JPWO2000068203A1 - Cyclic compounds and their uses - Google Patents

Abstract

(57) [Abstract] A compound of formula (I) having preventive and therapeutic effects against HIV infection. [In the formula, R ¹ represents an optionally substituted 5- or 6-membered ring group, X ¹ represents a bond or the like, and W represents a group represented by the formula: (wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring; _E1 and _E4 each represent an optionally substituted carbon atom or the like; _E2 and _E3 each represent an oxygen atom or the like; a and b each represent a single bond or a double bond); ^X2 represents a divalent group or the like constituting a linear moiety; ^Z1 represents a divalent cyclic group or the like; ^Z2 represents a bond or the like; and ^R2 represents an optionally substituted amino group or the like], or a salt thereof.

Description

Description: TECHNICAL FIELD The present invention relates to novel cyclic compounds having CCR antagonistic activity, particularly CCR5 antagonistic activity, and uses thereof.

BACKGROUND ART In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome), and they are effective against two Hs that have been used conventionally.
Although the treatment of AIDS has made great progress by combining it with IV reverse transcriptase inhibitors, it is still not sufficient to eradicate AIDS, and there is a need for the development of new anti-AIDS drugs based on a different mechanism of action.

CD4 has long been known as the receptor through which HIV invades target cells. Recently, CCR5 has been identified as the second receptor for macrophage-targeting HIV, and CXCR4 as the second receptor for T-cell targeting HIV.
Transmembrane and G protein-coupled chemokine receptors have been found, and these chemokine receptors are thought to play an essential role in the establishment and propagation of HIV infection. In fact, it has been reported that humans who showed resistance to HIV infection despite repeated exposure had a homozygous deletion mutation in the CCR5 gene. Therefore, CCR5 antagonists are expected to become new anti-HIV drugs, and examples of the synthesis of novel anilide derivatives with CCR5 antagonistic activity have been reported in PCT/JP98/05708 (WO99/32100) and Japanese Patent Application No. 2008-2009.
4388 (WO00/10965), patent application No. 10-363404 (PCT/JP
However, to date, there have been no reports of CCR5 antagonists being commercialized as therapeutic agents for AIDS.

DISCLOSURE OF THE INVENTION The present invention is based on CCR antagonism, particularly CCR5 antagonism, and is directed to the treatment of HIV infection,
In particular, the present invention provides novel bicyclic compounds that are useful as prophylactic and therapeutic agents for AIDS.

As a result of extensive investigations into compounds having CCR5 antagonistic activity, the present inventors have found that a compound represented by the following formula (I) or a salt thereof (hereinafter, sometimes referred to as compound (I)) has clinically desirable pharmaceutical effects such as CCR antagonistic activity, particularly excellent CCR5 antagonistic activity, and have completed the present invention based on this finding.

That is, the present invention provides: (1) Formula (I) [In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is represented by the formula wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
an optionally substituted hydroxyl group or an optionally substituted amino group (preferably
is an optionally substituted hydrocarbon group or an optionally substituted amino group;
More preferably, R represents an optionally substituted hydrocarbon group,⁵' and R⁶
' may be bonded to each other to form a cyclic group together with the adjacent phosphorus atom)
(5) an optionally substituted amidino group or (6) a substituted
a compound represented by the formula R¹−X¹-W-X
²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear portion.
When R represents a group represented by²is an optionally substituted amidino group or
represents an optionally substituted guanidino group;¹−X¹-W-X²-Z¹-Z
²- The group represented by the formula(In the formula, R¹and X¹has the same meaning as defined above, and ring A" is optionally substituted.
represents a benzene ring, and Q¹represents a divalent group in which ring B″ forms a 5- to 7-membered ring, and Q²
is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group
represents a ring group, and Q³represents a bond or a divalent group, R
²is an expression (In the formula, R⁵'' and R⁶'' represents an optionally substituted hydroxyl group.
, R⁵'' and R⁶'' are bonded to each other and form a cyclic group with the adjacent phosphorus atoms.
(3) R does not represent a group represented by the formula (1) or a salt thereof; (2) A prodrug of the compound described in (1) or a salt thereof; (3) R¹benzene, furan, thiophene, and bis(phenyl)-
Lysine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine
one hydrogen atom from morpholine, thiomorpholine or tetrahydropyran
The compound according to (1), wherein R is a group formed by removing¹is an optionally substituted phenyl; (5) The compound according to (1) above, wherein X¹is a bond, -(CH₂)_a'- [a' represents an integer of 1 to 4], - (
CH₂)_b'−X³- [b' represents an integer of 0 to 3, and X³may be substituted
imino group, carbonyl group, oxygen atom or optionally oxidized sulfur atom.
-CH=CH-, -C≡C-, -CO-NH- or -SO₂-NH-
The compound according to (1) above; (6) X¹The compound according to (1) above, wherein X is a bond; (7) X¹- (CH₂)_b'−X³- [b' represents an integer of 0 to 3, and X³Ha
an optionally substituted imino group, a carbonyl group, an oxygen atom or an optionally oxidized
(8) The compound according to (1), wherein ring A is an optionally substituted furan, thiophene, pyrrole, or pyrrole;
The compound according to (1) above, wherein the ring A is lysine, pyran, or benzene; (9) The compound according to (1) above, wherein ring A is optionally substituted benzene; (10) The compound according to (1) above, wherein ring B is of the formula [In the formula, E₃is an optionally substituted carbon atom or an optionally substituted nitrogen atom
indicates an atom, E₄represents an optionally substituted carbon atom or nitrogen atom, and b represents an optionally substituted carbon atom or nitrogen atom;
represents a single bond or a double bond, and Y represents -Y'-(CH₂) m'-(Y'
is -S(O)_m-(m is an integer of 0 to 2), -O-, -NH- or -CH
₂-, and m' represents an integer of 0 to 2), -CH=, -CH=CH-, or -
N=CH—], and may have a substituent at any substitutable position.
The compound according to (1), wherein Y is a 5- to 7-membered ring; (11) Y is -Y'-(CH₂)₂-[Y' is -S(O)_m- (m is an integer between 0 and 2
indicates the number), —O—, —NH—, or —CH₂- represents].
The compound described above; (12) E₃represents an optionally substituted carbon atom, E₄Even if it is replaced
The compound according to (1) above, wherein X represents a carbon atom and b represents a double bond; (13) X²- (CH₂)_a'-[a' represents an integer of 1 to 4], -(CH₂
)_b'−X³- [b' represents an integer of 0 to 3, and X³is an optionally substituted imine
a hydroxyl group, a carbonyl group, an oxygen atom, or an optionally oxidized sulfur atom],
—CH═CH—, —C≡C—, —CO—NH—, or —SO₂Before it was —NH—
The compound described in (1); (14) X²The compound according to (1) above, wherein Z is —CO—NH—; (15) Z¹(1) a bond or (2) an optionally substituted benzene
furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidone
azine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydrofuran
(1) A divalent cyclic group formed by removing two hydrogen atoms from cyclohexylpyran.
The compound described above; (16) Z¹(1) a bond or (2) an optionally substituted benzene
Divalent aryl formed by removing two hydrogen atoms from benzene, cyclohexane, or piperidine
The compound according to (1) above, wherein Z is a cyclic group; (17) Z¹The compound according to the above (1), wherein
; (18) Z²is a bond or an optionally substituted C_1-3Before it was an alkylene
The compound described in (1); (19) Z²is -Z'-(CH₂)n-[Z' is -CH(OH)-, -C(O)
—or —CH₂-, and n represents an integer of 0 to 2],
A divalent group optionally having a substituent on any methylene group, as described in (1) above.
compound; (20) Z²The compound according to (1) above, wherein Z is a bond or methylene; (21) Z¹is a 6-membered divalent cyclic group, and Z²The substitution position of²It is the para-rank
The compound according to (1) above, wherein (22) R²(1) may be substituted, and the nitrogen atom may be quaternary ammonium or
(2) an amino group which may be substituted or oxidized,
It may contain a sulfur atom or an oxygen atom as a constituent atom, and the nitrogen atom may be a quaternary alkyl group.
(3) a nitrogen-containing heterocyclic group which may be ammoniumated or oxidized;
(3) an optionally substituted amidino group or (4) an optionally substituted guanidino group.
The compound according to (1) above; (23) R²is an optionally substituted amino group; (24) The compound according to (1),²is an optionally substituted amidino group or an optionally substituted group
The compound according to (1) above, wherein the compound is an anidino group; (25) N-[4-[N-methyl-N-(tetrahydropyran-4-yl)amino]
[2-(4-propoxyphenyl)ethoxy]-1
, 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide
, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl
-7-[(3-propoxybenzyl)oxy]-1,1-dioxa
so-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-
[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
]-7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl
-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(
4-propoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-
1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(thiepine)
4-( ...
(oxyethoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1
-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydrobenzophenone]
[3-(4-hydroxybenzoyl)aminomethyl]phenyl]-7-[( ...
(phenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-phenyl
(26) A prodrug of the compound described in (25) or a salt thereof; (27) A pharmaceutical composition containing the compound described in (1) or a salt thereof; (28) A compound of the formula [In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is a group represented by the formulawherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
, an optionally substituted hydroxyl group or an optionally substituted amino group, R
⁵' and R⁶' are bonded to each other to form a cyclic group with the adjacent phosphorus atom.
(5) an optionally substituted amidino group, or (6)
a compound represented by the formula R¹
−X¹-W-X²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear chain portion.
When R represents a group represented by²is an optionally substituted amidino group or
a CCR antagonist (representing an optionally substituted guanidino group) or a salt thereof
(29) The composition according to (28) above, which is a preventive or therapeutic agent for HIV infection; (30) The composition according to (28) above, which is a preventive or therapeutic agent for AIDS; (31) The composition according to (28) above, which is an agent for suppressing the progression of AIDS; (32) The composition according to (28) above, which is further combined with a protease inhibitor and/or a reverse transcriptase inhibitor;
(33) The composition according to (29) above, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, or lamivudine.
baclovir, stavudine, nevirapine, delavirdine, efavirenz, or abacavir
(34) The composition according to (32), wherein the protease inhibitor is saquinavir, ritonavir, indinavir, or amphibian.
The composition according to (32), which is lenavir or nelfinavir; (35) Formula [In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is a group represented by the formulawherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
, an optionally substituted hydroxyl group or an optionally substituted amino group, R
⁵' and R⁶' are bonded to each other to form a cyclic group with the adjacent phosphorus atom.
(5) an optionally substituted amidino group, or (6)
a compound represented by the formula R¹
−X¹-W-X²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear portion.
When R represents a group represented by²is an optionally substituted amidino group or
or a salt thereof with a protease inhibitor or
and/or in combination with a reverse transcriptase inhibitor for the prevention and treatment of HIV infection;
(36) An effective amount of the compound according to (28) or a salt thereof is administered to a mammal.
A method for antagonizing CCR in a mammal (preferably CCR5 antagonism),
(37) Preparation of a pharmaceutical for CCR antagonism (preferably CCR5 antagonism)
Use of the compound or salt thereof according to (28); etc.

In the above formula (I), the "optionally substituted 5- to 6-membered ring group" represented by R ¹ is
Examples of the "5- to 6-membered ring" include 6-membered aromatic hydrocarbons such as benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene,
5- to 6-membered aliphatic hydrocarbons such as cyclohexanediene; 5- to 6-membered aromatic heterocycles containing 1 to 4 heteroatoms of 1 or 2 kinds selected from nitrogen atoms, sulfur atoms, and oxygen atoms, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazole; tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, and thiazin Examples include groups formed by removing one hydrogen atom from a 5- or 6-membered non-aromatic heterocycle containing 1 to 4 heteroatoms of 1 or 2 kinds selected from a nitrogen atom, a sulfur atom, and an oxygen atom, such as diazine, morpholine, thiomorpholine, pyran, tetrahydropyran, and tetrahydrothiopyran. Among these, preferred examples of the "5- or 6-membered ring" include benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and tetrahydropyran (preferably a 6-membered ring), with benzene being particularly preferred.

Examples of the "substituent" that the "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring group" represented by R ¹ may include a halogen atom, nitro, cyano,
Examples of the group that can be used include an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl, an optionally esterified carboxyl group, and an optionally substituted aromatic group.

Examples of the halogen as a substituent for R ¹ include fluorine, chlorine, bromine, and iodine, with fluorine and chlorine being particularly preferred.

The alkyl in the optionally substituted alkyl as a substituent of R ¹ is a straight-chain or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl,
Examples of the alkyl group include C _1-10 alkyl, preferably lower (C _1-6 ) alkyl, such as propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl.
Halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group,
an optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.);
an optionally substituted amino group (e.g., amino, mono-C _1-4 alkylamino,
diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine,
5- or 6-membered cyclic amino groups such as morpholine, thiomorpholine, pyrrole, and imidazole), optionally esterified or amidated carboxyl groups (e.g.,
carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

R¹The cycloalkyl in the optionally substituted cycloalkyl
Examples of alkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
C such as cyclohexyl and cycloheptyl_3-7Cycloalkyl, etc.
The substituents in the optionally substituted cycloalkyl include halogen (
e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, substituted
Optional thiol group (e.g., thiol, C_1-4alkylthio, etc.), substituted
an optionally substituted amino group (e.g., amino, mono C_1-4Alkylamino, DiC_1-4
Alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine
5-6 membered cyclic amino such as thiomorpholine, pyrrole, imidazole, etc.)
, a carboxyl group which may be esterified or amidated (e.g., carboxy
Lu, C_1-4Alkoxycarbonyl, carbamoyl, mono C_1-4Alkylcal
Bamoil, J.C._1-4alkylcarbamoyl, etc.), which may be halogenated
I C_1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, tri
fluoromethoxy, trifluoroethoxy, etc.), optionally halogenated
C_1-4Alkoxy-C_1-4Alkoxy (e.g., methoxymethoxy, methoxyethoxy)
Trifluoroethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxy
oxyethoxy, etc.), formyl, C_2-4Alkanoyl (e.g., acetyl, propyl)
Onil, etc.), C_1-4Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl)
The number of the substituents is preferably 1 to 3.

The substituents in the optionally substituted hydroxyl group as the substituent of R ¹ include:
(1) optionally substituted alkyl (for example, C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C _1-6 ) alkyl); (2) optionally substituted and optionally heteroatom _- containing cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
C _3-7 cycloalkyl such as cycloheptyl; tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
(3) optionally substituted alkenyl (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower ( _C2-6 ) alkenyl, etc.); (4) optionally substituted cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) optionally substituted aralkyl (for example, phenyl- _C1-4 alkyl (e.g., benzyl, phenethyl, etc.)); (6) formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (e.g., methanesulfonyl, ethanesulfonyl, etc.)); (7) optionally substituted aryl (for example, phenyl, naphthyl, etc.), and the like. Examples of the substituents that the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl, and (7) optionally substituted aryl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.).
, nitro, cyano, hydroxyl group, optionally substituted thiol group (e.g., thiol,
C _1-4 alkylthio, etc.), optionally substituted amino groups (e.g., amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), optionally esterified or amidated carboxyl groups (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.; preferably optionally halogenated C _1-4 alkoxy), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), optionally substituted 5- or 6-membered aromatic heterocycles (e.g., furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,
5- or 6-membered aromatic heterocycles containing 1 to 4 heteroatoms of 1 or 2 kinds selected from nitrogen atom, sulfur atom and oxygen atom, such as pyridazine and triazole; examples of the substituents that the heterocycles may have include halogens (e.g., fluorine, chlorine, bromine,
iodine, etc.), nitro, cyano, hydroxyl group, thiol group, amino group, carboxyl group, optionally halogenated C _1-4 alkyl (e.g., trifluoromethyl,
methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, _C2-4 alkanoyl (e.g., acetyl, propionyl, etc.), _C1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.
The number of the substituents is preferably 1 to 3.

R¹As a substituent in an optionally substituted thiol group
is the above-mentioned "R¹Substitution in optionally substituted hydroxyl group as a substituent of
Examples of the "alkyl group" include those similar to the "alkyl group" and "alkyl group," among which: (1) optionally substituted alkyl (e.g., methyl, ethyl, propyl, propyl, propyl group)
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl
yl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,
C such as Sil_1-10Alkyl, preferably lower (C_1-6) alkyl
(2) optionally substituted cycloalkyl (e.g., cyclopropyl, cyclopropyl)
C such as butyl, cyclopentyl, cyclohexyl, and cycloheptyl_3-7Shik
(3) optionally substituted aralkyl (e.g., phenyl-C_1-4Alkyl
(4) aryl groups which may be substituted (e.g., phenyl, naphthyl, etc.);
(1) optionally substituted alkyl, (2) optionally substituted silyl, etc. are preferred,
(3) optionally substituted aralkyl, and (4) substituted
The substituents that the optionally substituted aryl may have include halogen (e.g., fluorine).
chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted
a small thiol group (e.g., thiol, C_1-4alkylthio, etc.), even if substituted
Good amino group (e.g., amino, mono C_1-4Alkylamino, DiC_1-4Alkyl
Amino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomo
5-6 membered cyclic amino such as pyrrole, imidazole, etc.), ester
a carboxyl group (e.g., carboxyl, C_1
−4Alkoxycarbonyl, carbamoyl, mono C_1-4Alkylcarbamoyl
, JiC_1-4alkylcarbamoyl, etc.), optionally halogenated C_1-
4Alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoro
methoxy, trifluoroethoxy, etc.), optionally halogenated C_1-4
Alkoxy-C_1-4Alkoxy (e.g., methoxymethoxy, methoxyethoxy,
Ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy
oxy, etc.), formyl, C_2-4Alkanoyl (e.g., acetyl, propionyl, etc.)
etc.), C_1-4Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl)
The number of the substituents is preferably 1 to 3.

R¹The substituent of the optionally substituted amino group as the substituent of the above is
"R"¹The same applies to "substituents in optionally substituted hydroxyl groups as substituents of the
and amino groups which may have one or two such substituents.
(1) Optionally substituted alkyl (e.g., methyl, ethyl, propyl, propyl)
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl
yl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,
C such as Sil_1-10Alkyl, preferably lower (C_1-6) alkyl
(2) optionally substituted cycloalkyl (e.g., cyclopropyl, cyclopropyl)
C such as butyl, cyclopentyl, cyclohexyl, and cycloheptyl_3-7Shik
(3) optionally substituted alkenyl (e.g., allyl, chloroalkyl, etc.);
alkenyl having 2 to 10 carbon atoms, such as 2-pentenyl, 2-pentenyl, and 3-hexenyl;
Or lower grade (C_2-6(4) optionally substituted cycloalkenyl (e.g., 2-cyclopentenyl, etc.);
, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenyl
(5) formyl or optionally substituted acyl (e.g., cycloalkenyl having 2 to 4 carbon atoms, such as methyl);
Alkyl (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), carbon
alkylsulfonyl having 1 to 4 prime atoms (e.g., methanesulfonyl, ethanesulfonyl, etc.)
(6) Optionally substituted aryl (e.g., phenyl, naphthyl, etc.)
(1) optionally substituted alkyl, (2) optionally substituted alkyl, etc. are preferred,
(3) optionally substituted alkenyl; (4) substituted
(5) optionally substituted acyl, and (6)
The substituents that the optionally substituted aryl may have include halogen (
e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, substituted
Optional thiol group (e.g., thiol, C_1-4alkylthio, etc.), substituted
an optionally substituted amino group (e.g., amino, mono C_1-4Alkylamino, DiC_1-4
Alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine
5-6 membered cyclic amino such as thiomorpholine, pyrrole, imidazole, etc.)
, a carboxyl group which may be esterified or amidated (e.g., carboxy
Lu, C_1-4Alkoxycarbonyl, carbamoyl, mono C_1-4Alkylcal
Bamoil, J.C._1-4alkylcarbamoyl, etc.), which may be halogenated
I C_1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, tri
fluoromethoxy, trifluoroethoxy, etc.), optionally halogenated
C_1-4Alkoxy-C_1-4Alkoxy (e.g., methoxymethoxy, methoxyethoxy)
Trifluoroethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxy
oxyethoxy, etc.), formyl, C_2-4Alkanoyl (e.g., acetyl, propyl)
Onil, etc.), C_1-4Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl)
The number of the substituents is preferably 1 to 3.

In addition, the optionally substituted amino group as a substituent of ^R1 may have substituents bonded to each other to form a cyclic amino group (for example, a cyclic amino group formed by removing one hydrogen atom from a nitrogen atom constituting a 5- or 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, or imidazole and having a bond on the nitrogen atom).
The substituent may be halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (e.g., amino, mono-C 1-4 alkylamino, di-C _1-4 alkylamino, 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), optionally esterified or amidated carboxyl group (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di _- C 1-4 alkylamino,
_1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.),
C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.)
The number of the substituents is preferably 1 to 3.

The optionally substituted acyl as the substituent of ^R1 includes: (1) hydrogen, (2) optionally substituted alkyl (for example, C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, _octyl , nonyl, decyl, etc., preferably lower ( _C1-6 ) alkyl, etc.); (3) optionally substituted cycloalkyl (for example, _C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) optionally substituted alkenyl (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower ( _C2-6 ) alkenyl, etc.); (5) optionally substituted cycloalkenyl (e.g., cycloalkenyl having 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl); (6) optionally substituted 5- to 6-membered monocyclic aromatic groups (e.g., phenyl, pyridyl, etc.) bonded to a carbonyl group or a sulfonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl , nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.), and examples of the substituents that the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5- to 6-membered monocyclic aromatic group may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (e.g.,
thiol, C _1-4 alkylthio, etc.), optionally substituted amino groups (e.g.,
amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-
4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, _C2-4 alkanoyl (e.g., acetyl, propionyl, etc.), _C1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

The optionally esterified carboxyl group as the substituent of ^R1 includes: (1) hydrogen, (2) optionally substituted alkyl (for example, C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, _octyl , nonyl, decyl, etc., preferably lower ( _C1-6 ) alkyl, etc.); (3) optionally substituted cycloalkyl (for example, _C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) optionally substituted alkenyl (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower ( _C2-6 ) alkenyl, etc.); (5) optionally substituted cycloalkenyl (e.g., cycloalkenyl having 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl); (6) optionally substituted aryl (e.g., phenyl, naphthyl, etc.) bonded to a carbonyloxy group, preferably carboxyl, lower (C _1-
6 ) alkoxycarbonyl, aryloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), and the like, including the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6)
Examples of the substituents that the optionally substituted aryl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C _1-4 alkylamino, di-C _1-
5- or 6-membered cyclic amino such as ₄ alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), optionally esterified or amidated carboxyl groups (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like, and the number of substituents is preferably 1 to 3.

R¹As an aromatic group in an optionally substituted aromatic group as a substituent of
is phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl
thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl
5- or 6-membered alkyl groups such as aryl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, etc.
Homo- or heterocyclic aromatic groups, benzofuran, indole, benzothiophene,
benzoxazole, benzthiazole, indazole, benzimidazole,
Quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, etc.
The substituents of these aromatic groups include:
, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group
, optionally substituted thiol groups (e.g., thiol, C_1-4Alkylthio etc.
), an optionally substituted amino group (e.g., amino, mono C_1-4Alkylamino
, JiC_1-4Alkylamino, tetrahydropyrrole, piperazine, piperidine
5- to 6-membered cyclic alkyl groups such as morpholine, thiomorpholine, pyrrole, and imidazole
amino, etc.), carboxyl groups which may be esterified or amidated (e.g.
, carboxyl, C_1-4Alkoxycarbonyl, carbamoyl, mono C_1-4
Alkylcarbamoyl, diC_1-4alkylcarbamoyl, etc.), halogenated
C that may be_1-4Alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.)
etc.), optionally halogenated C_1-4Alkoxy (e.g., methoxy, ethoxy)
silyl, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.
), formyl, C_2-4Alkanoyl (e.g., acetyl, propionyl, etc.), C
_1-4Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.)
The number of the substituents is preferably 1 to 3.

This R¹The substituents may be 1 to 4 (preferably 1 to 2) identical or different.
The substituent may be at any position on the ring.¹"Replaced"
When the "5- to 6-membered ring" of the "5- to 6-membered ring which may have one or more substituents,
Among these, two substituents may be bonded to each other to form, for example, a lower (C_1-6) Alki
ethylene (e.g., trimethylene, tetramethylene, etc.), lower (C_1-6) alkylene
Oxy (e.g., —CH₂—O—CH₂—, —O—CH₂-CH₂—, —O—CH₂
-CH₂-CH₂—, —O—CH₂-CH₂-CH₂-CH₂-, -O-C(C
H₃) (CH₃)-CH₂-CH₂- etc.), low grade (C_1-6) Alkylenchio
(e.g., -CH₂-S-CH₂-, -S-CH₂-CH₂-, -S-CH₂-CH
₂-CH₂-, -S-CH₂-CH₂-CH₂-CH₂-, -S-C(CH₃)
(CH₃)-CH₂-CH₂- etc.), low grade (C_1-6) alkylenedioxy (
For example, —O—CH₂—O—, —O—CH₂-CH₂—O—, —O—CH₂-CH₂
-CH₂-O-, etc.), lower (C_1-6) alkylenedithio (e.g., —S—CH₂
—S—, —S—CH₂-CH₂—S—, —S—CH₂-CH₂-CH₂-S-
etc.), oxy lower (C_1-6) alkyleneamino (e.g., —O—CH₂—NH—,
—O—CH₂-CH₂-NH-, etc.), oxy lower (C_1-6) Alkylenchio
(e.g., —O—CH₂—S—, —O—CH₂-CH₂-S-, etc.), lower (C_1-
6) alkyleneamino (e.g., —NH—CH₂-CH₂-, -NH-CH₂-CH
₂-CH₂- etc.), low grade (C_1-6) alkylenediamino (e.g., —NH—CH
₂-NH-, -NH-CH₂-CH₂-NH- etc.), low-level cheer (C_1-6)a
alkyleneamino (e.g., —S—CH₂-NH-, -S-CH₂-CH₂-NH-na
etc.), low grade (C_2-6) alkenylene (e.g., —CH₂-CH=CH-, -CH₂
-CH₂-CH=CH-, -CH₂—CH═CH—CH₂- etc.), low grade (C_4
−6) alkadienylene (e.g., —CH═CH—CH═CH—, etc.)
It may be possible.

Furthermore, the divalent group formed by bonding two of the substituents of ^R1 together may have 1 to 3 substituents (such as ^a halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized, or may form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl, a carboxyl group which may be esterified or amidated, or an optionally substituted aromatic group) similar to the "substituents" that the "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring" represented by R1 may have.

The "substituents" that the "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring group" represented by R ¹ may have include, in particular, halogenated or lower (C _1-
4 ) optionally alkoxylated lower (C _1-4 ) alkyl (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), optionally halogenated or lower (C _1-4 ) alkoxylated lower (C _1-4 ) alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), halogen (e.g., fluorine, chlorine, etc.), nitro, cyano, 1 to 2 lower (
and amino optionally substituted by lower (C _1-4 ) alkyl, formyl, or lower (C _2-4 ) alkanoyl (e.g., amino, methylamino, dimethylamino, formylamino, acetylamino, etc.), 5- to 6-membered cyclic amino groups (e.g., 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.).

Examples of the "divalent group having 1 to 4 atoms constituting the linear moiety" represented by ^X1 and ^X2 include -( _CH2 ) _a'- (a' represents an integer of 1 to 4 (preferably an integer of 1 to 2)), -( _CH2 ) _b' - ^X3- (b' represents an integer of 0 to 3 (preferably an integer of 0 to 1) and ^X3 represents an optionally substituted imino group (
For example, an imino group optionally substituted with lower (C _1-6 ) lower alkyl, lower (C _3-7 ) cycloalkyl, formyl, lower (C _2-7 ) lower alkanoyl, lower (C _1-6 ) lower alkoxy-carbonyl, etc.), a carbonyl group, an oxygen atom or an optionally oxidized sulfur atom (e.g., —S(O) _m — (m is an integer of 0 to 2), etc.)], —CH═CH—, —C≡C—, —CO—NH—, —S
O ₂ —NH—, etc. These groups may be bonded to W via either the left or right bond, but in the case of ^X1 , they are preferably bonded to W via the right bond, and in the case of ^X2 , they are preferably bonded to W via the left bond.

X ¹ is preferably a bond, —(CH ₂ ) _b′ —O— (b′ is an integer of 0, 1 or 2 (preferably an integer of 0 to 1)), —C≡C—, or the like, and more preferably a bond.

^X2 includes -( _CH2 ) _a'- (where a' represents an integer of 1 or 2), -(CH
₂ ) _b' - ^X3- [b' represents an integer of 0 to 1, and ^X3 represents an optionally substituted imino group, a carbonyl group, an oxygen atom, or an optionally oxidized sulfur atom]
, —CH═CH—, —CO—NH—, —SO ₂ —NH—, etc. are preferred, and —CO
More preferred is —NH—.

In the above formula (I), the formula represented by W wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
_E1 and _E4 each represent an optionally substituted carbon atom or an optionally substituted nitrogen atom, and _E2 and _E3 each represent an optionally substituted carbon atom, an optionally substituted nitrogen atom, an optionally oxidized sulfur atom (e.g., -S(
O) _m - (m is an integer of 0 to 2) or an oxygen atom, and a and b
Each of the groups represents a single bond or a double bond, and the divalent groups represented by the following formulas are ⁽ wherein each symbol is as defined above ⁾

In the above formula (I), the "5- to 7-membered ring" represented by A is
Examples of the "7-membered ring" include 5-7 rings such as _C5-7 cycloalkanes (e.g., cyclopentane, cyclohexane, cycloheptane, etc.), _C5-7 cycloalkenes (e.g., 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cyclohexene, 3-cyclohexene, etc.), and _C5-6 cycloalkadiene (e.g., 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, etc.).
6-membered aromatic hydrocarbons such as benzene; 5- to 7-membered aromatic heterocycles containing at least one (preferably 1 to 4, more preferably 1 or 2) heteroatom(s) of 1 to 3 kinds (preferably 1 or 2 kinds) selected from oxygen atom, sulfur atom, nitrogen atom, etc.; saturated or unsaturated non-aromatic heterocycles (aliphatic heterocycles); and the like.

Here, the term "aromatic heterocycle" refers to a 5- or 6-membered aromatic monocyclic heterocycle (e.g., furan, thiophene, pyrrole, oxazole, isoxazole, thiazole,
isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1
, 2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), and examples of the "non-aromatic heterocycle" include pyrrolidine, tetrahydrofuran,
Examples thereof include 5- to 7-membered (preferably 5- to 6-membered) saturated or unsaturated non-aromatic heterocycles (aliphatic heterocycles) such as thiolane, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, pyran, oxepin, thiepine, and azepine, and also 5- to 6-membered non-aromatic heterocycles in which some or all of the double bonds of the above-mentioned aromatic monocyclic heterocycles are saturated.

The "5- to 7-membered ring" of the "optionally substituted 5- to 7-membered ring" represented by A is preferably a 5- to 6-membered aromatic ring, more preferably benzene, furan, thiophene, pyrrole, pyridine (preferably a 6-membered ring), etc., and particularly preferably benzene.

The "substituent" that the "5- to 7-membered ring" of the "optionally substituted 5- to 7-membered ring" represented by A may have is, for example, the "optionally substituted 5- to 6-membered ring" represented by R ¹ .
Examples of the substituents for A include those similar to those that the "5- or 6-membered ring" in the " _5- or 6-membered ring group" may have. The substituents for A may be the same or different, and may be 1 to 4 (preferably 1 to 2) at any position on the ring. The substituents may be at any position available for substitution, whether at the positions indicated by E1 and _E2 or other positions.

In the above formula (I), the "5- to 7-membered ring" represented by B is
As the "7-membered ring", for example, and the like, which may have a substituent at any substitutable position, and the like.

In the above formula, the divalent group represented by Y is a 5- to 7-membered ring in which ring B is optionally substituted.
represents a divalent group that forms, for example, (1)-(CH₂)_a1—O—(CH₂)_a2- (a1 and a2 are the same or
a1 and a2 are different and represent 0, 1, or 2, provided that the sum of a1 and a2 is 2 or less.
, -O-(CH=CH)-, -(CH=CH)-O-, (2)-(CH₂)_b1-S(O)_m−(CH₂)_b2- (m is an integer from 0 to 2)
b1 and b2 may be the same or different and represent 0, 1 or 2.
and b2 is 2 or less), -S(O)_m-(CH=CH)-, -(C
H=CH)-S(O)_m-, (3)-(CH₂)_d1-(d1 represents 1, 2 or 3), -CH₂−(CH
=CH)-, -(CH=CH)-CH₂-, -CH=CH-, -CH=, (4)-(CH₂)_e1—NH—(CH₂)_e2- (e1 and e2 are the same or
are different and represent 0, 1 or 2, provided that the sum of e1 and e2 is 2 or less.
), -NH-(CH=CH)-, -(CH=CH)-NH-, -(CH₂)_e6
-(N=CH)-(CH₂)_e7-, -(CH₂)_e7-(CH=N)-(CH
₂)_e6- (either e6 or e7 represents 0, and the other represents 0 or 1)
, −(CH₂)_e8-(N=N)-(CH₂)_e9- (e8 and e9 are both
One of them indicates 0, and the other indicates 0 or 1).
For example, -O-, -O-CH₂—, —O—CH₂-CH₂-, -O-CH=CH-,
-S(O)_m- (m represents an integer of 0 to 2), -S(O)_m-CH₂−(m is 0
-S(O)_m-CH₂-CH₂- (m represents an integer from 0 to 2)
-S(O)_m-CH=CH- (m is an integer of 0 to 2), -CH₂−,
−(CH₂)₂-, -(CH₂)₃-, -CH=, -CH=CH-, -CH=C
H-CH₂-, -CH₂-CH=CH-, -NH-, -N=CH-, -CH=N
-, -N=N- (each of which indicates a bond originating from ring A), and other divalent groups are exemplified.
It can be obtained.

The divalent group may have a substituent, and examples of the substituent include the same as the "substituents" that the "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring group" represented by ^R1 may have, and oxo, etc., and among these, lower ( _C1-3 ) alkyl (e.g., methyl, ethyl, propyl, etc.), phenyl, oxo, hydroxyl group, etc. are preferred. Furthermore, the divalent group may be -O-C(O)-
(indicating a bond originating from ring A). Such a divalent group may have 1 to 4 (preferably 1 to 2) identical or different substituents. The substitution position may be any position as long as it is possible to bond to the divalent group.

The divalent group represented by Y is -Y'-(CH ₂ )m'-, starting from ring A.
(Y' represents -S(O) _m- (m represents an integer of 0 to 2), -O-, -NH- or _-CH2- , and m' represents an integer of 0 to 2), -CH=, -CH=CH-,
-N=CH-, -(CH ₂ ) m '-Y'- (Y' is -S(O) _m - (m is 0 to 2)
represents an integer of 0 to 2), -O-, -NH- or -CH ₂ -, and m' represents an integer of 0 to 2), and -CH=N- are preferred.
'-( _CH2 )m'- (Y' is -S(O) _m- (m is an integer of 0 to 2)), -
represents —O—, —NH—, or —CH ₂ —, and m′ represents an integer of 0 to 2), —CH
Groups such as -, -CH=CH-, and -N=CH- are preferred, and groups such as -Y'-( _CH2 ) _2- (Y' is -S(O) _m- (m is an integer of 0 to 2), -O-, -NH-, or _-CH2- ) (ring B is a 7-membered ring) are particularly preferred, starting from ring A.

The "substituent" that the "5- to 7-membered ring" of the "optionally substituted 5- to 7-membered ring" represented by B may have is, for example, the "optionally substituted 5- to 6-membered ring" represented by R ¹ .
The substituents of B may be 1 to 4 (preferably 1 to 4) or oxo.
The substituents may be the same or different and may be substituted at any position on the ring, but the _E3 position is preferably unsubstituted.

In the above formula (I), _E3 and _E4 each represent an optionally substituted carbon atom (
Preferably, b is an unsubstituted carbon atom), and compounds in which b is a double bond are preferred.

In the above formula (I), examples of the "divalent cyclic group" represented by ^Z1 include groups formed by removing two hydrogen atoms from ^the same "5- to 6-membered ring" as the "optionally substituted 5- to 6-membered ring group" represented by R1, and among these, divalent cyclic groups formed by removing two hydrogen atoms from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, etc. are preferred, and divalent cyclic groups formed by removing two hydrogen atoms from benzene, cyclohexane, or piperidine (preferably benzene) are particularly preferred.

The "divalent cyclic group" represented by ^Z1 may have the same "substituent" as the "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered cyclic group" represented by ^R1 , but preferably has no substituents other than ^X2 and ^Z2 . When ^Z1 is a 6-membered divalent cyclic group (preferably phenylene),
The substitution position of ^Z2 is preferably the para position of ^X2 .

In the above formula (I), the "divalent group having 1 to 4 carbon atoms constituting a linear moiety" represented by ^Z2 is a divalent group having a hydrocarbon chain of 1 to 4 carbon atoms which may have a substituent (e.g., _C1-4 alkylene, _C2-4 alkenylene, etc.,
Preferably, _C1-3 alkylene, more preferably methylene).

The divalent group represented by ^Z2 may be any divalent chain having 1 to 4 carbon atoms constituting the linear portion, and examples thereof include —(CH ₂ ) _k1 —(k1
is an integer of 1 to 4), an alkylene chain represented by —(CH ₂ ) _k2 —(CH═CH)
Examples include an alkenylene chain represented by —(CH ₂ ) _k3 — (k2 and k3 may be the same or different and represent 0, 1 or 2, provided that the sum of k2 and k3 is 2 or less).

The divalent groups represented by X ¹ , X ² and Z ² may have a substituent at any position (preferably on a carbon atom). Such a substituent may be any one that can be bonded to the divalent chain constituting the linear portion. For example, a lower (C _1-
6 ) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower ( _C3-7 ) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower ( _C2-7 ) alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), an optionally esterified phosphono group, an optionally esterified carboxyl group, a hydroxyl group, oxo, etc., preferably those having 1 to 6 carbon atoms.
Examples thereof include lower alkyl (preferably C _1-3 alkyl), a hydroxyl group, and oxo.

The optionally esterified phosphono group includes —P(O)(OR ⁷ ) (
OR ⁸ ) [wherein R ⁷ and R ⁸ each represent hydrogen, an alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms, and R ⁷ and R ⁸ may be bonded to each other to form a 5- to 7-membered ring].

In the above formula, examples of the alkyl group having 1 to 6 carbon atoms represented by ^R7 and ^R8 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl, and examples of the cycloalkyl group having 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
Preferably, it is a chain-like lower alkyl having 1 to 6 carbon atoms, more preferably a chain-like lower alkyl having 1 to 6 carbon atoms.
^R7 and ^R8 may be the same or different, but are preferably the same. When ^R7 and ^R8 are bonded to each other to form a 5- to 7-membered ring, ^R7 and ^R8 are bonded to each other to form a -(CH
_The side chain may have a _substituent , _such as _a hydroxyl group _{or a halogen} atom.

The esterified carboxyl group of the optionally esterified carboxyl group is a carboxyl group and an alkyl group having 1 to 6 carbon atoms or an alkyl group having 3 to 7 carbon atoms.
and the like, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.

The divalent group represented by ^Z2 is preferably an optionally substituted _C1-3 alkylene, particularly a C1-3 alkyl, a _C1-3 alkyl group optionally substituted with a hydroxyl group or an oxo group _.
-3 alkylene is preferred.

Furthermore, the divalent group represented by Z ² includes a group having a benzene ring as the starting point and a bond -Z'-
(CH ₂ ) n - or -(CH ₂ ) n -Z'- (Z' is -CH(OH)-, -C
(O)- or _-CH2- , n is an integer of 0 to 2, and each methylene group is 1
and a group represented by -Z'-(CH ₂ )n- (Z' is -CH(OH)-) starting from a benzene ring,
, —C(O)— or —CH ₂ —, n is an integer of 0 to 2 (preferably, n is 0), and each methylene group may have 1 to 2 identical or different substituents), and particularly methylene is preferred.

In the above formula (I), the "amino group" of the "amino group which may be substituted and whose nitrogen atom may be converted to quaternary ammonium or oxidized" represented by ^R2 includes an amino group which may have one to two substituents, an amino group which has three substituents and whose nitrogen atom is converted to quaternary ammonium, etc. When there are two or more substituents on the nitrogen atom, the substituents may be the same or different, and when there are three substituents on the nitrogen atom, the amino group may be any of the types of amino groups: -N ⁺ R ₃ , -N ⁺ R ₂ R', and -N ⁺ RR'R'' (R, R', and R'' are different and represent hydrogen or a substituent). Counter anions of amino groups in which the nitrogen atom is converted to quaternary ammonium include anions of halogen atoms (e.g., Cl ⁻ , Br ⁻ , I ^{− ,} etc.), as well as anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,
Examples of anions include anions derived from organic acids such as succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and anions derived from acidic amino acids such as aspartic acid and glutamic acid.
l ⁻ , Br ⁻ , I ⁻ and the like are preferred.

Substituents for the amino group include: (1) optionally substituted alkyl (e.g., C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably lower ( _C1-6 ) alkyl); ( ₂ ) optionally substituted cycloalkyl (e.g., _C3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyanooctyl); (2-1) the cycloalkyl contains one heteroatom selected from a sulfur atom, an oxygen atom, and a nitrogen atom, and is exemplified by oxirane, thiolane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, and tetrahydrothiopyran. (2-1) The cycloalkyl may be condensed with a benzene ring to form an indane (e.g., indan-1-yl, indan-2-yl, etc.), a tetrahydronaphthalene (e.g.,
tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, etc.)
(2-3) the cycloalkyl may be bridged via a linear carbon atom chain to form a bridged cyclic hydrocarbon residue such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl (preferably, cyclohexyl having a bridge via a linear carbon atom chain, more preferably, bicyclo[2.2.1]heptyl); (3) optionally substituted alkenyl (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, preferably lower ( _C2-6 ) alkenyl); (4) optionally substituted cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) optionally substituted aralkyl (for example, phenyl-C _1-4 alkyl (for example, benzyl, phenethyl, etc.)); (6) formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (for example, methanesulfonyl, ethanesulfonyl, etc.), alkoxycarbonyl having 1 to 4 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), aralkyloxycarbonyl having 7 to 10 carbon atoms (for example, benzyloxycarbonyl, etc.), etc.); (7) optionally substituted aryl (e.g., phenyl, naphthyl, etc.); (8) optionally substituted heterocyclic groups (e.g., furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine,
groups formed by removing one hydrogen atom from a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 or 2 kinds selected from a nitrogen atom, a sulfur atom, and an oxygen atom, such as triazole; tetrahydrofuran, tetrahydrothiophene, dithiolane;
Examples of the substituent include a group formed by removing one hydrogen atom from a 5- to 6-membered non-aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from nitrogen atoms, sulfur atoms, and oxygen atoms, such as oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, and tetrahydropyran; preferably, a group formed by removing one hydrogen atom from a 5- to 6-membered non-aromatic heterocycle; more preferably, a group formed by removing one hydrogen atom from a 5- to 6-membered non-aromatic heterocycle containing one heteroatom, such as tetrahydrofuran, piperidine, tetrahydropyran, and tetrahydrothiopyran. In addition, the substituents of the amino group may be bonded to each other to form a 5- to 7-membered cyclic amino, such as piperidine, piperazine, morpholine, or thiomorpholine.

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted alkyl,
(3) optionally substituted alkenyl; (4) substituted
(5) optionally substituted cycloalkenyl; (6) optionally substituted aralkyl;
(7) optionally substituted acyl, and (8) optionally substituted aryl.
) The optionally substituted heterocyclic group may have a substituent such as a halogen atom, a methyl group ...
(e.g., fluorine, chlorine, bromine, iodine, etc.), optionally halogenated lower (
C_1-4) alkyl, optionally halogenated C_1-4Alkoxy (e.g., methyl
ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoro
ethoxy, etc.), C_1-4Alkylenedioxy (e.g., —O—CH₂-O-, -
O-CH₂-CH₂—O—, etc.), formyl, C_2-4Alkanoyl (e.g., acetonitrile)
ethyl, propionyl, etc.), C_1-4Alkyl sulfonyl (e.g., methanesulfonyl)
phenyl, ethanesulfonyl, etc.), phenyl-lower (C_1-4) alkyl, C_3-7
Cycloalkyl, cyano, nitro, hydroxyl group, optionally substituted thiol group (
e.g., thiol, C_1-4alkylthio, etc.), optionally substituted amino groups (
e.g., Amino, Mono C_1-4Alkylamino, DiC_1-4Alkylamino, tetra
Hydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole
5-6 membered cyclic amino such as benzoyl, imidazole, etc.), esterification or amido
an optionally substituted carboxyl group (e.g., carboxyl, C_1-4Alkoxy
Carbonyl, carbamoyl, mono C_1-4Alkylcarbamoyl, diC_1-4a
alkylcarbamoyl, etc.), low-grade (C_1-4) alkoxy-carbonyl, lower (
C_7-10) aralkyloxy-carbonyl, oxo group (preferably halogen
, optionally halogenated lower (C_1-4) alkyl, halogenated
Good low grade (C_1-4) alkoxy, phenyl-lower (C_1-4) alkyl,
C_3-7cycloalkyl, cyano, hydroxyl group, etc.), and the number of substituents
Preferably, 1 to 3.

In the above formula (I), the "amino group which may be substituted and whose nitrogen atom may be quaternary ammonium or oxidized" represented by ^R2 is preferably (1) a straight-chain or branched lower ( _C1-6 ) alkyl which may have 1 to 3 halogen atoms, cyano, hydroxyl groups or _C3-7 cycloalkyl; (2) a sulfur atom which may have 1 to 3 halogen atoms, optionally halogenated lower ( _C1-4 ) alkyl or phenyl-lower ( _C1-4 ) alkyl;
C5-8 cycloalkyl (e.g., optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo[ _2.2.1 ]heptyl, etc.), which may contain one heteroatom selected from oxygen and nitrogen atoms, may be fused with a benzene ring, and may be bridged via a linear atomic chain having 1 to 2 carbon atoms; (3) phenyl-lower ( _C1-4 ) alkyl, which may have 1 to 3 halogens, optionally halogenated lower ( _C1-4 ) alkyls, or optionally halogenated lower ( _C1-4 ) alkoxys; (4) phenyl, which may have 1 to 3 halogens, optionally halogenated lower ( _C1-4 ) alkyls, or optionally halogenated lower ( _C1-4 ) alkoxys; and (5) halogens, optionally halogenated lower ( _C1-4 ) alkyls, ) alkyl, optionally halogenated lower (C _1-4 ) alkoxy, optionally halogenated lower (C _1-4 ) alkoxy-lower (C _1-4 ) alkoxy, phenyl-lower (C _1-4 ) alkyl, 5- to 6-substituted aryl groups optionally having 1 to 3 cyano or hydroxyl groups;
It is an amino group which may have 1 to 3 substituents selected from 6-membered aromatic heterocyclic groups (for example, groups formed by removing one hydrogen atom from furan, thiophene, pyrrole, pyridine, etc.).

In the above formula (I), examples of the "nitrogen-containing heterocycle" in the "nitrogen-containing heterocyclic group which may be substituted, which may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and whose nitrogen atom may be converted to a quaternary ammonium or oxidized group" include pyrrole,
5- or 6-membered aromatic heterocycles which may contain, in addition to one nitrogen atom, 1 to 3 heteroatoms of one or two kinds selected from nitrogen atoms, sulfur atoms, and oxygen atoms, such as imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazole; 5- or 6-membered aromatic heterocycles which may contain, in addition to one nitrogen atom, 1 to 3 heteroatoms of one or two kinds selected from nitrogen atoms, sulfur atoms, and oxygen atoms, such as pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, azacycloheptane, and azacyclooctane (azocane);
These nitrogen-containing heterocycles include non-aromatic heterocycles having 1 to 8 carbon atoms.
The heterocyclic ring may be bridged via a linear chain of atoms having 1 to 2 carbon atoms to form a bridged nitrogen-containing heterocycle such as azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane (quinuclidine), etc. (preferably, piperidine having a bridge via a linear chain of atoms having 1 to 2 carbon atoms, etc.).

Among the specific examples of the nitrogen-containing heterocycles mentioned above, pyridine, imidazole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azabicyclo[
2.2.2]octane (preferably a 6-membered ring) is preferred.

The nitrogen atom of the "nitrogen-containing heterocycle" may be quaternary ammonium or oxidized. When the nitrogen atom of the "nitrogen-containing heterocycle" is quaternary ammonium, the counter anion of the "nitrogen-containing heterocyclic group whose nitrogen atom is quaternary ammonium" may be an anion of a halogen atom (e.g., Cl ⁻ ,
In addition to anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid ^, anions derived from organic acids such as formic acid, acetic ^acid , trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and anions derived from acidic amino acids such as aspartic acid and glutamic acid, among which ^Cl- , ^Br- , and ^I- are preferred.

The "nitrogen-containing heterocyclic group" may be bonded to the divalent group represented by ^Z2 via either a carbon atom or a nitrogen atom, or may be bonded to a ring-constituting carbon atom such as 2-pyridyl, 3-pyridyl, 2-piperidinyl, etc. It is preferable that the bond is formed on a nitrogen atom constituting the ring, such as:

Substituents which the "nitrogen-containing heterocycle" may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), optionally substituted lower (C _1-4 ) alkyl, optionally substituted lower (C _1-4 ) alkoxy, optionally substituted phenyl, optionally substituted mono- or diphenyl-lower (C _1-4 ) alkyl, optionally substituted C _3-7 cycloalkyl, cyano, nitro, hydroxyl group, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (e.g., amino, mono-C 1-4 alkylamino, di-C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole and other 5- to 6-membered cyclic amino, etc.), optionally esterified or amidated carboxyl group (e.g., carboxyl, _{C 1-4 alkoxycarbonyl} , carbamoyl, mono-C _1-4 alkyl
alkylcarbamoyl, diC _1-4 alkylcarbamoyl, etc.), lower (C _1-
4 ) alkoxy-carbonyl, formyl, lower ( _C2-4 ) alkanoyl, lower ( _C1-4 ) alkylsulfonyl, optionally substituted heterocyclic groups (for example, groups formed by removing one hydrogen atom from a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from nitrogen atoms, sulfur atoms, and oxygen atoms, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazole, tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine,
Examples include groups formed by removing one hydrogen atom from a 5- or 6-membered non-aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom, and an oxygen atom, such as oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, and tetrahydrothiopyran, and the number of substituents is preferably 1 to 3. In addition, the nitrogen atom of the "nitrogen-containing heterocycle" may be oxidized.

The "nitrogen-containing heterocycle" may have, as a substituent, "optionally substituted lower (C _1-4 ) alkyl", "optionally substituted lower (C _1-4 ) alkoxy", "optionally substituted phenyl", "optionally substituted mono- or diphenyl-lower (C _1-4 ) alkyl", "optionally substituted C _3-
Examples of the substituents that the "optionally substituted cycloalkyl" and the "optionally substituted heterocyclic group" may have include halogen (e.g., fluorine, chlorine, bromine, iodine _, etc.), optionally halogenated lower (C _1-4 ) alkyl, lower (C _3
-10 ) cycloalkyl, lower (C _3-10 ) cycloalkenyl, optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (e.g.,
acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), C _1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), cyano, nitro, hydroxyl group, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (e.g., amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole and other 5- to 6-membered cyclic amino, etc.), optionally esterified or amidated carboxyl group (e.g., carboxyl,
C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), lower (C _1-4 ) alkoxy-
carbonyl, and the number of substituents is preferably 1 to 3.

In the above formula (I), "a sulfur atom or a ring-constituting atom which may be substituted"
It may contain oxygen atoms, and the nitrogen atoms may be quaternary ammonium or oxide.
The substituents that the "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocyclic group" may have are
The substituents include (1) halogen, (2) cyano, (3) hydroxyl, and (4) carboxy.
sil group, (5) lower (C_1-4) alkoxy-carbonyl, (6) halogen, water
Acid group or lower (C_1-4) lower alkyl (C_1-4
) alkyl, (7) halogen, hydroxyl group or lower (C_1-4) substituted with alkoxy
Lower grade (C)_1-4) alkoxy, (8) halogen, lower (C_1-
4) alkyl, hydroxyl, lower (C_1-4) alkoxy or C_1-3Alkylene
(9) phenyl optionally substituted with dioxy; (10) halogen;_1-4)
Alkyl, hydroxyl, lower (C_1-4) alkoxy or C_1-3Alkyleneggio
mono- or diphenyl-lower (C_1-4) alkyl
(10) 5- to 6-membered aromatic complexes such as furan, thiophene, pyrrole, and pyridine
A group formed by removing one hydrogen atom from a ring is preferred.

In the above formula (I), the "group bonded via a sulfur atom" represented by ^R2 is
Formula -S(O)m- ^Rs (wherein m represents an integer of 0 to 2, and ^Rs represents a substituent)
In the above formula, examples of the substituent represented by R ^S include (1) optionally substituted alkyl (for example, C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C _1-6 ) alkyl); (2) optionally substituted cycloalkyl (for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) optionally substituted aralkyl (for example, phenyl-C _1-4 alkyl (e.g., benzyl, phenethyl, etc.)); (4) optionally substituted aryl (for example, phenyl, naphthyl, etc.), and the above-mentioned (1) optionally substituted alkyl, (2)
(3) optionally substituted cycloalkyl, (4) optionally substituted aralkyl, and (5) optionally substituted aryl may have a substituent such as halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (e.g., amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), optionally esterified or amidated carboxyl group (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylamino,
C _1-4 alkylcarbamoyl, diC _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _{2
C 1-4} alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

In the above formula (I), R²The expression shown in(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
an optionally substituted hydroxyl group or an optionally substituted amino group (preferably
is an optionally substituted hydrocarbon group or an optionally substituted amino group;
More preferably, R represents an optionally substituted hydrocarbon group,⁵' and R⁶
' may be bonded to each other to form a cyclic group together with the adjacent phosphorus atom)
In the "group to be⁵' and R⁶Optionally substituted carbonyl groups represented by '
The "hydrocarbon group" in the hydrogen group includes: (1) optionally substituted alkyl (e.g., methyl, ethyl, propyl ...
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl
yl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,
C such as Sil_1-10Alkyl, preferably lower (C_1-6) alkyl
(2) optionally substituted cycloalkyl (e.g., cyclopropyl, cyclopropyl)
C such as butyl, cyclopentyl, cyclohexyl, and cycloheptyl_3-7Shik
(3) optionally substituted alkenyl (e.g., allyl, chloroalkyl, etc.);
alkenyl having 2 to 10 carbon atoms, such as 2-pentenyl, 2-pentenyl, and 3-hexenyl;
Preferably low grade (C_2-6(4) optionally substituted cycloalkenyl (e.g., 2-cyclopentenyl, etc.);
, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenyl
(5) optionally substituted alkynyl (e.g., ethynyl, 1-propynyl,
The carbon number of 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc.
2 to 10 alkynyl, preferably lower (C_2-6) alkynyl, etc.
(6) optionally substituted aralkyl (e.g., phenyl-C_1-4Alkyl
(7) optionally substituted aryl (e.g., phenyl, naphthyl, etc.);
(1) optionally substituted alkyl, (2)
(3) optionally substituted cycloalkyl; (4) optionally substituted alkenyl;
(4) optionally substituted cycloalkenyl; (5) optionally substituted
(6) optionally substituted alkynyl, and (7) optionally substituted aralkyl.
The substituents that the optionally substituted aryl may have include halogen (e.g., fluorine).
chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted
a small thiol group (e.g., thiol, C_1-4alkylthio, etc.), even if substituted
Good amino group (e.g., amino, mono C_1-4Alkylamino, DiC_1-4Alkyl
Amino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomo
5-6 membered cyclic amino such as pyrrole, imidazole, etc.), ester
a carboxyl group (e.g., carboxyl, C_1
−4Alkoxycarbonyl, carbamoyl, mono C_1-4Alkylcarbamoyl
, JiC_1-4alkylcarbamoyl, etc.), optionally halogenated C_1-
4Alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), halogenated
May be C_1-4Alkoxy (e.g., methoxy, ethoxy, trifluorometh
oxy, trifluoroethoxy, etc.), formyl, C_2-4Alkanoyl (e.g., a
Cetyl, propionyl, etc.), C_1-4Alkyl sulfonyl (e.g., methanesulfonyl)
The number of substituents is 1 to 3.
is preferred.

Examples of the "optionally substituted hydroxyl group" represented by ^R5 ' and ^R6 ' include: (1) optionally substituted alkyl (e.g., C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, _heptyl , octyl, nonyl, decyl, etc., preferably lower ( _C1-6 ) alkyl); (2) optionally substituted cycloalkyl (e.g., _C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) optionally substituted alkenyl (e.g., alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower ( _C2-6 ) alkenyl); (4) optionally substituted cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) optionally substituted aralkyl (for example, phenyl- _C1-4 alkyl (for example, benzyl, phenethyl, etc.)); (6) formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (for example, methanesulfonyl, ethanesulfonyl, etc.)); (7) optionally substituted aryl (for example, phenyl, naphthyl, etc.), etc., which may have a hydroxyl group, etc.

The substituents that the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl, and (7) optionally substituted aryl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (e.g., amino,
mono-C _1-4 alkylamino, di-C _1-4 alkylamino, 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C _1-4 alkoxycarbonyl,
carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.).
and C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), and the number of substituents is preferably 1 to 3.

In the above formula, R ⁵ ' and R ⁶ ' may be bonded to each other to form a cyclic group (preferably a 5- to 7-membered ring) together with the adjacent phosphorus atom. Such a cyclic group is
The alkyl group may have a substituent, and examples of the substituent include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino,
5- or 6-membered cyclic amino groups such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, and imidazole; optionally esterified or amidated carboxyl groups (e.g., carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C 1-4 alkylcarbamoyl, and the like _);
-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (e.g., acetyl,
propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

In the above formula (I), when the phosphorus atom forms a phosphonium salt, examples of the counter anion include anions of halogen atoms (e.g., ^Cl- , ^Br- , I- ^, etc.), as well as anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, anions derived from organic acids such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and anions derived from acidic amino acids such as aspartic acid and glutamic acid, with ^Cl- , ^Br- , ^I- , etc. being preferred.

The optionally substituted amino group represented by ^R5 ' and ^R6 ' includes: (1) optionally substituted alkyl (for example, _C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower ( _C1-6 ) alkyl); (2) optionally substituted cycloalkyl (for example, _C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) optionally substituted alkenyl (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower ( _C2-6 ) alkenyl); (4) optionally substituted cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) optionally substituted formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (for example, methanesulfonyl, ethanesulfonyl, etc.)); (6) optionally substituted aryl (for example, phenyl, naphthyl, etc.), etc., an amino group which may have 1 to 2 aryl groups, etc.

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted alkyl,
(3) optionally substituted alkenyl; (4) substituted
(5) optionally substituted acyl, and (6)
The substituents that the optionally substituted aryl may have include halogen (
e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, substituted
Optional thiol group (e.g., thiol, C_1-4alkylthio, etc.), substituted
an optionally substituted amino group (e.g., amino, mono C_1-4Alkylamino, DiC_1-4
Alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine
5-6 membered cyclic amino such as thiomorpholine, pyrrole, imidazole, etc.)
, a carboxyl group which may be esterified or amidated (e.g., carboxy
Lu, C_1-4Alkoxycarbonyl, carbamoyl, mono C_1-4Alkylcal
Bamoil, J.C._1-4alkylcarbamoyl, etc.), which may be halogenated
I C_1-4Alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), halogen
C, which may be fluorinated_1-4Alkoxy (e.g., methoxy, ethoxy, triflate)
fluoromethoxy, trifluoroethoxy, etc.), formyl, C_2-4Alkanoyl
(e.g., acetyl, propionyl, etc.), C_1-4Alkylsulfonyl (e.g., meth
The number of substituents may be as follows:
1 to 3 is preferred.

Substituents in the "optionally substituted amidino group" and "optionally substituted guanidino group" represented by ^R2 include the same as the substituents in the "optionally substituted amino group whose nitrogen atom may be converted to quaternary ammonium or oxidized" represented by ^R2 described above. ^R2 is preferably (1) an optionally substituted amino group whose nitrogen atom may be converted to quaternary ammonium or oxidized, (2) an optionally substituted nitrogen-containing heterocyclic group which may contain a sulfur atom or an oxygen atom as a ring-constituting atom and whose nitrogen atom may be converted to quaternary ammonium or oxidized, (3) an optionally substituted amidino group, or (4) an optionally substituted guanidino group. ^R2 is more preferably an optionally substituted amino group whose nitrogen atom may be converted to quaternary ammonium. Furthermore, ^R2 may be an optionally substituted amidino group or an optionally substituted guanidino group.

^R2 is a group represented by the formula -NRR" or -N ⁺ RR'R" (wherein R
It is more preferable that R′ and R″ each represent an optionally substituted aliphatic hydrocarbon group (an aliphatic chain hydrocarbon group and an aliphatic cyclic hydrocarbon group) or an optionally substituted alicyclic (non-aromatic) heterocyclic group.

In the above formula, R, R' and R" represent "optionally substituted aliphatic carbon
The "hydrogen group" and "optionally substituted alicyclic heterocyclic group" include the substituent R²
The "optionally substituted amino group" represented by the following formula may have a substituent:
The exemplified "optionally substituted aliphatic hydrocarbon groups (e.g., each of which is substituted)"
(Alkyl, cycloalkyl, alkenyl, cycloalkenyl, etc., which may be selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, etc.)
and "optionally substituted alicyclic heterocyclic group (e.g., optionally substituted 5 to 10 rings)"
and the like.

Among these, R and R' are preferably chain hydrocarbon groups which may be substituted (e.g., alkyl, alkenyl, etc., each of which may be substituted), more preferably C _alkyl groups which may be substituted, and particularly preferably methyl groups which may be substituted.

R" is preferably an optionally substituted alicyclic hydrocarbon group (preferably an optionally substituted _C3-8 cycloalkyl group; more preferably an optionally substituted cyclohexyl) or an optionally substituted alicyclic heterocyclic group (preferably an optionally substituted saturated alicyclic heterocyclic group (preferably a 6-membered ring group); more preferably an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl; particularly preferably an optionally substituted tetrahydropyranyl).

As the compound represented by formula (I), the following compounds are preferred.

N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[2-(4-propoxyphenyl)ethoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2
,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[[4-(propoxymethyl)benzyl]oxy]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]-7-(
N-[4-[(2-imidazolin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide; N-[4-[(2-imidazolin-2-yl)methyl]phenyl]-7-(4-
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyphenyl)methoxy]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[3-(4-propoxyphenyl)propoxy]-1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; etc. As the salt of the compound represented by formula (I) of the present invention, a pharmacologically acceptable salt is preferred, and examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts.
Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,
Examples of suitable salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of suitable salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Suitable examples of suitable salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Suitable examples of suitable salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. The compound represented by formula (I) of the present invention may be a hydrate or a non-hydrate. Furthermore, when the compound represented by formula (I) of the present invention exists as configurational isomers (configurational isomers), diastereomers, conformers, and the like, they can be isolated, if desired, by known separation and purification means. Furthermore, when the compound represented by formula (I) is a racemate, it can be separated into an (S) form and an (R) form by a conventional optical resolution means, and both the optically active forms and the racemate are encompassed by the present invention.

The compound represented by formula (I) or a salt thereof used in the present invention [hereinafter referred to as compound (
A prodrug of the compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, or the like. Compound (I)
Examples of the prodrug of the formula (I) include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxyl group of compound (I) is compounds in which the carboxyl group of compound (I) has been esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-
1,3-dioxolen-4-yl)methyl esterified compounds, cyclohexyloxycarbonylethyl esterified compounds, methylamidated compounds, etc. These compounds can be produced from compound (I) by methods known per se.

Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, Hirokawa Publishing, 1990.

