JP2001058988A - Anilide derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound showing an excellent antagonism on a specific chemokine receptor, especially on CCR5, capable of remarkably inhibiting HIV infection in human peripheral blood monocyte, useful for preventing and treating HIV infections diseases. SOLUTION: This compound is represented by formula I R1 is a (substituted) 5- to 6-membered ring; ring A is a (substituted) 6- to 7-membered ring; ring B is a (substituted) benzene ring; n is 1 or 2; Z is a direct bond or a bifunctional group; R2 is a (substituted) amino, a (substituted) nitrogen-containing heterocyclic group, a group bonded through S or a group of formula II [k is 0 or 1; R5 and R6 are each a (substituted) hydrocarbon group, a (substituted) hydroxy group or the like] such as N-[4-[N-methyl-N-(tetrahydropyran-4-yl) aminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1- benzothiepine-4-carboxamide. The compound of formula I is obtained by condensing a compound of formula III with a compound of formula IV R2' is a group [a (substituted) amino which may be protected or the like]}, deprotecting, oxidizing/reducing the resultant substance, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel anilide derivative, its production method and use.

[0002]

2. Description of the Related Art In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome) and can be combined with two HIV reverse transcriptase inhibitors conventionally used. As a result, the treatment of AIDS has been remarkably advanced, but it has not been sufficient for eradication of AIDS, and the development of a new anti-AIDS drug based on another mechanism of action has been desired. HI
CD4 as a receptor for V to enter target cells
Has been known for some time, but recently CCR5, a second receptor for macrophage-tropic HIV,
Seven transmembrane G protein-coupled chemokine receptors, called CXCR4, have been found as T cell-directed second receptors, and these chemokine receptors are thought to play an essential role in the establishment and transmission of HIV infection. Have been. In fact, humans who have shown resistance to HIV infection despite repeated exposure,
It has been reported that the CCR5 gene had a homozygously deleted mutation. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs, but there are no examples in which CCR5 antagonists have been developed as AIDS treatments to date.

[0003]

In order to search for an anti-AIDS drug based on CCR5 antagonism, the CCR5 gene is cloned from a cDNA library derived from a human tissue, ligated to an expression vector for animal cells, and added to animal cells. It is necessary to obtain a CCR5-expressing cell line by introduction. Next, using this transformed cell line, the natural ligand CC
It is necessary to screen for a compound that strongly inhibits the binding of the chemokine RANTES to CCR5. However, at present, no low-molecular-weight compound having the antagonistic activity has been reported. The present invention provides a novel alinide derivative which is useful as a prophylactic / therapeutic agent for HIV infection, particularly AIDS based on CCR5 antagonistic activity, and which is suitable for oral administration, a production method and a use thereof.

[0004]

Means for Solving the Problems The present inventors have developed CCR5.
As a result of intensive studies on compounds having an antagonistic action, an anilide derivative represented by the following formula (I) or a salt thereof (hereinafter sometimes abbreviated as compound (I)) has been reported to have excellent C
In addition to exhibiting CR5 antagonism, it has been found that it has a clinically desirable pharmaceutical effect, such as remarkably suppressing HIV infection to human peripheral blood mononuclear cells, and has excellent oral absorption. Based on this, the present invention has been completed.

That is, the present invention provides: (1) Formula (I)

Embedded image [Wherein, R ¹ represents a 5- or 6-membered ring which may be substituted, ring A represents a 6- or 7-membered ring which may be substituted, and ring B represents a benzene ring which may be substituted. , N represents 1 or 2, Z represents a bond or a divalent group, and R ² represents (1) an amino group which may be substituted and a nitrogen atom of which may be quaternized ammonium, 2) a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and a nitrogen atom may be quaternized ammonium, and (3) a sulfur atom. Or a group bonded through the formula (4)

Embedded image (In the formula, k represents 0 or 1, when k is 0, the phosphorus atom may form a phosphonium salt, and R ⁵ and R ⁶ may each be an optionally substituted hydrocarbon group, A hydroxyl group or an amino group which may be substituted, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom.) Or a salt thereof; and a prodrug of the compound or a salt thereof according to the above (1);

(2) The above (1), wherein R ¹ is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted. (3) The compound according to the above (1), wherein R ¹ is benzene which may be substituted;

Embedded image (Wherein, Y is _{- (CH 2) m - (} m is 1 or 2), - CH = CH- or an -N = CH-) having a skeleton represented by, any substitutable A compound according to the above (1), which is a 6- to 7-membered ring which may have a substituent at the position of (5); (5) Y is-(CH ₂ ) _m- (m represents 1 or 2) (6) the compound according to (4), wherein Y is-(CH ₂ ) _2- ; (7) ring B, a halogen atom, C ₁ optionally substituted with a halogen atom. (8) The compound according to the above (1), which is benzene which may be substituted with a substituent selected from a _-4 alkyl group and a C _1-4 alkoxy group which may be substituted with a halogen atom; (9) wherein Z is a good C _1-3 alkylene optionally substituted (1) the compound according; compound of claim 1, wherein it; 10) Z is _{-Z '- (CH 2) n} ' - (Z ' is -CH (O
H) -, - C (O ) - or -CH ₂ - indicates, n 'has a skeleton represented by showing) an integer of 0 to 2, have a substituent on any methylene group (11) the compound according to (1), wherein Z is methylene; (12) an amino group wherein R ² is (1) an optionally substituted group;
(2) a nitrogen-containing heterocyclic group which may be substituted and may contain a sulfur atom or an oxygen atom as a ring-constituting atom, (3) a group bonded via a sulfur atom, or (4)

Embedded image (In the formula, k represents 0 or 1, R ⁵ and R ⁶ each represent an optionally substituted hydrocarbon group or an optionally substituted amino group, and R ⁵ and R ⁶ are (1) a compound represented by the above (1), wherein R ² is (1) an amino group which may be substituted;
(2) a nitrogen-containing heterocyclic group which may be substituted and may contain a sulfur atom or an oxygen atom as a ring-constituting atom, or (3)

Embedded image (Wherein, R ⁵ and R ⁶ each represent an optionally substituted hydrocarbon group, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom). (14) a group represented by the above-mentioned (1), wherein R ² is a group represented by the formula —NRR ′ (wherein R and R ′ are each an optionally substituted aliphatic hydrocarbon group ( (15) the compound according to (1), which is an aliphatic chain hydrocarbon group or an aliphatic cyclic hydrocarbon group) or an optionally substituted alicyclic (non-aromatic) heterocyclic group; R represents an optionally substituted chain hydrocarbon group, and R ′ represents an optionally substituted alicyclic hydrocarbon group (aliphatic cyclic hydrocarbon group) or an optionally substituted alicyclic group. (16) The compound according to the above (14), which is a (non-aromatic) heterocyclic group; (16) R may be substituted (17) The compound according to the above (14), wherein the compound is a C _1-6 alkyl group, and R ′ is an optionally substituted C _3-8 cycloalkyl group or an optionally substituted saturated heterocyclic group; R 'is optionally substituted cyclohexyl,
The compound according to the above (16), which is an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl; (18) N- [4- [N-methyl -N- (Tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-propoxyphenyl)
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- (4-butoxyphenyl) -N- [4- [N-methyl-
N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-
Carboxamide, 7- [4- [N-methyl-N- (2-propoxyethyl) amino] phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] Phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- [4- (2-ethoxyethoxy) phenyl] -N- [4-[[N-methyl-N- (Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine
-4-carboxamide, N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4- (2-propoxyethoxy) phenyl] -1,1 -Dioxo-2,3-dihydro
-1-benzothiepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- [4- (2-ethoxyethoxy) -3,5-dimethylphenyl] -N- [4-[[N- Methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide, 7- [2-chloro-
4- (2-propoxyethyl) phenyl] -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- (3-methyl-4-propoxyphenyl) -N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide and 7- (3,4 -Dipropoxyphenyl) -N- (4-((N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -1,1-dioxo-2,3
A compound selected from -dihydro-1-benzothiepine-4-carboxamide or a salt thereof;

Equation (19)

Embedded image (Wherein each symbol is as defined in the above (1)), a salt thereof or a reactive derivative thereof and a compound represented by the formula

Embedded image (In the formula, B and Z have the same meanings as described in the above (1), R ² ′ may be each protected or (1) may be substituted, and the nitrogen atom may be quaternized ammonium. An amino group, (2) a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and may have a nitrogen atom which may be quaternized ammonium, ) A group bonded via a sulfur atom or formula (4)

Embedded image (In the formula, k represents 0 or 1, when k is 0, the phosphorus atom may form a phosphonium salt, and R ⁵ and R ⁶ may each be an optionally substituted hydrocarbon group, Represents an optionally substituted hydroxyl group or an optionally substituted amino group, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom). Wherein the compound represented by the formula (I) or a salt thereof is subjected to a condensation reaction and, if desired, to a deprotection reaction, an oxidation / reduction reaction and / or a quaternization reaction.

