohols (especially a mixed solvent of dichloromethane and ethanol)
It is.

The reducing agent used can be an aluminum hydride compound such as lithium aluminum hydride or diisobutyl aluminum hydride, sodium borohydride or diborane, 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 -78 ° C to 100 ° C, preferably from 0 ° C to 100 ° C.
C. to 50.degree.

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, and then the extracted organic compound is extracted. The 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.

(Steps 7 and 8) This step is performed according to the general formula (1)
1) a step for preparing a compound having the formula HCCCH ₂
Reacting a compound having O-Pro (wherein Pro has the same meaning as described above) with catecholborane in an inert solvent or in the absence of a solvent (preferably in the absence of a solvent) (8) The obtained intermediate compound was treated in an inert solvent in the presence of a palladium catalyst and a base by the general formula (1)
This is achieved by reacting with a compound having 0).

The solvent used in the seventh step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or diethyl It can be an ether such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons (especially hexane or petroleum ether) or aromatic hydrocarbons (especially toluene) It is.

The reaction temperature in the seventh step varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C.
Preferably it is 30 ° C to 80 ° C.

The reaction time in the seventh step is based on the starting compound, the reagent,
Although it depends on the reaction temperature, it 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 the reaction is completed, the target compound is obtained by distilling off the solvent. In addition, it can also be used for the 8th step without 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. Examples thereof include hexane, cyclohexane, heptane, ligroin and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether; Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol, ethanol, propanol, 2-propanol,
Alcohols such as butanol or isobutanol;
Alternatively, it may be a mixed solvent of the above organic solvents, and is preferably an aromatic hydrocarbon (particularly toluene).

The palladium catalyst used in the eighth step is
For example, tetrakis (triphenylphosphine) palladium, palladium bis (triphenylphosphine) chloride
Complex, palladium phosphine complex such as palladium chloride bis (diphenylphosphinoferrocene) complex or palladium bis (triphenylphosphine) acetate; or tris (dibenzylideneacetone) dipalladium chloroform complex, bis (dibenzylideneacetone) palladium, palladium acetate Alternatively, it may be dimer of piarylpalladium chloride, preferably tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex or palladium chloride bis (diphenylphosphinoferrocene) complex, more preferably Is tetrakis (triphenylphosphine) 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 bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N
-Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] Octane (DABCO) or 1,8
Organic amines such as -diazabicyclo [5.4.0] undec-7-ene (DBU);
Alkali metal alkoxides (particularly sodium ethoxide).

The reaction temperature in the eighth step varies depending on the starting compounds, reagents and the like, but is usually 0 ° C to 150 ° C, preferably 50 ° C 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 (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water, and anhydrous magnesium sulfate, etc. After drying using, 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.

(Ninth Step) The ninth step is a step of producing the compound (2), which is achieved by removing the protecting group of the hydroxyl group of the compound (11), and the reaction (e) of the second step is carried out.
Under the same conditions as described above.

(Tenth Step) The tenth step is represented by the general formula (1)
4) a step of producing a compound having the general formula (1)
In the compound having 2), when X represents a leaving group,
(A) a compound represented by the general formula (13)

[0221]

Embedded image [Wherein, R ^6b , R ⁷ , R ⁸ and n have the same meaning as described above. ]
Is reacted with compound (12) in an inert solvent in the presence of a base, or in the case where X represents a hydroxyl group in compound (12), (b) It is achieved by performing dehydration condensation with compound (12) in the presence of a phosphine and an azo compound in an active solvent. This step can be performed in the same manner as in the first step.

Method (a): The solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N- Amides such as methylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably amides (particularly 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 bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; Alkali metal acetates such as sodium acetate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N
-Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] Octane (DABCO) or 1,8
Organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; or like lithium diisopropylamide or lithium dicyclohexylamide Lithium amides, preferably alkali metal hydrides (especially lithium hydride or sodium hydride), metal alkoxides (especially sodium methoxide) or alkyllithiums (especially butyllithium).

The reaction temperature in this step varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C.
Preferably, it is -5 ° C to 50 ° C.

The reaction time in this step is based on the starting compound, reagent,
Although it depends on the reaction temperature, it is usually from 5 minutes to 24 hours, preferably from 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 water-immiscible solvent (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 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.

(Eleventh Step) This step is carried out according to the general formula (15)
This is a process performed when R ^6b is a substituent different from R ^6a in the general formula (17). Deprotection of the amino-protecting 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 omitted.

(Twelfth Step) This step is a reaction of the general formula (16)
Is a method for producing a compound having the general formula (15)
To the compound having the formula (1), in an inert solvent, the reagent R ⁶ -Xa
(Xa represents the reaction of a halogen atom (especially a chlorine or bromine atom) or an alkoxy group (especially a methoxy or ethoxy group) in the presence of a base, or (2) reacting a reagent R ⁶
-Xa (Xa is a halogen atom (especially a chlorine or bromine atom), a trifluoromethanesulfonyloxy group) in the presence of a palladium catalyst, phosphines and a base, or (3) a carbon atom in an inert solvent. A chain ketone having 1 to 6 carbon atoms or a cyclic ketone having 3 to 8 carbon atoms,
Reacting in the presence of acetic acid and sodium cyanoborohydride or sodium triacetoxyborohydride,
This is performed by any of the methods described above. In this step,
If the eleventh step is omitted, it 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 materials to some extent. Examples thereof include hexane, cyclohexane, heptane, ligroin and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether Ethers such as isopropyl, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; Be a mixture of solvents, preferably,
Aromatic hydrocarbons (particularly toluene).

The palladium catalyst used is, for example, tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex, palladium chloride bis (diphenylphosphinoferrocene) complex or palladium bis (triphenylphosphine) acetate
Or a dimer of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or diaryl palladium chloride, preferably palladium acetate or tris (dibenzylideneacetone). (Acetone) dipalladium.

The phosphines used include, for example, tri C ₁ -C ₆ alkyl phosphines such as trimethyl phosphine, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tri-t-butyl phosphine, tripentyl phosphine or trihexyl phosphine; phenyl phosphine, tri C ₆ -C ₁₀ arylphosphine such as tri indenyl phosphine or trinaphthylphosphine; tolyl diphenyl phosphine, tritolylphosphine, trimesitylphosphine phosphine, tributyl triphenylphosphine or tri-6-ethyl-2-naphthyl phosphines such as , C ₁ -C ₄ alkyl optionally having a substituent as a substituent
₆ -C ₁₀ arylphosphine; or 2- (di-t- butylphosphino) biphenyl, 2- (dicyclohexyl phosphino) biphenyl or 2- (dicyclohexyl phosphino) -2 '- (N, N-dimethylamino) Biphenyl or the like, preferably tri-t-butylphosphine, 2-
(Di-t-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, or 2- (dicyclohexylphosphino) -2 ′-(N, N-dimethylamino) biphenyl.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or lithium methoxide;
Alternatively, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N
-Dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane (DA
BCO) or organic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal alkoxides, especially sodium t-butoxide. .

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 50 ° C.
To 100 ° C.

The reaction time varies depending on the starting compounds, reagents and 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 the reaction is completed, 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, acetaldehyde, propan-1-one, propan-2-one (acetone), butan-2-one, pentane -2-one, hexane-2-one and the like, preferably acetone, and examples of the cyclic ketone having 3 to 8 carbon atoms include cyclopropanone, cyclobutanone, cyclopentanone, cyclohexanone and cycloheptanone. , Cyclooctanone,
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 aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol;
Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; dimethylsulfoxide or Sulfoxides such as sulfolane; or a mixed solvent of the above organic solvents, preferably a halogenated hydrocarbon (particularly dichloromethane), an alcohol (methanol or ethanol) or a mixed solvent thereof (particularly dichloromethane and methanol) Mixed solvent).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 150 ° C, preferably 0 ° C to 150 ° C.
C. to 100.degree.

The reaction time varies depending on the starting compound, the reagent and the 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 anhydrous magnesium sulfate, etc. After drying using, 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. In addition, this step includes the first
If one step is omitted, it is omitted.

(Thirteenth Step) In this step, compound (17)
Wherein the compound (14) or the compound (1
6) is reduced by using a catalytic reduction catalyst in a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm) in an inert solvent, or (2) acetic acid in the presence of a metal powder. This is usually achieved by applying a method of reducing an organically known nitro group to an amino group, for example, by stirring in an aqueous solution.

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.
Aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene Halogenated hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; And preferably a mixed solvent of alcohols (particularly methanol) or ethers and alcohols (particularly tetrahydrofuran and methanol or ethanol). A mixed solvent) of.

The catalytic reduction catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction.
For example, it can be palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, Raney nickel, rhodium-aluminum oxide, 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 100 ° C, preferably from 0 ° 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 then 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, 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 100 ° C, preferably from 0 ° 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 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

(14th step) This step is a step for producing a compound having the general formula (3),
In an inert solvent, in the presence or absence of a base (preferably in the presence of a base), a general formula R ^3a -Xa (wherein R ^3a 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 aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin and petroleum ether. Kind;
Aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-
Amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone;
Alternatively, it may be a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably a halogenated hydrocarbon (particularly dichloromethane), an ether (diethyl ether or tetrahydrofuran) or an amide (particularly N, N-dimethylformamide). is there.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methylamine, dimethylamine, ethylamine, triethylamine , Tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU), preferably alkali metal carbonates (especially sodium or potassium carbonate), alkali metal bicarbonates (especially sodium or potassium hydrogen carbonate) 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 from -10 ° C to 100 ° C, preferably from 0 ° C to 100 ° C.
C. to 50.degree.

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 anhydrous magnesium sulfate, etc. After drying using, 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) of the present invention,
(8) and (12) are known or 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) [ Tetrahe
dron Letters , 37 , 6439 (1996)] et al.

The compound of the present invention having the above general formula (1), a pharmaceutically acceptable salt thereof or a prodrug thereof is
Since it has an excellent activated blood coagulation factor X inhibitory action and has low toxicity, it can be used as a medicine [in particular, a prophylactic agent for blood coagulation diseases (for example, thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulatory disorders) or (Especially therapeutic agents)].

When the compound having the general formula (1) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned diseases, the compound itself or an appropriate pharmacologically acceptable salt is used. And tablets, capsules, granules, powders, syrups and the like, orally or parenterally by injection or suppository.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
starch derivatives such as α-starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; DL
Leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives. ), Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (for example, low-substituted hydroxypropylcellulose) , Carboxymethylcellulose, calcium carboxymethylcellulose, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; and chemically modified starch and celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.), Emulsifier (for example,
Colloidal clays such as bentonite and veegum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cationic interfaces such as benzalkonium chloride Activators; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol);
Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid;
Sorbic acid can be mentioned. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 1000 mg (preferably 500 mg) per dose.
In the case of intravenous administration, the lower limit is 0.5 mg (preferably 5 mg) and the upper limit is 500 mg (preferably 250 mg) per dose.
Is preferably administered to adults 1 to 6 times per day depending on the symptoms.

[0264]

The present invention will be described in more detail with reference to the following Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

In the NMR spectrum, tetramethylsilane was used as an internal standard, the δ value was shown in ppm, and the coupling constant was shown in J value (Hz) (approximate to 0.5 Hz unit). Coupling patterns are: d: doublet, dd: double doublet, ddd: double double doublet, dt: double triplet, t: triplet, q: quartet, m: multiplet, s: singlet, bs: wide or shape Abbreviated as the signal observed like a broken singlet.

Example 1 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-methylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1) N- [3-Chloro-4- (1-methylpiperidin-4-yloxy) phenyl] -N- [3 obtained in Reference Example 7
-(3-cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate (938 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 the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (189 mg dissolved in 10 ml of water) and 28%
After adding aqueous ammonia (0.35 ml), the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack
ODS-A; YMC, elution solvent: 22% acetonitrile / water)
Was 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 841 mg of the title compound (yield 7).
7%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.90-2.08 (2H, m), 2.14-2.26 (2H, m), 2.74 (3
H, 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 (1
H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.31 (1
H, t, J = 9.0), 7.41 (1H, m), 7.55 (1H, t, J = 8.0),
7.60 (1H, m), 7.69 (1H, d, J = 8.0), 7.73 (1H, d, J =
8.0), 7.89 (1H, s); IR (KBr, cm ^-1 ): 1737, 1675, 1352, 1156.

Example 2 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-methylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 505) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 1.
4- (1-Methylpiperidin-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride (435 m
g) in 3N hydrochloric acid (20 ml) and
Stir for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was separated 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. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.94 and 2.03 (total 2
H, m), 2.19 (2H, m), 2.74 (3H, m), 3.00-3.10 (2
H, m), 3.30-3.50 (2H, m), 4.28 (2H, s), 4.47 (2H,
d, J = 6.0), 4.61 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, m),
7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (1H, m),
7.69 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1
H, s); IR (KBr, cm ^-1 ): 1732, 1676, 1348, 1155.

Example 3 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-ethylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 2) N- [3-Chloro-4- (1-ethylpiperidin-4-yloxy) phenyl] -N- obtained in Reference Example 13
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1240 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 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (243 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.41 ml) were added, and the mixture was stirred at room temperature overnight. did. A 4N hydrogen chloride dioxane solution was added to the reaction solution, which was then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YM
Purified with C-Pack ODS-A; YMC, elution solvent: 22% 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 807 mg of the title compound.
(56% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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, m each), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.
47 (2H, d, J = 6.0), 4.64 and 4.90 (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, 1155.

Example 4 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-ethylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 506) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 3.
4- (1-Ethylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (400 m
g) was dissolved in 3N 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 (1.00 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 324 mg of the title compound (yield 85
%) Was obtained as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 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 (1
H, d, J = 16.0), 7.29 (1H, d, J = 9.0), 7.43 (1H, dd,
J = 9.0, 2.5), 7.54 (1H, t, J = 8.0), 7.62 (1H, d, J = 2.
5), 7.68 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88
(1H, s); IR (KBr, cm ^-1 ): 1731, 1676, 1348, 1154.

Example 5 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 3) N- [3-Chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl]-obtained in Reference Example 17
Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1171 mg) was dissolved in dichloromethane (30 ml) and ethanol (15 m
After dissolving in the mixed solvent of 1) 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),
After adding an aqueous ammonium chloride solution (224 mg in 10 ml of water) and 28% aqueous ammonia (0.42 ml), the mixture was stirred at room temperature overnight. A 4N hydrogen chloride dioxane solution was added to the reaction solution, and the mixture was concentrated under reduced pressure.
Purified by LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid is 1N
After being dissolved in hydrochloric acid, the solution was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give the title compound 90
4 mg (67% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.28 (6H, m), 2.00-2.12 (2H, m), 2.18-2.36 (2
H, 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.

Example 6 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 507) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 5.
4- (1-isopropylpiperidin-4-yloxy)
Phenyl] sulfamoyl acetate ethyl dihydrochloride (61
5 mg) in 3N hydrochloric acid (20 ml).
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 HPLC (YMC-Pack ODS-A; YMC, elution solvent: 17% 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 433 mg of the title compound (yield 7).
4%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, 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 (1H, d, J = 2.5), 7.67 (1H,
d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1677, 1344, 1151.

Example 7 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-butylpiperidine-4-
Ethyloxy) -3-chlorophenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 4) N- [4- (1-butylpiperidin-4-yloxy) -3-chlorophenyl] -N- obtained in Reference Example 21
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1177 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. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (219 mg in 10 ml of water) and 28% aqueous ammonia (0.41 ml) were added, and the mixture was stirred at room temperature overnight. did. A 4N hydrogen chloride dioxane solution was added to the reaction solution, which was then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YM
Purified with C-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 742 mg of the title compound.
(55% yield) as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 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), 2.95-3.1
0 (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 1H, m each), 6.43 (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), 7.67 (1H, d, J = 8.0), 7.73
(1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675, 1353, 1156.

Example 8 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-butylpiperidin-4-
(Iloxy) -3-chlorophenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 508) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4 obtained in Example 7 -(1-butylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate dihydrochloride (600 m
g) was dissolved in 3N hydrochloric acid (20 ml),
Stir for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YMC,
Elution solvent: 20% 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 450 mg (yield 78%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (2
H, s), 4.48 (2H, d, J = 6.0), 4.70 (1H, m), 6.44 (1
H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.27 (1
H, d, J = 9.0), 7.45 (1H, 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.

Example 9 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-benzylpiperidine-4)
-Yloxy) -3-chlorophenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 5) N- [4- (1-benzylpiperidin-4-yloxy) -3-chlorophenyl] -N- obtained in Reference Example 25
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1531 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 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (233 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.40 ml) were added, and the mixture was stirred at room temperature overnight. did. A 4N hydrogen chloride dioxane solution was added to the reaction solution, which was then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YM
Purified with C-Pack ODS-A; YMC, elution solvent: 30% 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 931 mg of the title compound.
(Yield 53%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.94-2.05 (2H, m), 2.16-2.28 (2H, m), 3.01 (2
H, m), 3.24-3.44 (2H, m), 4.18 (2H, q, J = 7.0), 4.3
1 (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 (1
H, d, J = 9.0), 7.38 (1H, m), 7.43-7.51 (3H, m), 7.5
2-7.59 (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.

Example 10 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-benzylpiperidine-4)
-Yloxy) -3-chlorophenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 509) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [obtained in Example 9 Ethyl 4- (1-benzylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate dihydrochloride (731 m
g) was dissolved in 3N hydrochloric acid (30 ml),
Stir for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YMC,
Elution solvent: 20% 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 547 mg (yield 87%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.90-2.08 (2H, m),
2.12-2.26 (2H, m), 2.92-3.02 (2H, m), 3.20-3.50 (2
H, 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, m each), 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, cm ^-1 ): 1732, 1675, 1349, 1154.

Example 11 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-phenethylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplified Compound No. 6) N- [3-Chloro-4- (1-phenethylpiperidin-4-yloxy) phenyl] -N obtained in Reference Example 29
-[3- (3-Cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (1013 mg) was dissolved in 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 the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (174 mg in 10 ml of water) and 28% aqueous ammonia (0.33 ml) were added, and the mixture was stirred at room temperature overnight. did. After adding a 4N hydrogen chloride dioxane solution 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: 30% 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 the title compound 788m
g (68% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.96-2.12 (2H, m), 2.19-2.32 (2H, m), 3.02-3.1
8 (4H, m), 3.24-3.40 (2H, m), 3.49 and 3.62 (2H,
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 1H, m each), 6.44 (1H, d
t, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.22-7.38 (6
H, m), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (1
H, 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.

Example 12 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-phenethylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 510) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 11.
Ethyl 4- (1-phenethylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (588
mg) was dissolved in 3N hydrochloric acid (30 ml).
Stir for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and the residue was separated 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 freeze-dried to obtain 405 mg (yield: 72%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 2.02 (2H, m), 2.18
-2.28 (2H, m), 3.07 (4H, m), 3.20-3.50 (4H, m), 4.2
6 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.44
(1H, 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 (1H,
t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.67 (1H, d, J = 8.
0), 7.73 (1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1732, 1675, 1349, 1154.

Example 13 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-phenylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 7) N- [3-Chloro-4- (1-phenylpiperidin-4-yloxy) phenyl] -N- obtained in Reference Example 33
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1440 mg) was dissolved in a mixed solvent of dichloromethane (18 ml) and ethanol (18 ml), and hydrogen chloride was passed through under ice cooling. The mixture was sealed and stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), an aqueous ammonium chloride solution (233 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.49 ml) were added, and the mixture was stirred at room temperature overnight. did. After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 60%
Purification with (acetonitrile / water) yielded 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 278 mg (yield 61%) of the title compound as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.93-2.14 (2H, m), 2.16-2.37 (2H, m), 3.17-3.9
4 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.48
(2H, d, J = 6.0), 4.85 (1H, 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 (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), 7.74 (1H, d, J = 8.0), 7.89
(1H, s); IR (KBr, cm ^-1 ): 1738, 1675, 1353, 1156.

Example 14 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-phenylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 511) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 13.
Ethyl 4- (1-phenylpiperidin-4-yloxy) phenyl] sulfamoylacetate (676 mg)
It was dissolved in a mixed solvent of hydrochloric acid (9 ml) and dioxane (3 ml) and stirred at 80 ° C. for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-
Pack ODS-A; YMC, elution solvent: 40% acetonitrile /
Water). The obtained amorphous solid was washed with 1N hydrochloric acid (1
0 ml) and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound 3
85 mg (53% yield) were obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.88-2.08 (2H, m),
2.10-2.32 (2H, m), 3.04-3.91 (4H, m), 4.28 (2H, m
s), 4.47 (2H, d, J = 6.0), 4.82 (1H, m), 6.44 (1H, d
t, 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
(1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.60 (1
H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.74 (1H, d, J =
8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1733, 1676, 1349, 1155.

Example 15 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-methoxycarbonylmethylpiperidin-4-yloxy) Ethyl phenyl] sulfamoylacetate dihydrochloride (Exemplary Compound No. 8) N- [3-chloro-4- (1-methoxycarbonylmethylpiperidin-4-yloxy) obtained in Reference Example 37
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -propenyl] sulfamoyl acetate (17
00 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) 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 the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (227 mg was added to water 10).
ml) and 28% aqueous ammonia (0.42 ml)
And then stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 35).
% 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 950 mg (yield 48%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.84-2.32 (4H, m), 2.90-3.68 (4H, m), 3.76 (3
H, s), 4.19 (2H, q, J = 7.0), 4.30 (2H, m), 4.41 (2
H, s), 4.47 (2H, d, J = 6.0), 4.63 and 4.84 (total 1H, each
m), 6.43 (1H, 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 (1H,
d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1742, 1675, 1353, 1156.

Example 16 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-carboxymethylpiperidin-4-yloxy) -3-chlorophenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 512) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 15.
4- (1-methoxycarbonylmethylpiperidine-4-
Yloxy) phenyl] sulfamoylethyl acetate 2
The hydrochloride (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 separated by preparative HPLC (YMC-Pack
ODS-A; YMC, elution solvent: 15% 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 581 mg of the title compound (yield 76
%) Was obtained as a colorless amorphous solid. ¹ H 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, m
s), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.65 and 4.8
4 (Total 1H, m each), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1
H, 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), 7.7
2 (2H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1737, 1676, 1348, 1155.

Example 17 N- [4- (1-acetylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate hydrochloride (Exemplified Compound No. 9) N- [4- (1-acetylpiperidin-4-yloxy) -3-chlorophenyl] -N- obtained in Reference Example 39
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (733 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 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (175 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.22 ml) were added, and the mixture was stirred at room temperature overnight. did. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-
Pack ODS-A; YMC, elution solvent: 35% acetonitrile /
Water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. Dissolve this in water,
Lyophilization afforded 488 mg (64% yield) of the title compound as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.55 (1H, m), 1.65 (1H, m), 1.84 (1H, m), 1.93
(1H, m), 2.01 (3H, s), 3.28-3.44 (2H, m), 3.56-3.7
2 (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 (1H, dt, J = 16.
0, 6.0), 6.58 (1H, d, J = 16.0), 7.29 (1H, d, J = 9.0),
7.38 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0),
7.57 (1H, d, J = 2.5), 7.67 (1H, d, J = 8.0), 7.73 (1
H, d, J = 8.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1739, 1677, 1354, 1157.

Example 18 N- [4- (1-Acetylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Acetic acid hydrochloride (Exemplified Compound No. 513) N- [4- (1-acetylpiperidin-4-yloxy) -3-chlorophenyl] -N- obtained in Example 17
[3- (3-Amidinophenyl) -2- (E) -propenyl] ethyl sulfamoyl acetate hydrochloride (352 m
g) 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 the title compound 10
9 mg (32% yield) were obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.54 (1H, m), 1.65
(1H, m), 1.83 (1H, m), 1.92 (1H, 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 (1H, dt, J = 16.0, 6.0),
6.53 (1H, d, J = 16.0), 7.26 (1H, d, J = 9.0), 7.48 (1
H, dd, J = 9.0, 2.5), 7.52 (1H, t, J = 8.0), 7.66 (1H,
d, J = 8.0), 7.68 (1H, d, J = 2.5), 7.71 (1H, d, J = 8.
0), 7.85 (1H, s); IR (KBr, cm ^-1 ): 1682, 1345, 1152.

Example 19 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoyl Ethyl acetate hydrochloride (Exemplified Compound No. 10) N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl]-obtained in Reference Example 43
Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1015 mg) was added to dichloromethane (30 ml) and ethanol (15 m
After dissolving in the mixed solvent of 1) and passing hydrogen chloride under ice-cooling, the mixture was 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),
After adding an ammonium chloride aqueous solution (194 mg in 10 ml of water) and 28% aqueous ammonia (0.36 ml), the mixture was stirred at room temperature overnight. A 4N hydrogen chloride dioxane solution was added to the reaction solution, and the mixture was concentrated under reduced pressure.
Purified by LC (YMC-Pack ODS-A; YMC, elution solvent: 30% acetonitrile / water). The obtained amorphous solid is 1N
After being dissolved in hydrochloric acid, the solution was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound 73
7 mg (66% yield) were obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, m),
6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0),
7.28 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 2.5), 7.
55 (1H, t, J = 8.0), 7.57 (1H, d, J = 2.5), 7.68 (1H,
d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675, 1352, 1156.

Example 20 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoyl Acetic acid hydrochloride (Exemplary Compound No. 514) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-carbamoylpiperidine-4- obtained in Example 19 Yloxy) -3-chlorophenyl] sulfamoyl acetate ethyl hydrochloride (600
mg) was dissolved in 3N hydrochloric acid (20 ml) 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 HPLC (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 is suspended in water and dioxane (1 drop),
Lyophilization gave 466 mg (81% yield) of the title compound as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.48-1.58 (2H, m),
1.80-1.90 (2H, m), 3.14-3.24 (2H, m), 3.50-3.60 (2
H, 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 = 1
6.0), 7.27 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 2.
5), 7.55 (1H, t, J = 8.0), 7.57 (1H, d, J = 2.5), 7.67
(1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s)
; IR (KBr, cm ^-1 ): 1676, 1348, 1155.

Example 21 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-methanesulfonylpiperidin-4-yloxy) phenyl Ethyl sulfamoyl acetate hydrochloride (Exemplary Compound No. 11) N- [3-Chloro-4- (1-methanesulfonylpiperidin-4-yloxy) phenyl] -N- [3- (3- Cyanophenyl) -2- (E)
-Propenyl] sulfamoyl ethyl acetate (835 m
g) in dichloromethane (30 ml) and ethanol (1
(5 ml) and mixed 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 ammonium chloride solution (150 mg was added to water 10 ml).
) And 28% aqueous ammonia (0.19 ml), and the mixture was stirred at room temperature 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 HPLC (YMC-Pack ODS-A; YMC, elution solvent: 40% 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 685 mg (yield 75%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.72-1.82 (2H, m), 1.93-2.03 (2H, m), 2.89 (3
H, 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 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1
H, 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), 7.8
5 (1H, s); IR (KBr, cm ^-1 ): 1739, 1677, 1346, 1156.

Example 22 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-methanesulfonylpiperidin-4-yloxy) phenyl ] Sulfamoylacetic acid hydrochloride (Exemplary Compound No. 515) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 21
4- (1-Methanesulfonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl hydrochloride (5
02 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 2).
(5-50% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and concentrated under reduced pressure to dryness to obtain 346 mg of the title compound (yield 72%).
%) Was obtained as a colorless amorphous solid. ¹ H 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 (1H, 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 (1
H, dd, J = 9.0, 2.5), 7.54 (1H, 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.

Example 23 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2-pyridyl) piperidine-4- Ethyloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 1
2) N- [3-chloro-4- [1-] obtained in Reference Example 51
(2-Pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-cyanophenyl) -2- (E)
-Propenyl] sulfamoyl ethyl acetate (1095m
g) in dichloromethane (30 ml) and ethanol (1
(5 ml) and mixed 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 ammonium chloride solution (197 mg was added to water 10 ml).
And 28% aqueous ammonia (0.37 ml) were added, and the mixture was stirred at room temperature overnight. After adding 4N hydrogen chloride dioxane solution to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 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 freeze-dried to obtain 533 mg (yield 42%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.72-1.84 (2H, m), 2.01-2.13 (2H, m), 3.68-3.7
9 (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 (1H, m),
6.45 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0),
6.92 (1H, m), 7.35 (1H, d, J = 9.0), 7.32-7.44 (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), 7.70 (1H, d, J = 8.0), 7.74
(1H, d, J = 8.0), 7.90 (1H, s), 7.96 (1H, m), 8.02
(1H, d, J = 4.5); IR (KBr, cm ^-1 ): 1738, 1674, 1353, 1155.