Compound (I) may also contain isotopes (e.g., ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).
It may be labeled with, for example,

The compound represented by formula (I) of the present invention or a salt thereof (hereinafter, when the compound represented by formula (I) is abbreviated, it includes salts thereof and the compound represented by formula (I) and its salts) can be administered orally or parenterally either alone or in combination with a pharmaceutically acceptable carrier in the form of a solid preparation such as a tablet, capsule, granule, or powder; or in the form of a liquid preparation such as a syrup or injection.

Examples of parenteral administration forms include injections, drip infusions, suppositories, vaginal suppositories, etc., and vaginal suppositories are particularly useful for preventing HIV infection.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as formulation materials are used, and are compounded as excipients, lubricants, binders, disintegrants in solid formulations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can also be used as needed. Suitable examples of excipients include, for example, lactose,
Examples of suitable lubricants include sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, and carboxymethylstarch sodium. Suitable examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, and corn oil. Suitable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Suitable examples of suspending agents include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin,
Examples of suitable surfactants include benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of isotonicity agents include sodium chloride, glycerin, and D-mannitol. Suitable examples of buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates. Suitable examples of soothing agents include benzyl alcohol. Suitable examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acid.

The compound of the present invention represented by formula (I) or a salt thereof may be used in combination with other agents for the prophylaxis or treatment of HIV infection (particularly, agents for the prophylaxis or treatment of AIDS). In this case, these drugs may be mixed separately or simultaneously with pharmacologically acceptable carriers, excipients, binders, diluents, etc. to prepare pharmaceutical compositions for the prophylaxis or treatment of HIV infection, which can be administered orally or parenterally.
When drugs are formulated separately, they can be mixed and administered using a diluent or the like when used, but the separately formulated individual preparations can also be administered to the same subject simultaneously or separately at different times.The pharmaceutical compositions of the present invention also include kit products for mixing and administering the separately formulated drugs using a diluent or the like when used (for example, an injection kit containing ampoules containing powdered individual drugs and a diluent for mixing and dissolving two or more drugs when used), and kit products for administering the separately formulated individual preparations simultaneously or separately at different times to the same subject (for example, a tablet kit for administering two or more tablets simultaneously or separately at different times, in which tablets containing individual drugs are placed in the same or different bags and, if necessary, have a column for writing the time of drug administration).

used in combination with the compound represented by formula (I) of the present invention or a salt thereof,
Specific examples of other preventive and therapeutic agents for HIV infection include zidovudine (
ovudine), didanosine, zalcitabine
lucitabine, lamivudine, stavudine
tavudine, abacavir, adefovir
adefovir, adefovir dipivoxil
xil), fozivudine tidoxil
Nucleic acid reverse transcriptase inhibitors such as nevirapine, delavirdine, and efavirenz
non-nucleoside reverse transcriptase inhibitors (immunocals) such as loviride, immunocal, and oltipraz;
including drugs with antioxidant properties such as oltipraz, saquinavir, ritonavir, etc.
itonavir), indinavir, nelfinavir (
protease inhibitors such as nelfinavir, amprenavir, parinavir, and lasinavir; and the like.

Nucleic acid reverse transcriptase inhibitors include zidovudine, didanosine, and zalcitabine.
, lamivudine, stavudine, etc. are preferred, and the non-nucleoside reverse transcriptase inhibitor is nevirapine.
Preferred are saquinavir, ritonavir, and the like as protease inhibitors.
itonavir), indinavir, nelfinavir (
nelfinavir) and the like are preferred.

The compound of formula (I) or a salt thereof can be produced as follows.

The compound represented by formula (I) or a salt thereof can be produced by a method known per se. For example, it can be produced according to the following method. The compound represented by formula (I) or a salt thereof can also be produced by the method described in JP-A-8-73476 or a method analogous thereto.

The compounds used in the following production methods may form salts similar to compound (I) as long as they do not interfere with the reaction.

In each of the reactions described below, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the protecting group for an amino group include optionally substituted C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (e.g., methoxycarbonyl,
Examples of the substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), _{C 1-6} alkylcarbonyl (e.g., acetyl, propionyl, butyryl), and nitro groups.
There are about 100 pieces.

Examples of the protecting group for the carboxyl group include optionally substituted C_1-6
Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl)
t-butyl, phenyl, trityl, silyl, etc. are used.
Substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C
_1-6Alkylcarbonyl (e.g., acetyl, propionyl, butyryl, etc.)
, formyl, nitro groups, etc. are used, and the number of substituents is about 1 to 3.

Examples of the protecting group for the hydroxy group include optionally substituted C _1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methyl, ethyl, propyl, butyl, tert- ...
-butyl, etc.), phenyl, C _7-10 aralkyl (e.g., benzyl, etc.),
Examples of the substituent include _C1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, phenyloxycarbonyl, _C7-10 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. Substituents for these groups include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), _C1-6 alkyl, phenyl, _C7-10 aralkyl, and nitro groups, and the number of substituents is about 1 to 4.

The protecting groups can be introduced and removed by known methods or methods based thereon (for example, the method described in Protective Groups in Organic Chemistry (J. F. W. McOmie et al., Plenum Press)). Protective groups can be removed by treatment with, for example, an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or the like.

[Method A] Compound (I) or a salt thereof can be prepared by reacting compound [II] or a salt thereof with compound [III] or a salt thereof according to the reaction shown below.

[wherein Xa ² reacts with the substituent Xb ² of the compound [III] or a salt thereof to form X
^Xb2 represents a group (e.g., an amino group) which reacts with the substituent ^Xa2 of compound [II] or a salt thereof to form ^{X2 .}
and other symbols have the same meanings as defined above.] Xa ² is a carboxyl group, Xb ² is an amino group, and X ² is -CO-N
The production method when it is H- is shown below.

[Each symbol in the formula has the same meaning as defined above] In this method, a carboxylic acid derivative [II-1] is reacted with an amine derivative [III-1] to produce a compound [I-1].

The condensation reaction of [II-1] and [III-1] is carried out by a conventional peptide synthesis method. The peptide synthesis method may be any known method, for example, the method described by M. B.
Odansky and M. A. Ondetti, Peptide Synthesis
Peptide Synthesis), Interscience, New York, 19
1966; The Proteins by F. M. Finn and K. Hofmann
Proteins), Vol. 2, edited by H. Nenrath and R. L. Hill,
Academic Press, Inc., New York, 1976; Nobuo Izumiya et al.
The method described in "Fundamentals and Experiments of Peptide Synthesis", Maruzen Co., Ltd., 1985, etc.
For example, the azide method, the chloride method, the acid anhydride method, the mixed acid anhydride method, the DCC method, the activated ester method, the method using Woodward's reagent K, the carbonyldiimidazole method,
In addition to the oxidation-reduction method, DCC/HONB method, WSC method, diethyl cyanophosphate (
Examples of the method include a method using N,N-dimethylformamide (DEPC). This condensation reaction can be carried out in a solvent. Examples of the solvent include anhydrous or hydrous N,N-dimethylformamide, dimethyl sulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, or a suitable mixture thereof. The reaction temperature is usually about -20°C to about 50°C, preferably about -10°C to about 30°C.
The reaction time is about 1 to about 100 hours, preferably about 2 to about 40 hours.
The compound [I-1] thus obtained can be separated and purified by known separation and purification means, for example, concentration,
The compound can be isolated and purified by vacuum concentration, solvent extraction, crystallization, recrystallization, transfer, chromatography, and the like.

[Method B] When R ² ″ in compound [I-2] is, for example, a tertiary amine residue, compound [I-2] can be reacted with an alkyl halide or an aralkyl halide to produce a quaternized compound [I′]. Examples of the halogen atom include chlorine, bromine, and iodine. An alkyl halide (e.g., a lower (C _1-6 ) alkyl halide, etc.) or an aralkyl halide (e.g., a lower (C _1-4 ) alkyl-phenyl halide) can be used to produce compound [I-
[0033] Generally, about 1 to 5 moles of the toluene are used per mole of 2. This reaction can be carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylacetamide, etc., or a mixture thereof. The reaction temperature ranges from about 10°C to about 160°C, preferably from about 20°C to about 120°C. The reaction time ranges from about 1 hour to about 100 hours, preferably from about 2 hours to about 40 hours.
In addition, this reaction is preferably carried out under an inert gas atmosphere (eg, nitrogen, argon, etc.).

When R ² ″ in compound [I-2] is, for example, a secondary amine residue, compound [I-2] can be reacted with an alkyl halide or an aralkyl halide to produce a tertiary compound [I′]. Examples of the halogen atom include chlorine, bromine, and iodine, and the alkyl halide or aralkyl halide is usually used in an amount of about 1 to 2 moles per mole of compound [I-2]. This reaction can be carried out, if necessary, using an equimolar to 3-fold molar amount of triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate,
The reaction can be made to proceed smoothly by adding potassium carbonate, sodium hydrogen carbonate, or the like as a base, and further by adding sodium iodide, potassium iodide, or the like.

This tertiary amination reaction can be carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DNSO), pyridine, etc., or a mixture thereof. The reaction can be carried out at a temperature ranging from about 0° C. to 180° C. for about 1 hour to about 40 hours. This reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

When R ² ″ in compound [I-2] is, for example, a secondary amine residue, compound [I-2] is reacted with an aldehyde compound in the presence of a reductive amino reagent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride to give tertiary compound [I′].
The reductive amination reaction can be carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran (THF), diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF), or a mixture thereof, and the like, preferably in the presence of sodium triacetoxyborohydride. The reductive amination reaction can be carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran (THF), diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF), or a mixture thereof ...
The reaction is usually carried out at a temperature ranging from about 0° C. to about 80° C. for about 1 hour to about 40 hours. The reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

When R ² " in compound [I-2] is, for example, a sulfide residue or a tertiary amine residue, compound [I'] having a sulfinyl group, sulfonyl group or amine oxide group can be produced by reacting compound [I-2] with an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, paranitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, sodium periodate or potassium periodate. It is desirable to change the reaction conditions for this oxidation reaction depending on the oxidizing agent used. For example, when m-chloroperbenzoic acid is used, the reaction can be carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, acetone, ethyl acetate or a mixture thereof. The oxidizing agent is used in an amount of about 1 to 3 molar equivalents per mole of compound [I-2]. The reaction is usually carried out at a temperature ranging from about -25°C to about 80°C (preferably from -25°C to 25°C) for about 1 hour to about 40 hours.

[C method] In compound [IV], V represents a halogen atom (e.g., chlorine, bromine, iodine), a sulfonyloxy group (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy), and the other symbols are as defined above.

The quaternized compound [I'] can be prepared by reacting the compound [IV] with a tertiary amine. This reaction is carried out in an inert solvent such as toluene,
The reaction can be carried out in a solvent such as benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylacetamide, or a mixture thereof. The tertiary amine is used in an amount of about 1 to 3 moles per mole of compound [IV]. The reaction is carried out at a temperature ranging from about 10°C to about 120°C.
The reaction is carried out for about 1 hour to about 40 hours.
The reaction is carried out under an atmosphere of, for example, nitrogen, argon, etc.

The quaternized compound [I'] can be prepared by reacting compound [IV] with a tertiary phosphine. This reaction can be carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF), etc., or a mixture thereof. About 1 to 2 moles of the tertiary phosphine are used per mole of compound [IV]. This reaction is carried out at a temperature ranging from about 20°C to about 150°C for about 1 hour to about 50 hours. This reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

Compound [I'] having a secondary or tertiary amino group or thio group can be produced by reacting compound [IV] with a primary or secondary amine compound or a thiol compound. The primary or secondary amine compound or thiol compound is usually used in an amount of about 1 to 3 moles per mole of compound [IV]. This reaction can be smoothly carried out by adding an equal to three times moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, or sodium bicarbonate, or by further adding sodium iodide, potassium iodide, or the like, as needed.
This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol,
isopropanol, n-butanol, tetrahydrofuran, diethyl ether,
Dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (
The reaction can be carried out in a solvent such as ethanol (DMF), dimethyl sulfoxide (DMSO), pyridine, or a mixture thereof. The reaction is carried out at a temperature ranging from about -10°C to about 180°C for about 1 hour to about 40 hours. The reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

[D method] Compound [V] [wherein V′ represents a halogen atom (e.g., bromine, iodine, etc.) or a sulfonyloxy group (e.g., trifluoromethanesulfonyloxy group), and the other symbols are as defined above] can be subjected, for example, to Suzuki reaction [a palladium-catalyzed cross-condensation reaction of an arylboronic acid with, for example, an aryl halide or aryloxytrifluoromethanesulfonate; A. Suzuki et al., Synth. Commun.
1981 , 11, 513], compound [I″] in which X ¹ represents a bond and R ¹ ′ represents a 5- or 6-membered aromatic group can be produced. Compound [I″] can be obtained by using arylboronic acid in an amount of about 1 to 1.5 times the moles per mole of compound [V].

Alternatively, compound [V] can be cross-condensed with an arylacetylene compound in the presence of a palladium catalyst such as dichlorobis(triphenylphosphine)palladium [K. S. Y. Lau et al., J. Org. Chem., 1981 , 46, 228
0;J. W. Tilley, S. Zawoisky et al., J. Org. Chem.
, 1988 , 53, 386], compound [I″] in which X ¹ is —C≡C— and has an acetylene bond can be produced. The arylacetylene compound can be usually used in an amount of about 1 to 2 moles per mole of compound [V] to obtain compound [I″].

Compound [V] [wherein V' represents a hydroxyl group, and the other symbols are as defined above]
] can be subjected to, for example, the Mitsunobu reaction [etherification reaction using, for example, triphenylphosphine and diethyl azodicarboxylate as condensing agents; O. Mitsunobu
bu et al., Synthesis., 1981 , 1], the compound [I″] having an ether bond can be prepared. The corresponding alcohol compound or phenol compound can be used in an amount of about 1 to 3 times the moles of the compound [V] to give the compound [I″].

The compound [I″] having an ether bond can be reacted with the compound [V] and a halide (
The compound [V] can also be produced by an etherification reaction with a reactive compound such as a chloride, bromide, iodide, etc., tosylate compound, or mesylate compound. The reactive compound is usually used in an amount of about equal to 2 moles per mole of compound [V]. This reaction can be smoothly carried out by adding, as necessary, about an equimolar to 3 moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, or sodium bicarbonate, and further adding sodium iodide, potassium iodide, etc. This reaction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane,
Toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMS
The reaction can be carried out in a solvent such as hexane, hexanediamine, hexanediol, hexanediamine diol, hexanediamine dimethylformamide, hexanediamine diol ...
In addition, the reaction is preferably carried out under an inert gas atmosphere (eg, nitrogen, argon, etc.).

Compound [V] [wherein V' represents an optionally substituted carbonyl group, a phosphonium salt or a phosphonate residue, and the other symbols are as defined above] can be reacted, for example, by the Wittig reaction [A. Maercker, Org. React.
., 14 , 270 (1965)] and Wittig-Horner-Emmons
Reaction [J. Boutagy, R. Thomas, Chem. Rev., 74 , 8
7 (1974)] to produce compound [I″] having a vinyl bond. The corresponding carbonyl compound, phosphonium salt or phosphonate compound is used in an amount of about 1 to 1.5 times by mole per mole of compound [V].

[E method] First, compound [VI] [wherein V" represents a cyano group, and the other symbols are as defined above] is reacted with a lower alcohol such as methanol, ethanol, or propanol in the presence of an acid such as hydrochloric acid to obtain an imidate compound. This reaction is usually carried out using an excess amount of the alcohol at a temperature ranging from about -10°C to 50°C for about 1 hour to about 40 hours. This reaction can also be carried out in an inert solvent such as diethyl ether, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, or a mixture thereof.

The resulting imidate compound is then subjected to a substitution reaction with a primary or secondary amine compound to produce amidine compound [I''']. The primary or secondary amine compound is usually used in an amount of about 1 to 5 moles per mole of the imidate compound. This reaction can be smoothly carried out by adding a desalting agent, such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, or potassium carbonate, in an amount of about equimolar to about 3 times the molar amount, if necessary. This substitution reaction can be carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol,
n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane,
The reaction can be carried out in a solvent such as 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, or a mixture thereof. The reaction can be carried out at a temperature ranging from about 0° C. to 150° C. for about 1 hour to about 5 minutes.
The reaction is carried out for 0 hours. The reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

The compound [VI] (wherein V" represents an amino group, and the other symbols are as defined above) can be subjected to a substitution reaction with an S-alkyl (e.g., methyl, ethyl, etc.)-isothiourea compound to produce the guanidine compound [I'"].
The alkyl-isothiourea compound is usually used in an amount of
The reaction can be carried out smoothly by adding a desalting agent such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, or potassium carbonate in an amount of about equimolar to about 3 times the molar amount, if necessary. This substitution reaction can be carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, or dimethylformamide (DMF).
The reaction can be carried out in a solvent such as ethanol, dimethyl sulfoxide (DMSO), pyridine, or a mixture thereof. The reaction is carried out at a temperature ranging from about 0° C. to 150° C. for about 1 hour to about 50 hours. The reaction is preferably carried out under an inert gas atmosphere (e.g., nitrogen, argon, etc.).

The compound (I) thus obtained can be separated and purified by known separation and purification methods, such as concentration,
The compound can be isolated and purified by vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution transfer, chromatography, and the like.

Compound [II-1] used as a starting material can be prepared by a known method (e.g., JP-A-2005-102252).
For example, it can be produced by the method shown in Reaction Scheme I, the method shown in the Reference Examples below, or a method similar thereto. [In the formula, ^R9 represents a _C1-4 alkyl group, Y'' represents a divalent group containing no unsaturated bond and in which ring B forms a 5- to 7-membered ring, and the other symbols are as defined above.] In this method, a compound represented by formula [VII] is first heated with polyphosphoric acid, or compound [VII] is converted into an acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, or the like, and then subjected to a conventional Friedel-Crafts reaction (
The compound [VIII] is then cyclized by a Friedel-Crafts reaction to produce compound [VIII]. Compound [VIII] is then reacted with a carbonate ester in the presence of a base to produce a ketoester [IX]. Compound [IX] is converted to compound [X] by catalytic hydrogenation or reduction with sodium borohydride or the like. Compound [X] can be subjected to a dehydration reaction in a conventional manner to produce an unsaturated carboxylic acid ester [XI], which can then be subjected to an ester hydrolysis reaction to produce an unsaturated carboxylic acid [II'].

In the compound [II] used as a starting material, Xa ² is not a carboxyl group (for example, Xa ² is a chlorosulfonyl group, a hydroxymethyl group, a halo(
Compound [II]) in which the substituent is a (chloro or bromo)methyl group, a formyl group, an acetamide group, or the like can be prepared, for example, by the method shown in Reaction Scheme II, the method shown in the Reference Examples below, or a method analogous thereto. [The symbols in the formula are as defined above.] The sulfonyl chloride compound [II'a] can be produced by reducing the compound of formula [VIII] in a conventional manner (reduction with sodium borohydride or catalytic hydrogenation, etc.), followed by dehydration to produce compound [XII], which is then reacted with sulfuryl chloride.

The hydroxymethyl compound [II'b] can be obtained by reducing the ester compound represented by the formula [XI] by a conventional method (using sodium borohydride, lithium aluminum hydride,
The resulting hydroxymethyl compound [II'b] can be subjected to a chlorination reaction with thionyl chloride or the like or a bromination reaction with triphenylphosphine-carbon tetrabromide or the like to produce a halomethyl compound [II'c].

Alternatively, the hydroxymethyl compound [II'b] can be subjected to oxidation with activated manganese dioxide or the like to produce the formyl compound [II'd].

Furthermore, the amine compound [II'f] can be produced by subjecting the carboxylic acid compound represented by formula [II'] to a rearrangement reaction using, for example, diphenylphosphoramide (DPPA)-t-butanol in a conventional manner to produce a urethane compound [II'e], which can then be subjected to an acid hydrolysis reaction.

The compounds [II'a], [II'b], and [II'c] thus obtained
The compound represented by formula (I) in which X2 is not a carbonylamide group can be obtained by subjecting [II'd], [II'e] or [II'f] and the compound represented by formula [ ^III ] to various reactions such as the amidation reaction, tertiary amination reaction, reductive amination reaction, vinylation reaction, etherification reaction, and alkylation (aralkylation) reaction.

Compound [III-1] can also be synthesized by a known method (e.g., JP-A-8-73476
and the like) or a method similar thereto,
For example, it can be produced by the method shown in Reaction Scheme III, the method shown in the Reference Examples below, or a method similar thereto. [Each symbol in the formula has the same meaning as defined above.] The reduction reaction of compound [XIII] can be carried out by a method known per se. For example, reduction with a metal, reduction with a metal hydride, reduction with a metal hydride complex compound,
Reduction with diborane or substituted borane, catalytic hydrogenation, etc. are used. That is, this reaction is carried out by treating compound [XIII] with a reducing agent. Examples of reducing agents include metals such as reduced iron and zinc powder, alkali metal borohydrides (e.g., sodium borohydride, lithium borohydride, etc.), metal-hydrogen complex compounds such as lithium aluminum hydride, metal hydrides such as sodium hydride, organotin compounds (e.g., triphenyltin hydrogen), metals and metal salts such as nickel compounds and zinc compounds, catalytic reduction agents using a transition metal catalyst such as palladium, platinum, or rhodium with hydrogen, and diborane, etc., but catalytic reduction using a transition metal catalyst such as palladium, platinum, or rhodium with hydrogen, or reduction with a metal such as reduced iron is advantageously carried out. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, tetrahydrofuran, dioxane, methanol,
Ethanol, propanol, isopropanol, 2-methoxyethanol, N,
N-dimethylformamide, acetic acid, or a mixture thereof may be used depending on the type of reducing agent. The reaction temperature is preferably about -20°C to about 150°C, more preferably about 0°C to about 100°C, and the reaction time is about 1 to about 24 hours.

The compound [III'] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution, chromatography and the like.

The compound represented by formula (I) of the present invention or a salt thereof has a strong CCR5 antagonistic activity and is therefore used for the prevention and treatment of various HIV infections in humans, such as AIDS.
It is low in toxicity and can be used safely.

The compound of the present invention represented by formula (I) or a salt thereof can be used as a CCR5 antagonist in the following manner:
For example, it can be used as an agent for preventing and treating AIDS and as an agent for suppressing the progression of AIDS pathology.

The daily dose of the compound represented by formula (I) or a salt thereof varies depending on the condition, body weight, and administration method of the patient. In the case of oral administration, the daily dose of the active ingredient [the compound represented by formula (I) or a salt thereof] per adult (body weight 50 kg) is about 5 to 10 mg/day.
00 mg, preferably about 10 to 600 mg, more preferably about 10 to 600 mg.
The preferred dose is about 15 to 150 mg, administered once or in 2 to 3 divided doses per day.

When the compound represented by formula (I) or a salt thereof is used in combination with a reverse transcriptase inhibitor and/or a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor is, for example, about 1/200 to 1/200 of the usual dose.
The dose is appropriately selected from the range of 2 or more to about 2 to 3 times. Furthermore, when two or more drugs are used in combination, if one drug affects the metabolism of the other drug, the dose of each drug is adjusted appropriately, but generally the dose of each drug when administered alone is used.

Typical dosages for representative reverse transcriptase inhibitors and protease inhibitors are, for example, as follows:

Zidovudine: 100 mg Didanosine: 125 to 200 mg Zalcitabine: 0.75 mg Lamivudine: 150 mg Stavudine: 30 to 40 mg Saquinavir: 600 mg Ritonavir: 600 mg Indinavir: 800 mg Nelfinavir: 750 mg Specific embodiments for the use of a compound represented by formula (I) or a salt thereof in combination with a reverse transcriptase inhibitor and/or a protease inhibitor are shown below.

Approximately 10 to 300 mg of the compound represented by formula (I) or a salt thereof is administered to an adult (body weight 50 kg) in combination with approximately 50 to 200 mg of zidovudine. The individual drugs may be administered simultaneously or at intervals of up to 12 hours.

Approximately 10 to 300 mg of the compound represented by formula (I) or a salt thereof is administered to an adult (body weight 50 kg) in combination with approximately 300 to 1,200 mg of saquinavir. The individual drugs may be administered simultaneously or at intervals of up to 12 hours.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in more detail below by showing Experimental Examples, Formulation Examples, Reference Examples, and Examples. However, these are merely examples and are not intended to limit the present invention in any way.

The genetic manipulation methods described below are based on the textbook (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory,
The method described in (1989) or the method described in the protocol attached to the reagent was followed.

EXAMPLES Experimental Example (1) Cloning of Human CCR5 Chemokine Receptor The CCR5 gene was cloned from human spleen cDNA by PCR.
Using 5 ng of spleen cDNA (Toyobo, QUICK-Clone cDNA) as a template, the cDNA was cloned according to the method reported by Samson et al. (Biochemistry 35(11), 33
A primer set prepared with reference to the CCR5 gene base sequence described in WO99/32100 (62-3367 (1996)) was prepared using SEQ ID NO: 1 [sequence length: 34
; sequence type: nucleic acid; number of strands: single-stranded; topology: linear; sequence type: other nucleic acid synthetic DNA] and SEQ ID NO: 2 [sequence length: 34
25 pmol of each of the following DNA fragments was added: [Sequence type: nucleic acid; Strand number: single-stranded; Topology: linear; Sequence type: other nucleic acid, synthetic DNA], and PCR was performed using TaKaRa EX Taq (Takara Shuzo) in a DNA Thermal Cycler 480 (PerkinElmer) (reaction conditions: 95°C for 1 minute, 60°C for 1 minute, and 75°C for 5 minutes, for 30 cycles). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of approximately 1.0 kb was recovered and then purified using the Original TA Cloning Kit (Funakoshi).
The CCR5 gene was cloned using the method described above.

(2) Preparation of a Plasmid for Expressing Human CCR5 The plasmid obtained above was digested with restriction enzymes XbaI (Takara Shuzo) and BamHI (Takara Shuzo), and then subjected to agarose gel electrophoresis to recover a DNA fragment of approximately 1.0 kb. This DNA fragment was mixed with an expression plasmid for animal cells, pcDNA3.1 (Funakoshi), which had been digested with XbaI and BamHI, and the DNA fragment was ligated using DNA Ligation Kit (Kanagawa University).
The resulting fragment was ligated with ribosomal DNA fragment Ver. 2 (Takara Shuzo) and transformed into competent cells of Escherichia coli JM109 (Takara Shuzo) to obtain the plasmid pCKR5.

(3) Introduction and Expression of Human CCR5 Expression Plasmid into CHO-K1 Cells CHO-K1 cells were grown in a 750 ml tissue culture flask (Becton Dickinson) using Ham's F12 medium (Nihon Pharmaceutical) containing 10% fetal bovine serum (Lifetech Oriental).
After detachment with EDTA (Life Tech Oriental), the cells were washed with PBS (Life Tech Oriental), centrifuged (1000 rpm, 5 minutes), and suspended in PBS. Next, DNA was introduced into the cells using a Gene Pulser (Bio-Rad) under the following conditions: 8 x 1000 μL of DNA was introduced into a 0.4 cm gap cuvette.
^0.6 cells and 10 μg of human CCR5 expression plasmid pCKR5 were added, and the voltage was 0
The cells were electroporated at 25 kV and a capacitance of 960 μF. After that, the cells were transferred to Ham's F12 medium containing 10% fetal bovine serum and cultured for 24 hours.
The cells were again detached and centrifuged, and then resuspended in Ham's F12 containing 10% fetal bovine serum and Geneticin (Lifetech Oriental) at 500 μg/ml.
The cells were suspended in the medium, diluted to 10 ⁴ cells/ml, and inoculated onto a 96-well plate (Becton Dickinson) to obtain geneticin-resistant clones.

Next, the obtained geneticin-resistant clones were cultured in a 96-well plate (Becton Dickinson), and then CCR5-expressing cells were selected from the resistant clones.
The assay buffer (0.5% BSA, 20 mM HEPES (Wako Pure Chemical Industries, Ltd.)) was added with 100 pM of [ ¹²⁵ I]-RANTES (Amersham) as a ligand.
The binding reaction was carried out at room temperature for 40 minutes in Ham's F12 medium containing PBS (pH 7.2), and after washing with ice-cold PBS, 50 μl/well of 1 M NaOH was added and mixed.
Radioactivity was measured using a γ-counter to select cells, CHO/CCR5 cell line, to which the ligand specifically bound.

(4) Evaluation of Compounds Based on CCR5 Antagonism CHO/CCR5 cells were seeded at 5 x 10 ⁴ cells/well in a 96-well microplate and cultured for 24 hours. After the medium was removed by aspiration, an assay buffer containing a test compound ( ¹ μM) was added to each well.
After adding 100 pM of 100 μM PBS (Amersham), the wells were incubated for 30 minutes at room temperature. The assay buffer was then removed by aspiration, and the wells were washed twice with chilled PBS. 200 μl of MicroScinti-20 (Packard) was added to each well, and radioactivity was measured using a TopCount (Packard).

The CCR5 binding inhibitory rate of the test compound was measured according to the method described above. The results are shown in Table 1.

CCR5 antagonists (e.g., preventive and therapeutic agents for HIV infection, preventive and therapeutic agents for AIDS, etc.) containing the compound represented by formula (I) or a salt thereof of the present invention as an active ingredient
can be produced, for example, by the following formulation:

Formulation Example 1. Capsules (1) 40 mg of the compound obtained in Example 21 (2) 70 mg of lactose (3) 9 mg of microcrystalline cellulose (4) 1 mg of magnesium stearate (120 mg per capsule) (1), (2), (3), and half of (4) are mixed and granulated. The remaining (4) is added, and the whole is enclosed in a gelatin capsule.

2. Tablets (1) 40 mg of the compound obtained in Example 21 (2) 58 mg of lactose (3) 18 mg of cornstarch (4) 3.5 mg of microcrystalline cellulose (5) 0.5 mg of magnesium stearate (120 mg tablet) Two-thirds of (1), (2), (3), and (4) and one-half of (5) are mixed and granulated. The remaining (4) and (5) are added to these granules, and the mixture is compressed into tablets.

Reference Example 1 4-Methoxythiophenol (9.66 g), ethyl 4-bromobutyrate (13.
A solution of 1.5 g of methyl 4-methyl-2-propanol (4-methyl-2-propanol) and potassium carbonate (18.8 g) in DMF (200 ml) was stirred at room temperature for 4 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and a 1N aqueous solution of sodium hydroxide (85 ml) was added to a solution of the residue in ethanol (200 ml) at room temperature, and the mixture was stirred for 4 hours. The ethanol was evaporated under reduced pressure, and the mixture was extracted with diethyl ether. 1N hydrochloric acid (100 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with hexane, and 4-[
(4-Methoxyphenyl)thio]butyric acid (13.09 g) was obtained.

^1H -NMR (200MHz, _CDCl3 ) δ1.81-1.96 (2H, m
), 2.51 (2H, t, 7.3Hz), 2.87 (2H, t, J=7.1Hz
), 3.80 (3H, s), 6.85 (2H, d, J=8.8Hz), 7.35
(2H, d, J = 8.8 Hz). Reference Example 2: A mixture of 4-[(4-methoxyphenyl)thio]butyric acid (10.0 g) and polyphosphoric acid (145 g) was stirred at 80-90°C for 25 minutes. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution, and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate/hexane 1:7) to give 7-methoxy-3,4-dihydro-1-benzothiepin-5(2H)-one (3.87%) as a yellow oil.
g) was obtained.

^1H -NMR (200MHz, _CDCl3 ) δ2.17-2.31 (2H, m
), 2.94 (2H, t, J = 6.8Hz), 3.07 (2H, t, J = 6.6
Hz), 3.83 (3H, s), 6.94 (1H, dd, J=8.6, 3.0H
z), 7.383 (1H, d, J = 8.6Hz), 8.384 (1H, d, J =
3.0 Hz). Reference Example 3 7-methoxy-3,4-dihydro-1-benzothiepin-5(2H)-one (
3.87 g) and sodium methoxide (5.0 g) in dimethyl carbonate (50 m
l) The suspension was heated to reflux for 4 hours. 1N hydrochloric acid (100 ml) was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Concentration under reduced pressure gave a yellow oil (4.96 g). A mixture of the obtained oil, sodium borohydride (0.7 g), and THF (50 ml) was heated at -40°C.
Methanol (5 ml) was added dropwise at -10°C to -20°C and stirred for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Concentration under reduced pressure gave a yellow oil (4.80 g). A solution of the oil and triethylamine (7.5 ml) in THF (50 ml) was added.
To the solution was added methanesulfonyl chloride (2.09 ml) at 0° C., and the mixture was stirred at 0° C. for 0.5 hours and at room temperature for 1 hour.
7-Undecene (DBU) (4.0 ml) was added and stirred for 2.5 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate/hexane 1:5) to give 7-methoxy-2,3-dimethyl-2,4-dimethyl-4-methyl ...
Methyl 1-dihydro-1-benzothiepine-4-carboxylate (3.00 g) was obtained.

^1H -NMR (200MHz, _CDCl3 ) δ2.86-2.92 (2H, m
), 3.18-3.24 (2H, m), 3.81 (3H, s), 3.84 (3H
, s), 6.78 (1H, dd, J=8.4, 3.0Hz), 6.90 (1H,
d, J = 3.0Hz), 7.41 (1H, d, J = 8.4Hz), 7.77 (1
H, s). Reference Example 4: To a solution of methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate (3.00 g) in THF (30 ml), 70% 3-chloroperbenzoic acid (6.5 g) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours and at room temperature for 1 hour. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, followed by extraction with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate (three times) and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give methyl 7-methoxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (3.15 g) as colorless crystals.

m. p. 144-145°C ^1H -NMR (200MHz, _CDCl3 ) δ3.04-3.10 (2H, m
), 3.59-3.65 (2H, m), 3.86 (3H, s), 3.90 (3H
, s), 6.96-7.02 (2H, m), 7.79 (1H, s), 8.10 (
1H, d, J=10.0Hz). Elemental analysis C ₁₃ H ₁₄ O ₅ S Calcd. C, 55.31; H, 5.00
Found. C, 55.18; H, 5.01. Reference Example 5 7-Methoxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
A mixture of methyl 4-carboxylate (300 mg), 48% hydrobromic acid (3 ml) and acetic acid (3 ml) was heated under reflux for 4 hours. After concentration under reduced pressure, 48% hydrobromic acid (3 ml) and acetic acid (3 ml) were added, and the mixture was heated under reflux for 8 hours. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-hydroxy-1,1-dioxo-2,3-dihydro-1-(2-methyl-4-hydroxybenzoyl)-2,3-dihydrobenzoyl)-2,3-dihydrobenzoyl ...
Benzothiepine-4-carboxylic acid (224 mg) was obtained.

m. p. 260-265°C ^1H -NMR (200MHz, DMSO- _d6 ) δ2.84-2.90 (2H
, m), 3.61-3.68 (2H, m), 6.92-7.02 (2H, m),
7.62 (1H, s), 7.85 (1H, d, J=8.4Hz). Elemental analysis C ₁₁ H ₁₀ O ₅ S・0.1H ₂ O Calcd. C, 51.59
Found. C, 51.38; H, 3.87. Reference Example 6: To a solution of 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (856 mg) in methanol (10 ml) was added sulfuric acid (0.1
ml) was added and the mixture was heated to reflux for 23 hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (848 mg) as pale yellow crystals.

m. p. 176-178°C ^1H -NMR (200MHz, _CDCl3 ) δ3.04-3.10 (2H, m
), 3.59-3.66 (2H, m), 3.86 (3H, s), 6.01 (1H
, br s), 6.90-6.94 (2H, m), 7.74 (1H, s), 8.
05 (1H, d, J=9.4Hz). Elemental analysis C ₁₂ H ₁₂ O ₅ S Calcd. C, 53.72; H, 4.51
Found. C, 53.67; H, 4.58. Reference Example 7 Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-chlorobenzyl chloride (210 mg)
A mixture of 2,3-dimethyl-1,4-dioxo-2,3-dione (214 mg), potassium carbonate (214 mg), and DMF (10 ml) was stirred at room temperature for 13 hours and at 50° C. for 3 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/hexane 1:1) to obtain 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dioxo-2,3-dioxo-1,4 ...
Methyl-dihydro-1-benzothiepine-4-carboxylate (272 mg) was obtained.

m. p. 130-133°C ^1H -NMR (200MHz, _CDCl3 ) δ3.07 (2H, t, J=6.
2Hz), 3.58-3.65 (2H, m), 3.86 (3H, s), 5.12
(2H, s), 7.00-7.05 (2H, m), 7.32-7.42 (4H,
m), 7.77 (1H, s), 8.10 (1H, d, J=8.4Hz). Elemental analysis C ₁₉ H ₁₇ O ₅ SCl Calcd. C, 58.09; H, 4.
36: Found. C, 58.11; H, 4.61. Reference Example 8 To a solution of methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (3/1.5 ml), an aqueous solution (0.7 ml) of potassium carbonate (140 mg) was added at room temperature, and the mixture was stirred at 65-70°C for 23 hours. After cooling to room temperature, 1N hydrochloric acid was added to the reaction system until the pH reached 5, and the precipitated crystals were collected by filtration. The crystals were washed with water, 2-propanol, and diisopropyl ether to give 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate as pale yellow crystals.
3-Dihydro-1-benzothiepine-4-carboxylic acid (149 mg) was obtained.

^1H -NMR (200MHz, DMSO- _d6 ) δ2.91 (2H, t, J=
6.6Hz), 3.68 (2H, t, J=6.6Hz), 5.26 (2H, s)
, 7.22 (1H, dd, J = 8.8, 2.6Hz), 7.37-7.54 (5
1H, m), 7.72 (1H, s), 7.95 (1H, d, J = 8.8 Hz). Reference Example 9: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-ethoxybenzyl alcohol (0
To a solution of 0.36 g of diphenylphosphine and 0.62 g of triphenylphosphine in 10 ml of THF, diisopropyl azodicarboxylate (0.47 ml) was added at 0°C, and the mixture was stirred for 3 hours at room temperature.
After stirring for 5 days, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/hexane 1:1) to give methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (279 mg) as colorless crystals.

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.43 (3H, t, J=7.
0Hz), 3.03-3.10 (2H, m), 3.58-3.65 (2H, m)
, 3.85 (3H, s), 4.05 (2H, q, J = 7.0Hz), 5.07 (
2H, s), 6.92 (2H, d, J = 8.8Hz), 7.01-7.06 (2
H, m), 7.33 (2H, d, J = 8.8Hz), 7.77 (1H, s), 8
.08 (1H, d, J = 9.2 Hz). Reference Example 10: To a suspension of methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (6/3 ml), an aqueous solution (0.7 ml) of potassium carbonate (137 mg) was added at room temperature, and the mixture was stirred at 70°C for 16.5 hours. After cooling to room temperature, 1N hydrochloric acid was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give colorless crystals of 7-[(
4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxylic acid (147 mg) was obtained.

m. p. 180-184°C ^1H -NMR (200MHz, DMSO- _d6 ) δ1.33 (3H, t, J=
7.0Hz), 2.86-2.93 (2H, m), 3.65-3.71 (2H,
m), 4.03 (2H, q, J=7.0Hz), 5.15 (2H, s), 6.9
5 (2H, d, J = 8.8Hz), 7.21 (1H, dd, J = 8.6, 2.4
Hz), 7.37-7.41 (3H, m), 7.72 (1H, m), 7.94 (
1H, d, J=8.6Hz). Elemental analysis C ₂₀ H ₂₀ O ₆ S Calcd. C, 61.84; H, 5.19
Found. C, 61.85; H, 5.35. Reference Example 11: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg), 4-fluorobenzyl chloride (0.09
A mixture of potassium carbonate (134 mg) and DMF (5 ml) was heated at 55°C for 7 min.
The mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/hexane 1:1) to obtain 7% by weight of colorless crystals.
Methyl-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (162 mg) was obtained.

m. p. 141-143°C ^1H -NMR (200MHz, _CDCl3 ) δ3.03-3.10 (2H, m
), 3.58-3.65 (2H, m), 3.85 (3H, s), 5.11 (2H
, s), 7.01-7.14 (4H, m), 7.37-7.44 (2H, m),
7.77 (1H, m), 8.10 (1H, d, J=9.2Hz). Elemental analysis C ₁₉ H ₁₇ O ₅ SF Calcd. C, 60.63; H, 4.5
5: Found. C, 60.52; H, 4.66. Reference Example 12: Methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (327.4 mg) in THF
To a suspension of 7-(2,4-dimethylaminobenzoate) in methanol (4 ml/2 ml) was added an aqueous solution (1.0 ml) of potassium carbonate (240 mg) at room temperature, and the mixture was stirred at 60°C for 20 hours. After cooling to room temperature, 1N hydrochloric acid (5 ml) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether and obtained as pale yellow crystals.
[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-
1-Benzothiepine-4-carboxylic acid (241 mg) was obtained.

m. p. 270-273°C ^1H -NMR (200MHz, DMSO- _d6 ) δ2.87-2.94 (2H
, m), 3.65-3.72 (2H, m), 5.23 (2H, s), 7.20-
7.29 (3H, m), 7.43 (1H, d, J=2.2Hz), 7.50-7
．． 57 (2H, m), 7.72 (1H, s), 7.95 (1H, d, J = 8.8
Hz). Elemental analysis C ₁₈ H ₁₅ O ₅ SF Calcd. C, 59.66; H, 4.1
7: Found. C, 59.43; H, 4.41. Reference Example 13: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg), 3-pyridinemethanol (405 mg)
), triphenylphosphine (0.98 g) in THF (10 ml),
Diethyl azodicarboxylate (40% toluene solution) (1.62 g) was added thereto, and the mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate) to obtain 7-(3-pyridylmethoxy)-1,
Methyl 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (694 mg) was obtained.

7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-
Methyl benzothiepine-4-carboxylate (650 mg) in THF/methanol (
6/3 ml) suspension was added to an aqueous solution (1.4 ml) of potassium carbonate (415 mg) at room temperature.
The reaction mixture was stirred at 60° C. for 19 hours. Potassium carbonate (207 ml) was further added to the reaction mixture.
An aqueous solution (0.7 ml) of 7-(3 mg) was added, and the mixture was further stirred at 60° C. for 3 days. After cooling to room temperature, 2N hydrochloric acid was added until the pH reached 7-8, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(3 mg) as colorless crystals.
From this, 493 mg of (-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained.

^1H -NMR (200MHz, DMSO- _d6 ) δ2.87-2.94 (2H
, m), 3.66-3.72 (2H, m), 5.31 (2H, s), 7.25 (
1H, dd, J=8.8, 2.6Hz), 7.43-7.49 (2H, m), 7
．． 73 (1H, s), 7.89-7.93 (1H, m), 7.96 (1H, d,
J=8.8Hz), 8.58 (1H, dd, J=4.8, 1.4Hz), 8.7
0 (1H, d, J = 1.4 Hz). Reference Example 14: To a solution of methyl 4-hydroxymethylbenzoate (5.0 g) in DMF (100 ml) was added 60% sodium hydride (1.3 g) at 0°C and stirred for 1 hour. Propyl iodide (3 ml) was added to the reaction system and stirred at room temperature for 4 days. Water was added to the reaction system, and the system was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate/hexane 1:9) to give methyl 4-(propoxymethyl)benzoate (2.09 g) as a colorless oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ0.95 (3H, t, J=7.
3Hz), 1.57-1.74 (2H, m), 3.46 (2H, t, J = 6.6
Hz), 3.92 (3H, s), 4.56 (2H, s), 7.41 (2H, d,
J = 8.7 Hz), 8.02 (2H, d, J = 8.7 Hz). Reference Example 15 Lithium aluminum hydride (0.40 g) in diethyl ether (25 ml)
To the suspension, a solution of methyl 4-(propoxymethyl)benzoate (2.09 g) in diethyl ether (25 ml) was added dropwise over 1 hour at 0°C. After stirring at room temperature for 2 hours, water (0.4 ml), 15% aqueous sodium hydroxide solution (0.4 ml), and water (1.2 ml) were added to the reaction system at 0°C, and the mixture was stirred at room temperature for 2 hours. Magnesium sulfate was added, and the solid was removed by filtration. The solvent was evaporated under reduced pressure to give 4-(propoxymethyl)benzyl alcohol (1.81 g) as a colorless oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ0.94 (3H, t, J=7.
3Hz), 1.57-1.69 (3H, m), 3.43 (2H, t, J = 6.6
Hz), 4.51 (2H, s), 4.69 (2H, d, J=5.8Hz), 7.
35 (4H, s). Reference Example 16: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-(propoxymethyl)benzyl alcohol (502 mg), and triphenylphosphine (782 mg) in THF (1
100 ml) solution was added with diethyl azodicarboxylate (40% toluene solution) (1
30 g) was added and stirred at room temperature for 68 hours. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate/hexane 1:1) to obtain 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g)
obtained.

7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g)
In a THF/methanol (10/5 ml) solution, potassium carbonate (622 ml) was added at room temperature.
An aqueous solution (2.1 ml) of 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-(2,3-dihydro ...
The carboxylic acid (425 mg) was obtained.

m. p. 210-213°C ^1H -NMR (200MHz, DMSO- _d6 ) δ0.88 (3H, t, J=
7.4Hz), 1.46-1.64 (2H, m), 2.87-2.93 (2H,
m), 3.38 (2H, t, J = 6.6Hz), 3.65-3.71 (2H, m
), 4.46 (2H, s), 5.24 (2H, s), 7.22 (1H, dd, J
=8.8, 2.6Hz), 7.33-7.47 (5H, m), 7.72 (1H,
s), 7.94 (1H, d, J=8.8Hz). Elemental analysis C ₂₂ H ₂₄ O ₆ S Calcd. C, 63.44; H, 5.81
Found, C, 63.29; H, 5.76. Example 1 (Preparation of Compound 1) To a suspension of 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (110 mg) in THF (5 ml), thionyl chloride (0.042 ml) and one drop of DMF were added at room temperature and stirred for 1 hour. After distilling off the solvent under reduced pressure, the residue was dissolved in THF (5 ml) and the mixture was stirred at room temperature with 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (70 mg) and triethylamine (0.2 ml) in THF (5 ml).
The mixture was stirred at room temperature for 2.5 hours, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was purified by column chromatography (ethanol/ethyl acetate 1:3) and recrystallization (ethanol) to give 7-[(4-chlorobenzyl)oxy]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 1) (104 mg) as colorless crystals.

m. p. 237-239°C ^1H -NMR (200MHz, _CDCl3 ) δ1.67-1.82 (4H, m
), 2.21 (3H, s), 2.55-2.72 (1H, m), 3.09 (2H
, t, J=6.8Hz), 3.30-3.44 (2H, m), 3.58 (2H,
s), 3.69 (2H, t, J = 6.8Hz), 3.98-4.09 (2H, m
), 5.12 (2H, s), 6.98-7.06 (2H, m), 7.21 (1H
, s), 7.32 (2H, d, J=8.4Hz), 7.37-7.42 (4H,
m), 7.54 (2H, d, J=8.4Hz), 7.91 (1H, s), 8.1
0 (1H, d, J=8.8Hz). Elemental analysis C ₃₁ H ₃₃ N ₂ O ₅ SCl Calcd. C, 64.07; H,
5.72; N, 4.82: Found, C, 64.03; H, 5.81; N, 5
.00. Example 2 (Preparation of Compound 2) 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (110 mg) in THF (5 ml)
To the solution, thionyl chloride (0.041 ml) and one drop of DMF were added at room temperature, and the mixture was stirred for 1 hour. After the solvent was removed under reduced pressure, the residue was dissolved in THF (5 ml) and stirred at room temperature with 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (69 mg) and triethylamine (0.2 ml) in THF (5 ml).
The mixture was stirred at room temperature for 1.5 hours, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was purified by column chromatography (ethanol/ethyl acetate 1:3) and recrystallization (ethanol) to give 7-[(4-ethoxybenzyl)oxy]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 2) (109 mg) as colorless crystals.

m. p. 211-213°C ^1H -NMR (200MHz, _CDCl3 ) δ1.43 (3H, t, J=7.
2Hz), 1.68-1.82 (4H, m), 2.21 (3H, s), 2.54
-2.74 (1H, m), 3.05-3.12 (2H, m), 3.29-3.4
4 (2H, m), 3.58 (2H, s), 3.66-3.72 (2H, m), 3
．． 98-4.10 (4H, m), 5.07 (2H, s), 6.92 (2H, d,
J = 8.8Hz), 6.98 (1H, d, J = 2.6Hz), 7.04 (1H,
dd, J=8.4, 2.6Hz), 7.20 (1H, s), 7.30-7.35
(4H, m), 7.54 (2H, d, J=8.8Hz), 7.91 (1H, s)
, 8.09 (1H, d, J=8.4Hz). Elemental analysis C ₃₃ H ₃₈ N ₂ O ₆ S Calcd, C, 67.10; H, 6.
48;N, 4.74:Found. C, 66.94; H, 6.50; N, 4.8
9. Example 3 (Preparation of Compound 3) To a suspension of 7-(4-fluorobenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (170 mg) in THF (5 ml), thionyl chloride (0.068 ml) and one drop of DMF were added at room temperature and stirred for 1 hour. After the solvent was evaporated under reduced pressure, the residue was dissolved in THF (10 ml) and heated to 0°C.
A solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (114 mg) and triethylamine (0.2 ml) in THF (5 ml
The mixture was stirred at room temperature for 20 hours, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was purified by column chromatography (ethanol/ethyl acetate 1:3) and recrystallization (ethanol) to give 7-(4-fluorobenzyloxy)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)]]-[ ...]-[(4-fluorobenzyloxy)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)]]]]-[(4-fluorobenzyloxy)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]
As a result, 206 mg of [aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 3) was obtained.

m. p. 232-234°C ^1H -NMR (200MHz, _CDCl3 ) δ1.67-1.83 (4H, m
), 2.20 (3H, s), 2.55-2.72 (1H, m), 3.06-3.
13 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s),
3.65-3.72 (2H, m), 3.99-4.10 (2H, m), 5.11
(2H, s), 6.98-7.15 (4H, m), 7.21 (1H, s), 7.
32 (2H, d, J = 8.4Hz), 7.37-7.44 (2H, m), 7.5
3 (2H, d, J = 8.4Hz), 7.80 (1H, s), 8.10 (1H, d
, J=8.8Hz). Elemental analysis C ₃₁ H ₃₃ N ₂ O ₅ SF Calcd. C, 65.94; H, 5
．． 89;N, 4.96:Found. C, 65.59; H, 5.67; N, 4.
97. Example 4 (Preparation of Compound 4) 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-
To a solution of benzothiepine-4-carboxylic acid (200 mg) in DMF (5 ml), thionyl chloride (0.084 ml) was added at room temperature and stirred for 1 hour. After the solvent was distilled off under reduced pressure, the residue was dissolved in DMF (5 ml) and the 4-[N-methyl-N-
The mixture was added dropwise to a solution of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (141 mg) and triethylamine (0.4 ml) in THF (5 ml). After stirring at room temperature for 18 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography using basic silica gel (ethyl acetate) and recrystallization (ethanol) to obtain colorless crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(3-pyridylmethoxy)
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 4) (77 mg) was obtained.

m. p. 225-229°C ^1H -NMR (200MHz, _CDCl3 ) δ1.67-1.80 (4H, m
), 2.21 (3H, s), 2.55-2.74 (1H, m), 3.07-3.
14 (2H, m), 3.30-3.44 (2H, m), 3.57 (2H, s),
3.67-3.73 (2H, m), 3.99-4.09 (2H, m), 5.17
(2H, s), 7.01-7.08 (2H, m), 7.22 (1H, s), 7.
30-7.40 (3H, m), 7.53 (2H, d, J=8.4Hz), 7.7
3-7.81 (1H, m), 7.83-7.89 (1H, m), 8.12 (1H
, d, J=8.6Hz), 8.62-8.70 (2H, m). Elemental analysis C ₃₀ H ₃₃ N ₃ O ₅ S・0.2H ₂ O Calcd. C, 65.
36; H, 6.11; N, 7.62: Found. C, 65.13; H, 6.0
7; N, 7.50. Example 5 (Preparation of Compound 5) 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (200 mg) TH
To the solution of F (5 ml), thionyl chloride (0.070 ml) and DMF (1 drop) were added at room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml
), and the resulting solution was added with 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (116 mg) and triethylamine (0.27 m
The mixture was added dropwise to a THF (5 ml) solution of N-[1]. After stirring at room temperature for 2 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol/ethyl acetate 1:3) and recrystallization (ethanol) to obtain colorless crystals of N-[
4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 5
) (199 mg) was obtained.

m. p. 201-203°C ^1H -NMR (200MHz, _CDCl3 ) δ0.95 (3H, t, J=7.
5Hz), 1.58-1.84 (6H, m), 2.20 (3H, s), 2.56
-2.73 (1H, m), 3.05-3.12 (2H, m), 3.31-3.4
4 (2H, m), 3.46 (2H, t, J = 6.6Hz), 3.57 (2H, s
), 3.65-3.72 (2H, m), 3.99-4.10 (2H, m), 4.
52 (2H, s), 5.15 (2H, s), 6.98-7.07 (2H, m),
7.20 (1H, s), 7.32 (2H, d, J = 8.6Hz), 7.39 (4
H, m), 7.53 (2H, d, J = 8.6Hz), 7.85 (1H, s), 8
．． 09 (1H, d, J=8.8Hz). Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.
84;N, 4.53:Found. C, 67.86; H, 6.69; N, 4.5
7. Reference Example 17 Ethynylbenzene (511 mg, 5.00 mmol), 7-bromo-2,3-
Methyl dihydro-1-benzoxepin-4-carboxylate (708 mg, 2.5
0 mmol), dichlorobis(triphenylphosphine)palladium (176 m
A mixture of copper iodide (48 mg, 0.25 mmol), copper iodide (48 mg, 0.25 mmol), and triethylamine (15 ml) was stirred at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (70 ml) was added. The mixture was then diluted with 1N hydrochloric acid (5 ml × 3), saturated saline (5 ml × 10 ml), and the like.
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 35 g, ethyl acetate/hexane = 1
The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give methyl 7-phenylethynyl-2,3-dihydro-1-benzoxepin-4-carboxylate (525 mg, 1.73 mmol, 69%).

IR (KBr): 1709, 1501 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 2.9-3.05 (2H, m), 3.83 (3
H, s), 4.2-4.35 (2H, m), 6.96 (1H, d, J = 8.6H
Reference Example 18: To methyl 7-phenylethynyl-2,3-dihydro-1-benzoxepin-4-carboxylate (463 mg, 1.52 mmol), methanol (10 ml), T
HF (10 ml) and 1N aqueous sodium hydroxide solution (4.56 ml) were added and stirred at room temperature for 24 hours. 1N hydrochloric acid (4.56 ml) was added and concentrated under reduced pressure. Water was added and the insoluble matter was filtered off. The insoluble matter was washed with water and diisopropyl ether in turn and concentrated under reduced pressure to give 7-phenylethynyl-2,3-dihydro-1-benzoxepine-4-carboxylic acid (417 mg, 1.44 mmol, 94%). ^1H -NMR (DMSO- _d6 ) δ: 2.8-2.95 (2H, m), 4.2-
4.35 (2H, m), 7.02 (1H, d, J=8.6Hz), 7.35-7
6 (7H, m), 7.72 (1H, d, J = 2.2 Hz). Example 6 (Preparation of Compound 6) 7-phenylethynyl-2,3-dihydro-1-benzoxepin-4-carboxylic acid (140 mg, 0.48 mmol) was dissolved in DMF (7 ml), and the solution was heated at 0°C to prepare a 1-hydroxybenzotriazole (72 mg, 0.53 mmol) and 4-[N
-methyl-N-(4-tetrahydropyranyl)aminomethyl]aniline (117
mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)
Carbodiimide hydrochloride (139 mg, 0.73 mmol), triethylamine (
0.202 ml, 1.45 mmol), 4-dimethylaminopyridine (3 mg)
The reaction mixture was concentrated under reduced pressure, and ethyl acetate (60 ml) was added. The mixture was washed successively with water (5 ml x 3), saturated sodium bicarbonate solution (5 ml x 3), and saturated saline (5 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to filter out the insoluble matter. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give N-[4-[N-methyl-N-(4-tetrahydropyranyl)aminomethyl]phenyl]-7-phenylethynyl-2,
3-Dihydro-1-benzoxepine-4-carboxamide (Compound 6) (20
2 mg, 0.41 mmol, 85%) was obtained.

IR (KBr): 1653, 1595, 1514 ^{, 1501 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.5-1.85 (4H, m), 2.22 (3
H, s), 2.5-2.8 (1H, m), 3.0-3.15 (2H, m), 3.
3-3.45 (2H, m), 3.58 (2H, s), 3.95-4.15 (2H
, m), 4.3-4.45 (2H, m), 6.99 (1H, d, J=8.4Hz
), 7.15 (1H, s), 7.25-7.6 (11H, m). Reference Example 19: 3-Hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) was dissolved in DMF (10 ml) and the mixture was added with potassium carbonate (2.76 g, 20.0 mmol), benzyl bromide (1.3
The reaction mixture was concentrated under reduced pressure, and water (20 ml) was added to the residue, followed by extraction with ethyl acetate (20 ml x 3).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 35 g, ethyl acetate/hexane=1/19) The target fraction was concentrated under reduced pressure to give 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.79 g).

IR (KBr): 1674 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.7-1.95 (4H, m), 2.65-2
．． 8 (2H, m), 2.8-2.95 (2H, m), 5.08 (2H, s), 7
．． 04 (1H, dd, J = 2.6, 8.4Hz), 7.13 (1H, d, J = 8
.4 Hz), 7.25-7.5 (6H, m). Reference Example 20 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.72 g) was dissolved in dimethyl carbonate (30 ml), sodium methoxide (2.70 g, 50.0 mmol) was added, and the mixture was heated under reflux (110
The mixture was stirred at 4°C for 6 hours. Under ice-cooling, 1N hydrochloric acid (60 ml) was added, the organic solvent was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (30 ml x 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 4
The target fraction was concentrated under reduced pressure to give 300 ml of ethyl acetate/hexane (ethyl acetate/hexane = 1/30).
Methyl-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.88 g, 8.88 mmol) was obtained.

Reference Example 21 Methyl 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.81 g, 8.66 mmol)
was dissolved in a mixed solvent of dichloromethane (40 ml) and methanol (10 ml),
Sodium borohydride (500 mg, 13.2 mmol) at −40° C. (internal temperature)
The reaction mixture was cooled to -40°C, water (20 ml) was added, and the mixture was extracted with dichloromethane (40 ml, 10 ml x 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (30 ml)
The solution was dissolved in 1 ml of ethanol, and triethylamine (6.04 ml, 43.3 mmol) and methanesulfonyl chloride (1.01 ml, 13.0 mmol) were added at 0°C. The mixture was then heated at room temperature for 2
The mixture was stirred for 0 hours. To complete the reaction, DBU (3.89 ml, 26.0 mmol) was added.
1) was added and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) was added, and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layer was washed with 1N hydrochloric acid (5 ml x 3), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 60 g, ethyl acetate/hexane = 1/30 → 1/9). The target fraction was concentrated under reduced pressure to obtain methyl 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.32 g, 7.52 mmol,
87%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.1 (2H, m), 2.55-2
．． 65 (2H, m), 2.7-2.8 (2H, m), 3.81 (3H, s), 5
．． 06 (2H, s), 6.84 (1H, dd, J=2.6, 8.4Hz), 6.
94 (1H, d, J = 2.6Hz), 7.06 (1H, d, J = 8.4Hz),
7.5-7.7 (5H, m), 7.64 (1H, s). Reference Example 22 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-
Methyl carboxylate (2.28 g, 7.39 mmol) in methanol (25 ml)
To the mixture was added 1N aqueous sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature for 13 hours. To complete the reaction, tetrahydrofuran (25 ml) was added and the mixture was stirred at 60° C. for 2 hours.
The mixture was stirred for 1 hour. 1N hydrochloric acid (23 ml) was added at room temperature, and the mixture was concentrated under reduced pressure. Water was then added, and the insoluble matter was filtered off. The insoluble matter was washed with water and dried under reduced pressure to give 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2.09 g, 7.10
^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.7 (2H, m), 2.7-2.85 (2H, m), 5.07 (2H, s),
6.87 (1H, dd, J = 2.7, 8.3Hz), 6.96 (1H, d, J =
2.7Hz), 7.08 (1H, d, J = 8.3Hz), 7.25-7.5 (5
1H,m), 7.77 (1H,s). Example 7 (Preparation of Compound 7) 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-
Carboxylic acid (200 mg, 0.68 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (165 mg, 0.75 mmol),
mol), 1-hydroxybenzotriazole (101 mg, 0.75 mmol
), DMF (10 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (235 mg, 1.23 mmol) and triethylamine (0.284 ml, 2.04 mmol) were added at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, and water (5 ml) was added.
The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to obtain 2-benzyloxy-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-
5H-benzocycloheptene-8-carboxamide (compound 7) (276 mg,
0.56 mmol, 82%) was obtained.

IR (KBr): 1651, 1601, ^{1514 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.6-1.85 (4H, m), 2.0-2.
25 (2H, m), 2.21 (3H, s), 2.5-2.85 (5H, m), 3
．． 3-3.45 (2H, m), 3.57 (2H, s), 3.95-4.1 (2H
, m), 5.07 (2H, s), 6.85 (1H, dd, J=2.7, 8.2H
z), 6.92 (1H, d, J=2.7Hz), 7.09 (1H, d, J=8.
2Hz), 7.25-7.5 (5H, m), 7.31 (2H, d, J = 8.6H
δ), 7.55 (2H, d, J = 8.6 Hz), 7.58 (1H, s). Reference Example 23: 3-Hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) was dissolved in DMF (10 ml), and potassium carbonate (2.76 g, 20.0 mmol) and 4-methylbenzyl bromide (2.04 g, 11.0 mmol) were added, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and water (20 ml) was added to the residue, followed by extraction with ethyl acetate (20 ml x 3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 40 g, ethyl acetate/hexane = 1/30). The target fraction was concentrated under reduced pressure to give 3-(4-methylbenzyloxy)-5-oxo-
6,7,8,9-tetrahydro-5H-benzocycloheptene (2.74 g, 9
. 77 mmol, 98%) was obtained.

IR (KBr): 1674 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.7-1.95 (4H, m), 2.36 (3
H, s), 2.7-2.8 (2H, m), 2.8-2.95 (2H, m), 5.
04 (2H, s), 7.03 (1H, dd, J=2.8, 8.5Hz), 7.1
2 (1H, d, J = 8.5Hz), 7.19 (2H, d, J = 7.9Hz), 7
．． 32 (2H, d, J = 7.9Hz), 7.36 (1H, d, J = 2.8Hz)
Reference Example 24 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.67 g, 9.52 mmol) was dissolved in dimethyl carbonate (40 ml) and sodium methoxide (2.57 g, 47.6 mmol) was added.
mol) was added and the mixture was stirred for 6 hours under reflux (110°C). Under ice-cooling, 1N hydrochloric acid (60 ml) was added and the organic solvent was evaporated under reduced pressure. The aqueous layer was then diluted with ethyl acetate (30 ml x 3).
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 40 g, ethyl acetate/hexane = 1/30).
The target fraction was concentrated under reduced pressure to give methyl 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.84 g, 8.39 mmol, 88%).