Embedded image (Wherein each symbol is as defined in the above (1)) or a method for producing a compound thereof or a salt thereof;

Embedded image (Wherein R ¹ represents a 5- or 6-membered ring which may be substituted) or a salt thereof;

(21) A pharmaceutical composition comprising the compound according to (1) or a salt thereof; (22) a composition according to (21), which is a CCR antagonist (preferably a CCR5 antagonist); (23) (2) which is a preventive / therapeutic agent for HIV infection.
(24) The composition according to (21), which is a prophylactic / therapeutic agent for AIDS; (25) The composition (21), which is an agent for suppressing AIDS pathological progression.
(26) the composition according to (23), further comprising a protease inhibitor or / and a reverse transcriptase inhibitor; (27) a reverse transcriptase inhibitor comprising zidovudine, didanosine,
Zalcitabine, lamivudine, stavudine, nevirapine,
(28) The composition according to the above (26), which is delavirdine, efavirenz or abacavir; (28) the composition according to the above (26), wherein the protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir or nelfinavir; (29) the above (1) Of a compound of the formula (I) or a salt thereof with a protease inhibitor and / or a reverse transcriptase inhibitor
V for use in the prevention and treatment of infectious diseases;

In the above formula (I), the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” represented by R ¹ includes a 6-membered aromatic hydrocarbon such as benzene, 5- to 6-membered aliphatic hydrocarbons (alicyclic hydrocarbon groups) such as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexanediene, furan, thiophene, pyrrole, imidazole,
Contains 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, such as pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole 5- to 6-membered aromatic heterocycle, tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran Containing one to two heteroatoms selected from nitrogen, sulfur and oxygen, such as tetrahydropyran and tetrahydrothiopyran;
Examples include 6-membered non-aromatic heterocycles, among which benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and tetrahydropyran (preferably a 6-membered ring) Are preferred, and benzene is particularly preferred. Examples of the “substituent” that the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” represented by R ¹ may have include, for example, a halogen atom, nitro,
A 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 an optionally substituted sulfonyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl, an esterified or amidated carboxyl And an optionally substituted aromatic group. Examples of halogen as a substituent of R ¹ include fluorine, chlorine, bromine, iodine and the like, and fluorine and chlorine are particularly preferred.

The alkyl in the alkyl which may be substituted as a substituent of R ¹ is a straight-chain or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , S
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,
C _1-10 alkyl such as nonyl and decyl, preferably lower (C _1-6 ) alkyl. Examples of the substituent on the optionally substituted alkyl include halogen (eg,
Fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,
Hydroxyl group, thiol group which may be substituted (eg, thiol, C _1-4 alkylthio), amino group which may be substituted (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkyl) A 5- or 6-membered cyclic amino such as amino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4) Alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc., optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated and C _1-4 alkoxy -C _1-4 a Kokishi (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy,
Trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C _2-4 alkanoyl (eg,
Acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.)
And the like, and the number of substituents is preferably 1 to 3. Examples of cycloalkyl in cycloalkyl which may be substituted as a substituent of R ¹ include, for example,
C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned. Examples of the substituent in the optionally substituted cycloalkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol group (eg, thiol,
C _1-4 alkylthio), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4
Alkylamino, tetrahydropyrrole, piperazine,
Piperidine, morpholine, thiomorpholine, pyrrole,
A 5- to 6-membered cyclic amino such as imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C _{1) -Four}
Alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, Ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

The substituent in the optionally substituted hydroxyl group as a substituent of R ¹ includes: (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) may be substituted, a hetero atom Cycloalkyl which may be contained (for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl,
(3) a saturated 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms such as thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like (preferably tetrahydropyranyl and the like); Alkenyl which may be substituted (for example, alkenyl having 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, and 3-hexenyl, preferably lower (C _2-6 ) alkenyl and the like); 4) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl, 2
- cyclopentenyl, 2- cyclohexenyl methyl, etc. cycloalkenyl having 3 to 7 carbon atoms and the like); (5) an optionally substituted aralkyl (e.g., phenyl -C _1-4 alkyl (e.g., benzyl, (6) Formyl or an optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), 1 carbon atom)
And (4) alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.); (7) optionally substituted aryl (e.g., phenyl, naphthyl, etc.); The above-mentioned (1) optionally substituted alkyl,
(2) cycloalkyl which may be substituted, (3) alkenyl which may be substituted, (4) cycloalkenyl which may be substituted, (5) aralkyl which may be substituted, (6) substitution The optionally substituted acyl and (7) the optionally substituted substituent of the optionally substituted aryl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, An optionally substituted thiol group (eg, thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, Tetrahydropyrrole, piperazine, piperidine,
A 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole and the like), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl,
Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy and the like; preferably optionally halogenated C _1-4 alkoxy), formyl, C _2-4 alkanoyl (eg, , Acetyl,
Propionyl, etc.), C _1-4 alkylsulfonyl (eg,
Methanesulfonyl, ethanesulfonyl, etc.), an optionally substituted 5- to 6-membered aromatic heterocycle [eg, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine , Pyrimidine,
1-2 kinds of hetero atoms 1-4 selected from nitrogen, sulfur and oxygen such as pyridazine and triazole
A 5- or 6-membered aromatic heterocyclic ring containing the same; a substituent which the heterocyclic ring may have is halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, Thiol group, amino group, carboxyl group, optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy , Ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) And the number of substituents is preferably 1 to 3. And the like, and as the number of substituents,
1-3 are preferred.

[0012] Examples of the substituent in the optionally substituted thiol group as the substituent for R ^1, and the "R ¹
And the same as the substituent of the optionally substituted hydroxyl group as a substituent of the above (1) alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) an optionally substituted aralkyl (e.g., phenyl -C _1-4 alkyl (e.g., benzyl, (4) optionally substituted aryl (eg, phenyl, naphthyl, etc.) and the like, and the above-mentioned (1) optionally substituted alkyl, (2) substituted Examples of the cycloalkyl which may be substituted, (3) optionally substituted aralkyl, and (4) optionally substituted aryl may include halogen (eg, fluorine, chlorine, bromine, Iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol groups (eg, thiol,
C _1-4 alkylthio), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4
Alkylamino, tetrahydropyrrole, piperazine,
Piperidine, morpholine, thiomorpholine, pyrrole,
A 5- to 6-membered cyclic amino such as imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C _{1) -Four}
Alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, Ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

[0013] The substituent of the optionally substituted amino group as the substituent of R ^1, the above-mentioned "substituents in the optionally substituted hydroxyl group as the substituent of R ^1"
And amino groups which may have 1 to 2 substituents, such as (1) alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) , Sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 And alkenyl having 2 to 10 carbon atoms, such as hexenyl, and preferably lower (C _2-6 ) alkenyl .; (4) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) , 2
-Cyclopentenylmethyl, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclohexenylmethyl and the like); (5) formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, Acetyl, propionyl, butyryl, isobutyryl, etc.), having 1 carbon atom
And (4) alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.); and (6) optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like, and the above (1) A) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) substituted And the optionally substituted acyl and (6) the optionally substituted substituent of the optionally substituted aryl include halogen (eg, fluorine, chlorine,
Bromine, iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (eg, thiol, C _1-4 alkylthio etc.), optionally substituted amino group (eg,
Amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 5- to 6-membered cyclic amino such as imidazole, etc.), esterification or amidation Optionally substituted carboxyl groups (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, diC _1-4 alkylcarbamoyl), optionally halogenated C
_1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy,
Trifluoromethoxy, trifluoroethoxy, etc.),
Formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), and the like,
The number of substituents is preferably 1 to 3. Also, R ¹
The amino group which may be substituted as a substituent is a cyclic amino group (for example, tetrahydropyrrole, piperazine, piperidine,
A 5- or 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole and imidazole). The cyclic amino group may have a substituent. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol. (Eg, thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine,
A 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole and the like), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl,
Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, Methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

The optionally substituted acyl as a substituent of R ¹ includes (1) hydrogen, (2) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (3) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (4) an optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 And alkenyl having 2 to 10 carbon atoms such as -hexenyl, preferably lower ( _C2-6 ) alkenyl and the like); (5) optionally substituted cycloalkenyl (for example, 2-cyclopentenyl, 2-cyclohexenyl) , 2
-Cyclopentenylmethyl, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclohexenylmethyl); (6) a 5- or 6-membered monocyclic aromatic group which may be substituted (for example, phenyl, And the like bonded to a carbonyl group or a sulfonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, Cycloheptanecarbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.), and 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 Examples of the substituent which the monocyclic aromatic group may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol group (eg, thiol , C _1-4 alkylthio), an optionally substituted amino group (eg, amino,
Mono-C _1-4 alkylamino, di-C _1-4 alkylamino, tetrahydropyrrole, 5- or 6-membered cyclic amino such as piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), esterified or amidated Carboxyl group (eg, 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 (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl,
C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like are preferable, and the number of substituents is preferably 1 to 3.

The carboxyl group which may be esterified as a substituent of R ¹ includes (1) hydrogen, (2) alkyl which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (3) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (4) an optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 And alkenyl having 2 to 10 carbon atoms such as -hexenyl, preferably lower ( _C2-6 ) alkenyl and the like); (5) optionally substituted cycloalkenyl (for example, 2-cyclopentenyl, 2-cyclohexenyl) , 2
And cycloalkenyl having 3 to 7 carbon atoms such as -cyclopentenylmethyl and 2-cyclohexenylmethyl); (6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) is bonded to a carbonyloxy group; And preferably, carboxyl, lower (C _1-6 ) alkoxycarbonyl, aryloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), and the above-mentioned (2) Alkyl which may be substituted, (3) cycloalkyl which may be substituted, (4) alkenyl which may be substituted,
Examples of the (5) cycloalkenyl which may be substituted and (6) the substituent which the aryl which may be substituted may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro , Cyano, hydroxyl group, thiol group which may be substituted (eg, thiol, C _1-4 alkylthio), amino group which may be substituted (eg, amino, mono C _1-4 alkylamino, di C _{1 -4} alkylamino, tetrahydropyrrole, piperazine, piperidine,
A 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole and the like), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl,
Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, Methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3. As the amidated carboxyl group which may be as a substituent of R ^1, described above may be "substituted similar to" R ¹ of the optionally substituted amino group as a substituent " Examples thereof include those in which an “amino group” and the like are bonded to a carbonyl group, preferably carbamoyl, mono-C _1-6 alkylcarbamoyl, di-C _1-6 alkylcarbamoyl and the like.