Example 24 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2-pyridyl) piperidine-4- Iloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 516) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 23
Ethyl 4- [1- (2-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (533 mg) was dissolved in 3N hydrochloric acid (30 ml) to give 6
Stirred at 0 ° C. for 6 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
YMC, elution solvent: 30-50% 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 of the title compound (yield 84
%) Was obtained as a colorless amorphous solid. ¹ H 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 (2
H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H,
m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 1
6.0), 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 (1H, s), 7.93 (1H, m),
8.02 (1H, J = 6.0); IR (KBr, cm ^-1 ): 1733, 1676, 1349, 1155.

Example 25 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3-pyridyl) piperidine-4- Ethyloxy] phenyl] sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1
3) N- [3-chloro-4- [1-] obtained in Reference Example 55
(3-Pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-cyanophenyl) -2- (E)
-Propenyl] sulfamoyl acetate (490 m
g) in dichloromethane (15 ml) and ethanol (1
(5 ml), mixed with hydrogen chloride under ice-cooling, sealed, and stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (9 ml), an aqueous ammonium chloride solution (79 mg in 3 ml of water) and 28% aqueous ammonia (0.17 ml) were added, and the mixture was stirred at room temperature overnight. did. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 40).
(Acetonitrile / water) to give 306 mg of an amorphous solid. 44 mg of this solid was dissolved in ethanol (4 ml), 4N hydrogen chloride dioxane solution (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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.69-1.82 (2H, m), 1.96-2.08 (2H, m), 3.42 (2
H, m), 3.66 (2H, m), 4.19 (2H, q, J = 7.0), 4.43 (2
H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.45 (1
H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.33 (1
H, 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 (1H, 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.

Example 26 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3-pyridyl) piperidine-4- Iloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplified Compound No. 517) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 25
Ethyl 4- [1- (3-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate (247 m
g) was dissolved in 3N hydrochloric acid (12 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: 27% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid (10 ml),
It was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 427 mg of the title compound (84% yield).
Was obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.69-1.81 (2H, m),
1.97-2.08 (2H, m), 3.42 (2H, m), 3.67 (2H, m), 4.2
9 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (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 (1
H, 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 (1H, dd, J = 9.0, 2.0), 8.15
(1H, d, J = 5.5), 8.48 (1H, d, J = 2.0); IR (KBr, cm ^-1 ): 1731, 1675, 1348, 1154.

Example 27 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4-pyridyl) piperidine-4- Yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1
4)

[0293]

Embedded image N- [3-chloro-4- [1-
(4-pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-cyanophenyl) -2- (E)
-Propenyl] sulfamoyl acetate (637 m
g) in dichloromethane (30 ml) and ethanol (1
(5 ml) in a mixed solvent, and after passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 5.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (115 mg was added to water 10 m
1) and 28% aqueous ammonia (0.21 ml), and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (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 456 mg (yield 62%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.72-1.82 (2H, m), 2.00-2.10 (2H, m), 3.71 (2
H, m), 3.86 (2H, m), 4.19 (2H, q, J = 7.0), 4.42 (2
H, s), 4.48 (2H, d, J = 6.0), 4.87 (1H, m), 6.44 (1
H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.23 (2
H, J = 7.5), 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 (1H, d, J = 2.5),
7.68 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (1
H, s), 8.24 (2H, d, J = 7.5); IR (KBr, cm ^-1 ): 1738, 1675, 1352, 1155.

Example 28 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4-pyridyl) piperidine-4- [Iloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 518)

[0295]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 27
Ethyl 4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (315 mg) was dissolved in 3N hydrochloric acid (20 ml).
Stirred at 0 ° C. for 8 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was washed with 1N hydrochloric acid (0.50 ml).
, And concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 286 mg of the title compound.
(95% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.70-1.80 (2H, m),
1.99-2.09 (2H, m), 3.69 (2H, m), 3.85 (2H, m), 4.2
6 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.45
(1H, 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 (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), 7.73 (1H, d, J = 8.0), 7.
89 (1H, s), 8.24 (2H, d, J = 7.5); IR (KBr, cm ^-1 ): 1731, 1675, 1347, 1154.

Example 29 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2-pyrimidyl) piperidine-4- Ethyloxy] phenyl] sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1
5) N- [3-chloro-4- [1-] obtained in Reference Example 63
(2-Pyrimidyl) piperidin-4-yloxy] phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -propenyl] sulfamoyl acetate (15
90 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) 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 the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (285 mg was added to water 10).
ml) and 28% aqueous ammonia (0.53 ml)
And then stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (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 freeze-dried to obtain 1280 mg (yield: 70%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.58-1.68 (2H, m), 1.89-1.99 (2H, m), 3.68 (2
H, m), 4.04 (2H, m), 4.19 (2H, q, J = 7.0), 4.41 (2
H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.43 (1
H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 6.63 (1
H, t, J = 4.5), 7.31 (1H, d, J = 9.0), 7.39 (1H, dd, J =
9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.57 (1H, 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.

Example 30 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2-pyrimidyl) piperidine-4- Iloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 519) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 29
Ethyl 4- [1- (2-pyrimidyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (800 mg) was dissolved in 3N hydrochloric acid (40 ml) to give 6
Stirred at 0 ° C. for 9 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
YMC, elution solvent: 35-50% 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 673 mg of the title compound (88% yield).
%) Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.60-1.70 (2H, m),
1.90-2.00 (2H, m), 3.60-3.80 (2H, m), 4.00-4.10 (2
H, m), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.81 (1H,
m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 1
6.0), 6.68 (1H, t, J = 5.0), 7.31 (1H, d, J = 9.0), 7.
40 (1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.58
(1H, d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.73 (1H, d,
J = 8.0), 7.89 (1H, s), 8.40 (2H, J = 5.0); IR (KBr, cm ^-1 ): 1732, 1675, 1345, 1154.

Example 31 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3-pyridylmethyl) piperidine-4 -Yloxy] phenyl]
Ethyl sulfamoyl acetate trihydrochloride (Exemplified Compound No. 16) N- [3-chloro-4- [1-
(3-pyridylmethyl) piperidin-4-yloxy]
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl acetate (94
5 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and after passing 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 ethanol (20 ml).
And dissolved in aqueous ammonium chloride (166 mg of water 1
0 ml) and 28% aqueous ammonia (0.31 m
After l) was added, the mixture was stirred at room temperature overnight. 4N in the reaction solution
After adding a hydrogen chloride dioxane solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent:
(25% 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 freeze-dried to obtain 328 mg (yield: 29%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.96-2.09 (2H, m), 2.18-2.31 (2H, m), 3.07 (2
H, 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 (1H, m each), 6.43 (1H, dt, J =
16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.4
0 (1H, m), 7.55 (1H, t, J = 8.0), 7.58 (1H, s), 7.68
(1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.75 (1H, m),
7.87 (1H, s), 8.36-8.48 (1H, m), 8.79 (1H, d, J = 4.
5), 8.96 (1H, m); IR (KBr, cm ^-1 ): 1736, 1674, 1350, 1154.

Example 32 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3-pyridylmethyl) piperidine-4 -Yloxy] phenyl]
Sulfamoylacetic acid trihydrochloride (Exemplary Compound No. 52
0) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 31
Ethyl 4- [1- (3-pyridylmethyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3 hydrochloride (175 mg) was dissolved in 3N hydrochloric acid (10 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 subjected to preparative HPLC (YMC-Pack O
DS-A; YMC, elution solvent: 15-20% acetonitrile /
Water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. Dissolve this in water,
Lyophilization gave 74 mg (44% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.97-2.12 (2H, m),
2.17-2.34 (2H, m), 3.00-3.17 (2H, m), 3.33 and 3.46
(Total 2H, m each), 4.27 (2H, s), 4.47 (2H, d, J = 6.0), 4.
48-4.56 (2H, m), 4.62 and 4.90 (total 1H, m each), 6.44 (1
H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1
H, m), 7.36-7.45 (1H, m), 7.54 (1H, t, J = 8.0), 7.5
8 (1H, s), 7.69 (1H, 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.

Example 33 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4-pyridylmethyl) piperidine-4 -Yloxy] phenyl]
Ethyl sulfamoyl acetate trihydrochloride (Exemplified Compound No. 17) N- [3-chloro-4- [1-
(4-pyridylmethyl) piperidin-4-yloxy]
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl acetate (97
1 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) 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 the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), and an aqueous ammonium chloride solution (171 mg was added to water 10 m
1) and 28% aqueous ammonia (0.32 ml), and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 10 to 10).
(35% acetonitrile / 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 freeze-dried to obtain 580 mg (yield 49%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.98-2.16 (2H, m), 2.16-2.40 (2H, m), 3.07 (2
H, 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 each), 6.43 (1H, dt, J
= 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m), 7.
40 (1H, m), 7.54 (1H, t, J = 8.0), 7.58 (1H, s), 7.6
8 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H,
s), 8.00 (2H, m), 8.82 (2H, m); IR (KBr, cm ^-1 ): 1737, 1675, 1351, 1155.

Example 34 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4-pyridylmethyl) piperidine-4 -Yloxy] phenyl]
Sulfamoylacetic acid trihydrochloride (Exemplary Compound No. 52
1) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 33
Ethyl 4- [1- (4-pyridylmethyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3 hydrochloride (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 subjected to preparative HPLC (YMC-Pack O
DS-A; YMC, elution solvent: 10-20% acetonitrile /
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 155 m of the title compound.
g (37% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.97-2.16 (2H, m),
2.16-2.40 (2H, m), 3.10 (2H, m), 3.32 and 3.44 (total 2
H, m each), 4.28 (2H, s), 4.47 (2H, d, J = 6.0), 4.56
(2H, m), 4.61 and 4.90 (total 1H, m each), 6.44 (1H, dt, J
= 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.31 (1H, m),
7.41 (1H, m), 7.54 (1H, t, J = 8.0), 7.59 (1H, s),
7.71 (2H, m), 7.90 (1H, s), 8.18 (2H, m), 8.91 (2
H, m); IR (KBr, cm ^-1 ): 1731, 1675, 1347, 1154.

Example 35 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- [2- (2
-Pyridyl) ethyl] piperidin-4-yloxy] phenyl] sulfamoylacetate ethyl trihydrochloride (Exemplified Compound No. 18) N- [3-chloro-4- [1-
[2- (2-pyridyl) ethyl] piperidin-4-yloxy] -N- [3- (3-cyanophenyl) -2-
(E) -propenyl] sulfamoyl acetate (17
27 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and after passing 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 ethanol (20 m
l), an aqueous solution of ammonium chloride (296 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.72
ml), and the mixture was stirred at room temperature overnight. 4N in the reaction solution
After adding a hydrogen chloride dioxane solution, the mixture was concentrated under reduced pressure,
The residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25-30% 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 freeze-dried to obtain 944 mg (yield: 45%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 2.00-2.12 (2H, m), 2.21-2.33 (2H, m), 3.10-3.7
0 (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 (1H, dd, J = 9.0, 2.5), 7.
55 (1H, t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.67-7.75
(1H, m), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0),
7.80 (1H, m), 7.90 (1H, s), 8.26 (1H, m), 8.73 (1
(H, d, J = 5.0); IR (KBr, cm ^-1 ): 1736, 1674, 1350, 1154.

Example 36 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- [2- (2
-Pyridyl) ethyl] piperidin-4-yloxy] phenyl] sulfamoylacetic acid trihydrochloride (Exemplary Compound No. 522) N- [3- (3-amidinophenyl) -2- (E) -propenyl obtained in Example 35 ] -N- [3-chloro-
Ethyl 4- [1- [2- (2-pyridyl) ethyl] piperidin-4-yloxy] phenyl] sulfamoylacetate 3 hydrochloride (400 mg) in 3N hydrochloric acid (20 ml)
And stirred at 60 ° C. for 4.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure.
(YMC-PackODS-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 201 mg of the title compound.
(Yield 52%) was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 2.00-2.12 (2H, m),
2.20-2.32 (2H, m), 3.20-3.60 (4H, m), 3.39-3.48 (2
H, m), 3.50-3.59 (2H, m), 4.28 (2H, s), 4.47 (2H,
d, J = 6.0), 4.81 (1H, m), 6.45 (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), 7.50-7.58 (1H, m), 7.55 (1
H, t, J = 8.0), 7.58-7.66 (1H, m), 7.60 (1H, d, J = 2.
5), 7.69 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89
(1H, s), 8.07 (1H, m), 8.65 (1H, d, J = 4.5); IR (KBr, cm ^-1 ): 1730, 1675, 1347, 1154.

Example 37 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 19) N- [3-Chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] obtained in Reference Example 81
-N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (1.30 g) was added to dichloromethane (30 ml) and ethanol (15 m
After dissolving in the mixed solvent of 1) and passing hydrogen chloride under ice-cooling, the mixture was 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),
After adding an ammonium chloride aqueous solution (0.24 g in 10 ml of water) and 28% aqueous ammonia (0.45 ml), the mixture was stirred at room temperature overnight. A 4N hydrogen chloride dioxane solution was added to the reaction solution, and the mixture was concentrated under reduced pressure.
Purified by LC (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid is 1N
It was dissolved in hydrochloric acid and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 1.20 of the title compound.
g (yield 80%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.47-1.60 (2H, m), 1.64-1.76 (2H, m), 1.76-1.9
0 (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 4.9
2 (1H, m in each), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1
H, d, J = 16.0), 7.32 (1H, m), 7.42 (1H, m), 7.55 (1
(H, t, J = 8.0), 7.60 (1H, m), 7.68-7.76 (2H, m), 7.9
2 (1H, s); IR (KBr, cm ^-1 ): 1739, 1674, 1354, 1156.

Example 38 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 523) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 37
Ethyl 4- (1-cyclopentylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (790 mg) was dissolved in 3N hydrochloric acid (20 ml).
Stirred at 0 ° C. for 4.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (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 522 mg (yield 69%) of the title compound.
Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.48-1.63 (2H, m),
1.63-1.76 (2H, m), 1.76-1.88 (2H, m), 1.93-2.10 (4
H, 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, m each), 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.

Example 39 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1,2-dimethylpiperidin-4-yloxy) Phenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 20) N- [3-chloro-4- (1,2) obtained in Reference Example 89
-Dimethylpiperidin-4-yloxy) phenyl]-
Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1100 mg) was dissolved in dichloromethane (20 ml) and ethanol (20 m2).
After dissolving in the mixed solvent of 1) and passing hydrogen chloride under ice-cooling, the mixture was sealed and stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml),
After adding an ammonium chloride aqueous solution (240 mg in 5 ml of water) and 28% aqueous ammonia (0.54 ml), the mixture was stirred at room temperature overnight. After concentrating the reaction solution 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 hydrogen chloride dioxane solution (0.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 420 mg of the title compound.
(33% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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), 3.0
5-3.15 (1H, 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 (1H, d, J = 9.0), 7.40 (1
H, 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), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675.

Example 40 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1,2-dimethylpiperidin-4-yloxy) Phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 524) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 39
4- (1,2-dimethylpiperidin-4-yloxy)
Phenyl] sulfamoyl acetate ethyl dihydrochloride (26
0 mg) in 3N hydrochloric acid (20 ml).
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 HPLC (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 220 mg of the title compound (yield 8).
9%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.33 (3H, d, J = 6.
5), 1.70-1.80 (1H, m), 1.85-1.95 (1H, m), 2.20-2.3
5 (2H, m), 2.76 (3H, s), 3.05-3.15 (1H, m), 3.20-3.
35 (1H, m), 3.45-3.60 (1H, m), 4.28 (2H, s), 4.47
(2H, d, J = 6.0), 4.64 (1H, m), 6.43 (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), 7.59 (1H, d, J = 2.5), 7.68 (1H, d, J = 8.0), 7.73
(1H, d, J = 8.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1733, 1676.

Example 41 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (indolizine-
7-yloxy) phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 21) N- [3-chloro-4- (indolizin-7-yloxy) phenyl] -N- [3- (3
-Cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (600 mg) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through under ice-cooling. Stir at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml), an aqueous ammonium chloride solution (130 mg dissolved in 5 ml of water) and 28% aqueous ammonia (0.29 ml) were added, and the mixture was stirred at room temperature overnight. did. After the reaction solution was concentrated under reduced pressure, the residue was separated 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 dioxane solution (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 140 mg (yield 20%) of the title compound as yellow. Obtained as an amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.60-2.35 (8H, m), 3.00-3.10 (2H, m), 3.25-3.3
5 (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 (1H, m),
6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0),
7.30-7.35 (1H, m), 7.40-7.45 (1H, m), 7.55 (1H, t,
J = 8.0), 7.55-7.65 (1H, m), 7.68 (1H, d, J = 8.0), 7.
73 (1H, d, J = 8.0), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675.

Example 42 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (indolizine-
7-yloxy) phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 525)

[0310]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 41
4- (Indolizin-7-yloxy) phenyl] sulfamoyl acetate dihydrochloride (130 mg) in 3N
It was dissolved in hydrochloric acid (15 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 1)
(5% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure to obtain 110 mg (yield 88%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.60-2.35 (8H, m),
2.95-3.10 (2H, m), 3.15-3.50 (3H, m), 4.28 (2H, m
s), 4.47 (2H, d, J = 6.0), 4.99 (1H, m), 6.44 (1H, d
t, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.30-7.35
(1H, 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.

Example 43 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidine-4-
Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (Exemplified Compound No. 57) N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidin-4-yloxy) obtained in Reference Example 99 ) Phenyl] sulfamoyl acetate (570 mg) in dichloromethane (2
0 ml) and ethanol (20 ml), and hydrogen chloride was passed through under ice cooling.
Stirred for hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (140 mg dissolved in 5 ml of water) and 28% aqueous ammonia (0.31 ml) were added, and the mixture was stirred at room temperature overnight. did.
After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HPLC (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 150 mg (yield: 22%) of the title compound. Obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-2.05 (2H, m), 2.05-2.25 (2H, m), 2.73 (3
H, s), 3.00-3.15 (2H, m), 3.20-3.30 (1H, m), 3.40-
3.50 (1H, 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 1H,
M), 6.43 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 1
6.0), 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 (1H, d,
J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1674.

Example 44 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidine-4-
Yloxy) phenyl] sulfamoylacetic acid dihydrochloride
(Exemplified Compound No. 561) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidin-4-yloxy) phenyl obtained in Example 43 Ethyl sulfamoyl acetate dihydrochloride (250 mg) was dissolved in 3N hydrochloric acid (30 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: 10% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid and concentrated to dryness under reduced pressure to obtain 160 mg (yield 58%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.80-1.95 (1H, m),
1.95-2.05 (1H, m), 2.05-2.25 (2H, m), 2.70-2.80 (3
H, 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, m each), 6.44 (1H, dt, J = 16.0, 6.
0), 6.55 (1H, 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.

Example 45 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidine-4-
Ethyloxy) -3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 8
5) N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidin-4-yloxy) -3-trifluoro obtained in Reference Example 104 Methylphenyl] sulfamoyl acetate (1298
mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and after passing 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 ethanol (20 ml).
And an aqueous ammonium chloride solution (246 mg in water 1).
0 ml) and 28% aqueous ammonia (0.32 m
After l) was added, the mixture was stirred at room temperature overnight. 4N in the reaction solution
After adding a hydrogen chloride dioxane solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent:
(25% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid, and then concentrated to dryness under reduced pressure to give 1115 mg of the title compound (yield 74%).
Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.91 and 2.06 (total 2H, m each), 2.17-2.27 (2H, m),
2.73 (3H, m), 2.87 and 3.50 (total 2H, m each), 3.37 and 3.
44 (2H, m in each), 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), 7.3
9 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.

Example 46 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidine-4-
Iloxy) -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 589) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N obtained in Example 45 -[4- (1-Methylpiperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl acetate dihydrochloride (803 mg) was dissolved in 3N hydrochloric acid (20 ml), and
Stirred at 0 ° C. for 8 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (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 (yield 79%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, CD ₃ OD) δppm: 1.93 and 2.17 (2H,
M), 2.28 and 2.39 (total 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, m
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 in 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.

Example 47 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-formimidoylpiperidin-4-yloxy) Phenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 2
2)

[0316]

Embedded image (A) N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride N- [4- (1-t-butoxycarbonyl) obtained in Reference Example 70 Piperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2-
(E) -propenyl] sulfamoyl ethyl acetate (12
00 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml), and after passing hydrogen chloride under ice-cooling, the mixture was 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 ammonium chloride solution (208 mg was added to water 10).
ml) and 28% aqueous ammonia (0.40 ml)
And then stirred at room temperature overnight. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (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. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, d, J = 8.0), 7.73 (1
H, d, J = 8.0), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1737, 1675.

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-
Ethyl 4- (1-formimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E)-obtained in Example 47 (a) Propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.79 g) was dissolved in ethanol (25 ml), ethylformimidate hydrochloride (0.29 g) and triethylamine (0.72 ml) were added at room temperature, and then at the same temperature for 16 hours. I left it. A 4N hydrogen chloride dioxane solution (10 m
After adding l), the mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC.
(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 (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. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 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 (1H, d, J = 2.5), 7.69
-7.75 (2H, m), 7.90 (1H, s), 7.99 (1H, dd, J = 15.0,
7.0); IR (KBr, cm ^-1 ): 1737, 1702, 1675, 1351, 1155.

Example 48 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-formimidoylpiperidin-4-yloxy) Phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 526)

[0319]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-formimidoylpiperidine-4- obtained in Example 47 (b) [Iloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (0.35 g) was dissolved in 3N hydrochloric acid (15 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 separated by preparative HPLC (YMC-Pa
ck ODS-A; YMC, elution solvent: 15% acetonitrile / water)
Was purified. The obtained amorphous solid was washed with 1N hydrochloric acid (3 m
After dissolving in 1), the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.17 g (yield 52%) of the title compound as a colorless amorphous solid. ¹ H 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, m
s), 4.47 (2H, d, J = 6.0), 4.79-4.86 (1H, m), 6.44 (1
H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.32 (1
H, 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 (1H, d, J = 8.
0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s), 7.99 (1H, d
d, J = 15.0, 7.0); IR (KBr, cm ^-1 ): 1731, 1703, 1675, 1347, 1154.

Example 49 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (1-iminopropyl) piperidine-4 -Yloxy] phenyl]
Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 23)

[0321]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] obtained in Example 47 (a)
Ethyl sulfamoyl acetate dihydrochloride (0.77 g) was dissolved in ethanol (25 ml) and at room temperature was added to the Journal of American Chemical Society, No. 98.
Vol., P. 567 (1976) [J. Amer. Chem. Soc.,
98, 567 (1976)], ethylpropionimidate hydrochloride (0.54 g) and triethylamine (0.88 ml) synthesized from propionitrile.
Was added and left at the same temperature for 22 hours. Due to the slow progress of the reaction, ethyl propionimidate hydrochloride (0.1
8g) and triethylamine (0.35 ml) were added,
Stirred at room temperature for another 4.5 hours. After adding a 4N hydrogen chloride dioxane solution (10 ml) to the reaction solution, 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 (10 ml) and 4N
After adding a hydrogen chloride dioxane solution (2 ml), 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 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, cm ^-1 ): 1738, 1671, 1619, 1352, 1157.

Example 50 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (1-iminopropyl) piperidine-4 -Yloxy] phenyl]
Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 52
7)

[0323]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 49
Ethyl 4- [1- (1-iminopropyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.42 g) was dissolved in 3N hydrochloric acid (15 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 separated by preparative HPLC (YMC-Pa
ck ODS-A; YMC, elution solvent: 18% acetonitrile / water)
Was purified. The obtained amorphous solid was washed with 1N hydrochloric acid (3 m
After dissolving in 1), the mixture was 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.15 (3H, t, J = 7.
5), 1.71-1.87 (2H, m), 2.00-2.12 (2H, m), 2.63 (2
(H, q, J = 7.5), 3.59-3.81 (4H, m), 4.30 (2H, s), 4.4
8 (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), 7.43 (1H, dd, J = 9.0, 2.5), 7.55 (1H, 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.

Example 51 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-iminophenylmethylpiperidin-4-yloxy) -3-chlorophenyl Ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 24) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro obtained in Example 47 (a) -4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.69 g) was dissolved in ethanol (20 ml), and ethyl benzimidate hydrochloride (0.63 g) and triethylamine (0.94 ml) were added at room temperature. After stirring for an hour, it was left at room temperature for 16.5 hours. After further stirring at 60 ° C. for 11.5 hours, it was left at room temperature for 60.5 hours. Add 4N hydrogen chloride dioxane solution (5 ml) to the reaction solution
, And concentrated under reduced pressure, and the residue is purified by preparative HPLC (YMC-
Pack ODS-A; YMC, elution solvent: 25% acetonitrile /
Water). The obtained amorphous solid was dissolved in ethanol (5
ml) and dissolved in a 4N hydrogen chloride dioxane solution (2 m
After l) was added, the mixture was concentrated to dryness under reduced pressure to give the title compound (0.36 g, yield 45%) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.73-1.81 (1H, m), 1.90-2.03 (2H, m), 2.17-2.2
4 (1H, m), 3.30-3.51 (2H, m), 3.78-3.86 (1H, m),
3.89-3.95 (1H, m), 4.18 (2H, q, J = 7.0), 4.41 (2H,
s), 4.47 (1H, d, J = 6.0), 4.83-4.88 (1H, m), 6.43 (1
H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.33 (1
H, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.53-7.73
(9H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1671, 1605, 1353, 1156.

Example 52 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1-iminophenylmethylpiperidin-4-yloxy] -3-chlorophenyl ] Sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 52
8) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (1-iminophenylmethylpiperidin-4-yloxy) -3 obtained in Example 51
-Chlorophenyl] sulfamoyl acetate dihydrochloride (0.25 g) was dissolved in 3N hydrochloric acid (12 ml),
Stir at 60 ° C. for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to 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 freeze-dried to give 0.21 g of the title compound.
(89% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.70-1.78 (1H, m),
1.88-2.02 (2H, m), 2.14-2.22 (1H, m), 3.28-3.50 (2
H, m), 3.83-3.90 (1H, m), 3.91-4.01 (1H, m), 4.27
(2H, s), 4.45 (2H, d, J = 5.0), 4.82-4.89 (1H, m),
6.44 (1H, dt, J = 16.0, 5.0), 6.56 (1H, 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.

Example 53 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydro-3H-pyrrol-2-yl) piperidine-4
-Yloxy] phenyl] sulfamoylethyl acetate
Dihydrochloride (Exemplary Compound No. 25)

[0327]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] obtained in Example 47 (a)
Ethyl sulfamoyl acetate dihydrochloride (0.75 g) is dissolved in ethanol (25 ml) and, at room temperature, Organic Preparation and Procedures International, Vol. 24, p. 147 (1992).
Year), 5-methoxy-3,4-dihydro-2H-pyrrole (0.25) synthesized from 2-pyrrolidinone according to the method described in [Org. Prep. Proced. Int., 24, 147 (1992)].
g) and triethylamine (0.69 ml) were added, and 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 HPLC (YMC-Pack ODS).
-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml).
And 4N hydrogen chloride dioxane solution (2 ml) was added, followed by concentration under reduced pressure to dryness. This was dissolved in water and freeze-dried to give 0.52 g of the title compound.
(62% yield) as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.75-1.86 (2H, m), 2.02-2.14 (4H, m), 2.97 (2
H, 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
(1H, 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 (1H, d, J = 2.5), 7.
70-7.74 (2H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1738, 1672, 1352, 1156.

Example 54 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydro-3H-pyrrol-2-yl) piperidine-4
-Yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 529)

[0329]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 53
4- [1- (4,5-dihydro-3H-pyrrole-2-
Yl) piperidin-4-yloxy] phenyl] sulfamoyl acetate dihydrochloride (0.36 g) in 3N
It was dissolved in hydrochloric acid (15 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15
(18% 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 0.32 g (yield 90%) of the title compound as a colorless amorphous solid. ¹ 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 (1
H, 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.

Example 55 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2,3,3)
Ethyl 4,5-tetrahydropyridin-6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplary Compound No. 26) N- [3- (3-amidino) obtained in Example 47 (a) Phenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.81 g) is dissolved in ethanol (20 ml) and, at room temperature, Organic Preparation and Procedures International, Vol. 24, pp. 147 (1992).
Proped. Int., 24, 147 (1992)] and synthesized from piperidin-2-one.
Ethoxy-2,3,4,5-tetrahydropyridine (0.33 g) and triethylamine (0.74 ml)
Was added, and the mixture was stirred at 35 ° C. for 3.5 hours, left at room temperature for 11 hours, and further stirred at 45 ° C. for 24 hours. After adding a 4N hydrogen chloride dioxane solution (5 ml) to the reaction solution,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
(YMC, elution solvent: 23% acetonitrile / water). 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.65-1.80 (6H, m), 2.00-2.09 (2H, m), 2.66-2.7
2 (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 (1H, 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), 7.69-7.7
4 (2H, m), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1674, 1637, 1354, 1155.