Reference Example 25 Methyl 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.77 g, 8.
19 mmol) was dissolved in a mixed solvent of dichloromethane (40 ml) and methanol (10 ml), and the resulting solution was cooled to −40° C. (internal temperature) with sodium borohydride (465 mg, 12
3 mmol) was added and the mixture was stirred at -20°C to -10°C for 2 hours.
Cool to ℃, add water (20 ml) and dichloromethane (40 ml, 10 ml × 2)
The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in THF (30 ml) and stirred at 0° C. with triethylamine (5.70 ml, 40.9 ml).
To the mixture was added methanesulfonyl chloride (0.95 ml, 12.3 mmol), and the mixture was stirred at room temperature for 12 hours.
24.5 mmol) and dichloromethane (30 ml) were added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) was added, and extracted with ethyl acetate (30 ml x 3). The organic layer was washed with 1N hydrochloric acid (5 ml x 3), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 60 g, ethyl acetate/hexane = 1/30 → 1/9). The target fraction was concentrated under reduced pressure to obtain 2-(
Methyl 4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.40 g, 7.44 mmol, 91%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.1 (2H, m), 2.36 (3
H, s), 2.55-2.65 (2H, m), 2.7-2.8 (2H, m), 3
．． 81 (3H, s), 5.01 (2H, s), 6.83 (1H, dd, J=3.
0,8.4Hz), 6.92 (1H, d, J=3.0Hz), 7.05 (1H,
d, J = 8.4Hz), 7.19 (2H, d, J = 8.0Hz), 7.32 (2
Reference Example 26: Methyl 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.34 g, 7.26 mmol) was dissolved in a mixed solvent of methanol (25 ml) and THF (25 ml), and 1N aqueous sodium hydroxide solution (23 ml) was added and the mixture was stirred at room temperature for 18 hours. 1N hydrochloric acid (23 ml) was added at room temperature.
The insoluble matter was washed with water and hexane in that order and dried under reduced pressure to give 2-(4-methylbenzyloxy)-6,7-dihydro-
5H-benzocycloheptene-8-carboxylic acid (2.11 g, 6.84 mmol)
, 94%) was obtained.

IR (KBr): 1663 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.1 (2H, m), 2.36 (3
H, s), 2.55-2.7 (2H, m), 2.7-2.85 (2H, m), 5
．． 02 (2H, s), 6.86 (1H, dd, J=2.7, 8.1Hz), 6.
95 (1H, d, J = 2.7Hz), 7.07 (1H, d, J = 8.1Hz),
7.19 (2H, d, J = 8.1Hz), 7.32 (2H, d, J = 8.1Hz
), 7.77 (1H, s). Example 8 (Preparation of Compound 8) 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (200 mg, 0.65 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (157 mcg).
g, 0.71 mmol), 1-hydroxybenzotriazole (96 mg, 0.
To a mixture of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) and DMF (10 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) at 0° C.
mol), triethylamine (0.271 ml, 1.94 mmol) were added and stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed successively with water (5 ml x 3), saturated sodium bicarbonate water (5 ml x 3), and saturated saline (5 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added, and the insoluble matter was filtered out. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to obtain 2-(4-methylbenzyloxy)-N-[
4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 8) (273 mg, 0.53 mmol, 82%) was obtained.

IR (KBr): 1651, 1601, ^{1518 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.6-1.85 (4H, m), 2.0-2.
2 (2H, m), 2.21 (3H, s), 2.36 (3H, s), 2.5-2.
85 (5H, m), 3.3-3.45 (2H, m), 3.57 (2H, s), 3
．． 95-4.1 (2H, m), 5.02 (2H, s), 6.84 (1H, dd,
J=2.5, 8.1Hz), 6.91 (1H, d, J=2.5Hz), 7.08
(1H, d, J=8.1Hz), 7.19 (2H, d, J=8.3Hz), 7.
31 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.3Hz),
7.55 (2H, d, J = 8.6 Hz), 7.60 (1H, s). Reference Example 27: 3-Hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) was dissolved in DMF (20 ml), and potassium carbonate (2.76 g, 20.0 mmol) and 4-phenylbenzyl bromide (2.72 g, 11.0 mmol) were added, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (30 ml) and THF (30 ml) were added to the residue, followed by washing with water (10 ml, 5 ml × 2) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give a 3% yield.
4-Phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (3.00 g, 8.76 mmol, 88%) was obtained.

IR (KBr): 1674 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.7-1.95 (4H, m), 2.7-2.
8 (2H, m), 2.8-2.95 (2H, m), 5.13 (2H, s), 7.
06 (1H, dd, J=2.6, 8.4Hz), 7.14 (1H, d, J=8.
Reference Example 28: 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.90 g, 8.47 mmol) was dissolved in dimethyl carbonate (80 ml) and added with sodium methoxide (2.29 g, 42.4 m
mol) was added and the mixture was stirred for 6 hours under reflux (110°C). Under ice-cooling, 1N hydrochloric acid (60 ml) was added and the organic solvent was evaporated under reduced pressure. The aqueous layer was then extracted with a mixed solvent of ethyl acetate and THF ((30 ml/15 ml) x 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g,
The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 3-(4-phenylbenzyloxy)-5-oxo-6,7,
Methyl 8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (
2.47 g, 6.17 mmol, 73%) was obtained.

Reference Example 29 Methyl 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.31 g, 5
77 mmol) was dissolved in a mixed solvent of dichloromethane (50 ml) and methanol (15 ml), and the solution was cooled to -40°C (internal temperature) with sodium borohydride (327 mg, 8
64 mmol) was added and the mixture was stirred at -20°C to -10°C for 2 hours.
Cool to 0°C, add water (30 ml), and add dichloromethane (50 ml, 10 ml x 2)
The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (40 ml) and diluted with triethylamine (4.02 ml) at 0°C.
, 28.8 mmol), methanesulfonyl chloride (0.67 ml, 8.7 mm
mol) was added and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was concentrated under reduced pressure, water (30 ml) was added, and the mixture was extracted with ethyl acetate (40 ml, 15 ml x 2).
The organic layer was washed with 1N hydrochloric acid (5 ml x 4), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 60 g, toluene). The target fraction was concentrated under reduced pressure, and ethyl acetate and diisopropyl ether were added to the concentrate. The insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to obtain 2-(4
Methyl 5H-benzocycloheptene-8-carboxylate (1.31 g, 3.41 mmol, 59%) was obtained from the reaction mixture.

IR (KBr): 1707 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.7 (2H, m), 2.7-2.8 (2H, m), 3.82 (3H, s), 5
．． 10 (2H, s), 6.87 (1H, dd, J=2.7, 8.3Hz), 6.
96 (1H, d, J = 2.7Hz), 7.08 (1H, d, J = 8.3Hz),
7.3-7.7 (10H, m). Reference Example 30: Methyl 2-(4-phenylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1.22 g, 3.17 mmol) was dissolved in a mixed solvent of methanol (20 ml) and THF (35 ml), and 1N aqueous sodium hydroxide solution (10 ml) was added. The mixture was stirred at room temperature for 18 hours and at 60° C. for 2 hours. 1N hydrochloric acid (12 ml) was added at room temperature, and the mixture was concentrated under reduced pressure. Water was then added, and the insoluble matter was filtered off. The insoluble matter was washed with water and hexane in that order, and dried under reduced pressure to give 2-(4-phenylbenzyloxy)
-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (1.38
g). ¹ H-NMR (DMSO-d ₆ ) δ: 1.8-2.0 (2H, m), 2.4-2
．． 55 (2H, m), 2.65-2.8 (2H, m), 5.16 (2H, s),
6.91 (1H, dd, J = 2.6, 8.4Hz), 7.08 (1H, d, J =
2.6Hz), 7.12 (1H, d, J = 8.4Hz), 7.3-7.75 (1
0H, m). Example 9 (Preparation of Compound 9) 2-(4-phenylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (200 mg, 0.54 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (131
mg, 0.59 mmol), 1-hydroxybenzotriazole (80 mg, 0
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) was added to a mixture of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) and DMF (10 ml) at 0° C.
The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed successively with water (5 ml x 3), saturated aqueous sodium bicarbonate (5 ml x 3), and saturated saline (5 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-(4-phenylbenzyloxy)-N
-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]
phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 9) (243 mg, 0.42 mmol, 79%) was obtained.

IR (KBr): 1651, 1601, ^{1516 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.55-1.85 (4H, m), 2.0-2
．． 25 (2H, m), 2.21 (3H, s), 2.5-2.85 (5H, m),
3.25-3.45 (2H, m), 3.58 (2H, s), 3.95-4.15
(2H, m), 5.11 (2H, s), 6.87 (1H, dd, J=2.9,8
．． 0Hz), 6.94 (1H, d, J = 2.9Hz), 7.10 (1H, d, J
= 8.0 Hz), 7.2-7.7 (14H, m). Reference Example 31: Methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) was dissolved in DMF (6 ml), potassium carbonate (415 mg, 3.00 mmol) and 4-fluorobenzyl bromide (0.206 ml, 1.65 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with water (5 ml × 2) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 15 g, ethyl acetate/hexane = 1/25). The target fraction was concentrated under reduced pressure to give methyl 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (485 mg, 1.49 mmol, 99%).

IR (KBr): 1707 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.8 (4H, m), 3.82 (3H, s), 5.02 (2H, s), 6.83
(1H, dd, J=2.7, 8.2Hz), 6.92 (1H, d, J=2.7H
z), 7.0-7.15 (2H, m), 7.07 (1H, d, J=8.2Hz)
, 7.35-7.45 (2H, m), 7.64 (1H, s). Reference Example 32: Methyl 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (462 mg, 1.42 mmol) was dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml), and 1N aqueous sodium hydroxide solution (4.3 ml) was added and the mixture was stirred at 50° C. for 2 hours.
After adding water and concentrating under reduced pressure, the insoluble material was filtered off, washed with water and dried under reduced pressure to give 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (458 mg).

Example 10 (Preparation of Compound 10) 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.54 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (144
mg, 0.65 mmol), 1-hydroxybenzotriazole (88 mg, 0
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (209 mg, 1.09 mmol) was added to a mixture of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (209 mg, 1.09 mmol) and DMF (6 ml) at 0° C.
mol) and triethylamine (0.228 ml, 1.64 mmol) were added and stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 15 g
The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-(4-fluorobenzyloxy)-N-[4-[N-methyl-N-
(Tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 10) (228
mg, 0.44 mmol, 81%) was obtained.

IR (KBr): 1651, 1603, ^{1514 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.5-1.85 (4H, m), 2.0-2.
25 (2H, m), 2.21 (3H, s), 2.55-2.85 (5H, m),
3.3-3.45 (2H, m), 3.58 (2H, s), 3.95-4.15 (
2H, m), 5.02 (2H, s), 6.83 (1H, dd, J=2.7, 8.
3Hz), 6.90 (1H, d, J=2.7Hz), 7.0-7.15 (2H,
m), 7.09 (1H, d, J=8.3Hz), 7.29 (1H, s), 7.3
1 (2H, d, J = 8.5Hz), 7.35-7.45 (2H, m), 7.55
(2H, d, J = 8.5 Hz), 7.59 (1H, s). Reference Example 33: Methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) was dissolved in DMF (6 ml), and potassium carbonate (415 mg, 3.00 mmol) and 2,4-difluorobenzyl bromide (0.212 ml, 1.65 mmol) were added and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, followed by water (5 ml x 2).
The organic layer was dried over anhydrous magnesium sulfate, and then washed with saturated saline (5 ml).
The residue was subjected to column chromatography (silica gel 15 g, ethyl acetate/hexane=1/25). The target fraction was concentrated under reduced pressure to give 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8
Methyl carboxylate (500 mg, 1.45 mmol, 97%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.1 (2H, m), 2.55-2
．． 8 (4H, m), 3.82 (3H, s), 5.07 (2H, s), 6.75-
7.0 (4H, m), 7.07 (1H, d, J=8.0Hz), 7.4-7.5
Reference Example 34: Methyl 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (477 mg, 1.39 mmol) was dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml), and 1N aqueous sodium hydroxide solution (4.2 ml) was added and the mixture was stirred at 50° C. for 2 hours.
The insoluble matter was washed with water and dried under reduced pressure to give 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (436 mg, 1.32 mmol).
1,95%) was obtained.

Example 11 (Preparation of Compound 11) 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.51 mmol), 4-[
N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (
136 mg, 0.62 mmol), 1-hydroxybenzotriazole (83 m
g, 0.61 mmol) and DMF (6 ml) at 0° C.
The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (40 ml).
) was added and washed with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-(2,4-difluorobenzyloxy)-N-[4-[N-
Methyl-N-(tetrahydropyran-4-yl)aminomethyl [phenyl[-6
,7-dihydro-5H-benzocycloheptene-8-carboxamide (Compound 1
1) (228 mg, 0.43 mmol, 83%) was obtained.

IR (KBr): 1651, 1601, ^{1510 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.5-1.85 (4H, m), 2.0-2.
25 (2H, m), 2.21 (3H, s), 2.55-2.85 (5H, m),
3.25-3.45 (2H, m), 3.57 (2H, s), 3.95-4.1 (
2H, m), 5.07 (2H, s), 6.75-7.0 (4H, m), 7.09
(1H, d, J=8.0Hz), 7.29 (1H, s), 7.31 (2H, d,
J = 8.6Hz), 7.4-7.65 (1H, m), 7.55 (2H, d, J =
8.6 Hz), 7.59 (1H, s). Reference Example 35: Methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) was dissolved in DMF (6 ml), potassium carbonate (415 mg, 3.00 mmol) and 2,6-difluorobenzyl chloride (268 mg, 1.65 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with water (5 ml × 2) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 15 g, ethyl acetate/hexane = 1/25). The target fraction was concentrated under reduced pressure to give methyl 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (507 mg, 1.47 mmol, 98%).

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.8 (4H, m), 3.82 (3H, s), 5.11 (2H, s), 6.85
-7.0 (2H, m), 6.87 (1H, dd, J=2.8, 8.2Hz), 7
．． 08 (1H, d, J=8.2Hz), 7.25-7.45 (1H, m), 7.
66 (1H, s). Reference Example 36 Methyl 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (486 mg, 1.41 mmol) was dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml), and 1N aqueous sodium hydroxide solution (4.4 ml) was added and the mixture was stirred at 50°C for 6 hours.
The insoluble matter was washed with water and dried under reduced pressure to give 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (450 mg, 1.36 mmol).
1,97%) was obtained.

Example 12 (Preparation of Compound 12) 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.51 mmol), 4-[
N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (
136 mg, 0.62 mmol), 1-hydroxybenzotriazole (83 m
g, 0.61 mmol) and DMF (8 ml) at 0° C.
The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (40 ml).
) was added and washed with saturated sodium bicarbonate water (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and the residue was washed with ethyl acetate (1
0.5 ml of 4N hydrogen chloride (ethyl acetate solution) was added at 0°C, and the insoluble matter was filtered off. The insoluble matter was washed with ethyl acetate and then dried under reduced pressure to give 2-(2,6
-difluorobenzyloxy)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide hydrochloride (Compound 12) (255 mg, 0
. 45 mmol, 87%) was obtained.

IR (KBr): 1651, 1597, ^{1522 cm −1} . ^1H -NMR (DMSO- _d6 ) δ: 1.55-2.2 (6H, m), 2.45
-2.65 (2H, m), 2.59 (3H, s), 2.65-2.85 (2H,
m), 3.2-3.6 (3H, m), 3.9-4.1 (2H, m), 4.12 (
1H, d, J = 12.4Hz), 4.44 (1H, d, J = 12.4Hz), 5
．． 11 (2H, s), 6.93 (1H, dd, J=2.4, 8.1Hz), 7.
07 (1H, d, J = 2.4Hz), 7.1-7.3 (3H, m), 7.25 (
1H, s), 7.45-7.65 (1H, m), 7.53 (2H, d, J=8.
4 Hz), 7.82 (2H, d, J = 8.4 Hz). Reference Example 37: Methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) was dissolved in DMF (6 ml), potassium carbonate (415 mg, 3.00 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.302 ml, 1.65 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with water (5 ml × 2) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 1
The target fraction was concentrated under reduced pressure, and hexane was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with hexane and then dried under reduced pressure to give methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (524 mg, 1
. 22 mmol, 81%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.7 (2H, m), 2.7-2.85 (2H, m), 3.82 (3H, s),
5.16 (2H, s), 6.85 (1H, dd, J=2.7, 8.2Hz), 6
．． 95 (1H, d, J = 2.7Hz), 7.11 (1H, d, J = 8.2Hz)
, 7.66 (1H,s), 7.86 (1H,s), 7.91 (2H,s). Reference Example 38 Methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (494 mg, 1.
The compound (15 mmol) was dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml), and a 1N aqueous solution of sodium hydroxide (3.5 ml) was added, followed by stirring at 50° C. for 4 hours.
1N hydrochloric acid (3.5 ml) was added at 0°C, and the mixture was concentrated under reduced pressure, and then water was added and the insoluble matter was filtered off.
The insoluble material was washed with water and dried under reduced pressure to obtain 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (475 mg, 1.10 mmol, 96%).

Example 13 (Preparation of Compound 13) 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.40 m
mol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline dihydrochloride (127 mg, 0.43 mmol), 1-hydroxybenzotriazole (64 mg, 0.47 mmol), and DMF (8 ml) were added to a mixture of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (151 mg, 0.79 mmol), triethylamine (0.275 ml), and 1-hydroxybenzotriazole (64 mg, 0.47 mmol) at 0° C.
, 1.97 mmol) was added and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, followed by washing with saturated aqueous sodium bicarbonate (10 ml, 5 ml × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was collected by filtration. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-[3,5-bis(trifluoromethyl)benzyloxy]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (Compound 13) (189 mg, 0.30 mmol)
1, 76%) was obtained.

IR (KBr): 1653, 1601, ^{1514 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.6-1.85 (4H, m), 2.0-2.
25 (2H, m), 2.21 (3H, s), 2.55-2.85 (5H, m),
3.25-3.45 (2H, m), 3.58 (2H, s), 3.95-4.1 (
2H, m), 5.16 (2H, s), 6.85 (1H, dd, J=2.7, 8.
2Hz), 6.94 (1H, d, J = 2.7Hz), 7.13 (1H, d, J =
8.2Hz), 7.31 (1H, s), 7.32 (2H, d, J=8.6Hz)
, 7.55 (2H, d, J = 8.6Hz), 7.60 (1H, s), 7.86 (
1H,s), 7.91 (2H,s). Reference Example 39 Triphenylphosphine (590 mg, 2.25 mmol), 4-ethoxybenzyl alcohol (342 mg, 2.25 mmol), 2-hydroxy-6,7
-dihydro-5H-benzocycloheptene-8-carboxylic acid methyl ester (327 mg
, 1.50 mmol) in THF (6 ml), and the resulting mixture was stirred at 0° C. for 1 hour at 37° C. for 1 hour at 37° C.
The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 50 g, ethyl acetate/hexane = 1/25 → 1/19)
The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-
Methyl (4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (308 mg, 0.87 mmol, 58%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0 Hz), 1.
95-2.1 (2H, m), 2.55-2.8 (4H, m), 3.81 (3H,
s), 4.05 (2H, q, J=7.0Hz), 4.97 (2H, s), 6.8
4 (1H, dd, J = 2.7, 8.3Hz), 6.91 (2H, d, J = 8.7
Hz), 6.92 (1H, d, J = 2.7Hz), 7.34 (2H, d, J = 8
Reference Example 40: Methyl 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (296 mg, 0.84 mmol) was dissolved in a mixed solvent of methanol (4 ml) and THF (4 ml), and 1N aqueous sodium hydroxide solution (2.5 ml) was added and the mixture was stirred at 50° C. for 4 hours.
The mixture was concentrated under reduced pressure, water was added, and the insoluble material was filtered off, washed with water, and dried under reduced pressure to give 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (283 mg, 0.84 mmol).

Example 14 (Preparation of Compound 14) 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.50 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (133
mg, 0.60 mmol), 1-hydroxybenzotriazole (81 mg, 0
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol) was added to a mixture of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.01 mmol) and DMF (8 ml) at 0° C.
mol) and triethylamine (0.21 ml, 1.51 mmol) were added and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 15 g
The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-(4-ethoxybenzyloxy)-N-[4-[N-methyl-N-
(tetrahydropyran-4-yl)aminomethyl]phenyl[-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 14) (234
mg, 0.43 mmol, 86%) was obtained.

IR (KBr): 1651, 1601, ^{1514 cm −1} . ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0 Hz), 1.
55-1.85 (4H, m), 2.0-2.25 (2H, m), 2.21 (3H
, s), 2.55-2.85 (5H, m), 3.3-3.45 (2H, m), 3
．． 57 (2H, s), 3.95-4.15 (2H, m), 4.04 (2H, q,
J=7.0Hz), 4.98 (2H, s), 6.84 (1H, dd, J=2.8
, 8.4Hz), 6.90 (1H, d, J=2.8Hz), 6.91 (2H, d
, J=8.8Hz), 7.08 (1H, d, J=8.4Hz), 7.28 (1H
, s), 7.31 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8
.8 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.61 (1H, s). Reference Example 41 3-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (20.32 g, 107 mmol) was dissolved in dimethyl carbonate (500 ml).
The mixture was dissolved in 100°C, sodium methoxide (28.85g, 534mmol) was added, and the mixture was stirred under reflux (100°C) for 6 hours. Under ice-cooling, 2N hydrochloric acid (320ml) was added, and the organic solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (200ml, 150ml x 2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 150g, ethyl acetate/hexane = 1/19). The target fraction was concentrated under reduced pressure to obtain 3-methoxy-5-oxo-6,7,8.9-
Methyl tetrahydro-5H-benzocycloheptene-6-carboxylate (24.2
0 g, 97.51 mol, 91%) was obtained.

Reference Example 42 Methyl 3-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (1079 mg, 4.35 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (2.5 ml), and the resulting mixture was
Sodium borohydride (300 mg, 7.93 mmol) was added at 40°C (internal temperature), and the mixture was stirred at -15 to -10°C for 1.5 hours. The reaction mixture was cooled to -40°C, water (10 ml) was added, and the mixture was extracted with dichloromethane (x3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 ml), and triethylamine (3.03 ml, 21.7 mmol) and methanesulfonyl chloride (0.505 ml, 6.52 mmol) were added at 0°C, and the mixture was stirred at room temperature for 18 hours. DBU (1.95 ml, 13.0 mmol) was added to complete the reaction.
The reaction mixture was concentrated under reduced pressure, water was added, and ethyl acetate (×
The organic layer was washed with 1N hydrochloric acid (×3) and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, ethyl acetate/hexane = 1/19). The target fraction was concentrated under reduced pressure to give methyl 2-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (730 mg, 3.14 mmol, 72%).

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.1 (2H, m), 2.55-2
．． 8 (4H, m), 3.80 (3H, s), 3.82 (3H, s), 6.77 (
1H, dd, J = 2.7, 8.3Hz), 6.85 (1H, d, J = 2.7Hz
) 7.06 (1H, d, J = 8.3 Hz), 7.66 (1H, s). Reference Example 43 Methyl 2-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (5.07 g, 21.8 mmol) in dichloromethane (100 ml)
Boron tribromide (1M dichloromethane solution, 87 ml) was added dropwise at −60° C. to −70° C. (internal temperature), and the mixture was stirred for 5 hours while the temperature was raised from −70° C. to room temperature. Diethyl ether and water (100 ml) were added in this order, and dichloromethane (100 ml) was added.
The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (150 ml), sulfuric acid (0.5 ml) was added, and the mixture was stirred under reflux (100°C) for 24 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (30 ml x 3). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure.
Methyl 5H-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (4.31 g, 19.7 mmol, 90%) was obtained.

IR (KBr): 1686 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.95-2.15 (2H, m), 2.55-
2.8 (4H, m), 3.82 (3H, s), 6.71 (1H, dd, J=2.
5,8.1Hz), 6.81 (1H, d, J=2.5Hz), 7.02 (1H,
Reference Example 44: Methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (400 mg, 1.83 mmol) was dissolved in DMF (8 ml), and potassium carbonate (507 mg, 3.67 mmol) and cyclohexylmethyl bromide (0.511 ml, 3.66 mmol) were added. The mixture was stirred at room temperature for 23 hours and at 100° C. for 6 hours.
The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate (x3). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate/hexane = 1/19). The target fraction was concentrated under reduced pressure, and hexane was added to the residue to filter out the insoluble matter. The insoluble matter was washed with hexane and then dried under reduced pressure to obtain 2-cyclohexylmethyloxy-6,7-
Methyl dihydro-5H-benzocycloheptene-8-carboxylate (452 mg,
1.44 mmol, 78%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 0.9-2.1 (13H, m), 2.55-2
．． 8 (4H, m), 3.74 (2H, d, J = 6.2Hz), 3.81 (3H,
s), 6.76 (1H, dd, J=2.5, 8.1Hz), 6.84 (1H, d
, J=2.5Hz), 7.04 (1H, d, J=8.1Hz), 7.65 (1H
Reference Example 45: Methyl 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (425 mg, 1.35 mmol) was dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml), and 1N aqueous sodium hydroxide solution (4 ml) was added and the mixture was stirred at 50°C for 6 hours. 1N hydrochloric acid (4 ml) was added at 0°C, and the mixture was concentrated under reduced pressure. Water was then added and the insoluble matter was filtered off. The insoluble matter was washed with water and dried under reduced pressure to give 2-
Cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (389 mg, 1.29 mmol, 96%) was obtained.

Example 15 (Preparation of Compound 15) 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.57 mmol), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (150 mg
, 0.68 mmol), 1-hydroxybenzotriazole (84 mg, 0.6
2 mmol) and DMF (6 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (217 mg, 1.13 mmol) was added at 0° C.
1), triethylamine (0.237 ml, 1.70 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, followed by washing with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10 ml). 4N hydrogen chloride (ethyl acetate solution, 0.285 ml) was added at 0°C, and the insoluble matter was collected by filtration. The insoluble matter was washed with ethyl acetate and then dried under reduced pressure to give 2-cyclohexylmethyloxy-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide hydrochloride (Compound 15) (258 mg, 0.48 mmol,
85%) was obtained.

IR (KBr): 1651, 1601, ^{1522 cm −1} . ¹ H-NMR (DMSO-d ₆ ) δ: 0.9-1.4 (5H, m), 1.5-2
．． 2 (12H, m), 2.4-2.65 (2H, m), 2.59 (3H, s),
2.65-2.8 (2H, m), 3.2-3.6 (3H, m), 3.77 (2H
, d, J=5.8Hz), 3.9-4.1 (2H, m), 4.12 (1H, d,
J = 12.4Hz), 4.43 (1H, d, J = 12.4Hz), 6.80 (1
H, dd, J=2.5, 8.6Hz), 6.94 (1H, d, J=2.5Hz)
, 7.12 (1H, d, J=8.6Hz), 7.25 (1H, s), 7.54 (
2H, d, J=8.6Hz), 7.81 (2H, d, J=8.6Hz), 10.
14 (1H, s). Reference Example 46 Triphenylphosphine (1.18 g, 4.50 mmol), cyclohexanol (0.468 ml, 4.50 mmol), methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.5
The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 45 g, ethyl acetate/hexane = 1/25). The target fraction was concentrated under reduced pressure to give methyl 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (434 mg, 1.44 mmol, 96%).
%) was obtained.

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.15-2.1 (12H, m), 2.55-
2.65 (2H, m), 2.65-2.8 (2H, m), 3.81 (3H, s)
, 4.1-4.3 (1H, m), 6.77 (1H, dd, J = 2.7, 8.1H
z), 6.85 (1H, d, J=2.7Hz), 7.03 (1H, d, J=8.
Reference Example 47: Methyl 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (412 mg, 1.37 mmol) was dissolved in methanol (5 m
The mixture was dissolved in a mixed solvent of 1N sodium hydroxide (4.
1N hydrochloric acid (4.0 ml) was added at 0°C and the mixture was stirred at 50°C for 6 hours. After adding 1N hydrochloric acid (4.0 ml) at 0°C and concentrating under reduced pressure, water was added and the insoluble matter was filtered off. The insoluble matter was washed with water and dried under reduced pressure to give 2
-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8
-carboxylic acid (388 mg, 1.35 mmol, 99%) was obtained.

Example 16 (Preparation of Compound 16) 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (170 mg, 0.59 mmol), 4-[N-methyl-N-
(tetrahydropyran-4-yl)aminomethyl]aniline (157 mg, 0.
71 mmol), 1-hydroxybenzotriazole (96 mg, 0.71 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (228 mg, 1.19 mmol), ...
Triethylamine (0.248 ml, 1.78 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, followed by washing with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the residue, and the insoluble matter was collected by filtration. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give 2-cyclohexyloxy-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (Compound 16) (248 mg, 0.51 mm
ol, 85%) was obtained.

IR (KBr): 1651, 1601, ^{1514 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.15-2.25 (16H, m), 2.21
(3H, s), 2.5-2.85 (5H, m), 3.25-3.45 (2H, m
), 3.57 (2H, s), 3.95-4.1 (2H, m), 4.1-4.3 (
1H, m), 6.77 (1H, dd, J=2.7, 8.2Hz), 6.85 (1
H, d, J = 2.7Hz), 7.06 (1H, d, J = 8.2Hz), 7.29
(1H, s), 7.31 (2H, d, J=8.4Hz), 7.55 (2H, d,
J = 8.4 Hz), 7.60 (1H, s). Reference Example 48 Triphenylphosphine (2361 mg, 9.00 mmol), 1-tert
-Butoxycarbonyl-4-hydroxypiperidine (1812 mg, 9.00 m
mol), 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-
Methyl 8-carboxylate (655 mg, 3.00 mmol) in THF (15 ml)
Diisopropyl azodicarboxylate (1.772 ml, 9
A solution of 2 ml of 2-[0.00 mmol] ...
(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7
-dihydro-5H-benzocycloheptene-8-carboxylic acid methyl ester (1270m
g) was obtained.

IR (KBr): 1698 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.47 (9H, s), 1.6-2.1 (6H
, m), 2.55-2.7 (2H, m), 2.7-2.8 (2H, m), 3.2
-3.45 (2H, m), 3.6-3.8 (2H, m), 3.82 (3H, s)
, 4.35-4.55 (1H, m), 6.78 (1H, dd, J=2.7, 8.
3Hz), 6.87 (1H, d, J = 2.7Hz), 7.05 (1H, d, J =
8.3 Hz), 7.63 (1H, s). Reference Example 49 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]
Methyl 6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1
245 mg, 3.10 mmol) in methanol (10 ml) and THF (10 ml
), and 1N aqueous sodium hydroxide solution (9.3 ml) was added and the mixture was stirred at room temperature for 23 hours. 1N hydrochloric acid (9.3 ml) was added at 0°C, and the mixture was concentrated under reduced pressure. Water was added and the insoluble matter was filtered off. The insoluble matter was washed with water and dried under reduced pressure to obtain 2-[(1-tert-
butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H
-benzocycloheptene-8-carboxylic acid (1150 mg, 2.97 mmol,
96%) was obtained.

Example 17 (Preparation of Compound 17) 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]
-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (1088
mg, 2.81 mmol), 4-[N-methyl-N-(tetrahydropyran-4
-yl)aminomethyl]aniline hydrochloride (742 mg, 3.37 mmol), 1
-hydroxybenzotriazole (455 mg, 3.37 mmol), DMF (
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1077 mg, 5.62 mmol) and triethylamine (1.174 ml, 8.42 mmol) were added to a mixture of 1,000 ml of ethyl acetate and 30 ml of ethyl acetate at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (160 ml) was added to the residue, and saturated aqueous sodium bicarbonate (40 ml) was added.
The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 70 g, ethyl acetate). The target fraction was concentrated under reduced pressure to give 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (Compound 17) (1446 mg, 2.45 m
mol, 87%) was obtained.

IR (KBr): 1694, 1667, 1599 ^{, 1514 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.47 (9H, s), 1.5-2.0 (8H
, m), 2.0-2.25 (2H, m), 2.21 (3H, s), 2.5-2.
85 (5H, m), 3.2-3.45 (4H, m), 3.57 (2H, s), 3
．． 6-3.8 (2H, m), 3.95-4.1 (2H, m), 4.35-4.5
(1H, m), 6.78 (1H, dd, J=2.6, 8.2Hz), 6.85 (
1H, d, J = 2.6Hz), 7.07 (1H, d, J = 8.2Hz), 7.2
9 (1H, s), 7.31 (2H, d, J = 8.4Hz), 7.55 (2H, d
, J = 8.4 Hz), 7.61 (1H, s). Reference Example 50 Triphenylphosphine (1.18 g, 4.50 mmol), tetrahydropyran-4-ol (0.429 ml, 4.50 mmol), 2-hydroxy-6
,7-dihydro-5H-benzocycloheptene-8-carboxylic acid methyl ester (327
mg, 1.50 mmol) in THF (10 ml), and a solution of diisopropyl azodicarboxylate (0.886 ml, 4.50 mmol) in THF (2
A solution of 2,3-dimethyl-5H-benzocycloheptene-8-carboxylic acid (2,3-dimethyl-5H-benzocycloheptene-8-yl) was added to the reaction mixture and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 45 g, ethyl acetate/hexane = 1/25). The target fraction was concentrated under reduced pressure to give methyl 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (427 mg, 1.41 mmol, 94%).

IR (KBr): 1709 cm ⁻¹ . ^1H -NMR ( _CDCl3 ) δ: 1.65-1.9 (2H, m), 1.9-2.
1 (4H, m), 2.55-2.7 (2H, m), 2.7-2.8 (2H, m)
, 3.5-3.65 (2H, m), 3.82 (3H, s), 3.9-4.05 (
2H, m), 4.35-4.55 (1H, m), 6.79 (1H, dd, J=2
．． 4,8.3Hz), 6.87 (1H, d, J=2.4Hz), 7.05 (1H
, d, J = 8.3 Hz), 7.63 (1H, s). Reference Example 51 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H
- methyl benzocycloheptene-8-carboxylate (406 mg, 1.34 mmol)
l) was dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml), and 1N aqueous sodium hydroxide solution (4.0 ml) was added, followed by stirring at 60°C for 5 hours.
Hydrochloric acid (4.0 ml) was added, and the mixture was concentrated under reduced pressure. Water was then added, and the insoluble matter was filtered off. The insoluble matter was washed with water and dried under reduced pressure to give 2-[(tetrahydropyran-4-yl)oxy]-6,
7-Dihydro-5H-benzocycloheptene-8-carboxylic acid (370 mg, 1
. 28 mmol, 96%) was obtained.

Example 18 (Preparation of Compound 18) 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H
-benzocycloheptene-8-carboxylic acid (170 mg, 0.59 mmol),
A mixture of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline dihydrochloride (190 mg, 0.65 mmol), 1-hydroxybenzotriazole (96 mg, 0.71 mmol), and DMF (8 ml) was added at 0° C. for 1 hour.
-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2
26 mg, 1.18 mmol), triethylamine (0.411 ml, 2.95
The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) was added to the residue, which was then washed with saturated aqueous sodium bicarbonate (10 ml, 5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate). The target fraction was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10 ml). 4N hydrogen chloride (ethyl acetate solution, 0
The insoluble matter was washed with ethyl acetate and then dried under reduced pressure to give 2-[(tetrahydropyran-4-yl)oxy]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6,7-
Dihydro-5H-benzocycloheptene-8-carboxamide hydrochloride (Compound 1
8) (264 mg, 0.50 mmol, 85%) was obtained.

IR (KBr): 1649, 1597, ^{1522 cm −1} . ^1H -NMR (DMSO- _d6 ) δ: 1.45-2.2 (10H, m), 2.4
5-2.65 (2H, m), 2.59 (3H, s), 2.65-2.8 (2H,
m), 3.2-3.55 (5H, m), 3.75-4.1 (4H, m), 4.1
2 (1H, d, J = 13.1Hz), 4.44 (1H, d, J = 13.1Hz)
, 4.45-4.65 (1H, m), 6.86 (1H, dd, J=2.4, 8.
1Hz), 7.02 (1H, d, J = 2.4Hz), 7.13 (1H, d, J =
8.1Hz), 7.25 (1H, s), 7.55 (2H, d, J=8.4Hz)
, 7.82 (2H, d, J = 8.4 Hz). Reference Example 52: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-propoxyphenethyl alcohol (537 mg), triphenylphosphine (782 mg) in THF (10 ml).
To the solution, diethyl azodicarboxylate (40% toluene solution) (1.36 m
After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/hexane 1:1) to give methyl 7-[(4-propoxyphenethyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.2 g).

7-[(4-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (1.2 g) in THF/
To a solution of methanol (10/5 ml) was added an aqueous solution (2.1 ml) of potassium carbonate (622 mg) at room temperature, and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[(4-propoxyphenethyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (330 mg) as colorless crystals.

^1H -NMR (200MHz, DMSO- _d6 ) δ0.97 (3H, t, J=
7.5Hz), 1.62-1.80 (2H, m), 2.86-2.92 (2H,
m), 2.99 (2H, t, J = 7.0Hz), 3.63-3.70 (2H, m
), 3.89 (2H, t, J = 6.6Hz), 4.28 (2H, t, J = 7.0
Hz), 6.86 (2H, d, J=8.8Hz), 7.13 (1H, dd, J=
8.8, 2.6Hz), 7.23 (2H, d, J = 8.8Hz), 7.33 (1
H, d, J = 2.6Hz), 7.72 (1H, s), 7.91 (1H, d, J =
8.8 Hz). Reference Example 53: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-propoxybenzyl alcohol (
To a solution of 495 mg of diethyl azodicarboxylate and 782 mg of triphenylphosphine in 10 ml of THF, diethyl azodicarboxylate (40% solution in toluene) (1.36 ml) was added at 0° C.
The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/hexane 1:2) to give 7-(3-propoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-
Methyl 4-carboxylate (650 mg) was obtained.

Methyl 7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/
To a solution of methanol (5/2.5 ml) was added an aqueous solution (2.1 ml) of potassium carbonate (622 mg) at room temperature, and the mixture was stirred at 60°C for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure.
The precipitated crystals were collected by filtration, washed with diisopropyl ether, and
There was obtained 7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (379 mg) as colorless crystals.

m. p. 205-206°C ^1H -NMR (200MHz, DMSO- _d6 ) δ0.97 (3H, t, J=
7.3Hz), 1.63-1.82 (2H, m), 2.87-2.93 (2H,
m), 3.65-3.71 (2H, m), 3.93 (2H, t, J=6.4Hz
), 5.22 (2H, s), 6.88-6.93 (1H, m), 6.99-7.
03 (2H, m), 7.22 (1H, dd, J=8.7, 2.5Hz), 7.3
0 (1H, t, J = 8.8Hz), 7.43 (1H, d, J = 2.5Hz), 7
．． 72 (1H, s), 7.94 (1H, d, J=8.7Hz). Elemental analysis C ₂₁ H ₂₂ O ₆ S Calcd. C, 62.67; H, 5.51
Found. C, 62.35; H, 5.45. Reference Example 54: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-propoxybenzyl alcohol (
To a solution of 537 mg of diethyl azodicarboxylate and 782 mg of triphenylphosphine in 10 ml of THF, diethyl azodicarboxylate (40% solution in toluene) (1.36 ml) was added at 0° C.
After stirring at room temperature for 22 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/hexane 1:2) to give methyl 7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.67 g).

Methyl 7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.67 g) in THF/
To a solution of methanol (10/5 ml) was added an aqueous solution (2.1 ml) of potassium carbonate (622 mg) at room temperature, and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1N hydrochloric acid (15 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (270 mg) as pale yellow crystals.

m. p. 157-160°C ^1H -NMR (200MHz, DMSO- _d6 ) δ0.96 (3H, t, J=
7.4Hz), 1.64-1.82 (2H, m), 2.91 (2H, t, J=6
．． 4Hz), 3.68 (2H, t, J = 6.4Hz), 4.00 (2H, t, J
= 6.4Hz), 5.20 (2H, s), 6.96 (1H, t, J = 7.2Hz
), 7.05 (1H, d, J=8.4Hz), 7.20 (1H, dd, J=8.
8, 2.4Hz), 7.28-7.44 (3H, m), 7.72 (1H, s),
7.94 (1H, d, J=8.8Hz). Elemental analysis C ₂₁ H ₂₂ O ₆ S Calcd. C, 62.67; H, 5.51
Found. C, 62.40; H, 5.38. Example 19 (Preparation of Compound 19) 7-[(4-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (5 m
To the solution of N-methyl-N-(tetrahydropyran-4-yl)aminomethyl-aniline (105 mg) and triethylamine (0.18 ml) were added thionyl chloride (0.063 ml) and DMF (1 drop) at room temperature, and the mixture was stirred for 1 hour. After the solvent was evaporated under reduced pressure, the residue was dissolved in THF (10 ml) and stirred at room temperature with 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (105 mg) and triethylamine (0.18 ml) for 1 hour.
The mixture was added dropwise to a HF (2 ml) solution. After stirring at room temperature for 5 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol/ethyl acetate 1:2).
and purified by recrystallization (ethanol) to give N-[4-[N
-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-
7-[(4-propoxyphenethyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 19) (153 mg
) was obtained.

m. p. 157-158°C ^1H -NMR (200MHz, _CDCl3 ) δ1.03 (3H, t, J=7.
3Hz), 1.62-1.86 (6H, m), 2.21 (3H, s), 2.54
-2.71 (1H, m), 2.99-3.13 (4H, m), 3.29-3.4
5 (2H, m), 3.57 (2H, s), 3.63-3.70 (2H, m), 3
．． 90 (2H, t, J=6.6Hz), 3.97-4.09 (2H, m), 4.
19 (2H, t, J = 7.0Hz), 6.84-6.95 (4H, m), 7.1
8 (2H, d, J = 8.4Hz), 7.19 (1H, s), 7.32 (2H, d
, J=8.4Hz), 7.53 (2H, d, J=8.4Hz), 7.79 (1H
, s), 8.06 (1H, d, J=8.8Hz). Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.
84;N, 4.53:Found. C, 68.13; H, 6.83; N, 4.4
9. Example 20 (Preparation of Compound 20) 7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) was dissolved in THF (5 ml
To the solution of N-methyl-N-(tetrahydropyran-4-yl)aminomethyl-aniline (108 mg) and triethylamine (0.19 ml), thionyl chloride (0.065 ml) and DMF (1 drop) were added at room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
The mixture was stirred at room temperature for 67 hours, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol/ethyl acetate 1:3).
and purified by recrystallization (ethanol) to give N-[4-[N
-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-
7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 20) (204 mg)
obtained.

m. p. 197-199°C ^1H -NMR (200MHz, _CDCl3 ) δ1.04 (3H, t, J=7.
3Hz), 1.64-1.87 (6H, m), 2.20 (3H, s), 2.54
-2.72 (1H, m), 3.06-3.13 (2H, m), 3.29-3.4
5 (2H, m), 3.57 (2H, s), 3.65-3.72 (2H, m), 3
．． 93 (2H, t, J=6.4Hz), 3.98-4.09 (2H, m), 5.
12 (2H, s), 6.85-7.07 (4H, m), 7.20 (1H, s),
7.30-7.34 (4H, m), 7.53 (2H, d, J=8.4Hz), 7
．． 76 (1H, s), 8.09 (1H, d, J=8.8Hz). Elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S Calcd. C, 67.53; H, 6.
67;N, 4.63:Found. C, 67.49; H, 6.63; N, 4.4
6. Example 21 (Preparation of Compound 21) 7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) was dissolved in THF (5 ml
To the solution of N-methyl-N-(tetrahydropyran-4-yl)aminomethyl-aniline (108 mg) and triethylamine (0.18 ml), thionyl chloride (0.065 ml) and DMF (1 drop) were added at room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
The mixture was stirred at room temperature for 2 days, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol/ethyl acetate 1:3) and recrystallization (ethanol) to obtain N-[4-[N-
Methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 21) (139 mg) was obtained.

m. p. 190-192°C ^1H -NMR (200MHz, _CDCl3 ) δ1.03 (3H, t, J=7.
3Hz), 1.63-1.87 (6H, m), 2.20 (3H, s), 2.55
-2.73 (1H, m), 3.09 (2H, t, J=6.6Hz), 3.31-
3.43 (2H, m), 3,57 (2H, s), 3.68 (2H, t, J=6.
6Hz), 4.00 (2H, t, J=6.4Hz), 3.98-4.10 (2H
, m), 5.21 (2H, s), 6.90-7.02 (3H, m), 7.07 (
1H, dd, J=8.8, 2.6Hz), 7.21 (1H, s), 7.28-7
．． 41 (4H, m), 7.53 (2H, d, J = 8.4Hz), 7.77 (1H
, s), 8.08 (1H, d, J=8.4Hz). Elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S Calcd. C, 67.53; H, 6.
67;N, 4.63:Found. C, 67.69; H, 6.65; N, 4.5
3. Reference Example 55 2-hydroxy-5-bromobenzyl alcohol (3.00 g), 2-bromo-4′-methylacetophenone (3.50 g) and potassium carbonate (2.45 g)
and acetone (50 ml) was stirred at 80° C. for 4 hours. After cooling to room temperature,
The solid was removed by filtration and concentrated under reduced pressure. The residue was purified by column chromatography (
Separation and purification were carried out using ethyl acetate/hexane (2:3 → 1:1) to obtain colorless crystals of 2-[
4-Bromo-2-(hydroxymethyl)phenoxy]-1-(4-methylphenyl)-1-ethanone (3.60 g) was obtained.

m. p. 125-127℃¹ H-NMR (200MHz, CDCl₃) δ2.44 (3H, s), 3.43
(1H, t, J=6.8Hz), 4.73 (2H, d, J=6.8Hz), 5.
36 (2H, s), 6.72 (1H, d, J=8.8Hz), 7.24-7.3
6 (3H, m), 7.45 (1H, d, J = 2.6Hz), 7.86 (2H, d
, J=8.4Hz). IR (KBr) 3412, 1686, 1606, 1483, 1412, 1234
,1018,810cm⁻¹ Elemental analysis C₁₆H₁₅O₃Br Calcd. C, 57.33; H, 4.51
;Br, 23.84: Found. C, 57.33; H, 4.41; Br, 23
. 86. Reference Example 56 2-[4-bromo-2-(hydroxymethyl)phenoxy]-1-(4-methyl
A solution of (1-phenyl)-1-ethanone (3.00 g) in acetonitrile (20 ml)
Triphenylphosphine hydrobromide (3.17 g) was added to the mixture at room temperature, and the mixture was placed under a nitrogen atmosphere.
After cooling to room temperature, diethyl ether was added and the resulting solution was
The crystals were collected by filtration, and the resulting product was 5-bromo-2-[2-(4-
(methylphenyl)-2-oxoethoxy]benzyl](triphenyl)phosphony
As a result, 5.94 g of methylcellulose was obtained.¹ H-NMR (200MHz, CDCl₃) δ2.44 (3H, s), 4.82
(2H, s), 5.29 (2H, d, J=14.0Hz), 6.75 (1H, d
, J=8.8Hz), 7.25-7.39 (4H, m), 7.52-7.81 (
15H, m), 7.88 (2H, d, J=8.2Hz). IR (KBr) 1691, 1489, 1437, 1234, 1120, 816,
748,717,689,505cm⁻¹ Reference Example 57 5-bromo-2-[2-(4-methylphenyl)-2-oxoethoxy] bromide
]benzyl](triphenyl)phosphonium (5.53 g) in ethanol (20
ml) suspension was added to a 20% ethanol solution of sodium ethoxide (2.8 ml) at room temperature.
After adding water (15 ml) to the reaction mixture, the solid was filtered off.
The solid was collected by filtration and washed with water. It was purified by recrystallization (ethanol) to give a colorless solid.
6-Bromo-3-(4-methylphenyl)-2H-1-benzopyran as a crystal
(2.16 g) was obtained.

m. p. 143℃ (dec.)¹ H-NMR (200MHz, CDCl₃) δ2.38 (3H, s), 5.15
(2H, d, J=1.4Hz), 6.69-6.74 (2H, m), 7.16-
7.28 (4H, m), 7.33 (2H, d, J=8.4Hz). IR (KBr) 1479, 1217, 898, 813cm⁻¹ Elemental analysis C₁₆H₁₃OBr Calcd. C, 63.81; H, 4.35;
Br, 26.53: Found. C, 63.67; H, 4.37; Br, 26.
50. Reference Example 58 Under a nitrogen atmosphere, 6-bromo-3-(4-methylphenyl)-2H-1-benzothiazolinone was
A solution of pyran (0.5 g) in THF (15 ml) was added to 1.6 M butyl phosphate buffer at -78°C.
The mixture was stirred at -78°C for 1 hour.
After that, dry ice was added to the reaction mixture and stirred for another hour.
After adding 100 ml of ethyl acetate, the organic layer was washed with saturated saline and added with magnesium sulfate.
The resulting crystals were collected by filtration and dried over sodium hydroxide.
Washing with ethyl ether and hexane yielded 3-(4-methylphenyl)-
To the obtained product, 218 mg of methyl-2H-1-benzopyran-6-carboxylic acid was obtained.

m. p. 255℃ (dec.)¹ H-NMR (200MHz, CDCl₃) δ2.33 (3H, s), 5.27
(2H, d, J=1.0Hz), 6.89 (1H, d, J=8.2Hz), 7.
10 (1H, s), 7.24 (2H, d, J = 8.3Hz), 7.48 (2H,
d, J = 8.3Hz), 7.71 (1H, dd, J = 8.2, 2.2Hz), 7
．． 77 (1H, d, J=2.2Hz). IR (KBr) 2976, 1676, 1302, 1223, 806cm⁻¹ Elemental analysis C₁₇H₁₄O₃ Calcd. C, 76.68; H, 5.30: F
sound. C, 76.47; H, 5.37. Example 22 (Preparation of Compound 22) 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (13
To a solution of 0.000 mg of oxalyl chloride (0.07 mcg) in THF (10 ml),
The solvent was evaporated under reduced pressure, and the residue was
Dissolved in THF (20 ml) and heated at 0° C. to prepare 4-[N-methyl-N-(tetrahydrofuran)]
pyran-4-yl)aminomethyl]aniline (118 mg), and triethyl
Amine (0.15 ml) was added and stirred at room temperature for 3 hours.
The reaction was stopped by adding water to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline.
After concentration under reduced pressure, the residue was recrystallized (ethanol
) and obtained as pale yellow crystals 3-(4-methylphenyl)-N-[4
-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
[0046] -2H-1-benzopyran-6-carboxamide (compound 22) (162m
g) was obtained.

m. p. 230-235℃¹ H-NMR (200MHz, CDCl₃) δ1.52-1.84 (4H, m)
, 2.21 (3H, s), 2.39 (3H, s), 2.56-2.74 (1H,
m), 3.30-3.45 (2H, m), 3.58 (2H, s), 3.99-4
．． 10 (2H, m), 5.26 (2H, d, J = 1.6Hz), 6.82 (1H
, s), 6.90 (1H, d, J = 9.2Hz), 7.22 (2H, d, J = 8
．． 0Hz), 7.30-7.37 (4H, m), 7.56-7.66 (4H, m
), 7.72 (1H, br s). IR (KBr) 3305, 2947, 2843, 1647, 1599, 1518
,1491,1406,1315,1238,1140,810cm⁻¹ Elemental analysis C₃₀H₃₂N2O₃・0.2H₂O Calcd. C, 76.31
; H, 6.92; N, 5.93: Found. C, 76.31; H, 7.02;
N, 5.88. Reference Example 59 Sodium ethoxide (20% ethanol solution, 22.2 g) in toluene (1
4-Bromobenzaldehyde (10 g) and azide acetate were added to a solution of 100 ml of 4-bromobenzaldehyde at 0° C.
A solution of ethyl acetate (7.0 g) in toluene (50 ml) was added over 10 minutes.
After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate.
After concentration under reduced pressure, the residue was purified by column chromatography.
The product was purified by chromatography (ethyl acetate/hexane 1:19) to give a yellow oil.
and (Z)-2-azido-3-(4-bromophenyl)-ethyl acrylate (6.
24 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.40 (3H, t, J=7.2
Hz), 4.38 (2H, q, J=7.2Hz), 6.83 (1H, s), 7.
51 (2H, d, J=8.6Hz), 7.69 (2H, d, J=8.6Hz).
IR (neat) 2121, 1713, 1398, 1379, 1315, 128
1,1250,1076,1011,824cm⁻¹ Reference Example 60 (Z)-2-azido-3-(4-bromophenyl)ethyl acrylate (6.2
A solution of 4 g of the compound in xylene (200 ml) was heated under reflux for 4 hours. After cooling to room temperature,
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
Washing with water gave colorless crystals of 6-bromo-1H-indole-2-carboxone.
Ethyl acetate (3.21 g) was obtained.

m. p. 187-188℃¹ H-NMR (200MHz, CDCl₃) δ1.43 (3H, t, J=7.2
Hz), 4.41 (2H, q, J = 7.2Hz), 7.18-7.28 (2H,
m), 7.53-7.59 (2H, m), 8.78-8.97 (1H, m). IR (KBr) 3321, 1695, 1522, 1315, 1240, 1201
,1020,822,763,733cm⁻¹ Elemental analysis C₁₁H₁₀NO₂Br Calcd. C, 49.28; H, 3.7
6; N, 5.22: Found. C, 49.45; H, 3.63; N, 5.06
Reference Example 61 Under an argon atmosphere, 6-bromo-1H-indole-2-ethyl carboxylate (
2.5 g), 4-methylphenylboronic acid (1.39 g) and potassium carbonate (2.
58 g) in a toluene/ethanol/water (90/9/9 ml) mixture at room temperature for 1 hour.
The reaction mixture was stirred for 1 hour. Tetrakistriphenylphosphine palladium (0.32
g) was added and the mixture was heated under reflux for 18 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue
Column chromatography (ethyl acetate/hexane 1:5 → 1:2 → 1:1) and
and recrystallization (ethyl acetate/hexane) to give colorless crystals of 6-(4-methyl-
1.92 g of ethyl 1H-indole-2-carboxylate was obtained.
.

m. p. 163-165℃¹ H-NMR (200MHz, CDCl₃) δ1.43 (3H, t, J=7.2
Hz), 2.41 (3H, s), 4.42 (2H, q, J=7.2Hz), 7.
23-7.27 (2H, m), 7.29 (1H, s), 7.41 (1H, dd,
J=8.4, 1.6Hz), 7.51-7.61 (3H, m), 7.73 (1H
, d, J=8.4Hz), 8.86-8.98 (1H, m). IR (KBr) 3290, 1689, 1520, 1333, 1282, 1217
,820,795cm⁻¹ Elemental analysis C₁₈H₁₇NO₂ Calcd. C, 77.40; H, 6.13;
N, 5.01: Found. C, 77.48; H, 6.21; N, 4.89. Reference Example 62 6-(4-methylphenyl)-1H-indole-2-carboxylate ethyl ester (0
6 g) in a mixed solution of ethanol/THF (10/10 ml), and 2N hydroxylase was added at room temperature.
Aqueous sodium chloride solution (5 ml) was added and stirred for 64 hours.
After adding 5 ml of the mixture, the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The precipitated crystals were collected by filtration. The crystals were washed with hexane to give colorless crystals.
6-(4-methylphenyl)-1H-indole-2-carboxylic acid (509m
g) was obtained.

m. p. 260℃ (dec.)¹ H-NMR (200MHz, DMSO-d₆) δ2.35 (3H, s), 7.
10 (1H, s), 7.28 (2H, d, J = 8.0Hz), 7.35 (1H,
dd, J=8.4, 1.8Hz), 7.56 (2H, d, J=8.0Hz), 7
．． 61 (1H, d, J = 1.8Hz), 7.71 (1H, d, J = 8.4Hz)
, 11.81 (1H, s). IR (KBr) 3410, 1666, 1525, 1439, 1273, 1215
, 800 cm⁻¹ Elemental analysis C₁₆H₁₃NO₂ Calcd. C, 76.48; H, 5.21;
N, 5.57: Found. C, 76.66; H, 5.05; N, 5.34. Example 23 (Preparation of Compound 23) 6-(4-methylphenyl)-1H-indole-2-carboxylic acid (200 ml)
g) in THF (10 ml) at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in TH
F (20 ml), and 4-[N-methyl-N-(tetrahydropyridine)
(4-aminomethyl)aniline (193 mg), and triethylaminomethyl
The reaction mixture was stirred vigorously at room temperature for 18 hours.
The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
After concentration under reduced pressure, the precipitated crystals were recrystallized (ethanol).
The compound was purified by ethanol and obtained as colorless crystals of 6-(4-methylphenyl)-N-[
4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
[Nyl]-1H-indole-2-carboxamide (compound 23) (97 mg)
Got it.

m. p. 246-250℃¹ H-NMR (200MHz, DMSO-d₆) δ1.45-1.79 (4H,
m), 2.12 (3H, s), 2.36 (3H, s), 2.46-2.69 (1
H, m), 3.19-3.38 (2H, m), 3.54 (2H, s), 3.84
-3.96 (2H, m), 7.24-7.46 (6H, m), 7.57 (2H,
d, J=8.0Hz), 7.66 (1H, s), 7.69-7.80 (3H, m
), 10.20 (1H, s), 11.78 (1H, s). IR (KBr) 3298, 1655, 1601, 1537, 1333, 812c
m⁻¹ Elemental analysis C₂₉H₃₁N₃O₂・0.2H₂O Calcd. C, 76.19
; H, 6.92; N, 9.19: Found. C, 76.01; H, 6.81;
N, 9.12. Reference Example 63 6-(4-methylphenyl)-1H-indole-2-carboxylate ethyl ester (0
To a solution of 0.9 g of methylpropanol in DMF (10 ml) was added sodium hydride (60%, 0.
14 g) was added and stirred for 15 minutes. Methyl iodide (0.22 ml) was added to the reaction system.
The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine and dried over magnesium sulfate.
The product was separated and purified by column chromatography (ethyl acetate/hexane 1:4), and then
Recrystallization (ethyl acetate/hexane) gave 1-methyl-6-(2-methyl-2-methyl-4-methyl-2-methyl-2-methyl-1 ...
Ethyl (4-methylphenyl)-1H-indole-2-carboxylate (0.80
g) was obtained.

m. p. 98-99℃¹ H-NMR (200MHz, CDCl₃) δ1.42 (3H, t, J=7.0
Hz), 2.41 (3H, s), 4.12 (3H, s), 4.38 (2H, q,
J=7.0Hz), 7.26-7.32 (3H, m), 7.40 (1H, dd,
J=8.4, 1.4Hz), 7.54-7.60 (3H, m), 7.71 (1H
, d, J=8.4Hz). IR (KBr) 1705, 1504, 1400, 1223, 1153, 1084
,822,798cm⁻¹ Elemental analysis C₁₉H₁₉NO₂ Calcd. C, 77.79; H, 6.53;
N, 4.77: Found. C, 77.99; H, 6.50; N, 4.60. Reference Example 64 1-Methyl-6-(4-methylphenyl)-1H-indole-2-carvone
A solution of ethyl acetate (0.7 g) in ethanol/THF (20/10 ml) was added to the chamber.
A 2N aqueous solution of sodium hydroxide (1.5 ml) was added at room temperature, and the mixture was stirred for 24 hours.
After adding 1N hydrochloric acid (5 ml) to the reaction mixture, it was concentrated under reduced pressure. Water was added to the residue, and acetic acid was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with hexane.
1-methyl-6-(4-methylphenyl)-1H-indoline as colorless crystals
To give 600 mg of 2-methyl-2-carboxylic acid.

m. p. 259℃ (dec.)¹ H-NMR (200MHz, DMSO-d₆) δ2.36 (3H, s), 4.
09 (3H, s), 7.23 (1H, s), 7.29 (2H, d, J = 7.6H
z), 7.42 (1H, dd, J=8.4, 1.4Hz), 7.66-7.74
(3H, m), 7.80 (1H, s). IR (KBr) 2916, 1680, 1512, 1470, 1433, 1257
,1228,920,820,798cm⁻¹ Elemental analysis C₁₇H₁₅NO₂ Calcd. C, 76.96; H, 5.70;
N, 5.28: Found. C, 76.87; H, 5.76; N, 5.22. Example 24 (Preparation of Compound 24) 1-Methyl-6-(4-methylphenyl)-1H-indole-2-carvone
A solution of the acid (200 mg) in THF (10 ml) was added with oxalyl chloride (0
20 ml) and one drop of DMF were added and stirred for 1 hour. After distilling off the solvent under reduced pressure,
The residue was dissolved in THF (30 ml) and the resulting solution was cooled to 0° C. to give 4-[N-methyl-N-(tetrahydrofuran)].
(4-aminomethyl)-(4-hydroxypyran-4-yl)aniline (183 mg), and
Triethylamine (0.21 ml) was added and the mixture was stirred at room temperature for 18 hours.
After adding to vigorously stirred water, the mixture was concentrated under reduced pressure and the precipitate was collected by filtration.
The crude product was obtained by recrystallization (ethanol).
The compound was purified by the method described above and obtained as colorless crystals.
4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
Nyl]-1H-indole-2-carboxamide (Compound 24) (298 mg)
obtained.

m. p. 225-226℃¹ H-NMR (200MHz, CDCl₃) δ1.62-1.83 (4H, m)
, 2.22 (3H, s), 2.42 (3H, s), 2.56-2.75 (1H,
m), 3.29-3.45 (2H, m), 3.59 (2H, s), 3.98-4
．． 11 (2H, m), 4.14 (3H, s), 7.02 (1H, s), 7.26
-7.36 (4H, m), 7.43 (1H, dd, J=8.0, 1.4Hz),
7.57-7.61 (5H, m), 7.71 (1H, d, J=8.8Hz), 7
．． 91 (1H, s). IR (KBr) 3298, 1647, 1516, 1462, 1389, 1300
,1250,1142,810cm⁻¹ Elemental analysis C₃₀H₃₃N₃O₂ Calcd. C, 77.06; H, 7.11
; N, 8.99: Found. C, 76.98; H, 7.02; N, 8.99. Reference Example 65 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
- carboxylic acid (280 mg) suspended in methanol (20 ml)/acetic acid (10 ml)
10% palladium carbon (50% water content, 70 mg) was added to the solution.
The mixture was stirred at room temperature for 17 hours and at 50°C for 3 hours, and then the catalyst was removed by filtration. The filtrate was concentrated.
Further, the product was recrystallized from ethyl acetate/hexane, and 7-(4-methylphenyl)-2,
3,4,5-tetrahydro-1-benzoxepine-4-carboxylic acid (187m
g) was obtained as colorless crystals.

m. p. 182-184℃¹ H-NMR (200MHz, CDCl₃) δ: 2.2-2.3 (2H, m),
2.38 (3H, s), 2.7-2.85 (1H, m), 3.05-3.3 (2
H, m), 3.8-3.9 (1H, m), 4.3-4.4 (1H, m), 7.0
4 (1H, d, J = 8.6), 7.22 (2H, d, J = 8.2), 7.3-7
．． 4 (2H, m), 7.44 (2H, d, J=8.4). IR (KBr) 1692, 1491, 1310, 1250, 1227, 1051
,964,814cm⁻¹ Elemental analysis C₁₈H₁₈O₃ Calcd. C, 76.57; H, 6.43: F
sound. C, 76.48; H, 6.30. Example 25 (Preparation of Compound 25) 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzo[a]thiazolinone
Xepin-4-carboxylic acid (141 mg), 4-[N-methyl-N-(tetrahydrofuran)
[Dropyran-4-yl]aminomethylaniline (110 mg) in DMF (4 m
l) To the solution, diethyl cyanophosphate (0.08 ml) and triethylamine were added under ice cooling.
(0.08 ml) was added. After stirring at 0°C for 30 minutes and at room temperature for 8 hours, the mixture was cooled on ice and decomposed.
Sodium chloride solution was added, extracted with ethyl acetate, and washed with brine. The extract was dried (anhydrous
The mixture was concentrated under reduced pressure using an aqueous solution of magnesium sulfate.
The mixture was purified by filtration (ethyl acetate/hexane = 4/1) and further purified by ethyl acetate/
Recrystallization from hexane gave N-[4-[(N-methyl-N-(tetrahydropyran
-4-yl)]aminomethyl]phenyl]-7-(4-methylphenyl)-2,
3,4,5-tetrahydro-1-benzoxepin-4-carboxamide (compound
25) (43 mg) was obtained as colorless crystals.