Examples of the aromatic group in the aromatic group which may be substituted as R ¹ include phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, 5- to 6-membered homo- or heterocyclic aromatic groups such as pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl, benzofuran, indole, benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline And condensed heterocyclic aromatic groups such as cinnoline. Examples of the substituent of these aromatic groups include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol (eg,
Thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole,
5- or 6-membered cyclic amino such as piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy,
Propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3. Such R ¹ substituents may be the same or different and may be substituted at any position of the ring at 1 to 4 (preferably 1 to 2). When the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” represented by R ¹ has two or more substituents, two of these substituents By bonding, for example, lower (C _1-6 ) alkylene (eg, trimethylene, tetramethylene, etc.), lower (C
_1-6) alkyleneoxy (for _{example, -CH 2 -O-CH 2 -} ,
_{-O-CH 2 -CH 2 -,} - O-CH 2 -CH 2 -CH
_{2 -, - O-CH 2} -CH 2 -CH 2 -CH 2 -, - O-C
(CH ₃ ) (CH ₃ ) —CH ₂ —CH ₂ —, etc.), lower (C _1-6 ) alkylenethio (eg, —CH ₂ —S—CH)
_{2 -, - S-CH 2} -CH 2 -, - S-CH 2 -CH 2 -C
_{H 2 -, - S-CH} 2 -CH 2 -CH 2 -CH 2 -, - S-
C (CH ₃ ) (CH ₃ ) —CH ₂ —CH ₂ —, etc.), lower (C
_1-6) alkylenedioxy _{(e.g., -O-CH 2 -O -,} -
_{O-CH 2 -CH 2 -O -} , - O-CH 2 -CH 2 -CH 2
—O—), lower (C _1-6 ) alkylenedithio (eg,
_{-S-CH 2 -S -, -} S-CH 2 -CH 2 -S -, - S
—CH ₂ —CH ₂ —CH ₂ —S—), oxy lower (C
_1-6) alkyleneamino (for _{example, -O-CH 2 -NH -,} -
O-CH ₂ -CH ₂ -NH-, etc.), oxy-lower (C _1-6) alkylenethio (for _{example, -O-CH 2 -S -,} -
O-CH ₂ -CH ₂ -S-, etc.), lower (C _1-6) alkyleneamino (for _{example, -NH-CH 2 -CH 2 -} , - NH-C
H ₂ -CH ₂ -CH ₂ -, etc.), lower (C _1-6) alkylene amino _{(e.g., -NH-CH 2 -NH -,} - NH-CH 2
—CH ₂ —NH—, etc., thia lower (C _1-6 ) alkyleneamino (eg, —S—CH ₂ —NH—, —S—CH ₂ —CH
_2- NH-), lower ( _C2-6 ) alkenylene (eg,-
_{CH 2 -CH = CH -, -} CH 2 -CH 2 -CH = CH
_{-, - CH 2 -CH = CH} -CH 2 - , etc.), lower (C
_4-6 ) Alkadienylene (eg, -CH = CH-CH = C
H-) and the like. When two substituents of R ¹ are bonded to each other to form a divalent group containing a hetero atom (an oxygen atom, a sulfur atom, a nitrogen atom, or the like), the divalent group has an unsaturated bond. And specific examples thereof include -O-CH = CH-, -O-
_{CH = CH-CH 2 -,} - O-CH 2 -CH = CH -, -
S-CH = CH -, - S-CH = CH-CH 2 -, - S
_{-CH 2 -CH = CH -, -} O-CH = CH-O -, -
_{O-CH = CH-CH 2} -O -, - S-CH = CH-S
-, - S-CH = CH -CH 2 -S -, - O-CH = N
_{-, - O-CH 2 -CH} = N -, - O-CH = CH-N
H -, - S-CH = N -, - S-CH 2 -CH = N-,
-S-CH = CH-NH-, -O-CH = CH-S-,
_{-N = CH-CH 2 -,} - NH-CH = CH -, - N =
_{CH-CH 2 -CH 2 -,} - NH-CH = CH-CH
_{2 -, - NH-CH 2} -CH = CH -, - N = CH-NH
-, - NH-CH = CH -NH -, - N = CH-CH 2
-NH- or the like (preferably -O-CH = CH-, -S
-CH = CH-, -O-CH = N-, -S-CH = N-
Etc.). Further, the divalent group formed by bonding two substituents of R ¹ to each other has a “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” represented by R ^1. The same substituents as the "substituent" (halogen atom, nitro, cyano, alkyl which may be substituted,
Optionally substituted cycloalkyl, optionally substituted hydroxyl group, optionally substituted thiol group (sulfur atom may be oxidized, optionally substituted sulfinyl group or optionally substituted Which may form a good sulfonyl group), an amino group which may be substituted, an acyl which may be substituted, a carboxyl group which may be esterified or amidated, an aromatic group which may be substituted Groups).
As the “substituent” which the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” for R ¹ may have, halogenated or lower (C _{1- 4} ) lower alkoxy (C _1-4 ) alkyl which may be alkoxylated (eg, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, etc. butoxyethyl), halogenated, or lower (C _1-4) which may lower optionally be alkoxylated (C _1-4)
Alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, Ethoxypropoxy,
Propoxypropoxy, butoxypropoxy, etc.), halogen (eg, fluorine, chlorine, etc.), nitro, cyano,
Amino (optionally substituted with ２2 lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy-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 (e.g., 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino,
-Imidazolyl, 4-tetrahydropyranyl, etc.), and when R ¹ is benzene, the substitution position is preferably the para position.

In the above formula (I), the "substituent" which may be possessed by the "6- to 7-membered ring" of the "optionally substituted 6- to 7-membered ring" represented by A is R ^{The same} “substituent” as the “substituent” which the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” represented by 1 may have. Further, the substituent of A is 1 to 3 (preferably 1 to
2) may be the same or different and may be substituted at any position of the ring,

Embedded image In the group represented by, the carbon atom at position a is preferably unsubstituted. As the “optionally substituted 6- to 7-membered ring” for A, for example,

Embedded image And a 6- to 7-membered ring which may have a substituent at any substitutable position.

In the above formula, the divalent group represented by Y is a ring A
There a divalent group forming a 6-7 membered ring which may be substituted, for _{example, (1) -CH 2 -O -} , (2) -CH 2 -
S -, (3) - ( CH 2) d1 - (d 1 is 1 or 2), - CH = CH - , (4) - (CH 2) e1 -NH- (C
H _{2) e2} - (one is 0 e ₁ and e _2, the other is 0 or 1), -. N = CH -, - CH = , etc. N- can be mentioned. Specifically, for _{example, -CH 2 -O -, - CH} 2
_{-S -, - CH 2 -,} - (CH 2) 2 -, - CH = CH
And divalent groups such as-, -NH-, -N = CH- and -CH = N-. Further, the divalent group may have a substituent, and the substituent may be a “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” for R ^1. And the like, and oxo, etc. which may be possessed by "), among which lower (C _1-3 ) alkyl (eg, methyl, ethyl, propyl, etc.), phenyl, oxo, Hydroxyl groups are preferred. Further, the divalent group may be a group such as -OC (O)-. One or two substituents of such a divalent group may be the same or different. The substitution position may be any position as long as it can bind to the divalent group.

The divalent group represented by Y includes-(CH
₂ ) _m- (m represents 1 or 2), -CH = CH-,-
Preferably a group such as N = CH-, among others - (CH _{2) m}
-(M represents 1 or 2) is preferable, and-
(CH _{2) 2} - are preferred. The "substituent" which the "benzene ring" of the "optionally substituted benzene ring" for B may have is a "optionally substituted 5- to 6-membered ring" for R ¹ And the same as the "substituent" which the "5- to 6-membered ring" may have, among which halogen (eg, fluorine, chlorine, bromine, iodine, etc.),
Nitro, cyano, hydroxyl group, thiol group which may be substituted (eg, thiol, C _1-4 alkylthio), amino group which may be substituted (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc., optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.) ), halogenated which may be C _1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy Shi, trifluoromethoxy, etc. trifluoroethoxy), formyl, C _2-4 alkanoyl (e.g.,
Acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.)
And the like, particularly preferably halogen, C _1-4 alkyl which may be halogenated, C _1-4 alkoxy which may be halogenated, and the number of substituents is preferably
1-3 are preferred. In the above formula (I), n is 1 or 2
(Preferably 2).

In the above formula (I), the divalent group represented by Z is a divalent group having a carbon chain of 1 to 4 atoms which may have a substituent (for example, C _{1- 4} alkylene, C _2-4 alkenylene and the like, preferably C _1-3 alkylene, more preferably methylene) and the like. The divalent group represented by Z may be any divalent chain having 1 to 4 atoms constituting the straight-chain portion. For example,-(CH ₂ ) _k1- (k ₁ is 1 An alkylene chain represented by — (CH ₂ ) _k2 — (CH ＝ CH) — (CH ₂ ) _k3 —
(K ₂ and k ₃ are the same or different and each represents 0, 1 or 2, provided that the sum of k ₂ and k ₃ is 2 or less). The substituent of the divalent group represented by Z may be any substituent as long as it can be bonded to the divalent chain constituting the straight-chain portion. For example, lower alkyl having 1 to 6 carbon atoms (eg, , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C _3-7 )
Cycloalkyl (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C _2-7 ) alkanoyl (eg, acetyl, propionyl, butyryl, etc.), optionally esterified phosphono group, optionally esterified carboxyl group, A hydroxyl group, oxo, etc., and preferably a lower alkyl having 1 to 6 carbon atoms (preferably,
C _1-3 alkyl), a hydroxyl group, oxo and the like.