Example 56 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2,3,
4,5-tetrahydropyridin-6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid 2
Hydrochloride (Exemplified Compound No. 530) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 55
4- [1- (2,3,4,5-tetrahydropyridine-
Ethyl 6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.28 g)
Dissolved in N hydrochloric acid (12 ml) 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 1)
(8% 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 0.19 g (yield 71%) of the title compound as a colorless amorphous solid. ¹ H 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 (2
H, 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), 7.6
7-7.74 (2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1734, 1675, 1637, 1352, 1156.

Example 57 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3,4,4)
5,6-Tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate ethyl dihydrochloride (Exemplary Compound No. 27) N- [3- () obtained in Example 47 (a) 3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.75 g) was dissolved in ethanol (25 ml) and, at room temperature, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.39 g) and triethylamine (0. 85ml)
, And the mixture was stirred at the same temperature for 7 hours, and then left for 15 hours.
Due to the slow progress of the reaction, 7-methoxy-3,4,5,6
-Tetrahydro-2H-azepine (0.22 g) and triethylamine (0.51 ml) were added and
After stirring for 11 hours, the mixture was left at room temperature for 11 hours.
For 10 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 HPLC (YMC-PackODS-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. This was dissolved in water and lyophilized to give 0.30 g (yield 35%) of the title compound as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.21 (3H, t, J = 7.
0), 1.52-1.63 (4H, m), 1.68-1.81 (4H, m), 2.04-2.1
0 (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), 4.41 (2H,
s), 4.46 (2H, d, J = 6.0), 4.81-4.87 (1H, m), 6.44 (1
H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.32 (1
H, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.52-7.5
9 (2H, m), 7.66-7.74 (2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1674, 1628, 1353, 1156.

Example 58 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3,4,4)
5,6-Tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 531) N- [3- (3-amidinophenyl) obtained in Example 57 ) -2- (E) -Propenyl] -N- [3-chloro-
Ethyl 4- [1- (3,4,5,6-tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.24
g) was dissolved in 3N hydrochloric acid (10 ml) and stirred at 60 ° C. 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: 18% 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 0.18 g of the title compound (yield 76
%) Was obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.52-1.62 (4H, m),
1.67-1.82 (4H, m), 2.00-2.09 (2H, m), 2.84-2.88 (2
H, 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 (1H, 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.

Example 59 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride
(Exemplary Compound No. 81) (a) N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [4- (piperidine-4-
Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl]-obtained in Reference Example 108
Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.46 g) in dichloromethane (50 ml) and ethanol (25 ml)
The mixture was dissolved in a mixed solvent of, and hydrogen chloride was passed through the mixture under ice-cooling for 1 hour, sealed, and stirred at room temperature for 8 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (40 ml),
An aqueous ammonium chloride solution (0.30 g dissolved in 15 ml of water) and 28% aqueous ammonia (0.58 ml) were added, and the mixture was allowed to stand at room temperature for 12 hours. The reaction mixture was added with a 4N hydrogen chloride dioxane solution, concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water) to give the title compound. 0.98 g (68% yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, t, J = 8.0), 7.69
(1H, 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-amidinophenyl) -2- (E) -propenyl] -N- [4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoylacetate dihydrochloride N- [3- (3-amidinophenyl) obtained in Example 59 (a) -2- (E) -propenyl] -N- [4-
Ethyl (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (0.52 g) is dissolved in ethanol (5 ml) and at room temperature, Organic Preparation and Procedures International, Vol. 24, no. 147 pages (1992) [ Org. Pre
p. Proced. Int. , 24 , 147 (1992)]. 5-Methoxy-3,4 synthesized from 2-pyrrolidinone.
-Dihydro-2H-pyrrole (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 separated by preparative HPL
Purified by C (YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (40 ml), 4N 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.68-1.80 (2H, m), 2.00-2.14 (4H, m), 2.96 (2
H, 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); IR (KBr, cm ^-1 ): 1738, 1671, 1349, 1157.

Example 60 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 585)

[0337]

Embedded image N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- obtained in Example 59 (b)
Ethyl [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.38 g) was dissolved in 3N hydrochloric acid (10 ml), and the solution was dissolved at 60 ° C. Stir for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure.
Purification was performed by PLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was
After dissolving in N hydrochloric acid (3 ml), the mixture was 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 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.

Example 61 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4-
[1- (2,3,4,5-tetrahydropyridine-6-
Yl) piperidin-4-yloxy] phenyl] ethyl sulfamoylacetate dihydrochloride (Exemplified Compound 82) N- [3- (3-amidinophenyl) -2- (E) -propenyl obtained in Example 59 (a) ] -N- [4-
Ethyl (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (0.50 g) in ethanol (5 ml) and at room temperature, Organic Preparation and Procedures International, Vol. 24, no. 147 pages (1992) [ Org. Pre
p. Proced. Int. , 24 , 147 (1992)] and 6- ethoxy- synthesized from piperidin-2-one.
2,3,4,5-tetrahydropyridine (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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 25%
(Acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (25 ml), added with a 4N hydrogen chloride dioxane solution (2 ml), and concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.27 g (yield 47%) of the title compound as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.65-1.78 (6H, m), 1.99-2.07 (2H, m), 2.68-2.7
2 (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 (1H, m), 6.44 (1
H, dt, J = 16.0, 5.5), 6.55 (1H, d, J = 16.0), 7.03 (2
H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.55 (1H, t, J =
7.7Hz), 7.68-7.73 (2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1738, 1674, 1637, 1351, 1157.

Example 62 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (2,3,4,5-tetrahydropyridine-6) -Yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 586) N- [3- (3-amidinophenyl) -2- (E) -propenyl]-obtained in Example 61 N- [4- [1-
(2,3,4,5-tetrahydropyridin-6-yl)
Ethyl piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.76 g) was dissolved in 3N hydrochloric acid (15 ml) and stirred at 60 ° C. for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure.
Purified by PLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was
After dissolving in N hydrochloric acid (5 ml), the solution was 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.65-1.78 (6H, m),
2.00-2.07 (2H, m), 2.68-2.71 (2H, m), 3.30-3.55 (4
H, 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), 7.67-7.7
3 (2H, m), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1734, 1674, 1637, 1348, 1156.

Example 63 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (3,4,5,6-tetrahydro-2H- Azepin-7-yl) piperidine-4
-Yloxy] phenyl] sulfamoylethyl acetate
Dihydrochloride (Exemplified Compound No. 83) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- obtained in Example 59 (a)
Ethyl (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (0.51 g) was dissolved in ethanol (5 ml), and the mixture was dissolved at room temperature with 7-methoxy-3,4,4.
5,6-tetrahydro-2H-azepine (0.34 g)
And triethylamine (0.60 ml) were added, and the mixture was stirred at the same temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the residue was separated 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 (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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.46-1.76 (8H, m), 2.01-2.10 (2H, m), 2.86-2.8
9 (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 (1
H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.39 (2
H, d, J = 9.0), 7.54 (2H, d, J = 9.0), 7.54 (1H, t, J =
8.0Hz), 7.69-7.73 (2H, m), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1737, 1674, 1629, 1351, 1158.

Example 64 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (3,4,5,6-tetrahydro-2H- Azepin-7-yl) piperidine-4
-Yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 587) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [ 1-
(3,4,5,6-tetrahydro-2H-azepine-7
-Yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.96 g) in 3N
It was dissolved in hydrochloric acid (25 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 2).
(0% 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.53-1.64 (4H, m),
1.68-1.77 (4H, m), 2.02-2.10 (2H, m), 2.86-2.88 (2
H, 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, 1344, 1154.

Example 65 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetate ethyl dihydrochloride (Exemplary Compound No. 53)

[0343]

Embedded image (A) N- [3- (3-amidinophenyl) -2-
(E) -Propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride N- [4- (1-t-butoxycarbonyl) obtained in Reference Example 112 Piperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-cyanophenyl) -2-
(E) -propenyl] sulfamoyl acetate (1.
90 g) was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (40 ml). After passing hydrogen chloride under ice-cooling, the mixture was 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 ammonium chloride solution (0.34 g was added to 15 ml of water).
1) and 28% aqueous ammonia (0.64 ml), and then left at room temperature for 13 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction mixture, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 2).
(0% acetonitrile / 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 1.36 g of the title compound (yield 73).
%) Was obtained as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 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
(1H, dt, J = 16.0,6.0), 6.56 (1H, d, J = 16.0), 7.05
(1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0, 2.5), 7.29 (1
H, d, J = 2.5), 7.54 (1H, t, J = 8.0), 7.71 (2H, m),
7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1675.

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetate dihydrochloride N- [3- (3 -Amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate (700 mg) is dissolved in ethanol (15 ml) and, at room temperature, Organic Preparation and Procedures International, Vol. 24, p. 147 (1992) [Org. Pr.
ep. Proced. Int., 24, 147 (1992)], 5-methoxy-3 synthesized from 2-pyrrolidinone,
4-Dihydro-2H-pyrrole (405 mg) and triethylamine (0.57 ml) were added, and the mixture was stirred at the same temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HPLC.
(YMC-Pack ODS-A; YMC, elution solvent: 22% acetonitrile / water) to obtain 565 m of amorphous solid.
g was obtained. 151 mg of this solid was added to ethanol (4 ml).
And 4N hydrogen chloride dioxane solution (2 ml) was added, followed by concentration under reduced pressure to dryness. This was dissolved in water and lyophilized to give 157 mg of the title compound.
(66% yield) as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.72-1.85 (2H, m), 1.98-2.14 (4H, m), 2.16 (3
H, s), 2.96 (2H, t, J = 8.0), 3.46-3.81 (6H, m), 4.2
0 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.
0), 4.73 (1H, m), 6.44 (1H, 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 (1H, d, J = 2.5), 7.55 (1H, t, J =
8.0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.
89 (1H, s); IR (KBr, cm ^-1 ): 1738, 1671, 1350, 1157.

Example 66 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-Pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 557)

[0346]

Embedded image N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- obtained in Example 65 (b)
Ethyl [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetate (409 mg) in 4N.
It was dissolved in 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 17%
(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 266 mg (yield 60%) of the title compound as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.72-1.86 (2H, m),
1.97-2.14 (4H, m), 2.16 (3H, s), 2.96 (2H, m), 3.4
7-3.80 (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 (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 (1H, d, J = 8.0), 7.72
(1H, d, J = 8.0), 7.89 (1H, s); IR (KBr, cm ^-1 ): 1733, 1672, 1347, 1155.

Example 67 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- [1- (2,3,3
4,5-Tetrahydropyridin-6-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoylacetate dihydrochloride (Exemplary Compound No. 54) N- [3- (3-amidino) obtained in Example 65 (a) Phenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate (730 mg) is dissolved in ethanol (15 ml) and, at room temperature, Organic Preparation and Procedures International, Vol. 24, p. 147 (1992) [ Org. Pr.
ep. Proced. Int. , 24 , 147 (1992)] and 6- ethoxy- synthesized from piperidin-2-one.
2,3,4,5-tetrahydropyridine (482 mg)
And triethylamine (0.59 ml) were 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 separated by preparative HPLC (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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.64-1.70 (6H, m), 1.96-2.08 (2H, m), 2.16 (3
H, s), 2.70 (2H, t, J = 6.0), 3.25-3.37 (2H, m), 3.4
6-3.83 (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 (1H, dt,
J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.06 (1H, d, J
= 9.0), 7.24 (1H, dd, J = 9.0, 2.5), 7.29 (1H, d, J =
2.5), 7.55 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.7
2 (1H, d, J = 8.0), 7.90 (1H, s); IR (KBr, cm ^-1 ): 1738, 1674, 1637, 1351, 1157.

Example 68 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- [1- (2,3,3
4,5-tetrahydropyridin-6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid 2
Hydrochloride (Exemplified Compound No. 558) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl- obtained in Example 67
4- [1- (2,3,4,5-tetrahydropyridine-
Ethyl 6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (265 mg)
Dissolved in N 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 separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 2).
(0% 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. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.64-1.82 (6H, m),
1.96-2.08 (2H, m), 2.16 (3H, s), 2.70 (2H, m), 3.3
3 (2H, m), 3.46-3.83 (4H, m), 4.21 (2H, s), 4.44
(2H, d, J = 6.0), 4.73 (1H, m), 6.44 (1H, dt, J = 16.
0, 6.0), 6.56 (1H, 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 (1H, d, J = 8.0), 7.72
(1H, d, J = 8.0), 7.89 (1H, s); IR (KBr, cm ^-1 ): 1733, 1676, 1637, 1347, 1156.

Example 69 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- [1- (3,4,4
5,6-tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplified Compound No. 55) N- [3- () obtained in Example 65 (a) 3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate (640 mg) was dissolved in ethanol (12 ml), and 7-methoxy-3,
4,5,6-tetrahydro-2H-azepine (348 m
g) and triethylamine (0.26 ml) were added, and the mixture was stirred at the same temperature for 2.5 days. After concentrating the reaction solution 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 dioxane solution (0.42 ml) was added, and the mixture was concentrated and dried under reduced pressure. This was dissolved in water and lyophilized to give 336 mg of the title compound (yield 40
%) Was obtained as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.52-1.64 (4H, m), 1.68-1.82 (4H, m), 1.98-2.0
9 (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 (2
H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0),
4.74 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1
H, 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 (1H, t, J = 8.
0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.89
(1H, s); IR (KBr, cm ^-1 ): 1738, 1675, 1628, 1351, 1157.

Example 70 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- [1- (3,4,4)
5,6-Tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 559) N- [3- (3-amidinophenyl) obtained in Example 69 ) -2- (E) -Propenyl] -N- [3-methyl-
Ethyl 4- [1- (3,4,5,6-tetrahydro-2H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (335 m
g) was dissolved in 3N hydrochloric acid (10 ml) 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 HPLC (YMC-Pack ODS-A; YMC, elution solvent: 20% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid (10 ml),
It was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give 258 mg of the title compound (yield 80
%) Was obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 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 (4
H, m), 4.19 (2H, s), 4.40 (2H, d, J = 6.0), 4.74 (1
H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.56 (1H, d, J = 1
6.0), 7.05 (1H, d, J = 9.0), 7.26 (1H, dd, J = 9.0, 2.
5), 7.29 (1H, d, J = 2.5), 7.55 (1H, t, J = 8.0), 7.69
(1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.89 (1H, s)
; IR (KBr, cm ^-1 ): 1732, 1676, 1628, 1348, 1156.

Example 71 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplary Compound No. 137)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-cyanophenyl) obtained in Reference Example 119
Ethyl-2- (E) -propenyl] sulfamoylacetate (2.40 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through the mixture under ice cooling for 2.5 hours. 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 ammonium chloride solution (0.
50 g was dissolved in 5 ml of water) and 28% aqueous ammonia (1.10 ml), and the mixture was allowed to stand at room temperature for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HPLC.
(YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), added with a 4N solution of hydrogen chloride in ethyl acetate (0.90 ml), and then concentrated to dryness under reduced pressure to give 0.60 g of the title compound (yield: 25%). ) Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.85-2.00 (2H, m), 2.05-2.20 (2H, m), 3.00-3.1
0 (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 (1H, m),
6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0),
7.24 (1H, m), 7.50 (1H, m), 7.54 (1H, m), 7.65-7.75
(3H, m), 7.90 (1H, m); IR (KBr, cm ^-1 ): 1736, 1671, 1658.

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrole- 2-yl) piperidin-4-yloxy] phenyl]
Ethyl sulfamoyl acetate dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidine-4) obtained in Example 71 (a) -Yloxy) phenyl] sulfamoyl acetate (500 mg) in ethanol (15 ml) was dissolved in organic
Preparation and Procedures International, Vol. 24, pp. 147 (1992) [O
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 stirred overnight at the same temperature. After concentrating the reaction solution under reduced pressure, the residue was separated by preparative H
Purification was performed by PLC (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 (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 420 mg of the title compound (67% yield).
Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.80-1.95 (2H, m), 2.00-2.15 (4H, m), 2.96 (2
H, m), 3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 3.61
(2H, m), 3.65-3.75 (1H, m), 3.75-3.85 (1H, m), 4.2
0 (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 (1H, d, J = 9.0), 7.51 (1H, d
d, J = 9.0, 2.5), 7.55 (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),
7.87 (1H, s); IR (KBr, cm ^-1 ): 1737, 1670.

Example 72 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 641)

[0355]

Embedded image N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4,5-dihydro-) obtained in Example 71 (b) 3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (380 m
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: 13% acetonitrile / water). The obtained amorphous solid was washed with 1N hydrochloric acid (1.2 ml) and water (5 ml).
l) and then concentrated to dryness under reduced pressure to give
240 mg (yield 65%) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1
H, 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
(1H, dd, J = 9.0, 2.5), 7.55 (1H, t, J = 8.0), 7.67
(1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.77 (1H, d,
J = 2.5), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1731, 1670.

Example 73 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(2,3,4,5-tetrahydropyridin-6-yl)
Ethyl piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplary Compound No. 138) N- [3- (3-amidinophenyl) -2- (E) -propenyl] obtained in Example 71 (a) -N- [3-Carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoylacetate (500 mg) was dissolved in ethanol (15 ml), and the organic solution was dissolved at room temperature.
Preparation and Procedures International, Vol. 24, pp. 147 (1992) [ O
Int. , 24 , 147 (1992)], 6-ethoxy-2,3,4,5-tetrahydropyridine (360) synthesized from piperidin-2-one.
mg) and triethylamine (0.77 ml).
The mixture was stirred overnight at the same temperature. Due to the slow progress of the reaction, 6-ethoxy-2,3,4,5-tetrahydropyridine (630)
mg) and triethylamine (0.77 ml).
After stirring at the same temperature for 1 day, 6-ethoxy-2,3,4,4
5-Tetrahydropyridine (320 mg) and triethylamine (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 separated by preparative HP
Purified by LC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (6 ml), 4N hydrogen dioxane solution (0.25 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 200 mg (yield 31%) of the title compound as a colorless substance. Obtained as an amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.24 (3H, t, J = 7.
0), 1.65-1.90 (6H, m), 2.00-2.10 (2H, m), 2.70 (2
H, 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.

Example 74 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(2,3,4,5-tetrahydropyridin-6-yl)
Piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 642) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [obtained in Example 73 Ethyl 3-carbamoyl-4- [1- (2,3,4,5-tetrahydropyridin-6-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (200 m
g) 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% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (0.9 ml) and concentrated to dryness under reduced pressure to give the title compound 13
7 g (yield 71%) were obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.65-1.90 (6H, m),
2.00-2.10 (2H, m), 2.69 (2H, m), 3.34 (2H, m), 3.4
0-3.60 (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 (1H, dt, J
= 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.27 (1H, d, J =
9.0), 7.52 (1H, dd, J = 9.0, 3.0), 7.55 (1H, t, J = 8.
0), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.77
(1H, d, J = 3.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1731, 1674.

Example 75 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(3,4,5,6-tetrahydro-2H-azepine-7
-Yl) piperidin-4-yloxy] phenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 1
39) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl obtained in Example 71 (a) Ethyl sulfamoyl acetate (400 mg) was dissolved in ethanol (10 ml), and the mixture was dissolved at room temperature in 7-methoxy-
3,4,5,6-tetrahydro-2H-azepine (28
0 mg) and triethylamine (0.31 ml) were added, and the mixture was stirred overnight at the same temperature. Since the progress of the reaction is slow, 7-
Methoxy-3,4,5,6-tetrahydro-2H-azepine (280 mg) and triethylamine (0.31 m
l) was added, and the mixture was further stirred at 40 ° C for 12 hours, and then left at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was separated 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 dioxane solution (0.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 140 mg of the title compound (yield 26).
%) Was obtained as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.24 (3H, t, J = 7.
0), 1.50-1.65 (4H, m), 1.70-1.75 (2H, m), 1.80-1.9
0 (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 (1
H, m), 3.75-3.85 (1H, 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 (1
H, 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 (1H, d, J = 8.0), 7.78 (1H, d, J = 2.5), 7.
86 (1H, s); IR (KBr, cm ^-1 ): 1737, 1672.

Example 76 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(3,4,5,6-tetrahydro-2H-azepine-7
-Yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 643) N- [3- (3-amidinophenyl) -2- (E) -propenyl]-obtained in Example 75 N- [3-carbamoyl-4- [1- (3,4,5,6-tetrahydro-2
H-azepin-7-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (130 mg) was dissolved in 3N hydrochloric acid (10 ml), and 6
Stirred at 0 ° C. for 2 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
YMC, elution solvent: 12% acetonitrile / water). The obtained amorphous solid was washed with 1N hydrochloric acid (0.25 ml).
And 50 ml (yield 40%) of the title compound was obtained as a colorless amorphous solid by concentrating to dryness under reduced pressure. ¹ H 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 (2
H, m), 2.85-2.90 (2H, m), 3.45-3.50 (2H, m), 3.55-
3.65 (1H, m), 3.65-3.75 (1H, m), 3.80-3.90 (1H,
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 (1
H, 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.

Example 77 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (Exemplary Compound No. 109)

[0361]

Embedded image

(A) Ethyl N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl acetate N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-cyanophenyl) -2 obtained in Reference Example 122 -(E) -Propenyl] sulfamoylethyl acetate (2.06 g) was dissolved in a mixed solvent of dichloromethane (50 ml) and ethanol (25 ml), and hydrogen chloride was passed through under ice-cooling. Stirred. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), and an aqueous ammonium chloride solution (0.1 mL) was added.
34 g was dissolved in 15 ml of water) and 28% aqueous ammonia (0.63 ml), and the mixture was allowed to stand at room temperature for 12 hours. A 4N hydrogen chloride dioxane solution (2.5 m
After adding l), the mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC.
(YMC-Pack ODS-A; YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (20 ml), 4N hydrogen chloride / dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 1.21 g of the title compound (yield: 60%). Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, t, J = 8.0), 7.66-7.73 (4H, m), 7.85 (1
H, s); IR (KBr, cm ^-1 ): 1738, 1676.

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride N- [3- obtained in Example 77 (a) (3-amidinophenyl) -2- (E) -propenyl] -N- [4-
Ethyl (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (800 mg) in ethanol (20 ml) was dissolved at room temperature in Organic Preparation and Procedures International, No. 24th, 14th
7 (1992) [ Org. Prep. Proced. Int. , 24 , 14]
7 (1992)] and 5-methoxy-3,4-dihydro-2H-pyrrole (370 mg) and triethylamine (0.87 m) synthesized from 2-pyrrolidinone.
l) was added and the mixture was stirred overnight at the same temperature. Due to the slow progress of the reaction, 5-methoxy-3,4-dihydro-2H-pyrrole (120 mg) and triethylamine (0.26 ml)
Was added and further stirred at room temperature for 4 hours. 4N in the reaction solution
After adding a hydrogen chloride dioxane solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent:
(26% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. By dissolving this in water and subjecting to lyophilization,
622 mg (70% yield) of the title compound were obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 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), 4.9
6 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d,
J = 16.0), 7.44 (1H, 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.

Example 78 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-Pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 613)

[0365]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- obtained in Example 77 (b)
Ethyl [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (471 mg) was dissolved in 3N hydrochloric acid (20 ml). , 6
Stirred at 0 ° C. for 5.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (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 of the title compound (89% yield).
%) Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1H, 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 (1H, s); IR (KBr, cm ^-1 ): 1739, 1672, 1353, 1144.

Example 79 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (2,3,4,5-tetrahydropyridine-6) -Yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetic acid ethyl dihydrochloride (Exemplary Compound No. 110) N- [3- (3-amidinophenyl) obtained in Example 77 (a) -2- (E) -propenyl] -N- [4-
Ethyl (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (900 mg) in ethanol (20 ml) and at room temperature, Organic Preparation and Procedures International, No. 24th, 14th
7 (1992) [ Org. Prep. Proced. Int. , 24 , 14]
7 (1992)], 6-methoxy-2,3,4,5-tetrahydropyridine (480 mg) and triethylamine (0.98 ml) synthesized from piperidin-2-one were added, and the mixture was added at the same temperature. Stirred overnight. Since the progress of the reaction was slow, 6-ethoxy-2,3,4,5-tetrahydropyridine (480 mg) and triethylamine (0.98 ml) were added, and the mixture was stirred at room temperature for 1 day.
The mixture was further stirred at 40 ° C. for one day. After adding a 4N hydrogen chloride dioxane solution (2.5 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). . 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.64-1.85 (6H, m), 1.99-2.10 (2H, m), 2.70 (2
H, 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 (1
H, 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.

Example 80 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (2,3,4,5-tetrahydropyridine-6) -Yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 614) N- [3- (3-amidinophenyl) -2- () obtained in Example 79 E) -Propenyl] -N- [4- [1-
(2,3,4,5-tetrahydropyridin-6-yl)
Piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (2
91 mg) in 3N hydrochloric acid (20 ml).
For 5.5 hours. After cooling the reaction to room temperature,
After concentration under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A;
(YMC, elution solvent: 22% 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 240 mg (86% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.63-1.85 (6H, m),
2.03 (2H, m), 2.70 (2H, m), 3.20-3.48 (2H, m), 3.5
2-3.76 (4H, m), 4.12 (2H, s), 4.50 (2H, d, J = 6.0),
4.94 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.56 (1
H, d, J = 16.0), 7.42 (1H, d, J = 9.0), 7.54 (1H, t, J
= 8.0), 7.69 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0),
7.73-7.78 (2H, m), 7.89 (1H, s); IR (KBr, cm ^-1 ): 1732, 1675, 1352, 1143.

Example 81 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (3,4,5,6-tetrahydro-2H- Azepin-7-yl) piperidine-4
-Yloxy] -3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 111) N- [3- (3-amidinophenyl) -2- (E) obtained in Example 77 (a) -Propenyl] -N- [4-
Ethyl (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride (900 mg) was dissolved in ethanol (20 ml), and the mixture was dissolved at room temperature in 7-methoxy-3,4,5,6-tetrahydro-.
2H-azepine (540 mg) and triethylamine (0.98 ml) were added, and the mixture was stirred overnight at the same temperature. Due to the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (540 mg) and triethylamine (0.98 ml) were added, and the mixture was further stirred at room temperature for 5 hours. Stirred for days. 4N in the reaction solution
After adding a hydrogen chloride dioxane solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent:
(30% 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 340 mg (yield 33%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.
0), 1.52-1.67 (4H, m), 1.67-1.85 (4H, m), 2.06 (2
H, 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 (1H, d, J = 16.0), 7.44 (1H, d, J = 9.5), 7.5
5 (1H, t, J = 8.0), 7.67-7.75 (4H, m), 7.90 (1H, s)
; IR (KBr, cm ^-1 ): 1739, 1675, 1354, 1142.

Example 82 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (3,4,5,6-tetrahydro-2H- Azepin-7-yl) piperidine-4
-Yloxy] -3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary Compound No. 615) N- [3- (3-amidinophenyl) -2- (E) -propenyl] obtained in Example 81 -N- [4- [1-
(3,4,5,6-tetrahydro-2H-azepine-7
-Yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoyl acetate dihydrochloride (307 mg) was dissolved in 3N hydrochloric acid (20 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 separated by preparative HPLC (YMC-Pa
ck ODS-A; YMC, elution solvent: 23% acetonitrile /
Water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. Dissolve this in water,
Lyophilization gave 218 mg (74% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 1.46-1.67 (4H, m),
1.67-1.87 (4H, m), 2.07 (2H, m), 2.87 (2H, m), 3.4
2-3.52 (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 (1H, d, J =
10.0), 7.55 (1H, t, J = 8.0), 7.66-7.76 (4H, m), 7.8
9 (1H, s); IR (KBr, cm ^-1 ): 1733, 1676, 1351, 1144.