m. p. 172-174℃¹ H-NMR (200MHz, CDCl₃) δ: 1.4-2.0 (4H, m),
2.15-2.45 (2H, m), 2.38 (6H, s), 2.65-2.85
(1H, m), 2.9-3.1 (2H, m), 3.2-3.4 (3H, m), 3
．． 7-3.9 (3H, m), 3.9-4.1 (2H, m), 4.4-4.55 (
1H, m), 7.05 (2H, d, J = 8.8), 7.22 (2H, d, J = 8
．． 2), 7.3-7.5 (5H, m), 7.6-7.75 (2H, m). IR (KBr) 1665, 1609, 1541, 1491, 1418, 1252
,1061,818cm⁻¹ Reference Example 66 1,4-Dibromobenzene (25 g) was added to concentrated sulfuric acid (30 ml) and dissolved.
Then, under ice cooling, a mixture of concentrated sulfuric acid (30 ml) and nitric acid (8.9 ml) was added dropwise.
After 14 hours at room temperature, the mixture was poured into ice water, potassium carbonate was added, and the mixture was extracted with ethyl acetate.
The extract was washed with sodium bicarbonate water and brine, and then dried over anhydrous magnesium sulfate.
The residue was purified by silica gel column chromatography (hexane).
1,4-Dibromo-2-nitrobenzene (13.3 g) was obtained as pale yellow crystals.
I got it.¹ H-NMR (200MHz, CDCl₃) δ: 7.56 (dd, 1H, J=2
．． 2, 8.6), 7.62 (d, 1H, J = 8.6), 7.99 (d, 1H, J
=2.2). IR (KBr) 1537, 1458, 1352, 1034cm⁻¹Reference Example 67 1,4-Dibromo-2-nitrobenzene (5.4 g) in THF (300 ml)
phenyllithium (11) was cooled to -100°C in a liquid nitrogen/diethyl ether bath.
After stirring for 30 minutes, DMF (5.9 ml) was added dropwise, and the mixture was stirred for 30 minutes.
The bath was changed to ice/acetone and stirred for 1 hour. 1N sulfuric acid (40 ml) was added.
Extraction with ethyl acetate, washing with brine, drying (anhydrous magnesium sulfate),
The residue was purified by silica gel column chromatography (ethyl acetate/hexane
The product was purified by ethanol (3.
53 g) was obtained as a brown solid.¹ H-NMR (200MHz, CDCl₃) δ: 7.85 (d, 1H, J=8.
2), 7.94 (dd, 1H, J = 1.8, 8.2), 8.27 (d, 1H, J
=1.8), 10.39(s, 1H). IR (KBr) 1699, 1595, 1559, 1534, 1346, 1190
,878,820cm⁻¹ Reference Example 68 4-Dibromo-2-nitrobenzaldehyde (1.89 g) was mixed with 4-methylphenyl
Boron acid (1.23 g), 2 M potassium carbonate solution (10 ml), ethanol (
10 ml) and toluene (30 ml) were added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere.
After stirring, tetrakistriphenylphosphine palladium (380 mg) was added.
The mixture was refluxed overnight, extracted with ethyl acetate, washed with water and brine, and the extract was dried.
The residue was purified by silica gel column chromatography.
The resulting product was purified by solvent extraction (ethyl acetate/hexane = 1/9) and 4-(4-methylphenyl)
From this, 1.17 g of (2-nitrobenzaldehyde) was obtained as a pale brown powder.
¹H-NMR (200MHz, CDCl₃) δ: 2.44 (s, 3H), 7.3
3 (d, 2H, J = 8.4), 7.57 (d, 2H, J = 8.4), 7.96 (
dd, 1H, J=1.6, 8.2), 8.04 (d, 1H, J=8.2), 8.
29 (d, 1H, J=1.6), 10.44 (s, 1H). IR (KBr) 1696, 1609, 1534, 1520, 1350, 1188
, 814 cm⁻¹ Reference Example 69 4-(4-methylphenyl)-2-nitrobenzaldehyde (590 mg)
A solution of sodium dithionite (2.66 g) in THF (50 ml) and water (25 ml)
After stirring at room temperature for 10 minutes, the mixture was extracted with ethyl acetate and washed with brine.
The extract was dried (anhydrous magnesium sulfate) and concentrated to give 2-amino-4-
(4-Methylphenyl)benzaldehyde (0.26 g) was obtained as a light brown powder.
Ta.¹ H-NMR (200MHz, CDCl₃) δ: 2.41 (s, 3H), 5.8
-6.4 (br, 2H), 6.84 (d, 1H, J=1.6), 6.98 (dd
, 1H, J=1.6, 8.2), 7.26 (d, 2H, J=8.2), 7.45
-7.6 (m, 3H), 9.89 (s, 1H). IR (KBr) 1671, 1620, 1591, 1539, 1393, 1208
,1192,795cm⁻¹ Reference Example 70 2-amino-4-(4-methylphenyl)benzaldehyde (0.23 g),
A solution of pyruvic acid (192 mg) in methanol (20 ml) was diluted with sodium hydroxide (
A solution of 349 mg of ethanol (20 ml) was added. The mixture was stirred at 50-60°C for 9 hours.
The mixture was extracted with water, washed twice with diethyl ether, and the aqueous layer was diluted with 1N hydrochloric acid.
The pH was adjusted to 1-2 by adding ethyl acetate, and the extract was washed with brine.
After drying (anhydrous magnesium sulfate), the mixture was concentrated. The residue was purified by silica gel column chromatography.
The 4-(4-methyl-2- propanol) was purified by chromatography (ethyl acetate/methanol = 4/1).
(117 mg) ethylphenylquinoline-2-carboxylic acid as an orange powder
I got it.¹ H-NMR (200MHz, CDCl₃) δ: 2.40 (s, 3H), 7.3
7 (d, 2H, J = 8.2), 7.80 (d, 2H, J = 8.2), 8.0-8
．． 2 (m, 3H), 8.39 (s, 1H), 8.59 (d, 1H, J=8.0)
．． IR (KBr) 1620, 1555, 1454, 1404, 1173, 816c
m⁻¹ Example 26 (Preparation of Compound 26) 4-(4-methylphenyl)quinoline-2-carboxylic acid (100 mg) TH
To a solution of F (5 ml) was added DMF (1 drop) and oxalyl chloride (0.04 ml) under ice cooling.
The mixture was stirred at 0°C for 30 minutes.
(4-aminomethyl)-4-pyran-4-yl]aniline (92 mg) in THF (5 ml)
To the solution, triethylamine (0.33 ml) was added under ice cooling, followed by the acid chloride solution prepared above.
The solution was added and stirred at room temperature for 1 hour. Water was added under ice cooling, and the mixture was extracted with ethyl acetate.
After washing with brine, the extract was dried (anhydrous magnesium sulfate) and concentrated.
The product was purified by silica gel column chromatography (ethyl acetate/methanol = 9/1).
The product was purified by the above procedure and further recrystallized from ethyl acetate/diethyl ether to give N-[4-
[(N-methyl-N-(tetrahydropyran-4-yl)]aminomethyl]phen
[0047] [0048] [0049] [0050] [0051] [0052] [0053] [0054] [0055] [0056] [0057] [0058] [0059] [0060] [0059] [0059] [0061] [0059 ...62] [
) (27 mg) was obtained as colorless crystals.

m. p. 148-150℃¹ H-NMR (200MHz, CD₃OD) δ: 1.6-1.9 (m, 4H),
2.25 (s, 3H), 2.43 (s, 3H), 2.6-2.8 (m, 1H),
3.3-3.5 (m, 2H), 3.66 (s, 2H), 3.9-4.1 (m, 2H)
H), 7.35 (d, 2H, J = 7.8), 7.39 (d, 2H, J = 7.8)
,7.74(d,2H,J=7.8),7.85(d,2H,J=7.8),7
．． 95-8.05 (m, 1H), 8.08 (d, 1H, J=8.8), 8.26
(d, 1H, J=8.2), 8.45-8.5 (m, 1H), 8.51 (d, 1
H, J=8.2). IR (KBr) 1678, 1522, 1497, 1410, 812cm⁻¹ Elemental analysis C₃₀H₃₁N₃O₂・0.2H₂O Calcd. C, 76.80
; H, 6.75; N, 8.96: Found. C, 76.84; H, 6.59;
N, 8.86. Example 27 (Preparation of Compound 27) 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (1
To a solution of 50 mg of oxalyl chloride (0.07%) in THF (10 ml) was added oxalyl chloride (0.07%) at room temperature.
ml) was added, and then one drop of DMF was added and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure.
The residue was then dissolved in THF (20 ml) and heated at 0° C. with 1-(4-aminobenzyl)
(138 mg) phosphorinane-1-oxide, and triethylamine (0
16 ml) was added and stirred at room temperature for 4 hours. The reaction mixture was poured into vigorously stirred water.
The reaction was stopped by adding chloroform and the organic layer was extracted with chloroform.
After drying over magnesium, the residue was recrystallized (ethanol)
Purified and obtained as pale yellow crystals, 3-(4-methylphenyl)-N-(4-pentamethasone).
(ethylenephosphorylmethylphenyl)-2H-1-benzopyran-6-carboxamide
The compound 27 (204 mg) was obtained.

m. p. 235℃ (dec.)¹ H-NMR (200MHz, CDCl₃) δ1.40-2.16 (10H, m
), 2.39 (3H, s), 3.15 (2H, d, J=13.6Hz), 5.2
5 (2H, d, J = 1.4Hz), 6.82 (1H, s), 6.89 (1H, d
, J=9.2Hz), 7.18-7.29 (4H, m), 7.35 (2H, d,
J = 8.4Hz), 7.62-7.70 (4H, m), 8.21-8.32 (1
H, m). IR (KBr) 3226, 1645, 1603, 1541, 1514, 1491
,1410,1329,1201,1165,1134,837cm⁻¹ Elemental analysis C₂₉H₃₀NO₃P 0.3H₂O Calcd. C, 73.03
; H, 6.47; N, 2.94: Found. C, 73.07; H, 6.57;
N, 2.87 Example 28 (Preparation of Compound 28) 3-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydro)phenyl]- ...
pyran-4-yl)aminomethyl]phenyl]-2H-1-benzopyran-6-
A solution of carboxamide (80 mg) in DMF (30 ml) was added with methyl iodide at room temperature.
(0.04 ml) was added and stirred for 3 days. The solvent was evaporated under reduced pressure, and the residue was treated with ethyl acetate.
Chilling was added and the resulting crystals were collected by filtration to give iodide-N, as pale yellow crystals.
N-dimethyl-N-[4-[[3-(4-methylphenyl)-2H-1-benzo
Pyran-6-carbonyl]amino]benzyl]-4-tetrahydropyranyl
Monomium (compound 28) (87 mg) was obtained.

m. p. 215-218℃¹ H-NMR (200MHz, DMSO-d₆) δ1.75-2.00 (2H,
m), 2.10-2.23 (2H, m), 2.34 (3H, s), 2.89 (6
H, s), 3.26-3.43 (2H, m), 3.49-3.68 (1H, m)
, 4.01-4.12 (2H, m), 4.47 (2H, s), 5.29 (2H,
d, J = 1.0Hz), 6.96 (1H, d, J = 8.0Hz), 7.10 (1
H, s), 7.26 (2H, d, J = 8.0Hz), 7.48-7.57 (4H
, m), 7.75-7.80 (2H, m), 7.92 (2H, d, J = 8.8H
z), 10.34 (1H, s). IR (KBr) 3273, 1647, 1597, 1524, 1493, 1323
, 810cm⁻¹ Elemental analysis C₃₁H₃₅N₂O₃I・1.2H₂O Calcd. C, 58.9
0; H, 5.96; N, 4.43: Found. C, 58.85; H, 5.66
; N, 4.48. Reference Example 71 Sulfuric acid (28 ml) was added dropwise to acetic acid (42 ml) under ice cooling, followed by N-(2-(
(4-bromophenyl)ethyl)trifluoroacetamide (7.8 g) and paraformaldehyde
To the mixture was added methylformamide (1.27 g), and the mixture was stirred overnight under a nitrogen atmosphere.
The organic layer was poured into a glass and extracted with ethyl acetate.
After washing with brine, the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.
, 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroiso
Quinoline (8.1 g) was obtained as a colorless oil.¹ H-NMR (δppm, CDCl₃) 2.87-2.94 (2H, m), 3.
81-3.91 (2H, m), 4.72 (0.7H, s), 4.77 (1.3H
, s), 7.02-7.09 (1H, m), 7.27-7.37 (2H, m).
IR(neat)ν:2907,1696cm⁻¹Reference Example 72 7-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisopropyl
Quinoline (8.1 g), 4-methylphenylboronic acid (3.9 g), 2M potassium carbonate
Aqueous solution of ethanol (40 ml), toluene (100 ml)
The mixture was stirred at room temperature for 30 minutes under an argon atmosphere.
Suphine palladium (1.26 g) was added, and the mixture was refluxed under an argon atmosphere for 4.5 hours.
After extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and then
The solvent was removed under reduced pressure, and the residue was diluted with methanol (200 ml).
1), 2M aqueous potassium carbonate solution (50 ml) was added, and the mixture was stirred at room temperature overnight.
The organic layer was washed with water and then back-extracted with 1N hydrochloric acid.
After making it alkaline using a N sodium hydroxide solution, it was saturated with salt and
The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure to give 7-(4-methylphenyl)-1,2,3,4
-Tetrahydroisoquinoline (4.2 g) was obtained as colorless crystals.¹ H-NMR (δppm, CDCl₃) 2.39 (3H, s), 2.83 (1.
5H, t, J = 6.0Hz), 2.91-2.93 (1H, m), 3.17 (1
．． 5H, t, J = 6.0Hz), 3.33 (0.5H, s), 3.82 (0.5
H, s), 4.08 (1.5H, s), 7.13-7.25 (4H, m), 7.
36 (1H, dd, J=1.8, 7.8), 7.44-7.49 (2H, m).
IR(KBr)ν:2919,1427cm⁻¹．． Anal. calcd. for C₁₆H₁₇N 0.1H₂O:C, 85.3
7; H, 7.70; N, 6.22. Found C, 85.34; H, 7.57
;N,6.10. Reference Example 73 4-(chloromethyl)phenyl isocyanate (0.38 g) tetrahydrofuran
The furan solution was diluted with 7-(4-methylphenyl)-1,2,3,4-tetrahydroisopropyl
The mixture was added dropwise to a solution of quinoline (0.5 g) in tetrahydrofuran under ice cooling.
After stirring, the solvent was distilled off to obtain 4-(7-(4-methylphenyl)-1,2,3,4-tetramethylphenyl)-
tetrahydroisoquinolin-2-ylcarbonylamino)benzyl chloride (0.
82 g) was obtained as colorless crystals.¹ H-NMR (δppm, CDCl₃) 2.40 (3H, s), 2.98 (2H
t, J = 5.8 Hz), 3.77 (2H, t, J = 6.1 Hz), 4.57 (
2H, s), 4.73 (2H, s), 6.48 (1H, br), 7.23-7.
30 (4H, m), 7.34-7.49 (7H, m). IR (KBr) ν: 3303, 3023, 1645cm⁻¹．． Anal. calcd. for C₂₄H₂₃ClN₂O.0.2H₂O:C,
73.07; H, 5.98; N, 7.10. Found C, 73.04; H,
5.86; N, 7.10. Reference Example 74 Under ice cooling, oxalyl chloride (0.4 ml) was dissolved in 4-bromomethylphenylacetic acid (0
The mixture was added to a suspension of 52 g of benzoyl perfluorooctanoate in 4 ml of dichloromethane.
An amide (catalytic amount) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residual tetrahydrofuran was
The hydrofuran solution was diluted with 7-(4-methylphenyl)-1,2,3,4-tetrahydrofuran.
The mixture of diisoquinoline (0.5 g) and diisopropylethylamine (0.5 ml)
The mixture was added dropwise to the tetrahydrofuran solution under ice cooling. After stirring at room temperature for 30 minutes, ethyl acetate was added.
The filtrate was washed with water and saturated saline, and then added with magnesium sulfate anhydride.
The solvent was distilled off under reduced pressure, and 2-(4-bromomethylphenyl)
(4-methylphenyl)-7-(4-phenylacetyl)-1,2,3,4-tetrahydro-
Soquinoline (0.7 g) was obtained as a pale yellow oil.¹ H-NMR (δppm, CDCl₃) 2.39 (3H, s), 2.75 (1.
1H, t, J = 5.9Hz), 2.89 (0.9H, t, J = 6.0Hz), 3
．． 69 (1.1H, t, J = 5.9Hz), 3.82 (2H, s), 3.88 (
0.9H, t, J=6.0Hz), 4.44-4.57 (2H, m), 4.66
(0.9H, s), 4.82 (1.1H, s), 7.13-7.47 (11H,
m). IR (neat) ν: 3023, 2922, 1642cm⁻¹Example 29 (Preparation of Compound 29) 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline
(2-methyl- ...
Piperidine (0.19 ml) was dissolved in dimethylformamide (5 ml) and the mixture was
The mixture was stirred overnight at room temperature under atmospheric pressure. The solvent was evaporated, ethyl acetate was added, and the precipitate was collected by filtration.
Recrystallization from ethanol gave 1-methyl-1-(4-((7-(4-methyl) chloride.
(1,2,3,4-tetrahydroisoquinolin-2-yl)phenyl
(Bonylamino)benzyl)piperidinium (Compound 29) (0.23 g) was added to a colorless
Obtained as crystals.

mp 179-180℃ (dec.).¹ H-NMR (δppm, DMSO-d₆) 1.45-1.65 (2H, m),
1.75-1.95 (4H, m), 2.34 (3H, s), 2.86-2.92
(5H, m), 3.24-3.32 (4H, m), 3.76 (2H, t, J=5
．． 9Hz), 4.48 (2H, s), 4.73 (2H, s), 7.25-7.2
9 (3H, m), 7.38-7.49 (4H, m), 7.55 (2H, d, J=
8.2Hz), 7.65 (2H, d, J=8.6Hz), 8.91 (1H, br
). IR (KBr) ν: 3364, 3285, 2948, 1663cm⁻¹．． Anal. calcd. for C₃₀H₃₆ClN₃O.H.₂O: C, 70.
92; H, 7.54; N, 8.27. Found C, 70.97; H, 7.8
0; N, 8.03. Example 30 (Preparation of Compound 30) 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline
1-ethyl-2-methyl ...
Piperidine (0.21 ml) was dissolved in dimethylformamide (5 ml) and the mixture was
The mixture was stirred overnight at room temperature under atmospheric pressure. The solvent was evaporated, ethyl acetate was added, and the precipitate was collected by filtration.
and 1-ethyl-1-(4-((7-(4-methylphenyl)-1,2,3
,4-tetrahydroisoquinolin-2-yl)carbonylamino)benzyl)pi
Peridinium (Compound 0) (0.24 g) was obtained as a pale red amorphous substance.¹ H-NMR (δppm, DMSO-d₆) 1.33 (3H, t, J=7.2H
z), 1.40-1.65 (2H, m), 1.75-1.95 (4H, m), 2
．． 35 (3H, s), 2.89 (2H, t, J=5.6Hz), 3.10-3.
33 (6H, m), 3.76 (2H, t, J=5.6Hz), 4.45 (2H,
s), 4.73 (2H, s), 7.24-7.29 ((3H, m), 7.35-
7.48 (4H, m), 7.55 (2H, d, J = 8.2Hz), 7.65 (2
H, d, J=8.4Hz), 8.91 (1H, br). IR (KBr) δ: 3236, 2948, 1651 cm⁻¹．． Anal. calcd. for C₃₁H₃₈ClN₃O.0.8H₂O:C,
71.81; H, 7.70; N, 8.10. Found C, 71.87; H,
7.79; N, 7.91. Example 31 (Preparation of Compound 31) 2-(4-bromomethylphenylacetyl)-7-(4-methylphenyl)-
1,2,3,4-tetrahydroisoquinoline (0.2 g), 1-methylpiperidinyl
Dissolve 0.17 ml of dimethylformamide in 5 ml of dimethylformamide under a nitrogen atmosphere.
The mixture was stirred at room temperature overnight. The solvent was evaporated, ethyl acetate was added, and the precipitate was collected by filtration.
The solvent was distilled off to obtain 1-methyl-1-(4-((7-(4-methyl) bromide.
(1,2,3,4-tetrahydroisoquinolin-2-yl)phenyl
(Bonylmethyl)benzyl)piperidinium (Compound 31) (0.24 g) was added to a colorless
Obtained as amorphous.¹ H-NMR (δppm, DMSO-d₆)1.40-1.70 (2H, m),
1.78-1.91 (4H, m), 2.34 (3H, s), 2.77-2.88
(2H, m), 2.93 (3H, s), 3.21-3.27 (4H, m), 3.
69-3.82 (2H, m), 3.90 (2H, s), 4.53 (2H, d, J
= 8.0Hz), 4.76 (2H, d, J = 20.8Hz), 7.20-7.3
0 (3H, m), 7.39-7.56 (8H, m). IR (KBr) ν: 3345, 2942, 1636cm⁻¹．． Anal. calcd. for C₃₁H₃₇BrN₂O.0.5H₂O:C
, 68.63; H, 7.06; N, 5.16. Found C, 68.54; H
, 7.06; N, 4.95. Example 32 (Preparation of Compound 32) 2-(4-bromomethylphenylacetyl)-7-(4-methylphenyl)-
1,2,3,4-tetrahydroisoquinoline (0.2 g), 1-ethylpiperidinyl
Dissolve 0.19 ml of dimethylformamide in 5 ml of dimethylformamide under a nitrogen atmosphere.
The mixture was stirred at room temperature overnight. The solvent was evaporated, ethyl acetate was added, and the precipitate was collected by filtration.
The solvent was distilled off to obtain 1-ethyl-1-(4-((7-(4-methyl-
(1,2,3,4-tetrahydroisoquinolin-2-yl)phenyl
(Bonylmethyl)benzyl)piperidinium (compound 32) (0.23 g) was added to a colorless
Obtained as amorphous.¹ H-NMR (δppm, DMSO-d₆) 1.34 (3H, t, J=7.2H
z), 1.40-1.65 (2H, m), 1.75-1.90 (4H, m), 2
．． 34 (3H, s), 2.75-2.85 (2H, m), 3.20-3.33 (
6H, m), 3.70-3.80 (2H, m), 3.89 (2H, s), 4.4
9 (2H, d, J = 8.4Hz), 4.76 (2H, d, J = 22.0Hz),
7.23-7.27 (3H, m), 7.40-7.56 (8H, m). IR (KBr) ν: 3353, 2942, 1638cm⁻¹．． Anal. calcd. for C₃₂H₃₉BrN₂O.0.5H₂O:C,
69.06; H, 7.24; N, 5.03. Found C, 68.82; H,
7.38; N, 4.78. Reference Example 75 4-Methoxybenzylamine (4.12 g) and tetrahydro-4H-pyran-
A solution of 4-one (3.00 g) in 1,2-dichloroethane (50 ml) (triacetone
Sodium borohydride (6.99 g) was added. After stirring at room temperature for 2 hours,
37% formalin (2.5 ml) solution, sodium triacetoxyborohydride
After stirring for another hour, sodium bicarbonate water was added, and dichloromethane
The extract was washed with brine, dried (anhydrous magnesium sulfate), and then extracted with
The residue was purified by silica gel column chromatography (ethyl acetate).
and purified from N-methyl-N-(tetrahydropyran-4-yl)-4-methoxy
Dibenzylamine (3.56 g) was obtained as a pale yellow oil.¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.19 (3H, s), 2.55-2.75 (1H, m), 3.37 (2H, d
t, J=3.0, 11.2), 3.53 (2H, s), 3.80 (3H, s),
4.0-4.1 (2H, m), 6.85 (2H, d, J = 8.6), 7.22 (
2H, d, J=8.6). IR (KBr) 1613, 1510, 1456, 1300, 1246, 1173
,1142,1038cm⁻¹ Reference Example 76 N-methyl-N-(tetrahydropyran-4-yl)-4-methoxybenzyl
A solution of the amine (2.19 g) in dichloromethane (20 ml) was added to the solution of chlorinated tribromide at -78°C.
A solution of iodine in dichloromethane (11 ml) was added. The temperature was slowly increased from -78°C to room temperature.
The temperature was raised to 100°C and stirred for 2 hours, and then the mixture was again heated to -78°C and stirred in a dichloromethane solution of boron tribromide.
(5 ml) was added and the mixture was stirred at room temperature for another 30 minutes.
The mixture was extracted with dichloromethane and concentrated under reduced pressure.
The aqueous layer was extracted. Sodium carbonate was added to the extract to adjust the pH to 8, and then acetic acid was added.
The extract was washed with brine, and the extract was dried (anhydrous magnesium sulfate).
The residue was purified by silica gel column chromatography (ethyl acetate).
Purification with ethanol/methanol was carried out, and N-methyl-N-(tetrahydropyran-4-
(206 mg)-4-hydroxybenzylamine was obtained as a pale yellow oil.
Ta.¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.21 (3H, s), 2.55-2.75 (1H, m), 3.37 (2H, d
t, J=2.8, 11.2), 3.54 (2H, s), 4.0-4.1 (2H,
m), 6.74 (2H, d, J = 8.6), 7.17 (2H, d, J = 8.6)
．． IR (KBr) 1613, 1520, 1458, 1246cm⁻¹ Reference Example 77 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
- Carboxylic acid (841 mg) and triethylamine (0.42 ml) in THF (1
ethyl chlorocarbonate (0.29 ml)/THF (2 ml) at -5°C.
The solution was added dropwise. After stirring at -5°C for 30 minutes, the insoluble matter was removed by filtration. The filtrate was cooled with ice.
A solution of sodium borohydride (284 mg) in water (6 ml) was added dropwise.
After stirring for 1.5 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate.
Wash with thorium, water, and brine in that order, and then dry the extract (anhydrous magnesium sulfate).
The mixture was concentrated under reduced pressure, and recrystallized from ethyl acetate/diethyl ether/hexane.
4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-
Benzoxepin (708 mg) was obtained as colorless crystals.

m. p. 91-92℃¹ H-NMR (200MHz, CDCl₃) δ: 2.39 ((3H, s), 2.
71 (2H, t, J = 4.8), 4.25 (2H, s), 4.30 (2H, t,
J=4.8), 6.46 (1H, s), 7.00 (1H, d, J=8.4), 7
．． 23 (2H, d, J=8.2), 7.3-7.5 (4H, m). IR (KBr) 1497, 1331, 1265, 1231, 1125, 1040
,1028,918,901,806cm⁻¹ Elemental analysis C₁₈H₁₈O₂ Calcd. C, 81.17; H, 6.81: F
sound. C, 81.29; H, 6.88. Example 33 (Preparation of Compound 33) 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1
- Benzoxepin (89 mg), N-methyl-N-(tetrahydropyran-4
-yl)-4-hydroxybenzylamine (92 mg) and tributylphosphine
(0.13 ml) was added to 1,1-(azodicarbonyl)dipiperidine (12 ml) under ice cooling.
After stirring at 0° C. for 10 minutes and at room temperature for 1 hour, the insoluble material was removed by filtration.
The extract was extracted with ethyl acetate and washed twice with brine. After drying the extract (anhydrous magnesium sulfate),
The residue was purified by silica gel column chromatography (
Purify with ethyl acetate/hexane (4/1) and then with ethyl acetate/hexane.
The compound was recrystallized from 4-[4-[(N-methyl-N-(tetrahydropyran-4-yl)
)aminomethyl]phenoxymethyl]-7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin (compound 33) (45 mg) as colorless crystals
Got it.

m. p. 135-136℃¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.20 (3H, s), 2.39 (3H, s), 2.55-2.75 (1H, m
), 2.75-2.8 (2H, m), 3.36 (2H, dt, J = 2.8, 11
．． 2), 3.53 (2H, s), 4.0-4.1 (2H, m), 4.32 (2H
, t, J=4.6), 4.61 (2H, s), 6.55 (1H, s), 6.91
(2H, d, J=8.8), 7.00 (1H, d, J=8.0), 7.2-7.
3 (4H, m), 7.3-7.4 (2H, m), 7.44 (2H, d, J=8.
2). IR (KBr) 1508, 1493, 1235, 1161, 1003, 816c
m⁻¹ Elemental analysis C₃₁H₃₅NO₂・H₂O Calcd. C, 78.95; H, 7
．． 91;N, 2.97:Found. C, 78.83; H, 7.55; N, 2.
88. Reference Example 78 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1
- A solution of benzoxepin (320 mg) in dichloromethane (10 ml) was added to triflate
Add phenylphosphine (378 mg) and carbon tetrabromide (597 mg) and let the mixture stand at room temperature for 2
The mixture was stirred for 1 hour. Triphenylphosphine (157 mg), carbon tetrabromide (249 mg),
g) was added, and the mixture was stirred at room temperature for another 30 minutes. Then, under ice cooling, sodium bicarbonate water was added, and ethyl acetate was added.
The extract was washed with brine, dried (anhydrous magnesium sulfate), and then
The residue was purified by silica gel column chromatography (ethyl acetate/
The mixture was purified with diethyl ether/hexane (hexane = 1/9) and further washed with diethyl ether/hexane.
, 4-bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzyl
Benzoxepin (286 mg) was obtained as a white powder.¹ H-NMR (200MHz, CDCl₃) δ: 2.39 ((3H, s), 2.
85 (2H, t, J = 4.6), 4.20 (2H, s), 4.30 (2H, t,
J=4.6), 6.59 (1H, s), 7.00 (1H, d, J=8.8), 7
．． 23 (2H, d, J = 8.2), 7.3-7.4 (2H, m), 7.43 (2
H, d, J = 8.2). IR (KBr) 1493, 1265, 1236, 1196, 912, 808cm
⁻¹ Reference Example 79 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]a
A solution of 551 mg of dimethylformamide in 50 ml of THF was diluted with 0.42 ml of triethylamine.
Then, THF (0.26 ml) and acetic anhydride (0.26 ml) were added and stirred at room temperature for 3 hours.
The extract was washed with sodium bicarbonate water and brine in that order, and the extract was dried (
The mixture was concentrated under reduced pressure using anhydrous magnesium sulfate. The residue was extracted with ethyl acetate and hexane.
Recrystallization from this gave N-[4-[N-methyl-N-(tetrahydropyran-4-yl)]
As a result, [aminomethyl]phenyl]acetamide (472 mg) was obtained as pale yellow crystals.

m. p. 105-106℃¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.17 (3H, s), 2.19 (3H, s), 2.55-2.7 (1H, m)
, 3.36 (2H, dt, J=3.2, 11.4), 3.55 (2H, s), 3
．． 95-4.1 (2H, m), 7.1-7.2 (1H, br), 7.27 (2H
, d, J=8.8), 7.44 (2H, d, J=8.8). IR (KBr) 1665, 1601, 1537, 1408, 1316, 1140
,1009,839cm⁻¹ Elemental analysis C₁₅H₂₂N₂O₂ Calcd. C, 68.67; H, 8.45
;N, 10.68: Found. C, 68.56; H, 8.38; N, 10.7
6. Example 34 (Preparation of Compound 91) N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]
A solution of [phenyl]acetamide (227 mg) in DMF (4 ml) was added to water under ice cooling.
Sodium chloride (36 mg) was added. After stirring at room temperature for 20 minutes, the mixture was cooled with ice and cooled to 4-bromo-2-methylpropional.
bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzox
Sepin (285 mg) was added. After stirring at room temperature for 1 hour, water was added under ice cooling.
The extract was dried (anhydrous magnesium sulfate) and then extracted with ethyl acetate/THF.
The residue was purified by silica gel column chromatography (ethyl acetate).
The mixture was purified by diisopropyl ether/hexadecyl ether/methanol (40/1).
The powder was collected by filtration, washed with diisopropyl ether, and
[(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
-N-[[7-(4-methylphenyl)-2,3-dihydro-1-benzo[
[Xepin-4-yl]methyl]acetamide (Compound 91) (209 mg) was added to a pale yellow
Obtained as amorphous.¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
1.91 ((3H, s), 2.16 (3H, s), 2.37 (3H, s), 2.
5-2.65 (1H, brm), 2.65-2.75 (2H, m), 3.25-
3.45 (2H, m), 3.55 (2H, s), 3.9-4.1 (2H, m),
4.23 (2H, d, J = 4.8), 4.50 (2H, s), 6.06 (1H,
s), 6.96 (1H, d, J = 8.6), 7.08 (2H, d, J = 7.6)
, 7.15-7.4 (8H, m). IR (KBr) 1661, 1508, 1491, 1387, 1235, 814c
m⁻¹ Reference Example 80 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1
-Benzoxepine (0.21 g) in dichloromethane (10 ml)
Manganese (687 mg) was added, and the mixture was stirred at room temperature for 3 hours.
The dichloromethane was distilled off. The residue was recrystallized from ethyl acetate/hexane to give 7-(4
-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbal
The aldehyde (192 mg) was obtained as colorless crystals.

m. p. 132-133℃.¹ H-NMR (200MHz, CDCl₃) δ: 2.40 ((3H, s), 2.
90 (2H, t, J = 4.4), 4.31 (2H, t, J = 4.4), 7.09
(1H, d, J=8.4), 7.2-7.3((3H, m), 7.4-7.6(
4H, m), 9.58 (1H, s). IR (KBr) 1672, 1626, 1495, 1296, 1242, 1163
,1134,1080,1028,810cm⁻¹ Elemental analysis C₁₈H₁₆O₂・0.1H₂O Calcd. C, 81.24; H
, 6.14: Found. C, 81.43; H, 6.09. Example 35 (Preparation of Compound 34) 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carbaldehyde (191 mg), 4-[N-methyl-N-(tetrahydropyridine)
1,2-Dichloroethene (4-aminomethyl)aniline (159 mg)
Sodium triacetoxyborohydride (168 mg) was added to a solution of ethanol (5 ml).
After stirring at room temperature for 4.5 hours, sodium triacetoxyborohydride (76
mg) was added and the mixture was stirred for another 4 days.
The extract was dried (anhydrous magnesium sulfate) and then washed with brine.
The residue was purified by silica gel column chromatography (ethyl acetate/
The mixture was purified with 4N hydrochloric acid, and the precipitate was collected by filtration.
and washed with ethyl acetate to obtain N-[4-[(N-methyl-N-(tetrahydropyran-4
-N-[7-(4-methylphenyl)-2,
3-Dihydro-1-benzoxepin-4-yl]methylamine (compound 34)
(88 mg) was obtained as a pale yellow powder.

m. p. 158-160℃¹ H-NMR (200MHz, DMSO-d₆) δ: 1.6-2.1 (4H, m
), 2.33 (3H, s), 2.56 (3H, s), 2.6-2.7 (2H, m
), 3.2-3.4 (3H, m), 3.8-4.0 (5H, m), 4.15-4
．． 3 (3H, m), 6.50 (1H, s), 6.67 (2H, d, J = 8.8)
, 6.94 (1H, d, J = 8.0), 7.2-7.3 (4H, m), 7.3-
7.45 (2H, m), 7.48 (2H, d, J = 8.2), 8.32 (1H,
s), 9.8-10.0 (1H, br). IR (KBr) 1493, 1456, 1238, 816cm⁻¹ Reference Example 81 4-Bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzyl
A solution of benzoxepin (329 mg) in toluene (10 ml) was diluted with triphenylphosphine.
After adding ethanol (393 mg), the mixture was refluxed for 2 hours. After cooling, the precipitate was collected by filtration and
The mixture was dried under reduced pressure and the residue was purified by filtration.
[Dro-1-benzoxepin-4-yl]methyltriphenylphosphonium bromide
The salt (549 mg) was obtained as a white powder.¹ H-NMR (200MHz, CDCl₃) δ: 2.35 (3H, s), 2.3
5-2.45 (2H, m), 4.07 (2H, t, J = 4.4), 4.48, 4
．． 55 (1H, s), 6.22, 6.25 (1H, s), 6.93 (1H, d,
J=8.0), 6.95-7.05 (1H, m), 7.21 (2H, d, J=8
．． 6), 7.3-7.4 (3H, m), 7.7-8.0 (15H, m). IR (KBr) 1489, 1435, 1235, 1115, 810, 723cm
⁻¹ Reference Example 82 N-methyl-N-(tetrahydropyran-4-yl)-4-hydroxybenzoate
A solution of dimethylamine (0.94 g) in dichloromethane (20 ml) was added to manganese dioxide (
3.48 g) was added and stirred at room temperature for 24 hours.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane).
Purification by HPLC (solvent ratio 2/1) and 4-[N-methyl-N-(tetrahydropyran-
4-yl)aminomethyl]benzaldehyde (931 mg) as a colorless oil
Got it.¹ H-NMR (200MHz, CDCl₃) δ: 1.5-1.85 (4H, m)
, 2.22 (3H, s), 2.55-2.75 (1H, m), 3.38 (2H,
dt, J = 2.8, 11.4), 3.67 (2H, s), 3.95-4.15 (
2H, m), 7.51 (2H, d, J = 8.0), 7.84 (2H, d, J = 8
．． 0), 10.01 (1H, s). IR (KBr) 1699, 1607, 1209, 1142, 1086cm⁻¹ Example 36 (Preparation of Compounds 35 and 36) [7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-
4-yl]methyltriphenylphosphonium bromide (549 mg), 4-[N-
Methyl-N-(tetrahydropyran-4-yl)aminomethyl]benzaldehyde
To a solution of 217 mg of t-butoxide in 10 ml of THF was added potassium t-butoxide (
After stirring at 0°C for 1 hour, water was added under ice cooling, salting out, and acetic acid was added.
The extract was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2
The first distillate was recrystallized from ethyl acetate/hexane to give (Z).
-4-[2-[4-[(N-methyl-N-(tetrahydropyran-4-yl)a
[aminomethyl]phenyl]ethenyl]-7-(4-methylphenyl)-2,3-di
Hydro-1-benzoxepin (compound 35) (80 mg) was obtained as colorless crystals.
The second distillate was recrystallized from ethyl acetate/hexane to give (E)-4-[2-[
4-[(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl
phenyl]ethenyl]-7-(4-methylphenyl)-2,3-dihydro-1-phenyl
Benzoxepin (compound 36) (22 mg) was obtained as colorless crystals.

Compound 35: m. p. 115-116℃.¹ H-NMR (200MHz, CDCl₃) δ: 1.5-1.8 (4H, m),
2.18 (3H, s), 2.38 (3H, s), 2.5-2.7 (3H, m),
3.36 (2H, dt, J=2.2, 11.2), 3.56 (2H, s), 3.
95-4.1 (2H, m), 4.16 (2H, t, J = 4.6), 6.32 (1
H, d, J = 12.2), 6.49 (1 H, d, J = 12.2), 6.52 (1
H, s), 6.97 (1H, d, J = 8.4), 7.15-7.35 (8H, m
), 7.42 (2H, d, J=8.4). IR (KBr) 1493, 1264, 1240, 1136, 1080, 1028
,1007,912,862,845,816cm⁻¹ Elemental analysis C₃₂H₃₅NO₂ Calcd. C, 82.54; H, 7.58;
N, 3.01: Found. C, 82.38; H, 7.75; N, 2.84. Compound 36: m. p. 119-120℃¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.23 (3H, s), 2.40 (3H, s), 2.6-2.8 (1H, m),
2.95 (2H, t, J = 4.6), 3.38 (2H, dt, J = 3.0, 11
．． 2), 3.59 (2H, s), 4.0-4.1 (2H, m), 4.38 (2H
, t, J=4.6), 6.58 (1H, d, J=17.0), 6.59 (1H,
s), 6.98 (1H, d, J = 17.0), 7.01 (1H, d, J = 8.4
), 7.2-7.45 (8H, m), 7.46 (2H, d, J=8.4). IR (KBr) 1491, 1377, 1262, 1231, 1140, 1086
,963,810cm⁻¹ Elemental analysis C₃₂H₃₅NO₂ Calcd. C, 82.54; H, 7.58;
N, 3.01: Found. C, 82.19; H, 7.33; N, 2.85. Reference Example 83 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carboxylic acid (561 mg), diphenylphosphoryl azide (0.43 ml), tri
Ethylamine (0.28 ml) and methanol (10 ml) were mixed and refluxed for 5 hours.
The solvent was removed by distillation, and the mixture was extracted with ethyl acetate.
The extract was washed with brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1
Purification by HPLC (HPLC: 4-methoxycarbonylamino-7-(4-methylphenyl)
(180 mg) of dihydro-2,3-benzoxepin was added as a pale yellow solid.
And got it.¹ H-NMR (200MHz, CDCl₃) δ: 2.38 (3H, s), 2.9
3 (2H, t, J = 5.2), 3.74 (3H, s), 4.28 (2H, t, J
=5.2), 6.13 (1H, brs), 6.62 (1H, s), 6.96 (1
H, d, J = 8.2), 7.2-7.4 (4H, m), 7.44 (2H, d, J
=8.2). IR (KBr) 1715, 1489, 1269, 1186, 1047, 1026
,959,812cm⁻¹ Reference Example 84 N-methyl-N-(tetrahydropyran-4-yl)-4-(hydroxymethyl)
benzylamine (0.68 g), triphenylphosphine (0.91 g)
Carbon tetrabromide (1.44 g) was added to a dichloromethane (10 ml) solution and the mixture was stirred at room temperature for 2
The mixture was stirred for 1 hour, and then aqueous sodium bicarbonate solution was added under ice cooling, and the mixture was extracted with ethyl acetate.
The extract was dried (anhydrous magnesium sulfate) and then concentrated under reduced pressure.
Purified by gel column chromatography (ethyl acetate/hexane = 1/9)
and washed with diethyl ether/hexane to obtain N-methyl-N-(tetrahydrofuran).
Dropyran-4-yl)-4-(bromomethyl)benzylamine (687 mg)
was obtained as a white solid.¹ H-NMR (200MHz, CDCl₃) δ: 1.6-1.8 (4H, m),
2.20 (3H, s), 2.55-2.75 (1H, m), 3.37 (2H, d
t, J = 3.0, 11.4), 3.58 (2H, s), 4.0-4.1 (2H,
m), 4.50 (2H, s), 7.3-7.6 (4H, m). IR (KBr) 1474, 1456, 1431, 1387, 1248, 1142
,1084,1013,853cm⁻¹ Example 37 (Preparation of Compound 37) 4-Methoxycarbonylamino-7-(4-methylphenyl)-2,3-dihydro-
To a solution of 179 mg of dro-1-benzoxepin in 4 ml of DMF was added under ice cooling.
Sodium hydride (27 mg) was added. After stirring at room temperature for 30 minutes, the mixture was cooled with ice and then cooled with N-
Methyl-N-(tetrahydropyran-4-yl)-4-(bromomethyl)benzene
After stirring at room temperature for 1 hour, water was added under ice-cooling.
The extract was dried (anhydrous magnesium sulfate) and then extracted with ethyl acetate.
The residue was purified by silica gel column chromatography (ethyl acetate/
hexane = 4/1) and diisopropyl ether/hexane was added.
The powder was collected by filtration, washed with diisopropyl ether, and
-N-[7-(4-methylphenyl)-2,3-dihydro-1-benzoxa
4-[N-methyl-N-(tetrahydropyran-4-yl)-N-[[4-[N-methyl-N-(tetrahydropyran-4
[0047] [0048] [0049] [0050] [0049] [0051] [0049] [0049] [0052] [0049] [0049] [0053] [0049 ...
was obtained as a pale yellow amorphous solid.¹ H-NMR (200MHz, CDCl₃) δ: 1.5-1.8 (4H, m),
2.23 (3H, brs), 2.2-2.3 (1H, m), 2.6-2.7 (2
H, m), 3.25-3.4 (2H, m), 3.6-3.7 (2H, m), 3.
76 (3H, s), 4.0-4.1 (2H, m), 4.1-4.2 (2H, m)
, 4.72 (2H, s), 6.24 (1H, s), 6.96 (1H, d, J=8
．． 4), 7.2-7.7 (10H, m). IR (KBr) 1701, 1493, 1449, 1375, 1264, 1236
, 1121 cm⁻¹ Example 38 (Preparation of Compound 38) N-methyl-N-(tetrahydropyran-4-yl)-4-((7-(4-methylpyran-4-yl)-4-methylpyran-4-yl)-4-methylpyran-4-yl
(2,3-dihydro-1-benzoxepin-4-yl)methyl
(amino)benzylamine dihydrochloride (0.25 g) in 1,2-dichloroethane (5
ml), triethylamine (0.13 ml), 37% formaldehyde
Aqueous solution (0.05 ml) was added, and the mixture was cooled with ice and cooled with sodium triacetoxyborohydride.
The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated.
The organic layer was neutralized with 1N aqueous sodium hydroxide solution and then extracted with ethyl acetate.
The mixture was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain crude crystals, which were recrystallized from ethyl acetate/hexane to give N-methyl-
N-(tetrahydropyran-4-yl)-4-((N-methyl-N-(7-(4
-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)methyl
(Ci)methylamino)benzylamine (compound 38) (0.11 g) as colorless crystals
Got it.

mp 110-114℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.60-1.75 (4H, m), 2.
21 (3H, s), 2.37 (3H, s), 2.61 (2H, t, J = 4.8H
z), 2.63-2.75 (1H, m), 2.97 (3H, s), 3.36 (2
H, dt, J = 3.0, 9.7Hz), 3.52 (2H, s), 3.98 (2H
, s), 3.98-4.05 (2H, m), 4.29 (2H, t, J = 4.8H
z), 6.33 (1H, s), 6.72 (2H, d, J=8.8Hz), 6.9
9 (1H, d, J = 9.2Hz), 7.15-7.23 (4H, m), 7.28
-7.33 (2H, m), 7.43 (2H, d, J=8.2Hz). IR (KBr) ν: 2949, 1615, 1520 ^{, 1491 cm −1} . Anal. calcd. _{for C32H38N2O2 ・ 0.2H2O} :C, ₇
9.04; H, 7.96; N, 5.76. Found C, 79.18; H, 7
.89; N, 5.75. Reference Example 85: 7-(4-Methylphenyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-one (1 g) was dissolved in ethanol (50 ml), and sodium borohydride (0.3 g) was added under ice-cooling. The mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was concentrated. Extraction was performed with ethyl acetate, and the organic layer was washed with water and then concentrated. The residue was dissolved in bis(2-methoxyethyl)ether (20 ml), and hydrochloric acid (5 ml) was added. The mixture was then heated at 75°C.
The mixture was heated and stirred for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The precipitated 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin (0
The product (78 g) was collected by filtration using hexane as colorless crystals.

mp 98-100℃. ¹ H-NMR (δppm, CDCl ₃ ) 2.38 ((3H, s), 2.65-2
．． 74 (2H, m), 4.27 (2H, t, J = 4.9Hz), 6.01 (1H
, dt, J = 11.7, 4.4 Hz), 6.39 (1H, d, J = 11.7 Hz
), 7.01 (1H, d, J = 8.0Hz), 7.23 (2H, d, J = 8.2
Hz), 7.31-7.38 (2H, m), 7.45 (2H, d, J = 8.0H
z). IR (KBr) ν: 3025, 1491 cm ⁻¹ . Anal. calcd. for C ₁₇ H ₁₆ O: C, 86.41; H, 6.8
2. Found C, 86.17; H, 6.61. Reference Example 86: Under ice cooling, sulfuryl chloride (0.17 ml) was dissolved in dimethylformamide (0.2 ml).
1) was added dropwise, and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin (0.3 g) was added, and the mixture was heated at 90°C under a nitrogen atmosphere for 3 hours. Ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
The 4,4'-sulfonyl chloride (0.36 g) was obtained as pale yellow crystals.

mp 162-166℃. ¹ H-NMR (δppm, CDCl ₃ ) 2.40 ((3H, s), 3.27 (2
H, t, J = 4.7Hz), 4.41 (2H, t, J = 4.7Hz), 7.11
(1H, d, J=9.6Hz), 7.26 (2H, d, J=8.2Hz), 7.
44 (2H, d, J = 8.2Hz), 7.57-7.62 (2H, m), 7.7
0(1H,s). IR (KBr) ν: 3027, 1634, ^{1493 cm −1} . Anal. calcd. for _C17H15ClO3S :C _{, 60.98} ;H
, 4.52. Found C, 61.14; H, 4.26. Example 39 (Preparation of Compound 39) 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.13 g) and triethylamine (0.22 ml) were dissolved in tetrahydrofuran (10 ml), and 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-sulfonyl chloride (0.18 g) was added under ice-cooling.
The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was removed by distillation, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by a silica gel column (ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to give 7-(4-methylphenyl)-
N-(4-((N-methyl-N-tetrahydropyran-4-yl)aminomethyl)phenyl)-2,3-dihydro-1-benzoxepin-4-sulfonamide (Compound 39) (0.19 g) was obtained as colorless crystals.

mp 157-162℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.54-1.71 (4H, m), 2.
12 (3H, s), 2.39 (3H, s), 2.50-2.65 (1H, m),
2.98 (2H, t, J = 4.5Hz), 3.31 (2H, dt, J = 0.8,
11.0Hz), 3.49 (2H, s), 3.97-4.11 (2H, m), 4
．． 25 (2H, t, J = 4.5Hz), 7.02 (1H, d, J = 9.2Hz)
, 7.11 (2H, d, J = 8.8Hz), 7.22-7.26 (4H, m),
7.40-7.50 (5H, m). IR (KBr) ν: 2949, 2847, ^{1493 cm −1} . Anal. calcd. for _C30H34N2O4S :C _{, 69.47} ; _H
, 6.61; N, 5.40. Found C, 69.27; H, 6.50; N,
5.37. Reference Example 87 4-Nitrobenzylamine (5.24 g, 34.4 mmol), S-methyl-
N,N'-bis(tert-butoxycarbonyl)isothiourea (5.00 g
, 17.2 mmol) in THF (60 ml) was stirred at 55° C. for 9 hours and at room temperature for 11 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (150 ml) was added, followed by stirring with 1N hydrochloric acid (
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 150 g, ethyl acetate/hexane = 1/9 → 1/6). The target fraction was concentrated under reduced pressure, and diisopropyl ether was added to the concentrate, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to obtain N-(4-nitrobenzyl)-N',N'
'-bis(tert-butoxycarbonyl)guanidine (5.67 g, 14.4
The yield was 83 mmol.

IR (KBr): 1723, 1644, 1620, 1570, 1524cm⁻¹
．¹ H-NMR (CDCl₃) δ: 1.50 (18H, s), 4.7-4.8 (2
H, m), 7.48 (2H, d, J = 8.5Hz), 8.21 (2H, d, J =
8.5 Hz). Reference Example 88 N-(4-nitrobenzyl)-N',N''-bis(tert-butoxycarbonyl)
(bornyl)guanidine (1.97 g, 4.99 mmol) in THF (25 ml)
Nickel bromide (109 mg) was dissolved in a mixed solvent of 25 ml of methanol at 0° C.
, 0.50 mmol), sodium borohydride (757 mg, 20.0 mmol)
1) was added in this order and stirred at room temperature for 30 minutes. 1N hydrochloric acid (40 ml) was added at 0°C and the mixture was stirred for 30 minutes.
The mixture was stirred at room temperature for 5 minutes, and the pH was adjusted to about 8 by adding saturated aqueous sodium bicarbonate.
The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and
The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure.
and 4-[N',N''-bis(tert-butoxycarbonyl)guanidinium
To the obtained product was added 1.21 g (3.32 mmol) of methylaniline (66%).

IR (KBr): 1622, 1516 cm ⁻¹ . ¹ H-NMR ( _CDCl3 ) δ: 1.47 (9H, s), 1.52 (9H, s)
, 4.45-4.55 (2H, m), 6.66 (2H, d, J=8.6Hz),
7.11 (2H, d, J = 8.6 Hz). Example 40 (Preparation of Compound 40) 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
The carboxylic acid (300 mg, 1.07 mmol) was dissolved in DMF (10 ml) and added with 1-hydroxybenzotriazole (159 mg, 1.18 mmol) at 0° C.
, 4-[N',N''-bis(tert-butoxycarbonyl)guanidinomethyl]aniline (429 mg, 1.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (308 mg, 1.61 mmol)
Triethylamine (0.447 ml, 3.21 mmol) and 4-dimethylaminopyridine (6 mg) were added and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (70 ml) was added. The mixture was washed successively with water (5 ml x 3), saturated sodium bicarbonate water (5 ml x 3), and saturated brine (5 ml). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g, ethyl acetate/
The target fraction was concentrated under reduced pressure, and a mixed solvent (ethyl acetate/hexane = 1/1) was added, and the insoluble matter was filtered off. The insoluble matter was washed with a mixed solvent (ethyl acetate/hexane = 1/1), and then dried under reduced pressure to give N-[4-[N',N''-bis(t
[0113] To give [0114] 390 mg (0.62 mmol, 58%) of [(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (compound 40) (4,4-dimethylphenyl)-4-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (compound 40).

IR (KBr): 1723, 1647, 1617, 1576, 1518cm⁻¹
．¹ H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.52 (9H, s)
, 2.40 (3H, s), 3.0-3.15 (2H, m), 4.3-4.45 (
2H, m), 4.55-4.7 (2H, m), 7.06 (1H, d, J = 8.4
Hz), 7.2-7.7 (11H, m). Example 41 (Preparation of Compound 41) N-[4-[N',N''-bis(tert-butoxycarbonyl)guanidinium]
4-methylphenyl)-2,3-dihydro-1-(4-methylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1 ...
Benzoxepin-4-carboxamide (170 mg, 0.27 mmol)
N Hydrogen chloride (ethyl acetate solution, 5 ml) was added and the mixture was stirred at room temperature for 18 hours.
The mixture was concentrated under reduced pressure, diethyl ether was added, and the insoluble matter was filtered off.
After washing with ether, it was dried under reduced pressure to give N-(4-guanidinomethylphenyl)-7-(4
-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbox
To obtain 130 mg (0.28 mmol) of samidinohydrochloride (compound 41).

IR (KBr): 1655, 1613, 1597 ^{, 1522 cm −1} . ^1H -NMR (DMSO- _d6 ) δ: 2.35 (3H, s), 2.9-3.05
(2H, m), 4.2-4.4 (4H, m), 7.06 (1H, d, J=8.4
Hz), 7.2-7.8 (7H, m). Reference Example 89 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
A solution of carboxylic acid (0.93 g) in dichloromethane (20 ml) was added to DMSO under ice cooling.
F (4 drops) and oxalyl chloride (0.34 ml) were added. After 2 hours at room temperature, the mixture was concentrated and dissolved in THF (20 ml). 4-aminobenzonitrile (412 ml) was also added.
To a solution of the above compound (g) in THF (10 ml) was added triethylamine (1.38 ml) under ice cooling.
The acid chloride solution prepared above was then added, and the mixture was stirred at room temperature for 17 hours. Under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. After washing with brine, the extract was dried (anhydrous magnesium sulfate) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4) and further recrystallized from ethyl acetate/hexane to give N-(4-cyanophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (986 mg) as colorless crystals.

m. p. 187-189℃¹ H-NMR (200MHz, CDCl₃) δ: 2.40 (s, 3H), 3.0
7 (t, 2H, J = 4.6), 4.36 (t, 2H, J = 4.6), 7.07 (
d, 1H, J = 8.0), 7.2-7.3 (m, 3H), 7.4-7.55 (m
, 4H), 7.64 (d, 2H, J=8.8), 7.74 (d, 2H, J=8.
8). IR (KBr) 2222, 1671, 1588, 1514, 1404, 1316
,1225,1175,837,812cm⁻¹ Elemental analysis C₂₅H₂₀N₂O₂ Calcd. C, 78.93; H, 5.30
; N, 7.36: Found. C, 78.98; H, 5.24; N, 7.26. Reference Example 90 N-(4-cyanophenyl)-7-(4-methylphenyl)-2,3-dihydro
1-benzoxepin-4-carboxamide (347 mg) in 28% aqueous chloride
A solution of chlorine in ethanol and dioxane (5 ml) was added. The mixture was stirred at room temperature for 20 hours.
Thereafter, the precipitate was collected by filtration, washed with ethyl acetate, and
[4-(4-methylphenyl)-2,3-dihydro-1-phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-phenyl
Benzoxepin-4-carboxamide hydrochloride (369 mg) was obtained as yellow crystals.
Ta.¹ H-NMR (DMSO-d₆) δ: 1.50 (t, 2H, J=7.0), 2.
34 (s, 3H), 2.9-3.1 (m, 2H), 4.1-4.4 (m, 2H)
, 4.60 (q, 2H, J = 7.0), 7.06 (d, 1H, J = 8.8), 7
．． 26 (d, 2H, J = 8.4), 7.45-7.65 (m, 4H), 7.7-
7.85 (m, 1H), 8.01 (d, 2H, J=8.8), 8.12 (d, 2
H, J = 8.8), 10.59 (s, 1H), 10.8-11.2 (br, 1H
) Example 42 (Preparation of Compound 42) N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-
(phenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide hydrochloride
To the salt (364 mg) was added 14% ammonia/ethanol solution (5 ml).
After stirring overnight at room temperature, the mixture was stirred at 50° C. for 3 hours.
N hydrochloric acid/ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate, and then
Recrystallization from acetonitrile/methanol/ethyl acetate yielded N-(4-amidinophenoxy)
(4-methylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin
Benzene-4-carboxamide hydrochloride (compound 42) (127 mg) as colorless crystals
Got it.

m. p. 294-296℃¹ H-NMR (200MHz, DMSO-d₆) δ: 2.35 (s, 3H), 2
．． 95-3.05 (m, 2H), 4.25-4.35 (m, 2H), 7.06 (
d, 1H, J = 8.4), 7.26 (d, 2H, J = 8.0), 7.45 (s,
1H), 7.56 (d, 2H, J = 8.0), 7.5-7.6 (m, 1H), 7
．． 75-7.85 (m, 1H), 7.84 (d, 2H, J=8.8), 7.96
(d, 2H, J=8.8), 8.8-9.0 (brm, 2H), 9.2-9.3
(brm, 2H), 10.45 (s, 1H). IR (KBr) 1676, 1644, 1597, 1493, 1329, 1258
,845,814cm⁻¹ Elemental analysis C₂₅H₂₃N₃O₂HCl 0.3H₂O Calcd. C,6
8.35; H, 5.64; N, 9.56: Found. C, 68.09; H, 5
.56; N,9.87. Example 43 (Preparation of Compound 43) N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-
(phenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide hydrochloride
A solution of the salt (169 mg) in ethanol (4 ml) was added with ethylamine (1 ml).
After stirring at room temperature for 4 days, the mixture was concentrated. The mixture was suspended in ethyl acetate and diluted with 4N hydrochloric acid/
Ethyl acetate was added, and the precipitate was collected by filtration. It was recrystallized from ethyl acetate/methanol.
N-(4-ethylamidinophenyl)-7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin-4-carboxamide hydrochloride (compound 43)
25 mg) was obtained as colorless crystals.

m. p. >300℃.¹ H-NMR (200MHz, DMSO-d₆) δ: 1.25 (t, 3H, J=
7.2), 2.34 (s, 3H), 2.9-3.1 (m, 2H), 3.3-3.
5 (m, 2H), 4.25-4.4 (m, 2H), 7.06 (d, 1H, J=8
．． 6), 7.26 (d, 2H, J = 7.6), 7.46 (s, 1H), 7.5-
7.65 (m, 3H), 7.75 (d, 2H, J=8.6), 7.7-7.8 (
m, 1H), 7.95 (d, 2H, J=8.6), 8.9 (brs, 1H), 9
．． 33 (brs, 1H), 9.6-9.7 (m, 1H), 10.12 (s, 1H
). IR (KBr) 1671, 1518, 1456, 1318, 1231, 816c
m⁻¹ Elemental analysis C₂₇H₂₇N₃O₂HCl 0.5H₂O Calcd. C,6
8.85; H, 6.21; N, 8.92: Found. C, 68.61; H, 6
.21; N,8.94. Example 44 (Preparation of Compound 44) N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-
(phenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide hydrochloride
To a solution of the salt (200 mg) in ethanol (4 ml) was added morpholine (1 ml).
After stirring overnight at room temperature, the mixture was concentrated and sodium bicarbonate water was added.
The extract was dried (anhydrous magnesium sulfate) and then washed with 4N hydrochloric acid/acetic acid.
Chill was added, and the precipitate was collected by filtration, washed with ethyl acetate, and N-[4-(4-morpholino)
[0023] carbonimidoylphenyl]-7-(4-methylphenyl)-2,3-di
Hydro-1-benzoxepin-4-carboxamide hydrochloride (compound 44) (1
04 mg) was obtained as colorless crystals.

m. p. 209-211℃¹ H-NMR (200MHz, DMSO-d₆) δ: 2.3 (s, 3H), 2.
9-3.1 (m, 2H), 3.3-3.55 (m, 2H), 3.6-3.75 (
m, 2H), 3.75-3.9 (m, 4H), 4.25-4.4 (m, 2H),
7.07 (d, 1H, J=8.6), 7.27 (d, 2H, J=7.6), 7.
45 (s, 1H), 7.5-7.7 (m, 3H), 7.60 (d, 2H, J=7
．． 6), 7.75-7.8 (m, 1H), 7.98 (d, 2H, J=8.6),
9.30 (s, 1H), 9.54 (s, 1H), 10.43 (s, 1H). IR (KBr) 1663, 1603, 1522, 1493, 1460, 1318
,1248,1184,1115,850,812cm⁻¹ Elemental analysis C₂₉H₂₉N₃O₃HCl 0.6H₂O Calcd. C,6
7.66; H, 6.11; N, 8.16: Found. C, 67.45; H, 5
.96; N,7.94. Example 45 (Preparation of Compound 45) N-(4-cyanomethylphenyl)-7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin-4-carboxamide (200 mg) 28%
Hydrogen chloride/ethanol/dioxane solution (2 ml) was added.
After storage, the mixture was concentrated, and ethanol (4 ml) and morpholine (1 ml) were added to the residue.
After stirring at room temperature for 1 hour, the mixture was concentrated, and sodium bicarbonate water was added. The mixture was extracted with ethyl acetate.
The extract was dried (magnesium sulfate) and concentrated, and the residue was extracted with methanol/ethyl acetate.
Recrystallization from hexane yielded N-[4-[(4-morpholino)carbonimidoyl
methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-phenyl
Benzoxepin-4-carboxamide (compound 45) (93 mg) was obtained as colorless crystals.
And got it.

m. p. 196-198℃¹ H-NMR (200MHz, CDCl₃) δ: 2.39 (3H, s), 3.0
7 (2H, t, J = 4.8), 3.4-3.55 (4H, m), 3.6-3.7
(6H, m), 4.34 (2H, t, J=4.8), 7.04 (1H, d, J=
8.4), 7.19 (2H, d, J = 8.8), 7.2-7.3 (2H, m),
7.4-7.55 (5H, m), 7.60 (2H, d, J=8.0), 7.79
(1H, brs). IR (KBr) 1659, 1582, 1522, 1493, 1318, 1171
,1123,1030,814cm⁻¹ Elemental analysis C₃₀H₃₁N₃O₃・0.5H₂O Calcd. C, 73.45
; H, 6.57; N, 8.57: Found. C, 73.46; H, 6.43;
N,8.48 Example 46 (Preparation of Compound 46) N-(4-cyanomethylphenyl)-7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin-4-carboxamide (200 mg) 28%
Hydrogen chloride/ethanol/dioxane solution (2 ml) was added.
After storage, the mixture was concentrated, and ethanol (4 ml) and piperidine (1 ml) were added to the residue.
After stirring at room temperature for 1 hour, the mixture was concentrated and sodium bicarbonate water was added.
The extract was dried (magnesium sulfate) and concentrated. The residue was diluted with 4N hydrochloric acid.
Ethyl acetate was added, and the precipitate was collected by filtration, washed with ethyl acetate, and N-[4-[(1
-piperidino)carbonimidoylmethyl]phenyl]-7-(4-methylphenyl
(compound)-2,3-dihydro-1-benzoxepine-4-carboxamide
Compound 46) (103 mg) was obtained as a white powder.

m. p. 195-197℃¹ H-NMR (200MHz, DMSO-d₆) δ: 1.2-1.35 (2H,
m), 1.5-1.65 (4H, m), 2.34 (3H, s), 2.95-3.
05 (2H, m), 3.42 (4H, s), 3.5-3.7 (2H, m), 3.
95-4.05 (2H, m), 4.25-4.35 (2H, m), 7.05 (1
H, d, J = 8.6), 7.2-7.4 (5H, m), 7.5-7.6 (3H,
m), 7.7-7.8 (3H, m), 8.88 (1H, brs), 9.4-9.
5 (1H, m), 10.07 (1H, s). IR (KBr) 1647, 1630, 1518, 1491, 1321, 1264
, 814 cm⁻¹ Elemental analysis C₃₁H₃₃N₃O₂HCl H₂O Calcd. C, 69.7
1; H, 6.79; N, 7.87: Found. C, 69.67; H, 6.84
;N,7.81. Reference Example 91 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
- Carboxylic acid (1402 mg, 5.00 mmol) was dissolved in DMF (30 ml).
and 1-hydroxybenzotriazole (743 mg, 5.50 mmol) at 0°C.
, 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl
Amine (1256 mg, 5.50 mmol), 1-[3-(dimethylamino)propanol]
propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol
) was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (1
20 ml) and water (30 ml), saturated sodium bicarbonate solution (20 ml x 3), saturated saline solution (
The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, ethyl acetate/hexane = 1
The target fraction was concentrated under reduced pressure and diisopropyl ether was added.
The insoluble matter was collected by filtration. The insoluble matter was washed with diisopropyl ether, dried under reduced pressure, and
-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl
[4-methylphenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin
4-carboxamide (1.64 g, 3.34 mmol, 67%) was obtained.