The phosphono group which may be esterified includes P (O) (OR ⁷ ) (OR ⁸ ) wherein R ⁷ and R ⁸
Represents 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. Are performed. In the above formula, the alkyl group having 1 to 6 carbon atoms represented by R ⁷ and R ⁸ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, and the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, but preferably A chain lower alkyl having 1 to 6 carbon atoms, more preferably 1 to 6 carbon atoms
And 3 lower alkyls. R ⁷ and R ⁸ may be the same or different, but are preferably the same. Further, when R ⁷ and R ⁸ to form a 5- to 7-membered ring bonded to each other to bond and R ⁷ and R ⁸ _{together, - (CH 2) 2 -} , - (CH 2) 3 -, A linear C _2-4 alkylene side chain represented by — (CH ₂ ) ₄ — is formed. The side chain may have a substituent. Examples of the substituent include a hydroxyl group and a halogen. Examples of the esterified carboxyl group which may be esterified include a carboxyl group and an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, And propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

Examples of the divalent group represented by Z, an optionally substituted C _1-3 alkylene, inter alia C _1-3 alkyl, optionally C _1-3 optionally substituted by hydroxyl or oxo
Alkylene is preferred. Further, examples of the divalent group represented by Z, -Z a benzene ring starting from '- (CH _{2) n}
— Or — (CH ₂ ) _{n ′} —Z ′ — (Z ′ is —CH (OH)
—, —C (O) — or —CH ₂ —, and n ′ is 0 to
2 represents an integer, each methylene group 1-2 of the same or different substituted represented by may also be) groups, among others, -Z a benzene ring starting from '- (CH ₂ ) _{N '}
-(Z 'is -CH (OH)-, -C (O)-or -C
H _2- , wherein n ′ is an integer of 0 to 2 (preferably n ′
Represents 0), and each methylene group may have 1 to 2 same or different substituents), and methylene is particularly preferable. In the above formula (I),
R ^{4 represents} an optionally substituted nitrogen atom having 4
"Amino group" of an amino group which may be quaternized ammonium (preferably an amino group which may be substituted)
Examples thereof include an amino group which may have 1 to 2 substituents, an amino group having 3 substituents, and a quaternary ammonium nitrogen atom. When there are two or more substituents on the nitrogen atom, those substituents may be the same or different, and the substituent on the nitrogen atom may be 3 or more.
If a ^{_{number, -N + R 3, -N +}} R 2 R ' and -N ⁺ R
R′R ″ (R, R ′ and R ″ are each different;
(Indicating hydrogen or a substituent). Also, as a counter anion of an amino group in which a nitrogen atom is quaternary ammonium,
In addition to halogen atom anions (eg, Cl ⁻ , Br ⁻ , I ^−, etc.), anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid ,
Anions derived from organic acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid And anions derived from acidic amino acids such as glutamic acid and the like. Among them, Cl ⁻ , Br ⁻ , I ^{− and the} like are preferable.

Examples of the substituent of the amino group include: (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
_3-8 cycloalkyl and the like); (2-1) the cycloalkyl is a sulfur atom, a hetero atom selected from oxygen and nitrogen atoms containing one, oxirane, thiolane, aziridine, tetrahydrofuran, tetrahydrothiophene , Pyrrolidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, piperidine and the like (preferably,
(6-membered tetrahydropyran, tetrahydrothiopyran, piperidine, etc.), and the bonding position with the amino group is preferably at the 3- or 4-position (preferably at the 4-position); (2-2) The cycloalkyl may be condensed with a benzene ring to form indane, tetrahydronaphthalene or the like (preferably, indane or the like);
3) Further, the cycloalkyl is cross-linked through a linear atom chain having 1 to 2 carbon atoms to form bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3 2.2.1] octyl, bicyclo [3.2.2] nonyl and the like (preferably cyclohexyl having a bridge through a linear atom chain having 1 to 2 carbon atoms, more preferably bicyclo [2. 2.1] heptyl and the like; (3) optionally substituted alkenyl (eg, allyl, crotyl, 2-pentenyl, 3-hexenyl) an alkenyl of 2 to 10 carbon atoms, preferably lower (C _2-6) such as alkenyl and the like); (4) optionally substituted cycloalkenyl (e.g., 2-cyclopentenyl, 2-cyclohexenyl,
- cyclopentenyl, 2- cyclohexenyl methyl, etc. cycloalkenyl having 3 to 7 carbon atoms and the like); (5) an optionally substituted aralkyl (e.g., phenyl -C _1-4 alkyl (e.g., benzyl, (6) Formyl or an optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), 1 carbon atom)
And (4) alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); (7) optionally substituted aryl (eg, phenyl, naphthyl, etc.); (8) optionally substituted complex A ring group (for example, one selected from a nitrogen atom, a sulfur atom, and an oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazole; A 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms, tetrahydrofuran, tetrahydrothiophene, dithiolane,
Oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran and other nitrogen, sulfur and oxygen atoms 1-2 kinds of hetero atoms 1-4
5 to 6-membered non-aromatic heterocyclic ring or the like; preferably 5 to 6-membered non-aromatic heterocyclic ring or the like; more preferably one such as tetrahydrofuran, piperidine, tetrahydropyran or tetrahydrothiopyran And a 5- or 6-membered non-aromatic heterocyclic ring containing a hetero atom. Further, 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, and thiomorpholine.

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl,
(3) alkenyl optionally substituted, (4) cycloalkenyl optionally substituted, (5) aralkyl optionally substituted, (6) acyl optionally substituted, (7) substituted acyl Examples of the aryl which may be substituted and (8) the substituent which the heterocyclic group which may be substituted may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), halogenated Lower (C _1-4 ) alkyl, optionally halogenated C _1-4
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _1-4 alkylenedioxy (eg, —O—CH ₂ —
_{O -, - O-CH 2} -CH 2 -O- , etc.), formyl, C _2-4
Alkanoyl (eg, acetyl, propionyl, etc.), C
_1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), phenyl-lower (C _1-4 ) alkyl, C _3-7 cycloalkyl, cyano, nitro, hydroxyl,
An optionally substituted thiol group (eg, thiol, C
_An optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, etc.) A 5- to 6-membered cyclic amino such as imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C _{1) -Four}
Alkylcarbamoyl, etc.), lower (C _1-4 ) alkoxy-carbonyl, oxo group (preferably halogen, lower (C _1-4 ) alkyl which may be halogenated, lower (C _1-4 ) which may be halogenated _1-4 ) alkoxy,
Phenyl-lower (C _1-4 ) alkyl, C _3-7 cycloalkyl, cyano, hydroxyl group and the like; and the number of substituents is preferably 1 to 3. In the above formula (I), R ²
As the “amino group which may be substituted and the nitrogen atom may be quaternary ammonium” represented by (1), there are (1) 1 to 3 halogen, cyano, hydroxyl or C _3-7 cycloalkyl. Optionally substituted linear or branched lower (C _1-6 ) alkyl; (2) halogen, optionally halogenated lower (C _1-6 )
_1-4 ) alkyl or phenyl-lower (C _1-4 ) alkyl which may have 1 to 3 alkyl (s) and may contain one hetero atom selected from a sulfur atom, an oxygen atom and a nitrogen atom. , Which may be condensed with a benzene ring,
C _5-8 which may be crosslinked via a linear atom chain of 2
Cycloalkyl (eg, each optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo [2.2.1] heptyl and the like (3) Halogen, optionally halogenated lower (C
_1-4 ) phenyl-lower (C _1-4 ) alkyl optionally having 1 to 3 alkyl or optionally halogenated lower (C _1-4 ) alkoxy; (4) halogen, halogenated Low-grade (C
_1-4 ) phenyl optionally having 1 to 3 alkyl or optionally halogenated lower (C _1-4 ) alkoxy; and (5) halogen, optionally halogenated lower (C
_1-4 ) alkyl, optionally halogenated lower (C
_1-4 ) _{1 to 3} alkoxy, optionally halogenated lower (C _1-4 ) alkoxy-lower (C _1-4 ) alkoxy, phenyl-lower (C _1-4 ) alkyl, cyano or hydroxyl groups 5- to 6-membered aromatic heterocyclic ring (eg, furan, thiophene, pyrrole, pyridine, etc.)
1 to 3 (preferably 1 to 2
Amino groups which may be present are preferred.

In the above formula (I), "a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and may have a quaternary ammonium nitrogen atom. Examples of the "nitrogen-containing heterocycle" of the ring group (preferably a nitrogen-containing heterocycle which may be substituted and may contain a sulfur atom or an oxygen atom as a ring-constituting atom) include pyrrole, imidazole, Pyrazole,
One selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom such as thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole.
5 to 6-membered aromatic heterocycle containing from 1 to 2 heteroatoms, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,
Piperazine, oxazine, oxadiazine, thiazine,
1 such as thiadiazine, morpholine, thiomorpholine, azacycloheptane, azacyclooctane (azocan)
A nitrogen atom, a 5- to 8-membered non-aromatic heterocyclic ring containing 1 to 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a nitrogen atom. The nitrogen-containing heterocyclic ring is cross-linked via a linear atom chain having 1 to 2 carbon atoms, and is preferably azabicyclo [2.2.1] heptane, azabicyclo [2.2.2] octane (quinuclidine) (preferably , A piperidine having a bridge through a straight-chain atom chain having 1 to 2 carbon atoms, etc.). Among the specific examples of the nitrogen-containing heterocycle described above, pyridine, imidazole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,
Azabicyclo [2.2.2] octane (preferably 6
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 heterocycle group in which the nitrogen atom is quaternary ammonium” is a halogen atom anion ( examples, Cl ^-, B
r ^-, I ^- in addition to etc.), hydrochloric acid, hydrobromic acid, nitric acid,
Anions derived from inorganic acids such as sulfuric acid and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , anions derived from organic acids such as p- toluenesulfonic acid, aspartic acid, etc. anions derived from acidic amino acids such as glutamic acid, among others, Cl ^-, B
r ^-, I ^- and the like are preferable. The "nitrogen-containing heterocyclic ring" may be bonded to the divalent group represented by Z via any of a carbon atom and a nitrogen atom, and may be, for example, 2-pyridyl, 3-pyridyl, 2-piperidinyl and the like. May be bonded via a carbon atom,

Embedded image It is preferable to bond through a nitrogen atom as in, for example.