Example 83 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (5,6-
Dihydro-2H- [1,4] thiazin-3-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (Exemplified Compound No. 28) N- [3- obtained in Example 47 (a) (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.25 g) was dissolved in ethanol (10 ml) and at room temperature, Indian Journal of Chemistry, Vol. 10, No. 3
23 (1972) [ Indian J. Chem. , 10 , 323 (197
2)]-Ethoxy-3,6-dihydro-2H- [1, synthesized from 3-thiomorpholine according to the method described in [1].
4] Thiazine (0.24 g) and triethylamine (0.23 ml) were added, and the mixture was stirred at the same temperature for 4 hours.
The mixture was stirred at 5 ° C for 3 hours and left at room temperature for 11 hours. After stirring at 45 ° C. for 12 hours, the mixture was left at room temperature for 11 hours. After adding a 4N hydrogen chloride dioxane solution (2 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pa
ck ODS-A; YMC, elution solvent: 20% acetonitrile /
Water). The obtained amorphous solid was dissolved in ethanol (4
ml) and dissolved in a 4N hydrogen chloride dioxane solution (1 m
After l) was added, the mixture was concentrated to dryness under reduced pressure to give the title compound (0.07 g, yield 24%) as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.73-1.82 (2H, m), 2.02-2.10 (2H, m), 2.91-2.9
6 (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 (1H, d, J = 15.
5), 7.33 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 2.
5), 7.51- 7.60 (2H, m), 7.64-7.75 (2H, m), 7.87 (1
H, s); IR (KBr, cm ^-1 ): 1737, 1674, 1633, 1350, 1155.

Example 84 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2,3,3)
5,6-Tetrafluoropyridin-4-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoylacetate dihydrochloride (Exemplary Compound No. 1045) N- [3- (3-) obtained in Example 47 (a) Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (930 mg) was dissolved in ethanol (20 ml),
5,6-Tetrafluoropyridine (0.16 ml) and triethylamine (0.64 ml) were added, and the mixture was stirred at the same temperature for 5 hours. After adding a 4N hydrogen chloride dioxane solution to the reaction solution, the mixture is concentrated under reduced pressure, and the residue is subjected to preparative HPLC (YMC-Pa
ck ODS-A; YMC, elution solvent: 55% acetonitrile /
Water). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. Dissolve this in water,
Lyophilization gave 893 mg (81% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.73-1.84 (2H, m), 2.01-2.12 (2H, m), 3.38-3.4
8 (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 (1H, 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 (1H, 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.

Example 85 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (2,3,3
5,6-tetrafluoropyridin-4-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid
Dihydrochloride (Exemplified Compound No. 1063) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 84
4- [1- (2,3,5,6-tetrafluoropyridin-4-yl) piperidin-4-yloxy] phenyl]
Ethyl sulfamoyl acetate dihydrochloride (356 mg) was dissolved in a mixed solvent of 3N hydrochloric acid (20 ml) and 4N hydrogen chloride in dioxane (20 ml), and the mixture was stirred at 60 ° C. for 8.5 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: only 40% acetonitrile / water to acetonitrile). After dissolving the obtained amorphous solid in 1N hydrochloric acid, it was concentrated to dryness under reduced pressure. Dissolve this in water,
Lyophilization gave 322 mg (94% yield) of the title compound as a colorless amorphous solid. ¹ H 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 (2
H, m), 4.21 (2H, s), 4.47 (2H, d, J = 6.0), 4.79 (1H,
m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 1
6.0), 7.31 (1H, d, J = 9.0), 7.42 (1H, dd, J = 9.0, 2.
5), 7.55 (1H, t, J = 8.0), 7.60 (1H, d, J = 2.5), 7.66
(1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s)
; IR (KBr, cm ^-1 ): 1678, 1346, 1147.

Example 86 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (N-ethylformimidoyl) piperidine -4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1081) N- [3- (3-amidinophenyl) -2- (E) -propenyl]-obtained in Example 47 (a) N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.38 g) was dissolved in ethanol (20 ml) and, at room temperature, Angevante Chemii, Vol. 75, p. 790 (1963) [ Ang.
ew. Chem. , 75 , 790 (1963)], add methyl N-ethylformimidate (0.09 g) synthesized from N-ethylformamide and triethylamine (0.30 ml). Stirred at warm for 46 hours. 4N hydrogen chloride in dioxane solution (2 ml)
, And concentrated under reduced pressure, and the residue is purified by preparative HPLC (YMC-
Pack ODS-A; YMC, elution solvent: 20% acetonitrile /
Water). The obtained amorphous solid was dissolved in ethanol (5
ml) and dissolved in a 4N hydrogen chloride dioxane solution (1 m
After l) was added, the mixture was concentrated to dryness under reduced pressure to give 0.14 g (yield 35%) of the title compound as a colorless amorphous solid. ¹ H NMR (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 (2
H, m), 3.51-3.73 (4H, m), 4.19 (2H, q, J = 7.5), 4.4
2 (2H, s), 4.47 (2H, d, J = 5.5), 4.79-4.85 (1H, m),
6.45 (1H, dt, J = 16.0, 5.5), 6.58 (1H, d, J = 16.0),
7.32 (1H, 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 (1H, d, J = 13.5); IR (KBr, cm ^-1 ): 1738, 1697, 1675, 1350, 1156.

Example 87 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (N-ethylformimidoyl) piperidine -4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1099)

[0375]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 86
Ethyl 4- [1- (N-ethylformimidoyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.38 g) 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 separated by preparative HPLC (YMC-
Pack ODS-A; YMC, elution solvent: 18% acetonitrile /
Water). The obtained amorphous solid was washed with 1N hydrochloric acid (2 m
After dissolving in 1), the mixture was 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 1.19 (3H, t, J = 7.
0), 1.72-1.88 (2H, m), 1.98-2.09 (2H, m), 3.51-3.7
9 (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 (1
H, 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.

Example 88 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoylacetate dihydrochloride (Exemplary Compound No. 1009) N- [3- (3-amidinophenyl) -2 obtained in Example 47 (a) -(E) -Propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.75 g) was dissolved in ethanol (25 ml) and, at room temperature, European Journal of Organic Chemistry,
Vol. 10, p. 2645 (1999) [ Eur. J. Org.
Chem. , 10 , 2645 (1999)], 2-ethoxy-4,5-dihydrooxazole (0.28 g) synthesized from 2-oxazolidone and triethylamine (0.68 ml). Stirred for 22 hours. After adding a 4N hydrogen chloride dioxane solution (5 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-PackODS-
A; YMC, elution solvent: 23% acetonitrile / 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 to give the title compound (0.56 g, yield 67%) as colorless. Obtained as an amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.22 (3H, t, J = 7.
0), 1.75-1.86 (2H, m), 1.98-2.10 (2H, m), 3.51-3.7
8 (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 (1H, d,
J = 16.0), 7.32 (1H, d, J = 9.0), 7.40 (1H, 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 (1H, s); MS (FAB, M ⁺ -2HCl): 604.

Example 89 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride
(Exemplary Compound No. 1027)

[0378]

Embedded image N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 88
Ethyl 4- [1- (4,5-dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.29 g) was dissolved in 3N hydrochloric acid (12 ml), and the solution was dissolved at 60 ° C. for 10 hours. 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 HPLC (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 give 0.23 g of the title compound (yield 8).
2%) as a colorless amorphous solid. ¹ 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 (1H, dt, J = 16.0, 5.5), 6.58 (1
H, d, J = 16.0), 7.31 (1H, d, J = 9.0), 7.41 (1H, dd, J
= 9.0, 2.5), 7.52-7.61 (2H, m), 7.68 (1H, d, J = 7.5),
7.73 (1H, d, J = 7.5), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1733, 1685, 1349, 1155.

Example 90 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (tropane-3-
Yloxy) phenyl] sulfamoylethyl acetate 2
Hydrochloride (Exemplified Compound No. 1117) N- [3-chloro-4- (tropan-3-yloxy) phenyl] -N- [3- (3-
Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.30 g) in dichloromethane (2
After dissolving in a mixed solvent of 5 ml) and ethanol (35 ml) and passing hydrogen chloride under ice-cooling, the mixture was 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), an aqueous ammonium chloride solution (0.40 g in 5 ml of water) and 28% aqueous ammonia (0.90 ml) were added, and the mixture was added at room temperature. Stirred overnight. After the reaction solution was concentrated under reduced pressure, the residue was separated 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 chloride dioxane solution (1.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.07 g of the title compound (yield 70%). Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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, cm ^-1 ): 1737, 1675.

Example 91 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (tropane-3-
Yloxy) phenyl] sulfamoylacetic acid dihydrochloride
(Exemplified Compound No. 1135) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro- obtained in Example 90
Ethyl 4- (tropan-3-yloxy) phenyl] sulfamoylacetate dihydrochloride (700 mg) was dissolved in 3N 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 (3.3 ml) and water (10 ml), and concentrated to dryness under reduced pressure to give the title compound 5
80 mg (86% yield) were obtained as a colorless amorphous solid.
¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 2.05-2.30 (8H, m),
2.66 (3H, s), 3.93 (2H, m), 4.27 (2H, s), 4.47 (2
H, d, J = 6.0), 4.83 (1H, m), 6.44 (1H, dt, J = 6.0, 1
6.0), 6.57 (1H, d, J = 16.0), 7.35-7.45 (2H, m), 7.5
0-7.60 (2H, m), 7.68 (1H, m), 7.73 (1H, m), 7.87
(1H, m); IR (KBr, cm ^-1 ): 1732, 1675.

Example 92 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (3,4,4)
5,6,7,8-hexahydro-2H-azonin-9-
Il) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1171) N- [3- (3-amidinophenyl) -2- (E) -propenyl obtained in Example 47 (a) ] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.78 g) is dissolved in ethanol (20 ml) and, at room temperature, Organic Preparation and Procedures International. 24, 147 (1992).
Year) [ Org. Prep. Proced. Int. , 24 , 147 (1992)] .
Methoxy-3,4,5,6,7,8-hexahydro-2
After adding H-azonin (0.80 g) and triethylamine (0.71 ml), the mixture was stirred at the same temperature for 18 hours. Due to the slow progress of the reaction, 9-methoxy-3,4,4
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 a 4N hydrogen chloride dioxane solution (5 ml) to the reaction mixture, the mixture was concentrated under reduced pressure.
The residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 30% 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. This was dissolved in water and freeze-dried to give N- [3- (3-amidinophenyl) -2.
-(E) -propenyl] -N- [3-chloro-4- [1
-(3,4,5,6,7,8-Hexahydro-2H-azonin-9-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.28 g) and a mixture of impurities as a colorless amorphous solid As obtained. This mixture was then dissolved in 3N hydrochloric acid (10 ml) and
After stirring at 0 ° C. for 6 hours, the mixture was left at room temperature for 61 hours,
Stirred at C for an additional 7 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack ODS
-A; YMC, elution solvent: 23% acetonitrile / water). The obtained amorphous solid was dissolved in 1N hydrochloric acid (2 ml), and concentrated under reduced pressure to dryness to obtain 0.09 g (yield 58%) of the title compound as a colorless amorphous solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm: 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), 4.2
7 (2H, s), 4.46 (2H, d, J = 5.5), 4.80-4.88 (1H, m),
6.44 (1H, dt, J = 16.0, 5.5), 6.57 (1H, d, J = 16.0),
7.31 (1H, d, J = 9.0), 7.40 (1H, dd, J = 9.0, 2.5), 7.5
1-7.60 (2H, m), 7.64-7.75 (2H, m), 7.87 (1H, s); IR (KBr, cm ^-1 ): 1733, 1675, 1627, 1352, 1156.

Example 93 N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydrooxazol-2-yl) piperidine -4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1011) N- [3- (3-amidinophenyl) -2- (E) -propenyl]-obtained in Example 59 (a) N- [4-
Ethyl (piperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride (533 mg) in ethanol (10 ml) was dissolved at room temperature at room temperature in the European Journal of Organic Chemistry, Vol. 10,
2645 (1999) [ Eur. J. Org. Chem. , 10 ,
2645 (1999)] and 2-ethoxy-4,5-dihydrooxazole (235 mg) synthesized from 2-oxazolidone and triethylamine (0.43).
ml) and stirred at the same temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was separated by preparative HPLC (YMC-Pack ODS-A; YM
C, elution solvent: 22% acetonitrile / 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 as colorless. Obtained as an amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.23 (3H, t, J = 7.
0), 1.66-1.80 (2H, m), 1.94-2.10 (2H, m), 3.62-3.8
2 (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), 7.3
9 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (2H,
m), 7.88 (1H, s); MS (FAB, M + -2HCl): 570.

Example 94 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydrooxazol-2-yl) piperidine -4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1029) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4 obtained in Example 93 -[1-
(4,5-Dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (272 mg) was added to 3N hydrochloric acid (10 m).
1) and stirred at 60 ° C. for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure.
(YMC-Pack ODS-A; YMC, elution solvent: 15% 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. ¹ H 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 (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), 7.70
(2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1687, 1346, 1156.

Example 97 N- [3- (3-Amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [4- [1- (4,5
-Dihydro-3H-pyrrol-2-yl) piperidine-
4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 1462)

(A) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
Ethyl [4- (piperidin-4-yloxy) phenyl] sulfamoylacetate N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl]-obtained in Reference Example 131
N- [3- (3-cyanophenyl) -2-fluoro-2
-(Z) -Propenyl] sulfamoylethyl acetate (1.41 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed through the mixture under ice-cooling, and the mixture was sealed and sealed at room temperature for 10 hours. Stirred.
After the reaction solution was concentrated under reduced pressure, the residue was treated with ethanol (30 m
l), an aqueous solution of ammonium chloride (0.25 g dissolved in 10 ml of water) and 28% aqueous ammonia (0.47
ml) was added and left at room temperature for 8 hours. 4 in the reaction solution
N Hydrochloric acid dioxane solution (1 ml) was added, and the mixture was concentrated under reduced pressure. The residue was separated by preparative HPLC (YMC-Pack ODS-A;
C, elution solvent: 20% acetonitrile / water) to give 1.00 g (yield 75%) of the title compound as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 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 (1H, 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).

(B) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
[4- [1- (4,5-dihydro-3H-pyrrole-2]
-Yl) piperidin-4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl obtained in Example 97 (a) ]
Ethyl -N- [4- (piperidin-4-yloxy) phenyl] sulfamoylacetate (1.27 g) is dissolved in ethanol (50 ml) and the organic preparation and procedures international, Vol. 24 at room temperature. 147 (1992) [ Org.
Prep. Proced. Int. , 24 , 147 (1992)]. 5-Methoxy-synthesized from 2-pyrrolidinone.
3,4-Dihydro-2H-pyrrole (0.73 g) and triethylamine (2.10 ml) were added, and the mixture was stirred at the same temperature for 4 hours, and then added with 5-methoxy-3,4-dihydro-2H.
-Pyrrole (0.73 g) and triethylamine (2.
10 ml) and left to stand overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YM
C, elution solvent: 20% acetonitrile / water)
The obtained amorphous solid was dissolved in ethanol (5 ml),
A 4N hydrogen 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, yield 37%) as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.24 (3H, t, J = 7.
0), 1.68-1.82 (2H, m), 2.02-2.13 (4H, m), 2.97 (2
H, t, J = 8.0), 3.47-3.53 (1H, m), 3.58-3.73 (4H,
m), 3.85-3.92 (1H, 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 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0),
7.76 (1H, d, J = 8.0), 7.82 (1H, s); IR (KBr, cm ^-1 ): 1672, 1354, 1161.

Example 98 N- [3- (3-Amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [4- [1- (4,5
-Dihydro-3H-pyrrol-2-yl) piperidine-
4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1484) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl obtained in Example 97 (b) ]
-N- [4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate ethyl hydrochloride (0.47
g) was dissolved in 3N hydrochloric acid (20 ml),
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative H
Purification was performed by PLC (YMC-Pack ODS-A; YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was
The compound was dissolved in N hydrochloric acid (2.5 ml) and concentrated to dryness under reduced pressure to give 0.39 g (yield 86%) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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
(1H, 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.

Example 99 N- [3- (3-Amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [3-carbamoyl-
4- [1- (4,5-dihydro-3H-pyrrole-2-
Il) piperidin-4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplary Compound No. 14
72)

(A) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
[Ethyl 3-carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoylacetate N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] obtained in Reference Example 132 -N- [3- (3-cyanophenyl)
-2-fluoro-2- (Z) -propenyl] sulfamoylacetate (4.30 g) in dichloromethane (35
dissolved in a mixed solvent of ethanol (35 ml) and ethanol (35 ml).
Stirred for hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), and an aqueous ammonium chloride solution (0.80 g was dissolved in 5 ml of water) and 28% aqueous ammonia (1.80 ml) were added. Left overnight.
The reaction solution is concentrated under reduced pressure, and the residue is separated by preparative HPLC (YMC-Pack
ODS-A; YMC, elution solvent: 15% acetonitrile / water)
2.20 g of the title compound (yield 58).
%) Was obtained as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.24 (3H, t, J = 7.
0), 1.88-1.96 (2H, m), 2.09-2.17 (2H, m), 3.02-3.0
9 (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 (1
H, dd, J = 9.0, 3.0), 7.57-7.71 (2H, m), 7.73-7.78
(2H, m), 7.81 (1H, s).

(B) N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N-
[3-carbamoyl-4- [1- (4,5-dihydro-
3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] ethyl sulfamoyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2-fluoro-2- obtained in Example 99 (a) (Z) -propenyl]
Ethyl -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoylacetate (1.
20 g) was dissolved in ethanol (40 ml) and the mixture was dissolved at room temperature in Organic Preparation and Procedures International, Vol. 24, p. 147 (1).
992) [ Org. Prep. Proced. Int. , 24 , 147 (199
2)], 5-methoxy-3,4-dihydro-2H-pyrrole (0.64 g) synthesized from 2-pyrrolidinone and triethylamine (1.80 ml).
Was added, and the mixture was stirred at the same temperature for 1 hour and left overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS
-A; YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in ethanol (5 ml), and 4N hydrogen chloride dioxane solution (1.60 ml)
Was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.40 g, yield 26%) as a colorless amorphous solid. ^{1 H NMR (500MHz, DMSO-} d 6) δppm: 1.24 (3H, t, J = 7.
0), 1.81-1.92 (2H, m), 2.02-2.14 (4H, m), 2.96 (2
H, 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 (1H, d, J = 39.0), 7.30 (1H, 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.

Example 100 N- [3- (3-Amidinophenyl) -2-fluoro-
2- (Z) -propenyl] -N- [3-carbamoyl-
4- [1- (4,5-dihydro-3H-pyrrole-2-
Il) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound No. 1494) N- [3- (3-amidinophenyl) -2-fluoro-2- ( Z) -Propenyl]
Ethyl -N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetate (0.
27g) was dissolved in 3N hydrochloric acid (20ml) and stirred at 70 ° C for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 10%
(Acetonitrile / water). The resulting amorphous solid was dissolved in 1N hydrochloric acid (1.2 ml) and concentrated to dryness under reduced pressure to give 0.20 g of the title compound (yield 77).
%) Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 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 (1H, m), 4.27 (2H, s), 4.62 (2H,
d, J = 16.0), 4.87 (1H, m), 5.98 (1H, 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.

Example 101 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (Exemplary Compound No. 1384)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl]
Methanesulfonamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-cyanophenyl) obtained in Reference Example 134
-2- (E) -propenyl] methanesulfonamide (1.01 g) was dissolved in a mixed solvent of dichloromethane (7.5 ml) and ethanol (7.5 ml), and the mixture was dissolved under ice-cooling.
After passing hydrogen chloride, the mixture was sealed and stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was treated with ethanol (1
5 ml) and an aqueous ammonium chloride solution (0.24
g in 3 ml of water) and 28% aqueous ammonia (0.4%).
(3 ml) was added and left at room temperature overnight. The reaction solution was concentrated under reduced pressure, and ethanol (10 ml) and 4N
After adding a hydrogen chloride dioxane solution (2 ml), the mixture was again concentrated under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YM
C, elution solvent: 10% acetonitrile / 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. After dissolving this in water,
Lyophilization gave 0.95 g (yield 98%) of the title compound as a pale yellow amorphous solid. ¹ H 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 (1
H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J =
16.0), 7.23 (1H, d, J = 9.0), 7.48-7.59 (2H, m), 7.6
8-7.75 (3H, m), 7.90 (1H, s);

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrole- 2-yl) piperidin-4-yloxy] phenyl]
Methanesulfonamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-
Carbamoyl-4- (piperidin-4-yloxy) phenyl] methanesulfonamide dihydrochloride (0.95
g) in ethanol (15 ml) and at room temperature, organic preparation and procedure-
International, Vol. 24, p. 147 (19
92) [ Org. Prep. Proced. Int. , 24 , 147 (1992)]
5 synthesized from 2-pyrrolidinone according to the method described in
-Methoxy-3,4-dihydro-2H-pyrrole (0.
52 g) and triethylamine (1.20 ml) were added, and the mixture was allowed to stand at the same temperature overnight. Then, 5-methoxy-3,4-dihydro-2H-pyrrole (0.17 g) and triethylamine (0.24 ml) were added. Stir for 6 hours. The reaction solution was concentrated under reduced pressure, and ethanol (10 m
l) and 4N hydrogen chloride dioxane solution (4 ml) were added, and the mixture was concentrated again under reduced pressure. The residue was subjected to preparative HPLC (YM
Purification with C-Pack ODS-A; YMC, elution solvent: 10% acetonitrile / water), and the obtained amorphous solid was treated with 1N hydrochloric acid (5 m
After l) was added, the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give the title compound 0.1.
67 g (63% yield) were obtained as a colorless amorphous solid. ¹ H 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), 7.4
9-7.58 (2H, m), 7.67-7.77 (3H, m), 7.91 (1H, s); IR (KBr, cm ^-1 ): 1669, 1334, 1151.

Example 102 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] ethanesulfonamide dihydrochloride (Exemplary Compound No. 1406)

(A) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl]
Ethane sulfonamide dihydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-cyanophenyl) obtained in Reference Example 135
-2- (E) -propenyl] ethanesulfonamide (1.08 g) was dissolved in a mixed solvent of dichloromethane (8 ml) and ethanol (8 ml), hydrogen chloride was passed through under ice-cooling, the solution was sealed, 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 ammonium chloride solution (0.26 g was added to water 3 m
1) and 28% aqueous ammonia (0.46 ml), and then allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethanol (10 ml) and 4N hydrogen chloride dioxane solution (2 ml) were added to the residue. The mixture was concentrated again under reduced pressure, and the residue was separated by preparative HPLC (YMC-Pack ODS-A; YMC, eluted). (Solvent: 10% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (10 ml) and 4N
After adding a hydrogen chloride dioxane solution (2 ml), the mixture was concentrated to dryness under reduced pressure to give the title compound (0.68 g).
(64% yield) as a pale yellow amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.26 (3H, t, J = 7.
5), 1.86-1.94 (2H, m), 2.07-2.14 (2H, m), 3.01-3.0
9 (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 (1
H, d, J = 16.0), 7.20 (1H, d, J = 9.0), 7.46-7.75 (5H,
m), 7.87 (1H, s).

(B) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrole- 2-yl) piperidin-4-yloxy] phenyl]
Ethane sulfonamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-
Carbamoyl-4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride (0.68
g) in ethanol (15 ml) and at room temperature, organic preparation and procedure-
International, Vol. 24, p. 147 (19
92) [ Org. Prep. Proced. Int. , 24 , 147 (1992)]
5 synthesized from 2-pyrrolidinone according to the method described in
-Methoxy-3,4-dihydro-2H-pyrrole (0.
36 g) and triethylamine (0.85 ml) were added, and the mixture was allowed to stand at the same temperature overnight. Then, 5-methoxy-3,4-dihydro-2H-pyrrole (0.19 g) and triethylamine (0.34 ml) were added. Stir for 5 hours. The reaction solution was concentrated under reduced pressure, and ethanol (10 m
l) and 4N hydrogen chloride dioxane solution (4 ml) were added, and the mixture was concentrated again under reduced pressure. The residue was subjected to preparative HPLC (YM
Purification with C-Pack ODS-A; YMC, elution solvent: 10% acetonitrile / water), and the obtained amorphous solid was treated with 1N hydrochloric acid (8 m
After l) was added, the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and freeze-dried to give the title compound 0.1.
56 g (73% yield) were obtained as a light brown amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.27 (3H, t, J = 7.
5), 1.79-1.91 (2H, m), 2.02-2.14 (4H, m), 2.97 (2
H, t, J = 7.0), 3.21 (2H, q, J = 7.5), 3.47-3.73 (5H,
m), 3.90 (1H, 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.

Example 103 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (Exemplary Compound No. 1211) N- [3- (3-) obtained in Example 101 (a) Amidinophenyl) -2- (E) -propenyl] -N- [3-
Carbamoyl-4- (piperidin-4-yloxy) phenyl] methanesulfonamide (0.32 g) was dissolved in methanol (15 ml) and the solution was dissolved at room temperature in a European journal. Of Organic Chemistry, No. 10
Vol., Pp. 2645 (1999) [ Eur. J. Org. Chem. ,
10 , 2645 (1999)] and 2-ethoxy-4,5-dihydrooxazole (0.21 g) synthesized from 2-oxazolidone and triethylamine (0.
After stirring at the same temperature for 2 hours, the mixture was allowed to stand overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (YM
Purified with C-Pack ODS-A; YMC, elution solvent: 12% acetonitrile / water). 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. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 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 (1
H, dt, J = 16.0, 5.5), 6.59 (1H, d, J = 16.0), 7.25 (1
H, 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.

Example 104 N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-
(4,5-dihydrothiazol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide
Dihydrochloride (Exemplary Compound No. 1269) N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- obtained in Example 101 (a)
Carbamoyl-4- (piperidin-4-yloxy) phenyl] methanesulfonamide (0.32 g) in tetrahydrofuran (3 ml), 1,4-dioxane (3 m
l) and water (3 ml) in a mixed solvent.
-Chloroisothiocyanate (0.05 ml) and triethylamine (0.07 ml) were added, and the mixture was stirred at room temperature for 1.5 hours and left overnight. The reaction solution was concentrated under reduced pressure,
The residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, elution solvent: 12% acetonitrile / water). After dissolving the obtained amorphous solid in 1N hydrochloric acid (1.2 ml),
The residue was concentrated to dryness under reduced pressure to give the title compound 0.15.
g (yield 59%) was obtained as a colorless amorphous solid. ¹ H 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 (2
H, d, J = 6.0), 4.85 (1H, 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.

Example 105 N- [3-Chloro-4- (1-methylpiperidine-4-
Yloxy) phenyl] -N- [3- [3- (ethoxycarbonylamino) (imino) methylphenyl] -2-
(E) -Propenyl] sulfamoyl acetate ethyl dihydrochloride 4-nitrophenol (1.00 g) was dissolved in dichloromethane (20 ml), and ethyl chloroformate (0.70 ml) and pyridine (0.70 ml) were added under ice-cooling. After the dropwise addition, the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium chloride. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting white solid was collected by filtration with hexane to give 1.44 g (95% yield) of ethyl 4-nitrophenyl carbonate. Obtained as a white solid. The N- [3- (3-
Amidinophenyl) -2- (E) -propenyl] -N-
Ethyl [3-chloro-4- [1-methylpiperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.42 g) was dissolved in water (5 ml), and a solution of ethyl 4-nitrophenylcarbonate in dichloromethane (0 ml) was added. .14g
Was dissolved in 5 ml of dichloromethane) and sodium hydrogen carbonate (0.11 g), and the mixture was stirred at room temperature for 3 hours.
After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethanol = 1/1). The obtained amorphous solid was dissolved in ethanol (5 ml), 1N hydrochloric acid (1.4 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.36 g of the title compound.
(78% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.33 (3H, t, J = 7.0), 1.90-2.07 (2H, m), 2.15-
2.25 (2H, m), 2.74 (3H, m), 3.00-3.10 (2H, m), 3.3
3 (1H, m), 3.40-3.50 (1H, m), 4.19 (2H, q, J = 7.0),
4.35 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J
= 6.0), 4.62 and 4.87 (total 1H, m each), 6.42 (1H, dt, J = 1
6.0, 6.0), 6.59 (1H, d, J = 16.0), 7.31 (1H, m), 7.4
0 (1H, m), 7.54 (1H, t, J = 8.0), 7.59 (1H, m), 7.66
(1H, d, J = 8.0), 7.75 (1H, d, J = 8.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1742, 1674, 1354, 1157.