IR (KBr): 1694, 1674, 1653, 1617, 1539cm⁻¹
．¹ H-NMR (CDCl₃) δ: 1.0-1.8 (7H, m), 1.46 (9H
, s), 2.39 (3H, s), 2.6-2.8 (2H, m), 2.9-3.0
5 (2H, m), 3.35-3.5 (2H, m), 4.0-4.2 (2H, m)
, 4.25-4.35 (2H, m), 5.75-5.85 (1H, m), 7.0
3 (1H, d, J = 8.2Hz), 7.16 (1H, s), 7.24 (2H, d
, J=8.0Hz), 7.43 (1H, dd, J=2.5, 8.2Hz), 7.
45 (2H, d, J = 8.0 Hz), 7.49 (1H, d, J = 2.5 Hz). Example 47 (Preparation of Compound 47) N-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]
[ethyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxane
Pine-4-carboxamide (491 mg, 1.00 mmol) was dissolved in 4N hydrogen chloride (
A solution of 10 ml of ethyl acetate was added and the mixture was stirred at room temperature for 3 hours.
Ethyl acetate (15 ml) was added to the residue, and water (10 ml) and 1N hydrochloric acid (5 ml × 2
The aqueous layer was adjusted to pH > 11 with 8N aqueous sodium hydroxide solution, and extracted with dichloromethane.
The organic layer was extracted with methane (15 ml x 3). After drying with anhydrous sodium sulfate,
The mixture was concentrated under reduced pressure, diethyl ether was added, and the insoluble matter was filtered off.
After washing with ethyl acetate, the product was dried under reduced pressure to give N-[2-(4-piperidyl)ethyl]-7-(4-methyl-
(ethylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide
Compound 47 (361 mg, 0.92 mmol, 92%) was obtained.

IR (KBr): 1649, 1607, ^{1537 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.05-1.8 (7H, m), 2.39 (3
H, s), 2.5-2.7 (2H, m), 2.9-3.15 (4H, m), 3.
35-3.5 (2H, m), 4.25-4.4 (2H, m), 5.75-5.8
5 (1H, m), 7.03 (1H, d, J = 8.3Hz), 7.16 (1H, s
), 7.24 (2H, d, J=8.2Hz), 7.43 (1H, dd, J=2.
5, 8.3Hz), 7.45 (2H, d, J = 8.2Hz), 7.49 (1H,
d, J=2.5 Hz). Example 48 (Preparation of Compound 48) N-[2-(4-piperidyl)ethyl]-7-(4-methylphenyl)-2,
3-Dihydro-1-benzoxepin-4-carboxamide (150 mg, 0.
38 mmol), tetrahydropyran-4-one (38 mg, 0.38 mmol)
) was dissolved in 1,2-dichloroethane (6 ml) and sodium triacetoxyborohydride (122 mg, 0.58 mmol), acetic acid (0.022 ml, 0.38
A 1N aqueous solution of sodium hydroxide (2 mmol) was added and the mixture was stirred at room temperature for 23 hours.
0 ml) was added and extracted with dichloromethane (20 ml, 10 ml × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, dichloromethane/methanol = 1/0 → 9/1). The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and dried under reduced pressure to give N-[2-[1-(tetrahydropyran-4-yl)piperidin-4-yl)ethyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (
Compound 48) (119 mg, 0.25 mmol, 65%) was obtained.

IR (KBr): 1651, 1615, ^{1539 cm −1} . ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.9 (11H, m), 2.1-2.
3 (2H, m), 2.39 (3H, s), 2.4-2.65 (1H, m), 2.
9-3.1 (4H, m), 3.25-3.5 (4H, m), 3.95-4.1 (
2H, m), 4.35-4.4 (2H, m), 5.75-5.9 (1H, m),
7.03 (1H, d, J = 8.3Hz), 7.16 (1H, s), 7.24 (2
H, d, J = 8.2Hz), 7.43 (1H, dd, J = 2.4, 8.3Hz)
, 7.45 (2H, d, J = 8.2Hz), 7.49 (1H, d, J = 2.4H
z). Example 49 (Preparation of Compound 49) N-[2-(4-piperidyl)ethyl]-7-(4-methylphenyl)-2,
3-Dihydro-1-benzoxepin-4-carboxamide (150 mg, 0.
38 mmol) was dissolved in DMF (4 ml) and potassium carbonate (106 mg, 0.7
To the mixture, benzyl bromide (0.7 mmol), benzyl bromide (0.046 ml, 0.39 mmol) were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and water (15 ml) was added to the residue, followed by extraction with ethyl acetate (15 ml x 3). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, ethyl acetate/methanol = 1/0 → 95/5). The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to obtain N-[2-(1-benzylpiperidin-4-yl)ethyl]
-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carboxamide (compound 49) (154 mg, 0.32 mmol, 83%) was obtained.

IR (KBr): 1651, 1615, ^{1537 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.15-1.8 (7H, m), 1.85-2
．． 1 (2H, m), 2.39 (3H, s), 2.8-3.0 (4H, m), 3.
3-3.5 (2H, m), 3.50 (2H, s), 4.25-4.35 (2H,
m), 5.7-5.85 (1H, m), 7.03 (1H, d, J=8.5Hz)
, 7.15 (1H, s), 7.2-7.35 (5H, m), 7.24 (2H, d
, J=8.0Hz), 7.43 (1H, dd, J=2.4, 8.5Hz), 7.
45 (2H, d, J = 8.0 Hz), 7.48 (1H, d, J = 2.4 Hz). Reference Example 92 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
The carboxylic acid (1402 mg, 5.00 mmol) was dissolved in DMF (30 ml) and cooled to 0° C. with 1-hydroxybenzotriazole (743 mg, 5.50 mmol).
To the mixture were added [1-(tert-butoxycarbonyl)piperidin-4-yl]methylamine (1393 mg, 6.50 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the mixture was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (10
0 ml) and water (10 ml x 3), 10% potassium hydrogen sulfate aqueous solution (10 ml
The extract was washed sequentially with saturated sodium bicarbonate solution (10 ml × 3), saturated sodium bicarbonate solution (10 ml × 3), and saturated saline solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 80 g, ethyl acetate/hexane = 1/2 → 1/1). The target fraction was concentrated under reduced pressure to give N-[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (2409 mg).

IR (KBr): 1671, 1617, ^{1537 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.0-1.85 (5H, m), 1.46 (9
H, s), 2.39 (3H, s), 2.6-2.8 (2H, m), 2.9-3.
05 (2H, m), 3.2-3.35 (2H, m), 4.0-4.25 (2H,
m), 4.25-4.4 (2H, m), 5.85-6.05 (1H, m), 7.
03 (1H, d, J = 8.3Hz), 7.17 (1H, s), 7.24 (2H,
d, J = 8.0Hz), 7.44 (1H, dd, J = 2.3, 8.3Hz), 7
．． 45 (2H, d, J = 8.0Hz), 7.49 (1H, d, J = 2.3Hz)
Example 50 (Preparation of Compound 50) N-[1-(tert-butoxycarbonyl)piperidin-4-yl)methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
To N-(4-piperidylmethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (1430 mg, 3.00 mmol), 4N hydrogen chloride (ethyl acetate solution, 50 ml) was added and stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 ml) was added to the residue. The insoluble matter was filtered off. The insoluble matter was washed with ethyl acetate and dried under reduced pressure to give N-(4-piperidylmethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide hydrochloride (Compound 50) (1195 mg, 2.89 mmol, 96%).

IR (KBr): 1647, 1609, ^{1535 cm −1} . ^1H -NMR (DMSO- _d6 ) δ: 1.2-1.55 (2H, m), 1.65
-1.95 (3H, m), 2.34 (3H, s), 2.65-2.95 (4H,
m), 3.05-3.35 (4H, m), 4.15-4.3 (2H, m), 7.
02 (1H, d, J = 8.4Hz), 7.26 (1H, s), 7.26 (2H,
d, J = 8.1Hz), 7.51 (1H, dd, J = 2.2, 8.4Hz), 7
．． 55 (2H, d, J = 8.1Hz), 7.67 (1H, d, J = 2.2Hz)
, 8.15-8.3 (1H, m). Example 51 (Preparation of Compound 51) N-(4-piperidylmethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide hydrochloride (250 mg, 0.61
mmol) was suspended in 1,2-dichloroethane (10 ml) and triethylamine (
0.101 ml, 0.72 mmol), tetrahydropyran-4-one (0.0
67 ml, 0.73 mmol), sodium triacetoxyborohydride (20
The mixture was added with 1N aqueous sodium hydroxide solution (10 ml) and extracted with dichloromethane (10 ml x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g,
The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and then dried under reduced pressure to give N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 51) (183 mg, 0
. 40 mmol, 66%) was obtained.

IR (KBr): 1651, 1615, ^{1537 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.2-1.9 (9H, m), 2.15-2.
3 (2H, m), 2.39 (3H, s), 2.45-2.65 (1H, m), 2
．． 9-3.1 (4H, m), 3.2-3.45 (4H, m), 3.95-4.1
(2H, m), 4.25-4.35 (2H, m), 5.9-6.05 (1H, m
), 7.03 (1H, d, J=8.4Hz), 7.18 (1H, s), 7.24
(2H, d, J = 8.2Hz), 7.43 (1H, dd, J = 2.4, 8.4H
z), 7.45 (2H, d, J=8.2Hz), 7.50 (1H, d, J=2.
4 Hz). Reference Example 93 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
The carboxylic acid (1402 mg, 5.00 mmol) was dissolved in DMF (30 ml) and cooled to 0° C. with 1-hydroxybenzotriazole (743 mg, 5.50 mmol).
, 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propylamine (1333 mg, 5.50 mmol), 1-[3-(dimethylamino)
Propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol)
The reaction mixture was concentrated under reduced pressure, and ethyl acetate (100 ml) was added to the residue. Water (10 ml x 3), a 10% aqueous potassium hydrogen sulfate solution (1
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 80 g, ethyl acetate/hexane = 1/3 → 1/1).
The target fraction was concentrated under reduced pressure to give N-[3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propyl]-7-(4-methylphenyl)-
2,3-Dihydro-1-benzoxepine-4-carboxamide (2498 mg
, 4.95 mmol, 99%) was obtained.

IR (KBr): 1694, 1671, 1653, 1620, 1537cm⁻¹
．¹ H-NMR (CDCl₃) δ: 0.9-1.8 (9H, m), 2.39 (3H
, s), 2.55-2.8 (2H, m), 2.9-3.0 (2H, m), 3.3
-3.45 (2H, m), 4.0-4.15 (2H, m), 4.25-4.4 (
2H, m), 5.8-5.9 (1H, m), 7.03 (1H, d, J = 8.2H
z), 7.16 (1H, s), 7.24 (2H, d, J=8.0Hz), 7.4
3 (1H, dd, J = 2.3, 8.2Hz), 7.45 (2H, d, J = 8.0
Hz), 7.49 (1H, d, J = 2.3 Hz). Example 52 (Preparation of Compound 52) N-[3-[1-(tert-butoxycarbonyl)piperidin-4-yl]
[propyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxyl
Sepin-4-carboxamide (1514 mg, 3.00 mmol) was dissolved in 4N aqueous chloride.
After adding chlorine (ethyl acetate solution, 50 ml), the mixture was stirred at room temperature for 16 hours.
After concentration, ethyl acetate (50 ml) was added to the residue, and the insoluble material was filtered off.
After washing with ethyl acetate, it was dried under reduced pressure to give N-[3-(4-piperidyl)propyl]-7-
(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-chlor
Voxamide hydrochloride (compound 52) (1286 mg, 2.92 mmol, 97%)
obtained.

IR (KBr): 1647, 1599, ^{1545 cm −1} . ¹ H-NMR (DMSO-d ₆ ) δ: 1.1-1.9 (9H, m), 2.34 (
3H, s), 2.7-2.95 (4H, m), 3.05-3.4 (4H, m),
4.15-4.3 (2H, m), 7.02 (1H, d, J=8.4Hz), 7.
24 (1H, s), 7.26 (2H, d, J=8.0Hz), 7.51 (1H,
dd, J=2.2, 8.4Hz), 7.55 (2H, d, J=8.0Hz), 7
64 (1H, d, J = 2.2 Hz), 8.0-8.15 (1H, m). Example 53 (Preparation of Compound 53) N-[3-(4-piperidyl)propyl]-7-(4-methylphenyl)-2
,3-Dihydro-1-benzoxepin-4-carboxamide hydrochloride (250m
g, 0.57 mmol) was suspended in 1,2-dichloroethane (10 ml), and the suspension was treated with triethylamine (0.095 ml, 0.68 mol), tetrahydropyran-4-one (0.084 ml, 0.91 mmol), sodium triacetoxyborohydride (192 mg, 0.91 mmol), acetic acid (0.039 ml, 0.68 mmol), and
ol) were added in this order and stirred at room temperature for 16 hours.
The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 15 g, dichloromethane/methanol = 1/0 → 9/1). The target fraction was concentrated under reduced pressure, diisopropyl ether was added, and the insoluble matter was filtered off. The insoluble matter was washed with diisopropyl ether and dried under reduced pressure to give N-[3-[1-(4-tetrahydropyranyl)piperidin-4-yl]propyl]-7-(4-methylphenyl)-
2,3-Dihydro-1-benzoxepine-4-carboxamide (Compound 53)
(198 mg, 0.41 mmol, 71%) was obtained.

IR (KBr): 1649, 1605, ^{1541 cm −1} . ^1H -NMR ( _CDCl3 ) δ: 1.15-1.9 (13H, m), 2.05-
2.3 (2H, m), 2.39 (3H, s), 2.4-2.65 (1H, m),
2.9-3.1 (4H, m), 3.25-3.5 (4H, m), 3.95-4.
1 (2H, m), 4.25-4.4 (2H, m), 5.8-5.95 (1H, m
), 7.03 (1H, d, J=8.3Hz), 7.16 (1H, s), 7.24
(2H, d, J = 8.2Hz), 7.43 (1H, dd, J = 2.3, 8.3H
z), 7.45 (2H, d, J=8.2Hz), 7.49 (1H, d, J=2.
3 Hz). Reference Example 94 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-
Carboxylic acid (1.0 g) was suspended in dichloromethane (14 ml), and oxalyl chloride (0.93 ml) and dimethylformamide (1 drop) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours. After the solvent was evaporated, the mixture was dissolved in tetrahydrofuran (20 ml) and added dropwise to a solution of 1-(t-butoxycarbonyl)piperidine (1.4 g) and triethylamine (1.5 ml) in tetrahydrofuran (10 ml) under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-[1-(t-butoxycarbonyl)piperidin-4-yl]-7-
(4-Methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.54 g) was obtained as colorless prisms.

mp 205-208℃. ^1H -NMR (δppm, _CDCl3 ) 1.37-1.42 (2Hm), 1.4
7 (9H, s), 1.96-2.04 (2H, m), 2.39 (3H, s), 2
．． 84-2.98 (4H, m), 3.99-4.11 (3H, m), 4.31 (
2H, t, J = 4.7Hz), 5.72 (1H, d, J = 7.4Hz), 7.0
3 (1H, d, J = 8.4Hz), 7.13 (1H, s), 7.24 (2H, d
, J=9.2Hz), 7.41-7.49 (4H, m). IR (KBr) ν: 2976, 1694 cm ⁻¹ . Anal. calcd. for C ₂₈ H ₃₄ N ₂ O ₄ :C, 72.70; H,
7.41; N, 6.06. Found C, 72.51; H, 7.20; N, 6
20. Reference Example 95 Cyclooctanone (4.07 g), p-toluenesulfonyl hydrazide (6 g)
) was suspended in methanol (40 ml), hydrochloric acid (1 ml) was added, and the mixture was stirred at room temperature for 3 days. After concentration, the precipitated crystals were collected by filtration, washed with methanol, hexane, and diethyl ether, and cyclooctanone p-toluenesulfonylhydrazone (7.29 g) was obtained.
) was obtained as colorless crystals.

mp 140-143℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.10-1.25 (2H, m), 1.
35-1.45 (4H, m), 1.55-1.73 (4H, m), 1.88 (1
H, br), 2.19-2.35 (4H, m), 2.42 (3H, s), 7.3
0 (2H, d, J=8.3Hz), 7.84 (2H, d, J=8.3Hz). IR (KBr) ν: 3221, 2926, ^{2857 cm −1} . Anal. calcd. for _{C15H22N2O2S :} C _{, 61.19} ;H
, 7.53; N, 9.52. Found C, 61.22; H, 7.31; N,
9.66. Reference Example 96 Cyclooctanone p-toluenesulfonylhydrazone (4.5 g) was reacted with N,N
The mixture was suspended in N,N',N'-tetraethylenediamine (46 ml) and heated at -55°C for 1.
A 6M n-butyllithium hexane solution (38 ml) was added dropwise. After stirring at room temperature for 30 minutes under an argon atmosphere, the mixture was cooled on ice, DMF (5.9 ml) was added, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified using a silica gel column (ethyl acetate:hexane = 1:9) to obtain cyclooctene-1-carbaldehyde (1.5 g) as a pale yellow oil. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.39-1.69 (8H, m), 2.
38-2.52 (4H, m), 6.72 (1H, t, J=8.3Hz), 9.4
1 (1H, s). IR (neat) ν: 2932, 2859, 1675 ^{cm −1} . Reference Example 97 Cyclononanone (1.36 g), p-toluenesulfonylhydrazide (1.8
1 g) was suspended in methanol (12 ml), hydrochloric acid (0.3 ml) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the precipitated crystals were collected by filtration and washed with cold methanol and diethyl ether-hexane to give cyclononanone p-toluenesulfonylhydrazone (2.29 g) as colorless crystals.

mp 135-138℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.00-1.10 (2H, m), 1.
10-1.25 (2H, m), 1.38-1.76 (8H, m), 2.18-2
．． 24 (2H, m), 2.28-2.34 (2H, m), 2.41 (3H, s)
, 7.30 (2H, d, J=8.0Hz), 7.32 (1H, br), 7.85
(2H, d, J=8.0Hz). IR (KBr) ν: 3223, 2922 cm ⁻¹ . Anal. calcd. for C ₁₆ H ₂₄ N ₂ O ₂ S:C, 62.30; H
, 7.84; N, 9.08. Found C, 62.42; H, 7.66; N,
9.21. Reference Example 98 Cyclononanone p-toluenesulfonylhydrazone (2.0 g) was reacted with N,N,N
The solution was suspended in ',N'-tetraethylenediamine (20 ml) and heated at -55°C to a concentration of 1.6 M.
A solution of n-butyllithium in hexane (16.2 ml) was added dropwise. After stirring at room temperature for 30 minutes under an argon atmosphere, the mixture was cooled on ice, DMF (2.5 ml) was added, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water,
After washing with saturated brine, the mixture was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified using a silica gel column (ethyl acetate:hexane = 1:10) to obtain cyclononene-1-carbaldehyde (0.7 g) as a pale yellow oil. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.35-1.60 (8H, m), 1.
60-1.75 (2H, m), 2.36-2.54 (4H, m), 6.61 (1
IR (neat) ν: 2928, 2857, 1684 ^{cm −1} . Example 54 (Preparation of Compound 54) N-[1-(t-butoxycarbonyl)piperidin-4-yl]-7-(4-
N-(4-piperidinyl)-7-(methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (1.56 g) was dissolved in ethyl acetate (100 ml), and 4N hydrochloric acid/ethyl acetate (25 ml) was added, followed by stirring at room temperature overnight. 1N sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give N-(4-piperidinyl)-7-((
(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 54) (1.1 g) was obtained as colorless prisms.

mp 183-185℃.¹ H-NMR (δppm, CDCl₃)1.31-1.50 (2Hm), 1.9
8-2.06 (2H, m), 2.39 (3H, s), 2.75 (2H, dt, J
= 2.6, 12.0Hz), 2.97 (2H, t, J = 4.5Hz), 3.12
(2H, dt, J=12.8, 3.4Hz), 3.90-4.10 (1H, m)
, 4.32 (2H, t, J = 4.5Hz), 5.75 (1H, d, J = 8.2H
z), 7.03 (1H, d, J=8.2Hz), 7.14 (1H, s), 7.2
4 (2H, d, J=8.0Hz), 7.40-7.50 (4H, m). IR (KBr) ν: 3299, 2938, 1651cm⁻¹ Anal. calcd. for C₂₃H₂₆N₂O₂・0.2H₂O:C,
75.46; H, 7.27; N, 7.65. Found C, 75.49; H,
7.15; N, 7.56. Example 55 (Preparation of Compound 55) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro
-1-benzoxepin-4-carboxamide (0.15 g), cyclohexane
Carbaldehyde (0.056 g) was dissolved in 1,2-dichloroethane (10 ml).
Then, sodium triacetoxyborohydride (0.13 g) was added under ice cooling, and
The mixture was stirred overnight at room temperature under nitrogen atmosphere. After neutralization with 1N aqueous sodium hydroxide solution,
The organic layer was washed with water and saturated brine, and then extracted with sulfuric anhydride.
The mixture was dried over magnesium, and the solvent was removed under reduced pressure to obtain crude crystals.
Recrystallization from ethyl acetate/hexane gave N-(1-cyclohexylmethylpiperidine-4
-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxane
Pine-4-carboxamide (compound 55) (0.13 g) as colorless prisms
Got it.

mp 180-181℃. ¹ H-NMR (δppm, CDCl ₃ ) 0.80-1.00 (2H, m), 1.
10-1.17 (4H, m), 1.40-1.80 (7H, m), 1.95-2
．． 14 (4H, m), 2.16 (2H, d, J = 7.0Hz), 2.39 (3H
, s), 2.81-2.88 (2H, m), 2.96 (2H, t, J = 4.5H
z), 3.80-4.00 (1H, m), 4.31 (2H, t, J = 4.5Hz
), 5.74 (1H, br), 7.02 (1H, d, J=8.4Hz), 7.1
4 (1H, s), 7.24 (2H, d, J=8.8Hz), 7.36-7.50
(4H, m). IR (KBr) ν: 2924, 2851, ^{1651 cm −1} . Anal. calcd. for C ₃₀ H ₃₈ N ₂ O ₂ :C, 78.56; H,
8.35; N, 6.11. Found C, 78.31; H, 8.17; N, 6
16. Example 56 (Preparation of Compound 56) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g), tetrahydro-
4H-pyran-4-one (0.06 g) was dissolved in 1,2-dichloroethane (7 ml), and sodium triacetoxyborohydride (0.13 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After neutralization with 1N aqueous sodium hydroxide solution, the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-(1-(tetrahydropyran-4-yl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-
1-Benzoxepine-4-carboxamide (compound 56) (0.13 g) was obtained as colorless prisms.

mp 199-204℃ (dec.). ¹ H-NMR (δppm, CDCl ₃ ) 1.40-1.80 (6H, m), 2.
00-2.15 (2H, m), 2.25-2.39 (2H, m), 2.39 (3
H, s), 2.43-2.55 (1H, m), 2.90-3.00 (4H, m)
, 3.28 (2H, dt, J = 1.8, 11.6Hz), 3.80-4.00 (
1H, m), 4.00-4.10 (2H, m), 4.31 (2H, t, J=4.
7Hz), 5.72 (1H, d, J = 9.2Hz), 7.03 (1H, d, J =
8.0Hz), 7.14 (1H, s), 7.24 (2H, d, J=9.2Hz)
, 7.40-7.50 (4H, m). IR (KBr) ν: 3287, 2951, ^{1651 cm −1} . Anal. calcd. _{for C28H34N2O3 ・ 0.2H2O} :C, ₇
4.70; H, 7.70; N, 6.22. Found C, 74.90; H, 7
.89; N,6.39. Example 57 (Preparation of Compound 57) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and cyclooctene-1-carbaldehyde (0.08 g) were dissolved in 1,2-dichloroethane (10 ml). Sodium triacetoxyborohydride (0.12 g) was added under ice cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After neutralization with 1N aqueous sodium hydroxide solution, the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate) to obtain crude crystals. Recrystallization from ethyl acetate/diethyl ether/hexane gave N-(1-(cycloocten-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-
1-Benzoxepine-4-carboxamide (compound 57) (0.11 g) was obtained as colorless prisms.

mp 148-151℃. ^1H -NMR (δppm, _CDCl3 ) 1.48-1.65 (10H, m), 1
．． 69-2.20 (8H, m), 2.39 (3H, s), 2.78-2.84 (
4H, m), 2.96 (2H, t, J = 4.6Hz), 3.80-4.00 (1
H, m), 4.31 (2H, t, J = 4.6Hz), 5.49 (1H, t, J =
8.0Hz), 5.72 (1H, d, J = 7.8Hz), 7.03 (1H, d,
J = 8.2Hz), 7.14 (1H, s), 7.24 (2H, d, J = 8.8H
z), 7.40-7.50 (4H, m). IR (KBr) ν: 3295, 2924, 1647 ^{, 1609 cm −1} . Anal. calcd. for C ₃₂ H ₄₀ N ₂ O ₂ :C, 79.30; H
, 8.32; N, 5.78. Found C, 79.02; H, 8.12; N,
5.71. Example 58 (Preparation of Compound 58) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (0.15 g) and benzaldehyde (0.05 g) were dissolved in 1,2-dichloroethane (10 ml), and sodium triacetoxyborohydride (0.12 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-(1-benzylpiperidin-4-yl)-7-(4-
Methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 58) (0.17 g) was obtained as colorless prisms.

mp 161-162℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.45-1.60 (2H, m), 1.
95-2.05 (2H, m), 2.18 (2H, t, J=11.5Hz), 2.
39 (3H, s), 2.83-2.89 (2H, m), 2.96 (2H, t, J
=4.7Hz), 3.53 (2H, s), 3.80-4.00 (1H, m), 4
．． 31 (2H, t, J = 4.7Hz), 5.71 (1H, d, J = 8.0Hz)
,7.03(1H,d,J=8.4Hz),7.13(1H,s),7.22-
7.30 (3H, m), 7.32-7.34 (4H, m), 7.40-7.50
(4H, m). IR (KBr) ν: 3250, 2942, 1649 ^{, 1609 cm −1} . Anal. calcd. _{for C30H32N2O2 ・ 0.2H2O} :C, ₇
8.99; H, 7.16; N, 6.14. Found C, 78.97; H, 7
.10; N,6.20. Example 59 (Preparation of Compound 59) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (0.15 g), cyclononene-
1-Carbaldehyde (0.085 g) was dissolved in 1,2-dichloroethane (10 ml), and sodium triacetoxyborohydride (0.12 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, and a 1N aqueous solution of sodium hydroxide was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate) to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-(1-(cyclononen-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-
4-Carboxamide (compound 59) (0.08 g) was obtained as colorless prisms.

mp 128-130℃. ^1H -NMR (δppm, _CDCl3 ) 1.46-1.67 (12H, m), 1
．． 96-2.25 (8H, m), 2.39 (3H, s), 2.75-2.85 (
2H, m), 2.84 (2H, s), 2.96 (2H, t, J=4.5Hz),
3.80-4.00 (1H, m), 4.31 (2H, t, J=4.5Hz), 5
．． 43 (1H, t, J = 8.6Hz), 5.74 (1H, d, J = 8.0Hz)
, 7.03 (1H, d, J = 8.4Hz), 7.14 (1H, s), 7.24 (
2H, d, J=8.8Hz), 7.40-7.50 (4H, m). IR (KBr) ν: 3299, 2926, 1647 ^{, 1609 cm −1} . Anal. calcd. for C ₃₃ H ₄₂ N ₂ O ₂ :C, 79.48; H
, 8.49; N15.62. Found C, 79.60; H, 8.44; N,
5.61. Example 60 (Preparation of Compound 60) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and cyclohexylacetaldehyde (0.07 g) were dissolved in 1,2-dichloroethane (10 ml), and sodium triacetoxyborohydride (0.12 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, and a 1N aqueous solution of sodium hydroxide was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-(1-(2-cyclohexylethyl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 60) (0.16 g) as colorless prisms.

mp 193-196℃. ¹ H-NMR (δppm, CDCl ₃ ) 0.80-1.00 (2H, m), 1.
10-1.50 (6H, m), 1.50-1.74 (7H, m), 1.95-2
．． 19 (4H, m), 2.34-2.42 (2H, m), 2.39 (3H, s)
, 2.86-2.98 (4H, m), 3.80-4.00 (1H, m), 4.3
2 (2H, t, J = 4.7Hz), 5.74 (1H, d, J = 7.6Hz), 7
．． 03 (1H, d, J = 8.4Hz), 7.14 (1H, s), 7.25 (2H
, d, J=9.2Hz), 7.40-7.51 (4H, m). IR (KBr) ν: 3287, 2924, 2851 ^{, 1651 cm −1} . Anal. calcd. for C ₃₁ H ₄₀ N ₂ O ₂ :C, 78.77; H
, 8.53; N, 5.93. Found C, 78.76; H, 8.42; N,
6.05. Example 61 (Preparation of Compound 61) N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (0.13 g) and 37% aqueous formaldehyde solution (0.04 ml) were suspended in 1,2-dichloroethane (5 ml), and sodium triacetoxyborohydride (0.11 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate/hexane gave N-(1-methylpiperidin-4-yl)-7
1-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 61) (0.11 g) was obtained as colorless prisms.

mp 180-182℃. ^1H -NMR (δppm, _CDCl3 ) 1.47-1.64 (2H, m), 1
．． 99-2.10 (2H, m), 2.16 (2H, dt, J = 2.2, 11.5
Hz), 2.31 (3H, s), 2.39 (3H, s), 2.81-2.87 (
2H, m), 2.96 (2H, t, J = 4.6Hz), 3.83-3.94 (1
H, m), 4.32 (2H, t, J = 4.6Hz), 5.72 (1H, d, J =
6.8Hz), 7.03 (1H, d, J=8.6Hz), 7.14 (1H, s)
, 7.24 (2H, d, J=9.2Hz), 7.40-7.51 (4H, m). IR (KBr) ν: 3287, 2940, 1647 ^{, 1607 cm −1} . Anal. calcd. _{for C24H28N2O2 ・ 0.1H2O} :C _,
76.20; H, 7.51; N, 7.41, Found C, 76.19; H,
7.53; N, 7.38. Reference Example 99 2-Bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.0
To a solution of benzyl chloroformate (4.6 g) in THF/water (20/5 ml) was added benzyl chloroformate (4.6 g) at 0°C.
16 g) was added and stirred at room temperature for 16 hours. Water was added to the reaction system, and the system was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The system was concentrated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g).

Benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinylcarbamate formate (4.63 g), and triethylamine (
A solution of 8 ml of the crude product in acetonitrile (30 ml) was heated under reflux for 24 hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by column chromatography (ethyl acetate/
hexane) to give benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as a colorless solid.
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.22-1.43 (2H, m)
, 1.44 (9H, s), 1.84-1.97 (2H, m), 2.01-2.1
6 (2H, m), 2.39-2.49 (2H, m), 2.71-2.85 (2H
, m), 3.23-3.35 (2H, m), 3.36-3.54 (1H, m),
4.29-4.54 (1H, m), 5.10 (2H, s), 5.18-5.32
(1H, m), 7.29-7.42 (5H, m). Reference Example 100 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]
A mixture of benzyl ethylcarbamate (3.0 g) and Pd—C (0.3 g) in ethanol (100 ml) was vigorously stirred under a hydrogen atmosphere for 3 days.
The residue was filtered off and concentrated under reduced pressure to give tert-butyl 1-(2-aminoethyl)-4-piperidinylcarbamate (2.4 g) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.28-1.46 (2H, m)
, 1.45 (9H, s), 1.84-2.00 (2H, m), 2.02-2.1
5 (2H, m), 2.39 (2H, t, J = 6.3Hz), 2.67-2.88
(4H, m), 3.30-3.56 (1H, m), 4.36-4.57 (1H,
Reference Example 101: To a solution of tert-butyl 1-(2-aminoethyl)-4-piperidinylcarbamate (2.4 g) and tetrahydro-4H-pyran-4-one (0.79 g) in dichloroethane (35 ml), sodium triacetoxyborohydride (2.19 g) was added at room temperature, and the mixture was stirred for 2.5 hours. 37% formalin (0.
65 g) and sodium triacetoxyborohydride (2.19 g),
The mixture was stirred for 64 hours. Sodium bicarbonate water was added to the reaction system, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give tert-butyl 1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]-4-piperidinylcarbamate (2.72 g) as a yellow oil.
) was obtained.

1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl
Ethyl]-4-piperidinylcarbamate-tert-butyl (2.72 g)
To the alcohol (30 ml) solution, concentrated hydrochloric acid (10 ml) was added and the mixture was stirred for 7 hours.
After concentration, ethanol and methanol were added to the residue, which was then further concentrated.
The solid was collected by filtration, washed with ethanol and diethyl ether, and a pale yellow powder was obtained.
and 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)
To the residue was obtained [(1.65 g) of]amino[ethyl]piperidine dihydrochloride.¹ H-NMR (200MHz, DMSO-d₆) δ1.64-2.30 (8H,
m), 2.76 (3H, s), 2.96-3.84 (12H, m), 3.90-
4.06 (2H,m), 8.30-8.54 (1H,m). Example 62 (Synthesis of Compound 62) 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.14
g) in acetonitrile (10 ml), and
Methylaminopropyl)carbodiimide hydrochloride (0.20 g) was added and stirred for 1 hour.
The reaction mixture was stirred.
(4-yl)amino]ethyl]piperidine dihydrochloride (282 mg), and
Triethylamine (0.15 ml) and diazabicyclo[5,4,0]-7-
A solution (15 ml) of undecene (0.37 g) in acetonitrile was added, and the mixture was stirred for 18 hours.
After concentrating under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The mixture was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was
Column chromatography (triethylamine/ethanol/ethyl acetate 1:1
The product was purified by recrystallization (ethyl acetate/hexane) and then purified to obtain a colorless
As a crystal, 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-
(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-
2,3-Dihydro-1-benzoxepine-4-carboxamide (Compound 62)
(99 mg) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.51-1.87 (8H, m)
, 1.95-2.08 (2H, m), 2.17-2.32 (2H, m), 2.3
4 (3H, s), 2.39 (3H, s), 2.52-2.76 (4H, m), 2
．． 89-3.04 (3H, m), 3.29-3.44 (2H, m), 3.80-
4.10 (3H, m), 4.32 (2H, t, J=4.8Hz), 5.69-5
．． 79 (1H, m), 7.03 (1H, d, J = 8.4Hz), 7.15 (1H
, s), 7.24 (2H, d, J=8.8Hz), 7.41-7.51 (4H,
m). IR (KBr) 3317, 1641, 1616, 1530, 1493, 1331
,1238,1140,816cm⁻¹ Elemental analysis C₃₁H₄₁N₃O₃・0.5H₂O Calcd. C, 72.63
; H, 8.26; N, 8.20: Found. C, 72.53; H, 8.26;
N, 8.20. Reference Example 102 trans-4-(tert-butoxycarbonylaminomethyl)cyclohexane
carboxylic acid (19.76 g), diphenylphosphoryl azide (25.36 g),
A solution of 12 ml of triethylamine in 210 ml of toluene was added at room temperature for 3 minutes.
The reaction mixture was stirred for 10 minutes at 100°C for 30 minutes. Benzyl alcohol (9.7 ml) was added to the reaction mixture.
After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated saline, and then magnesium sulfate
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate).
Purification was carried out by elution with ethyl acetate/hexane (1:2) and recrystallization (ethyl acetate/hexane).
trans-4-(tert-butoxycarbonylaminomethyl)
) Benzyl cyclohexylcarbamate (18.93 g) was obtained.

m. p. 130-131℃¹ H-NMR (200MHz, CDCl₃) δ0.95-1.16 (4H, m)
, 1.44 (9H, s), 1.32-1.50 (1H, m), 1.70-1.8
3 (2H, m), 1.98-2.12 (2H, m), 2.97 (2H, t, J=
6.4Hz), 3.31-3.56 (1H, m), 4.48-4.65 (2H,
m), 5.08 (2H, s), 7.27-7.39 (5H, m). IR (KBr) 3369, 3344, 1689, 1529, 1282, 1250
, 1176 cm⁻¹ Elemental analysis C₂₀H₃₀N₂O₄ Calcd. C, 66.27; H, 8.34
; N, 7.73: Found. C, 66.16; H, 8.11; N, 7.97. Reference Example 103 trans-4-(tert-butoxycarbonylaminomethyl)cyclohexane
Concentrated hydrochloric acid (60 ml) was added to benzyl silcarbamate (18.93 g), and the mixture was heated at room temperature.
The mixture was stirred at rt for 16 hours. Ethanol was added to the reaction mixture, which was then concentrated under reduced pressure.
Diethyl ether was added and the precipitated crystals were collected by filtration.
Wash with ether to obtain trans-4-aminomethylcyclohexane as colorless crystals.
Benzyl silcarbamate hydrochloride (11.76 g) was obtained.¹ H-NMR (200MHz, DMSO-d₆) δ0.86-1.32 (4H,
m), 1.39-1.62 (1H, m), 1.69-1.91 (4H, m), 2
．． 53-2.70 (2H, m), 3.12-3.31 (1H, m), 5.00 (
2H, s), 7.20 (1H, d, J = 7.8Hz), 7.29-7.46 (5
H, m), 7.92-8.28 (3H, m). IR (KBr) 3365, 1693, 1527, 1267, 1232, 1041
, 698 cm⁻¹ Reference Example 104 trans-4-aminomethylcyclohexylcarbamate benzyl hydrochloride
(11.56 g), tetrahydro-4H-pyran-4-one (3.85 g),
Triethylamine (8 ml) and 1,8-diazabicyclo[5,4,0]-7-(2-methyl-2-propanol)
A solution of 5.85 g of benzophenone in 100 ml of 1,2-dichloroethane was added at room temperature.
Sodium triacetoxyborohydride (8.96 g) was added and stirred for 14 hours.
The reaction mixture was added with 37% formalin (3.43 g) and triacetoxyborohydride.
Sodium hydroxide was added and the mixture was stirred for another 7 hours. Water was added to the reaction mixture, and dichloromethane was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol/ethyl acetate 1:4
→1:2) and purified to give trans-4-[N-methyl-N
-(tetrahydropyran-4-yl)aminomethyl]cyclohexylcarbamine
Benzyl acetate (8.45 g) was obtained.

m. p. 81-84℃¹ H-NMR (200MHz, CDCl₃) δ0.81-1.16 (4H, m)
, 1.22-1.42 (2H, m), 1.48-1.71 (3H, m), 1.7
6-1.91 (2H, m), 1.96-2.10 (2H, m), 2.19 (2H
, d, J=7.0Hz), 2.23 (3H, s), 2.41-2.59 (1H,
m), 3.25-3.55 (1H, m), 3.35 (2H, dt, J=2.8,
11.4Hz), 3.93-4.07 (2H, m), 4.50-4.64 (1H
, m), 5.09 (2H, s), 7.26-7.39 (5H, m). IR (KBr) 3317, 1713, 1682, 1539, 1265, 1232
,1041,741cm⁻¹ Elemental analysis C₂₁H₃₂N₂O₃ Calcd. C, 69.97; H, 8.95
; N, 7.77: Found. C, 69.57; H, 8.80; N, 7.81. Reference Example 105 trans-4-[N-methyl-N-(tetrahydropyran-4-yl)amine
benzyl [benzyl methyl]cyclohexylcarbamate (6.00 g) and 10% Pd
To a mixture of 0.6 g of HCl in 100 ml of ethanol, formic acid (2.5 mcg) was added at room temperature.
The mixture was stirred for 16 hours, and the Pd-C was removed by filtration.
Ethanol (100 ml) and concentrated hydrochloric acid (6 ml) were added to the residue, and the mixture was stirred under reduced pressure.
Diethyl ether was added to the residue, and the resulting powder was collected by filtration and
The product was washed with ethanol and diethyl ether to give trans-4-[
N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexane
Silamine dihydrochloride (4.07 g) was obtained.¹ H-NMR (200MHz, DMSO-d₆) δ0.89-1.19 (2H,
m), 1.22-1.50 (2H, m), 1.59-2.21 (9H, m), 2
．． 65-3.12 (6H, m), 3.25-3.52 (2H, m), 3.89-
4.03 (2H, m), 8.00-8.21 (3H, m), 10.00-10.
19 (1H, m). IR (KBr) 3440, 1462, 1086, 1012cm⁻¹ Example 63 (Preparation of Compound 63) 7-(4-methylphenyl)-2,3-dihydrobenzoxepin-4-carboxamide
of benzoic acid (200 mg) and 1-hydroxybenzotriazole (145 mg)
A suspension of 1-ethyl-3-(3'-dimethylamino)-
(aminopropyl)carbodiimide hydrochloride (205 mg) was added and stirred for 2 hours.
The reaction system contained trans-4-[N-methyl-N-(tetrahydropyran-4-
1,8-Dimethyl-1,8-dihydrochloride (320 mg),
-diazabicyclo[5,4,0]-7-undecene (326 mg) and triethyl
A solution of 10 ml of dimethylamine (0.2 ml) in acetonitrile was added, and the mixture was stirred for 4 hours.
After concentrating under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The solvent was removed by distillation under reduced pressure, and the residue was
The product was purified by column chromatography (ethanol/ethyl acetate 1:1) and recrystallization (ethyl acetate).
The product was purified by ethanol/hexane to give trans-7-(4-methyl-
phenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl
) aminomethyl]cyclohexyl]-2,3-dihydro-1-benzoxepin
To this was obtained 233 mg of 4-carboxamide (compound 63).

m. p. 144-146℃¹ H-NMR (200MHz, CDCl₃) δ0.92-1.26 (4H, m)
, 1.46-1.73 (5H, m), 1.82-1.96 (2H, m), 2.0
2-2.17 (2H, m), 2.23 (2H, d, J=8.4Hz), 2.25
(3H, s), 2.39 (3H, s), 2.43-2.63 (1H, m), 2.
96 (2H, t, J=4.8Hz), 3.29-3.45 (2H, m), 3.7
3-3.92 (1H, m), 3.96-4.09 (2H, m), 4.31 (2H
, t, J = 4.8 Hz), 5.64 (1H, d, J = 7.4 Hz), 7.02 (
1H, d, J = 8.4Hz), 7.12 (1H, s), 7.24 (2H, d, J
=9.2Hz), 7.40-7.50 (4H, m). IR (KBr) 3323, 1612, 1527, 1493, 1319, 1238
, 812 cm⁻¹ Elemental analysis C₃₁H₄₀N₂O₃ Calcd. C, 76.19; H, 8.25
; N, 5.73: Found. C, 75.90; H, 8.10; N, 5.75. Example 64 (Preparation of Compound 64) 2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptane
1-hydroxybenzotriazole (1
A suspension of 46 mg of 1-ethyl-3-(
3'-dimethylaminopropyl)carbodiimide hydrochloride (207 mg) was added.
The mixture was stirred for 2 hours.
[pyran-4-yl]aminomethyl]cyclohexylamine dihydrochloride (323m
g), 1,8-diazabicyclo[5,4,0]-7-undecene (326 mg)
and a solution of triethylamine (0.2 ml) in acetonitrile (15 ml) was added.
The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
The layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure.
The residue was then purified by column chromatography (ethanol/ethyl acetate 1:1) and purified again.
Purification by crystallization (ethyl acetate/hexane) gave the trans-
2-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydrophenyl)
cyclohexyl]-6,7-dihydro-5H-
Benzocycloheptene-8-carboxamide (compound 64) (253 mg) was obtained.
Ta.

m. p. 163-165℃¹ H-NMR (200MHz, CDCl₃) δ0.88-1.23 (4H, m)
, 1.31-1.71 (5H, m), 1.80-1.95 (2H, m), 1.9
9-2.18 (4H, m), 2.23 (2H, d, J=8.4Hz), 2.25
(3H, s), 2.39 (3H, s), 2.43-2.65 (3H, m), 2.
76-2.88 (2H, m), 3.26-3.43 (2H, m), 3.69-3
．． 92 (1H, m), 3.95-4.06 (2H, m), 5.64-5.75 (
1H, m), 7.17-7.26 (3H, m), 7.38-7.50 (5H, m
). IR (KBr) 3354, 1641, 1616, 1514, 1446, 812c
m⁻¹ Elemental analysis C₃₂H₄₂N₂O₂・0.1H₂O Calcd. C, 78.68
; H, 8.71; N, 5.73: Found. C, 78.44; H, 8.64;
N, 5.70. Reference Example 106 trans-4-aminomethylcyclohexylcarbamate benzyl hydrochloride
(5.0 g), tert-butyl 4-piperidone-1-carboxylate (3.31
g) and 1,8-diazabicyclo[5,4,0]-7-undecene (2.53 g
) in acetonitrile/THF (50/100 ml) at room temperature.
Sodium cethoxyborohydride (3.87 g) was added and the mixture was stirred for 9 hours.
The system contained 37% formalin (1.48 g) and sodium triacetoxyborohydride.
The solvent was evaporated under reduced pressure, and water was added to the mixture.
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
The product was washed with ethyl ether to give trans-4-[N-[4-(N-
benzyloxycarbonylamino)cyclohexylmethyl]-N-methylamino]
Tert-butyl piperidine-1-carboxylate (5.28 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.04-1.28 (4H, m)
, 1.46 (9H, s), 1.53-1.72 (4H, m), 1.80-2.4
4 (5H, m), 2.52-3.00 (4H, m), 2.77 (3H, s), 3
．． 19-3.56 (2H, m), 4.19-4.41 (2H, m), 4.61-
4.71 (1H, m), 5.08 (2H, s), 7.29-7.42 (5H, m
). IR (KBr) 3242, 1713, 1687, 1537, 1422, 1248
,1169,1045,746cm⁻¹ Reference Example 107 trans-4-[N-[4-(N-benzyloxycarbonylamino)cyclo
hexylmethyl]-N-methylamino]piperidine-1-carboxylic acid-tert
-butyl (4.5 g) and Pd-C (0.43 g) in ethanol (300 ml)
The mixture was stirred vigorously under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
The resulting product was washed with water to give trans-4-[N-(4-aminocyclohexyl)
(N-methylamino)piperidine-1-carboxylic acid-tert-butyl
The obtained product was 2.80 g.¹ H-NMR (200MHz, CDCl₃) δ0.75-1.00 (2H, m)
, 1.24-1.56 (5H, m), 1.45 (9H, s), 1.59-1.7
4 (2H, m), 1.79-1.95 (2H, m), 2.00-2.26 (4H
, m), 2.21 (3H, s), 2.33-2.52 (1H, m), 2.55-
2.76 (2H, m), 2.81-3.04 (1H, m), 3.45-4.00
(2H, m), 4.04-4.28 (2H, m). IR (KBr) 2925, 1687, 1433, 1267, 1246, 1169
cm⁻¹ Example 65 (Preparation of Compound 65) 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carboxylic acid (400 mg) and 1-hydroxybenzotriazole (289 mg)
g) in acetonitrile (20 ml), and
Dimethylaminopropyl)carbodiimide hydrochloride (0.41 g) was added and the mixture was stirred for 2 hours.
The reaction mixture was stirred.
)-N-methylamino]piperidine-1-carboxylate-tert-butyl (69
8 mg) and triethylamine (0.4 ml) in acetonitrile (30 ml
After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over magnesium sulfate.
After evaporation, the residue was purified by column chromatography (ethanol/ethyl acetate 1:3
→ 1:2) and purified by recrystallization (ethyl acetate/hexane) to give colorless crystals.
and trans-N-[4-[N-(1-tert-butoxycarbonylpiperidine
[0033] -7-(4-methyl-N-methylaminomethyl)cyclohexyl
(ethylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide
Compound 65 (560 mg) was obtained.

m. p. 146-150℃¹ H-NMR (200MHz, CDCl₃) δ0.94-1.32 (4H, m)
, 1.46 (9H, s), 1.55-1.79 (5H, m), 1.81-1.9
6 (2H, m), 2.01-2.12 (2H, m), 2.22 (2H, d, J=
9.0Hz), 2.25 (3H, s), 2.39 (3H, s), 2.36-2.
54 (1H, m), 2.57-2.76 (2H, m), 2.96 (2H, t, J
= 4.4Hz), 3.72-3.93 (1H, m), 4.04-4.22 (2H
, m), 4.31 (2H, t, J = 4.4Hz), 5.66 (1H, d, J = 7
．． 8Hz), 7.02 (1H, d, J=8.4Hz), 7.12 (1H, s),
7.19-7.28 (2H, m), 7.38-7.52 (4H, m). IR (KBr) 3352, 1701, 1686, 1618, 1527, 1491
,1425,1240,1163,1043,812cm⁻¹ Elemental analysis C₃₆H₄₉N₃O₄ Calcd. C, 73.56; H, 8.40
; N, 7.15: Found. C, 73.38; H, 8.13; N, 7.16. Example 66 (Preparation of Compound 66) trans-N-[4-[N-(1-tert-butoxycarbonylpiperidinyl)
[0033] cyclohexyl]-7-(4-methyl-4-yl)-N-methylaminomethyl]cyclohexyl]-
(phenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide
To a solution of (0.41 g) in ethanol (30 ml), concentrated hydrochloric acid (5 ml) was added at room temperature.
After concentrating under reduced pressure, the resulting crystals were recrystallized (ethanol/diethyl
The product was purified by hexane (diethyl ether) to give trans-N-[4-[N-
(Piperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-
(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-chlor
Voxamide dihydrochloride (compound 66) (381 mg) was obtained.

m. p. 249℃ (dec.)¹ H-NMR (200MHz, DMSO-d₆) δ0.93-1.47 (4H,
m), 1.62-2.28 (9H, m), 2.34 (3H, s), 2.73 (3
H, s), 2.79-3.10 (4H, m), 3.25-3.71 (3H, m)
, 4.15-4.54 (5H, m), 7.01 (1H, d, J=8.4Hz),
7.19-7.28 (3H, m), 7.48-7.57 (3H, m), 7.62
-7.68 (1H, m), 7.91 (1H, d, J=7.8Hz), 8.98-
9.29 (1H, m). IR (KBr) 3390, 2939, 1639, 1493, 1460, 1352
, 1267cm⁻¹ Elemental analysis C₃₁H₄₃N₃O₂・2.5H₂O Calcd. C, 61.48
; H, 7.99; N, 6.94: Found. C, 61.68; H, 7.54;
N, 6.91. Example 67 (Preparation of Compound 67) 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (1
acetonite of 1-hydroxybenzotriazole (114 mg)
A suspension of 1-ethyl-3-(3'-dimethylaminopropyl)propanol (15 ml) was added at room temperature.
Hydroxypropylcarbodiimide hydrochloride (162 mg) was added and the mixture was stirred for 2 hours.
trans-4-[N-methyl-N-(tetrahydropyran-4-yl)amine]
[0036]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabi
Cyclo[5,4,0]-7-undecene (257 mg) and triethylamine (
A solution of 0.16 ml of the mixture in acetonitrile (20 ml) was added and stirred for 5 hours.
After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline.
The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography.
HPLC (ethanol/ethyl acetate 1:1) and recrystallization (ethyl acetate/hexane
The product was purified by HPLC using a HPLC-MS/MS system to obtain trans-6-(4-methylphenyl)-
N-methyl-N-(tetrahydropyran-4-yl)amino
Methyl]cyclohexyl]-2H-1-benzopyran-3-carboxamide (chemical
Compound 67) (144 mg) was obtained.

m. p. 141-143℃¹ H-NMR (200MHz, CDCl₃) δ0.92-1.31 (4H, m)
, 1.49-1.71 (5H, m), 1.82-1.95 (2H, m), 1.9
8-2.13 (2H, m), 2.24 (2H, d, J=8.8Hz), 2.26
(3H, s), 2.39 (3H, s), 2.44-2.63 (1H, m), 3.
28-3.42 (2H, m), 3.70-3.92 (1H, m), 3.95-4
．． 06 (2H, m), 5.02 (2H, s), 5.65 (1H, d, J = 8.8
Hz), 6.90 (1H, d, J=8.6Hz), 6.97 (1H, s), 7.
21-7.30 (3H, m), 7.40-7.44 (3H, m). IR (KBr) 3315, 1647, 1606, 1545, 1487, 1336
,1240,1142,808cm⁻¹ Elemental analysis C₃₀H₃₈N₂O₃ Calcd. C, 75.92; H, 8.07
; N, 5.90: Found. C, 75.22; H, 7.96; N, 5.90. Example 68 (Preparation of Compound 68) 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (1
acetonite of 1-hydroxybenzotriazole (114 mg)
A suspension of 1-ethyl-3-(3'-dimethylaminopropyl)propanol (15 ml) was added at room temperature.
Hydroxypropylcarbodiimide hydrochloride (162 mg) was added and the mixture was stirred for 2 hours.
trans-4-[N-methyl-N-(tetrahydropyran-4-yl)amine]
[0036]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabi
Cyclo[5,4,0]-7-undecene (257 mg) and triethylamine (
A solution of 0.16 ml of the mixture in acetonitrile (20 ml) was added and stirred for 4 hours.
After concentration under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline.
The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography.
Chromatography (ethanol/ethyl acetate 1:2) and recrystallization (ethanol)
The product was purified by the method described above to obtain trans-3-(4-methylphenyl)-N as colorless crystals.
-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]
cyclohexyl]-2H-1-benzopyran-6-carboxamide (Compound 68
) (190 mg) was obtained.

m. p. 205-207℃¹ H-NMR (200MHz, CDCl₃) δ0.96-1.27 (4H, m)
, 1.52-1.76 (5H, m), 1.83-1.96 (2H, m), 2.0
4-2.20 (2H, m), 2.24 (2H, d, J=7.8Hz), 2.26
(3H, s), 2.38 (3H, s), 2.45-2.62 (1H, m), 3.
29-3.45 (2H, m), 3.83-4.09 (3H, m), 5.22 (2
H, d, J = 1.4Hz), 5.82 (1H, d, J = 6.8Hz), 6.79
(1H, s), 6.84 (1H, d, J=7.8Hz), 7.21 (2H, d,
J=8.0Hz), 7.34 (2H, d, J=8.0Hz), 7.46-7.5
1 (2H, m). IR (KBr) 3356, 1633, 1529, 1493, 1331, 1221
,1140,808cm⁻¹ Elemental analysis C₃₀H₃₈N₂O₃ Calcd. C, 75.92; H, 8.07
; N, 5.90: Found. C, 75.82; H, 8.08; N, 5.93. Example 69 (Preparation of Compound 69) 2-(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]
Thiophene-5-carboxylic acid (150 mg) and 1-hydroxybenzotriazo
A suspension of 107 mg of ethanol in 15 ml of acetonitrile was added to 1-ethylpropional at room temperature.
-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (152 mg
) was added to the reaction mixture and stirred for 2 hours.
(4-aminomethyl)cyclohexylamine dihydrochloride (
236m), 1,8-diazabicyclo[5,4,0]-7-undecene (240
mg) and triethylamine (0.15 ml) in acetonitrile (20 ml
After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over magnesium sulfate.
After evaporation, the residue was purified by column chromatography (ethanol/ethyl acetate 1:2
→ 2:3) and purified by recrystallization (ethyl acetate/hexane) to give pale yellow crystals
trans-2-(4-methylphenyl)-N-[4-[N-methyl-N
-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-7,8
-dihydro-6H-cyclohepta[b]thiophene-5-carboxamide (compound
Product 69) (137 mg) was obtained.

m. p. 192-197℃¹ H-NMR (200MHz, CDCl₃) δ0.81-1.23 (4H, m)
, 1.52-1.72 (5H, m), 1.80-1.95 (2H, m), 2.0
0-2.15 (4H, m), 2.24 (2H, d, J=8.8Hz), 2.26
(3H, s), 2.36 (3H, s), 2.43-2.63 (1H, m), 2.
65-2.77 (2H, m), 3.01-3.10 (2H, m), 3.27-3
．． 44 (2H, m), 3.66-3.92 (1H, m), 3.96-4.07 (
2H, m), 5.62 (1H, d, J=8.0Hz), 7.05 (2H, s),
7.17 (2H, d, J = 7.8Hz), 7.42 (2H, d, J = 7.8Hz
). IR (KBr) 3278, 1641, 1608, 1535, 1452, 1319
,1236,1140,810cm⁻¹ Elemental analysis C₃₀H₄₀N₂O₂S・0.2H₂O Calcd. C, 72.6
0; H, 8.20; N, 5.64: Found. C, 72.58; H, 8.03
N, 5.65. Example 70 (Preparation of Compound 70) 2-methyl-6-(4-methylphenyl)quinoline-3-carboxylic acid (150
mg) and 1-hydroxybenzotriazole (109 mg) in acetonitrile
(15 ml) suspension was added to 1-ethyl-3-(3'-dimethylaminopropyl)
Carbodiimide hydrochloride (156 mg) was added and stirred for 2 hours.
trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl
1,8-Diazabicyclo[4.2.1.2]cyclohexylamine dihydrochloride (242 mg), ...
2) [5,4,0]-7-undecene (246 mg) and triethylamine (0.
A solution of 15 ml of acetonitrile (15 ml) was added, and the mixture was stirred for 4 days.
After concentration, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and
The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography.
Roughening (ethanol/ethyl acetate 1:2 → 1:1) and recrystallization (ethyl acetate/
hexane) to obtain trans-2-methyl-6-(
4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-
4-yl)aminomethyl]cyclohexyl]quinoline-3-carboxamide (chemical
Compound 70) (142 mg) was obtained.

m. p. 163-165℃¹ H-NMR (200MHz, CDCl₃) δ0.93-1.34 (4H, m)
, 1.52-1.75 (5H, m), 1.86-2.00 (2H, m), 2.1
2-2.32 (2H, m), 2.26 (2H, d, J=5.4Hz), 2.27
(3H, s), 2.43 (3H, s), 2.45-2.65 (1H, m), 2.
83 (3H, s), 3.29-3.43 (2H, m), 3.86-4.09 (3
H, m), 5.84 (1H, d, J = 8.8Hz), 7.30 (2H, d, J =
8.1Hz), 7.59 (2H, d, J = 8.1Hz), 7.91 (1H, d,
J=2.2Hz), 7.98 (1H, dd, J=8.8, 2.2Hz), 8.0
4-8.09 (2H, m). IR (KBr) 3277, 1639, 1539, 1491, 1448, 1140
, 812 cm⁻¹ Elemental analysis C₃₁H₃₉N₃O₂・0.2H₂O Calcd. C, 76.10
; H, 8.12; N, 8.59: Found. C, 76.00; H, 8.03;
N, 8.60 Example 71 (Preparation of Compound 71) (E)-3-[5-(4-methylphenyl)thiophen-2-yl]acrylic
Acetate (200 mg) of 1-hydroxybenzotriazole (166 mg)
A suspension of 1-ethyl-3-(3'-dimethylamino)-2-(2-methyl-2-propanol) in 10 ml of toluene was added at room temperature.
To the mixture was added (aminopropyl)carbodiimide hydrochloride (235 mg), and the mixture was stirred for 2 hours.
The reaction system contained trans-4-[N-methyl-N-(tetrahydropyran-4-yl)
) aminomethyl]cyclohexylamine dihydrochloride (368 mg), triethyl
Amine (0.23 ml) and 1,8-diazabicyclo[5,4,0]-7-une
A solution of decene (374 mg) in acetonitrile (10 ml) was added, and the mixture was further stirred for 18 hours.
The solvent was evaporated under reduced pressure, and then water was added and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over magnesium sulfate.
Chromatography (ethanol/ethyl acetate 1:1) and recrystallization (ethanol/
ethyl acetate) to give trans-(E)-N-[4
-(N-methyl-N-(tetrahydropyran-4-yl)aminomethylcyclohexane
xyl]-3-[5-(4-methylphenyl)thiophen-2-yl]acrylic
The amide (compound 71) (246 mg) was obtained.

m. p. 199-201℃¹ H-NMR (200MHz, CDCl₃) δ0.95-1.27 (4H, m)
, 1.48-1.70 (5H, m), 1.80-1.93 (2H, m), 2.0
2-2.14 (2H, m), 2.23 (2H, dd, J=8.8Hz), 2.2
5 (3H, s), 2.37 (3H, s), 2.42-2.61 (1H, m), 3
．． 28-3.43 (2H, m), 3.74-3.93 (1H, m), 3.96-
4.06 (2H, m), 5.35 (1H, d, J = 8.2Hz), 6.13 (1
H, d, J = 15.2Hz), 7.14-7.22 (4H, m), 7.49 (2
H, d, J=8.0Hz), 7.69 (1H, d, J=15.2Hz). IR (KBr) 3273, 1645, 1603, 1549, 1456, 1236
,1211,797cm⁻¹ Elemental analysis C₂₇H₃₆N₂O₂S・0.2H₂O Calcd. C, 71.0
8; H, 8.04; N, 6.14: Found. C, 71.11; H, 7.99
; N, 6.17 Example 72 (Preparation of Compound 72) (E)-3-[4-(4-methylphenyl)thiophen-2-yl]acrylic
Acetate (150 mg) of 1-hydroxybenzotriazole (124 mg)
A suspension of 1-ethyl-3-(3'-dimethylamino)-2-(2-methyl-2-propanol) in 10 ml of toluene was added at room temperature.
To the mixture was added (aminopropyl)carbodiimide hydrochloride (177 mg), and the mixture was stirred for 2 hours.
The reaction system contained trans-4-[N-methyl-N-(tetrahydropyran-4-yl)
) aminomethyl]cyclohexylamine dihydrochloride (276 mg), 1,8-di
Azabicyclo[5,4,0]-7-undecene (281 mg) and triethylamine
A solution of amine (0.17 ml) in acetonitrile (15 ml) was added and stirred for 16 hours.
After concentrating under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The solvent was removed by distillation under reduced pressure, and the residue was
The product was purified by column chromatography (ethanol/ethyl acetate 1:2) and recrystallization (ethanol
The compound was purified by HPLC and obtained as colorless crystals (trans,E)-3-[4-(4-
methylphenyl)thiophen-2-yl]-N-[4-[N-methyl-N-(thene
[tetrahydropyran-4-yl]aminomethyl]cyclohexyl]acrylamide
(Compound 72) (191 mg) was obtained.