Examples of the substituent which the “nitrogen-containing heterocycle” may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.) and 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, optionally substituted thiol (eg, thiol, C _1-4 alkylthio), optionally substituted amino (eg, amino, mono C _1-4 alkylamino, di C _{1- 4-} alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 5- or 6-membered cyclic amino such as imidazole, etc., carboxyl group which may be esterified or amidated (eg, carboxyl, C _{1) -4} alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), lower (C _1-4) alkoxy - carbonyl, formyl, lower (C _2-4) alkanoyl, lower (C _1-4) alkylsulfonyl, optionally substituted Hajime Tamaki (e.g., furan, thiophene, pyrrole, Imi One to two types of heteroatoms selected from nitrogen, sulfur and oxygen, such as azole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc. Containing a 5- to 6-membered aromatic heterocycle, tetrahydrofuran, tetrahydrothiophene, dithiolane,
Nitrogen, sulfur and oxygen atoms such as oxathiolane, pyrrolidine, pyrroline, imidazolidin, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran and the like. 1 selected from
A 5- to 6-membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms, and the like.
Three are preferred. Further, the nitrogen atom of the “nitrogen-containing heterocycle” may be oxidized. “Optionally substituted lower (C _1-4 ) alkyl” and “optionally substituted lower (C _1-4 ) alkoxy” as substituents that the “nitrogen-containing heterocycle” may have "Optionally substituted phenyl", "optionally substituted mono- or diphenyl-lower ( _C1-4 ) alkyl", "optionally substituted _{C3-7cycloalkyl} " and "substituted Examples of the substituent which the “optionally substituted heterocyclic group” may have include, for example, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and optionally halogenated lower (C _{1- 4} )
Alkyl, lower (C _3-10 ) cycloalkyl, lower (C
_3-10 ) Cycloalkenyl, optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, Acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.),
C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), cyano, nitro, hydroxyl, optionally substituted thiol group (eg, thiol, C _1-4 alkylthio, etc.), substituted Amino group (eg, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole, etc. Carboxyl group which may be esterified or amidated (eg, 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 like.
1-3 are preferred.

In the above formula (I), "a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and may have a nitrogen atom which may be quaternized ammonium. Examples of the substituent which the “nitrogen-containing heterocyclic ring” of the “ring group” may have include (1) halogen, (2) cyano, (3) hydroxyl, (4) carboxyl, and (5) lower (C _{1 -4)} alkoxy - carbonyl, (6) halogen, hydroxy or lower (C _1-4) which may lower substituted with alkoxy (C _1-4) alkyl, (7) halogen, hydroxyl or a lower (C _{1- 4} ) lower (C _1-4 ) alkoxy optionally substituted with alkoxy, (8) halogen, lower (C _1-4 ) alkyl, hydroxyl group, lower (C _1-4 ) alkoxy or C _1-3 alkylenediyl Phenyl optionally substituted with oxy, (9) Androgenic, lower (C _1-4)
Alkyl, hydroxyl, lower (C _1-4 ) alkoxy or C
Mono- or diphenyl-lower (C _1-4 ) alkyl optionally substituted with _1-3 alkylenedioxy, (10) 5- to 6-membered aromatic heterocycle such as furan, thiophene, pyrrole, pyridine and the like are preferable. .

In the above formula (I), the “group bonded via a sulfur atom” represented by R ² is a group represented by the formula —S (O) _{m ′} —R ^S
(Wherein m ′ represents an integer of 0 to 2, and R ^S represents a substituent). In the above formula, the substituent represented by R ^S includes, for example, (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) an optionally substituted aralkyl (e.g., phenyl -C _1-4 alkyl (e.g., benzyl, (4) optionally substituted aryl (eg, phenyl, naphthyl, etc.), and the like; (1) optionally substituted alkyl, (2) Examples of the substituent which the optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) optionally substituted aryl may have include halogen (eg, fluorine, chlorine) , Bromine, iodine, etc.), nitro,
Cyano, hydroxyl group, thiol group which may be substituted (eg, thiol, C _1-4 alkylthio), amino group which may be substituted (eg, amino, mono C _1-4 alkylamino, di C _{1- 4} alkylamino, tetrahydropyrrole, piperazine, piperidine, 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole, etc.), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _{1 -4} alkoxycarbonyl, carbamoyl, mono C _1-4 alkyl carbamoyl, di C _1-4 alkyl carbamoyl, etc., optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), good C _1-4 alkoxy (eg be halogenated, methoxy, ethoxy, propoxy, butoxy, tri Ruorometokishi and trifluoroethoxy), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, etc. ethanesulfonyl), and the like, as the number of the substituents Is 1 to
Three are preferred.

In the above formula (I), the formula represented by R ²

Embedded image (In the formula, k represents 0 or 1, and when k is 0, the phosphorus atom may form a phosphonium salt (preferably does not form a phosphonium salt), and R ⁵ and R ⁶ are each substituted. An optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group (preferably an optionally substituted hydrocarbon group or an optionally substituted amino group), R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with the adjacent phosphorus atom), and the hydrocarbon group which may be substituted and represented by R ⁵ and R ⁶ Examples of the “hydrocarbon group” in (1) include (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 Alkenyl having 2 to 10 carbon atoms such as hexenyl, preferably lower (C _2-6 ) alkenyl and the like; (4) cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, 2-cyclo Hexenyl, 2
-Cyclopentenylmethyl, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclohexenylmethyl and the like); (5) alkynyl which may be substituted (for example, ethynyl, 1-propynyl, 2-propynyl, 1- C2-C2 such as butynyl, 2-pentynyl and 3-hexynyl
(6) alkynyl, preferably lower (C _2-6 ) alkynyl; and (6) optionally substituted aralkyl (eg, phenyl-C _1-4 alkyl (eg, benzyl, phenethyl and the like) and the like. (7) aryl which may be substituted (for example, phenyl, naphthyl and the like), and the like; (1) alkyl which may be substituted, (2) substituted Cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted alkynyl, (6) optionally substituted aralkyl, And (7) substituents which the optionally substituted aryl may have include halogens (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, Bruno, hydroxyl, 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, tetrahydropyrrole, piperazine, piperidine,
A 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole and the like), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl,
Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, Methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3.

The “optionally substituted hydroxyl group” represented by R ⁵ and R ⁶ includes, for example, (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 And alkenyl having 2 to 10 carbon atoms, such as hexenyl, and preferably lower (C _2-6 ) alkenyl .; (4) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) , 2
- cyclopentenyl, 2- cyclohexenyl methyl, etc. cycloalkenyl having 3 to 7 carbon atoms and the like); (5) an optionally substituted aralkyl (e.g., phenyl -C _1-4 alkyl (e.g., benzyl, (6) Formyl or an optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), 1 carbon atom)
And (4) alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and (7) optionally substituted aryl (eg, phenyl, naphthyl, etc.). And a hydroxyl group.

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) substituted Examples of the substituent which the optionally substituted aryl may have include halogen (eg, fluorine,
Chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl,
An optionally substituted thiol group (eg, thiol, C
_An optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, etc.) A 5- to 6-membered cyclic amino such as imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C _{1) -Four}
Alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, Ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3. Examples of the optionally substituted amino group represented by R ⁵ and R ⁶ include: (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, C _1-10 alkyl such as decyl, preferably lower (C _1-6) such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (3) optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 And alkenyl having 2 to 10 carbon atoms, such as hexenyl, and preferably lower (C _2-6 ) alkenyl .; (4) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) , 2
-Cyclopentenylmethyl, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclohexenylmethyl and the like); (5) formyl or optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, Acetyl, propionyl, butyryl, isobutyryl, etc.), having 1 carbon atom
(4) alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like; (6) optionally substituted aryl (e.g., phenyl, naphthyl, etc.) And an optionally substituted amino group.

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl,
(3) alkenyl which may be substituted, (4) cycloalkenyl which may be substituted, (5) acyl which may be substituted, and (6) aryl which may be substituted. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol (eg,
Thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole,
5- or 6-membered cyclic amino such as piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, Mono C _1-4 alkylcarbamoyl, di C _1-4 alkylcarbamoyl, etc.), optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy,
Propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3. In the above formula, R ⁵ and R ⁶ are bonded to each other to form a cyclic group (preferably 5
To a 7-membered ring). Such a cyclic group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro,
Cyano, hydroxyl group, thiol group which may be substituted (eg, thiol, C _1-4 alkylthio), amino group which may be substituted (eg, amino, mono C _1-4 alkylamino, di C _{1- 4} alkylamino, tetrahydropyrrole, piperazine, piperidine, 5- to 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole, etc.), a carboxyl group which may be esterified or amidated (eg, carboxyl, C _{1 -4} alkoxycarbonyl, carbamoyl, mono C _1-4 alkyl carbamoyl, di C _1-4 alkyl carbamoyl, etc., optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), good C _1-4 alkoxy (eg be halogenated, methoxy, ethoxy, propoxy, butoxy, tri Ruorometokishi and trifluoroethoxy), formyl, C _2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (e.g., methanesulfonyl, etc. ethanesulfonyl), and the like, as the number of the substituents Is 1 to
Three are preferred. In the above formula, as the counter anion when the phosphorus atom forms a phosphonium salt, in addition to an anion of a halogen atom (eg, Cl ⁻ , Br ⁻ , I ^{− and the} like), hydrochloric acid, hydrobromic acid, Anions derived from inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Examples include anions derived from organic acids such as 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 them, Cl ⁻ , Br ⁻ , I ^{− and the} like are preferable.