Example 106 N- [3-Chloro-4- (1-methylpiperidine-4-
Yloxy) phenyl] -N- [3- [3- (imino)
(4-Methoxyphenoxycarbonylamino) methylphenyl] -2- (E) -propenyl] sulfamoylacetate dihydrochloride 4-methoxyphenol (1.00 g) was dissolved in dichloromethane (20 ml), and chloroformic acid was added under ice cooling. 4-methoxyphenyl (1.25 ml) and pyridine (0.72
ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated saline. After drying the organic layer over anhydrous magnesium sulfate,
By concentrating to dryness under reduced pressure, 2.37 g (quantitative yield) of bis (4-methoxyphenyl) dicarbonate was obtained as a white solid. N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3 obtained in Example 1
-Chloro-4- [1-methylpiperidin-4-yloxy] phenyl] sulfamoyl acetate dihydrochloride (0.50 g) was dissolved in water (10 ml), and a solution of bis (4-methoxyphenyl) dicarbonate in dichloromethane ( 0.
22 g was dissolved in 10 ml of dichloromethane) and sodium hydrogen carbonate (0.14 g), and the mixture was stirred at room temperature overnight. After adding water and sodium hydrogen carbonate to the reaction solution,
The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethanol = 5/2). The obtained amorphous solid was dissolved in ethanol (5 ml), 1N hydrochloric acid (1.6 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give 0.42 g of the title compound.
(67% yield) as a colorless amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.
0), 1.83-1.93 (1H, m), 2.00-2.18 (2H, m), 2.20-2.2
7 (1H, m), 2.76 (3H, m), 3.00-3.10 (2H, m), 3.30-3.
50 (2H, m), 3.77 (3H, s), 4.19 (2H, q, J = 7.0), 4.4
2 (2H, s), 4.48 (2H, d, J = 6.0), 4.60 and 4.85 (total 1
H, m each), 6.39 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J
= 16.0), 6.99 (2H, d, J = 9.0), 7.17 (2H, d, J = 9.0),
7.31 (1H, m), 7.41 (1H, m), 7.51 (1H, t, J = 7.5),
7.60 (1H, m), 7.69 (1H, d, J = 7.5), 7.80 (1H, d, J =
7.5), 7.97 (1H, s); IR (KBr, cm ^-1 ): 1740, 1671, 1354, 1161.

Example 107 N- [3- [3- (t-butoxycarbonylamino)
Ethyl (imino) methylphenyl] -2- (E) -propenyl] -N- [3-chloro-4- (1-methylpiperidin-4-yloxy) phenyl] sulfamoylacetate N- [ 3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-
Ethyl 4- [1-methylpiperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride (0.43
g) was dissolved in water (10 ml), and a solution of di (t-butyl) dicarbonate in dichloromethane (0.15 g dissolved in 10 ml of dichloromethane) and sodium hydrogen carbonate (0.12 g) were dissolved.
After adding g), the mixture was stirred at room temperature for 5 hours. After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethanol = 5/1) to give 0.36 g of the title compound (yield 81).
%) Was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0),
1.54 (9H, s), 1.87-1.96 (2H, m), 1.97-2.06 (2H,
m), 2.32 (3H, s), 2.39 (2H, m), 2.68 (2H, m), 3.99
(2H, s), 4.30 (2H, q, J = 7.0), 4.41 (1H, m), 4.44
(2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.42 (1
H, d, J = 16.0), 6.91 (1H, d, J = 9.0), 7.29 (1H, m),
7.34 (1H, t, J = 8.0), 7.45 (1H, d, J = 8.0), 7.52 (1
H, d, J = 2.5), 7.66 (1H, d, J = 8.0), 7.78 (1H, s); IR (KBr, cm ^-1 ): 1740, 1655, 1365, 1163.

Example 108 N- [3-Chloro-4- (1-methylpiperidin-4-
Ethyloxy) phenyl] -N- [3- [3- (4-fluorophenoxycarbonylamino) (imino) methylphenyl] -2- (E) -propenyl] sulfamoyl acetate 4-fluorophenol (2.00 g) in dichloromethane (40 ml), and a solution of 4-fluorophenyl chloroformate in dichloromethane (2.35 ml dissolved in 5 ml of dichloromethane) and pyridine (1.59 m
After l) was added dropwise, the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was concentrated under reduced pressure, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the white solid obtained was filtered with hexane to obtain bis (4-fluorophenyl) dicarbonate.
4.25 g (95% yield) was obtained as a white solid. N- [3- (3-amidinophenyl)-obtained in Example 1
2- (E) -propenyl] -N- [3-chloro-4-
[1-Methylpiperidin-4-yloxy] phenyl]
Ethyl sulfamoyl acetate dihydrochloride (0.50 g) was dissolved in water (10 ml), and a dichloromethane solution of bis (4-fluorophenyl) dicarbonate (0.20 g was dissolved in 10 ml of dichloromethane) and sodium hydrogen carbonate (0.
After adding 20 g), the mixture was stirred at room temperature overnight. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / ethanol = 1/1).
By purifying in 1), 0.47 g (yield 85%) of the title compound was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.86-1.95 (2H, m), 1.95-2.04 (2H, m), 2.31 (3H,
s), 2.35 (2H, m), 2.66 (2H, m), 3.99 (2H, s), 4.31
(2H, q, J = 7.0), 4.40 (1H, m), 4.46 (2H, d, J = 6.
5), 6.26 (1H, dt, J = 16.0, 6.5), 6.47 (1H, d, J = 16.
0), 6.91 (1H, d, J = 9.0), 7.08 (2H, m), 7.17 (2H,
m), 7.31 (1H, dd, J = 9.0, 2.5), 7.42 (1H, t, J = 8.
0), 7.53 (1H, d, J = 2.5), 7.54 (1H, d, J = 8.0), 7.75
(1H, d, J = 8.0), 7.86 (1H, s); IR (KBr, cm ^-1 ): 1739, 1668, 1355, 1162.

Example 109 N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] -N- [3- [ 3- (ethoxycarbonylamino) (imino) methylphenyl] -2-
(E) -Propenyl] methanesulfonamide dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-
Carbamoyl-4- [1- (4,5-dihydro-3H-
Pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (0.23
g) was dissolved in a mixed solvent of dichloromethane (4.5 ml) and N, N-dimethylformamide (1.5 ml),
Ethyl 4-nitrophenyl carbonate (0.10 g) obtained in Example 105 and triethylamine (0.16 ml)
And then stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 50/0).
47/3). The obtained oil was dissolved in ethanol (2 ml), 4N hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. After adding the obtained amorphous solid to dichloromethane, 1N
The mixture was extracted with hydrochloric acid, and the aqueous layer was concentrated to dryness under reduced pressure. This was dissolved in water and lyophilized to give the title compound 0.1.
20 g (84% yield) were obtained as a colorless amorphous solid. ^{1 H NMR (400MHz, DMSO-} d 6) δppm: 1.33 (3H, t, J = 7.
0), 1.80-1.92 (2H, m), 2.02-2.14 (4H, m), 2.96 (2
(H, t, J = 7.5), 3.06 (3H, s), 3.47-3.73 (4H, m), 3.8
3-3.91 (2H, m), 4.35 (2H, q, J = 7.0), 4.46 (2H, d,
J = 6.0), 4.87 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0),
6.60 (1H, d, J = 16.0), 7.28 (1H, d, J = 9.0), 7.49-7.
69 (3H, m), 7.73-7.78 (2H, m), 7.88 (1H, s); IR (KBr, cm ^-1 ): 1754, 1667, 1334, 1151.

Example 110 N- [3-carbamoyl-4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] -N- [3- [ 3- (Imino) (pivaloylamino) methylphenyl] -2- (E) -propenyl] methanesulfonamide N- [3- (3-amidinophenyl) -2- (E) obtained in Example 101 (b) -Propenyl] -N- [3-
Carbamoyl-4- [1- (4,5-dihydro-3H-
Pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (0.20
g) was dissolved in a mixed solvent of dichloromethane (2.5 ml) and acetonitrile (2.5 ml), and under ice-cooling, 4-nitrophenyl pivalate (0.09 g) and triethylamine (0.23 ml) were added. Stirred at room temperature for 4 hours. After dichloromethane was added to the reaction solution, the mixture was washed successively with a 1N aqueous solution of sodium hydroxide and saturated saline, and the organic layer was dried using anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 50 /
0-47 / 3) to give the title compound 0.1.
17 g (86% yield) were obtained as a colorless amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.28 (9H, s), 1.78-
1.88 (2H, m), 1.96-2.05 (2H, m), 2.07-2.14 (2H, m
m), 2.51 (2H, t, J = 8.0), 2.96 (3H, s), 3.22-3.31
(2H, m), 3.67-3.76 (4H, m), 4.44 (2H, d, J = 6.5),
4.67 (1H, m), 6.23 (1H, dt, J = 16.0, 6.5), 6.52 (1H,
d, J = 16.0), 7.01 (1H, d, J = 9.0), 7.38 (1H, t, J =
8.0), 7.45 (1H, d, J = 8.0), 7.52 (1H, dd, J = 9.0, 2.
5), 7.82-7.88 (2H, m), 8.19 (1H, d, J = 2.5); IR (KBr, cm ^-1 ): 1670, 1339, 1153.

Example 111 N- [3- [3- (Benzoylamino) (imino) methylphenyl] -2- (E) -propenyl] -N- [3-
Carbamoyl-4- [1- (4,5-dihydro-3H-
Pyrrole-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- obtained in Example 101 (b). [3-
Carbamoyl-4- [1- (4,5-dihydro-3H-
Pyrrole-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (0.30
g) was dissolved in a mixed solvent of dichloromethane (4 ml) and acetonitrile (4 ml), and benzoic acid 4-
After adding nitrophenyl (0.15 g) and triethylamine (0.28 ml), the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a 0.5N aqueous sodium hydroxide solution and saturated saline, and the organic layer was dried using anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 50/0).
４７47/3). This was dissolved in water and lyophilized to give 0.24 g of the title compound (yield 75
%) Was obtained as a pale yellow amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.77-1.87 (2H, m),
1.94-2.12 (4H, m), 2.50 (2H, t, J = 8.0), 2.97 (3H,
s), 3.20-3.28 (2H, m), 3.65-3.74 (4H, m), 4.45 (2
H, d, J = 6.5), 4.66 (1H, m), 6.27 (1H, dt, J = 15.5,
6.5), 6.56 (1H, d, J = 15.5), 7.01 (1H, d, J = 9.0), 7.
42-7.56 (6H, m), 7.94-8.02 (2H, m), 8.20 (1H, d, J
= 2.5), 8.36 (2H, d, J = 7.5); IR (KBr, cm ^-1 ): 1670, 1339, 1153.

(Example 112) N- [3- [3- (acetylamino) (imino) methylphenyl] -2- (E) -propenyl] -N- [3-carbamoyl-4- [1- (4 , 5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide N- [3- (3-amidinophenyl) -2- (E) obtained in Example 101 (b) ) -Propenyl] -N- [3-
Carbamoyl-4- [1- (4,5-dihydro-3H-
Pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (0.29
g) was dissolved in a mixed solvent of dichloromethane (3 ml) and acetonitrile (3 ml), and under ice-cooling, 4-nitrophenyl acetate (0.09 g) and triethylamine (0.
After adding 26 ml), the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed with a 0.5N aqueous sodium hydroxide solution and saturated saline, and the organic layer was dried using anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluting solvent: dichloromethane / methanol = 50/0).
47/3). This was dissolved in water and freeze-dried to give 0.16 g of the title compound (yield 58
%) Was obtained as a pale yellow amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.78-1.88 (2H, m),
1.97-2.15 (4H, m), 2.30 (3H, s), 2.52 (2H, t, J = 8.
0), 2.96 (3H, s), 3.22-3.31 (2H, m), 3.66-3.77 (4
H, m), 4.44 (2H, d, J = 6.5), 4.68 (1H, m), 6.26 (1
H, dt, J = 15.5, 6.5), 6.50 (1H, d, J = 15.5), 7.01 (1
H, d, J = 9.0), 7.37-7.53 (3H, m), 7.72-7.78 (2H,
m), 8.18 (1H, d, J = 3.0); IR (KBr, cm ^-1 ): 1668, 1338, 1152.

Example 113 N- [3-Carbamoyl-4- [1- (4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] -N- [3- [ 3- (imino) (4
-Methoxyphenoxycarbonylamino) methylphenyl] -2- (E) -propenyl] methanesulfonamide 4-nitrophenol (1.00 g) was dissolved in dichloromethane (30 ml), and 4-methoxyphenyl chloroformate (30 ml) was cooled with ice. 1.10 ml) and pyridine (0.64 m)
After l) was added dropwise, the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with saturated saline. After drying the organic layer over anhydrous sodium sulfate,
The white solid obtained by evaporating the solvent under reduced pressure was collected by filtration with hexane to give 1.72 g (83% yield) of (4-methoxyphenyl) (4-nitrophenyl) carbonate.
Was obtained as a white solid. N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- [1-] obtained in Example 101 (b)
(4,5-Dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] methanesulfonamide dihydrochloride (0.29 g) in dichloromethane (3.
5 ml) and acetonitrile (3.5 ml) were dissolved in a mixed solvent, and (4-methoxyphenyl) carbonate (4-nitrophenyl) (0.15 g) and triethylamine (0.
After adding 27 ml), the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane, washed with a 0.5N aqueous sodium hydroxide solution and saturated saline, and the organic layer was dried using anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 20/0).
１９19/1). This was dissolved in water and freeze-dried to give 0.23 g of the title compound (yield 6
9%) as a colorless amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.77-1.88 (2H, m),
1.94-2.13 (4H, m), 2.51 (2H, t, J = 8.0), 2.97 (3H,
s), 3.21-3.31 (2H, m), 3.64-3.84 (7H, m), 4.43 (2
H, d, J = 6.5), 4.68 (1H, m), 6.27 (1H, dt, J = 15.5,
6.5), 6.51 (1H, d, J = 15.5), 6.91 (2H, d, J = 8.5), 7.
01 (1H, d, J = 9.0), 7.13 (2H, d, J = 8.5), 7.40 (1H,
t, J = 7.5), 7.47-7.54 (2H, m), 7.80-7.90 (2H, m),
8.18 (1H, d, J = 2.5); IR (KBr, cm ^-1 ): 1668, 1338, 1152.

(Reference Example 1) 3-cyanocinnamic aldehyde 3-cyanobenzaldehyde (4.5 g) was dissolved in toluene (200 ml), and triphenylphosphoranylideneacetaldehyde (13.6 g) was added.
For 4 hours. The reaction solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (elution solvent: dichloromethane), and then recrystallized from toluene and hexane to give 3.09 g of the title compound.
(57% yield) as pale yellow needles. _{^{1 H NMR (500MHz, CDCl 3}} ) δppm: 6.76 (1H, dd, J = 16.
0, 7.5), 7.46 (1H, 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 (1
H, s), 9.75 (1H, d, J = 7.5).

Reference Example 2 3- (3-cyanophenyl) -2- (E) -propene-
1-ol 3-cyanocinnamic aldehyde (3.0) obtained in Reference Example 1
0g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (70 ml), and sodium borohydride (1.32 g) and cerium chloride (2.4) were added under ice-cooling.
After adding 9 g), the mixture was stirred at the same temperature for 1.5 hours. After a saturated aqueous ammonium chloride solution was added 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 / ethyl acetate = 3/2) to give 3.27 g (yield quantitative) of the title compound as a pale yellow oil As obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 4.37 (2H, m), 6.43
(1H, dt, J = 16.0, 5.0), 6.62 (1H, d, J = 16.0), 7.43
(1H, t, J = 8.0), 7.52 (1H, d, J = 8.0), 7.60 (1H, d,
J = 8.0), 7.65 (1H, s).

Reference Example 3 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene 1-tert-butoxycarbonyl-4-hydroxypiperidine (3.32 g), 2-chloro-4 -Nitrophenol (2.36 g) and triphenylphosphine (5.11)
g) in dichloromethane (60 ml), and
After dropwise addition of diethyl azodicarboxylate (3.10 ml), the mixture was stirred at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/2) to give 3.90 g (yield 76%) of the title compound as a pale yellow solid. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 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-4- (1-methylpiperidin-4-yloxy) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- obtained in Reference Example 3. Chloronitrobenzene (1.50 g) was suspended in 90% formic acid (4.00 g), and 37% formalin (2.50 g) was added.
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 obtain 1.12 g (yield 98%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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, d
d, J = 9.0, 3.0), 8.30 (1H, d, J = 3.0).

(Reference Example 5) 3-chloro-4- (1-methylpiperidin-4-yloxy) aniline 3-chloro-4- (1-methylpiperidin-4-yloxy) nitrobenzene obtained in Reference Example 4 8.48
g) was dissolved in acetic acid (200 ml), tin powder (18.59 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 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 is subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 3/1)
To give 6.95 g of the title compound (yield 9
2%) as a red-brown solid. ¹ H NMR (400 MHz, CDCl 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 6 N- [3-chloro-4- (1-methylpiperidine-4-
Ethyloxy) phenyl] sulfamoyl acetate Ethyl 3-chloro-4- (1-methylpiperidin-4-yloxy) aniline (6.95 g) obtained in Reference Example 5 was dissolved in dichloromethane (150 ml), and the solution was dissolved in chloroform under ice-cooling. After ethyl sulfonyl acetate (3.88 ml) and pyridine (4.67 ml) were added dropwise, the mixture was stirred at room temperature for 5 hours. After adding water to the reaction solution and extracting three times with ethyl acetate,
The extract 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: dichloromethane / methanol = 4/1).
１／1/1) to give the title compound 9.12.
g (81% yield) was obtained as a brown amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.30 (2H, q, J = 7.0), 4.41 (1H, m), 6.93 (1
H, d, J = 9.0), 7.21 (1H, dd, J = 9.0, 2.5), 7.40 (1H,
d, J = 2.5).

Reference Example 7 N- [3-chloro-4- (1-methylpiperidine-4-
Ethyloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (3.30 g), ethyl N- [3-chloro-4- (1-methylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 6 (7.37 g) ) And triphenylphosphine (5.93 g) were dissolved in dichloromethane (200 ml), and the mixture was cooled under ice-cooling with diethyl azodicarboxylate (3.49 m).
After l) was added dropwise, the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/3 to 2).
/ 1) to give 7.29 g of the title compound
(73% yield) as an orange amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.31 (2H, q, J = 7.0), 4.40 (1H, m), 4.46 (2
H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1
H, 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- (piperidin-4-yloxy) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene obtained in Reference Example 3 7.91 g) was dissolved in dioxane (80 ml) and 4N hydrogen chloride in dioxane (70 ml) was added at room temperature.
, And stirred overnight at the same temperature. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and neutralized by adding sodium hydrogen carbonate. Obtained as yellow needles. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm: 1.50-1.60 (2H, m),
1.90-2.00 (2H, m), 2.57-2.68 (2H, m), 2.90-3.00 (2
H, m), 3.96 (1H, m), 7.45 (1H, d, J = 9.0), 8.18 (1H,
dd, J = 9.0, 3.0), 8.31 (1H, d, J = 3.0).

Reference Example 9 4- (1-Acetylpiperidin-4-yloxy) -3
-Chloronitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (1.00 g) was dissolved in pyridine (20 ml) and acetic anhydride (0.55 g) was added under ice cooling.
ml) was added dropwise, followed by stirring 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 an 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 of the title compound (yield 90%).
Was obtained as a pale yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.88-2.03 (4H, m),
2.14 (3H, s), 3.50-3.63 (2H, m), 3.71 (1H, m), 3.9
4 (1H, m), 4.81 (1H, m), 7.01 (1H, d, J = 9.0), 8.15
(1H, dd, J = 9.0, 2.5), 8.32 (1H, d, J = 2.5).

Reference Example 10 4- (1-Acetylpiperidin-4-yloxy) -3
-Chloroaniline 4- (1-acetylpiperidine-4 obtained in Reference Example 9
-Yloxy) -3-chloronitrobenzene (1.05
g) was dissolved in acetic acid (30 ml), tin powder (2.09 g) was added at room temperature, and the mixture was 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. 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: ethyl acetate / methanol = 15/1) to give 0.82 g of the title compound (yield 86).
%) As an orange oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.78-1.94 (4H, m),
2.11 (3H, s), 3.33-3.43 (1H, 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 (1H, d, J = 3.0), 6.81 (1H, d, J =
8.5).

Reference Example 11 3-Chloro-4- (1-ethylpiperidin-4-yloxy) aniline Under a nitrogen atmosphere, lithium aluminum hydride (230 m
g) was suspended in tetrahydrofuran (5 ml), and a solution of 4- (1-acetylpiperidin-4-yloxy) -3-chloroaniline obtained in Reference Example 10 in tetrahydrofuran (10 ml) was added dropwise under ice-cooling. After heating under reflux for 3.5 hours, lithium aluminum hydride (115
mg), and the mixture was further heated under reflux for 2 hours. After cooling the reaction solution, sodium sulfate decahydrate was added, and the mixture was further stirred at room temperature overnight. After removing the insolubles by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 3/1 to 1/2) to give 448 mg of the title compound (yield 58).
%) As a brown oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.11 (3H, t, J = 7.0),
1.82-1.93 (2H, m), 1.93-2.04 (2H, m), 2.29 (2H, m
m), 2.45 (2H, q, J = 7.0), 2.78 (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).

Reference Example 12 N- [3-chloro-4- (1-ethylpiperidine-4-
Ethyloxy) phenyl] sulfamoylacetate Ethyl 3-chloro-4- (1-ethylpiperidin-4-yloxy) aniline (853 mg) obtained in Reference Example 11 was dissolved in dichloromethane (20 ml), and chlorosulfonylacetic acid was added under ice-cooling. After dropwise addition of ethyl (0.45 ml) and pyridine (0.54 ml), the mixture was stirred at room temperature for 4 hours. After adding water to the reaction solution and extracting twice with ethyl acetate,
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: dichloromethane / methanol = 3/1).
To 1/1) to give the title compound 1113.
mg (82% yield) as a tan amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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), 6.9
3 (1H, d, J = 9.0), 7.21 (1H, dd, J = 9.0, 2.5), 7.40
(1H, d, J = 2.5).

Reference Example 13 N- [3-chloro-4- (1-ethylpiperidine-4-
Ethyloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.48 g), ethyl N- [3-chloro-4- (1-ethylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 12 (1.11 g) ) And triphenylphosphine (0.87 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.51 m
After l) was added dropwise, the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/3 to 1).
/ 1) to give 1.24 g of the title compound
(83% yield) as an orange amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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-Chloro-4- (1-isopropylpiperidine-4-
(Iloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (1.50 g) was suspended in acetone (20 ml), and acetic acid (0.33 m
l) and sodium cyanoborohydride (0.18 g)
After stirring at room temperature for 4.5 hours, sodium cyanoborohydride (0.18 g) was added. After stirring for 3 hours, acetic acid (0.33 ml) and sodium cyanoborohydride (0%) were added. .18 g) and 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 give 1.36 g of the title compound (yield 78).
%) As a yellow solid. ¹ H NMR (400 MHz, CDCl 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 (2
H, m), 2.75-2.90 (3H, m), 4.59 (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 15 3-Chloro-4- (1-isopropylpiperidine-4-l
(Iloxy) aniline 3-chloro-4- (1-isopropylpiperidin-4-yloxy) nitrobenzene (1.36 g) obtained in Reference Example 14 was dissolved in acetic acid (30 ml), and tin powder (2.70 g) was added at room temperature. And stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous potassium carbonate solution, and extracted three times with ethyl acetate.
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: dichloromethane / methanol = 5/1).
~ 1/1) to give 0.99 of the title compound
g (81% yield) was obtained as a brown oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.15 (6H, d, J = 6.5),
1.80-2.20 (4H, m), 2.66 (2H, m), 2.97 (2H, m), 3.0
3 (1H, m), 4.27 (1H, m), 6.52 (1H, dd, J = 8.5, 3.
0), 6.73 (1H, d, J = 3.0), 6.80 (1H, d, J = 8.5).

(Reference Example 16) Ethyl N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] sulfamoylacetate 3-chloro-4- (1-isopropylpiperidine obtained in Reference Example 15 -4-yloxy) aniline (985 m
g) in dichloromethane (20 ml), and
Ethyl chlorosulfonyl acetate (0.49 ml) and pyridine (0.59 ml) were added dropwise, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, which was 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 subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 10 /
Purification by 1-3-1) gave the title compound 109
4 mg (71% yield) were obtained as an orange amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.29 (2H, q, J = 7.0), 4.39 (1H, m), 6.93 (1
H, d, J = 9.0), 7.20 (1H, dd, J = 9.0, 2.5), 7.39 (1H,
d, J = 2.5).

Reference Example 17 N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (0.46 g), ethyl N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 16 (1.09 g) ) And triphenylphosphine (0.82 g) were dissolved in dichloromethane (30 ml), and the mixture was dissolved under ice-cooling in diethyl azodicarboxylate (0.48 g).
ml), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/2 to 2).
Purification by 1/1) gave 1.17 g of the title compound.
(80% yield) as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.31 (2H, q, J = 7.0), 4.41 (1H, m), 4.46 (2
H, 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 18 4- (1-butylpiperidin-4-yloxy) -3-
Chloronitrobenzene 3-chloro- obtained in Reference Example 8
4- (piperidin-4-yloxy) nitrobenzene (1.50 g) and butyraldehyde (1.04 ml)
Was dissolved in dichloromethane (30 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 3 hours.
After adding sodium cyanoborohydride (0.18 g), 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 sequentially 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 obtain 0.88 g of the title compound (yield 48%).
Was obtained as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 0.94 (3H, t, J = 7.5),
1.35 (2H, m), 1.53 (2H, m), 1.92-2.04 (2H, m), 2.0
4-2.15 (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).

Reference Example 19 4- (1-butylpiperidin-4-yloxy) -3-
Chloroaniline 4- (1-butylpiperidine-4 obtained in Reference Example 18
-Yloxy) -3-chloronitrobenzene (1.48)
g) was dissolved in acetic acid (30 ml), tin powder (2.81 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 an aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate.
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: dichloromethane / methanol = 5/1).
~ 3/1) to give 1.09 of the title compound
g (82% yield) as a brown oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 0.93 (3H, t, J = 7.5),
1.34 (2H, m), 1.60 (2H, m), 1.92-2.02 (2H, m), 2.0
8-2.18 (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-butylpiperidin-4-yloxy)
Ethyl-3-chlorophenyl] sulfamoylacetate 4- (1-butylpiperidine-4 obtained in Reference Example 19
-Yloxy) -3-chloroaniline (1.09 g) was dissolved in dichloromethane (20 ml), and ethyl chlorosulfonyl acetate (0.52 ml) and pyridine (0.62 ml) were added dropwise under ice-cooling. Stirred overnight.
The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, and then 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 with dichloromethane / methanol = 20/1 to 9/1 gave 1.41 g of the title compound (yield 84
%) As a brown amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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), 2.40-2.6
0 (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).

Reference Example 21 N- [4- (1-butylpiperidin-4-yloxy)
Ethyl-3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.57 g), N- [4- (1-butylpiperidine-4) obtained in Reference Example 20.
-Yloxy) -3-chlorophenyl] sulfamoylacetate (1.41 g) and triphenylphosphine (1.02 g) were dissolved in dichloromethane (30 ml), and the mixture was cooled under ice-cooling with diethyl azodicarboxylate (0.60 m2).
After l) was added dropwise, the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1 / 20-
1/10) to give 1.17 of the title compound
g (63% yield) as a tan oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1H, m), 4.46 (2H, d, J =
6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 1
6.0), 6.93 (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 22 4- (1-benzylpiperidin-4-yloxy) -3
-Chloronitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (1.00 g) with N, N
After dissolving in dimethylformamide (20 ml) and adding benzyl bromamide (0.56 ml) and potassium carbonate (0.81 g) under ice-cooling, 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/5).
To ethyl acetate only) to give 1.02 g (yield 75%) of the title compound as a yellow oily substance. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.88-1.98 (2H, m),
1.98-2.08 (2H, m), 2.42 (2H, m), 2.72 (2H, m), 3.5
5 (2H, s), 4.58 (1H, m), 6.97 (1H, d, J = 9.0), 7.23
-7.37 (5H, m), 8.12 (1H, dd, J = 9.0, 2.5), 8.30 (1
(H, d, J = 2.5).