m. p. 180-183℃¹ H-NMR (200MHz, CDCl₃) δ0.94-1.26 (4H, m)
, 1.50-1.74 (5H, m), 1.79-1.94 (2H, m), 2.0
1-2.15 (2H, m), 2.23 (2H, d, J=8.4Hz), 2.25
(3H, s), 2.37 (3H, s), 2.42-2.62 (1H, m), 3.
36 (2H, dt, J=2.8, 11.0Hz), 3.75-3.94 (1H,
m), 3.96-4.06 (2H, m), 5.41 (1H, d, J = 8.4Hz
), 6.18 (1H, d, J=15.4Hz), 7.21 (2H, d, J=8.
0Hz), 7.36 (1H, s), 7.43-7.48 (3Hm), 7.75 (
1H, d, J=15.4Hz). IR (KBr) 3317, 1649, 1614, 1539, 1333, 1201
, 816 cm⁻¹ Elemental analysis C₂₇H₃₆N₂O₂S Calcd. C, 71.64; H, 8.0
2;N, 6.19:Found. C, 71.34; H, 7.97; N, 6.29
Example 73 (Preparation of Compound 73) (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid
(150 mg) and 1-hydroxybenzotriazole (134 mg)
To a suspension of 1-ethyl-3-(3'-dimethylamino)-2-propanol (15 ml) at room temperature,
(0.19 g) of diisopropylcarbodiimide hydrochloride was added and the mixture was stirred for 2 hours.
In the reaction system, trans-4-[N-methyl-N-(tetrahydropyran-4-yl)
[aminomethyl]cyclohexylamine dihydrochloride (198 mg), 1,8-dia
Zabicyclo[5,4,0]-7-undecene (0.2 g) and triethylamine
(0.18 ml) in acetonitrile (20 ml) was added and stirred for 64 hours.
After concentration under reduced pressure, water was added and the mixture was extracted with chloroform.
The solvent was removed by distillation under reduced pressure, and the precipitated solid
was purified by recrystallization (ethanol/ethyl acetate) as colorless crystals (tr
ans,E)-3-[5-(4-methylphenyl)pyridin-3-yl]-N-
[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]silyl
[Clohexyl]acrylamide (Compound 73) (226 mg) was obtained.

m. p. 233-236℃¹ H-NMR (200MHz, CDCl₃) δ0.96-1.30 (4H, m)
, 1.51-1.71 (5H, m), 1.81-1.95 (2H, m), 2.0
3-2.18 (2H, m), 2.23 (2H, d, J=8.0Hz), 2.25
(3H, s), 2.42 (3H, s), 2.45-2.61 (1H, m), 3.
36 (2H, dt, J=3.0, 11.4Hz), 3.77-4.08 (3H,
m), 5.53 (1H, d, J = 9.2Hz), 6.50 (1H, d, J = 15
．． 4Hz), 7.30 (2H, d, J = 8.1Hz), 7.49 (2H, d, J
= 8.1Hz), 7.67 (1H, d, J = 15.4Hz), 7.93 (1H,
dd, J=2.2, 2.2Hz), 8.69 (1H, d, J=2.2Hz), 8
．． 78 (1H, d, J=2.2Hz). IR (KBr) 3302, 1659, 1612, 1541, 1344, 976,
822 cm⁻¹ Elemental analysis C₂₈H₃₇N₃O₂ Calcd. C, 75.13; H, 8.33
; N, 9.39: Found. C, 75.06; H, 8.11; N, 9.34. Example 74 (Preparation of Compound 74) (E)-3-[4-(4-methylphenyl)furan-2-yl]acrylic acid (
acetonitrile (150 mg) and 1-hydroxybenzotriazole (133 mg)
To a suspension of 1-ethyl-3-(3'-dimethylamino)
Propyl)carbodiimide hydrochloride (189 mg) was added and the mixture was stirred for 2 hours.
The system was added with trans-4-[N-methyl-N-(tetrahydropyran-4-yl)amine].
[aminomethyl]cyclohexylamine dihydrochloride (295 mg), 1,8-diaza
Bicyclo[5,4,0]-7-undecene (0.3 g) and triethylamine (
A solution of 0.18 ml of the mixture in acetonitrile (15 ml) was added and the mixture was stirred for 4 days.
After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline.
The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography.
HPLC (ethanol/ethyl acetate 1:3 → 1:2) and recrystallization (ethyl acetate
The (trans,E)-3-
[4-(4-methylphenyl)furan-2-yl]-N-[4-[N-methyl-
N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylate
To obtain 137 mg of methyl amide (compound 74),

m. p. 165-167℃¹ H-NMR (200MHz, CDCl₃) δ0.87-1.28 (4H, m)
, 1.47-1.66 (5H, m), 1.76-1.96 (2H, m), 2.0
2-2.15 (2H, m), 2.22 (2H, d, J=8.4Hz), 2.24
(3H, s), 2.38 (3H, s), 2.42-2.60 (1H, m), 3.
28-3.42 (2H, m), 3.73-3.92 (1H, m), 3.95-4
．． 06 (2H, m), 5.40 (1H, d, J = 8.8Hz), 6.33 (1H
, d, J=15.4Hz), 6.60 (1H, d, J=3.4Hz), 6.65
(1H, d, J=3.4Hz), 7.20 (2H, d, J=8.0Hz), 7.
39 (1H, d, J = 15.4Hz), 7.60 (2H, d, J = 8.0Hz)
．． IR (KBr) 3319, 1651, 1614, 1541, 1989, 1219
,1142,955,779cm⁻¹ Elemental analysis C₂₇H₃₆N₂O₃ Calcd. C, 74.28; H, 8.31
; N, 6.42: Found. C, 74.13; H, 8.07; N, 6.36. Example 75 (Preparation of Compound 75) trans-(E)-N-[4-(N-methyl-N-(tetrahydropyran-
4-yl)aminomethylcyclohexyl]-3-[5-(4-methylphenyl)
Thiophen-2-yl]acrylamide (100 mg) in DMF (3 ml)
Methyl iodide (0.03 ml) was added to the mixture at room temperature and stirred for 24 hours.
The solvent was distilled off, and ethanol was added. The precipitated crystals were collected by filtration.
Crystals of N,N-dimethyl-N-[trans-4-[(E)-3-iodide
[5-(4-methylphenyl)-2-thienyl]-2-propenoylamino]
[Clohexylmethyl]-4-tetrahydropyranylammonium (Compound 75)
(87 mg) was obtained.

m. p. 229-232℃¹ H-NMR (200MHz, DMSO-d₆) δ1.12-1.37 (4H,
m), 1.63-2.05 (8H, m), 2.33 (3H, s), 2.99 (6
H, s), 3.10-3.23 (2H, m), 3.26-3.42 (3H, m)
, 3.46-3.80 (2H, m), 3.97-4.11 (2H, m), 6.3
5 (1H, d, J = 15.4Hz), 7.25 (2H, d, J = 8.0Hz),
7.34 (1H, d, J = 4.1Hz), 7.44 (1H, d, J = 4.1Hz
), 7.53 (1H, d, J=15.4Hz), 7.56 (2H, d, J=8.
0Hz), 8.03 (1H, d, J=7.6Hz). IR (KBr) 3442, 3240, 2933, 1653, 1606, 1543
,1452,808cm⁻¹ Elemental analysis C₂₈H₃₉N₂O₂SI 0.3H₂O Calcd. C, 56.
05; H, 6.65; N, 4.67: Found. C, 55.95; H, 6.5
0; N, 4.70. Reference Example 108 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
The carboxylic acid (1.2 g) was suspended in dichloromethane (10 ml) and cooled with ice.
Add 1.1 ml of methylalanine chloride and dimethylformamide (catalytic amount)
The mixture was stirred at room temperature for 2 hours. After the solvent was removed by distillation, the residue was dissolved in tetrahydrofuran (15 ml).
Then, 4-trifluoroacetamidopiperidine (0.85 g) and triethylamine were added.
The mixture was added dropwise to a solution of 1.8 ml of ethanol in 10 ml of tetrahydrofuran under ice cooling.
The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, water was added, and the mixture was washed with ethyl acetate.
The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give crude crystals (1.8 g).
Recrystallization from ethyl acetate yielded 1-(7-(4-methylphenyl)-2,3-dihydro-1-methylphenyl).
-benzoxepin-4-carbonyl)-4-trifluoroacetamidopiperi
The gin was obtained as colorless prisms.

mp 189-192℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.40-1.62 (2H, m), 2.
05-2.15 (2H, m), 2.39 (3H, s), 2.90 (2H, t, J
=4.4Hz), 2.98-3.15 (2H, m), 4.00-4.20 (1H
, m), 4.34 (2H, t, J=4.4Hz), 4.34-4.45 (2H,
m), 6.30 (1H, d, J=8.0Hz), 6.47 (1H, s), 7.0
4 (1H, d, J = 8.0Hz), 7.24 (2H, d, J = 7.8Hz), 7
．． 35-7.45 (4H, m). IR (KBr) ν: 3250, 2926, ^{1715 cm −1} . Anal. calcd. for C ₂₅ H ₂₅ F ₃ N ₂ O ₃ :C, 65.49;
H, 5.50; N, 6.11. Found C, 65.32; H, 5.57; N
, 6.08. Example 76 (Preparation of Compound 76) 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carbonyl)-4-trifluoroacetamidopiperidine (1.6 g)
The residue was dissolved in methanol (100 ml), 1N sodium hydroxide (7 ml) was added, and the mixture was stirred at room temperature overnight. After concentration, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.
Crude crystals were obtained. Recrystallization from ethyl acetate/hexane gave 4-amino-1-(7-(
(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl)piperidine (Compound 76) (1.1 g) was obtained as colorless prisms.

mp 123-127℃. ¹ H-NMR (δppm, CDCl ₃ ) 1.22-1.40 (2H, m), 1.
80-1.95 (2H, m), 2.39 (3H, s), 2.90 (2H, t, J
= 4.4Hz), 2.92-3.05 (3H, m), 4.14-4.36 (2H
, m), 4.34 (2H, t, J=4.4Hz), 6.46 (1H, s), 7.
04 (1H, d, J = 8.0Hz), 7.24 (2H, d, J = 8.0Hz),
7.37-7.46 (4H, m). IR (KBr) ν: 2938, 1605 cm ⁻¹ . Anal. calcd, for C ₂₃ H ₂₆ N ₂ O ₂ :C, 76.21; H,
7.23; N, 7.73. Found C, 75.92; H, 7.14; N, 7
77. Example 77 (Preparation of Compound 77) 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carbonyl)piperidine (0.3 g), tetrahydro-4
H-pyran-4-one (0.083 g) was dissolved in 1,2-dichloroethane (6 ml), and sodium triacetoxyborohydride (0.25 g) was added under ice cooling.
The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was removed by distillation, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. 4N hydrochloric acid/ethyl acetate (0.5 ml) was added, and the precipitated powder was collected by filtration. It was washed with hexane and 1-(7-(4-methylphenyl)-2,3-dihydro-
1-benzoxepin-4-carbonyl)-4-((tetrahydropyran-4-
⁽ 4H, br), 1.93 _.
-2.13 (4H, m), 2.34 (3H, s), 2.80 (2H, s-lik
e), 2.98 (2H, br), 3.40-3.53 (4H, m), 3.89-
3.94 (2H, m), 4.17-4.28 (4H, m), 6.54 (1H, s
), 7.02 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 7.8
Hz), 7.46-7.61 (4H, m), 9.07 (2H, br). IR (KBr) ν: 2951, 2791, 2737, 2693, 1620 ^{cm −
1} . Anal. calcd. for C ₂₈ H ₃₄ N ₂ O ₃・HCl・0.2H ₂ O
:C, 69.11; H, 7.33; N, 5.76. Found C, 69.08
H, 7.20; N, 5.97. Example 78 (Preparation of Compound 78) 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-((tetrahydropyran-4-yl)amino)piperidine hydrochloride (0.2 g), 37% formalin (0.05 ml), and triethylamine (0.06 ml) were suspended in 1,2-dichloroethane (5 ml), and the suspension was stirred under ice-cooling.
Sodium triacetoxyborohydride (0.13 g) was added, and the mixture was stirred under a nitrogen atmosphere.
The mixture was stirred at room temperature overnight. The solvent was evaporated, the mixture was neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in 4N ethyl acetate.
Hydrochloric acid/ethyl acetate (0.5 ml) was added, and the precipitated powder was collected by filtration, washed with diethyl ether, and 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carbonyl)-4-((N-methyl-N-(tetrahydropyran-4-yl))amino)piperidine hydrochloride (Compound 78) (0.19 g) was obtained.
was obtained as a colorless amorphous substance. ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.60-1.85 (4H, m),
1.85-2.20 (4H, m), 2.34 (3H, s), 2.67 (3H, d
, J=4.6Hz), 2.80 (2H, t-like), 2.96 (2H, br
), 3.29-3.46 (3H, m), 3.70 (1H, br), 3.94-4
．． 00 (2H, m), 4.25 (2H, br), 4.28 (2H, t-like
), 6.59 (1H, s), 7.03 (1H, d, J=8.4Hz), 7.25
(2H, d, J=8.0Hz), 7.46-7.55 (3H, m), 7.64 (
1H, d, J=2.6Hz), 10.07 (1H, br). IR (KBr) ν: 2963, 2649, ^{1605 cm −1} . Anal. calcd. for _{C29H36N2O3 ・ HCl ・ H2O} :C,
67.62; H, 7.63; N, 5.44. Found C, 67.48; H,
7.65; N, 5.43. Reference Example 109 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4
-carbaldehyde (2.0 g), 4-trifluoroacetamidopiperidine (1
.56 g) was dissolved in 1,2-dichloroethane (50 ml), and under ice-cooling, sodium triacetoxyborohydride (1.8 g) was added, followed by stirring at room temperature under a nitrogen atmosphere. Triethylamine (1.1 ml) and sodium triacetoxyborohydride (0.8 g) were added, followed by stirring at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude crystals (3.0 g). A portion was recrystallized from ethyl acetate/hexane,
1-(7-(4-Methylphenyl)-2,3-dihydro-1-benzoxepin-4-ylmethyl)-4-trifluoroacetamidopiperidine was obtained as pale yellow crystals.

mp 94-96℃. ^1H -NMR (δppm, _CDCl3 ) 1.43-1.61 (2H, m), 1
．． 96-2.17 (4H, m), 2.38 (3H, s), 2.69 (2H, t,
J=4.8Hz), 2.82-2.88 (2H, m), 3.05 (2H, s),
3.75-3.95 (1H, m), 4.26 (2H, t, J=4.8Hz), 6
．． 13 (1H, d, J = 7.2Hz), 6.35 (1H, s), 6.99 (1H
, d, J=8.0Hz), 7.22 (2H, d, J=8.1Hz), 7.29-
7.36 (2H, m), 7.44 (2H, d, J=8.1Hz). IR (KBr) ν: 3299, 2948, ^{1703 cm −1} . Anal. calcd. _{for C25H27F3N2O2 ・ 0.2H2O : ​}
C, 67.01; H, 6.16; N, 6.25. Found C, 67.16;
H, 6.13; N, 6.07. Example 79 (Preparation of Compound 79) 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)methyl-4-(trifluoroacetamido)piperidine (2.7
g) was dissolved in methanol (200 ml) and 1N sodium hydroxide (20 ml)
The mixture was stirred at room temperature for 2 days. After concentration, the mixture was extracted with ethyl acetate. The organic layer was washed with water,
The residue was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-
1-benzoxepin-4-yl)methylpiperidine (compound 79) (1.44
g) was obtained as a colorless amorphous solid. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.26-1.47 (2H, m), 1.
77-1.83 (2H, m), 1.92-2.05 (2H, m), 2.38 (3
H, s), 2.61-2.69 (1H, m), 2.71 (2H, t, J = 4.8
Hz), 2.80-2.85 (2H, m), 3.03 (2H, s), 4.26 (
2H, t, J = 4.8Hz), 6.34 (1H, s), 6.99 (1H, d, J
= 8.4Hz), 7.22 (2H, d, J = 8.0Hz), 7.28-7.36
(2H, m), 7.45 (2H, d, J=8.0Hz). IR (KBr) ν: 2936, 1576, ^{1493 cm −1} . Anal. calcd. _{for C23H28N2O ・ 0.2H2O} :C,78
．． 46; H, 8.13; N, 7.96. Found C, 78.35; H, 7.
97; N, 7.56. Example 80 (Preparation of Compound 80) 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)methylpiperidine (0.4 g), tetrahydro-4
H-pyran-4-one (0.12 g) was dissolved in 1,2-dichloroethane (10 ml), and sodium triacetoxyborohydride (0.34 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified using a silica gel column (methanol/triethylamine/ethyl acetate) to obtain crude crystals.
Recrystallization from ethyl acetate/hexane gave 1-(7-(4-methylphenyl)-2,
3-Dihydro-1-benzoxepin-4-yl)methyl-4-((tetrahydropyran-4-yl)amino)piperidine (Compound 80) (0.17 g) was obtained as colorless crystals.

mp 101-103℃. ^1H -NMR (δppm, _CDCl3 ) 1.26-1.50 (4H, m), 1
．． 78-2.05 (6H, m), 2.38 (3H, s), 2.60-2.72 (
3H, m), 2.76-2.89 (3H, m), 3.04 (2H, s), 3.4
0 (2H, dt, J = 2.2, 11.7Hz), 3.94-4.00 (2H, m
), 4.26 (2H, t, J=5.0Hz), 6.34 (1H, s), 6.99
(1H, d, J=8.0Hz), 7.22 (2H, d, J=8.1Hz), 7.
28-7.36 (2H, m), 7.45 (2H, d, J=8.1Hz). IR (KBr) ν: 2936, 1493 cm ⁻¹ . Anal. calcd, for C ₂₈ H ₃₆ N ₂ O ₂ :C, 77.74; H
, 8.39; N, 6.48. Found C, 77.49; H, 8.44; N,
6.71. Example 81 (Preparation of Compound 81) 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)methylpiperidine (0.3 g), tetrahydro-4
H-pyran-4-one (0.09 g) was dissolved in 1,2-dichloroethane (10 ml), and sodium triacetoxyborohydride (0.26 g) was added under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. A 37% aqueous formaldehyde solution (0.
1 ml) was added, and sodium triacetoxyborohydride (0.3 g) was added under ice cooling.
The mixture was added and stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified using a silica gel column (methanol/triethylamine/ethyl acetate). The mixture was dissolved in ethyl acetate, and 4N hydrochloric acid/ethyl acetate (0.4 ml) and hexane were added, and the precipitated powder was collected by filtration. It was washed with hexane and 1-(7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin-4-yl)methyl-4-(N-methyl-N-
(Tetrahydropyran-4-yl)amino)piperidine dihydrochloride (Compound 81)
(0.21 g) was obtained as a colorless amorphous substance. ¹ H-NMR (δ ppm, DMSO-d ₆ ) 1.70-1.99 (2H, m),
2.07-2.24 (2H, m), 2.34 (3H, s), 2.34-2.39
(2H, m), 2.63-2.74 (3H, m), 2.91 (2H, br), 3
．． 00-3.20 (2H, m), 3.26-3.40 (2H, m), 3.45-
3.61 (2H, m), 3.70-3.90 (3H, m), 3.90-4.20
(3H, m), 4.25 (2H, br), 6.77 (1H, s), 7.02 (1
H, d, J = 8.4Hz), 7.26 (2H, d, J = 8.2Hz), 7.45
-7.53 (4H, m), 11.06 (2H, br). IR (KBr) ν: 2940, 2654, 1493 ^{cm −1} . Reference Example 110 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (1.00 g)
The residue was dissolved in methanol (25 ml), concentrated sulfuric acid (0.1 ml) was added, and the mixture was heated to reflux for 48 hours. After cooling to room temperature, 5% aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in ethanol (50 ml), dried 10% palladium-carbon (0.05 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 48 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate/hexane = 1/2) to obtain an oil. This oil was dissolved in methanol (15 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 7-phenyl-1,2,3,4
-Tetrahydronaphthalene-2-carboxylic acid (677 mg) was obtained as colorless crystals.

mp 164-166°C. Elemental analysis _{for C17H16O2} : Calcd: C, 80.93; H, 6.39. Found: C, 80.83; H, 6.30. IR (KBr) cm ^-1 : 3030, 2924, 1693, 1483, ₁₂₉₄ .
, 1234,764,700 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.83-2.05 (1 H, m
), 2.22-2.35 (1H, m), 2.75-3.05 (3H, m), 3.
12 (2H, d, J = 7.4Hz), 7.18 (1H, d, J = 7.8Hz),
7.27-7.46 (5H,m), 7.52-7.60 (2H,m). Example 82 (Preparation of Compound 82) 7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (
The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was then dissolved in THF (7 ml).
F (7 ml), and 1-(4-aminobenzyl)piperidine (33
The reaction mixture was stirred at room temperature for 17 minutes.
After stirring for 1 hour, water (100 ml) was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was recrystallized with ethyl acetate/diisopropyl ether to give N-
[4-(piperidinomethyl)phenyl]-7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide (Compound 82) (604 mg) was obtained as pale brown crystals.

mp 185-187°C _. Elemental analysis for _C29H32N2O : Calcd: C, 82.04; H, 7.60; N, 6.60. Found: C, 81.98; H, 7.45; N, 6.63. IR (KBr) cm ^-1 : 3288, 2933 _, 1657, 1603, 1537.
, 1485, 1410, 1321, 760, 696 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.35-1.75 (6 H, m
), 1.90-2.15 (1H, m), 2.18-2.42 (5H, m), 2.
60-2.78 (1H, m), 2.88-3.05 (2H, m), 3.08-3
．． 30 (2H, m), 3.44 (2H, m), 7.15-7.60 (13H, m
Example 83 (Preparation of Compound 83) N-[4-(piperidinomethyl)phenyl]-7-phenyl-1,2,3,4
Tetrahydronaphthalene-2-carboxamide (300 mg) was dissolved in DMF (3 m
Methyl iodide (132 μL) was added and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration to give 1-[4-(7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamido)benzyl]-1-methylpiperidinium iodide (Compound 83) (374 mg) as colorless crystals.

mp 205-208°C _Elemental analysis Calcd _{as C30H35N2OI.0.5H2O :} C, 62.61; H, 6.30; N, 4.87. Found: C, 62.94; H, 6.08; N, 5.05. IR (KBr) cm ⁻¹ : 3439, 1660, 1599, 1531, 1485
, 1417, 1321, 760 ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (6H
, m), 2.05-2.20 (1H, m), 2.75-3.10 (9H, m),
3.20-3.35 (4H, m), 4.52 (2H, s), 7.20 (1H, d
, J=8.4Hz), 7.35-7.55 (7H, m), 7.64 (2H, d,
J = 7.6Hz), 7.78 (2H, d, J = 8.2Hz), 10.28 (1H
, s). Reference Example 111 Ethyl 3-hydroxybenzoate (5.00 g), benzyl bromide (4.29 ml)
A mixture of 1,2-dimethyl-2,2-trimethyl-1,2-dichloro-2 ...
), 1N aqueous sodium hydroxide solution (50 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, acidified with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 3-benzyloxybenzoic acid (5.10 g) as colorless crystals.

mp 140-141°C. Elemental analysis _{as C14H12O3} : Calcd: C, 73.67; H, 5.30. Found: C, 73.70; H, 5.32. IR (KBr) cm ^-1 : 3030, 2897, 1684 _, 1603, 1450.
, 1323, 1296, 1250, 1039, 760, 733 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 5.13 (2H, s), 7.1
8-7.28 (1H, m), 7.28-7.48 (6H, m), 7.70-7.
77 (2H, m). Reference Example 112 Ethyl 3-hydroxybenzoate (5.00 g), 4-methylbenzyl chloride (4
78 ml), potassium carbonate (6.24 g), sodium iodide (5.41 g)
A mixture of acetone (50 ml) and ethanol (200 ml) was heated to reflux for 15 hours. After the solvent was removed under reduced pressure, water (200 ml) was added to the residue, and the mixture was extracted with ethyl acetate. After concentrating the organic layer, the residue was dissolved in methanol (50 ml), and 1N aqueous sodium hydroxide solution (50 ml) was added, followed by heating to reflux for 3 hours. The reaction mixture was cooled to room temperature.
After adding concentrated hydrochloric acid to make the mixture acidic, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was recrystallized with ethyl acetate/hexane to give 3-(4-methylbenzyloxy)
Benzoic acid (5.92 g) was obtained as colorless crystals.

mp 152-154°C. Elemental analysis _{for C15H14O3} : Calcd: C, _74.36 ; H, 5.82. Found: C, 74.16; H, 5.77. IR (KBr) cm ^-1 : 3010, 2897, 1684, 1605, 1454.
, 1298, 1248, 1041, 802, 760 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 5.0
8 (2H, s), 7.17-7.27 (3H, m), 7.31-7.43 (3H
,m), 7.70-7.77 (2H,m). Reference Example 113: A mixture of ethyl 3-hydroxybenzoate (5.00 g), 1-(chloromethyl)naphthalene (5.40 ml), potassium carbonate (6.24 g), sodium iodide (catalytic amount), and acetone (50 ml) was heated under reflux for 24 hours. The solvent was removed under reduced pressure, and water (200 ml) was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in methanol (50 ml), to which 1N aqueous sodium hydroxide solution (50 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, acidified with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 3-(1-naphthylmethoxy)benzoic acid (7.14 g) as colorless crystals.

mp 177-179°C. Elemental analysis _{for C18H14O3} : Calcd: C, _77.68 ; H, 5.07. Found: C, 77.41; H, 4.89. IR (KBr) cm ^-1 : 3049, 2887, 1714, 1691, 1595.
, 1439, 1308, 1277, 1238, 1014, 781, 756 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 5.55 (2H, s), 7.2
4-7.32 (1H, m), 7.35-7.65 (5H, m), 7.73-7.
95 (4H, m), 8.02-8.10 (1H, m). Example 84 (Preparation of Compound 84) 3-benzyloxybenzoic acid (800 mg) was dissolved in THF (10 ml),
Oxalyl chloride (397 μl) and one drop of DMF were added, and the mixture was stirred at room temperature for 1 hour. After the solvent was evaporated under reduced pressure, the residue was dissolved in THF (15 ml) and the 1-(4-
(aminobenzyl)piperidine (733 mg) and triethylamine (589 μl)
The reaction mixture was stirred at room temperature for 17 hours, and then water (100 ml) was added.
The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 3-benzyloxy-4'-(piperidinomethyl)benzanilide (Compound 84) (1.06 g) as colorless crystals.

mp 137-138°C _. Elemental analysis _{for C26H28N2O2} : Calcd: C, _77.97 ; H, 7.05; N, 6.99. Found: C, 77.73; H, 7.15; N, 6.91. IR (KBr) cm ^-1 : 3348, 2929, 1645, 1597, 1524.
, 1319, 1273, 750, 698 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.38-1.70 (6H, m
), 2.32-2.43 (4H, m), 3.46 (2H, s), 5.13 (2H
, s), 7.11-7.20 (1H, m), 7.28-7.60 (12H, m)
, 7.77 (1H,s). Example 85 (Preparation of Compound 85) 3-(4-methylbenzyloxy)benzoic acid (1.00 g) was dissolved in THF (15 ml
), and oxalyl chloride (468 μl) and one drop of DMF were added, followed by stirring at room temperature for 1 hour. After the solvent was evaporated under reduced pressure, the residue was dissolved in THF (15 ml), and 1-(4-aminobenzyl)piperidine (864 mg) and triethylamine (695 μl) were added at room temperature. This reaction solution was stirred at room temperature for 3 hours, and then water (100 ml) was added.
The resulting mixture was added with 1,000 ml of ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 3-(4-methylbenzyloxy)-4'-(piperidinomethyl)benzanilide (Compound 85) (1.25 g) as colorless crystals.

mp 153-155°C _. Elemental analysis _{for C27H30N2O2} : Calcd: C, 78.23; H, 7.29; N, 6.76. Found: C, 78.05; H, 7.25; N, 6.75. IR (KBr) cm ^-1 : 3348, 2941 _, 1655, 1597, 1581.
, 1524, 1410, 1321, 1269, 1051, 800 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.35-1.75 (6 H, m
), 2.30-2.45 (7H, m), 3.47 (2H, s), 5.09 (2H
, s), 7.10-7.40 (9H, m), 7.47-7.60 (3H, m),
7.78 (1H, s). Example 86 (Preparation of Compound 86) 3-(1-naphthylmethoxy)benzoic acid (1.00 g) was dissolved in THF (10 ml).
The residue was dissolved in THF (15 ml), and the mixture was stirred at room temperature with 1-(4-aminobenzyl)piperidine (751 mg) and triethylamine (
The reaction mixture was stirred at room temperature for 96 hours, and then water (100 ml) was added.
The resulting mixture was added with 1,000 ml of ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to give 3-(1-naphthylmethoxy)-4'-(piperidinomethyl)benzanilide (Compound 86) (1.25 g) as colorless crystals.

mp 171-173° _{C . Elemental analysis as C30H30N2O2.0.1H2O : Calcd} : C, 79.65; H, 6.73; N, 6.19. Found: C, _79.55 ; H, 6.76; N, 6.19. IR (KBr) cm ^-1 : 3350, 2929, 1655, 1597, 1581.
, 1522, 1410, 1321, 1290, 1269, 793 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.35-1.70 (6 H, m
), 2.33-2.43 (4H, m), 3.47 (2H, s), 5.57 (2H
, s), 7.20-7.65 (12H, m), 7.78 (1H, s), 7.84
-7.93 (2H, m), 8.03-8.08 (1H, m). Example 87 (Preparation of Compound 87) 3-benzyloxy-4'-(piperidinomethyl)benzanilide (560 mg)
) was dissolved in DMF (3 ml), methyl iodide (261 μl) was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (100 ml) was added to the reaction solution, and the resulting precipitate was collected by filtration to give 1-[4-(3-benzyloxybenzoylamino)benzyl]-1-methylpiperidinium iodide (Compound 87) (724 mg) as colorless crystals.

mp 192-194°C _. Elemental analysis as _C27H31N2O2I : Calcd: C, _59.78 ; H, 5.76; N, 5.16. Found: C, 59.51; H, 5.67; N, 5.46. IR (KBr) cm ^-1 : 3437, 3317 _, 1662, 1593, 1520.
, 1317, 1273, 1016, 750, 700 ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.00 (6H
, m), 2.92 (3H, s), 3.20-3.40 (4H, m), 4.54 (
2H, s), 5.20 (2H, s), 7.23-7.60 (11H, m), 7.
92 (2H, d, J = 8.4 Hz), 10.42 (1H, s). Example 88 (Preparation of Compound 88) 3-(4-methylbenzyloxy)-4'-(piperidinomethyl)benzanilide (900 mg) was dissolved in DMF (5 ml) and methyl iodide (405 μl) was added.
To this reaction mixture was added ethyl acetate (200 ml), and the resulting precipitate was collected by filtration to give 1-methyl-1-[4-[3-
(4-methylbenzyloxy)benzoylamino]benzyl]piperidinium (Compound 88) (1.05 g) was obtained as colorless crystals.

mp 210-212°C _{. Elemental analysis: Calcd for C28H33N2O2I.0.5H2O : C} , 59.47; H, 6.06; N, 4.95. Found: C, 59.77; H, 5.94 _; N, 5.10. IR (KBr) cm ^-1 : 3298 _, 2949, 1657, 1595, 1520.
, 1483, 1416, 1321, 1275, 1213, 1012, 804 ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.00 (6H
, m), 2.32 (3H, s), 2.93 (3H, s), 3.20-3.40 (
4H, m), 4.56 (2H, s), 5.15 (2H, s), 7.17-7.6
0 (10H, m), 7.93 (2H, d, J = 8.4Hz), 10.43 (1H
, s). Example 89 (Preparation of Compound 89) 3-(1-naphthylmethoxy)-4'-(piperidinomethyl)benzanilide (950 mg) was dissolved in DMF (8 ml), and methyl iodide (394 μl) was added thereto, followed by stirring at room temperature for 38 hours. Ethyl acetate (200 ml) was added to this reaction solution, and the resulting precipitate was collected by filtration to obtain 1-methyl-1-[4-[3-(
[0113] The compound 89 (1.21 g) was obtained as colorless crystals.

mp 211-213°C _. Elemental analysis as _C31H33N2O2I : Calcd: C, _62.84 ; H, 5.61; N, _4.73 . Found: C, 62.47; H, 5.61; N, 4.73. IR (KBr) cm ^-1 : 3442, 3282, 1655, 1597, 1520.
, 1485, 1417, 1325, 1273, 793 ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.00 (6H
, m), 2.92 (3H, s), 3.20-3.40 (4H, m), 4.54 (
2H, s), 5.66 (2H, s), 7.35-7.75 (10H, m), 7.
80-8.05 (4H, m), 8.07-8.17 (1H, m), 10.44 (
1H,s). Example 90 (Preparation of Compound 90) 3-(4-methylbenzyloxy)-4'-(piperidinomethyl)benzanilide (150 mg) was dissolved in THF (5 ml) and the solution was added to 70% mCPBA (m
-chloroperbenzoic acid (116 mg) was added and stirred at 0° C. for 1 hour. A saturated aqueous solution of sodium thiosulfate (10 ml) and a saturated aqueous solution of potassium carbonate (1
0 ml) was added, and the mixture was stirred at room temperature for 30 minutes, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/methanol to give 3-(4-methylbenzyloxy)-4'-(1-oxypiperidinomethyl)benzanilide (Compound 90) (77 mg) as colorless crystals.

mp 128-130° _{C . Elemental analysis as C27H30N2O3.1.0H2O : Calcd} : C, 72.30; H, 7.19; N, 6.25. Found: C, _72.53 ; H, 6.96; N, 6.28. IR (KBr) cm ^-1 : 3388, 2939, 1662, 1597, 1520.
, 1414, 1321, 1271, 1211, 806, 748 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.15-1.80 (4 H, m
), 2.10-2.50 (5H, m), 3.00-3.18 (4H, m), 4.
33 (2H, s), 5.09 (2H, s), 7.09-7.60 (10H, m)
, 7.77 (2H, d, J = 8.0 Hz), 8.69 (1H, s). Example 91 (Preparation of Compound 92) A solution of N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide hydrochloride (200 mg) in ethanol (4 ml) was added with ethylenediamine (0.0
After stirring overnight at room temperature, the mixture was concentrated and sodium bicarbonate water was added.
The extract was extracted with tetrahydrofuran and washed with brine. After drying (anhydrous magnesium sulfate), the extract was concentrated and recrystallized from ethyl acetate/methanol to give N-[4-(
2-imidazolin-2-yl)phenyl]-7-(4-methylphenyl)-2,
3-Dihydro-1-benzoxepine-4-carboxamide (Compound 92) (6
0 mg) was obtained as colorless crystals.

m. p. 282-283℃¹ H-NMR (200MHz, DMSO-d₆) δ: 2.34 (s, 3H), 2
．． 9-3.1 (m, 2H), 3.60 (brs, 4H), 4.2-4.4 (m,
2H), 6.87 (brs, 1H), 7.06 (d, 1H, J=8.0), 7.
27 (d, 2H, J = 8.4), 7.37 (s, 1H), 7.5-7.6 (m,
3H), 7.7-7.8 (m, 5H), 10.15 (s, 1H). IR (KBr) 1649, 1605, 1525, 1508, 1489, 1321
,1260,810cm⁻¹ Elemental analysis C₂₇H₂₅N₃O₂ Calcd. C, 76.57; H, 5.95
; N, 9.92: Found. C, 76.45; H, 6.08; N, 9.97. Example 92 (Preparation of Compound 93) N-[4-(2-imidazolin-2-yl)phenyl]-7-(methylphenyl)
(120)-2,3-dihydro-1-benzoxepin-4-carboxamide
A solution of 0.0 mg of triethylamine in THF/DMF (10 ml/1 ml) was
Then, acetyl chloride (0.024 ml) was added and the mixture was stirred at room temperature for 1 hour.
Water was added under cooling, and the mixture was extracted with ethyl acetate.
The residue was purified by silica gel column chromatography.
(ethyl acetate/methanol), and then purified with ethyl acetate/methanol.
Recrystallization gave N-[4-(1-acetyl-2-imidazolin-2-yl)phenyl]
]-2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 9
3) (56 mg) was obtained as colorless crystals.

m. p. 222-224℃¹ H-NMR (200MHz, CDCl₃) δ: 1.90 (3H, s), 2.3
9 (3H, s), 3.05-3.15 (2H, m), 3.85-4.15 (4H
, m), 4.36 (2H, t, J = 4.6), 7.06 (1H, d, J = 8.6
), 7.2-7.3 (2H, m), 7.4-7.6 (6H, m), 7.67 (2
H, d, J=8.8), 7.78 (1H, brs). IR (KBr) 1665, 1649, 1530, 1512, 1391, 1279
,841,814cm⁻¹ Elemental analysis C₂₉H₂₇N₃O₃ Calcd. C, 74.82; H, 5.85
; N, 9.03: Found. C, 74.58; H, 5.67; N, 8.95. Example 93 (Preparation of Compound 94) N-(4-cyanomethylphenyl)-7-(4-methylphenyl)-2,3-
Dihydro-1-benzoxepin-4-carboxamide (789 mg) was added under ice cooling.
Then, 24% hydrogen chloride/ethanol/dioxane solution (10 ml) was added.
After stirring for 3 hours, the mixture was concentrated. Ethanol (20 ml) was added to form a suspension, and the mixture was cooled on ice.
Ethylenediamine (0.4 ml) was added, and the mixture was stirred at room temperature for 15 hours, and then concentrated to give a heavy
Sodium chloride solution was added. The mixture was extracted with ethyl acetate and washed with brine. After drying (magnesium sulfate),
The mixture was concentrated and recrystallized from ethyl acetate/methanol to give N-[4-[(2-
imidazolin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-
2,3-Dihydro-1-benzoxepine-4-carboxamide (Compound 94)
(580 mg) was obtained as colorless crystals.

m. p. 210-212℃¹ H-NMR (200MHz, CDCl₃) δ: 2.38 (3H, s), 3.0
-3.1 (2H, m), 3.49 (2H, s), 3.59 (4H, s), 4.2
5-4.35 (2H, m), 7.03 (d, 1H, J=8.2), 7.15-7
．． 35 (5H, m), 7.4-7.6 (6H, m). IR (KBr) 1649, 1603, 1516, 1493, 1327, 1265
,1256,816cm⁻¹ Elemental analysis C₂₈H₂₇N₃O₂・0.1H₂O Calcd. C, 73.82
; H, 6.42; N, 9.22: Found. C, 73.85; H, 6.31;
N, 9.08 Example 94 (Preparation of Compound 95) N-[4-[(2-imidazolin-2-yl)methyl]phenyl]-7-(4
-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbox
A solution of 200 mg of thiaminamide in 10 ml of THF/1 ml of DMF was dissolved in triethylamine.
Add dimethylamine (0.095 ml) and acetyl chloride (0.036 ml) and add at room temperature.
The mixture was stirred for 1 hour, and then sodium bicarbonate water was added under ice cooling, followed by extraction with ethyl acetate and washing with brine.
The extract was dried (magnesium sulfate) and then concentrated.
Chromatography (ethyl acetate) followed by recrystallization (ethyl acetate/diethyl acetate)
Purification by ethyl acetate) and N-[4-[(1-acetyl-2-imidazoline-2-yl]
phenyl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1
-Benzoxepine-4-carboxamide (compound 95) (77 mg) was dissolved in water to give a colorless crystal.
Obtained as crystals.

m. p. 174-176℃ 1H-NMR (200MHz, CDCl₃) δ: 2.13 (3H, s), 2.3
9 (3H, s), 3.0-3.15 (2H, m), 3.8-3.9 (4H, m)
, 4.15 (2H, s), 4.36 (2H, t, J=4.8), 7.05 (1H
, d, J=8.0), 7.2-7.35 (4H, m), 7.4-7.6 (7H,
m). IR (KBr) 1655, 1532, 1516, 1493, 1395, 1319
,1244,814cm⁻¹ Elemental analysis C₃₀H₂₉N₃O₃・0.8H₂O Calcd. C, 72.94
; H, 6.24; N, 8.51: Found, C, 72.99; H, 6.00;
N, 8.53 Example 95 (Preparation of Compound 96) N-[4-[(2-imidazolin-2-yl)methyl]phenyl]-7-(4
-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbox
A suspension of 150 mg of thiaminamide in 5 ml of THF was treated with triethylamine (0.06
After stirring at 0°C for 1 hour, the mixture was cooled to 100°C and cooled to 200°C.
Under cooling, sodium bicarbonate water was added and extracted with ethyl acetate. After washing with brine, the extract was dried and
(magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
The product was purified by chromatography (ethyl acetate/hexane = 4/1) and further purified by ethyl acetate.
Recrystallization from hexane yielded N-[4-[(1-methoxycarbonyl-2-imidazoline)-
2,3-Diazolin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-di ...
-Dihydro-1-benzoxepin-4-carboxamide (compound 96) (71
mg) was obtained as colorless crystals.

m. p. 170-171℃¹ H-NMR (200MHz, CDCl₃) δ: 2.39 (3H, s), 3.0
7 (2H, t, J = 5.0), 3.73 (3H, s), 3.81 (4H, s),
4.08 (2H, s), 4.36 (2H, t, J=5.0), 7.06 (1H,
d, J=8.6), 7.2-7.35 (4H, m), 7.4-7.6 (7H, m
). IR (KBr) 1730, 1663, 1514, 1491, 1381, 1318
,1265,1020,810cm⁻¹ Elemental analysis C₃₀H₂₉N₃O₄ Calcd. C, 72.71; H, 5.90
; N, 8.48: Found. C, 72.43; H, 5.94; N, 8.33. Reference Example 114 3-Hydroxybenzaldehyde (5.00 g) was dissolved in acetone (70 ml).
The mixture was dissolved in 4-methylbenzyl chloride (6.51 ml), potassium carbonate (8.49 g
) and sodium iodide (7.36 g) were added, and the mixture was heated under reflux for 24 hours.
The solvent was evaporated under reduced pressure. Water (200 ml) was added to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure.
The resulting residue was purified by column chromatography (ethyl acetate/hexane = 1/1
0) to obtain 3-(4-methylbenzyloxy)benzaldehyde
(7.86 g) was obtained as a colorless oil.

IR (KBr) cm ⁻¹ :2922, 1697, 1599, 1483, 1450
, 1383, 1261, 1147, 1020, 789, 683 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 5.0
9 (2H, s), 7.17-7.37 (5H, m), 7.52-7.60 (3H
, m), 9.98 (1H, s). Reference Example 115 α,α'-Dibromo-p-xylene (12.5 g) was dissolved in THF (100 ml), piperidine (4.68 ml) was added, and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid (100 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. After separating the two phases,
The aqueous layer was washed with diethyl ether, made basic by adding 1N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then purified directly by column chromatography (ethyl acetate/hexane = 2/1), and concentrated until the solvent volume was approximately 200 ml. This solution was added with triphenylphosphine (7.
The mixture was heated to reflux for 40 hours, and the resulting precipitate was collected by filtration to give triphenyl[4-(piperidinomethyl)benzyl]phosphonium bromide (8.14 g) as colorless crystals.

mp 234-236°C. Elemental analysis for _C31H33NBrP : Calcd: C, 70.19; H, 6.27; N, 2.64. Found: C, 70.03; H, 6.37; N, 2.65. IR (KBr) cm ^-1 : 2845 _, 1441, 1113, 995, 752, 7
19,689 ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.30-1.55 (6H
, m), 2.12-2.32 (4H, m), 3.28-3.40 (2H, m) 5
．． 14 (2H, d, J = 15.4Hz), 6.91 (2H, dd, J = 2.2,
8.0Hz), 7.12 (2H, d, J = 8.0Hz), 7.60-7.78 (
12H,m), 7.85-7.95 (3H,m). Example 96 (Preparation of Compound 97) Triphenyl[4-(piperidinomethyl)benzyl]phosphonium bromide (1.
A mixture of 1.06 g of ethanol and THF (10 ml) was added to a 1.6 ml solution at 0° C. under a nitrogen atmosphere.
A solution of 1.28 ml of M-butyllithium in hexane was added dropwise and stirred for 30 minutes. 3-(4-methylbenzyloxy)benzaldehyde (453 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was then added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/triethylamine=20/1) and recrystallized from hexane to give (E)-1-
[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidine (Compound 97) (330 mg) was obtained as colorless crystals.

mp 87-88°C. Elemental analysis: Calcd for _C28H31NO : C, 84.59; H, 7.86; N, 3.52. Found: C, 84.30; H, 7.78; N, 3.60. IR (KBr) cm ^-1 : 2924 _, 1601, 1578, 1443, 1281.
, 1157, 1036, 968, 797, 781, 685 ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.38-1.65 (6 H, m
), 2.33-2.46 (7H, m), 3.48 (2H, s), 5.07 (2H
, s), 6.83-6.90 (1H, m), 7.05-7.38 (11H, m)
, 7.46 (2H, d, J = 8.2 Hz). Example 97 (Preparation of Compound 98) (E)-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]
Piperidine (150 mg) was dissolved in DMF (3 ml), and methyl iodide (70
100 μl) of ethyl acetate was added to the reaction mixture and stirred at room temperature for 66 hours.
) was added, and the resulting precipitate was collected by filtration and recrystallized from ethyl acetate/methanol to give (E)-1-methyl-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidinium iodide (Compound 100) (183 mg) as colorless crystals.

mp 189-192℃ Elemental analysis C₂₉H₃₄NOI: Calcd: C, 64.56; H, 6.35; N, 2.60. Found: C, 64.29; H, 6.27; N, 2.88. IR (KBr) cm⁻¹: 3442, 2956, 1593, 1466, 1443
, 1267, 1211, 1189, 1014, 878, 806¹ H NMR (200MHz, CDCl₃) δ: 1.75-2.05 (6H, m
), 2.37 (3H, s), 3.21 (3H, s), 3.52-3.66 (2H
, m), 3.75-3.90 (2H, m), 5.04 (2H, s), 5.16 (
2H, s), 6.86-6.95 (1H, m), 7.03-7.15 (4H, m
), 7.18-7.37 (5H, m), 7.49 (2H, d, J = 8.4Hz)
, 7.66 (2H, d, J = 8.4 Hz). Reference Example 116 2-Hydroxybenzyl alcohol (3.00 g), 2-chloroethylpropyl
Dimethyl ether (4.0 ml), sodium iodide (4.75 g), potassium carbonate (
A mixture of 6.68 g of methylpropional (C14H2O3) and 30 ml of DMF was stirred at 90° C. for 24 hours.
Water was added to the system, and the system was extracted with ethyl acetate. The organic layer was washed with water and saturated brine,
After drying over magnesium sulfate and concentrating under reduced pressure, the residue was purified by column chromatography.
(ethyl acetate:hexane 1:2) to give 2-(2-proline) as a yellow oil.
As a result, 2.35 g of (epoxyethoxy)benzyl alcohol was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.92 (3H, t, J=7.4
Hz), 1.54-1.68 (2H, m), 3.31 (1H, t, J = 7.0H
z), 3.48 (2H, t, J=6.8Hz), 3.76-3.81 (2H, m
), 4.19-4.24 (2H, m), 4.67 (2H, d, J = 7.0Hz)
, 6.89-6.99 (2H, m), 7.22-7.30 (2H, m). IR (neat) 3427, 1603, 1601, 1495, 1454, 128
8,1244,1120,1051,754cm⁻¹ Reference Example 117 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (400 mg), 2-(2-propoxyethoxy)benzene
TH of diethyl alcohol (0.63 g), triphenylphosphine (782 mg)
To a solution of F (10 ml), diethyl azodicarboxylate (40% toluene solution) was added at 0°C.
1.36 ml) was added and stirred at room temperature for 20 hours.
The crude 7-[
[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2
,3-dihydro-1-benzothiepine-4-carboxylate methyl (1.04 g)
Got it.

Crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.
To a solution of 0.04 g of potassium carbonate (
An aqueous solution (2.1 ml) of 622 mg of 7-(2-(2-propoxyethoxy)benzyl)oxy]-1,1-dioxo-2,3-dihydro-1-(2-propoxyethoxy)benzyloxy) ...
Benzothiepine-4-carboxylic acid (136 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.5
Hz), 1.55-1.65 (2H, m), 3.05-3.12 (2H, m),
3.48 (2H, t, J=6.6Hz), 3.59-3.66 (2H, m), 3
．． 78-3.83 (2H, m), 4.17-4.24 (2H, m), 5.24 (
2H, s), 6.92-7.03 (2H, m), 7.09-7.12 (2H, m
), 7.28-7.41 (2H, m), 7.87 (1H, s), 8.09 (1H
, d, J = 9.4 Hz). Reference Example 118 4-Hydroxybenzyl alcohol (1.5 g), 1-bromopropane (1.
A mixture of potassium carbonate (2.5 g) and acetone (50 ml) was heated at 60°C.
The mixture was stirred at rt for 8 hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The extract was washed with a N aqueous sodium hydroxide solution and saturated brine, and then dried over magnesium sulfate. The extract was concentrated under reduced pressure to give 4-propoxybenzyl alcohol (
1.37 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.04 (3H, t, J = 7.3
Hz), 1.52 (1H, t, J=5.4Hz), 1.72-1.90 (2H,
m), 3.93 (2H, t, J=6.6Hz), 4.62 (2H, d, J=5.
4Hz), 6.89 (2H, d, J = 8.8Hz), 7.29 (2H, d, J =
8.8 Hz). Reference Example 119: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-propoxybenzyl alcohol (
To a solution of 495 mg of diphenylphosphine and 782 mg of triphenylphosphine in 10 ml of THF, diethyl azodicarboxylate (40% solution in toluene, 1.36 ml) was added at 0° C.
The mixture was stirred at room temperature for 64 hours, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane 1:2) to give methyl 7-[(4-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg).

Methyl 7-[(4-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg) in THF-
To a solution of 10.5 ml of methanol, 1.7 ml of an aqueous solution of potassium carbonate (498 mg) was added at room temperature, and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 10 ml of 1N hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[(4-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (255 mg) as pale yellow crystals.

m. p. 250-254℃¹ H-NMR (200MHz, DMSO-d₆) δ0.97 (3H, t, J=7
．． 3Hz), 1.63-1.81 (2H, m), 2.90 (2H, t, J=6.
6Hz), 3.78 (2H, t, J = 6.6Hz), 3.93 (2H, t, J =
6.6Hz), 5.15 (2H, s), 6.95 (2H, d, J=8.8Hz)
, 7.20 (1H, dd, J = 8.8, 2.6Hz), 7.36-7.40 (3
H, m), 7.71 (1H, s), 7.93 (1H, d, J=8.8Hz). IR (KBr) 3075, 1674, 1597, 1566, 1512, 1416
,1294,1277,1163,1128,1069cm⁻¹ Elemental analysis C₂₁H₂₂O₆S Calcd. C, 62.67; H, 5.51:
Found. C, 62.36; H, 5.60. Reference Example 120 To a solution of 2-ethoxybenzyl alcohol (0.46 g) in THF (10 ml),
Thionyl chloride (0.44 ml) and pyridine (1 drop) were added at room temperature, and the mixture was stirred for 2 hours.
The mixture was concentrated under reduced pressure, and a solution of the residue in DMF (10 ml) was added with 7-hydroxy-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid methyl
Add 400 mg of ethyl acetate and 615 mg of potassium carbonate, and heat at 60°C for 20 hours.
The reaction mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride solution, and the mixture was concentrated.
The mixture was washed with water and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography.
The compound was separated and purified by HPLC (ethyl acetate:hexane 1:2) as orange crystals.
7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydroxide
Methyl 1-benzothiepine-4-carboxylate (249 mg) was obtained.

To a solution of methyl 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (220 mg) in THF-methanol (5-2.5 ml) was added an aqueous solution (1.0 ml) of potassium carbonate (151 mg) at room temperature, and the mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine,
The mixture was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (156 mg) as colorless crystals.

m. p. 158-160°C ^1H -NMR (200MHz, DMSO- _d6 ) δ1.32 (3H, t, J=6
．． 9Hz), 2.87-2.93 (2H, m), 3.65-3.71 (2H, m
), 4.10 (2H, q, J = 6.9Hz), 5.19 (2H, s), 6.92
-7.07 (2H, m), 7.20 (1H, dd, J=8.6, 2.6Hz),
7.30-7.41 (3H, m), 7.72 (1H, s), 7.94 (1H, d
, J=8.6Hz). IR (KBr) 3076, 1690, 1591, 1564, 1494, 1292
, 1281, 1246, 1165, 1128, 1069 cm ^-1 Elemental analysis C ₂₀ H ₂₀ O ₆ S・0.2H ₂ O Calcd. C, 61.27;
H, 5.24: Found. C, 61.18; H, 5.17. Reference Example 121 To a solution of 2-methoxybenzyl alcohol (0.42 g) in THF (10 ml), thionyl chloride (0.44 ml) and pyridine (1 drop) were added at room temperature, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml) to give 7-hydroxy-
Methyl 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) and potassium carbonate (830 mg) were added, and the mixture was stirred at 60° C. for 16 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane 1:2) to give methyl 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (250 mg) as orange crystals.

To a solution of methyl 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (230 mg) in THF-methanol (5-2.5 ml) was added an aqueous solution (1.0 ml) of potassium carbonate (164 mg) at room temperature, and the mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine,
The mixture was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (172 mg) as colorless crystals.

m. p. 168-171℃¹ H-NMR (200MHz, DMSO-d₆) δ2.90 (2H, t, J=6
．． 4Hz), 3.68 (2H, t, J=6.4Hz), 3.83 (3H, s),
5.19 (2H, s), 6.98 (1H, t, J=7.3Hz), 7.07 (1
H, d, J = 7.8Hz), 7.21 (1H, dd, J = 8.8, 2.4Hz)
, 7.32-7.44 (3H, m), 7.73 (1H, s), 7.94 (1H,
d, J=8.8Hz). IR (KBr) 3185, 1676, 1588, 1497, 1325, 1296
,1283,1252,1165,1128cm⁻¹ Elemental analysis C₁₉H₁₈O₆S 0.25H₂O Calcd. C, 60.23
; H, 4.92: Found. C, 60.02; H, 5.20. Reference Example 122 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (400 mg), 2-chlorobenzyl chloride (0.25 m
A mixture of potassium carbonate (309 mg) and DMF (10 ml) was heated at 60°C for 5 min.
The reaction mixture was stirred for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydroxide, and ethyl acetate.
The mixture was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography.
The product was separated and purified by chromatography (ethyl acetate:hexane 1:2) to obtain colorless crystals.
7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydroxide
Methyl 1-benzothiepine-4-carboxylate (413 mg) was obtained.

m. p. 182-184℃¹ H-NMR (200MHz, CDCl₃) δ3.04-3.11 (2H, m)
, 3.59-3.66 (2H, m), 3.86 (3H, s), 5.25 (2H,
s), 7.04-7.09 (2H, m), 7.29-7.36 (2H, m), 7
．． 40-7.53 (2H, m), 7.79 (1H, s), 8.12 (1H, d,
J=8.4Hz). IR (KBr) 1701, 1588, 1433, 1329, 1312, 1285
,1260,1167,1128cm⁻¹ Elemental analysis C₁₉H₁₇O₅SCl Calcd. C, 58.09; H, 4.3
6: Found. C, 57.84; H, 4.42. Reference Example 123 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydrazine
Methyl 1-benzothiepine-4-carboxylate (350 mg) in THF-methan
A solution of 2M potassium carbonate (0.9 mg) in ethanol (73.5 ml) was added at room temperature.
) was added and stirred at 65°C for 20 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml)
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration.
The mixture was washed with propyl ether to give 7-[(2-chlorobenzyl)o
[oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-chlor
The carboxylic acid (303 mg) was obtained.

m. p. 238-241℃¹ H-NMR (200MHz, DMSO-d₆) δ2.88 (2H, m), 3.
66-3.73 (2H, m), 5.30 (2H, s), 7.25 (1H, dd,
J=8.8, 2.6Hz), 7.40-7.66 (5H, m), 7.74 (1H
, s), 7.97 (1H, d, J=8.8Hz). IR (KBr) 3086, 1672, 1590, 1318, 1296, 1260
,1167,1127cm⁻¹ Elemental analysis C₁₈H₁₅O₅SCl Calcd. C, 57.07; H, 3.9
9: Found. C, 56.81; H, 4.12. Reference Example 124 2-Hydroxybenzyl alcohol (2.00 g), 2-bromoethyl ethyl
A mixture of ether (2.7 ml), potassium carbonate (4.45 g) and DMF (20 ml)
The mixture was stirred for 3 days at 90° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate.
The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and then with magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane
Purification with hexane (1:2) gave 2-(2-ethoxyethoxy) as a pale yellow oil.
Benzyl alcohol (2.30 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.23 (3H, t, J=7.0
Hz), 3.58 (2H, q, J=7.0Hz), 3.76-3.81 (2H,
m), 4.19-4.24 (2H, m), 4.67 (2H, s), 6.89-6
．． 99 (2H, m), 7.22-7.31 (2H, m). IR (neat) 3441, 1603, 1590, 1493, 1453, 124
4,1119,1049cm⁻¹ Reference Example 125 2-(2-ethoxyethoxy)benzyl alcohol (0.60 g) in toluene
(5 ml) solution was added with thionyl chloride (0.33 ml) and pyridine (1 drop) at room temperature.
) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The residue was washed with saturated brine and dried over magnesium sulfate.
In a solution of MF (10 ml), 7-hydroxy-1,1-dioxo-2,3-dihydrazine
methyl 1-benzothiepine-4-carboxylate (400 mg) and potassium carbonate
C. for 3 hours. Water was added to the reaction mixture, and acetic acid was added.
The organic layer was washed with water and saturated brine, and then extracted with magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane
The compound was separated and purified using a 1:2 → 1:1 solvent to give 7-[[2-(2-
Ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro
Methyl 1-benzothiepine-4-carboxylate (0.64 g) was obtained.

7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate methyl ester (0.64
To a solution of (g) in THF-methanol (6-3 ml), 1 M aqueous potassium carbonate solution (2.9 ml) was added at room temperature, and the mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1 N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over magnesium sulfate. It was then concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1 as pale yellow crystals.
,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3
85 mg) was obtained.

m. p. 134-136℃¹ H-NMR (200MHz, DMSO-d₆) δ1.04 (3H, t, J=7
．． 0Hz), 2.90 (2H, t, J = 6.4Hz), 3.46 (2H, q, J
=7.0Hz), 3.65-3.71 (4H, m), 4.14-4.18 (2H
, m), 5.20 (2H, s), 6.95-7.10 (2H, m), 7.21 (
1H, dd, J=8.8, 2.6Hz), 7.30-7.44 (3H, m), 7
．． 72 (1H, s), 7.94 (1H, d, J=8.8Hz). IR (KBr) 3447, 1686, 1622, 1586, 1281, 1250
,1163,1127cm⁻¹ Elemental analysis C₂₂H₂₄O₇S Calcd. C, 61.10; H, 5.59:
Found. C, 60.90; H, 5.72. Reference Example 126 3-Hydroxyphenethyl alcohol (1.50 g), propane bromide (1.3
ml (14.9 mmol), potassium carbonate (2.25 g) in acetone (50 ml
The mixture was heated under reflux for 3 days. After concentrating under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and then with magnesium sulfate.
The mixture was dried over sodium hydroxide and concentrated under reduced pressure to give 3-propoxyphenyl ether as a pale yellow oil.
Ethyl alcohol (1.70 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.04 (3H, t, J=7.3
Hz), 1.40 (1H, t, J=5.8Hz), 1.72-1.80 (2H,
m), 2.84 (2H, t, J = 6.4Hz), 3.82-3.95 (4H, m
), 6.74-6.82 (3H, m), 7.18-7.26 (1H, m). IR (neat) 3289, 1601, 1583, 1487, 1449, 139
2,1259,1157,1047,779,696cm⁻¹ Reference Example 127 3-propoxyphenethyl alcohol (0.54 g) and triethylamine
(0.84 ml) in THF (10 ml) was added methanesulfonyl chloride (
0.35 ml) was added and stirred for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was dissolved in DMF (10 ml) and 7-hydroxy-1,1-dioxo-2
, 3-dihydro-1-benzothiepine-4-carboxylic acid methyl ester (400 mg) and
The reaction mixture was stirred at 70°C for 5 hours.
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:
The mixture was separated and purified with hexane (1:2) to give 7-[(3-propoxy)-2-methyl-2-propanol] as a pale yellow oil.
(phenethyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiene
Methyl pin-4-carboxylate (0.42 g) was obtained.

7-[(3-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (0.42 g) in THF
- A solution of methanol (10-5 ml) was added to a 1M aqueous potassium carbonate solution (2 ml) at room temperature.
) was added and stirred at 65° C. for 24 hours. After cooling to room temperature, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with hexane to obtain the target product (291 mg) as brown crystals.

m. p. 86-88℃¹ H-NMR (200MHz, DMSO-d₆) δ0.97 (3H, t, J=7
．． 3Hz), 1.63-1.81 (2H, m), 2.89 (2H, t, J=7.
0Hz), 3.03 (2H, t, J = 6.8Hz), 3.67 (2H, t, J =
6.8Hz), 3.91 (2H, t, J=6.4Hz), 4.33 (2H, t,
J = 7.0Hz), 6.76-6.81 (1H, m), 6.86-6.90 (2
H, m), 7.12-7.25 (2H, m), 7.34 (1H, d, J = 2.6
Hz), 7.72 (1H, s), 7.92 (1H, d, J=8.8Hz). IR (KBr) 3466, 1682, 1588, 1291, 1260, 1161
,1127,1067cm⁻¹ Elemental analysis C₂₂H₂₄O₆S 0.25H₂O Calcd. C, 62.77
; H, 5.87: Found. C, 62.66; H, 5.83. Reference Example 128 2-Hydroxyphenethyl alcohol (1.5 g), 1-bromopropane (1
A mixture of acetone (50 ml) and potassium carbonate (2.25 g) was added to 6
The mixture was stirred at 0°C for 64 hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with 1N sodium hydroxide solution and saturated saline, and then with magnesium sulfate.
The mixture was dried and concentrated under reduced pressure to give 2-propoxyphenethyl alcohol as a yellow oil.
As a result, 2.02 g of methyl alcohol was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.06 (3H, t, J=7.5
Hz), 1.68-1.92 (3H, m), 2.93 (2H, t, J = 6.4H
z), 3.81-3.87 (2H, m), 3.95 (2H, t, J = 6.4Hz
), 6.84-6.94 (2H, m), 7.15-7.25 (2H, m). IR (neat) 3343, 1601, 1494, 1474, 1454, 124
2,1119,1049,1019,982,752cm⁻¹ Reference Example 129 2-Propoxyphenethyl alcohol (0.54 g) and triethylamine
(0.84 ml) in THF (10 ml) was added methanesulfonyl chloride (
0.35 ml) was added and stirred for 1.5 hours. Water was added to the reaction mixture, and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
The mixture was concentrated, and the residue was dissolved in DMF (10 ml) and 7-hydroxy-1,1-dioxo
-2,3-dihydro-1-benzothiepine-4-carboxylic acid methyl ester (400 mg
) and potassium carbonate (414 mg) were added, and the mixture was stirred at 60°C for 22 hours.
Water was added to the system, and the system was extracted with ethyl acetate. The organic layer was washed with saturated saline and then with mag sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate).
The compound was separated and purified using a 1:2 mixture of ethyl acetate and hexane to give 7-[(2-proline)-
(hydroxyphenethyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzoxanthate
Methyl zothiepine-4-carboxylate (0.31 g) was obtained.