As R ² , (1) an amino group which may be substituted and a nitrogen atom of which may be quaternary ammonium (preferably an amino group which may be substituted); May contain a sulfur atom or an oxygen atom as a ring-constituting atom, and may contain a nitrogen-containing heterocyclic group in which a nitrogen atom may be quaternary ammonium (preferably, A nitrogen-containing heterocyclic group which may contain a sulfur atom or an oxygen atom as a ring-constituting atom),

Embedded image (In the formula, R ⁵ and R ⁶ each represent an optionally substituted hydrocarbon group, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom.) And the like are preferred.

R ² is preferably (1) an amino group which may be substituted and whose nitrogen atom is not quaternary ammonium, and a group represented by the formula —NRR ′ (wherein R and R ′) Represents an optionally substituted aliphatic hydrocarbon group (aliphatic chain hydrocarbon group and aliphatic cyclic hydrocarbon group) or an optionally substituted alicyclic (non-aromatic) heterocyclic group Is more preferred. In the above formula, the “optionally substituted aliphatic hydrocarbon group” and “optionally substituted alicyclic heterocyclic group” represented by R and R ′ are the same as those represented by the substituent R ^2. “Optionally substituted aliphatic hydrocarbon group (eg, optionally substituted alkyl, cycloalkyl, alkenyl”) exemplified as the substituent which the “optionally substituted amino group” may have , Cycloalkenyl, etc.) "and" optionally substituted alicyclic heterocyclic groups (eg, optionally substituted 5- to 6-membered non-aromatic heterocycles) ". Among them, R is preferably an optionally substituted chain hydrocarbon group (eg, optionally substituted alkyl, alkenyl, etc.), and further preferably is an optionally substituted C _1-6 alkyl group. Preference is given, in particular, to an optionally substituted methyl group. R ′ is an optionally substituted chain hydrocarbon group (eg, optionally substituted alkyl, alkenyl, etc .; preferably, an optionally substituted C _1-6 alkyl group; more preferably, , An optionally substituted ethyl group), an optionally substituted alicyclic hydrocarbon group (eg, optionally substituted cycloalkyl, cycloalkenyl, etc .; preferably an optionally substituted C _3-8 cycloalkyl group; more preferably optionally substituted cyclohexyl) or optionally substituted alicyclic heterocyclic group (preferably optionally substituted saturated heterocyclic group (preferably 6 Membered ring group); more preferably, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrothiopyranyl, or optionally substituted pipe Jyl; particularly preferably, optionally substituted tetrahydropyranyl), and particularly preferably an optionally substituted alicyclic hydrocarbon group, an optionally substituted alicyclic heterocyclic group and the like. .

The salt of the compound represented by the formula (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, Salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like are included. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, 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 -Salts with toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include:
For example, salts with arginine, lysine, ornithine and the like are mentioned, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid. The compound represented by the formula (I) of the present invention may be a hydrate or a non-hydrate. When the compound represented by the formula (I) of the present invention exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, if necessary, separation and separation known per se may be performed. Each can be isolated by purification means. When the compound represented by the formula (I) is in a racemic form, the compound represented by the formula (S)
And (R) -isomers, and each of the optically active isomers and the racemic isomers are included in the present invention. The compound represented by the formula (I) used in the present invention or a salt thereof [hereinafter may be referred to as compound (I). Is a compound that is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, is converted into compound (I) by enzymatically causing oxidation, reduction, hydrolysis, etc. The compound is a compound which undergoes hydrolysis or the like by gastric acid or the like to be converted into the compound (I). Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). ,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,
Compound (I) such as tert-butylated compound);
A compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated,
Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxyl group of compound (I) is esterified or amidated (eg, the carboxyl group of compound (I) is ethyl esterified) Phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolene) -4-yl) methylesterification, cyclohexyloxycarbonylethylesterification, methylamidated compound, etc.); These compounds can be produced from compound (I) by a method known per se. Further, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pages 163 to 198, Molecular Design. It may be. Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

The compound of the present invention represented by the formula (I) or a salt thereof (hereinafter sometimes abbreviated as compound (I))
Is used alone or in combination with a pharmaceutically acceptable carrier,
They can be administered orally or parenterally (preferably orally) as solid preparations such as tablets, capsules, granules and powders; or as liquid preparations such as syrups and injections. Parenteral administration forms include injections, infusions, suppositories, vaginal suppositories, etc.
Useful for prevention of infectious diseases. Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. , A suspending agent, an isotonic agent, a buffer, a soothing agent and the like. Also, if necessary, preservatives, antioxidants,
Pharmaceutical additives such as coloring agents and sweetening agents can also be used. Suitable examples of excipients include, for example, lactose, sucrose, D
-Mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferred examples of the lubricant include:
Examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, crystalline cellulose, sucrose,
D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferred examples of the solvent include:
For example, water for injection, alcohol, propylene glycol,
Macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Suitable examples of tonicity agents include, for example, sodium chloride, glycerin, D
-Mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like.
Preferred examples of preservatives include, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol,
Phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The present invention further provides a method for producing a compound represented by the formula (I) or a salt thereof. The compound represented by the formula (I) or a salt thereof can be produced by a method known per se (for example, the method described in JP-A-8-73476) or a method analogous thereto. Further, for example, it can be produced according to the following method. Equations (II) and (I
I '), (III), (IV), (V), (I-1), (I-
As the salts of the compounds represented by 2), (I-3) and (I-4), those similar to the salts with compound (I) are used. In each of the following reactions, when the raw material 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 is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 alkylcarbonyl optionally having a substituent (eg, acetyl, propionyl, etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg, methoxycarbonyl) , Ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzooxycarbonyl, etc.), C
_7-10 aralkyloxycarbonyl (for example, benzyloxycarbonyl), trityl, phthaloyl and the like are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), nitro groups and the like are used. Is about one to three. Examples of the carboxyl-protecting group include a C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, propyl, isopropyl,
Butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkylcarbonyl (eg, acetyl,
Propionyl, butyryl, etc.), formyl, nitro group and the like are used, and the number of substituents is about 1 to 3.

Examples of the protecting group for the hydroxyl group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert.
- butyl, etc.), phenyl, C _7-10 aralkyl (e.g., benzyl etc.), C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (e.g., Benzyloxycarbonyl), pyranyl, furanyl, silyl and the like. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10
Aralkyl, nitro group, etc. are used, and the number of substituents is 1
Or about four. As a method for introducing and removing the protecting group, a method known per se or a method analogous thereto (for example, a method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press)) is used. As a removal method, for example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

[Method A]

Embedded image [In the formula, each symbol has the same meaning as described above.] In the present method, the compound [II], a salt thereof or a reactive derivative thereof is reacted with the aniline derivative [III] or a salt thereof to prepare the anilide compound [I-1]. ] Can be manufactured. The condensation reaction of [II] and [III] is carried out by ordinary peptide synthesis means. The peptide synthesis means may be in accordance with any known method, for example, M. Bodansky and M.
A. Ondetti, Peptide Synt
hesis), Interscience, New York, 196
6 years; The Proteins, by FM Finn and K. Hofmann, Volume 2, H. Nenrath, RL Hill
Editing, Academic Press Inc. New York, 1976; Methods described in Nobuo Izumiya et al., "Basic and Experimental Peptide Synthesis", Maruzen Co., Ltd., 1985, for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method. , DCC method, active ester method, method using Woodward reagent K, carbonyl diimidazole method, redox method, DCC / HONB method, WSC method, method using diethyl cyanophosphate (DEPC), and the like. This condensation reaction can be performed in a solvent. Examples of the solvent include anhydrous or water-containing N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMS
O), pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile or an appropriate mixture thereof. In the present condensation reaction, about 1 to 2 mol of the compound [III] is usually used per 1 mol of the compound [II]. The reaction temperature is usually about -20
C. to about 50.degree. C., preferably about -10.degree. C. to about 30.degree. The reaction time is about 1 hour to about 100 hours, preferably about 2 hours.
About 40 hours. The anilide derivative [I-1] thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Also, the formula (II ')

Embedded image (Wherein R ¹ is as defined above) or a salt thereof is a novel compound, and is useful as a synthetic intermediate of the compound represented by the formula (I) or a salt thereof.