Reference Example 23 4- (1-benzylpiperidin-4-yloxy) -3
-Chloroaniline 4- (1-benzylpiperidine- obtained in Reference Example 22)
4-yloxy) -3-chloronitrobenzene (1.0
2 g) was dissolved in acetic acid (40 ml), tin powder (1.75 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and then extracted twice with ethyl acetate. After the extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated saline in this order, 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 0.78 g (yield 84%) of the title compound as a brown oil. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.80-1.90 (2H, m),
1.90-2.00 (2H, m), 2.26 (2H, m), 2.76 (2H, m), 3.5
2 (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) Ethyl N- [4- (1-benzylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate 4- (1-benzylpiperidine-ethyl) obtained in Reference Example 23
4-yloxy) -3-chloroaniline (780 mg)
Was dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (0.35 ml) and pyridine (0.40 ml) were added dropwise under ice cooling, 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol = 25 /
By purifying in 2), 1018 mg of the title compound was obtained.
(89% yield) as a tan amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.36 (2H, m
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-benzylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (0.36 g), N- [4- (1-benzylpiperidine-
4-yloxy) -3-chlorophenyl] sulfamoyl acetate (1.02 g) and triphenylphosphine (0.69 g) were dissolved in dichloromethane (20 ml), and the mixture was cooled under ice-cooling with diethyl azodicarboxylate (0.40 m2).
After l) was added dropwise, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 1.53 g (yield quantitative) of the title compound as a yellow-brown oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0),
1.84-1.93 (2H, m), 1.93-2.02 (2H, m), 2.36 (2H, m
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 (1H, d, J = 16.
0), 6.91 (1H, d, J = 9.0), 7.23-7.37 (6H, m), 7.40 (1
(H, t, J = 8.0), 7.44-7.58 (4H, m).

(Reference Example 26) 3-chloro-4- (1-phenethylpiperidin-4-yloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (957 mg) in N, N
After dissolving in dimethylformamide (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 distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 / 5-
Purification with ethyl acetate only) gave the title compound 9
36 mg (70% yield) were obtained as a pale yellow solid. ¹ H NMR (400 MHz, CDCl 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 (2
H, 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-phenethylpiperidin-4-yloxy) aniline 3-chloro-4- (1-phenethylpiperidin-4-yloxy) nitrobenzene obtained in Reference Example 26 93
6 mg) was dissolved in acetic acid (40 ml), tin powder (1540 mg) was added at room temperature, and the mixture was stirred at the same temperature overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and then extracted twice with ethyl acetate. After the extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated saline in this order, 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 720 mg (yield 84%) of the title compound as a pale yellow solid. . ¹ H NMR (400 MHz, CDCl 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
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).

Reference Example 28 N- [3-chloro-4- (1-phenethylpiperidine-
Ethyl 4-yloxy) phenyl] sulfamoylacetate 3-Chloro-4- (1-phenethylpiperidin-4-yloxy) aniline obtained in Reference Example 27 (720 m
g) in dichloromethane (20 ml), and
After ethyl chlorosulfonyl acetate (0.31 ml) and pyridine (0.35 ml) were added dropwise, 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 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 subjected to silica gel column chromatography (eluent: ethyl acetate / methanol = 25).
/ 2) to give 936 mg of the title compound
(89% yield) was obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 2.48 (2H, m
m), 2.60-2.70 (2H, m), 2.76-2.89 (4H, m), 3.92 (2
H, s), 4.30 (2H, q, J = 7.0), 4.41 (1H, m), 6.93 (1
H, d, J = 9.0), 7.18-7.24 (4H, m), 7.24-7.33 (2H,
m), 7.39 (1H, d, J = 2.5).

Reference Example 29 N- [3-chloro-4- (1-phenethylpiperidine-
Ethyl 4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (325 mg), ethyl N- [3-chloro-4- (1-phenethylpiperidin-4-yloxy) phenyl] sulfamoylacetate (936 mg) obtained in Reference Example 28 and triphenyl Phosphine (610 mg) was dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.36 m
After l) was added dropwise, the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / dichloromethane = 1 /
Purification by 2-ethyl acetate only) gave 1013 mg (84% yield) of the title compound as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.31 (2H, q, J = 7.0), 4.43 (1H, m), 4.46 (2
H, d, J = 6.5), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1
H, d, J = 16.0), 6.93 (1H, 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-4- (1-phenylpiperidin-4-yloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (2.68 g), bromobenzene (1.97 g), 2- (di-t-butylphosphino) biphenyl (0.62 g), tris (dibenzylideneacetone) dipalladium (0.95 g), And t-
Butoxy sodium (1.20 g) was added to toluene (30 m
After the suspension in 1), 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. The residue was diluted with ethyl acetate, washed sequentially with an aqueous sodium hydrogen carbonate solution and saturated saline, and 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 = 4/1) to obtain 1.86 g (yield 54%) of the title compound as a yellow solid. Was. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 2.00-2.10 (2H, m),
2.11-2.21 (2H, m), 3.24 (2H, m), 3.48 (2H, m), 4.7
3 (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).

Reference Example 31 3-Chloro-4- (1-phenylpiperidin-4-yloxy) aniline 3-chloro-4- (1-phenylpiperidin-4-yloxy) nitrobenzene obtained in Reference Example 30 1.8
6g) was dissolved in acetic acid (35 ml), tin powder (3.32 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, and washed with an 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. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.90-2.01 (2H, m),
2.03-2.12 (2H, m), 3.07 (2H, m), 3.55 (2H, m), 4.2
7 (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).

Reference Example 32 N- [3-chloro-4- (1-phenylpiperidine-4)
-Yloxy) phenyl] ethyl sulfamoyl acetate 3-chloro-4- (1-phenylpiperidin-4-yloxy) aniline obtained in Reference Example 31 (1.69 g)
Was dissolved in dichloromethane (25 ml), a solution of ethyl chlorosulfonyl acetate (1.15 g) in dichloromethane (5 ml) and pyridine (0.50 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium chloride was added to the reaction solution, followed by extraction 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 (eluent: ethyl acetate / hexane = 2/3) to obtain 2.23 g (yield 88%) of the title compound as a colorless oil. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.95-2.05 (2H, m), 2.06-2.15 (2H, m), 3.17 (2H, m
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 (1H, d, J = 2.5).

Reference Example 33 N- [3-chloro-4- (1-phenylpiperidine-4)
-Yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.41 g), ethyl N- [3-chloro-4- (1-phenylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 32 (1.16 g) ) And triphenylphosphine (0.87 g) were dissolved in dichloromethane (25 ml), and diethyl azodicarboxylate (0.52 m
After l) was added dropwise, the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / dichloromethane = 1 /
By purifying in 12), 1.45 g of the title compound was obtained.
(95% yield) as a colorless amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.95-2.05 (2H, m), 2.06-2.16 (2H, m), 3.18 (2H, m
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 (1H, d
t, J = 16.0, 6.0), 6.42 (1H, d, J = 16.0), 6.86 (1H, t,
J = 7.5), 6.93-6.99 (2H, m), 6.97 (1H, 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-Chloro-4- (1-methoxycarbonylmethylpiperidin-4-yloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8.
-Yloxy) nitrobenzene (1.00 g) with N, N
-Dissolved in dimethylformamide (20 ml), and after adding methyl bromoacetate (0.43 ml) and potassium carbonate (0.81 g) under ice-cooling, the mixture was stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate, washing with saturated saline,
The organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give
1.16 g (yield 90%) of the title compound were obtained as a yellow oily substance. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.93-2.04 (2H, m),
2.04-2.15 (2H, m), 2.59-2.69 (2H, m), 2.73-2.83 (2
H, 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-methoxycarbonylmethylpiperidin-4-yloxy) aniline 3-chloro-4- (1-methoxycarbonylmethylpiperidin-4- (Iloxy) nitrobenzene (1.16 g) was dissolved in acetic acid (30 ml),
Tin powder (2.09 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 diluted with ethyl acetate, and washed sequentially with an aqueous sodium hydrogen carbonate solution and saturated saline. 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: ethyl acetate / methanol = 25/1) to obtain
0.79 g (yield 75%) of the title compound was obtained as a yellow oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.87-1.95 (2H, m),
1.95-2.03 (2H, m), 2.43-2.53 (2H, m), 2.77-2.86 (2
H, 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).

Reference Example 36 Ethyl N- [3-chloro-4- (1-methoxycarbonylmethylpiperidin-4-yloxy) phenyl] sulfamoylacetate 3-chloro-4- (1- Methoxycarbonylmethylpiperidin-4-yloxy) aniline (0.79 g) was dissolved in dichloromethane (20 ml), and ethyl chlorosulfonyl acetate (0.37 m
l) and pyridine (0.43 ml) were added dropwise, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution,
The organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give
1.06 g (89% yield) of the title compound was obtained as a yellow oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.90-1.99 (2H, m), 1.99-2.08 (2H, m), 2.53-2.62 (2
H, 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-methoxycarbonylmethylpiperidin-4-yloxy) phenyl] -N- [3
-(3-cyanophenyl) -2- (E) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (0.39 g), ethyl N- [3-chloro-4- (1-methoxycarbonylmethylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 36 (1 0.06 g) and triphenylphosphine (0.74 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.44 ml) was added dropwise under ice-cooling, followed by stirring at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate) to give 1.70 g of the title compound (quantitative yield).
Was obtained as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.90-1.99 (2H, m), 1.99-2.08 (2H, m), 2.54-2.63 (2
H, 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 (1H, dt, J = 16.0, 6.
5), 6.41 (1H, d, J = 16.0), 6.92 (1H, d, J = 9.0), 7.3
1 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 8.0), 7.44-
7.58 (4H, m).

Reference Example 38 Ethyl N- [4- (1-acetylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate 4- (1-acetylpiperidin-ethyl) obtained in Reference Example 10
4-yloxy) -3-chloroaniline (650 mg)
Was dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (0.33 ml) and pyridine (0.39 ml) were added dropwise under ice cooling, and 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 (elution solvent: ethyl acetate only to ethyl acetate / methanol = 10/1) to give
773 mg (76% yield) of the title compound were obtained as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.82-1.98 (4H, m), 2.13 (3H, s), 3.47 (1H, m), 3.6
3 (1H, 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 (1H,
d, J = 9.0), 7.23 (1H, dd, J = 9.0, 2.5), 7.41 (1H, d,
J = 2.5).

Reference Example 39 N- [4- (1-Acetylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (323 mg), N- [4- (1-acetylpiperidine-
Ethyl 4-yloxy) -3-chlorophenyl] sulfamoylacetate (773 mg) and triphenylphosphine (581 mg) were dissolved in dichloromethane (20 ml), and cooled with ice to diethyl azodicarboxylate (0.34 m2).
After l) was added dropwise, the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate only to ethyl acetate / methanol = 9/1) to give the title compound 73.
3 mg (yield 71%) was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.82-1.98 (4H, m), 2.12 (3H, s), 3.48 (1H, m), 3.6
1 (1H, 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 (1H, d,
J = 16.0), 6.94 (1H, 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-carbamoylpiperidin-4-yloxy)
-3-chloronitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (500 mg) in N, N
-Dissolve in dimethylacetamide (10 ml), add potassium cyanate (790 mg) under ice-cooling, stir at room temperature overnight, add potassium cyanate (790 mg), stir at 40 ° C overnight, and add 4N A 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 successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the solvent was distilled off under reduced pressure to give 523 mg of the title compound (yield 88).
%) As a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.53-1.67 (2H, m),
1.86-2.00 (2H, m), 3.18-3.31 (2H, m), 3.51-3.64 (2
H, m), 4.92 (1H, m), 7.49 (1H, d, J = 9.0), 8.20 (1
H, dd, J = 9.0, 2.5), 8.33 (1H, d, J = 2.5).

Reference Example 41 4- (1-carbamoylpiperidin-4-yloxy)
-3-Chloroaniline 4- (1-carbamoylpiperidin-4-yloxy) -3-chloronitrobenzene (1.25 g) obtained in Reference Example 40 was dissolved in acetic acid (30 ml), and tin powder (2. 47 g) and stirred overnight at the same temperature. After filtering the reaction solution, 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 2).
0/1) to give 0.91 g of the title compound
(81% yield) was obtained as a pale orange amorphous solid. ¹ H NMR (500 MHz, CDCl 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 Ethyl N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate 4- (1-carbamoylpiperidin-4-yloxy) obtained in Reference Example 41 -3-chloroaniline (907m
g) in dichloromethane (20 ml), and
Ethyl chlorosulfonyl acetate (0.45 ml) and diisopropylethylamine (0.88 ml) were added dropwise, followed by stirring at room temperature overnight, followed by addition of ethyl chlorosulfonyl acetate (0.05 ml), and further stirring at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 30/1 to 20 /
By purifying in 1), 809 mg (yield 57%) of the title compound was obtained as a pale yellow amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.83-1.99 (4H, m), 3.47 (2H, m), 3.61 (2H, m), 3.9
2 (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 (1
(H, d, J = 2.5).

Reference Example 43 N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (322 mg), ethyl N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate (809 mg) obtained in Reference Example 42, and triphenylphosphine (610 mg) was dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.36
ml), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/10).
By purifying in 1), 1015 mg of the title compound was obtained.
(94% yield) was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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, d
d, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.49-7.57 (4
H, m).

Reference Example 44 3-Chloro-4- (1-methanesulfonylpiperidine-
4-yloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (1.00 g) was suspended in dichloromethane (20 ml), and methanesulfonyl chloride (0.33 ml) and triethylamine (1.09 ml) were added under ice-cooling, followed by stirring 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/1).
To give 0.96 g of the title compound (yield 7
3%) as a colorless amorphous solid. _{^{1 H NMR (500MHz, CDCl 3}} ) δppm: 2.06-2.14 (4H, m),
2.84 (3H, s), 3.29 (2H, m), 3.55 (2H, m), 4.82 (1
H, 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-4- (1-methanesulfonylpiperidine-
4-yloxy) aniline 3-chloro-4- (1-methanesulfonylpiperidin-4-yloxy) nitrobenzene (955 mg) obtained in Reference Example 44 was dissolved in acetic acid (30 ml), and tin powder (1690 mg) was added at room temperature. The mixture was stirred overnight at the same temperature.
After filtering the reaction solution, 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5/3).
737 mg (yield 8) of the title compound.
5%) as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.92-2.08 (4H, m),
2.81 (3H, s), 3.33-3.45 (4H, m), 4.38 (1H, m), 6.5
4 (1H, dd, J = 8.5, 3.0), 6.74 (1H, d, J = 3.0), 6.80
(1H, d, J = 8.5).

Reference Example 46 Ethyl N- [3-chloro-4- (1-methanesulfonylpiperidin-4-yloxy) phenyl] sulfamoylacetate 3-Chloro-4- (1-methane) obtained in Reference Example 45 Sulfonylpiperidin-4-yloxy) aniline (73
7 mg) was dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (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 brine, 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 (eluent: ethyl acetate / hexane = 3/2) to obtain 805 mg of the title compound (73% yield).
Was obtained as a pink amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.26 (3H, t, J = 7.0),
1.96-2.10 (4H, m), 2.82 (3H, s), 3.31 (2H, m), 3.4
7 (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).

Reference Example 47 N- [4- (1-carbamoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (296 mg), ethyl N- [3-chloro-4- (1-methanesulfonylpiperidin-4-yloxy) phenyl] sulfamoylacetate (805 mg) obtained in Reference Example 46, and triethylamine Phenylphosphine (560 mg) was added to dichloromethane (20 m
l), diethyl azodicarboxylate (0.33 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 20/1 to 10/1) to give 835 mg (79% yield) of the title compound as a colorless solid Obtained as a shaped solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.96-2.09 (4H, m), 2.82 (3H, s), 3.30 (2H, m), 3.4
8 (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 (1H, s), 7.56 (1H, d, J = 2.
Five).

Reference Example 48 3-Chloro-4- [1- (2-pyridyl) piperidine-
4-yloxy] nitrobenzene 3-chloro-4- (piperidine-4 obtained in Reference Example 8
-Yloxy) nitrobenzene (3.00 g) was suspended in pyridine (30 ml), and 2-bromopyridine (1.25 ml) was added at room temperature, followed by stirring 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 (eluent: ethyl acetate / hexane = 1/2) to obtain 0.80 g (yield 20%) of the title compound as a yellow solid. Was. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.93-2.06 (2H, m),
2.06-2.17 (2H, m), 3.60-3.72 (2H, m), 3.79-3.90 (2
H, 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).

Reference Example 49 3-Chloro-4- [1- (2-pyridyl) piperidine-
4-yloxy] aniline 3-Chloro-4- [1- (2-pyridyl) piperidin-4-yloxy] nitrobenzene (796 mg) obtained in Reference Example 48 was dissolved in acetic acid (40 ml), and the powder was dissolved at room temperature in powder ( 1420 mg) and stirred at the same temperature overnight.
After filtering the reaction solution, 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/1).
680 mg (yield 9
4%) as a pale reddish purple oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.83-1.95 (2H, m),
1.97-2.07 (2H, m), 3.41 (2H, m), 3.95 (2H, m), 4.3
4 (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) Ethyl N- [3-chloro-4- [1- (2-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3-chloro-4- [obtained in Reference Example 49 1- (2-pyridyl) piperidin-4-yloxy] aniline (68
0 mg) was dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (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 bicarbonate 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 / hexane = 1/1) to obtain 858 mg (yield 85%) of the title compound as a pale-yellow amorphous solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 3.56 (2H, m
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).

Reference Example 51 N- [3-chloro-4- [1- (2-pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-
Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (316 mg), ethyl N- [3-chloro-4- [1- (2-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate obtained in Reference Example 50 (858 mg) ) And triphenylphosphine (590 mg) in dichloromethane (20 m
l), diethyl azodicarboxylate (0.35 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature.
After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 10/1) to give the title compound 1.
100 mg (98% yield) was obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.88-1.98 (2H, m), 1.98-2.08 (2H, m), 3.57 (2H, m
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, d
t, J = 16.0, 6.5), 6.42 (1H, d, J = 16.0), 6.61 (1H, d
d, 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).

Reference Example 52 3-Chloro-4- [1- (3-pyridyl) piperidine-
4-yloxy] nitrobenzene 3-chloro-4- (piperidine-4 obtained in Reference Example 8
-Yloxy) nitrobenzene (2.72 g), 3-bromopyridine (2.01 g), 2- (di-t-butylphosphino) biphenyl (0.32 g), tris (dibenzylideneacetone) dipalladium (0.49 g) ) And sodium t-butoxide (1.22 g) were added to toluene (3
0 ml) and stirred at 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 sequentially with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / methanol = 9/1) yielded 1.56 g (yield 44%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 2.03-2.22 (4H, m),
3.31 (2H, m), 3.49 (2H, m), 4.77 (1H, m), 7.03 (1
H, 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-yloxy] aniline 3-chloro-4- [1- (3-pyridyl) piperidin-4-yloxy] nitrobenzene (1.54 g) obtained in Reference Example 52 was dissolved in acetic acid (30 ml), and the mixture was stirred at room temperature. Powder (2.74 g) was added, 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, and the residue was diluted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and brine, 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: dichloromethane / methanol = 9/1) to obtain 1.39 g (yield 99%) of the title compound as a yellow oil. Was. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.92-2.11 (4H, m),
3.14 (2H, m), 3.56 (2H, m), 4.31 (1H, m), 6.53 (1
H, dd, J = 9.0, 2.0), 6.74 (1H, d, J = 2.0), 6.84 (1H,
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).

Reference Example 54 Ethyl N- [3-chloro-4- [1- (3-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3-Chloro-4- [obtained in Reference Example 53 1- (3-Pyridyl) piperidin-4-yloxy] aniline (1.
38 g) was dissolved in dichloromethane (20 ml), and a solution of ethyl chlorosulfonyl acetate (0.93 g) in dichloromethane (5 ml) and pyridine (0.37 m
After l) was added dropwise, the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 9 /
By purifying in 1), 1.61 g (yield 78%) of the title compound was obtained as a pale brown amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.97-2.15 (4H, m), 3.24 (2H, m), 3.51 (2H, m), 3.9
3 (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 (1H, d, J = 2.5), 8.10 (1H, d, J = 4.
0), 8.35 (1H, s).

Reference Example 55 N- [3-chloro-4- [1- (3-pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-
Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (294 mg), ethyl N- [3-chloro-4- [1- (3-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate obtained in Reference Example 54 (840 mg) ) And triphenylphosphine (630 mg) in dichloromethane (20 m
l), diethyl azodicarboxylate (0.38 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature.
After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 97/3) to give the title compound 2.
060 mg (quantitative yield) were obtained as a yellow amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.97-2.16 (4H, m), 3.25 (2H, m), 3.49 (2H, m), 4.0
0 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.
5), 4.60 (1H, 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, d
d, J = 9.0, 2.5), 7.41 (1H, t, J = 8.0), 7.44-7.71 (6H,
m), 8.10 (1H, m), 8.35 (1H, m).

Reference Example 56 3-Chloro-4- [1- (4-pyridyl) piperidine-
4-yloxy] nitrobenzene 3-chloro-4- (piperidine-4 obtained in Reference Example 8
-Yloxy) nitrobenzene (3.00 g) with N, N
After dissolving in -dimethylformamide (30 ml) and adding 4-bromopyridine (2.50 g) and N-methylmorpholine (5.14 ml) at room temperature, 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 subjected to silica gel column chromatography (eluting solvent: dichloromethane / methanol = 30/1 to 1).
Purification by 10/1) gave 1.27 of the title compound.
g (33% yield) was obtained as a dark yellow amorphous solid. ¹ H NMR (500 MHz, CDCl 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 (1
(H, d, J = 3.0).

Reference Example 57 3-Chloro-4- [1- (4-pyridyl) piperidine-
4-yloxy] aniline 3-chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] nitrobenzene (1.26 g) obtained in Reference Example 56 was dissolved in acetic acid (50 ml), and the mixture was stirred at room temperature. Powder (2.24 g) was added, 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 potassium carbonate solution, 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 subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 10
/ 1-1) to give the title compound 0.1.
85 g (74% yield) were obtained as a pale yellow solid. ¹ H NMR (500 MHz, CDCl 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 Ethyl N- [3-chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3-chloro-4- [obtained in Reference Example 57 1- (4-pyridyl) piperidin-4-yloxy] aniline (85
4 mg) was dissolved in dichloromethane (20 ml), ethyl chlorosulfonyl acetate (0.40 ml) and pyridine (0.45 ml) were added dropwise under ice cooling, 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. After the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 5/1 to 2/1).
The title compound was purified by 8.8 mg (yield: 7 mg).
0%) was obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.94-2.07 (4H, m), 3.47 (2H, m), 3.65 (2H, m), 3.9
3 (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 (1
H, dd, J = 9.0, 2.5), 7.43 (1H, d, J = 2.5), 8.26 (2H,
dd, J = 5.0, 1.5).

Reference Example 59 N- [3-chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] -N- [3- (3-
Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (327 mg), ethyl N- [3-chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate obtained in Reference Example 58 (887 mg) ) And triphenylphosphine (620 mg) in dichloromethane (20 m
l), diethyl azodicarboxylate (0.36 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight.
The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 20/1 to 10/1) to give 637 mg (yield 55%) of the title compound as a colorless amorphous Obtained as a solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.97-2.07 (4H, m), 3.45 (2H, m), 3.62 (2H, m), 4.0
0 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.
0), 4.65 (1H, m), 6.22 (1H, dt, J = 16.0, 6.0), 6.42
(1H, d, J = 16.0), 6.70 (2H, d, J = 6.5), 6.96 (1H,
d, J = 9.0), 7.34 (1H, dd, J = 9.0, 2.5), 7.41 (1H, t,
J = 7.5), 7.53 (2H, m), 7.56 (1H, s), 7.56 (1H, d, J
= 2.5), 8.27 (2H, d, J = 6.5).

(Reference Example 60) 3-chloro-4- [1- (2-pyrimidyl) piperidin-4-yloxy] nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (2.50 g) was dissolved in ethanol (30 ml), 2-chloropyrimidine (1.12 g) was added at room temperature, and the mixture was stirred at 30 ° C for 8 hours. After the reaction solution was cooled to room temperature, the precipitated crystals were collected by filtration to obtain a mixture of the title compound and 2-chloropyrimidine. Dichloromethane was added thereto, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.29 g (yield 39%) of the title compound as a pale yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.90-2.00 (2H, m),
2.00-2.10 (2H, m), 3.92-4.00 (2H, m), 4.00-4.08 (2
H, m), 4.82 (1H, m), 6.51 (1H, t, J = 5.0), 7.04 (1
H, d, J = 9.0), 8.16 (1H, dd, J = 9.0, 3.0), 8.32 (1H,
d, J = 3.0), 8.33 (2H, d, J = 5.0).

Reference Example 61 3-Chloro-4- [1- (2-pyrimidyl) piperidin-4-yloxy] aniline 3-chloro-4- [1- (2-pyrimidyl) obtained in Reference Example 60 [Piperidin-4-yloxy] 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 filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then 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 (eluent: ethyl acetate / hexane = 2/1) to obtain 1.01 g (yield 86%) of the title compound as a brown oil. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.80-1.90 (2H, m),
1.92-2.02 (2H, m), 3.67 (2H, m), 4.20 (2H, m), 4.3
7 (1H, m), 6.46 (1H, t, J = 4.5), 6.53 (1H, 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) Ethyl N- [3-chloro-4- [1- (2-pyrimidyl) piperidin-4-yloxy] phenyl] sulfamoylacetate 3-Chloro-4- [obtained in Reference Example 61 1- (2-Pyrimidyl) piperidin-4-yloxy] aniline (1.01 g) was dissolved in dichloromethane (30 ml), and chlorosulfonyl acetate (0.47 m
l) and pyridine (0.53 ml) were added dropwise, followed by stirring 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 bicarbonate, 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 was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/1) to obtain 1.29 g (yield: 85%) of the title compound as a pale brown amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.85 (2H, m
m), 3.93 (2H, s), 4.09 (2H, m), 4.30 (2H, q, J = 7.
0), 4.61 (1H, m), 6.48 (1H, t, J = 4.5), 6.98 (1H,
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).

Reference Example 63 N- [3-chloro-4- [1- (2-pyrimidyl) piperidin-4-yloxy] phenyl] -N- [3- (3
-Cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.47 g), ethyl N- [3-chloro-4- [1- (2-pyrimidyl) piperidin-4-yloxy] phenyl] sulfamoylacetate obtained in Reference Example 62 (1.29 g) and triphenylphosphine (0.89 g) in dichloromethane (30 m
l), diethyl azodicarboxylate (0.52 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature.
After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 9/1) to give the title compound 1.
59 g (94% yield) were obtained as a colorless amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.87 (2H, m
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, d
t, J = 16.0, 6.5), 6.43 (1H, d, J = 16.0), 6.48 (1H, t,
J = 4.5), 6.98 (1H, d, J = 9.0), 7.34 (1H, dd, J = 9.0,
2.5), 7.41 (1H, t, J = 8.0), 7.50-7.55 (2H, m), 7.5
5 (1H, d, J = 2.5), 7.57 (1H, s), 8.31 (2H, d, J = 4.
Five).

Reference Example 64 3-Chloro-4- [1- (3-pyridylmethyl) piperidin-4-yloxy] nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8.
-Yloxy) nitrobenzene (1.00 g) with N, N
-Dimethylformamide (20 ml) and dissolved at room temperature in 3- (bromomethyl) pyridine hydrobromide (1.0
After adding 8 g) and potassium carbonate (1.08 g), the mixture was stirred at the same temperature for 2 hours. After diluting the reaction solution with ethyl acetate, it was washed successively with a saturated aqueous solution of sodium bicarbonate 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: dichloromethane / methanol = 25/1) to obtain the title compound 0.1.
98 g (72% yield) were obtained as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.88-1.98 (2H, m),
1.98-2.08 (2H, m), 2.39-2.49 (2H, m), 2.65-2.75 (2
H, 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.
Five).

(Reference Example 65) 3-chloro-4- [1- (3-pyridylmethyl) piperidin-4-yloxy] aniline 3-chloro-4- [1- (3-pyridyl) obtained in Reference Example 64 Methyl) piperidin-4-yloxy] nitrobenzene (980 mg) was dissolved in acetic acid (50 ml), tin powder (1670 mg) was added at room temperature, and the mixture was stirred at the same temperature overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted three times with ethyl acetate. After the extract was washed with saturated saline, 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: dichloromethane / methanol = 1).
0/1 to 5/1) to give the title compound 8
74 mg (98% yield) were obtained as a pale yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.80-1.90 (2H, m),
1.90-2.00 (2H, m), 2.32 (2H, m), 2.76 (2H, m), 3.5
5 (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-4- [1- (3-pyridylmethyl)
Ethyl piperidin-4-yloxy] phenyl] sulfamoylacetate 3-chloro-4- [1- (3-pyridylmethyl) piperidin-4-yloxy] aniline (874 mg) obtained in Reference Example 65 is dissolved in dichloromethane (20 ml). Chlorosulfonylacetate (0.39 m
1) and pyridine (0.44 ml) were added dropwise, followed by stirring 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 bicarbonate, 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 subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 20/1 to 10 /
Purification in 1) gave 770 mg (60% yield) of the title compound as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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-chloro-4- [1- (3-pyridylmethyl)
Piperidin-4-yloxy] phenyl] -N- [3-
(3-Cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (275 mg), ethyl N- [3-chloro-4- [1- (3-pyridylmethyl) piperidin-4-yloxy] phenyl] sulfamoylacetate obtained in Reference Example 66 ( 770 mg) and triphenylphosphine (520 mg) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.30 ml) was added dropwise under ice-cooling, followed by stirring at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1 to 5/1) to give 949 mg (yield 95%) of the title compound as a pale yellow color. Obtained as an amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (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), 7.26 (1H, dd, J = 7.5, 5.0),
7.30 (1H, dd, J = 9.0, 2.5), 7.40 (1H, t, J = 7.5),
7.48-7.54 (3H, m), 7.55 (1H, s), 7.68 (1H, d, J = 7.
5), 8.51 (1H, dd, J = 5.0, 1.5), 8.55 (1H, d, J = 1.
Five).