7-[(2-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (0.31 g) in THF
- A solution of methanol (10-5 ml) was added to a 1M aqueous potassium carbonate solution (1.5
ml) was added and stirred at 65°C for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give colorless crystals of 7-[(2-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxylic acid (136 mg) was obtained.

m. p. 184-186℃¹ H-NMR (200MHz, DMSO-d₆) δ0.99 (3H, t, J=7
．． 5Hz), 1.65-1.81 (2H, m), 2.85-2.94 (2H, m
), 3.01-3.09 (2H, m), 3.62-3.70 (2H, m), 3.
96 (2H, t, J = 6.4Hz), 4.25-4.32 (2H, m), 6.8
3-6.98 (2H, m), 7.12-7.32 (4H, m), 7.72 (1H
, s), 7.92 (1H, d, J=8.8Hz). IR (KBr) 1674, 1588, 1291, 1252, 1167, 1127
cm⁻¹ Elemental analysis C₂₂H₂₄O₆S Calcd. C, 63.44; H, 5.81:
Found. C, 63.06; H, 5.97. Reference Example 130 4-Hydroxybenzyl alcohol (3.00 g), 2-bromoethyl ethyl
A mixture of ether (4.1 ml), potassium carbonate (6.68 g) and DMF (30 ml)
The mixture was stirred at 90°C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water, 1N sodium hydroxide solution and saturated saline, and magnesium sulfate was added.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate).
The compound was separated and purified using a 1:2 → 1:1 mixture of ethanol and hexane to give 4-(2-
Ethoxyethoxy)benzyl alcohol (2.45 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.25 (3H, t, J=7.0
Hz), 1.56 (1H, t, J = 5.4Hz), 3.61 (2H, q, J = 7
．． 0Hz), 3.77-3.82 (2H, m), 4.10-4.15 (2H, m
), 4.62 (2H, d, J = 5.4Hz), 6.92 (2H, d, J = 8.6
Hz), 7.29 (2H, d, J=8.6Hz). IR (neat) 3385, 1613, 1514, 1248, 1175, 111
7,1065 cm⁻¹ Reference Example 131 4-(2-ethoxyethoxy)benzyl alcohol (0.60 g) in toluene
(5 ml) solution was added with thionyl chloride (0.33 ml) and pyridine (1 drop) at room temperature.
) was added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with sodium bicarbonate water and saturated saline, dried over magnesium sulfate, concentrated under reduced pressure,
To a solution of the residue in DMF (10 ml), 7-hydroxy-1,1-dioxo-2,3
- methyl dihydro-1-benzothiepine-4-carboxylate (400 mg) and
Potassium carbonate (414 mg) was added, and the mixture was stirred at 70°C for 3 hours.
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane
The compound was purified by HPLC using a 1:2 ratio of 7-[[4-(2-ethoxy)-2-methyl-2-propanol]-2-one as a pale yellow oil.
Ethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzyl
Methyl benzothiepine-4-carboxylate (0.59 g) was obtained.

7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate methyl ester (0.59
To a solution of 10-5 ml of benzothiepine-4-(2-methyl-2-propanol) in THF-methanol, 1 M aqueous potassium carbonate solution (2.6 ml) was added at room temperature, and the mixture was stirred at 65° C. for 24 hours. 1 M aqueous potassium carbonate solution (1.3 ml) was further added to the reaction system, and the mixture was stirred at 65° C. for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1 N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give pale yellow crystals of 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-(2-methyl-2-propanol)
The carboxylic acid (215 mg) was obtained.

m. p. 256-258℃¹ H-NMR (200MHz, DMSO-d₆) δ1.14 (3H, t, J=7
．． 0Hz), 2.90 (2H, t, J = 6.2Hz), 3.50 (2H, q, J
=7.0Hz), 3.65-3.71 (4H, m), 4.07-4.11 (2H
, m), 5.16 (2H, s), 6.97 (2H, d, J=8.4Hz), 7.
21 (1H, dd, J = 8.8, 2.6Hz), 7.37-7.41 (3H, m
), 7.72 (1H, s), 7.93 (1H, d, J=8.8Hz). IR (KBr) 3073, 1672, 1620, 1595, 1566, 1512
, 1415, 1292, 1269, 1223, 1161, 1128, 1067c
m⁻¹ Elemental analysis C₂₂H₂₄O₇S 0.25H₂O Calcd. C, 60.47
; H, 5.65: Found. C, 60.40; H, 5.62. Reference Example 132 4-Hydroxybenzyl alcohol (3.00 g), 2-bromoethylpropyl
Dimethyl ether (4.0 ml), sodium iodide (4.75 g), potassium carbonate (
A mixture of 6.68 g of methylpropional (C14H2O3) and 30 ml of DMF was stirred at 90° C. for 3 days.
Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate).
The mixture was separated and purified using a 1:2 → 1:1 mixture of ethyl acetate and hexane to give 4-(2-methyl-2-propanol) as a pale yellow oil.
2.27 g of (-propoxyethoxy)benzyl alcohol was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.5
Hz), 1.52-1.69 (3H, m), 3.50 (2H, t, J = 6.8H
z), 3.79 (2H, t, J=4.9Hz), 4.13 (2H, t, J=4.
9Hz), 4.62 (2H, d, J = 6.0Hz), 6.92 (2H, d, J =
8.6Hz), 7.28 (2H, d, J=8.6Hz). IR (neat) 3382, 1613, 1586, 1514, 1456, 130
2, 1246, 1175, 1125, 1065, 1022, 1069, 993,
824 cm⁻¹ Reference Example 133 4-(2-propoxyethoxy)benzyl alcohol (0.63 g) in toluene
A solution of thionyl chloride (0.33 ml) and pyridine (1 ml) was added at room temperature.
Water was added to the reaction mixture, which was then extracted with ethyl acetate.
The organic layer was washed with sodium bicarbonate water and saturated brine, and then dried over magnesium sulfate.
The residue was dissolved in DMF (10 ml) and 7-hydroxy-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg)
and potassium carbonate (414 mg) were added, and the mixture was stirred at 65° C. for 2 hours.
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate
The compound was separated and purified using a 1:2 mixture of 7-[[4-(2-propanediol)-hexane] and 2-[[4-(2-propanediol)-hexane]
(1,1-dioxo-2,3-dihydro)benzyloxy]oxy]-1,1-dioxo-2,3-dihydro
Methyl 1-benzothiepine-4-carboxylate (0.54 g) was obtained.

7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate methyl ester (0.5
To a solution of 4 g of benzothiepine-4-carboxylic acid in THF-methanol (10-5 ml) was added 2.4 ml (2.6 mmol) of 1 M aqueous potassium carbonate solution at room temperature, and the mixture was stirred at 65°C for 20 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. 1 N hydrochloric acid (10 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (321 mg) as pale yellow crystals.

m. p. 244-250℃¹ H-NMR (200MHz, DMSO-d₆) δ0.87 (3H, t, J=7
．． 5Hz), 1.44-1.61 (2H, m), 2.90 (2H, t, J=6.
7Hz), 3.41 (2H, t, J = 6.6Hz), 3.64-3.72 (4H
, m), 4.07-4.12 (2H, m), 5.16 (2H, s), 6.97 (
2H, d, J = 8.4Hz), 7.20 (1H, dd, J = 8.4, 2.4Hz
), 7.37-7.41 (3H, m), 7.72 (1H, s), 7.93 (1H
, d, J=8.4Hz). IR (KBr) 3418, 1688, 1615, 1588, 1566, 1514
,1417,1292,1250,1163,1128cm⁻¹ Elemental analysis C₂₃H₂₆O₇S・0.5H₂O Calcd. C, 60.65;
H, 5.97: Found. C, 60.61; H, 5.75. Reference Example 134 Protocatechualdehyde (4.45 g) was dissolved in dimethylformamide (65 ml).
), and 1-propyl bromide (9.91 g) and potassium carbonate (13.
4 g) was added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and
The organic layer was washed with 1N aqueous sodium hydroxide solution, water, and saturated brine.
The solvent was evaporated under reduced pressure, and the residue was filtered off on a silica gel column.
The product was purified by column chromatography (hexane:ethyl acetate=4:1) to give a yellow oil.
As a result, 3,4-dipropoxybenzaldehyde (6.72 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.06 (3H, t, J=7.5
Hz), 1.07 (3H, t, J=7.4Hz), 1.88 (2H, sexte
t, J=7.1Hz), 1.89, (2H, sextet, J=7.1Hz),
4.03 (2H, t, J = 6.6Hz), 4.05 (2H, t, J = 6.6Hz
), 6.96 (1H, d, J=8.4Hz), 7.40 (1H, s), 7.42
(1H, dd, J = 8.4, 2.0 Hz), 9.83 (1H, s). Reference Example 135 3,4-Dipropoxybenzaldehyde (6.65 g) was dissolved in methanol (90 ml).
) was added, and sodium borohydride (1.13 g) was added at 0° C. The mixture was
The mixture was stirred at 0°C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.
3,4-dipropoxybenzyl alcohol (6.22 g) was obtained as a yellow oil.
Ta.¹ H-NMR (200MHz, CDCl₃) δ1.040 (3H, t, J=7.
5Hz), 1.044 (3H, t, J=7.4Hz), 1.60 (1H, br
s), 1.84 (2H, sextet, J=7.2Hz), 1.85, (2H,
sextet, J = 7.1Hz), 3.96 (2H, t, J = 6.5Hz), 3
．． 98 (2H, t, J=6.6Hz), 4.60 (2H, s), 6.86-6.
93 (3H, m). Reference Example 136 3,4-Dipropoxybenzyl alcohol (673 mg) in toluene (5 ml
) solution was added with thionyl chloride (0.33 ml) and pyridine (1 drop) at room temperature.
The mixture was stirred for 2 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
, washed with saturated brine, and dried over magnesium sulfate.
In a solution of MF (10 ml), 7-hydroxy-1,1-dioxo-2,3-dihydrazine
methyl 1-benzothiepine-4-carboxylate (400 mg) and potassium carbonate
C. for 5 hours. Water was added to the reaction mixture, and acetic acid was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane 1:
2) and purified to give 7-[(3,4-dipropoxy)benzoxy]phenyl ether as a pale yellow oil.
[0033] 1,1-dioxo-2,3-dihydro-1-benzothiepine-
Methyl 4-carboxylate (0.45 g) was obtained.

7-[(3,4-dipropoxy)benzyl]oxy]-1,1-dioxo-2
To a solution of methyl 3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) in THF-methanol (5-2.5 ml) was added 1M aqueous potassium carbonate solution (2.0 ml) at room temperature, and the mixture was stirred at 65° C. for 24 hours. After cooling to room temperature, 1N hydrochloric acid (
The mixture was added with 10 ml of ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 7-[(3,4-dipropoxy)besidyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (306 mg) as colorless crystals.

m. p. 147-150℃¹ H-NMR (200MHz, DMSO-d₆) δ0.98 (6H, t, J=7
．． 6Hz), 1.63-1.81 (4H, m), 2.69-2.93 (2H, m
), 3.64-3.71 (2H, m), 3.92 (2H, t, J = 6.6Hz)
, 3.93 (2H, t, J=6.4Hz), 5.14 (2H, s), 6.90-
7.02 (2H, m), 7.07 (1H, s), 7.20 (1H, dd, J=8
．． 8, 2.6Hz), 7.41 (1H, d, J = 2.6Hz), 7.72 (1H
, s), 7.94 (1H, d, J=8.8Hz). IR (KBr) 3076, 1674, 1593, 1566, 1512, 1294
,1275,1256,1163,1128,1067cm⁻¹ Elemental analysis C₂₄H₂₈O₇S Calcd. C, 62.59; H, 6.13:
Found. C, 62.36; H, 6.14. Reference Example 137 Ethyl vanillin (5.0 g), 2-chloroethyl propyl ether (4.6 m
1), sodium iodide (5.46 g), potassium carbonate (6.23 g) in DMF
(50 ml) The mixture was stirred at 90° C. for 3 days. Water was added to the reaction system, and ethyl acetate was added.
The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and
After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:hexane
1:3) to separate and purify the compound, 3-ethoxy-4-(2-propanol) as a pale yellow oil.
As a result, 7.34 g of (oxyethoxy)benzaldehyde was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.4
Hz), 1.47 (3H, t, J=7.0Hz), 1.53-1.70 (2H,
m), 3.53 (2H, t, J=6.7Hz), 3.86 (2H, t, J=5.
0Hz), 4.14 (2H, q, J = 7.0Hz), 4.26 (2H, t, J =
5.0Hz), 7.02 (1H, d, J = 8.0Hz), 7.40-7.45 (
2H, m), 9.84 (1H, s). IR (neat) 1686, 1586, 1508, 1435, 1395, 126
5,1132,1042cm⁻¹ Reference Example 138 3-Ethoxy-4-(2-propoxyethoxy)benzaldehyde (7.34
g) in methanol (30 ml) at 0° C.
After concentrating under reduced pressure, 1N hydrochloric acid was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
Concentration gave 3-ethoxy-4-(2-propoxyethoxy)benzyl as a colorless oil.
Benzylic alcohol (7.35 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.3
Hz), 1.44 (3H, t, J=6.9Hz), 1.62-1.71 (3H,
m), 3.51 (2H, t, J=6.6Hz), 3.81 (2H, t, J=5.
1Hz), 4.04-4.19 (4H, m), 4.61 (2H, d, J = 5.8
Hz), 6.83-6.94 (3H, m). IR (neat) 3418, 1514, 1427, 1262, 1233, 113
6,1044 cm⁻¹ Reference Example 139 3-Ethoxy-4-(2-propoxyethoxy)benzyl alcohol (0.7
To a solution of 66.6 g of thionyl chloride (0.33 ml) and 10 ml of toluene (5 ml) was added at room temperature.
Pyridine (1 drop) was added and the mixture was stirred for 2 hours. Water was added to the reaction mixture and the mixture was diluted with ethyl acetate.
The organic layer was washed with sodium bicarbonate water and saturated saline, and then dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml) and 7-hydroxy-1,1-
Methyl dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4
00 mg) and potassium carbonate (414 mg) were added, and the mixture was stirred at 70° C. for 2 hours.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and
After concentration under reduced pressure, the residue was purified by column chromatography (
The compound was separated and purified using a 1:2 → 1:1 mixture of ethyl acetate and hexane to give 7 as a pale yellow oil.
-[[3-ethoxy-4-(2-propoxyethoxy)benzyl]oxy]-1
,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid methyl
The obtained product was 0.76 g.

7-[[3-ethoxy-4-(2-propoxyethoxy)benzyl]oxy]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid
A solution of methyl (0.76 g) in THF-methanol (10-5 ml) was added at room temperature.
Aqueous potassium carbonate solution (3.0 ml) was added, and the mixture was stirred at 65° C. for 20 hours.
After cooling to rt, the mixture was extracted with ethyl acetate. 1N hydrochloric acid (10 ml) was added to the aqueous layer, and acetic acid
The organic layer was washed with saturated saline and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration.
The crystals were washed with ether to obtain 7-[[3-ethoxy-4-(2-propoxy)-
(ethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxylic acid (178 mg) was obtained.¹ H-NMR (200MHz, DMSO-d₆) δ0.87 (3H, t, J=7
．． 3Hz), 1.32 (3H, t, J = 7.0Hz), 1.44-1.62 (2
H, m), 2.90 (2H, t, J = 6.2Hz), 3.43 (2H, t, J =
6.6Hz), 3.64-3.71 (4H, m), 3.98-4.10 (4H,
m), 5.14 (2H, s), 6.94-7.01 (2H, m), 7.08 (1
H, s), 7.20 (1H, dd, J = 8.8, 2.6Hz), 7.41 (1H
, d, J=2.6Hz), 7.72 (1H, s), 7.94 (1H, d, J=8
．． 8Hz). IR (KBr) 3422, 1674, 1593, 1568, 1514, 1294
,1258,1163,1128,1065cm⁻¹ Reference Example 140 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (400 mg), 4-propoxyphenylboronic acid (53
6 mg), copper(II) acetate (271 mg), MS (molecular sieves) 4A
(1.0 g) in dichloromethane (15 ml) at room temperature.
(1.04 ml) was added and stirred for 20 hours. After removing insoluble matter by filtration,
The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane 1:1).
: 2) and purified to give 7-(4-propoxyphenoxy) as a pale yellow oil.
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid
Methyl (0.31 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ1.06 (3H, t, J=7.5
Hz), 1.74-1.90 (2H, m), 3.04-3.10 (2H, m),
3.59-3.65 (2H, m), 3.84 (3H, s), 3.94 (2H, t
, J=6.4Hz), 6.91-7.03 (6H, m), 7.70 (1H, s)
, 8.07 (1H, d, J=8.8Hz). IR (neat) 1715, 1590, 1566, 1505, 1472, 143
5, 1323, 1294, 1279, 1240, 1202, 1125, 912,
839,747 cm⁻¹ Reference Example 141 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-
Methyl 1-benzothiepine-4-carboxylate (0.31 g) in THF-methanol
To the solution of 5-2.5 ml of ethanol, 1 M aqueous potassium carbonate solution (1.5 ml) was added at room temperature.
The mixture was stirred at 65°C for 40 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added.
The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
The product was washed with diethyl ether and the resulting pale yellow crystals were 7-(4-propoxyphenoxy)-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (
226 mg) was obtained.

m. p. 192-194℃¹ H-NMR (200MHz, DMSO-d₆) δ1.00 (3H, t, J=7
．． 3Hz), 1.65-1.83 (2H, m), 2.91 (2H, t, J=6.
7Hz), 3.71 (2H, t, J = 6.7Hz), 3.94 (2H, t, J =
6.4Hz), 6.99-7.13 (5H, m), 7.27 (1H, d, J=2
．． 2Hz), 7.66 (1H, s), 7.98 (1H, d, J=8.8Hz).
IR (KBr) 1696, 1508, 1472, 1296, 1242, 1202
, 1127cm⁻¹ Elemental analysis C₂₀H₂₀O₆S・0.5H₂O Calcd. C, 60.44;
H, 5.33: Found, C, 60.43; H, 5.25. Reference Example 142 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (400 mg), 3-propoxyphenylboronic acid (53
6 mg), copper(II) acetate (271 mg), MS4A (0.8 g)
To the mixture was added triethylamine (1.04 ml) at room temperature.
The mixture was stirred for 17 hours, and after removing insoluble matter by filtration, the mixture was concentrated under reduced pressure.
The product was separated and purified by column chromatography (ethyl acetate:hexane 1:2) to obtain a pale yellow
7-(3-propoxyphenoxy)-1,1-dioxo-2,
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) was obtained.
Ta.¹ H-NMR (200MHz, CDCl₃) δ1.04 (3H, t, J=7.3
Hz), 1.72-1.90 (2H, m), 3.05-3.12 (2H, m),
3.59-3.66 (2H, m), 3.84 (3H, s), 3.91 (2H, t
, J=6.6Hz), 6.60-6.66 (2H, m), 6.76-6.82 (
1H, m), 7.04-7.09 (2H, m), 7.26-7.35 (1H, m
), 7.12 (1H, s), 8.11 (1H, d, J=9.0Hz). IR (neat) 1715, 1609, 1586, 1566, 1487, 147
2, 1435, 1321, 1277, 1242, 1215, 1163, 1128
, 748cm⁻¹ Reference Example 143 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-
Methyl 1-benzothiepine-4-carboxylate (0.53 g) in THF-methanol
To a solution of 10-5 ml of ethanol, 1M aqueous potassium carbonate solution (2.6 ml) was added at room temperature.
The mixture was stirred at 65° C. for 40 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added and the mixture was diluted with vinegar.
The organic layer was washed with saturated brine, dried over magnesium sulfate, and
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
Washing with ether gave 7-(3-propoxyphenoxy)-1, which was obtained as pale yellow crystals.
,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (4
12 mg) was obtained.

m. p. 180-181℃¹ H-NMR (200MHz, DMSO-d₆) δ0.97 (3H, t, J=7
．． 3Hz), 1.63-1.82 (2H, m), 2.88-2.95 (2H, m
), 3.69-3.75 (2H, m), 3.93 (2H, t, J = 6.4Hz)
, 6.65-6.76 (2H, m), 6.81-6.85 (1H, m), 7.1
1 (1H, dd, J=8.8, 2.6Hz), 7.31-7.40 (2H, m)
, 7.68 (1H, s), 8.00 (1H, d, J=8.8Hz). IR (KBr) 3068, 1678, 1609, 1586, 1568, 1487
,1283,1242,1159,1128,1036cm⁻¹ Elemental analysis C₂₀H₂₀O₆S Calcd. C, 61.84; H, 5.19:
Found. C, 61.63; H, 5.16. Reference Example 144 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
4-Methyl 4-carboxylate (0.40 g), 4-propylphenylboronic acid (0.4
9 g), copper(II) acetate (0.27 g), MS4A (0.8 g)
To the mixture of 2,000 ml of ethanol and 1.04 ml of triethylamine was added at room temperature.
The mixture was stirred for 10 hours. After removing insoluble matter by filtration, the mixture was concentrated under reduced pressure.
The product was separated and purified by column chromatography (ethyl acetate:hexane 1:2) to give a pale yellow
7-(4-propylphenoxy)-1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (0.40 g) was obtained.
¹H-NMR (200MHz, CDCl₃) δ0.97 (3H, t, J=7.1
Hz), 1.57-1.77 (6H, m), 2.62 (2H, t, J = 7.7H
z), 3.04-3.11 (2H, m), 3.59-3.66 (2H, m), 3
．． 84 (3H, s), 6.96-7.05 (4H, m), 7.23 (2H, d,
J = 8.4Hz), 7.71 (1H, s), 8.09 (1H, d, J = 9.2H
z). IR (neat) 1714, 1586, 1564, 1505, 1323, 129
4,1279,1252,1215,1167,1127,748cm⁻¹ Reference Example 145 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1
- Methyl benzothiepine-4-carboxylate (0.40 g) in THF-methanol
(10-5 ml) solution at room temperature, 1 M potassium carbonate aqueous solution (3.0 ml) was added,
The mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added and acetic acid was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with hexane.
7-(4-propylphenoxy)-1,1-dioxo-2, as pale yellow crystals
,3-dihydro-1-benzothiepine-4-carboxylic acid (254 mg) was obtained.

m. p. 147-149℃¹ H-NMR (200MHz, DMSO-d₆) δ0.93 (3H, t, J=7
．． 4Hz), 1.52-1.71 (2H, m), 2.54-2.62 (2H, m
), 2.88-2.94 (2H, m), 3.68-3.75 (2H, m), 7.
03-7.09 (3H, m), 7.29 (2H, d, J=8.8Hz), 7.3
3 (1H, d, J = 2.6Hz), 7.66 (1H, s), 7.99 (1H, d
, J=8.4Hz), IR (KBr) 1692, 1588, 1566, 1505, 1294, 1254
,1211,1167,1127cm⁻¹ Elemental analysis C₂₀H₂₀O₅S Calcd. C, 64.50; H, 5.41:
Found. C, 64.32; H, 5.21. Reference Example 146 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
methyl 4-carboxylate (0.40 g), 3-ethoxy-4-(2-propoxy
Ethoxy)phenylboronic acid (0.80 g), copper(II) acetate (0.27 g), M
To a mixture of S4A (0.8 g) in dichloromethane (15 ml), triethyl ether was added at room temperature.
Amine (1.04 ml) was added and stirred for 16 hours. Insoluble matter was removed by filtration.
The residue was purified by column chromatography (ethyl acetate:hexane).
The product was purified by elution with 1:2 → 2:3 ethanol (7-[3-ethoxymethyl]-2-methyl-2-propanol) to give a pale yellow oil.
-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (0.45 g) was obtained.
¹H-NMR (200MHz, CDCl₃) δ0.95 (3H, t, J=7.4
Hz), 1.44 (3H, t, J=7.0Hz), 1.56-1.70 (2H,
m), 3.04-3.11 (2H, m), 3.53 (2H, t, J=6.8Hz
), 3.58-3.65 (2H, m), 3.80-3.85 (5H, m), 4.
03 (2H, q, J = 7.0Hz), 4.17-4.22 (2H, m), 6.5
6-6.63 (2H, m), 6.94-7.04 (3H, m), 7.70 (1H
, s), 8.08 (1H, d, J=8.4Hz). IR (neat) 1715, 1588, 1566, 1507, 1480, 132
1,1277,1244,1219,1165,1127cm⁻¹ Reference Example 147 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid methyl ester (
A solution of 0.45 g of the compound in THF-methanol (10 ml) was added to 1 M potassium carbonate at room temperature.
An aqueous solution of ammonium hydroxide (1.8 ml) was added and the mixture was stirred at 65° C. for 20 hours.
After adding 1N hydrochloric acid (10 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
The mixture was concentrated under reduced pressure, and the precipitated crystals were separated by filtration.
The crystals were washed with hexane and collected as pale yellow crystals.
4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-di
Hydro-1-benzothiepine-4-carboxylic acid (283 mg) was obtained.

m. p. 116-118℃¹ H-NMR (200MHz, DMSO-d₆) δ0.88 (3H, t, J=7
．． 5Hz), 1.31 (3H, t, J = 7.0Hz), 1.44-1.62 (2
H, m), 2.85-2.96 (2H, m), 3.44 (2H, t, J = 6.6
Hz), 3.68-3.73 (4H, m), 4.01 (2H, q, J = 7.0H
z), 4.08-4.12 (2H, m), 6.66 (1H, dd, J=8.8,
2.4Hz), 6.82 (1H, d, J = 2.4Hz), 7.01-7.07 (
2H, m), 7.28 (1H, d, J=2.6Hz), 7.66 (1H, s),
7.98 (1H, d, J=8.6Hz). IR (KBr) 3397, 1694, 1593, 1562, 1507, 1291
,1248,1223,1128cm⁻¹ Elemental analysis C₂₄H₂₈O₈S・0.5H₂O Calcd. C, 59.37;
H, 6.02: Found. C, 59.23; H, 6.03. Reference Example 148 2-Bromobenzyl alcohol (10.0 g) in THF (100 ml) was dissolved in
Sodium hydride (60%, 2.35 g) was added at 0°C, and the mixture was stirred at room temperature for 2 hours.
1-Bromopropane (5.8 ml) was added to the reaction mixture, and the mixture was stirred at 60°C for 20 hours.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline.
The extract was concentrated under reduced pressure and the residue was purified by column chromatography.
The compound was purified by distillation with ethyl acetate and hexane (1:9) to give 2-bromo-
Dibenzyl propyl ether (7.88 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.97 (3H, t, J=7.3
Hz), 1.59-1.77 (2H, m), 3.52 (2H, t, J = 6.6H
z), 4.57 (2H, s), 7.09-7.18 (1H, m), 7.28-7
.35 (1H, m), 7.45-7.56 (2H, m). Reference Example 149 Under an argon atmosphere, a mixture of magnesium (0.83 g) and THF (30 ml) was
1,2-dibromoethane (0.1 ml) was added at room temperature, and then the mixture was heated to 60°C for 2
- Bromobenzyl propyl ether (7.88 g) in THF (40 ml)
After the addition, the mixture was stirred at 60°C for another 2 hours and then cooled to -78°C.
The mixture was cooled, and a solution of trimethyl boric acid (12 ml) in THF (24 ml) was added dropwise.
After stirring at 78°C for 1 hour, the mixture was stirred at room temperature for 10 hours.
After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
The mixture was concentrated under reduced pressure, and the precipitated crystals were separated by filtration.
The crystals were washed with hexane and collected as colorless crystals.
Phenylboronic acid (2.95 g) was obtained.¹ H-NMR (200MHz, DMSO-d₆) δ0.88 (3H, t, J=7
．． 3Hz), 1.44-1.63 (2H, m), 3.38 (2H, t, J=6.
6Hz), 4.57 (2H, s), 7.19-7.33 (3H, m), 7.51
(1H, d, J = 6.6 Hz). Reference Example 150 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
-4-Methyl carboxylate (0.40 g), 2-propoxymethylphenylboronic acid
(0.80 g), copper(II) acetate (0.27 g), MS4A (0.8 g)
A mixture of 1.04 ml of triethylamine and 15 ml of chloromethane was added at room temperature.
The mixture was stirred for 20 hours, and insoluble matters were removed by filtration, followed by concentration under reduced pressure.
The residue was separated and purified by column chromatography (ethyl acetate:hexane 1:2).
7-(2-propoxymethylphenoxy)-1,1-diol as a pale yellow oil
Methyl oxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.
13 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.86 (3H, t, J=7.6
Hz), 1.44-1.62 (2H, m), 3.05-3.11 (2H, m),
3.39 (2H, t, J=6.8Hz), 3.59-3.65 (2H, m), 3
．． 84 (3H, s), 4.46 (2H, s), 6.97-7.02 (3H, m)
, 7.35-7.40 (2H, m), 7.58 (1H, dd, J=7.1, 2.
1 Hz), 7.70 (1H, s), 8.09 (1H, d, J = 9.6 Hz). Reference Example 151 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydroxybenzoate
Methyl 1-benzothiepine-4-carboxylate (0.37 g) in THF-methyl
A solution of ethanol (10-5 ml) was added to a 1M aqueous potassium carbonate solution (1.8 ml) at room temperature.
The mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1N hydrochloric acid (10 ml) was added.
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
The product was washed with propyl ether and the resulting pale yellow crystals were 7-(2-propoxymethylphenyl)
(1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate
The carboxylic acid (229 mg) was obtained.

m. p. 139-141℃¹ H-NMR (200MHz, DMSO-d₆) δ0.78 (3H, t, J=7
．． 5Hz), 1.32-1.50 (2H, m), 2.91 (2H, t, J=6.
3Hz), 3.16-3.46 (2H, m), 3.71 (2H, t, J=6.3
Hz), 4.42 (2H, s), 7.00 (1H, dd, J=8.4, 2.6H
z), 7.09-7.14 (1H, m), 7.27 (1H, d, J = 2.6Hz
), 7.31-7.48 (2H, m), 7.55 (1H, dd, J = 7.4, 1
．． 8Hz), 7.65 (1H, s), 7.98 (1H, d, J=8.4Hz). IR (KBr) 1676, 1563, 1296, 1264, 1219, 1123
cm⁻¹ Elemental analysis C₂₁H₂₂O₆S Calcd. C, 62.67; H, 5.51:
Found, C, 62.28; H, 5.79. Example 98 (Preparation of Compound 99) 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-diol
1,3-Dihydro-1-benzothiepine-4-carboxylic acid (136 mg)
In a THF (10 ml) solution, thionyl chloride (0.095 ml) and DMSO were added at room temperature.
F (1 drop) was added and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (
10 ml) and cooled to 0° C.
3-4-yl)amino]methyl]aniline (79 mg) and triethylamine (
THF (2 ml) (0.2 ml) was added dropwise to the solution. After stirring at room temperature for 40 hours,
Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol
The resulting crystals were purified by recrystallization (ethanol).
and purified as colorless crystals.
pyran-4-yl)amino]methyl]phenyl]-7-[[2-(2-propoxy
(ethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (compound 99) (65 mg) was obtained.

m. p. 136-138℃¹ H-NMR (200MHz, CDCl₃) δ0.89 (3H, t, J=7.5
Hz), 1.53-1.77 (6H, m), 2.21 (3H, s), 2.54-
2.74 (1H, m), 3.09 (2H, t, J=6.7Hz), 3.31-3
．． 45 (2H, m), 3.48 (2H, t, J = 6.7Hz), 3.57 (2H
, s), 3.69 (2H, t, J=6.7Hz), 3.78-3.83 (2H,
m), 3.99-4.09 (2H, m), 4.17-4.22 (2H, m), 5
．． 24 (2H, s), 6.91-7.09 (4H, m), 7.22 (1H, s)
, 7.30-7.41 (4H, m), 7.52 (2H, d, J=8.4Hz),
7.89 (1H, s), 8.07 (1H, d, J=8.4Hz). IR (KBr) 3235, 1653, 1636, 1591, 1532, 1514
,1495,1412,1316,1292,1258,1121cm⁻¹ Elemental analysis C₃₆H₄₄N₂O₇S Calcd. C, 66.64; H, 6.8
4;N, 4.32:Found. C, 66.45; H, 6.96; N, 4.22
Example 99 (Preparation of Compound 100) 7-[(4-propoxybenzyl)oxy]-1,1-dioxo-2,3-di
Hydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 m
l) To the solution, thionyl chloride (0.065 ml) and DMF (1 drop) were added at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
and 4-[[N-methyl-N-(tetrahydropyran-4-yl)amine]
[methyl]aniline (108 mg) and triethylamine (0.25 ml)
After stirring at room temperature for 40 hours, water was added and acetic acid was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:1).
: 3), and the resulting crystals were further purified by recrystallization (ethanol).
N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)]]-methyl-N-(tetrahydropyran-4-yl) ...
4-(4-(4-aminomethylphenyl)amino)methylphenyl)-7-[[4-propoxybenzyl)oxy]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide
The resulting product was 139 mg of the diol (compound 100).

m. p. 205-207℃¹ H-NMR (200MHz, CDCl₃) δ1.04 (3H, t, J=7.5
Hz), 1.64-1.87 (6H, m), 2.21 (3H, s), 2.56-
2.73 (1H, m), 3.09 (2H, t, J=7.0Hz), 3.30-3
．． 44 (2H, m), 3.57 (2H, s), 3.69 (2H, t, J = 7.0
Hz), 3.94 (2H, t, J=7.0Hz), 4.00-4.10 (2H,
m), 5.07 (2H, s), 6.93 (2H, d, J=8.8Hz), 6.9
8-7.07 (2H, m), 7.20 (1H, s), 7.31-7.35 (4H
, m), 7.53 (2H, d, J=8.4Hz), 7.83 (1H, s), 8.
09 (1H, d, J=8.4Hz). IR (KBr) 3244, 1653, 1634, 1599, 1514, 1410
,1319,1292,1254,1123cm⁻¹ Elemental analysis C₃₄H₄₀N₂O₆S Calcd. C, 67.53; H, 6.6
7;N, 4.63:Found. C, 67.31; H, 6.72; N, 4.62
Example 100 (Preparation of Compound 101) 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydroxybenzoate
Doro-1-benzothiepine-4-carboxylic acid (130 mg) in THF (10 ml
) solution at room temperature, thionyl chloride (0.045 ml) and DMF (1 drop) were added, and the resulting mixture was
The mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
and 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
]methyl]aniline (80 mg) and triethylamine (0.18 ml)
After stirring at room temperature for 16 hours, water was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:3
) and the resulting crystals were further purified by recrystallization (ethanol) to obtain a colorless
Crystals of 7-[(2-ethoxybenzyl)oxy]-N-[4-[[N-methyl
-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (
Compound 101) (103 mg) was obtained.

m. p. 211-214℃¹ H-NMR (200MHz, CDCl₃) δ1.42 (3H, t, J=7.0
Hz), 1.66-1.83 (4H, m), 2.21 (3H, s), 2.55-
2.74 (1H, m), 3.09 (2H, t, J=6.6Hz), 3.31-3
．． 42 (2H, m), 3.57 (2H, s), 3.69 (2H, t, J = 6.6
Hz), 3.99-4.09 (2H, m), 4.11 (2H, q, J = 7.0H
z), 5.21 (2H, s), 6.89-7.02 (3H, m), 7.08 (1
H, dd, J=8.8, 2.2Hz), 7.22 (1H, s), 7.30-7.
40 (4H, m), 7.53 (2H, d, J = 8.4Hz), 7.84 (1H,
s), 8.08 (1H, d, J=8.8Hz). IR (KBr) 3252, 1655, 1636, 1605, 1590, 1530
, 1497, 1412, 1318, 1292, 1250, 1167, 1121,
1044cm⁻¹ Elemental analysis C₃₃H₃₈N₂O₆S Calcd. C, 67.10; H, 6.4
8; N, 4.74: Found. C, 66.93; H, 6.34; N, 4.70
Example 101 (Preparation of Compound 102) 7-[(2-Methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydroxybenzoate
Doro-1-benzothiepine-4-carboxylic acid (140 mg) in THF (10 ml
) solution at room temperature, thionyl chloride (0.055 ml) and DMF (1 drop) were added, and the resulting mixture was
The mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
and 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
]methyl]aniline (91 mg) and triethylamine (0.21 ml)
After stirring at room temperature for 16 hours, water was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:3
) and the resulting crystals were further purified by recrystallization (ethanol) to obtain a colorless
Crystals of 7-[(2-methoxybenzyl)oxy]-N-[4-[[N-methyl
-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (
Compound 102) (101 mg) was obtained.

m. p. 223-225℃¹ H-NMR (200MHz, CDCl₃) δ1.62-1.82 (4H, m)
, 2.21 (3H, s), 2.55-2.73 (1H, m), 3.09 (2H,
t, J = 6.8Hz), 3.31-3.43 (2H, m), 3.57 (2H, s
), 3.69 (2H, t, J=6.8Hz), 3.88 (3H, s), 3.98
-4.10 (2H, m), 5.19 (2H, s), 6.92-7.02 (3H,
m), 7.07 (1H, dd, J = 8.8, 2.6Hz), 7.21 (1H, s
), 7.30-7.41 (4H, m), 7.53 (2H, d, J = 8.4Hz)
, 7.84 (1H, s), 8.08 (1H, d, J=8.8Hz). IR (KBr) 3256, 1655, 1603, 1590, 1528, 1497
,1412,1318,1292,1254,1167,1121cm⁻¹ Elemental analysis C₃₂H₃₆N₂O₆S Calcd. C, 66.64; H, 6.2
9;N, 4.86:Found. C, 66.41; H, 6.30; N, 4.80
Example 102 (Preparation of Compound 103) 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydrazine
1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml)
To the solution, thionyl chloride (0.070 ml) and DMF (1 drop) were added at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (15 ml).
, 0°C, 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
methyl]aniline (115 mg) and triethylamine (0.26 ml)
After stirring at room temperature for 20 hours, water was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:3
) and the resulting crystals were further purified by recrystallization (ethanol) to obtain a colorless
Crystals of 7-[(2-chlorobenzyl)oxy]-N-[4-[[N-methyl
-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (chemical
Compound 103) (131 mg) was obtained.

m. p. 205-207℃¹ H-NMR (200MHz, CDCl₃) δ1.68-1.83 (4H, m)
, 2.21 (3H, s), 2.55-2.72 (1H, m), 3.10 (2H,
t, J = 6.8Hz), 3.31-3.43 (2H, m), 3.57 (2H, s
). 3.70 (2H, t, J=6.8Hz), 3.98-4.09 (2H, m)
, 5.25 (2H, s), 7.01-7.10 (2H, m), 7.23 (1H,
s), 7.29-7.36 (4H, m), 7.40-7.56 (4H, m), 7
．． 90 (1H, s), 8.11 (1H, d, J=8.8Hz). IR (KBr) 3282, 1657, 1637, 1591, 1530, 1410
,1318,1292,1254,1167,1142,1123cm⁻¹ Elemental analysis C₃₁H₃₃N₂O₅SCl 0.3H₂O Calcd. C, 63
．． 48; H, 5.77; N, 4.78: Found, C, 63.29; H, 5.
73; N, 4.55. Example 103 (Preparation of Compound 104) 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxa
so-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg)
A solution of thionyl chloride (0.061 ml) and DMF was added to a THF (10 ml) solution at room temperature.
(1 drop) was added and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (1
0 ml), and the resulting solution was cooled to 0° C.
4-yl)amino]methyl]aniline (102 mg) and triethylamine (
The mixture was stirred at room temperature for 16 hours.
Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol
The resulting crystals were purified by recrystallization (ethanol).
and purified as colorless crystals, 7-[[2-(2-ethoxyethoxy)benzyl
]oxy]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl
)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzyl
To obtain 109 mg of benzothiepine-4-carboxamide (compound 104).

m. p. 132-136℃¹ H-NMR (200MHz, CDCl₃) δ1.20 (3H, t, J=7.0
Hz), 1.68-1.83 (4H, m), 2.21 (3H, s), 2.56-
2.75 (1H, m), 3.05-3.11 (2H, m), 3.31-3.45
(2H, m), 3.57 (2H, s), 3.59 (2H, q, J=7.0Hz)
, 3.65-3.72 (2H, m), 3.79-3.84 (2H, m), 3.9
9-4.10 (2H, m), 4.17-4.22 (2H, m), 5.25 (2H
, s), 6.90-7.10 (4H, m), 7.23 (1H, s), 7.30-
7.41 (4H, m), 7.53 (2H, d, J = 8.4Hz), 8.02 (1
H, s), 8.07 (1H, d, J=8.4Hz). IR (KBr) 3254, 1655, 1636, 1591, 1530, 1410
,1314,1292,1258,1121cm⁻¹ Elemental analysis C₃₅H₄₂N₂O₇S Calcd. C, 66.22; H, 6.6
7;N, 4.41:Found. C, 65.88; H, 6.56; N, 4.43
Example 104 (Preparation of Compound 105) 7-[(3-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxylic acid (140 mg) in THF (10
To the solution of 1 ml of thionyl chloride (0.049 ml) and 1 drop of DMF were added at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
The solution was dissolved in 4-[[N-methyl-N-(tetrahydropyran-4-yl)
)amino]methyl]aniline (82 mg) and triethylamine (0.19 m
After stirring at room temperature for 16 hours, water was added and the mixture was stirred.
The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate).
The resulting crystals were purified by recrystallization (ethanol).
, N-[4-[[N-methyl-N-(tetrahydropyran-
4-yl)amino]methyl]phenyl]-7-[(3-propoxyphenethyl)
Oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate
Ruboxamide (compound 105) (95 mg) was obtained.

m. p. 153-154℃¹ H-NMR (200MHz, CDCl₃) δ1.04 (3H, t, J=7.3
Hz), 1.67-1.90 (6H, m), 2.21 (3H, s), 2.54-
2.73 (1H, m), 3.02-3.14 (4H, m), 3.29-3.45
(2H, m), 3.57 (2H, s), 3.65-3.71 (2H, m), 3.
92 (2H, t, J=6.5Hz), 3.99-4.09 (2H, m), 4.2
4 (2H, t, J = 7.0Hz), 6.77-6.97 (5H, m), 7.19
(1H, s), 7.23-7.34 (3H, m), 7.53 (2H, d, J=8
．． 4Hz), 7.92 (1H, s), 8.06 (1H, d, J=8.8Hz).
IR (KBr) 3254, 1655, 1634, 1599, 1530, 1410
,1318,1292,1260,1159,1123cm⁻¹ Elemental analysis C₃₅H₄₂N₂O₆S Calcd. C, 67.94; H, 6.8
4;N, 4.53:Found. C, 67.78; H, 6.56; N, 4.39
Example 105 (Preparation of Compound 106) 7-[(2-propoxyphenethyl)oxy]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxylic acid (100 mg) in THF (10
To the solution of 1 ml of thionyl chloride (0.035 ml) and 1 drop of DMF were added at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
The solution was dissolved in 4-[[N-methyl-N-(tetrahydropyran-4-yl)
)amino]methyl]aniline (59 mg) and triethylamine (0.13 m
After stirring at room temperature for 20 hours, water was added and the mixture was stirred.
The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate).
The resulting crystals were purified by recrystallization (ethanol).
, N-[4-[[N-methyl-N-(tetrahydropyran-4
-7-[(2-propoxyphenethyl)amino]methyl]phenyl]- ...
oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-chlor
Voxamide (compound 106) (89 mg) was obtained.

m. p. 161-162℃¹ H-NMR (200MHz, CDCl₃) δ1.06 (3H, t, J=7.5
Hz), 1.63-1.94 (6H, m), 2.21 (3H, s), 2.55-
2.73 (1H, m), 3.05-3.18 (4H, m), 3.29-3.45
(2H, m), 3.57 (2H, s), 3.68 (2H, t, J=6.7Hz)
, 3.97 (2H, t, J=6.4Hz), 3.99-4.09 (2H, m),
4.25 (2H, t, J=7.5Hz), 6.83-7.03 (4H, m), 7
．． 19-7.23 (3H, m), 7.32 (2H, d, J=8.4Hz), 7.
53 (2H, d, J = 8.4Hz), 7.80 (1H, s), 8.06 (1H,
d, J=8.6Hz). IR (KBr) 3268, 1651, 1634, 1599, 1530, 1495
,1410,1316,1291,1256,1240,1121cm⁻¹ Elemental analysis C₃₅H₄₂N₂O₆S Calcd. C, 67.94; H, 6.8
4;N, 4.53:Found. C, 67.72; H, 6.56; N, 4.36
Example 106 (Preparation of Compound 107) 7-[[4-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxa
so-2,3-dihydro-1-benzothiepine-4-carboxylic acid (160 mg)
A solution of thionyl chloride (0.054 ml) and DMF was added to a THF (10 ml) solution at room temperature.
(1 drop) was added and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was
(10 ml) and heated at 0° C. in 4-[[N-methyl-N-(tetrahydropyridine)
(4-(4-methyl-4-yl)amino]methyl]aniline (90 mg) and triethylamine
(0.21 ml) in THF (2 ml). After stirring at room temperature for 3 days,
Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol
The resulting crystals were purified by recrystallization (ethanol).
and purified as colorless crystals.
pyran-4-yl)amino]methyl]phenyl]-7-[[4-(2-ethoxy
Ethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzyl
To obtain 135 mg of benzothiepine-4-carboxamide (compound 107).

m. p. 185-187℃¹ H-NMR (200MHz, CDCl₃) δ1.25 (3H, t, J=7.0
Hz), 1.66-1.82 (4H, m), 2.20 (3H, s), 2.56-
2.73 (1H, m), 3.04-3.11 (2H, m), 3.29-3.44
(2H, m), 3.57 (2H, s), 3.61 (2H, q, J=7.0Hz)
, 3.66-3.72 (2H, m), 3.78-3.83 (2H, m), 3.9
8-4.09 (2H, m), 4.11-4.16 (2H, m), 5.07 (2H
, s), 6.94-7.06 (4H, m), 7.20 (1H, s), 7.29-
7.35 (4H, m), 7.53 (2H, d, J = 8.0Hz), 7.96 (1
H, s), 8.08 (1H, d, J=8.8Hz). IR (KBr) 3227, 1655, 1638, 1597, 1518, 1410
,1314,1292,1254,1123cm⁻¹ Elemental analysis C₃₅H₄₂N₂O₇S Calcd. C, 66.22; H, 6.6
7;N, 4.41:Found. C, 65.95; H, 6.57; N, 4.30
Example 107 (Preparation of Compound 108) 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-diol
1,3-Dihydro-1-benzothiepine-4-carboxylic acid (180 mg)
In a THF (10 ml) solution, thionyl chloride (0.059 ml) and DMSO were added at room temperature.
F (1 drop) was added and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was
F (10 ml), and 4-[[N-methyl-N-(tetrahydropyridine)
(4-yl)amino]methyl]aniline (97 mg) and triethylamino
The mixture was stirred at room temperature for 18 hours.
After that, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol
The resulting crystals were purified from ethanol (ethanol:ethyl acetate 1:3).
and purified by HCl to give N-[4-[[N-methyl-N-(tetrahydrofuran)]] as colorless crystals.
dropyran-4-yl)amino]methyl]phenyl]-7-[[4-(2-pro
(1,1-dioxo-2,3-dihydro-)benzyl]oxy]-1,1-dioxo-2,3-dihydro-
1-Benzothiepine-4-carboxamide (compound 108) (141 mg) was obtained.
Ta.

m. p. 175-176℃¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.3
Hz), 1.56-1.78 (6H, m), 2.20 (3H, s), 2.55-
2.71 (1H, m), 3.05-3.11 (2H, m), 3.30-3.45
(2H, m), 3.50 (2H, t, J=6.7Hz), 3.57 (2H, s)
, 3.66-3.73 (2H, m), 3.77-3.82 (2H, m), 3.9
8-4.09 (2H, m), 4.11-4.16 (2H, m), 5.07 (2H
, s), 6.94-7.07 (4H, m), 7.20 (1H, s), 7.30-
7.51 (4H, m), 7.54 (2H, d, J = 8.4Hz), 7.94 (1
H, s), 8.08 (1H, d, J=8.4Hz). IR (KBr) 3258, 1655, 1636, 1595, 1516, 1410
, 1316, 1292, 1251, 1165, 1123cm⁻¹ Elemental analysis C₃₆H₄₄N₂O₇S Calcd. C, 66.64; H, 6.8
4;N, 4.32:Found. C, 66.78; H, 6.67; N, 4.08
Example 108 (Preparation of Compound 109) 7-[(3,4-dipropoxy)benzyl]oxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF
(10 ml) solution was added with thionyl chloride (0.057 ml) and DMF (1 drop) at room temperature.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (15
ml) and cooled to 0° C.
3-yl)amino]methyl]aniline (95 mg) and triethylamine (0.
The mixture was stirred at room temperature for 20 hours, and then added dropwise to a solution of 22 ml of the filtrate in THF (2 ml).
The organic layer was washed with saturated saline and extracted with magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:acetic acid
The resulting crystals were purified by recrystallization (ethanol).
Purified and obtained as colorless crystals was 7-[(3,4-dipropoxy)benzyl]oxy]
—N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
Methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepi
To obtain 161 mg of methyl-4-carboxamide (compound 109).

m. p. 186-187℃¹ H-NMR (200MHz, CDCl₃) δ1.04 (6H, t, J=7.4
Hz), 1.65-1.93 (8H, m), 2.20 (3H, s), 2.53-
2.71 (1H, m), 3.05-3.12 (2H, m), 3.31-3.44
(2H, m), 3.57 (2H, s), 3.65-3.72 (2H, m), 3.
97 (4H, t, J=6.5Hz), 3.99-4.10 (2H, m), 5.0
5 (2H, s), 6.90-6.99 (4H, m), 7.04 (1H, dd, J
=8.8, 2.6Hz), 7.20 (1H, s), 7.32 (2H, d, J = 8
．． 6Hz), 7.53 (2H, d, J=8.6Hz), 7.84 (1H, s),
8.09 (1H, d, J=8.8Hz). IR (KBr) 3238, 1653, 1634, 1593, 1514, 1410
,1316,1292,1258,1167,1140,1121cm⁻¹ Elemental analysis C₃₇H₄₆N₂O₇S Calcd. C, 67.04; H, 6.9
9;N, 4.23:Found. C, 66.83; H, 6.86; N, 4.31
Example 109 (Preparation of Compound 110) 7-[[3-ethoxy-4-(2-propoxyethoxy)benzyl]oxy]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid
(120 mg) in THF (10 ml) was added to thionyl chloride (0.036
ml) and DMF (1 drop) were added and stirred for 1.5 hours. The solvent was evaporated under reduced pressure.
The residue was then dissolved in THF (10 ml) and cooled to 0° C. with 4-[[N-methyl-N-(
Tetrahydropyran-4-yl)amino]methyl]aniline (58 mg) and
The mixture was added dropwise to a solution of triethylamine (0.13 ml) in THF (2 ml).
After stirring for 20 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
After concentration under reduced pressure, the residue was purified by column chromatography.
The resulting crystals were purified with a solvent (ethanol: ethyl acetate 1:3) and recrystallized.
(ethanol) to obtain 7-[[3-ethoxy-4-(2-methyl-2-propanol)-2-one as pale yellow crystals.
-(2-propoxyethoxy)benzyl]oxy]-N-[4-[[N-methyl
-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (chemical
Compound 110) (47 mg) was obtained.

m. p. 146-147℃¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.3
Hz), 1.44 (3H, t, J=7.0Hz), 1.54-1.81 (6H,
m), 2.22 (3H, s), 2.56-2.76 (1H, m), 3.05-3
．． 12 (2H, m), 3.30-3.44 (2H, m), 3.52 (2H, t,
J=6.8Hz), 3.59 (2H, s), 3.65-3.72 (2H, m),
3.82 (2H, t, J=5.2Hz), 3.98-4.12 (4H, m), 4
．． 18 (2H, t, J=5.2Hz), 5.06 (2H, s), 6.94-7.
07 (5H, m), 7.21 (1H, s) 17.33 (2H, d, J = 8.2H
z), 7.53 (2H, d, J=8.2Hz), 7.81 (1H, s), 8.0
9 (1H, d, J=8.4Hz). IR (KBr) 3115, 1653, 1595, 1514, 1410, 1316
,1291,1260,1123cm⁻¹ Elemental analysis C₃₈H₄₈N₂O₈S・1.0H₂O Calcd, C, 64.2
0; H, 7.09; N, 3.94: Found. C, 64.47; H, 6.86
N, 3.99 Example 110 (Preparation of Compound 111) 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-
A solution of 1-benzothiepine-4-carboxylic acid (110 mg) in THF (10 ml)
Thionyl chloride (0.041 ml) and DMF (1 drop) were added to the mixture at room temperature and the mixture was stirred for 1 hour.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml) and
4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]
A solution of [ethyl]aniline (69 mg) and triethylamine (0.16 ml) in THF (
After stirring at room temperature for 20 hours, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over magnesium sulfate.
After condensation, the residue was purified by column chromatography (ethanol: ethyl acetate 1:3).
The resulting crystals were purified by recrystallization (ethanol) to give colorless crystals.
and N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino
]methyl]phenyl]-7-(4-propoxyphenoxy)-1,1-dioxo
-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 111
) (68 mg) was obtained.

m. p. 139-141℃¹ H-NMR (200MHz, CDCl₃) δ1.05 (3H, t, J=7.3
Hz), 1.61-1.88 (6H, m), 2.20 (3H, s), 2.53-
2.72 (1H, m), 3.10 (2H, t, J=6.8Hz), 3.30-3
．． 46 (2H, m), 3.57 (2H, s), 3.70 (2H, t, J = 6.8
Hz), 3.93 (2H, t, J=6.6Hz), 3.99-4.10 (2H,
m), 6.91-7.04 (6H, m), 7.15 (1H, s), 7.31 (2
H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.86
(1H, s), 8.08 (1H, d, J=8.8Hz). IR (KBr) 3262, 1649, 1601, 1534, 1503, 1410
,1318,1308,1294,1236,1204,1125cm⁻¹ Elemental analysis C₃₃H₃₈N₂O₆S Calcd. C, 67.10; H, 6.4
8; N, 4.74: Found. C, 66.99; H, 6.38; N, 4.71
Example 111 (Preparation of Compound 112) 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-
A solution of 1-benzothiepine-4-carboxylic acid (200 mg) in THF (10 ml)
To the mixture, thionyl chloride (0.075 ml) and DMF (1 drop) were added at room temperature to obtain a 1.5
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
, 0°C, 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
methyl]aniline (124 mg) and triethylamine (0.28 ml)
After stirring at room temperature for 67 hours, water was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:3
) and the resulting crystals were further purified by recrystallization (ethanol) to obtain a colorless
Crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)
amino]methyl]phenyl]-7-(3-propoxyphenoxy)-1,1-di
Oxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound
112) (146 mg) was obtained.

m. p. 143-144℃¹ H-NMR (200MHz, CDCl₃) δ1.04 (3H, t, J=7.3
Hz), 1.67-1.89 (6H, m), 2.20 (3H, s), 2.54-
2.70 (1H, m), 3.08-3.14 (2H, m), 3.30-3.43
(2H, m), 3.56 (2H, s), 3.67-3.74 (2H, m), 3.
91 (2H, t, J=6.6Hz), 3.98-4.08 (2H, m), 6.6
2-6.66 (2H, m), 6.78 (1H, dd, J=9.0, 2.2Hz)
, 6.97 (1H, d, J = 2.2Hz), 7.06 (1H, dd, J = 8.8
, 2.2Hz), 7.16 (1H, s), 7.29-7.50 (3H, m), 7
．． 51 (2H, d, J = 8.4Hz), 7.88 (1H, s), 8.10 (1H
, d, J=8.8Hz). IR (KBr) 3241, 1651, 1630, 1599, 1563, 1530
, 1473, 1410, 1319, 1294, 1267, 1165, 1138,
1125cm⁻¹ Elemental analysis C₃₃H₃₈N₂O₆S Calcd. C, 67.10; H, 6.4
8; N, 4.74: Found. C, 67.34; H, 6.50; N, 4.88
Example 112 (Preparation of Compound 113) 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1
-Benzothiepin-4-carboxylic acid (150 mg) in THF (10 ml)
Thionyl chloride (0.059 ml) and DMF (1 drop) were added at room temperature and the mixture was stirred for 1.5 hours.
The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (10 ml).
At 0°C, 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]
[ethyl]aniline (97 mg) and triethylamine (0.22 ml) in THF
After stirring at room temperature for 13 hours, water was added and the mixture was diluted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration, the residue was purified by column chromatography (ethanol:ethyl acetate 1:3).
The resulting crystals are purified by recrystallization (ethanol) to give colorless crystals.
N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amine
methylphenyl]-7-(4-propylphenoxy)-1,1-dioxo
-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 113
) (124 mg) was obtained.

m. p. 147-149℃¹ H-NMR (200MHz, CDCl₃) δ0.97 (3H, t, J=6.8
Hz), 1.57-1.81 (6H, m), 2.20 (3H, s), 2.55-
2.73 (3H, m), 3.07-3.14 (2H, m), 3.29-3.44
(2H, m), 3.57 (2H, s), 3.67-3.74 (2H, m), 3.
98-4.10 (2H, m), 6.95-7.06 (4H, m), 7.15 (1
H, s), 7.23 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J =
8.4Hz), 7.51 (2H, d, J=8.4Hz), 7.88 (1H, s)
, 8.09 (1H, d, J=8.4Hz). IR (KBr) 3289, 1651, 1597, 1566, 1507, 1410
,1318,1294,1254,1206,1140,1121cm⁻¹ Elemental analysis C₃₃H₃₈N₂O₅S Calcd. C, 68.96; H, 6.6
6;N, 4.87:Found. C, 69.22; H, 6.48; N, 4.93
Example 113 (Preparation of Compound 114) 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1
-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180
To a solution of 100 mg of thionyl chloride (0.055 ml) and
The solvent was evaporated under reduced pressure, and the residue was
was dissolved in THF (10 ml) and heated at 0°C to give 4-[[N-methyl-N-(tetrahydrofuran)
(dropyran-4-yl)amino]methyl]aniline (92 mg) and triethyl
The mixture was stirred at room temperature for 4 hours.
After stirring, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and diluted with sulfuric acid.
After concentration under reduced pressure, the residue was purified by column chromatography (
The resulting crystals were purified with a mixture of ethanol and ethyl acetate (1:3).
The compound was purified by filtration and obtained as colorless crystals of 7-[3-ethoxy-4-(2-propanol)].
(ethoxy)phenoxy]-N-[4-[[N-methyl-N-(tetrahydro
pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (compound 114) (140
mg) was obtained.

m. p. 159-160℃¹ H-NMR (200MHz, CDCl₃) δ0.94 (3H, t, J=7.4
Hz), 1.44 (3H, t, J=7.0Hz), 1.50-1.83 (6H,
m), 2.20 (3H, s), 2.54-2.75 (1H, m), 3.07-3
．． 14 (2H, m), 3.30-3.43 (2H, m), 3.52 (2H, t,
J=6.7Hz), 3.57 (2H, s), 3.66-3.73 (2H, m),
3.82 (2H, t, J=5.0Hz), 3.98-4.08 (4H, m), 4
．． 18 (2H, t, J=5.0Hz), 6.57-6.63 (2H, m), 6.
91-7.04 (3H, m), 7.15 (1H, s), 7.31 (2H, d, J
= 8.3Hz), 7.52 (2H, d, J = 8.3Hz), 7.91 (1H, s
), 8.09 (1H, d, J = 8.8Hz). IR (KBr) 3310, 1655, 1601, 1534, 1508, 1408
,1312,1250,1219,1169,1140,1125cm⁻¹ Elemental analysis C₃₇H₄₆N₂O₈S 0.25H₂O Calcd. C, 65.
03; H, 6.86; N, 4.10: Found. C, 65.05; H, 6.9
4; N, 4.03. Example 114 (Preparation of Compound 115) 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydroxybenzoate
Doro-1-benzothiepine-4-carboxylic acid (150 mg) in THF (10 ml
) solution at room temperature, thionyl chloride (0.054 ml) and DMF (1 drop) were added, and the resulting mixture was
The mixture was stirred for 1.5 hours. After the solvent was removed under reduced pressure, the residue was dissolved in THF (10 ml).
The mixture was dissolved in 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]-
[amino]methyl]aniline (90 mg) and triethylamine (0.21 ml)
After stirring at room temperature for 20 hours, water was added and acetic acid was added.
The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol:ethyl acetate 1:1).
: 3), and the resulting crystals were further purified by recrystallization (ethanol).
N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)]]-methyl-N-(tetrahydropyran-4-yl) ...
-(2-propoxymethylphenoxy)-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamine
Compound 115 (130 mg) was obtained.

m. p. 162-164℃¹ H-NMR (200MHz, CDCl₃) δ0.86 (3H, t, J=7.5
Hz), 1.45-1.80 (6H, m), 2.20 (3H, s), 2.55-
2.72 (1H, m), 3.08-3.15 (2H, m), 3.30-3.42
(4H, m), 3.57 (2H, s), 3.67-3.74 (2H, m), 3.
99-4.11 (2H, m), 4.47 (2H, s), 6.92 (1H, d, J
=2.6Hz), 6.99-7.03 (2H, m), 7.14 (1H, s), 7
．． 24-7.40 (4H, m), 7.48-7.61 (3H, m), 7.74 (
1H, s), 8.10 (1H, d, J=8.8Hz). IR (KBr) 3329, 1646, 1626, 1599, 1562, 1531
,1512,1411,1314,1259,1159,1125cm⁻¹ Elemental analysis C₃₄H₄₀N₂O₆S Calcd, C, 67.53; H, 6.6
7;N, 4.63:Found. C, 67.25; H, 6.81; N, 4.51
Reference Example 152 3-methyl-4-propoxyethoxyphenylboronic acid (710 mg), 7-hydroxybenzoic acid
Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate
Methyl carboxylate (400 mg), cupric acetate (270 mg) were dissolved in dichloromethane (
The salt was suspended in 1.5 ml of water, and triethylamine (1.04 ml) was added thereto.
After stirring for one day with a calcium chloride tube attached, celite was added and insoluble matter was filtered off.
The liquid was concentrated and purified by silica gel column chromatography to give a brown oil.
7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-di
Methyl oxo-2,3-dihydro-1-benzothiepine-4-carboxylate (47
5 mg) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.95 (t, 3H, J=7.4
Hz), 1.55-1.70 (m, 2H), 2.25 (s, 3H), 3.07 (
t, 2H, J=7.2Hz), 3.53 (t, 2H, J=6.6Hz), 3.6
2 (t, 2H, J=5.8Hz), 3.80-3.85 (m, 5H), 4.15
(t, 2H, J=4.8Hz), 6.85-6.86 (m, 3H), 6.95-
7.02 (m, 2H), 7.70 (s, 1H), 8.07 (d, 1H, J=8.
2 Hz). Reference Example 153 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-
Methyl dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4
70 mg) in a mixture of tetrahydrofuran (10 ml) and methanol (5 ml).
A 1N aqueous solution of potassium carbonate (2.9 ml) was added to the solution, and the mixture was heated at 65°C for one day.
After cooling, water was added to the mixture and it was acidified with 1N hydrochloric acid (pH = 4).
The organic layer was washed with water and saturated brine, and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure to give 7-[3-methyl-4-(2-
propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1
-benzothiepine-4-carboxylic acid (375 mg) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.95 (t, 3H, J=7.4
Hz), 1.60-1.70 (m, 2H), 2.25 (s, 3H), 3.09 (
t, 2H, J=6.6Hz), 3.54 (t, 2H, J=6.6Hz), 3.6
3 (t, 2H, J = 6.2Hz), 3.83 (t, 2H, J = 5.2Hz), 4
．． 15 (t, 2H, J=4.8Hz), 6.85-6.86 (m, 3H), 6.
98-7.02 (m, 2H), 7.79 (s, 1H), 8.09 (d, 1H, J
= 8.8 Hz). Example 115 (Preparation of Compound 116) 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (370 m
g) was dissolved in tetrahydrofuran (10 ml) and DMF (0.1 ml) was added.
Then, thionyl chloride (196 mg) was added at 0°C, and the mixture was heated at room temperature under nitrogen
The mixture was stirred under nitrogen atmosphere for 1.5 hours. The solvent and excess thionyl chloride were removed under reduced pressure.
The residue obtained by evaporation was dissolved in tetrahydrofuran (10 ml) and 4-[[
N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline
(201 mg), triethylamine (185 mg) in tetrahydrofuran (10
The mixture was allowed to return to room temperature and stirred overnight, after which water was added and
The organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography.
It was separated and purified by hexane/ethyl acetate and recrystallized to obtain colorless crystals (chemical compound).
Compound 116) (94 mg) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.94 (t, 3H, J=6.2
Hz), 1.60-1.80 (m, 6H), 2.20 (s, 3H), 2.25 (
s, 3H), 2.64 (br, 1H), 3.10 (t, 2H, J=7.2Hz)
, 3.36 (dt, 2H, J=11.0, 2.2Hz), 3.52 (t, 2H,
J=6.6Hz), 3.57(s, 2H), 3.70(t, 2H, J=7.4H
z), 3.81 (t, 2H, J = 5.6Hz), 4.04 (d, 2H, J = 11
．． 8Hz), 4.14 (t, 2H, J=5.2Hz), 6.86-6.90 (m
, 4H), 6.99 (dd, 2H, J=9.2, 2.2Hz), 7.14 (s,
1H), 7.31 (d, 2H, J = 8.2Hz), 7.51 (d, 2H, J = 8
．． 4Hz), 7.87 (s, 1H), 8.08 (d, 1H, J=8.8Hz).
Elemental analysis C₃₆H₄₄N₂O₇S Calcd. C, 66.64; H, 6.8
4;N, 4.32:Found. C, 66.59; H, 6.76; N, 4.27
. Reference Example 154 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (400 mg), 3-methoxybenzyl chloride (35
60 mg) and potassium carbonate (412 mg) were suspended in DMF (15 ml), and
The mixture was stirred for 13 hours at 0° C. The reaction mixture was diluted with ethyl acetate, and water and saturated brine were added.
The organic layer was dried over anhydrous magnesium sulfate.
The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4
hexane:ethyl acetate = 3:1) to obtain 7-(3-methoxybenzyl
oxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-chlor
Methyl benzoate (459 mg) was obtained as a pale yellow amorphous substance.¹ H NMR (200MHz, CDCl₃) δ3.06 (2H, t, J=6.6
Hz), 3.61 (2H, t, J=7.0Hz), 3.83 (3H, s), 3.
85 (3H, s), 5.13 (2H, s), 6.87-7.02 (4H, m),
7.06 (1H, s), 7.32 (1H, t, J = 7.7Hz), 7.77 (1
H, s), 8.08 (1H, d, J=8.4Hz). IR (KBr) 1713, 1590, 1493, 1321, 1292, 1269
,1246,1217,1163,1128cm⁻¹. Reference Example 155 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-
Methyl 1-benzothiepine-4-carboxylate (436 mg) was dissolved in THF-methanol.
The solution was dissolved in 10-5 ml of ethanol, and 2 M aqueous potassium carbonate solution (1.2 ml) was added.
The mixture was stirred at 60° C. for 14.5 hours. The reaction mixture was treated with 1N hydrochloric acid to adjust the pH to
The mixture was diluted with ethyl acetate and washed with water and saturated brine.
The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with hexane.
Rinse with ethanol and ethyl acetate, and
so-2,3-dihydro-1-benzothiepine-4-carboxylic acid (271 mg)
Obtained as white crystals.

mp 220-222℃. ^1H NMR (200MHz, DMSO- _d6 ) δ2.91 (2H, t-lik
e), 3.69 (2H, t, J=6.2Hz), 3.77 (3H, s), 5.2
3 (2H, s), 6.90-6.94 (1H, m), 7.05 (2H, s, d-
like), 7.20-7.43 (3H, m), 7.72 (1H, s), 7.9
5 (1H, d, J=8.8Hz). IR (KBr) 1684, 1597, 1564, 1493, 1454, 1285
, 1256, 1173, 1130, 1073 ^{, 1032, 772 cm −1} . Anal. Calcd. for C ₁₉ H ₁₈ O ₆ S: C, 60.95; H, 4
. 85. Found: C, 60.70; H, 4.94. Example 116 (Preparation of Compound 117) 7-(3-Methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-
1-Benzothiepine-4-carboxylic acid (204 mg) was suspended in THF (10 ml), and DMF (1 drop) and thionyl chloride (0.079 ml) were added, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred for 1 hour, concentrated under reduced pressure, and dissolved in THF (10 ml). 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline dihydrochloride (192 mg) was suspended in THF (10 ml), and triethylamine (0.5
7 ml) was added dropwise to the mixture, followed by the dropwise addition of the THF solution of the acid chloride prepared above at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and ethyl acetate was added. The mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate:ethanol = 10:1), and further recrystallized from ethanol.
7-(3-Methoxybenzyloxy)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2
, 3-dihydro-1-benzothiepine-4-carboxamide (compound 117)
217 mg) was obtained as pale yellow crystals.

mp 181-185℃. ^1H NMR (200MHz, _CDCl3 ) δ1.69-1.77 (4H, m)
, 2.21 (3H, s), 2.57-2.69 (1H, m), 3.09 (2H,
t, J = 6.6Hz), 3.37 (2H, td, J = 11.1, 3.3Hz),
3.57 (2H, s), 3.69 (2H, t, J=6.8Hz), 3.83 (3
H, s), 4.01-4.07 (2H, m), 5.13 (2H, s), 6.87
-7.07 (5H, m), 7.20 (1H, s), 7.29-7.37 (3H,
m), 7.53 (2H, d, J=8.8Hz), 7.81 (1H, s), 8.0
9 (1H, d, J=8.4Hz). IR (KBr) 1667, 1597, 1566, 1522, 1491, 1410
, 1314, 1287, 1267, 1163, 1142, 1127, 1065,
737 cm ⁻¹ . Anal. Calcd. _{for C32H36N2O6S ( 0.4H2O} ): _C
, 65.82; H, 6.35; N, 4.80. Found: C, 65.76; H
, 6.33; N, 4.50. Reference Example 156: 3-Hydroxybenzyl alcohol (3.56 g) was dissolved in acetone (100 ml).
Add iodoethane (6.7 g) and potassium carbonate (7.9 g) and add 61
The mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, and ethyl acetate was added. The mixture was washed successively with water, a 1N aqueous solution of sodium hydroxide, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 3-ethoxybenzyl alcohol (4.15) as an oil. ^1H NMR (200 MHz, _CDCl3 ) δ 1.42 (3H, t, J = 7.0
Hz), 1.69-1.73 (1H, m), 4.05 (2H, q, J = 6.9H
z), 4.67 (2H, d, J = 5.8Hz), 6.83 (1H, dd, J = 8
．． 2, 2.6Hz), 6.91-6.95 (2H, m), 7.27 (1H, t,
J = 8.1 Hz). Reference Example 157: Toluene (50 ml) was added to 3-ethoxybenzyl alcohol (4.15 g), and then one drop of pyridine and thionyl chloride (3.0 ml) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-ethoxybenzyl chloride (5.34 g) as an oil.