[Method B]

Embedded image When R ² ″ in the compound [I-2] is, for example, a tertiary amine residue, the quaternized compound [I] is reacted by reacting the compound [I-2] with an alkyl halide or an aralkyl halide. -1] can be produced.
Here, examples of the halogen atom include chlorine, bromine and iodine, and alkyl halides (eg, lower (C _1-6 ) alkyl halides) and aralkyl halides (eg, lower halogen (C _1-4 )) ) Alkyl-phenyl) is generally used in an amount of about 1 to 5 mol per 1 mol of compound [I-2]. The reaction is carried out in an inert solvent such as toluene,
Benzene, xylene, dichloromethane, chloroform,
1,2-dichloroethane, dimethylformamide (DM
F), dimethylacetamide or the like, or a mixed solvent 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 is about 1 hour to about 100
Hours, preferably from about 2 hours to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, or the like). When R ² ″ in the compound [I-2] is, for example, a secondary amine residue, the compound [I-2] is reacted with an alkyl halide or an aralkyl halide to obtain a tertiary compound [ Here, examples of the halogen atom include chlorine, bromine, iodine and the like, and the alkyl halide or the aralkyl halide is usually about 1 mol per 1 mol of the compound [I-2]. The reaction is carried out, if necessary, from an equivalent amount to 3 mol.
By adding about twice the molar amount of triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc. as a base, sodium iodide is further added. By adding potassium iodide or the like, the reaction can be allowed to proceed smoothly. This tertiary amination reaction is
Inert solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane,
1,4-dioxane, toluene, benzene, xylene,
The reaction can be carried out in dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is performed at about 0 ° C to 1
The reaction is performed at a temperature of 80 ° C. for about 1 hour to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, or the like). When R ² ″ in the compound [I-2] is, for example, a secondary amine residue, the compound [I-2] and the aldehyde compound are combined with sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride. The tertiary compound [I-1] can be produced by reacting in the presence of a reductive amino reagent such as 1. The reductive amination reaction is performed by changing the reaction conditions depending on the reagent used. When sodium triacetoxyborohydride is used, for example, an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dimethylformamide (DM
F) or the like, or a mixed solvent thereof. This reagent is used in an amount of about 1 to 2 mol equivalent per 1 mol of compound [I-2]. The reaction is usually carried out at a temperature of about 0 ° C. to about 80 ° C. for about 1 hour to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, or the like). When R ² ″ in the compound [I-2] is, for example, a sulfide residue or a tertiary amine residue, the compound [I-2] is represented by m
-React with oxidizing agents such as chloroperbenzoic acid (m-CPBA), perbenzoic acid, paranitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, sodium periodate, potassium periodate, etc. As a result, a compound [I-1] having a sulfinyl group, a sulfonyl group, and an amine oxide group can be produced. 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, an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, or acetone is used. , Ethyl acetate, etc.
Alternatively, the reaction can be performed in a mixed solvent thereof. The oxidizing agent is used in an amount of about 1 to 3 molar equivalents per 1 mole of the compound [I-2]. The reaction is usually carried out at a temperature in the range of about -50C to about 100C (preferably -25C to 25C) for about 1 hour to about 40 hours.

[Method C]

Embedded image V in compound [IV] represents a halogen atom (eg, chlorine, bromine, iodine), a sulfonyloxy group (eg, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group); The symbols are as defined above. By reacting the compound [IV] with a tertiary amine, a quaternized compound [I-1] can be produced. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2
-Dichloroethane, dimethylformamide (DMF),
It can be carried out in dimethylacetamide or the like, or a mixed solvent thereof. The tertiary amine is used in an amount of about 1 to 3 mol per 1 mol of the compound [IV]. This reaction is carried out at a temperature in the range of about 10 ° C to about 120 ° C for about 1 hour to about 40 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, or the like). By reacting the compound [IV] with a tertiary phosphine, a quaternized compound [I-1] can be produced. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,
It can be carried out in 2-dichloroethane, acetonitrile, dimethylformamide (DMF) or the like, or a mixed solvent thereof. Tertiary phosphine is a compound of the formula [IV]
About 1 to 2 mol is used per 1 mol. The reaction is about 20
C. to about 150.degree. C. for about 1 hour to about 5 hours.
Performed for 0 hours. This reaction is preferably performed in an atmosphere of an inert gas (eg, nitrogen, argon, or the like). By reacting compound [IV] with a primary or secondary amine compound or thiol compound, compound [I-
1] can be manufactured. The primary or secondary amine compound or thiol compound is usually used in an amount of about 1 to 3 mol per 1 mol of the compound [IV]. In this reaction, if necessary, an equimolar to about 3-fold molar amount of triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, or the like is used as a base. By adding sodium iodide, potassium iodide, or the like, the reaction can be allowed to proceed smoothly. 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,
The reaction can be carried out in xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is about-
The reaction is performed at a temperature in the range of 10 ° C. to about 180 ° C. for about 1 hour to about 40 hours. This reaction is preferably performed in an inert gas (eg, nitrogen, argon, etc.) atmosphere.

[Method D]

Embedded image Compound [V] [wherein, V 'represents a halogen atom (bromine, iodine, etc.) or a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc.), and other symbols have the same meanings as described above. ] With the Suzuki reaction [palladium-catalyzed cross-condensation reaction of arylboric acid with, for example, an aryl halide or aryloxytrifluoromethanesulfonate; A. Suzuki et al., Synth. Commun. 1981 , 1].
1,513] to produce a compound [I-3] wherein R ¹ ′ represents a 5- to 6-membered aromatic group. Aryl boric acid is used in an amount of about 1 equivalent to 1.5 moles per 1 mole of compound [V].
Compound [I-3] can be obtained by using twice the molar amount.

[Method E]

Embedded image [Each symbol in the formula has the same meaning as described above.] Compound [I-4] is converted to m-chloroperbenzoic acid, perbenzoic acid,
Compound [I-1] can be produced by reacting with an oxidizing agent such as paranitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, sodium periodate, and 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, an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, acetone is used. , Ethyl acetate or the like, or a mixed solvent thereof. The oxidizing agent is used in an amount of about 1 to 3 molar equivalents per 1 mole of the compound [I-4]. The reaction is usually carried out at a temperature in the range of about -50C to about 100C (preferably -25C to 25C) for about 1 hour to about 40 hours.

The anilide derivative [I-1] or compound [I-3] thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like. Compound [II] used as a starting material can be produced by a known method (for example, the method described in JP-A-8-73476) or a method analogous thereto, for example, by using reaction formula I or reaction formula II. It can be produced by the method shown, the method shown in the following Reference Example or a method analogous thereto. Reaction Formula I

Embedded image [Wherein, R ⁹ represents a C _1-4 alkyl group, m represents 1 or 2, and other symbols have the same meanings as described above. In this method, first, the compound represented by the formula [VI] is heated together with polyphosphoric acid, or the compound [VI] is converted to an acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, or the like, Cyclization is carried out by the usual Friedel-Crafts reaction to give the compound [V
II]. Then, the compound [VII] is reacted with a carbonate in the presence of a base to produce a ketoester [VIII]. Compound [VIII] is obtained by catalytic hydrogenation or reduction reaction with sodium borohydride or the like.
And Compound [IX] is subjected to a dehydration reaction by a conventional method to obtain compound [X]. Compound [X] can be converted to compound [XI] by an oxidation reaction, and compound [XI] can be subjected to an ester hydrolysis reaction to produce unsaturated carboxylic acid [II-1]. Reaction formula II

Embedded image [Wherein, R ¹⁰ represents a C _1-4 alkyl group, and other symbols have the same meanings as described above. ] Dieckmann (type) condensation reaction of compound [XII] (JPSchae
fer and J. J. Bloomfield, Org. Reactions, 1967 , 1
Compounds [VIII] to [IX] can be produced by subjecting to 5, 1). Compound [VIII] to Compound [I
X] are successively reacted according to the method described in Reaction Formula I, whereby an unsaturated carboxylic acid [II-1] can be produced.

Compound [III] can also be prepared by a known method (for example, the method described in JP-A-8-73476).
Alternatively, it can be produced by a method analogous thereto, for example, by a method represented by Reaction Scheme III, a method shown in Reference Examples described later, or a method analogous thereto. Reaction formula III

Embedded image The reduction reaction of compound [XIII] can be performed 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 and substituted borane, catalytic hydrogenation, and the like are used. That is, this reaction is performed by treating compound [XIII] with a reducing agent. As the reducing agent, reduced iron,
Metals such as zinc dust, alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), metal hydride complex compounds such as lithium aluminum hydride, metal hydrides such as sodium hydride, organotin compounds ( Metal and metal salts such as nickel compounds and zinc compounds, palladium, platinum, a catalytic reducing agent using a transition metal catalyst such as rhodium and hydrogen, and diborane.
It is advantageously performed by catalytic reduction using a transition metal catalyst such as rhodium and hydrogen and reduction with a metal such as reduced iron. This reaction is performed 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 mixed solvent thereof is appropriately selected and used depending on the type of the reducing agent. The reaction temperature is about -20 ° C to about 150 ° C, particularly about 0 ° C to about 1 ° C.
00 ° C. is suitable, and the reaction time is about 1 to about 24 hours. The compound [II] or [III] thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Formula (I) of the present invention
Or a salt thereof may be used in combination with another preventive / therapeutic agent for HIV infection (particularly, a preventive / therapeutic agent for AIDS). In this case, these drugs
Separately or simultaneously, a pharmacologically acceptable carrier,
Formulated by mixing with excipients, binders, diluents, etc.
It can be orally or parenterally administered as a pharmaceutical composition for the prevention and treatment of V infection. When the drugs are separately formulated, those separately formulated can be administered by mixing with a diluent at the time of use,
Separately formulated individual preparations may be administered to the same subject simultaneously or separately at different times. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, mixing and dissolving a powdered ampoule containing each drug and two or more drugs at the time of use) Kit products for administration of the same formulation to the same subject simultaneously or separately at different times, such as injectable kits containing diluents for A tablet kit for putting two or more tablets simultaneously or separately with a time difference provided with a column for describing the time for administering the drug, if necessary, in the same or separate bags. And the like are also included in the pharmaceutical composition of the present invention. Specific examples of the preventive / therapeutic agent for other HIV infections used in combination with the compound represented by the formula (I) of the present invention or a salt thereof include zidovudine, didanosine, Nucleic acids such as zalcitabine (zalcitabine), lamivudine (lamivudine), stavudine (stavudine), abacavir (abacavir), adefovir (adefovir), adefovir dipivoxil (adefovir dipivoxil), fozivudine tidoxyl (fozivudine tidoxyline inhibitor); nevirapine),
Delavirdine, efavirenz (efavi)
renz), loviride, immunocal (immunoca)
l), non-nucleic acid reverse transcriptase inhibitors such as oltipraz (including drugs having an antioxidant effect such as immunocal and oltipraz); saquinavir, ritonavir (ritona)
vir), indinavir (indinavir), nelfinavir (nelfinavir), amprenavir (amprenavir), parinavir (palinavir), lacinavir (lasinavir) and the like; and the like. Nucleic acid reverse transcriptase inhibitors include zidovudine, didanosine, zalcitabine
e), lamivudine, stavudine (stavudi)
ne), abacavir, etc. are preferred, and as a non-nucleic acid reverse transcriptase inhibitor, nevirapine (nevirapin)
e), delavirdine, efavirenz, etc. are preferred, and the protease inhibitors include saquinavir, ritonavir (rito)
navir), indinavir (indinavir), nelfinavir (nelfinavir), amprenavir (amprenavir) and the like. The compound represented by the formula (I) or a salt thereof according to the present invention may be, for example, the above-mentioned protease inhibitor, nucleic acid reverse transcriptase inhibitor and the like. Antagonists (eg, A
MD-3100), antibodies against HIV-1 surface antigens, and HIV-1 vaccines.