Reference Example 68 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) obtained in Reference Example 3 -3-Chloronitrobenzene (2.40 g) was dissolved in acetic acid (50 ml), zinc powder (5.60 g) was added in four portions at room temperature, 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 / ethyl acetate = 1/1) to give 1.99 g of the title compound (87% yield). ) Was obtained as an orange oil. ¹ H NMR (500 MHz, CDCl 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 (1
H, d, J = 3.0), 6.80 (1H, d, J = 9.0).

Reference Example 69 N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) -3-chlorophenyl] sulfamoylacetate The 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline (1.50 g) obtained in Reference Example 68 was dissolved in dichloromethane (20 ml). After dissolving and cooling with ice, ethyl chlorosulfonyl acetate (0.74 m
1) and pyridine (0.56 ml) were added dropwise, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.19 g (yield 54%) of the title compound as a pale red oil. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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), 4.5
2 (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-
4-yloxy) -3-chlorophenyl] -N- [3-
(3-Cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.40 g), ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoylacetate (1) obtained in Reference Example 69 .19 g) and triphenylphosphine (0.79 g) were dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.50 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 10/1) to give 1.20 g (yield 78%) of the title compound as a pale red amorphous. Obtained as a solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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), 4.4
7 (2H, d, J = 6.5), 4.55 (1H, m), 6.23 (1H, dt, J = 1
6.0, 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- (piperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2
-(E) -propenyl] sulfamoyl acetate N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyano obtained in Reference Example 70 Phenyl) -2-
(E) -propenyl] sulfamoyl acetate (1.
25 g) in ethanol (15 ml), and
After adding N hydrogen chloride dioxane solution (15 ml),
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 sequentially with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure,
1.10 g (yield quantitative) of the title compound was obtained as a pale yellow oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.76-1.88 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m
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, d
t, 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-chloro-4- [1- (4-pyridylmethyl)]
Piperidin-4-yloxy] phenyl] -N- [3-
Ethyl (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate N- [4- (piperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3 −
Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (1.10 g) was dissolved in N, N-dimethylformamide (30 ml) and 4- (bromomethyl) pyridine hydrobromide (0. After adding 59 g) and potassium carbonate (0.59 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol = 1).
0/1) to give 0.97 g of the title compound
(75% yield) as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.86-1.95 (2H, m), 1.95-2.04 (2H, m), 2.38 (2H, m
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 73 2- (2-Bromoethyl) pyridine 2-Pyridineethanol (1.00 ml) was dissolved in tetrahydrofuran (20 ml), and triphenylphosphine (3.51 g) and carbon tetrabromide were dissolved at room temperature. (4.44
After adding g), the mixture was stirred overnight at the same temperature. Ether was added to the reaction solution, and the insoluble matter was removed by filtration. Then, the reaction solution was washed 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 distilling off the solvent under reduced pressure,
The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/3) to give 1.30 g (yield 78%) of the title compound as a yellow oily substance. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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-Chloro-4- [1- [2- (2-pyridyl) ethyl] piperidin-4-yloxy] nitrobenzene 3-chloro-4- (piperidin- obtained in Reference Example 8 4
-Yloxy) nitrobenzene (1.50 g) with N, N
-Dissolved in dimethylformamide (30 ml), and at room temperature, 2- (2-bromoethyl) pyridine (1.30 g) obtained in Reference Example 73 and potassium carbonate (1.21 g).
, And 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / methanol = 10/1 to 5/1 gave 1.57 g of the title compound (yield 74).
%) As a yellow solid. ¹ H NMR (500 MHz, CDCl 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
m), 2.83 (2H, m), 3.01 (2H, m), 4.59 (1H, m), 6.99
(1H, d, J = 9.0), 7.13 (1H, dd, J = 7.5, 5.0), 7.20 (1
H, 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).

(Reference Example 75) 3-chloro-4- [1- [2- (2-pyridyl) ethyl] piperidin-4-yloxy] aniline 3-chloro-4- [1- [2-
(2-Pyridyl) ethyl] piperidin-4-yloxy] nitrobenzene (1.57 g) in acetic acid (50 ml)
, And tin powder (2.58 g) was added at room temperature, followed by stirring at the same temperature overnight. After filtering the reaction solution, 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 (eluent: dichloromethane / methanol = 5/1 to 1/1) to obtain 1.26 g of the title compound (yield 87%). Obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.82-1.94 (2H, m),
1.94-2.06 (2H, m), 2.40 (2H, m), 2.81 (2H, m), 2.8
9 (2H, m), 3.02 (2H, m), 4.15 (1H, m), 6.51 (1H, d
d, 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-4- [1- [2- (2-pyridyl)]
Ethyl] piperidin-4-yloxy] phenyl] sulfamoylacetate Ethyl 3-chloro-4- [1- [2-] obtained in Reference Example 75
(2-Pyridyl) ethyl] piperidin-4-yloxy] aniline (1.26 g) was added to dichloromethane (30 m
l), ethyl chlorosulfonylacetate (0.54 ml) and pyridine (0.61 ml) were added dropwise under ice cooling, and the mixture was stirred 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. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10/1 to 5/1) to obtain 1.50 g (yield 82%) of the title compound. Obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.86-1.97 (2H, m), 1.97-2.08 (2H, m), 2.50 (2H, m
m), 2.77-2.92 (4H, m), 3.03 (2H, m), 3.92 (2H, s),
4.29 (2H, q, J = 7.0), 4.40 (1H, m), 6.93 (1H, d, J
= 9.0), 7.13 (1H, m), 7.21 (1H, dd, J = 9.0, 2.5), 7.
17-7.24 (1H, m), 7.40 (1H, d, J = 2.5), 7.61 (1H, m),
8.53 (1H, d, J = 5.0).

Reference Example 77 N- [3-chloro-4- [1- [2- (2-pyridyl)]
Ethyl] piperidin-4-yloxy] phenyl] -N
-[3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.52 g), N- [3-chloro-4- [1- [2-] obtained in Reference Example 76
(2-Pyridyl) ethyl] piperidin-4-yloxy] phenyl] sulfamoyl acetate (1.50
g) and triphenylphosphine (0.98 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.57 ml) was added dropwise under ice cooling, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30/1 to 10/1) to give 1.73 g (89% yield) of the title compound as a pale solid. Obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (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), 7.12 (1H, m), 7.20 (1H,
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
(1H, m), 8.53 (1H, d, J = 4.5).

Reference Example 78 3-Chloro-4- (1-cyclopentylpiperidine-4)
-Yloxy) nitrobenzene 3-chloro-4- (piperidine-4) obtained in Reference Example 8
-Yloxy) nitrobenzene (4.00 g) with N, N
-Dissolved in dimethylformamide (70 ml), added cyclopentyl bromide (1.96 ml) and potassium carbonate (3.23 g) at room temperature, and stirred at 100 ° C for 7 hours. Due to the slow progress of the reaction, cyclopentyl bromide (0.70 ml) was added.
The mixture was stirred at 120 ° C. for 5 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and washed with saturated saline,
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: dichloromethane / methanol = 30 /
1-10 / 1) to give the title compound 2.
35 g (46% yield) were obtained as a brown oil. ¹ H NMR (500 MHz, CDCl 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 (4
H, m), 2.00-2.10 (2H, m), 2.50 (2H, m), 2.57 (1H,
m), 2.75 (2H, m), 4.59 (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 79 3-Chloro-4- (1-cyclopentylpiperidine-4)
-Yloxy) aniline The 3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) nitrobenzene (2.35 g) obtained in Reference Example 78 was dissolved in acetic acid (50 ml), and the powder (4.29 g) was added at room temperature. ) And stirred overnight 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluting solvent: dichloromethane / methanol = 5/1 to 1/1).
By purifying in 1), 1.97 g (yield 92%) of the title compound was obtained as a pale brown amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.48-1.61 (2H, m),
1.61-1.78 (4H, m), 1.86-2.02 (4H, m), 2.06-2.19 (2
H, m), 2.76 (2H, m), 2.85 (1H, m), 2.94 (2H, m),
4.29 (1H, m), 6.52 (1H, dd, J = 8.5, 2.5), 6.73 (1H,
d, J = 2.5), 6.79 (1H, d, J = 8.5).

(Reference Example 80) Ethyl N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] sulfamoylacetate 3-chloro-4- (1-cyclopentylpiperidine obtained in Reference Example 79 -4-yloxy) aniline (1.9
7 g) was dissolved in dichloromethane (40 ml), and ethyl chlorosulfonyl acetate (0.94 ml) and pyridine (1.08 ml) were added dropwise under ice-cooling, 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 the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 25/1 to 10/1) to give
1.09 g (yield 37%) of the title compound was obtained as a pale brown amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.38-1.62 (4H, m), 1.62-1.77 (2H, m), 1.80-1.96 (4
H, 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, d
d, J = 9.0, 2.5), 7.39 (1H, d, J = 2.5).

Reference Example 81 N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (0.39 g), ethyl N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] sulfamoylacetate obtained in Reference Example 80 (1.09 g) ) And triphenylphosphine (0.77 g) in dichloromethane (30 ml)
And cooled under ice-cooling to diethyl azodicarboxylate (0.4%).
(5 ml) was added dropwise, followed by stirring at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/10).
1-5 / 1) to give the title compound 1.3
0 g (91% yield) was obtained as a tan amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.40-1.61 (4H, m), 1.64-1.80 (2H, m), 1.83-1.99 (4
H, 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 (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), 7.48-7.55 (3H, m), 7.56 (1H, s).

(Reference Example 82) 1-t-Butoxycarbonyl-2-methyl-4-piperidone ethylene ketal 4-Piperidone ethylene ketal (9.6 g) was dissolved in acetone (100 ml), and the mixture was dissolved in ice and cooled with ice. Butyl dicarbonate (16.0 g) was added, and the mixture was stirred 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 the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1-t-butoxycarbonyl-4-piperidoneethylene ketal (17.4 g) as a pale yellow solid. Then, this was dissolved in ether (200 ml), and at -78 ° C., N, N, N ′, N′-tetramethylethylenediamine (13.0 ml) and 1N s-butyllithium (mixed solution of cyclohexane and hexane)
(88.0 ml) was added dropwise, followed by stirring at −30 ° C. for 30 minutes. After the reaction solution was cooled again to -78 ° 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 was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to obtain 6.0 g of the title compound.
(34% yield) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.23 (3H, d, J = 7.0),
1.46 (9H, s), 1.55-1.70 (4H, m), 1.85-1.90 (1H,
m), 3.05-3.15 (1H, m), 3.90-4.05 (4H, m), 4.47 (1
H, m).

Reference Example 83 1-t-butoxycarbonyl-2-methyl-4-piperidone 1-t-butoxycarbonyl-2 obtained in Reference Example 82
-Methyl-4-piperidone ethylene ketal (6.0
0 g) was dissolved in acetone (150 ml), and p.
-Toluenesulfonic acid monohydrate (4.40 g) was added, and the mixture was stirred at room temperature overnight. 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 obtain 2.40 g (yield 48%) of the title compound as a yellow oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.18 (3H, d, J = 7.0),
1.49 (9H, s), 2.20-2.30 (1H, m), 2.30-2.40 (1H,
m), 2.45-2.55 (1H, m), 2.65-2.70 (1H, m), 3.25-3.3
5 (1H, m), 3.90-4.05 (1H, m), 4.20-4.30 (1H, m).

Reference Example 84 1-t-butoxycarbonyl-4-hydroxy-2-methylpiperidine Lithium aluminum hydride (1.30) under a nitrogen atmosphere.
g) was suspended in tetrahydrofuran (50 ml), and 1-t-butoxycarbonyl-2-methyl-4-piperidone (2.40 g) obtained in Reference Example 83 was added dropwise under ice-cooling, followed by 1 hour at room temperature. Stirred. Sodium sulfate decahydrate 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 (yield 39%) of the title compound and 1.02 g (yield 42%) of the high polarity compound as the title compound. Were each obtained as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm of highly polar compounds: 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 (1
H, m), 2.85-2.95 (1H, m), 3.90-4.00 (1H, m), 4.00-
4.10 (1H, m), 4.45-4.55 (1H, m). ¹ H NMR (500 MHz, CDCl ₃ ) δppm of low polarity compounds: 1.33
(3H, d, J = 7.0), 1.46 (9H, s), 1.60-1.75 (3H, m), 1.
80-1.90 (1H, m), 3.20-3.30 (1H, 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-butoxycarbonyl-2-methylpiperidin-4-yloxy) -3-chloronitrobenzene 1-t-butoxycarbonyl-4 obtained in Reference Example 84
-Hydroxy-2-methylpiperidine highly polar compound (1.02 g), 2-chloro-4-nitrophenol (0.83 g) and triphenylphosphine (1.62)
g) in dichloromethane (60 ml), and
After dropwise addition of diethyl azodicarboxylate (0.97 ml), the mixture was stirred at room temperature for 8 hours. Since the progress of the reaction was slow, triphenylphosphine (1.62 g) and diethyl azodicarboxylate (0.97 ml) were added, and the mixture was further stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluting solvent: hexane /
Purification by ethyl acetate (4/1) yielded 1.15 g (76% yield) of the title compound as a yellow oil. _{^{1 H NMR (500MHz, CDCl 3}} ) δppm: 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), 4.35-4.4
5 (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-4- (1,2-dimethylpiperidine-4-
(Iloxy) nitrobenzene 4- (1-t-butoxycarbonyl-2-methylpiperidin-4-yloxy) -3-chloronitrobenzene (1.15 g) obtained in Reference Example 85 was mixed with 90% formic acid (3.
10g), 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 distilling off the solvent under reduced pressure,
The residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 9/1) to give 0.80 g (yield 90%) of the title compound as a yellow oily substance. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.18 (3H, d, J = 6.0),
1.64 (1H, 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
(1H, d, J = 9.0), 8.12 (1H, dd, J = 9.0, 2.5), 8.30
(1H, d, J = 2.5).

Reference Example 87 3-Chloro-4- (1,2-dimethylpiperidin-4-
(Iloxy) aniline 3-chloro-4- (1,2-dimethylpiperidin-4-yloxy) nitrobenzene (8
00 mg) was dissolved in acetic acid (20 ml), tin powder (1700 mg) was added at room temperature, and 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 solution of potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 690 mg (yield: 96%) of the title compound as a red-brown oily substance. ¹ H NMR (500 MHz, CDCl 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 (1H, d, J = 3.0), 6.83
(1H, d, J = 8.5).

(Reference Example 88) Ethyl N- [3-chloro-4- (1,2-dimethylpiperidin-4-yloxy) phenyl] sulfamoylacetate 3-chloro-4- (1,4) obtained in Reference Example 87 2-dimethylpiperidin-4-yloxy) aniline (690 m
g) in dichloromethane (20 ml), and
After ethyl chlorosulfonyl acetate (0.40 ml) and pyridine (0.25 ml) were added dropwise, the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane /
By purifying with methanol = 9/1 to 3/1),
800 mg (73% yield) of the title compound were obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.18 (3H, t, J = 7.0),
1.26 (3H, m), 1.55-1.70 (1H, m), 1.75-1.90 (1H,
m), 2.15-2.30 (2H, m), 2.55-2.75 (3H, m), 2.80-3.3
0 (3H, m), 4.11 (2H, q, J = 7.0), 4.20 (2H, s), 4.45
-4.55 (1H, 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-4- (1,2-dimethylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E)- Propenyl] ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (320 mg), ethyl N- [3-chloro-4- (1,2-dimethylpiperidin-4-yloxy) phenyl] sulfamoylacetate (800 mg) obtained in Reference Example 88, and Triphenylphosphine (680 mg) was dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.40 ml) was added under ice cooling.
ml) was added dropwise, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 4).
/ 1-dichloromethane / methanol = 9/1) to give 1100 mg (quantitative yield) of the title compound.
Was obtained as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.14 (3H, d, J = 6.0),
1.36 (3H, t, J = 7.0), 1.50-1.65 (1H, m), 1.75-1.90
(1H, m), 1.95-2.20 (4H, m), 2.29 (3H, s), 2.95 (1
H, m), 3.98 (2H, s), 4.21 (1H, m), 4.31 (2H, q, J =
7.0), 4.46 (2H, d, J = 6.5), 6.22 (1H, dt, J = 16.0,
6.5), 6.41 (1H, d, J = 16.0), 6.94 (1H, m), 7.31 (1H,
m), 7.40 (1H, m), 7.45-7.50 (1H, m), 7.50-7.60 (2
H, m), 7.65-7.70 (1H, m).

Reference Example 90 Indolizin-7-ol Under a nitrogen atmosphere, lithium aluminum hydride (2.30)
g) was suspended in tetrahydrofuran (50 ml), and cooled under ice-cooling, Heterocycles, Vol. 43, p. 1391 (19).
1996) Indolidin-7-one (2.80 g) synthesized from 4,4-diethoxybutylamine and diethyl 1,3-acetone dicarboxylate according to the method described in [ Heterocycles , 43 , 1391 (1996)]. After dropwise addition, the mixture was stirred at the same temperature for 1 hour. Add sodium sulfate
Decahydrate was added, and the mixture was further stirred at room temperature for 1 hour. The insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 4/1) to give the title compound 1.
70 g (59% yield) were obtained as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1
H, m).

Reference Example 91 3-chloro-4-methoxymethoxyaniline 2-chloro-4-nitrophenol (5.2 g) was added to N,
After dissolving in N-dimethylformamdo (50 ml), methoxymethoxychloride (2.7 ml) and triethylamine (5.0 ml) were added dropwise under ice cooling, 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, 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 3-chloro-4-methoxymethoxynitrobenzene (8.1 g) as a yellow oily substance. Then, this was mixed with acetone (100 ml) and water (1).
00ml), zinc dust (9.8g) and ammonium chloride (8.0g) were added at room temperature, and the mixture was stirred at 60 ° C for 40 minutes. 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. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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) Ethyl N- (3-chloro-4-methoxymethoxyphenyl) sulfamoylacetate 3-chloro-4-methoxymethoxyaniline (5.4 g) obtained in Reference Example 91 was diluted with dichloromethane (50 ml).
Chlorosulfonyl acetate (4.
7 ml) and pyridine (2.9 ml) were added dropwise, followed by stirring 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 1).
9/1) to give 8.0 g of the title compound.
(82% yield) as a red-brown oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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).

Reference Example 93 N- [3-chloro-4-methoxymethoxyphenyl]-
Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (1.6 g), Reference Example 9
Ethyl N- (3-chloro-4-methoxymethoxyphenyl) sulfamoylacetate (3.4 g) and triphenylphosphine (3.2 g) obtained in Step 2 were dissolved in dichloromethane (50 ml), and the mixture was dissolved in azodicarboxylic acid under ice-cooling. After dropwise addition of diethyl acid (1.9 ml), the mixture was stirred at room temperature for 40 minutes. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane /
Purification with ethyl acetate (19/1) yielded 3.9 g (81% yield) of the title compound as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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).

Reference Example 94 N- [3-chloro-4-hydroxyphenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate N- [3-chloro-4-methoxymethoxyphenyl] -N- [3- (3- Ethyl cyanophenyl) -2- (E) -propenyl] sulfamoylacetate (3.9 g) was dissolved in a mixed solvent of ethyl acetate (50 ml) and dioxane (50 ml).
After adding a 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. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 = 1
6.0), 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- (indolizin-7-yloxy) phenyl] -N- [3- (3-cyanophenyl)-
Ethyl 2- (E) -propenyl] sulfamoylacetate N- [3-chloro-4-hydroxyphenyl] -N- [3- (3-cyanophenyl) -2 obtained in Reference Example 94
-(E) -propenyl] sulfamoyl acetate (2.0 g), indolizine-7 obtained in Reference Example 90
-Ol (1.7 g) and triphenylphosphine (3.2 g) are dissolved in dichloromethane (60 ml),
Under ice-cooling, diethyl azodicarboxylate (1.9 ml) was added dropwise, followed by stirring at room temperature for 6 hours. Since the progress of the reaction was slow, triphenylphosphine (3.2 g) and diethyl azodicarboxylate (1.9 ml) were added, and the mixture was further stirred at the same temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 2/1) to give
0.6 g of the title compound was obtained as a contaminant of an orange oil.

Reference Example 96 Ethyl N- (4-methoxymethoxyphenyl) sulfamoylacetate 4-Methoxymethoxyaniline (20.9 g) was dissolved in dichloromethane (400 ml), and ethyl chlorosulfonylacetate (18. 0 ml) and pyridine (33
ml) was added dropwise and stirred overnight at room temperature. 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 /
Purification in 2) gave 28.0 g (yield 67%) of the title compound as a brown oil. _{^{1 H NMR (270MHz, CDCl 3}} ) δppm: 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).

(Reference Example 97) Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- (4-methoxymethoxyphenyl) sulfamoylacetate 3-ethyl obtained in Reference Example 2 (3-cyanophenyl) -2-
(E) -propen-1-ol (0.53 g), N- (4-methoxymethoxyphenyl) obtained in Reference Example 96
Ethyl sulfamoyl acetate (1.00 g) and triphenylphosphine (1.12 g) were added to dichloromethane (30 g).
ml), diethyl azodicarboxylate (0.66 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give the title compound 1.
38 g (94% yield) were obtained as a yellow oil. _{^{1 H NMR (270MHz, CDCl 3}} ) δppm: 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 Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoylacetate N- [obtained in Reference Example 97 Ethyl 3- (3-cyanophenyl) -2- (E) -propenyl] -N- (4-methoxymethoxyphenyl) sulfamoylacetate (10.
7 g) was dissolved in ethyl acetate (120 ml),
After adding a 4N ethyl acetate solution of hydrogen chloride (80 ml), 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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1).
9.1 g (yield 95) of the title compound.
%) As a yellow oil. ¹ H NMR (270 MHz, CDCl 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 (1H, dt, J = 16.0, 6.0), 6.39 (1H, d, J = 1
6.0), 6.84 (2H, d, J = 9.0), 7.34 (2H, d, J = 9.0), 7.
39 (1H, t, J = 7.5), 7.50 (2H, m), 7.54 (1H, s).

(Reference Example 99) Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidin-4-yloxy) phenyl] sulfamoyl acetate Reference Ethyl N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoylacetate obtained in Example 98 (700 m
g), 4-hydroxy-1-methylpiperidine (410
mg) and triphenylphosphine (920 mg) were dissolved in dichloromethane (20 ml), diethyl azodicarboxylate (0.55 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. Since the progress of the reaction was slow, 4-hydroxy-1-methylpiperidine (410 mg), triphenylphosphine (920 mg) and diethyl azodicarboxylate (0.55 ml) were added, and the mixture was further stirred at the same temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / ethyl acetate).
By purifying with methanol = 2/1 to 1/1),
690 mg (yield 79%) of the title compound was obtained as a yellow oily substance. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.25-4.35 (1H, m), 4.30 (2H, q, J = 7.0), 4.4
7 (2H, d, J = 6.5), 6.23 (1H, dt, J = 16.0, 6.5), 6.40
(1H, d, J = 16.0), 6.90 (2H, d, J = 9.0), 7.35-7.45 (1
H, m), 7.38 (2H, d, J = 9.0), 7.45-7.55 (3H, m).

Reference Example 100 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.45 g), Journal of Japan ·organic·
Chemistry, 63, 4199 (1998)
[J. Org. Chem., 63 , 4199 (1998)] synthesized from 3-trifluoromethyl-nitrobenzene according to the method described in the 2-trifluoromethyl-4-nitrophenol (1.
38 g) and triphenylphosphine (2.27 g) were dissolved in dichloromethane (65 ml), diethyl azodicarboxylate (1.4 ml) was added dropwise under ice cooling, 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) to give the title compound 2.28.
g (88% yield) as a pale yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.49 (9H, s), 1.88-
1.99 (4H, m), 3.51 (2H, m), 3.64 (2H, m), 4.83 (1
H, m), 7.09 (1H, d, J = 9.0), 8.41 (1H, dd, J = 9.0,
3.0), 8.53 (1H, d, J = 3.0).

Reference Example 101 4- (1-Methylpiperidin-4-yloxy) -3-
Trifluoromethylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene (2.45 g) obtained in Reference Example 100 was suspended in 90% formic acid (8.80 g). , 37% formalin (5.50
g) was added and the mixture was stirred at 100 ° C. for 6 hours. After the reaction solution was cooled to room temperature and neutralized with an aqueous solution of sodium hydrogen carbonate,
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 the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/10).
By purifying in 1), 1.82 g (yield 95%) of the title compound was obtained as a yellow oily substance. ¹ H NMR (500 MHz, CDCl 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).

Reference Example 102 4- (1-Methylpiperidin-4-yloxy) -3-
Trifluoromethylaniline 4- (1-methylpiperidine- obtained in Reference Example 101
After dissolving 4-yloxy) -3-trifluoromethylnitrobenzene (1.82 g) in ethanol (30 ml) and adding a palladium-carbon catalyst (0.18 g),
The mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/1 to 1/1), whereby
1.55 g (95% yield) of the title compound was obtained as a light brown solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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).

Reference Example 103 N- [4- (1-Methylpiperidin-4-yloxy)
-3-trifluoromethylphenyl] sulfamoyl acetate 4- (1-methylpiperidine- obtained in Reference Example 102
4-yloxy) -3-trifluoromethylaniline (1.55 g) was dissolved in dichloromethane (30 ml), and ethyl chlorosulfonyl acetate (0.76 m
l) and pyridine (0.91 ml) were added dropwise, followed by stirring at room temperature for 1 hour. Water is added to the reaction solution, and the mixture is
After extraction twice, the extract was washed with 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: dichloromethane / methanol = 10/1 to 5 /
By purifying in 1), 2.39 g (quantitative yield) of the title compound was obtained as a pale brown amorphous solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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 (1H, m), 6.98 (1H, d, J = 9.0), 7.55 (1
H, dd, J = 9.0, 2.5), 7.62 (1H, d, J = 2.5).

Reference Example 104 N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- [4- (1-methylpiperidin-4-yloxy) -3-trifluoromethyl Phenyl] ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2
(E) -propen-1-ol (500 mg), N- [4- (1-methylpiperidine-
4-yloxy) -3-trifluoromethylphenyl]
Ethyl sulfamoyl acetate (1333 mg) and triphenylphosphine (990 mg) were added to dichloromethane (3
0ml), diethyl azodicarboxylate (0.58ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 15/1) to obtain 755 mg (yield 43%) of the title compound as a pale yellow amorphous solid. Was. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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 (1H, 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 (4
H, m), 7.71 (1H, d, J = 2.5).

Reference Example 105 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) nitrobenzene 1-tert-butoxycarbonyl-4-hydroxypiperidine (50.1 g) was added to N, N-dimethylacetamide (5
50 ml), and cooled under ice-cooling with sodium hydride (1
0.5 g), and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 4-fluoronitrobenzene (42.2 g) in N, N-dimethylacetamide (100 ml) was added dropwise, and the mixture was further 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 (eluent: hexane / ethyl acetate = 13/7) to give 75.1 g (yield 93%) of the title compound as a pale-yellow solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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).

Reference Example 106 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene (1) obtained in Reference Example 105
1.9 g) was dissolved in methanol (100 ml), and a palladium-carbon catalyst (1.9 g) was added, followed by stirring 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 = 1/1) to give 10.7 g of the title compound (yield 99).
%) As a pale red solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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).

Reference Example 107 N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) phenyl] sulfamoylacetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (4.39) obtained in Reference Example 106
g) was dissolved in dichloromethane (30 ml), and the mixture was cooled with ice.
After ethyl chlorosulfonyl acetate (2.4 ml) and pyridine (2.4 ml) were added dropwise, the mixture was stirred at room temperature overnight.
After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
3/2) to give 4.96 g of the title compound
(75% yield) as a pale red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0),
1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34 (2
H, 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).