7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate methyl (400 mg), the above 3-ethoxybenzyl chloride (
A suspension of 7-(3-ethoxybenzyloxy)-1,1-dioxo-2-(2-methyl-2-propanol)-1,1-diol (636 mg) and potassium carbonate (515 mg) in DMF (15 ml) was stirred at 60° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 7-(3-ethoxybenzyloxy)-1,1-dioxo-2-(2-methyl-2-propanol ...).
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (308 mg)
was obtained as a yellow amorphous solid. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.43 (3H, t, J = 7.2
Hz), 3.07 (2H, t, J = 6.6Hz), 3.61 (2H, t, J = 6
．． 7Hz), 3.86 (3H, s), 4.05 (2H, q, J=7.2Hz),
5.13 (2H, s), 6.91-7.06 (4H, m), 7.24-7.31
(2H, m), 7.77 (1H, s), 8.08 (1H, d, J=8.4Hz)
．． IR (KBr) 1713, 1590, 1289, 1267, 1215, 1163
, 1128 cm ⁻¹ . Reference Example 158 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-
Methyl 1-benzothiepine-4-carboxylate (298 mg) was dissolved in THF-methanol (10.5 ml), and 2M aqueous potassium carbonate solution (0.75 ml) was added, followed by stirring at 60° C. for 16.5 hours. The reaction mixture was treated with 1N hydrochloric acid to adjust its pH.
The resultant was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the precipitated crystals were rinsed with hexane-ethyl acetate to give 7-(3
The mother liquor was purified under reduced pressure to give (1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid) (45 mg) as white crystals.
Concentration gave 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (340 mg) as a brown oil, which was used in the next reaction without further purification.

mp 150-154℃. ^1H NMR (200MHz, DMSO- _d6 ) δ1.33 (3H, t, J=7
．． 0Hz), 2.90 (2H, t, J = 6.2Hz), 3.67 (2H, t, J
= 6.7Hz), 4.03 (2H, q, J = 7.1Hz), 5.21 (2H, s
), 6.86-6.91 (1H, m), 6.99-7.02 (2H, m), 7.
21 (1H, d, J = 8.8Hz), 7.30 (1H, t, J = 8.0Hz),
7.41 (1H, d-like), 7.72 (1H, s), 7.94 (1H, d-like)
, J=8.8Hz). IR (KBr) 1692, 1588, 1292, 1277, 1258, 1159
, 1127 cm ⁻¹ . Anal. Calcd. for _{C20H20O6S ( 0.2H2O} ):C, ₆
1.27; H, 5.19. Found: C, 61.06; H, 5.26. Example 117 (Preparation of Compound 118) 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-
1-Benzothiepine-4-carboxylic acid (250 mg) was suspended in THF (10 ml), and DMF (1 drop) and thionyl chloride (0.090 ml) were added, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (10 ml).
N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline dihydrochloride (226 mg) was suspended in THF (5.0 ml), and triethylamine (0.67 ml) was added dropwise. Then, the THF solution of the acid chloride prepared above was added dropwise.
The mixture was stirred at 0°C for 20 minutes and at room temperature for 16 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate:ethanol = 10:1), and further recrystallized from ethanol to give 7-(3-ethoxybenzyloxy)-N-[4-[
[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 118) (71 mg) was obtained as white crystals.

mp 189-192℃. ^1H NMR (200MHz, _CDCl3 ) δ1.42 (3H, t, J=6.9
Hz), 1.60-1.75 (4H, m), 2.21 (3H, s), 2.60-
2.69 (1H, m), 3.08 (2H, t, J = 6.8Hz), 3.37 (2
H, td, J = 11.2, 3.1Hz), 3.57 (2H, s), 3.68 (2
H, t, J = 6.8Hz), 4.04 (2H, q, J = 7.0Hz), 3.99
-4.10 (2H, m), 5.12 (2H, s), 6.86-7.06 (5H,
m), 7.20 (1H, s), 7.29-7.34 (3H, m), 7.53 (2
H, d, J = 8.4Hz), 7.85 (1H, s), 8.08 (1H, d, J =
8.4Hz). IR (KBr) 1663, 1597, 1566, 1410, 1291, 1264
, 1163, 1142, 1125 ^{, 1065, 735 cm −1} . Anal. Calcd. _{for C33H38N2O6S ( 0.3H2O} ): _C
,66.49;H,6.53;N,4.70,Found:C,66.29;H
, 6.42; N, 4.47. Reference Example 159 Salicylic aldehyde (12.2 g) was dissolved in DMF (100 ml) to give 1-
Bromopropane (14.7 g) and potassium carbonate (20.7 g) were added, and the mixture was stirred at room temperature for 21.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and 2-
Propoxybenzaldehyde (15.47 g) was obtained as an oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.08 (3H, t, J = 7.3
Hz), 1.89 (2H, sextet, J=7.0Hz), 4.05 (2H,
t, J=6.4Hz), 6.96-7.05 (2H, m), 7.54 (1H, t
d, J = 7.9, 1.9Hz), 7.84 (1H, dd, J = 7.6, 1.8H
z), 10.53 (1H, s). Reference Example 160: 2-Propoxybenzaldehyde (15.47 g) and methyl (triphenylphosphoranylidene)acetate (36.1 g) were suspended in toluene (150 ml) and heated under reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated triphenylphosphine oxide was removed and washed with ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give ethyl 2-propoxycinnamate (21.24 g).
was obtained as a yellow oil. ¹ H NMR (200 MHz, CDCl ₃ , ratio; ca. 5:1) δ 1.
03 (0.5H, t, J = 7.5Hz), 1.08 (2.5H, t, J = 7.5
Hz), 1.21 (0.5H, t, J=7.1Hz), 1.34 (2.5H, t
, J=7.1Hz), 1.85 and 1.89(2H, each sex
et, J=7.1Hz), 3.94 (0.33H, t, J=6.4Hz), 4.
00 (1.67H, t, J = 6.6Hz), 4.14 (0.33H, q, J = 7
．． 4Hz), 4.26 (1.67H, q, J = 7.2Hz), 5.95 (0.1
7H, d, J = 12.4Hz), 6.54 (0.83H, d, J = 16.2Hz
), 6.85 (0.17H, d, J=8.4Hz), 6.90 (0.83H, d
, J=9.2Hz), 6.94 (1H, t, J=7.1Hz), 7.00 (0.
17H, d, J = 12.8Hz), 7.32 (1H, td, J = 7.8, 1.6
Hz), 7.51 (0.83H, dd, J=7.5, 1.7Hz), 7.58 (
0.17H, dd, J = 7.5, 1.7Hz), 8.02 (0.83H, d, J
= 16.6 Hz). Reference Example 161 Lithium aluminum hydride (6.87 g) was suspended in ether (300 ml), and the suspension was added to an ether solution (100 ml) of ethyl 2-propoxycinnamate (21.2 g).
To the reaction mixture was added dropwise water (7 ml), 15% aqueous sodium hydroxide solution (7 ml), and water (21 ml) over 40 minutes at 0°C. After the addition, the mixture was stirred at room temperature for 1 hour.
The reaction mixture was diluted with ether, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-
(2-Propoxyphenyl)-1-propanol (17.01 g) was obtained as a colorless oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.3
Hz), 1.75-1.93 (4H, m), 2.75 (2H, t, J = 7.1H
z), 3.60 (2H, q, J=5.7Hz), 3.95 (2H, t, J=6.
4Hz), 6.83-6.92 (2H, m), 7.13-7.24 (2H, m)
Reference Example 162 3-(2-propoxyphenyl)-1-propanol (729 mg) was added to THE
(35 ml), and triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml) were added at 0°C. The mixture was stirred at 0°C for 20 minutes and at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) as a colorless oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.5
Hz), 1.83 (2H, sextet, J=7.0Hz), 2.07 (2H,
quint, J=6.9Hz), 2.76 (2H, t, J=7.3Hz), 2.
98 (3H, s), 3.93 (2H, t, J=6.4Hz), 4.24 (2H,
t, J=6.6Hz), 6.82-6.91 (2H, m), 7.11-7.22
(2H, m). Reference Example 163: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) and potassium carbonate (309 mg) were dissolved in DMF.
(15 ml) and stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and 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 (
Purification with hexane:ethyl acetate (3:1) gave methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) as a yellow oil.

7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) was dissolved in THF-methanol (15-7.5 ml), 2M aqueous potassium carbonate solution (1.5 ml) was added, and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was treated with 1N hydrochloric acid to adjust the pH to 2. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the precipitated crystals were rinsed with hexane-ethyl acetate to give 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (474 mg) as white crystals.

mp 153-157℃. ^1H NMR (200MHz, DMSO- _d6 ) δ0.98 (3H, t, J=7
．． 3Hz), 1.70 (2H, sextet, J=6.9Hz), 2.00 (2
H, quint-like), 2.72 (2H, t, J = 7.6Hz), 2.9
0 (2H, t, J = 6.4Hz), 3.67 (2H, t, J = 6.6Hz), 3
．． 90 (2H, t, J=6.3Hz), 4.11 (2H, t, J=6.3Hz)
, 6.84 (1H, t, J = 7.3Hz), 6.92 (1H, d, J = 7.2H
z), 7.09-7.19 (3H, m), 7.30 (1H, d, J = 2.2Hz
), 7.72 (1H, s), 7.92 (1H, d, J=8.8Hz), . IR (KBr) 1674, 1597, 1566, 1493, 1454, 1319
, 1296, 1279, 1251, 1167, 1130, 1071, 747, 5
27 cm ⁻¹ . Anal. Calcd. for _{C23H26O6S ( 0.4H2O} ):C, ₆
3.11: H, 6.17. Found: C, 62.92; H, 6.37. Example 118 (Preparation of Compound 119) 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (504 mg) in THF
(20 ml), DMF (1 drop) and thionyl chloride (0.17 ml) were added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (25 ml). 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline dihydrochloride (412 mg) was suspended in THF (12 ml), and triethylamine (1.22 ml) was added dropwise. Then, the T
The HF solution was added dropwise at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the solid residue was recrystallized from ethanol.
N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[3-(2-propoxyphenyl)propoxy]-1,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (
Compound 119) (469 mg) was obtained as white crystals.

mp 184-186℃. ^1H NMR (200MHz, _CDCl3 ) δ1.05 (3H, t, J=7.5
Hz), 1.64-1.82 (4H, m), 1.80 (2H, sextet, J
=7.1Hz), 2.12(2H, quint, J=7.3Hz), 2.21(
3H, s), 2.57-2.72 (1H, m), 2.82 (2H, t, J=7.
3Hz), 3.08 (2H, t, J = 6.6Hz), 3.37 (2H, td, J
= 11.2, 3.0Hz), 3.58 (2H, s), 3.68 (2H, t, J =
6.8Hz), 3.92 (2H, t, J=6.4Hz), 4.00-4.07 (
2H, m), 4.03 (2H, t, J = 6.4Hz), 6.82-6.96 (4
H, m), 7.11-7.22 (3H, m), 7.32 (2H, d, J = 8.4
Hz), 7.54 (2H, d, J=8.4Hz), 7.84 (1H, s), 8.
06 (1H, d, J=8.8Hz). IR (KBr) 2940 1667, 1595, 1522, 1493, 1454
, 1410, 1291, 1260, 1242, 1163, 1125, 1065,
754,735 cm ⁻¹ . Anal. Calcd. _{for C36H44N2O6S ( 0.1H2O} ): _C
, 68.13; H, 7.02; N, 4.41. Found: C, 67.93; H
, 7.02; N, 4.24. Reference Example 164: 3-Hydroxybenzaldehyde (12.2 g) was dissolved in DMF (100 ml), 1-bromopropane (14.7 g) and potassium carbonate (20.7 g) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 2-propoxybenzaldehyde (16.18 g) as an oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.05 (3H, t, J = 7.5
Hz), 1.84 (2H, sextet, J=7.0Hz), 3.98 (2H,
t, J=6.6Hz), 7.15-7.22 (1H, m), 7.38-7.46
(3H, m), 9.97 (1H, s). Reference Example 165: To ethyl diethylphosphonoacetate (24.7 g) was added THF (200 ml),
Sodium hydride (60%, 4.4 g) was added at 0°C, and then a solution of 3-propoxybenzaldehyde (16.1 g) in THF (100 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, neutralized with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give ethyl 3-propoxycinnamate (24.0
g) was obtained as a yellow oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.05 (3H, t, J=7.5
Hz), 1.34 (3H, t, J=7.1Hz), 1.82 (2H, sexte
t, J = 7.0Hz), 3.94 (2H, t, J = 6.4Hz), 4.27 (2
H, q, J = 7.2Hz), 6.42 (1H, d, J = 16.2Hz), 6.9
0-6.95 (1H, m), 7.05-7.12 (2H, m), 7.29 (1H
, t, J = 7.7 Hz), 7.65 (1H, d, J = 16.2 Hz). Reference Example 166 Lithium aluminum hydride (7.58 g) was suspended in ether (300 ml), and the suspension was added to an ether solution (100 ml) of ethyl 3-propoxycinnamate (24.0 g).
l) was added dropwise over 1 hour at 0° C. After the addition, the mixture was stirred at room temperature for 1 hour.
The reaction mixture was diluted with water (7.6 ml) and 15% aqueous sodium hydroxide solution (7.6 ml).
and water (22 ml) were added, and the mixture was stirred at room temperature for another 0.5 hours. The reaction mixture was diluted with ether, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-(3-propoxyphenyl)-1-propanol (
15.23 g) was obtained as a colorless oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.04 (3H, t, J=7.5
Hz), 1.27 (1H, t, J=3.7Hz), 1.83 (2H, sexte
t, J=7.1Hz), 1.81-1.96 (2H, m), 2.68 (2H, t
, J=7.7Hz), 3.68 (2H, q, J=5.9Hz), 3.91 (2H
, t, J=6.6Hz), 6.70-6.80 (3H, m), 7.19 (1H,
t, J = 8.1 Hz). Reference Example 167: 3-(3-propoxyphenyl)-1-propanol (731 mg) was treated with THE
(20 ml) was added, and triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml) were added at 0° C. The mixture was stirred at 0° C. for 20 minutes and then at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and 3-(3-propoxyphenyl)propyl methanesulfonate (1.10 g) was obtained.
) was obtained as a colorless oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.04 (3H, t, J = 7.3
Hz), 1.80 (2H, sextet, J=7.1Hz), 2.01-2.1
4 (2H, m), 2.72 (2H, t, J = 7.5Hz), 3.00 (3H, s
), 3.91 (2H, t, J = 6.6Hz), 4.23 (2H, t, J = 6.2
Hz), 6.74-6.78 (3H, m), 7.16-7.24 (1H, m). Reference Example 168: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (394 mg), 3-(3-propoxyphenyl)propyl methanesulfonate (1099 mg) and potassium carbonate (304 mg) were dissolved in DMSO.
The mixture was suspended in 15 ml of benzothiepine-4-methyl-2,3-dihydrobenzothiepine-4-carboxylate and stirred at 70° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (765 mg) as a yellow oil.

7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2
Methyl 1,3-dihydro-1-benzothiepine-4-carboxylate (765 mg) was dissolved in THF methanol (15-7.5 ml) and added to a 2M aqueous potassium carbonate solution (
1.5 ml) was added and stirred at 60° C. for 18 hours. The reaction mixture was treated with 1N hydrochloric acid to adjust its pH to 2. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
The solvent was distilled off under reduced pressure, and the precipitated crystals were rinsed with hexane-ethyl acetate and concentrated to give 7-[3-(3-propoxyphenyl)propoxy]
470 mg of 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as white crystals.

mp 128-131℃. ^1H NMR (200MHz, DMSO- _d6 ) δ0.95 (3H, t, J=7
．． 3Hz), 1.69 (2H, sextet, J=7.0Hz), 2.04 (2
H, quint, J = 7.1Hz), 2.71 (2H, t, J = 7.4Hz),
2.90 (2H, t, J = 6.6Hz), 3.67 (2H, t, J = 6.6Hz
), 3.87 (2H, t, J = 6.6Hz), 4.09 (2H, t, J = 6.2
Hz), 6.72-6.80 (3H, m), 7.14 (1H, dd, J=8.4
, 2.2Hz), 7.18 (1H, t, J = 7.9Hz), 7.32 (1H, d
-like), 7.72 (1H, s), 7.93 (1H, d, J=8.4Hz)
．． IR (KBr) 1698, 1595, 1564, 1319, 1291, 1277
, 1258, 1163, 1130 ^{, 1071, 748 cm −1} . Anal. Calcd. for _{C23H26O6S ( 0.4H2O} ):C, ₆
3.11; H, 6.17. Found: C, 62.95; H, 5.95. Example 119 (Preparation of Compound 120) 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (395 mg) in THF
(12 ml), DMF (1 drop) and thionyl chloride (0.13 ml) were added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (10 ml). 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline dihydrochloride (323 mg) was suspended in THF (12 ml), and triethylamine (0.96 ml) was added dropwise. Then, the T
The HF solution was added dropwise at 0°C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate:ethanol = 10:1) and further recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 120) (302 mg) as white crystals.

mp 145-146℃. ^1H NMR (200MHz, _CDCl3 ) δ1.02 (3H, t, J=7.5
Hz), 1.66-1.81 (4H, m), 1.79 (2H, sextet, J
=7.2Hz), 2.14(2H, quint, J=7.1Hz), 2.21(
3H, s), 2.57-2.70 (1H, m), 2.78 (2H, t, J=7.
5Hz), 3.09 (2H, t, J = 6.8Hz), 3.37 (2H, td, J
= 11.2, 2.9Hz), 3.57 (2H, s), 3.68 (2H, t, J =
6.7Hz), 3.89 (2H, t, J=6.6Hz), 4.00-4.06 (
2H, m), 4.03 (2H, t, J = 6.3Hz), 6.73-6.79 (3
H, m), 6.88 (1H, d, J = 2.2Hz), 6.94 (1H, dd, J
=8.8,2.6Hz),7.20(1H,s and 1H,t,J=8.1
Hz), 7.32 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8
．． 4Hz), 7.84 (1H, s), 8.07 (1H, d, J=8.8Hz).
IR (KBr) 2948, 1667, 1595, 1564, 1526, 1518
, 1408, 1316, 1289, 1262, 1161, 1142, 1125,
1065 cm ⁻¹ . Anal. Calcd. _{for C36H44N2O6S ( 0.4H2O} ) _:
C, 67.56; H, 7.06; N, 4.38, Found: C, 67.32;
H, 6.82; N, 4.30. Reference Example 169: A solution of 3-(4-hydroxyphenyl)-1-propanol (1.33 g), 1-bromopropane (1.2 ml) and potassium carbonate (2.25 g) in acetone (10
The mixture (0 ml) was heated under reflux for 2 days. After concentration under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and 3% ethanol was obtained as a colorless oil.
1.61 g of 4-(4-propoxyphenyl)-1-propanol was obtained. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.03 (3H, t, J = 7.5
Hz), 1.70-1.91 (4H, m), 2.61-2.69 (3H, m),
3.67 (2H, t, J = 6.5Hz), 3.90 (2H, t, J = 6.6Hz
), 6.83 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4
Hz). Reference Example 170: 3-(4-propoxyphenyl)-1-propanol (735 mg) was added to THE
(20 ml) was added, and triethylamine (1.58 ml) and methanesulfonyl chloride (0.44 ml) were added at 0° C. The mixture was stirred at 0° C. for 20 minutes and then at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and
3-(4-propoxyphenyl)propyl methanesulfonate (1.02 g) was obtained as a colorless oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.03 (3H, t, J = 7.5
Hz), 1.80 (2H, sextet, J=7.0Hz), 2.04 (2H,
quint, J=7.0Hz), 2.69 (2H, t, J=7.5Hz), 2.
99 (3H, s), 3.90 (2H, t, J=6.6Hz), 4.22 (2H,
t, J=6.4Hz), 6.81-6.87 (2H, m), 7.07-7.11
(2H, m). Reference Example 171: Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (401 mg), 3-(4-propoxyphenyl)propyl methanesulfonate (1017 mg), and potassium carbonate (310 mg) were dissolved in DMSO.
The mixture was suspended in 15 ml of HCl and stirred at 75° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) as a yellow oil.

7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2
Methyl 1,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) was dissolved in THF methanol (15-7.5 ml) and added to a 2M aqueous potassium carbonate solution (
1.5 ml) was added and stirred at 60° C. for 18.5 hours. The reaction mixture was treated with 1N hydrochloric acid to adjust the pH to 2. It was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were rinsed with hexane-ethyl acetate to obtain 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (333 mg) as white crystals.

mp 168-170℃. ^1H NNR (200MHz, DMSO- _d6 ) δ0.97 (3H, t, J=7
．． 3Hz), 1.71 (2H, sextet, J=7.1Hz), 2.00 (2
H, quint-like), 2.67 (2H, t, J = 7.3Hz), 2.9
0 (2H, t-like), 3.67 (2H, t, J=6.6Hz), 3.87
(2H, t, J=6.6Hz), 4.08 (2H, t-like), 6.83 (
2H, d, J = 8.4Hz), 7.10-7.14 (1H, m), 7.12 (2
H, d, J=8.4Hz), 7.30 (1H, d-like), 7.72 (1H
, s), 7.93 (1H, d, J=9.0Hz). IR (KBr) 1686, 1593, 1564, 1510, 1294, 1279
, 1240, 1163, 1130 ^{, 1073 cm −1} . Anal. Calcd. for _{C23H26O6S ( 0.3H2O} ):C, ₆
3.37; H, 6.15. Found: C, 63.07; H, 6.21. Example 120 (Preparation of Compound 121) 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (260 mg) in THF
(12 ml), DMF (1 drop) and thionyl chloride (0.088 ml)
The mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (10 ml). 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]
[Methyl]aniline dihydrochloride (213 mg) was suspended in THF (12 ml), triethylamine (0.63 ml) was added dropwise, and then the THF solution of the acid chloride prepared above was added dropwise at 0 °C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate:ethanol = 10:1) and further recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 121) (281 mg) as white crystals.

mp 178-181℃. ^1H NMR (200MHz, _CDCl3 ) δ1.02 (3H, t, J=7.4
Hz), 1.69-1.81 (4H, m), 1.79 (2H, sextet, J
=7.1Hz), 2.10(2H, quint, J=7.3Hz), 2.20(
3H, s), 2.57-2.67 (1H, m), 2.75 (2H, t, J=7.
4Hz), 3.08 (2H, t, J = 6.6Hz), 3.37 (2H, td, J
= 11.1, 3.1Hz), 3.57 (2H, s), 3.68 (2H, t, J =
6.7Hz), 3.89 (2H, t, J=6.6Hz), 4.01 (2H, t,
J = 6.2Hz), 4.01-4.06 (2H, m), 6.83 (2H, d, J
= 8.4Hz), 6.89 (1H, d, J = 2.2Hz), 6.94 (1H, d
d, J=8.6, 2.4Hz), 7.09 (2H, d, J=8.8Hz), 7.
20 (1H, s), 7.32 (2H, d, J = 8.8Hz), 7.53 (2H,
d, J=8.4Hz), 7.84 (1H, s), 8.07 (1H, d, J=8.
8Hz). IR (KBr) 2942, 1665, 1595, 1512, 1408, 1314
, 1289, 1244, 1163 ^{, 1125, 1065 cm −1} . Anal. Calcd. _{for C36H44N2O6S ( 0.6H2O} ): _C
, 67.18; H, 7.08; N, 4.35. Found: C, 66.93; H
, 6.93; N, 4.43. Reference Example 172 Protocatechualdehyde (5.15 g) was dissolved in DMF (70 ml),
Iodomethane (14.5 g) and potassium carbonate (15.5 g) were added, and the mixture was stirred at room temperature for 1
The mixture was stirred for 7.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water, a 1N aqueous solution of sodium hydroxide, water, and saturated brine, respectively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3,4-diethoxybenzaldehyde (6.73 g) as a yellow oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.48 (3H, t, J = 6.9
Hz), 1.51 (3H, t, J = 6.9Hz), 4.16 (2H, q, J = 7
．． 0Hz), 4.19 (2H, q, J = 6.9Hz), 6.96 (1H, d, J
=8.0Hz), 7.40 (1H, s), 7.43 (1H, dd, J=8.0,
1.8 Hz), 9.84 (1H, s). Reference Example 173: 3,4-diethoxybenzaldehyde (6.68 g) was dissolved in methanol (100 ml).
To the reaction mixture was added sodium borohydride (1.30 g) at 0°C, and the mixture was stirred at 0°C for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3,4-diethoxybenzyl alcohol (6.64 g) as a yellow oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.445 (3H, t, J = 7.
0Hz), 1.452 (3H, t, J=7.1Hz), 1.62 (1H, br
s), 4.09 (2H, q, J=6.9Hz), 4.11 (2H, q, J=7.
0 Hz), 4.60 (2H, s), 6.86-6.93 (3H, m). Reference Example 174: 3,4-diethoxybenzyl alcohol (736 mg) was dissolved in toluene (10 ml
The mixture was dissolved in 1,000 ml of ethyl acetate, and pyridine (1 drop) and thionyl chloride (0.41 ml) were added, followed by stirring at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3,4-diethoxybenzyl chloride (802 mg) as an oil.

Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (403 mg), 3,4-diethoxybenzyl chloride (802 mg), and potassium carbonate (311 mg) were suspended in DMF (15 ml) and stirred at 70° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine, respectively, and 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 (hexane:ethyl acetate=3:1) to obtain methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg).
mg) was obtained as a yellow amorphous solid.

Methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg) was dissolved in THF methanol (15 ml) and added to a 2M aqueous potassium carbonate solution (1.5 ml)
) was added and stirred at 60° C. for 14 hours. The reaction mixture was treated with 1N hydrochloric acid, and the p
The H was set to 2. The organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were rinsed with hexane-ethyl acetate to give 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (3.02 g) was obtained as white crystals.

mp 145-146℃ (dec.). ^1H NMR (200MHz, DMSO- _d6 ) δ1.32 (6H, t, J=6
．． 9Hz), 2.90 (2H, t, J = 6.6Hz), 3.68 (2H, t, J
= 6.4Hz), 4.02 (2H, q, J = 7.2Hz), 4.03 (2H, q
, J=7.0Hz), 5.14 (2H, s), 6.94 (1H, d, J=8.0
Hz), 6.99 (1H, d, J=9.8Hz), 7.07 (1H, s), 7.
21 (1H, dd, J=8.9, 2.3Hz), 7.41 (1H, d, J=2.
2Hz), 7.72 (1H, s), 7.94 (1H, d, J=8.8Hz). IR (KBr) 1674, 1593, 1566, 1514, 1292, 1258
, 1225, 1165, 1128 ^{, 1069, 1038 cm −1} . Anal. Calcd. for _{C22H24O7S ( 0.3H2O} ):C, ₆
0.34; H, 5.66. Found: C, 60.15; H, 5.58. Example 121 (Preparation of Compound 122) 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (293 mg) was dissolved in THF (13 ml).
The mixture was suspended in 4-chloro-2-(2-methyl-2-propanol), and DMF (1 drop) and thionyl chloride (0.15 ml) were added, followed by stirring at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (10 ml).
[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline dihydrochloride (298 mg) was suspended in THF (15 ml), and triethylamine (0.91 ml) was added dropwise thereto, followed by the dropwise addition of the previously prepared THF solution of the acid chloride at 0° C. The mixture was stirred at room temperature for 60.5 hours. The reaction mixture was concentrated,
The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (
Purification with ethyl acetate → ethyl acetate:ethanol = 10:1) and further recrystallization from ethanol was carried out to obtain N-[4-[[N-methyl-N-(tetrahydropyran-4
From this mixture, 212 mg of [3,4-diethoxybenzyloxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 122) was obtained as white crystals.

mp 186-188℃. ^1H NMR (200MHz, _CDCl3 ) δ1.46 (6H, t, J=7.0
Hz), 1.69-1.77 (4H, m), 2.21 (3H, s), 2.57-
2.70 (1H, m), 3.09 (2H, t, J = 6.8Hz), 3.37 (2
H, td, J = 11.2, 2.9Hz), 3.57 (2H, s), 3.69 (2
H, t, J = 6.8Hz), 4.01-4.05 (2H, m), 4.11 (4H
, q, J=7.1Hz), 5.05 (2H, s), 6.86-6.98 (4H,
m), 7.04 (1H, dd, J = 8.6, 2.4Hz), 7.21 (1H, s
), 7.32 (2H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.4
Hz), 7.87 (1H, s), 8.09 (1H, d, J=8.8Hz). IR (KBr) 1669, 1595, 1514, 1410, 1312, 1289
, 1260, 1236, 1163, 1140, 1125, 1063, 1042,
737 cm ⁻¹ . Anal. Calcd. _{for C35H42N2O7S ( 0.3H2O} ): _C
, 65.66; H, 6.71: N, 4.38. Found: C, 65.56; H
, 6.56; N, 4.35. Reference Example 175 Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) was dissolved in methylene chloride (15 ml).
4-(2-propoxyethoxy)phenylboronic acid (0.67 g) was added, and molecular sieves 4A (0.8 g) was added, followed by stirring for 5 minutes. Copper acetate (0.27 g)
), triethylamine (1.04 ml) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was filtered through Celite and washed with ethyl acetate. The solvent was removed from the resulting solution under reduced pressure, and
The mixture was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.23 g).
) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4
Hz), 1.57-1.71 (2H, m), 3.07 (2H, t, J = 6.6H
z), 3.55 (2H, t, J=6.6Hz), 3.65 (2H, t, J=6.
6Hz), 3.78-3.85 (2H, m), 3.84 (3H, s), 4.10
-4.17 (2H, m), 6.96-7.02 (6H, m), 7.69 (1H,
s), 8.08 (1H, d, J = 8.8 Hz) Reference Example 176 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) was dissolved in THF (12 ml)/methanol (6.0 ml), 1N potassium hydroxide (2.7 ml) was added, and the mixture was stirred at 65°C for 16 hours. After cooling to room temperature, the solvent was concentrated to half its original volume under reduced pressure. 1N sodium hydroxide (3.0 ml) was added, and the mixture was washed with ethyl acetate. After adjusting the pH to approximately 5 with 1N hydrochloric acid, the mixture was extracted with ethyl acetate.
After washing with saturated saline, the extract was dried over magnesium sulfate. The solvent was removed under reduced pressure.
The resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-[4-(2
-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-
1-Benzothiepine-4-carboxylic acid (0.25 g) was obtained. ¹ H-MR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4H
z), 1.56-1.74 (2H, m), 3.08 (2H, t, J = 6.2Hz
), 3.52 (2H, t, J=6.6Hz), 3.59-3.67 (2H, m)
, 3.79-3.84 (2H, m), 4.10-4.17 (2H, m), 6.9
7-7.03 (6H, m), 7.29 (1H, m), 8.09 (1H, d, J=
8.6 Hz) Example 122 (Preparation of Compound 123) 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (0.25 g) in THF
(7.5 ml), and DMF (two drops) and thionyl chloride (50 μl) were added.
The solution was stirred at room temperature for 1 hour, and then diluted with 4-[methyl(tetrahydropyranyl-4-yl)aminomethyl]aniline (140 mg), triethylamine (0.40 ml), and
The resulting mixture was added dropwise to a THF solution (7.5 ml) of N-[4-[N-methyl-N-(tetrahydropyranyl-4-yl)aminomethyl]phenyl]-7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 123) (115 mg) after ice-cooling and stirring at room temperature for 2 hours. The reaction mixture was added to water and extracted with ethyl acetate. The mixture was washed with saturated brine and then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/ethanol = 3/1) and recrystallized from hexane/ethyl acetate to give N-[4-[N-methyl-N-(tetrahydropyranyl-4-yl)aminomethyl]phenyl]-7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 123) (115 mg).

m. p. 106-109℃¹ H-NMR (200MHz, CDCl₃) δ0.94 (3H, t, J=7.4
Hz), 1.55-1.75 (6H, m), 2.20 (3H, s), 2.64 (
1H, m), 3.10 (2H, t, J=6.6Hz), 3.37 (2H, td,
J=11.0, 3.0Hz), 3.50 (2H, t, J=6.6Hz), 3.5
7 (2H, s), 3.70 (2H, t, J=6.6Hz), 3.77-3.83
(2H, m), 4.00-4.16 (4H, m), 6.89-7.02 (5H,
m), 7.04 (1H, s), 7.31 (2H, d, J=8.4Hz), 7.5
1 (2H, d, J = 8.6Hz), 7.89 (1H, s), 8.08 (1H, d
, J=8.4Hz) IR (KBr) 3281, 2955, 1649, 1599, 1501, 1410
,1238,1204,1125,988,829cm⁻¹ Reference Example 177 7-Hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine
Methyl 4-carboxylate (0.40 g) was dissolved in methylene chloride (15 ml),
3-(2-propoxyethoxy)phenylboronic acid (0.67 g) was added, and
Sieves 4A (0.8 g) was added and stirred for 5 minutes. Copper acetate (0.27 g)
), triethylamine (1.04 ml) was added, and the mixture was stirred at room temperature for 5 hours.
The resulting solution was filtered through a filter and washed with ethyl acetate. The solvent was removed under reduced pressure, and the resulting solution was
Purified by silica gel column chromatography (hexane/ethyl acetate = 3/2)
7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo
-2,3-dihydro-1-benzothiepine-4-carboxylic acid methyl ester (0.36 g)
) was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.4
Hz), 1.56-1.69 (2H, m), 3.09 (2H, t, J = 6.4H
z), 3.49 (2H, t, J=6.6Hz), 3.59-3.66 (2H, m
), 3.76-3.81 (2H, m), 3.84 (3H, s), 4.09-4.
14 (2H, m), 6.63-6.69 (2H, m), 6.79-6.85 (1
H, m), 7.03-7.09 (2H, m), 7.31-7.35 (1H, m)
, 7.71 (1H, s), 8.10 (1H, d, J = 8.4 Hz) Reference Example 178 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2
,3-dihydro-1-benzothiepine-4-carboxylate methyl (0.36 g)
Dissolved in THF (10.8 ml)/methanol (5.4 ml), 1N potassium hydroxide
Sodium (2.4 ml) was added and the mixture was stirred at 65°C for 16 hours.
The solvent was concentrated to half its original volume under reduced pressure. 1N sodium hydroxide (3.0 ml) was added, and vinegar was added.
The pH was adjusted to about 5 with 1N hydrochloric acid, and then extracted with ethyl acetate.
The extract was washed with saturated saline and then dried over magnesium sulfate. The solvent was removed under reduced pressure.
The residue was washed with hexane/ethyl acetate (=8/1) to give 7-[3
-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydroxy
0.27 g of dro-1-benzothiepine-4-carboxylic acid was obtained.¹ H-NMR (200MHz, CDCl₃) δ0.93 (3H, t, J=7.4
Hz), 1.54-1.71 (2H, m), 3.06-3.13 (2H, m),
3.50 (2H, t, J=6.6Hz), 3.60-3.67 (2H, m), 3
．． 76-3.82 (2H, m), 4.07-4.13 (2H, m), 6.64-
6.69 (2H, m), 6.79-6.85 (1H, m), 7.04-7.10
(2H, m), 7.26-7.36 (1H, m), 7.81 (1H, s), 8.
12 (1H, d, J = 9.4 Hz) Example 123 (Preparation of Compound 124) 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2
,3-Dihydro-1-benzothiepine-4-carboxylic acid (0.26 g) in THF
(7.8 ml), and DMF (two drops) and thionyl chloride (53 μl) were added.
The solution was stirred at room temperature for 1 hour, and then 4-[methyl(tetrahydropyranyl-4-yl)]
[(1-aminomethyl)aniline (146 mg), triethylamine (0.42 ml)
The mixture was added dropwise to a THF solution (7.8 ml) of the above-mentioned hexane-1-hydroxybenzoates under ice-cooling, and stirred at room temperature for 2 hours.
The reaction mixture was poured into water and extracted with ethyl acetate.
The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography.
The mixture was purified by chromatography (ethyl acetate/ethanol = 4/1) and hexane
/ Recrystallized from ethyl acetate to give N-[4-[N-methyl-N-(tetrahydropyridine)]
3-(2-propoxyethyl)-4-yl)aminomethyl]phenyl]-7-[3-(2-propoxyethyl)-4-yl] ...
[oxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepi
To obtain 108 mg of methyl-4-carboxamide (compound 124).

m. p. 98-102℃¹ H-NMR (200MHz, CDCl₃) δ0.92 (3H, t, J=7.2
Hz), 1.56-1.82 (6H, m), 2.20 (3H, s), 2.65 (
1H, m), 3.10 (2H, t, J=6.6Hz), 3.36 (2H, td,
J=11.0, 2.6Hz), 3.48 (2H, t, J=6.6Hz), 3.5
7 (2H, s), 3.64-3.72 (2H, m), 3.75-3.81 (2H
, m), 4.10-4.13 (4H, m), 6.63-6.68 (2H, m),
6.77-6.83 (1H, m), 6.95 (1H, d, J=2.2Hz), 7
．． 05 (1H, dd, J=8.8, 2.4Hz), 7.17 (1H, s), 7.
26-7.35 (3H, m), 7.52 (2H, d, J=8.4Hz), 8.0
5 (1H, s), 8.09 (1H, d, J = 8.4Hz) IR (KBr) 3289, 2942, 1647, 1599, 1530, 1410
,1304,1138,1055cm⁻¹ Example 124 (Preparation of Compound 125) 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,
3-Dihydro-1-benzothiepine-4-carboxylic acid (0.12 g) was dissolved in THF (
5 ml), and then, under ice cooling, thionyl chloride (0.05 ml), DMF (catalytic amount)
The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (1
0 ml) and add 4-[N-methyl-N-(tetrahydro-2H-pyran-4
-yl)aminomethyl]aniline (0.08 g), triethylamine (0.21
The mixture was added dropwise to a solution of 1 ml of the hydroxybenzoate in THF (5 ml) under ice cooling.
The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
The mixture was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
The residue was purified by silica gel column chromatography (ethyl acetate/methanol/
The crude crystals were obtained by recrystallization from ethyl acetate-hexane.
and 7-[4-(3-ethoxypropyl)phenoxy]-N-[4-[[N-methyl
methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl
[0043]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carbo
The oxamide (compound 125) (0.15 g) was obtained as colorless crystals.

mp 156-157℃. ^1H -NMR (δppm, _CDCl3 ) 1.22 (3H, t, J=6.9Hz)
, 1.57-1.76 (4H, m), 1.84-1.98 (2H, m), 2.2
0 (3H, s), 2.59-2.69 (1H, m), 2.72 (2H, t, J=
6.2Hz), 3.11 (2H, t, J = 6.6Hz), 3.30-3.54 (
6H, m), 3.56 (2H, s), 3.69 (2H, t, J=6.8Hz),
4.01-4.07 (2H, m), 6.95-7.05 (4H, m), 7.16
(1H, s), 7.23-7.33 (4H, m), 7.51 (2H, d, J=8
．． 4Hz), 7.75 (1H, s), 8.09 (1H, d, J=8.4Hz).
IR (KBr) ν: 2946, 2853, 1667, 1595, 1507 ^{cm −
1} . Anal. calcd. for _{C35H42N2O6S :} C, _{67.94 :} H
, 6.84; N, 4.53. Found C, 67.64; H, 6.82; N,
4.41. Example 125 (Preparation of Compound 126) 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.
25 g) was dissolved in THF (5 ml), and thionyl chloride (0.08 ml) was added under ice cooling.
A catalytic amount of DMF was added and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (10 ml) and added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.14 g) and triethylamine (0.4 ml) in THF (5 ml) under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol/triethylamine) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to give 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-
From this, 0.28 g of [4-yl]amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 126) was obtained as colorless crystals.

mp 111-113℃. ^1H -NMR (δppm, _CDCl3 ) 1.26 (3H, t, J=6.9Hz)
, 1.63-1.74 (4H, m), 2.20 (3H, s), 2.30 (6H,
s), 2.50-2.71 (1H, m), 3.11 (2H, t, J = 6.8Hz
), 3.37 (2H, dt, J = 3.0, 11.0Hz), 3.57 (2H, s
), 3.60-3.80 (6H, m), 3.94-4.06 (4H, m), 6.
72 (2H, s), 6.93 (1H, d, J=2.4Hz), 7.02 (1H,
dd, J=2.4, 8.4Hz), 7.16 (1H, s), 7.31 (2H, d
, J=8.6Hz), 7.51 (2H, d, J=8.6Hz), 7.72 (1H
, s), 8.09 (1H, d, J=8.8Hz). IR (KBr) ν: 2934, 2849, 1669, 1597, 1564, 15
20 cm ⁻¹ . Anal. calcd. for _C36H44N2O7S :C _{, 66.64} ; _H
, 6.84; N, 4.32. Found C, 66.52; H, 6.87; N,
4.10. Reference Example 179 Magnesium (0.37 g) was suspended in anhydrous THF (5 ml), and the suspension was stirred under a nitrogen atmosphere. Dibromoethane (catalytic amount) and then a solution of 1-bromo-4-(3-ethoxypropyl)benzene (3.4 g) in anhydrous THF (30 ml) were added dropwise.
After heating for 1.5 hours, the mixture was cooled to -78°C, and trimethyl borate (3.1 ml) was added dropwise. The mixture was returned to room temperature and stirred overnight. 1N hydrochloric acid was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol/triethylamine) to obtain 4-(3-ethoxypropyl)phenylboronic acid (1.25 g) as a pale yellow oil. ^1H -NMR (δ ppm, _CDCl3 ) 1.23 (3H, t, J = 7.0 Hz).
, 1.90-2.00 (2H, m), 2.79 (2H, t, J=7.7Hz),
3.42-3.55 (4H, m), 7.34 (2H, d, J=7.6Hz), 8
16 (2H, d, J = 7.6 Hz). Reference Example 180 Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(3-ethoxypropyl)phenylboronic acid (0.65 g), copper acetate (0.27 g), molecular sieves 4A (0
0.8 g) was suspended in dichloromethane (15 ml) and triethylamine (1.0 m
The mixture was added with methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) and stirred at room temperature overnight. The mixture was filtered through Celite, and the solvent in the filtrate was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g).
) was obtained as colorless crystals.

mp 93-94℃. ^1H -NMR (δppm, _CDCl3 ) 1.23 (3H, t, J=6.9Hz)
, 1.85-1.99 (2H, m), 2.73 (2H, t, J=7.7Hz),
3.08 (2H, t, J=6.6Hz), 3.43-3.66 (6H, m), 3
．． 84 (3H, s), 6.97-7.05 (4H, m), 7.25 (2H, d,
J = 8.4Hz), 7.71 (1H, s), 8.09 (1H, d, J = 9.6H
z). IR (KBr) ν: 2975, 2949, 2865 ^{, 1713 cm −1} . Reference Example 181 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) was dissolved in methanol (5 ml) and THF (10 ml), and 1N aqueous sodium hydroxide solution (0.6 ml) was added. The mixture was heated at 70°C for 5 hours. After concentration, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.12 g) as colorless crystals. ^1H -NMR (δ ppm, _CDCl3 ) 1.23 (3H, t, J = 7.2 Hz).
, 1.85-1.99 (2H, m), 2.73 (2H, t, J=7.9Hz),
3.09 (2H, t, J=6.6Hz), 3.43-3.56 (4H, m), 3
．． 64 (2H, t, J=6.8Hz), 6.96-7.05 (4H, m), 7.
23-7.26 (2H, m), 7.81 (1H, s), 8.10 (1H, d, J
= 9.6 Hz). IR (KBr) ν: 2975, 2934, 2870, 1713 ^{cm −1} . Reference Example 182: 60% sodium hydride (4.4 g) was suspended in DMF (50 ml), and the suspension was cooled with ice and added to 4-bromo-2,6-dimethylphenol (20 g) in DMF (100 ml).
The solution was added dropwise to the reaction mixture. After stirring for 2 hours at room temperature under a nitrogen atmosphere, bromoethyl ethyl ether (12.3 ml) and sodium iodide (16.4 g) were added, and the mixture was heated at 75°C overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 5-bromo-2
-(2-Ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) was obtained as a colorless oil. ¹ H-NMR (δ ppm, CDCl ₃ ) 1.25 (3H, t, J = 7.0 Hz).
, 2.26 (6H, s), 3.60 (2H, q, J=7.0Hz), 3.72-
3.77 (2H, m), 3.88-3.93 (2H, m), 7.13 (2H, s
IR (neat) ν: 2975, 2926, 2870, 1472 ^{cm −1} . Reference Example 183: Magnesium (2.36 g) was suspended in anhydrous THF (100 ml), and the suspension was stirred under a nitrogen atmosphere. Dibromoethane (catalytic amount) and then a solution of 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) in anhydrous THF (100 ml) were added.
A solution of 4-(2-ethoxyethoxy)-3,5-dimethylphenylboronic acid ( ...ethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid ( ² -ethoxyethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxyethoxy)-3,5-dimethylphenylboronic acid (2-ethoxyethoxyethoxyethoxy) _-3,5 -dimethylphenylboronic acid (2-ethoxy
, 2.21 (3H, s), 2.26 (3H, s), 3.46 (2H, q, J=7
．． 2Hz), 3.65-3.69 (2H, m), 3.85-3.90 (2H, m
), 7.48 (2H,s). Reference Example 184 Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(2-ethoxyethoxy)-3,5
Dimethylphenylboronic acid (0.71 g), copper acetate (0.27 g), and molecular sieves 4A (0.8 g) were suspended in dichloromethane (15 ml), triethylamine (1.0 ml) was added, and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite, and the solvent was distilled off from the filtrate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a pale yellow oil. ^1H -NMR (δ ppm, _CDCl3 ) 1.27 (3H, t, J = 7.0 Hz).
, 2.31 (6H, s), 3.08 (2H, t, J=6.4Hz), 3.58-
3.68 (4H, m), 3.76-3.81 (2H, m), 3.84 (3H, s
), 3.95-4.00 (2H, m), 6.71 (2H, s), 6.99-7.
04 (2H, m), 7.71 (1H, s), 8.08 (1H, d, J = 8.4H
z), IR (neat) ν: 2975, 2951, 2926, 2868, 1713 cm
^-1 . Reference Example 185 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,
Methyl 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) was dissolved in methanol (5 ml) and THF (10 ml), and 1M aqueous potassium carbonate solution (2.5 ml) was added, followed by heating at 70° C. overnight.
The mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3
1-Dihydro-1-benzothiepine-4-carboxylic acid (0.33 g) was obtained as colorless crystals.

mp 149-153℃. ^1H -NMR (δppm, _CDCl3 ) 1.27 (3H, t, J=7.0Hz)
, 2.31 (6H, s), 3.10 (2H, t, J=6.4Hz), 3.58-
3.69 (4H, m), 3.77-3.81 (2H, m), 3.96-4.00
(2H, m), 6.72 (2H, s), 7.02-7.06 (2H, m), 7.
83 (1H, s), 8.10 (1H, d, J=9.0Hz). IR (KBr) ν: 2976, 2865, 1709 ^{, 1694 cm −1} . Anal. calcd. for _C23H26O7S :C, _{61.87 ;} H,5
87. Found C, 61.59; H, 5.71. INDUSTRIAL APPLICABILITY The compound of the present invention represented by formula (I) or a salt thereof has a strong CCR5 antagonistic activity and can therefore be advantageously used for the prevention and treatment of various HIV infections in humans, such as AIDS.

───────────────────────────────────────────────────────── Continued from the front page (51) Int.Cl. ⁷ Identification Symbol FI A61K 31/44 A61K 31/44 31/4709 31/4709 31/4725 31/4725 31/661 31/661 A61P 31/18 A61P 31/18 C07D 309/14 C07D 309/14 401/12 401/12 405/12 405/12 407/12 407/12 409/12 409/12 409/14 409/14 C07F 9/655 C07F 9/655 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, SD, SL, SZ, TZ, UG, ZW), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CR, C U, CZ, DM, DZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MA, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, TR, TT, UA, US, UZ, VN, YU, ZA (Note) This publication is based on the publication of the internationally published Japanese patent application (Japanese utility model registration application) related to this publication. The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act) and is unrelated to this publication.

Claims (37)

[Claims] [Claim 1] Formula[In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is represented by the formula wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶'an optionally substituted hydrocarbon group,
represents an optionally substituted hydroxyl group or an optionally substituted amino group, R⁵
' and R⁶' are bonded to each other to form a cyclic group with the adjacent phosphorus atom
(5) an optionally substituted amidino group or (6) a group represented by the formula (I)
a compound represented by the formula R¹−
X¹-W-X²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear portion.
When R represents a group represented by²is an optionally substituted amidino group or
represents an optionally substituted guanidino group;¹−X¹-W-X²-Z¹-Z
²- The group represented by the formula(In the formula, R¹and X¹has the same meaning as defined above, and ring A" is optionally substituted.
represents a benzene ring, and Q¹represents a divalent group in which ring B″ forms a 5- to 7-membered ring, and Q²
is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group
represents a ring group, and Q³represents a bond or a divalent group, R
²is an expression (In the formula, R⁵'' and R⁶'' represents an optionally substituted hydroxyl group.
, R⁵'' and R⁶'' are bonded to each other and form a cyclic group with the adjacent phosphorus atoms.
(which may be present) does not represent a group represented by the formula (I), or a salt thereof. 2. A prodrug of the compound according to claim 1 or a salt thereof. 3. The compound according to claim 1, wherein R ¹ is a group formed by removing one hydrogen atom from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, or tetrahydropyran, each of which may be substituted. 4. The compound according to claim 1, wherein R ¹ is an optionally substituted phenyl. Claim 5: X ¹ is a bond, -(CH ₂ ) _a' - (a' is an integer of 1 to 4),
, -( _CH2 ) _b' - ^X3- [b' represents an integer of 0 to 3, and ^X3 represents an optionally substituted imino group, a carbonyl group, an oxygen atom, or an optionally oxidized sulfur atom], -CH=CH-, -O≡C-, -CO-NH-, or _-SO2 -N
The compound of claim 1, wherein H-. 6. The compound according to claim 1, wherein X ¹ is a bond. 7. The compound according to claim 1, wherein X ¹ is —(CH ₂ ) _b′ —X ³ —, wherein b′ represents an integer of 0 to 3, and X
³ represents an optionally substituted imino group, a carbonyl group, an oxygen atom or an optionally oxidized sulfur atom. [Claim 8] The compound according to claim 1, wherein ring A is furan, thiophene, pyrrole, pyridine, pyran or benzene, each of which may be substituted. [Claim 9] The compound according to claim 1, wherein ring A is an optionally substituted benzene. Claim 10: Ring B is a group represented by the formula [wherein _E3 represents an optionally substituted carbon atom or an optionally substituted nitrogen atom, _E4 represents an optionally substituted carbon atom or a nitrogen atom, b represents a single bond or a double bond, Y represents -Y'-( _CH2 )m'-(Y'
represents -S(O) _m- (m is an integer of 0 to 2), -O-, -NH- or -CH
_2- , and m' represents an integer of 0 to 2), -CH=, -CH=CH-, or -
2. The compound according to claim 1, which is a 5- to 7-membered ring optionally having a substituent at any substitutable position, represented by the formula: wherein N=CH-. 11. The compound according to claim 1, wherein Y is —Y′—(CH ₂ ) ₂ —, wherein Y′ is —S(O) _m — (m is 0 to 1).
2), -O-, -NH- or -OH ₂ -.
The compound according to claim 0. 12. The compound according to claim 1, wherein _E3 represents an optionally substituted carbon atom, _E4 represents an optionally substituted carbon atom, and b represents a double bond. Claim 13: ^X2 is -( _CH2 ) _a'- [a' represents an integer of 1 to 4], -(
The compound according to claim ₁ , which is -CH2) _b' - ^X3- (b' represents an integer of 0 to 3, and ^X3 represents an optionally substituted imino group, a carbonyl group, an oxygen atom, or an optionally oxidized sulfur atom), -CH=CH-, -C≡C-, -CO-NH-, or _-SO2 -NH-. 14. The compound according to claim 1, wherein ^X2 is --CO--NH--. 15. Z ¹ is (1) a bond or (2) benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, each of which may be substituted.
2. The compound according to claim 1, which is a divalent cyclic group formed by removing two hydrogen atoms from pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran. 16. The compound according to claim 1, wherein Z ¹ is (1) a bond or (2) a divalent cyclic group formed by removing two hydrogen atoms from benzene, cyclohexane or piperidine, each of which may be substituted. 17. The compound according to claim 1, wherein ^Z1 is an optionally substituted phenylene. 18. The compound according to claim 1, wherein ^Z2 is a bond or an optionally substituted _C1-3 alkylene. 19. Z ² is —Z′—(CH ₂ )n— [Z′ is —CH(OH)—, —C
The compound according to claim 1, which is a divalent group optionally having a substituent on any methylene group, having a skeleton represented by the following formula: (O)- or _-CH2- , and n is an integer of 0 to 2. [Claim 20] The compound according to claim 1, wherein ^Z2 is a bond or methylene. 21. The compound according to claim 1, wherein Z ¹ is a 6-membered divalent cyclic group, and Z ² is substituted at the para position of X ² . [Claim 22] ^R2 is (1) an amino group which may be substituted and the nitrogen atom may be converted to quaternary ammonium or oxidized, (2) an optionally substituted nitrogen-containing heterocyclic group which may contain a sulfur atom or an oxygen atom as a ring-constituting atom and the nitrogen atom may be converted to quaternary ammonium or oxidized, or (3)
2. The compound according to claim 1, which is (4) an optionally substituted amidino group or (5) an optionally substituted guanidino group. 23. The compound according to claim 1, wherein ^R2 is an amino group which may be substituted. 24. The compound according to claim 1, wherein R ² is an amidino group which may be substituted or a guanidino group which may be substituted. 25. N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[2-(4-propoxyphenyl)ethoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(3-propoxybenzyl)oxy]-1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-
[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2
, 3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-
Methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7
-[(4-propoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N
-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-
propoxyethoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-
(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[3-(4
-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-
1-benzothiepine-4-carboxamide or a salt thereof. 26. A prodrug of the compound according to claim 25 or a salt thereof. (27) A pharmaceutical composition comprising the compound according to (1) or a salt thereof. [Claim 28] Formula[In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is represented by the formula wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
, an optionally substituted hydroxyl group or an optionally substituted amino group, R
⁵' and R⁶' are bonded to each other to form a cyclic group with the adjacent phosphorus atom.
(5) an optionally substituted amidino group, or (6)
a compound represented by the formula R¹
−X¹-W-X²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear portion.
When R represents a group represented by²is an optionally substituted amidino group or
a CCR antagonist containing a guanidino group optionally substituted] or a salt thereof
A pharmaceutical composition for 29. The composition according to claim 28, which is an agent for preventing or treating HIV infection. 30. The composition according to claim 28, which is an agent for preventing or treating AIDS. 31. The composition according to claim 28, which is an agent for suppressing the progression of AIDS pathology. 32. The composition according to claim 29, further comprising a protease inhibitor and/or a reverse transcriptase inhibitor in combination. 33. The composition according to claim 32, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz or abacavir. 34. The protease inhibitor is saquinavir, ritonavir, indinavir,
33. The composition of claim 32, which is amprenavir or nelfinavir. [Claim 35] Formula[In the formula, R¹represents an optionally substituted 5- or 6-membered ring group; X¹is a bond or
A divalent group having 1 to 4 atoms constituting a linear chain portion, W is represented by the formula wherein ring A and ring B each represent an optionally substituted 5- to 7-membered ring;
₁and E₄are each an optionally substituted carbon atom or an optionally substituted
indicates a good nitrogen atom, E₂and E₃are each an optionally substituted carbon atom
an optionally substituted nitrogen atom, an optionally oxidized sulfur atom or an oxygen atom
a and b each represent a single bond or a double bond)
represents a divalent group, and X²The number of atoms constituting the linear chain portion is 1 to 4.
represents a divalent group, Z¹represents a bond or a divalent cyclic group; Z²is a bond or
represents a divalent group having 1 to 4 carbon atoms constituting a straight chain portion, and R²teeth(
1) A group which may be substituted, and in which the nitrogen atom is quaternary ammonium or oxidized.
(2) an optionally substituted amino group having sulfur as a ring-constituting atom;
The nitrogen atom may be a quaternary ammonium or oxygen atom.
(3) a nitrogen-containing heterocyclic group which may be oxidized; (4) a group bonded via a sulfur atom;
Formula (4)(wherein k represents 0 or 1, and when k is 0, the phosphorus atom forms a phosphonium salt.)
It may be R⁵' and R⁶' are each an optionally substituted hydrocarbon group
, an optionally substituted hydroxyl group or an optionally substituted amino group, R
⁵' and R⁶' are bonded to each other to form a cyclic group with the adjacent phosphorus atom.
(5) an optionally substituted amidino group, or (6)
a compound represented by the formula R¹
−X¹-W-X²-Z¹-Z²- The group represented by the formula(In the formula, R¹has the same meaning as above, and W' is the formula (wherein ring A' represents an optionally substituted 5- or 6-membered aromatic ring, and X represents a substituted
an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom, or an oxygen atom
and ring B' represents an optionally substituted 5- to 7-membered ring),
Z represents a divalent group having 1 to 4 carbon atoms constituting a linear portion.
When R represents a group represented by²is an optionally substituted amidino group or
or a salt thereof with a protease inhibitor or
and/or a reverse transcriptase inhibitor for the prevention and treatment of HIV infection. [36] A method for antagonizing CCR in a mammal, which comprises administering to the mammal an effective amount of the compound according to [28] or a salt thereof. [Claim 37] Use of the compound or salt thereof according to claim 28 for the manufacture of a medicament for CCR antagonism.