Reference Example 108 N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.80 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate obtained in Reference Example 107 (2.21 g) And triphenylphosphine (1.70 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (1.0 m
After l) was added dropwise, the mixture was stirred at the same temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 10).
/ 1) to give 2.15 g of the title compound
(74% yield) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0),
1.47 (9H, s), 1.75 (2H, m), 1.90 (2H, m), 3.34 (2
H, 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).

Reference Example 109 4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -3-methylnitrobenzene 1-tert-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4 Nitrophenol (2.55 g) and triphenylphosphine (5.25)
g) was dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (3.2 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to obtain 4.07 g of the title compound as a light yellow oily impurity. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 110 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) obtained in Reference Example 109 -3-Methylnitrobenzene (4.07 g) was dissolved in methanol (40 ml), and after adding a palladium-carbon catalyst (0.41 g), the mixture was stirred at room temperature under a hydrogen atmosphere for 4 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 / ethyl acetate = 3/2) to give the title compound 2.7.
3 g (53% in two steps from yield reference example 109) was obtained as a pale red oily substance. _{^{1 H NMR (500MHz, CDCl 3}} ) δppm: 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 111 N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) -3-methylphenyl] sulfamoylacetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline (1.63 g) obtained in Reference Example 110 was diluted with dichloromethane (30 ml). Chlorosulfonyl acetate (0.86m
l) and pyridine (0.81 ml) were added dropwise, followed by stirring at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 1.84 g (yield 76%) of the title compound as a pale brown amorphous. Obtained as a solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0),
1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.22 (3
H, 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).

Reference Example 112 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-methylphenyl] -N- [3-
(3-Cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.64 g), ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] sulfamoylacetate obtained in Reference Example 111 ( 1.84 g) and triphenylphosphine (1.26 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.76 ml) was added dropwise under ice-cooling, followed by stirring at the same temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane /
Purification by ethyl acetate (12/1) yielded 1.90 g (79% yield) of the title compound as a colorless amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.47 (9H, s), 1.78 (2H, m), 1.89 (2H, m), 2.21 (3
H, 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 (1
H, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 1
6.0), 6.80 (1H, d, J = 8.0), 7.24 (2H, m), 7.40 (1H,
t, J = 8.0), 7.50 (1H, d, J = 7.5), 7.52 (1H, d, J = 8.
0), 7.56 (1H, s).

Reference Example 113 Ethyl 5-nitrosalicylate 5-Nitrosalicylic acid (10.8 g) was added to ethanol (1
00ml), concentrated sulfuric acid (92.0 g) was added at room temperature, and the mixture was heated under reflux for 7.5 hours. The reaction solution was cooled to room temperature, neutralized by adding an aqueous sodium hydroxide solution, and extracted with ethyl acetate.
Washed sequentially with 0.5N hydrochloric acid and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 10.7 g of the title compound (yield 85%).
%) As a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.47 (3H, t, J = 7.0),
4.49 (2H, q, J = 7.0), 7.09 (1H, d, J = 9.0), 8.33 (1
H, dd, J = 9.0, 3.0), 8.79 (1H, d, J = 3.0).

Reference Example 114 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (10.2 g). The obtained ethyl 5-nitrosalicylate (10.7 g) and triphenylphosphine (17.3 g) were added to dichloromethane (200 ml).
And cooled under ice-cooling to diethyl azodicarboxylate (10.
(4 ml) was added dropwise, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 /
Purification in 1), hexane was added to the obtained yellow solid, and the mixture was collected by filtration to give 12.3 g of the title compound (yield 61).
%) As a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J = 7.0),
1.47 (9H, s), 1.91 (4H, m), 3.58 (4H, m), 4.39 (2
H, 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-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) obtained in Reference Example 114 -3-ethoxycarbonylnitrobenzene (1.0 g) was added to ethanol (10
ml) and an aqueous solution of potassium hydroxide (0.
2 g was dissolved in 0.5 ml of water), and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and the extract 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. ¹ H NMR (500 MHz, CDCl 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 (1H, m), 7.13 (1H, d,
J = 9.0), 8.39 (1H, dd, J = 9.0, 3.0), 8.93 (1H, d, J =
3.0).

Reference Example 116 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) obtained in Reference Example 115 -3-Carboxynitrobenzene (0.9 g) was added to dichloromethane (20 m
l) and isobutyl chloroformate (0.3
ml) and triethylamine (0.4 ml), and the mixture was stirred at the same temperature for 1 hour.
l) was added, and the mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 19).
/ 1) to give 0.9 g (yield 98%) of the title compound as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1H, d,
J = 9.0), 8.33 (1H, dd, J = 9.0, 3.0), 9.09 (1H, d, J =
3.0).

Reference Example 117 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) obtained in Reference Example 116 -3-Carbamoylnitrobenzene (5.7 g) in methanol (80 ml)
And a palladium-carbon catalyst (0.6 g) was added,
The mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 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 / methanol = 19/1) to give 4.8 g of the title compound (yield 91%). Was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-
1.80 (2H, m), 1.95-2.05 (2H, m), 3.19 (2H, m), 3.7
5-3.85 (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).

Reference Example 118 N- [4- (1-t-butoxycarbonylpiperidine-
Ethyl 4-yloxy) -3-carbamoylphenyl] sulfamoylacetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline (4.8 g) obtained in Reference Example 117 was mixed with dichloromethane (80 ml). Chlorosulfonyl acetate (2.5%) under ice-cooling.
ml) and pyridine (2.3 ml) were added dropwise, followed by stirring at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1), and ether was added to the obtained orange solid, which was collected by filtration to give the title compound 3. 7 g (53% yield) were obtained as a pale yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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).

Reference Example 119 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
Ethyl [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.7 g), Reference Example 1
Ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] sulfamoylacetate (2.0 g) and triphenylphosphine (1.5 g) obtained in 18 were added to dichloromethane (30 ml). ), And diethyl azodicarboxylate (0.9 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2) to give the title compound 2.5
g (94% yield) as a yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1
H, 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-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylaniline 4- (1-t-butoxycarbonylpiperidine-4- obtained in Reference Example 100 Yloxy) -3-trifluoromethylnitrobenzene (2.28 g) in methanol (5
0 ml), and dissolved in a palladium-carbon catalyst (0.20 ml).
After adding g), the mixture was stirred at room temperature under a hydrogen atmosphere for 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 (elution solvent: hexane / ethyl acetate = 3/2) to give 1.69 g of the title compound (80% yield). ) Was obtained as a pale red oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm: 1.47 (9H, s), 1.76-
1.88 (4H, m), 3.43 (2H, m), 3.59 (2H, m), 4.46 (1
H, m), 6.78 (1H, dd, J = 9.0, 3.0), 6.83 (1H, d, J = 9.
0), 6.91 (1H, d, J = 3.0).

Reference Example 121 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-trifluoromethylphenyl]
Ethyl sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylaniline (1.69 g) obtained in Reference Example 120 was added to dichloromethane (20
ml), ethyl chlorosulfonyl acetate (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. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 1.74 g (yield 73%) of the title compound as a pale red oil. As obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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-
4-yloxy) -3-trifluoromethylphenyl]
-N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (0.57 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoylacetic acid obtained in Reference Example 121 Ethyl (1.74
g) and triphenylphosphine (1.07 g) were dissolved in dichloromethane (27 ml), and diethyl azodicarboxylate (0.65 ml) was added dropwise under ice-cooling, 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: dichloromethane / ethyl acetate = 12/1) to give 2.06 g (yield 93%) of the title compound as a colorless amorphous solid As obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1H, m), 6.22 (1H, dt, J = 16.0, 6.5),
6.41 (1H, d, J = 16.0), 6.98 (1H, d, J = 7.5), 7.41 (1
H, dd, J = 8.0, 7.5), 7.52 (2H, m), 7.57 (1H, s), 7.
58 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.0).

Reference Example 123 3-Chloro-4- (tropan-3-yloxy) nitrobenzene 3-tropanol (6.7 g), 2-chloro-4-nitrophenol (8.2 g) and triphenylphosphine (16 g) .1 g) was dissolved in a mixed solvent of dichloromethane (200 ml) and tetrahydrofuran (50 ml), and diethyl azodicarboxylate (9.7 ml) was added dropwise under ice-cooling, 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 / methanol = 19/1) to give 8.5 g (yield 60%) of the title compound as a pale yellow amorphous solid As obtained. ¹ H NMR (500 MHz, CDCl 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).

Reference Example 124 3-Chloro-4- (tropan-3-yloxy) aniline 3-chloro-4- (tropane- obtained in Reference Example 123
3-yloxy) nitrobenzene (8.5 g) was dissolved in acetic acid (500 ml), and tin powder (17.0) was added at room temperature.
g) was added and 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 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: dichloromethane / methanol = 3/1) to obtain 2.5 g of the title compound (yield 32).
%) As a colorless solid. ¹ H NMR (500 MHz, CDCl 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).

Reference Example 125 N- [3-chloro-4- (tropan-3-yloxy)
Ethyl phenyl] sulfamoyl acetate 3-chloro-4- (tropane-
3-yloxy) aniline (2.5 g) was dissolved in dichloromethane (50 ml), and ethyl chlorosulfonyl acetate (1.5 ml) and pyridine (0.9 ml) were added dropwise under ice-cooling, and then at room temperature for 3.5 hours. Stirred. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 4 /
By purifying in 1), 3.5 g (yield 89%) of the title compound was obtained as a pale brown amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.0),
1.95-2.05 (2H, m), 2.20-2.25 (2H, m), 2.30-2.75 (4
H, m), 2.84 (3H, s), 3.89 (2H, m), 3.98 (2H, s),
4.28 (2H, q, J = 7.0), 4.49 (1H, m), 6.95 (1H, d, J =
8.5), 7.25 (1H, dd, J = 2.5, 8.5), 7.45 (1H, d, J = 2.
Five).

Reference Example 126 N- [3-chloro-4- (tropan-3-yloxy)
Phenyl] -N- [3- (3-cyanophenyl) -2-
(E) -Propenyl] sulfamoyl acetate 3- (3-cyanophenyl) -2- obtained in Reference Example 2.
(E) -propen-1-ol (1.4 g), Reference Example 1
N- [3-chloro-4- (tropane-3) obtained in 25.
-Yloxy) phenyl] sulfamoylethyl acetate (3.5 g) and triphenylphosphine (2.9 g)
Was dissolved in dichloromethane (50 ml), diethyl azodicarboxylate (1.8 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1 to 9/1) to give 1.3 g (yield 27%) of the title compound as a yellow color. Obtained as an amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0),
1.55-1.65 (2H, m), 1.90-2.00 (4H, m), 2.05-2.15 (2
H, 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 (1
H, m), 6.21 (1H, dt, J = 6.5, 16.0), 6.41 (1H, d, J =
16.0), 6.94 (1H, m), 7.29 (1H, m), 7.40 (1H, m),
7.50-7.60 (4H, m).

Reference Example 130 3- (3-Cyanophenyl) -2-fluoro-2-
(Z) -Propene-1-all Journal of Organometallic Chemistry, vol. 332, p. 1 (1987) [ J. Organomet. C
332 , 1 (1987)] .
-Diethylphosphono-2-fluoroacetic acid (4.35 g)
Was dissolved in tetrahydrofuran (90 ml), and the solution was dissolved at -78 ° C.
1.6N butyllithium hexane solution (28ml)
After stirring at the same temperature for 1 hour, 3-cyanobenzaldehyde (2.66 g) in tetrahydrofuran (10
ml) solution was added dropwise over 10 minutes and further stirred at the same temperature for 3 hours. After the temperature of the reaction solution was raised to 0 ° C., water was added, the aqueous layer was separated, and the organic layer was extracted twice with a saturated aqueous solution of sodium hydrogen carbonate. After all the aqueous layers were combined, the pH of the solution was adjusted to 4 with concentrated hydrochloric acid, extracted with t-butyl methyl ether five times, and the extract was dried over anhydrous sodium sulfate.
By evaporating the solvent under reduced pressure, the intermediate compound (3.
47g) was obtained as a white solid. Then, the obtained intermediate compound (1.15 g) and triethylamine (0.9
2 ml) was dissolved in dichloromethane (10 ml), ethyl chlorocarbonate (0.63 ml) was added under ice-cooling, and the mixture was stirred at room temperature 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 ml), and the mixture was cooled with ice and an aqueous solution of sodium borohydride (0.1 mL) was added.
45 g was dissolved in 5 ml of water), and the mixture was stirred at room temperature for 18 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, extraction was performed 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 (eluent: hexane / ethyl acetate = 3/2) to obtain 0.33 g (yield 31%) of the title compound as a colorless solid. Was. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (1H, d, J = 8.0), 7.81 (1
H, s).

Reference Example 131 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl]
Ethyl sulfamoyl acetate 3- (3-cyanophenyl)-obtained in Reference Example 130
2-fluoro-2- (Z) -propen-1-ol (0.45 g), N- [4-
(1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] ethyl sulfamoyl acetate (1.12
g) and triphenylphosphine (0.80 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.48 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 15/1) to give 1.40 g (yield 92%) of the title compound as a colorless oil. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0),
1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.34 (2
H, m), 3.68 (2H, m), 4.00 (2H, s), 4.30 (2H, q, J =
7.0), 4.46 (1H, m), 4.54 (2H, d, J = 15.0), 5.62 (1
H, d, J = 36.5), 6.92 (2H, d, J = 9.5), 7.42 (3H, m),
7.51 (1H, d, J = 7.0), 7.63 (1H, d, J = 8.0), 7.71 (1
H, s).

Reference Example 132 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-cyanophenyl) -2-fluoro-2-
(Z) -propenyl] sulfamoyl acetate 3- (3-cyanophenyl)-obtained in Reference Example 130
2-fluoro-2- (Z) -propen-1-ol (0.80 g), N- [4-
Ethyl (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] sulfamoylacetate (2.20 g) and triphenylphosphine (1.50 g) were dissolved in dichloromethane (50 ml). Diethyl dicarboxylate (0.86m
After l) was added dropwise, the mixture was stirred at room temperature for 2.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/4).
１ ／) to give 3.40 of the title compound.
g (yield quantitative) was obtained as a pale yellow amorphous solid. ¹ H NMR (500 MHz, CDCl ₃ ) δppm: 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 (2
H, s), 4.31 (2H, q, J = 7.0), 4.57-4.70 (3H, m), 5.6
5 (1H, d, J = 36.5), 7.03 (1H, d, J = 9.0), 7.38-7.74
(5H, m), 8.35 (1H, d, J = 3.0).

Reference Example 133 3- [3- [N- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] amino] -1- (E) -propenyl] benzo Nitrile 3-cyanocinnamic aldehyde obtained in Reference Example 1 (0.6
4g), 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline (1.36 g) obtained in Reference Example 117 and powdered molecular sieves 5A (5.06 g) were dissolved in toluene (30 ml). And heated to 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. Next, the obtained imine compound was suspended in ethanol (30 ml), sodium borohydride (0.31 g) and cerium chloride (0.32 g) were added thereto under ice cooling, and the mixture was stirred at room temperature overnight, and then hydrogenated. Sodium boron (0.16 g) was added, and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, 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 subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 7/3 to 0).
/ 10) to give 1.77 g of the title compound
(92% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm: 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 (1H, d,
J = 16.0), 6.75 (1H, dd, J = 9.0, 3.0), 6.89 (1H, d, J =
9.0), 7.41 (1H, t, J = 8.0), 7.49-7.53 (2H, m), 7.58
(1H, d, J = 8.0), 7.63 (1H, s).

Reference Example 134 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-cyanophenyl) -2- (E) -propenyl] methanesulfonamide 3- [3- [N- [4- (1-
t-butoxycarbonylpiperidin-4-yloxy)
-3-carbamoylphenyl] amino] -1- (E)-
Propenyl] benzonitrile (0.85 g) was dissolved in dichloromethane (15 ml), and methanesulfonyl chloride (0.17 ml) and pyridine (0.29 m
After l) was added dropwise, the mixture was stirred at room temperature overnight. After adding methanol (3 ml) to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/0 to 9/1) to obtain 1.01 g of the title compound. (Quantitative yield) was obtained as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.48 (9H, s), 1.74-
1.85 (2H, m), 2.03-2.12 (2H, m), 2.96 (3H, s), 3.2
3-3.32 (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 (1
H, t, J = 7.5), 7.49-7.57 (4H, m), 8.18 (1H, d, J = 3.
0).

Reference Example 135 N- [4- (1-t-butoxycarbonylpiperidine-
4-yloxy) -3-carbamoylphenyl] -N-
[3- (3-cyanophenyl) -2- (E) -propenyl] ethanesulfonamide 3- [3- [N- [4- (1-
t-butoxycarbonylpiperidin-4-yloxy)
-3-carbamoylphenyl] amino] -1- (E)-
Propenyl] benzonitrile (0.92 g) was dissolved in dichloromethane (15 ml), and ethanesulfonyl chloride (0.22 ml) and pyridine (0.31 m
After l) was added dropwise, the mixture was stirred at room temperature overnight, and then 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 solution, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/0).
~ 9/1) to give 1.08 of the title compound
g (90%) were obtained as a yellow oil. _{^{1 H NMR (400MHz, CDCl 3}} ) δppm: 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 (1H, m),
6.24 (1H, 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), 7.48-7.5
5 (4H, m), 8.16 (1H, d, J = 3.0).

(Test Example 1) Measurement of anti-factor Xa activity The anti-factor Xa activity was measured by the method of Hara et al. [Thrombosis and hemostasis, Vol. 71, p. 314 (1994) [ Thromb. Haemost. , 71 , 314 (1994)]]
Was partially modified. 0.9% sodium chloride, 0.
4 mM of chromogenic substrate S-2222 (Daiichi Pure Chemicals) and 50 mM of Tris-HCl buffer (pH 8.4) containing the test compound are mixed, and 0.25 unit / ml of human factor Xa (Cosmo Bio) is added. This initiated the reaction. In the control group, distilled water was added to the buffer instead of the test compound. The reaction solution (total volume 0.1 ml)
Incubated for minutes. The absorbance at 405 nm is 96
The measurement was continuously performed using a well microplate reader (model 550, Bio-Rad), and the increase in absorbance for 5 minutes was calculated as an index of the factor Xa activity. To evaluate the anti-factor Xa activity of the test compound, the concentration at which the test compound inhibits factor Xa activity by 50% (IC
₅₀ values). As a result, the general formula (1) of the present invention
Has been found to have an excellent inhibitory effect on activated blood coagulation factor X. Table 2 shows compounds having an IC ₅₀ of 15 nM or less. In the table, compound A is N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) described in WO98 / 31661 (EP97722). Ethyl] sulfamoylacetic acid dihydrochloride is shown.

[0542]

Table 2 Example compounds Factor Xa inhibitory activity No. [IC50 (nM)] ──────────── Example 4 10 Example 10 15 Example 12 13 Example 27 7.9 Example 28 6.4 Example 36 13 Example 38 12 Example 42 11 Example 45 7.9 Example 46 11 Example 47 6.1 Example 48 5.8 Example 49 6.8 Example 50 6.3 Example 51 6.9 Example 52 7.8 Example 53 6.8 Example 54 7 Example 56 10 Example 60 14 Example 65 12 Example 66 8.3 Example 67 15 Example 68 15 Example 72 9.8 Example 77 12 Example 78 11 Example 79 15 Example 80 11 Example 83 13 Example 86 15 Example 87 13 Example 89 1 1 化合物 Compound A 130 ──────────────────────

(Test Example 2) Measurement of antitrypsin activity The antitrypsin activity was measured by the method of Taniuchi et al. [Thrombosis and hemostasis, Vol. 79, p. 543 (1)
998) [ Thromb. Haemost. , 79 , 543 (1998)]. 50 with 0.9% sodium chloride
85 μl of mM Tris-HCl buffer (pH 8.4), 5 μl
Chromogenic substrate S-2222 (final concentration 0.4 mM, Daiichi Kagaku) and 5 μl of the test compound were mixed, and 5 μl of bovine
Trypsin (final concentration 0.25μg-protein / ml, Sigma)
The reaction was started by adding. In the control group, distilled water was added to the buffer instead of the test compound. The reaction solution (total volume 0.1 ml) was incubated at room temperature. The absorbance at 405 nm was continuously measured with a 96-well microplate reader (Model 550, Bio-Rad), and the increase in absorbance for 5 minutes was calculated as an indicator of trypsin activity. In order to evaluate the anti-trypsin activity of the test compound, the test compound has 5 trypsin activities.
The concentration (IC ₅₀ value) required to suppress 0% was determined. Table 3 shows the results.

[Table 3] Example compound Antitrypsin activity No. [IC50 (nM)]例 Example 27 540 Example 28 650 Example 42 7300 Example 47 790 Example 48 1200 Example 49 860 Example 50 1200 Example 53 2100 Example 54 2200 Example 60 3100 Example 65 2300 Example 66 5600 Example 72 4400 Example 77 3700 Example 78 5300 Example 87 3500 Example 89 2000 ─

Formulation Example 1 Hard Capsules 50 mg of the compound of Example 27 in powder form, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed and passed through a 60-mesh sieve. This powder is placed in a 250 mg No. 3 gelatin capsule to form a capsule.

(Formulation Example 2) Tablet 50 mg of the powdery compound of Example 27, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate were mixed, and the mixture was tableted with a tableting machine to give 20 tablets.
Take 0 mg tablets. The tablets can be sugar-coated as needed.

(Formulation Example 3) Injection 1.5% by weight of the compound of Example 27 was stirred in 10% by volume of propylene glycol, and then adjusted to a constant volume with water for injection, then sterilized and injected. Agent.

[0547]

The benzamidine derivative of the present invention having the above general formula (1) has an excellent activated blood coagulation factor X inhibitory activity and a low toxicity. , Cerebral infarction, myocardial infarction, or thrombotic diseases such as peripheral circulatory disorders).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/454 A61K 31/454 31/4545 31/4545 31/46 31/46 31/506 31/506 31 / 541 31/541 31/55 31/55 A61P 7/02 A61P 7/02 9/10 9/10 C07D 211/72 C07D 211/72 211/96 211/96 401/04 401/04 413/04 413 / 04 417/04 417/04 471/04 102 471/04 102 471/08 471/08 (72) Inventor Ikuko Shimada 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Fumitoshi Asai 1-58 Hiromachi, Shinagawa-ku, Tokyo F-term within Sankyo Co., Ltd. 4C054 AA02 CC02 CC04 CC08 DD01 EE01 FF25 4C063 AA01 BB02 CC10 CC12 CC29 CC52 CC64 DD04 DD10 EE01 4C065 AA03 AA09 BB04 CC01 DD01 HH01 HH09 JJ03 KK01 LL01 PP03 4C086 AA01 AA02 AA03 BC17 BC21 BC31 BC33 BC42 BC69 BC82 BC88 CB05 CB 15 GA07 GA08 GA09 GA10 GA12 MA01 MA04 NA14 ZA36 ZA54 ZC41

Claims (15)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group having 1 to 6 carbon atoms, R ² represents a hydrogen atom or a halogen atom, and R ³ represents a hydrogen atom, 1 carbon atom. To 6 alkyl groups, hydroxyl-substituted alkyl groups having 1 to 6 carbon atoms, 2 to 7 carbon atoms
Carboxyalkyl group, C3 to C13 alkoxycarbonylalkyl group, C1 to C6 alkylsulfonyl group, C3 to C13 alkoxycarbonylalkylsulfonyl group, C2 to C7 carboxy An alkylsulfonyl group or a carboxyalkylcarbonyl group having 3 to 8 carbon atoms, 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, 6 halogen-substituted alkyl groups, alkoxy groups having 1 to 6 carbon atoms, carboxyl groups, alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl groups, monoalkylcarbamoyl groups having 2 to 7 carbon atoms or 3 carbon atoms to indicate the 13 amino dialkylcarbamoyl group, R ⁶ is a hydrogen atom, 1 to 6 alkyl groups having a carbon number A cyclic alkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic ring, a carboxyalkyl group having 2 to 7 carbon atoms, 3 to 13 alkoxycarbonylalkyl groups, C2 to C7 aliphatic acyl groups, C7 to C11 aromatic acyl groups, carbamoyl groups, C1
To 6 alkylsulfonyl groups, aryl groups having 6 to 10 carbon atoms, heterocycles, formimidoyl groups, 1-iminoalkyl groups having 3 to 7 carbon atoms, N-alkylforms having 2 to 7 carbon atoms Imidoyl group or 7 to 1 carbon atoms
Represents one iminoarylmethyl group, R ⁷ and R ⁸ represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ⁶ and R ⁷ together or R ⁷ R ⁸ together represent an alkylene group having 2 to 5 carbon atoms, and n represents 0, 1 or 2. A pharmacologically acceptable salt thereof and a prodrug thereof. 2. The compound according to claim 1, wherein R ¹ is a hydrogen atom or a hydroxyl group. 3. The compound according to claim 1, wherein R ² is a hydrogen atom. 4. The compound according to claim 1, wherein R ³ is an alkoxycarbonylalkylsulfonyl group having 3 to 13 carbon atoms or a carboxyalkylsulfonyl group having 2 to 7 carbon atoms. 5. The compound according to claim 1, wherein R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group. 6. 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 carbamoyl group. A compound according to claim 1. 7. The compound according to claim 1, wherein 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 carbamoyl group. 8. A compound according to claim 1, wherein 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 a carbon atom having 1 to 6 carbon atoms substituted by a heterocyclic ring. 6
Alkyl groups, aryl groups having 6 to 10 carbon atoms, heterocycles, formimidoyl groups, 1-alkyl groups having 3 to 7 carbon atoms
8. The compound according to claim 1, which is an iminoalkyl group, an iminoarylmethyl group having 7 to 11 carbon atoms, or an N-alkylformimidoyl group having 2 to 7 carbon atoms. 9. 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-pyrrol-2-yl, 2,3,4,5-tetrahydropyridin-6-yl, 4,5-dihydrooxazol-2-yl, 5,6
The dihydro-2H- [1,4] thiazin-3-yl or 4-pyridyl group, formimidoyl group, 1-iminopropyl group, iminophenylmethyl group or N-ethylformimidoyl group. 8. The compound according to any one of items 1 to 7. 10. The compound according to claim 1, wherein R ⁷ and R ⁸ are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. 11. The compound according to claim 1, wherein R ⁶ and R ⁷ together or R ⁷ and R ⁸ together are an alkylene group having 2 to 5 carbon atoms. . 12. The compound according to claim 1, wherein R ⁶ and R ⁷ together or R ⁷ and R ⁸ together are an ethylene or trimethylene group. 13. The compound according to claim 1, wherein n is 1. 14. A compound selected from the following group, a pharmaceutically acceptable salt thereof and a prodrug thereof: N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3 -Chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetate dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N -[3-chloro-4- (1-formimidoylpiperidin-4-yloxy) phenyl] sulfamoylacetate dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl]- N- [3-chloro-4- [1- (1-iminopropyl) piperidin-4-yloxy] phenyl]
Ethyl sulfamoyl acetate dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydro-3H-pyrrol-2-yl) piperidine-4
-Yloxy] phenyl] sulfamoylethyl acetate
Dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetate dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetate dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl]- N- [3-chloro-4- (1-isopropylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-Chloro-4- [1- (4-pyridyl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl]- N- [3-chloro-4- (1-cyclopentylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinopheni )-2-(E) - propenyl]-N-[3- chloro-4- (indolizine -
7-yloxy) phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (1-formimidoylpiperidine- 4-yloxy) phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (1-iminopropyl) ) Piperidin-4-yloxy] phenyl]
Sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- [1- (4,5-
Dihydro-3H-pyrrol-2-yl) piperidine-4
-Yloxy] phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] -3-methylphenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [ 4- [1- (4,5-dihydro-3)
H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (1 -Methylpiperidine-4-
Yloxy) -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5- Dihydro-3
H-pyrrol-2-yl) piperidin-4-yloxy] -3-trifluoromethylphenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N -[3-carbamoyl-4- [1-
(4,5-dihydro-3H-pyrrol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl]- N- [3-chloro-4- [1- (4,5-
Dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride, N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- [1- (4,5-dihydrooxazol-2-yl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride and N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [ 3-Chloro-4- [1- (N-ethylformimidoyl) piperidin-4-yloxy] phenyl] sulfamoylacetic acid dihydrochloride. 15. A medicament comprising the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt thereof, or a prodrug thereof.