The compound of the present invention represented by the formula (I) or a salt thereof has a CCR antagonistic activity, particularly a strong CCR5 antagonistic activity, and therefore can be used for various HIV infections in humans.
For example, it is used for the prevention and treatment of AIDS. The compound represented by the formula (I) of the present invention or a salt thereof has low toxicity and can be used safely. Formula of the present invention
The compound represented by (I) or a salt thereof can be used as a CCR5 antagonist, for example, an agent for the prophylactic / therapeutic treatment of AIDS and an agent for suppressing the progression of AIDS. The daily dose of the compound represented by the formula (I) or a salt thereof is as follows:
Depending on the condition and weight of the patient and the method of administration, in the case of oral administration, about 5 to 1000 mg, preferably about 10 mg, of the active ingredient [compound represented by formula (I) or a salt thereof] per adult (body weight 50 kg) per person. And more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, and is administered once or twice or three times a day. Also, the formula (I)
When a compound represented by or a salt thereof is used in combination with a reverse transcriptase inhibitor or / and a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor is, for example, about 1 / 200 to 1 /
It is appropriately selected within a range of 2 or more and about 2 to 3 times or less.
In addition, when two or more drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted. The dose at the time of single administration of the drug is used. Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as follows. Zidovudine: 100 mg Zidanocin: 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 Reverse transcription with the compound represented by formula (I) or a salt thereof Specific embodiments when using in combination with an enzyme inhibitor and / or a protease inhibitor will be described below. About 10 to 300 mg of the compound represented by the formula (I) or a salt thereof is administered to the same subject in combination with about 50 to 200 mg of zidovudine per adult (body weight: 50 kg). Each drug may be administered simultaneously,
Also, the administration may be carried out with a time difference of 12 hours or less. About 10 to 300 mg of the compound represented by the formula (I) or a salt thereof is administered to the same subject in combination with about 300 to 1200 mg of saquinavir per adult (body weight: 50 kg). The individual drugs may be administered at the same time, or may be administered with a time difference of 12 hours or less.

[0048]

Industrial Applicability The compound represented by the formula (I) of the present invention or a salt thereof has a strong CCR5 antagonism, which is advantageous for prevention and treatment of various HIV infections in humans, for example, AIDS. Can be used.

[0049]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, experimental examples, preparation examples, reference examples,
The present invention will be described in more detail with reference to examples. However, these are merely examples and do not limit the present invention in any way. The genetic manipulation methods described below are
niatis et al., Molecular Cloning, Cold Spring
Harbor Laboratory, 1989) or according to the protocol attached to the reagent. Experimental Examples (1) Cloning of Human CCR5 Chemokine Receptor The CCR5 gene was cloned from human spleen cDNA by PCR. 0.5 ng of spleen cDNA (Toyobo,
QUICK-Clone cDNA) as a template and reported by Samson et al. (Biochemistry 35 (11), 3362-336).
7 (1996)), a primer set 5′-CAGGATCCGATGGATTA prepared with reference to the nucleotide sequence of the CCR5 gene.
TCAAGTGTCAAGTCCAA-3 '[SEQ ID NO: 1] and 5'-TCTAGAT
CACAAGCCCACAGATATTTCCTGCTCC-3 ′ (SEQ ID NO: 2) was added in an amount of 25 pmol each, and the PCR reaction was performed using TaKaRa EX Taq (Takara Shuzo) to perform a DNA thermal cycler 48.
0 (Perkin Elmer) (reaction conditions: 95 ° C.)
For 1 minute, 60 ° C. for 1 minute, and 75 ° C. for 5 minutes for 30 cycles). The PCR product is subjected to agarose gel electrophoresis,
After recovering a DNA fragment of about 1.0 kb, Original TA
The CCR5 gene was cloned using Cloning Kit (Funakoshi). (2) Preparation of plasmid for human CCR5 expression The plasmid obtained above was digested with the restriction enzyme XbaI (Takara Shuzo).
After digestion with BamHI (Takara Shuzo), a DNA fragment of about 1.0 kb was recovered by agarose gel electrophoresis. That D
The NA fragment and the expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with XbaI and BamHI were mixed, and DN
A Ligation Kit Ver. 2 (Takara Shuzo) and transformed into competent cells of Escherichia coli JM109 (Takara Shuzo) to obtain plasmid pCKR5.

(3) C of plasmid for human CCR5 expression
Introduction and expression into HO-K1 cells CHO-K1 cells grown in a 750 ml tissue culture flask (Becton Dickinson) using a Ham F12 medium (Nippon Pharmaceutical) containing 10% fetal bovine serum (Lifetech Oriental) were used. 5 g / L trypsin
After detachment with 0.2 g / L EDTA (Lifetech Oriental), the cells were washed with PBS (Lifetech Oriental), centrifuged (1000 rpm, 5 minutes), and PBS was removed.
And suspended. Next, Gene Pulsar (Bio-Rad)
Was used to introduce DNA into cells according to the following conditions. That is, 8 × 10 ⁶ in a 0.4 cm gap cuvette
Cells and 10 μg of plasmid pCK for expression of human CCR5
Add R5, voltage 0.25 kV, capacitance 960μ
Electroporated under F. The cells were then transferred to Ham's F12 medium containing 10% fetal calf serum and
After culturing for hours, the cells were detached again and centrifuged, and then Geneticin (Lifetech Oriental) was added at 500 μg /
Ham F containing 10% fetal bovine serum
The cells were suspended in 12 media, diluted to 10 ⁴ cells / ml, and seeded on a 96-well plate (Becton Dickinson) to obtain a geneticin-resistant strain. Next, after the obtained geneticin-resistant strain was cultured in a 96-well plate (Becton Dickinson), CCR5-expressing cells were selected from the resistant strains. That is, 200 pM [ ¹²⁵ I] -RA
Assay buffer (0.5% BSA, 20 mM HEPE) with NTES (Amersham) added as ligand
The binding reaction was performed at room temperature for 40 minutes in S (ham F12 medium containing Wako Pure Chemical Industries, pH 7.2) at room temperature, washed with ice-cold PBS, and then added with 1 M NaOH at 50 μl / well and stirred to obtain γ. -By measuring the radioactivity with a counter, cells to which the ligand specifically bound, the CCR5 / CHO strain, were selected.

(4) Evaluation of Compound Based on CCR5 Antagonism The CCR5 / CHO strain was seeded at 5 × 10 ⁴ cells / well in a 96-well microplate, cultured for 24 hours, the medium was removed by suction, and the test compound (1 μM) was removed. ) Was added to each well and the ligand [ ¹²⁵ I]
After adding RANTES (Amersham) to 100 pM, the mixture was reacted at room temperature for 40 minutes. Next, the assay buffer was removed by suction and then washed twice with cooled PBS. Next, 200 μl of Microscint-20 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard). According to the method described above, the CCR5 binding inhibition rate of the test compound was measured. The results are shown in [Table 1].

[Table 1]

(5) HIV for MAGI-CCR5 cells
-1 Infection Inhibiting Effect A plasmid in which a β-galactosidase gene is ligated downstream of the HIV-1 LTR is introduced into CD4-positive HeLa cells, and a human CCR5 gene-introduced transformed cell MAGI-CCR5 is used to transform HIV. The extent of -1 infection was determined using β-galactosidase activity (blue color due to decomposition of 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside) as an index. Specifically, M
AGI-CCR5 cells were adjusted to 5 × 10 ⁴ / ml with a DMEM medium containing 10% serum, and 200 μl of each was seeded in each well of a 96-well plate. After culturing at 37 ° C. overnight, the medium was removed by suction, and the medium 10 containing 1.6 μM drug was removed.
0 μl and 100 μl of the above medium containing 300 PFU of HIV-1 Ba-L strain were added and cultured at 37 ° C. for 2 days. After removing the medium by suction, the cell fixative (PBS containing 1% formaldehyde and 0.2% glutaraldehyde)
Was added and left at room temperature for 5 minutes.
Washed twice. Staining solution (4 μM potassium ferrocyanide,
4μM potassium ferricyanade, 2μM MgC
l _2, the PBS) containing 0.4mg / ml X-gal 10
After 0 μl was added and the mixture was allowed to stand at 37 ° C. for 50 minutes, it was washed twice with PBS. Count the number of blue cells with a microscope and count for HI
V-1 The number of infected cells. The results of measuring the HIV-1 infection inhibition rate by this method are shown in [Table 2].

[Table 2]

[0053]

Examples The CCR5 antagonists (eg, preventive and therapeutic agents for HIV infection, AIDS and the like) containing a compound represented by formula (I) or a salt thereof as an active ingredient in the present invention include, for example, It can be manufactured by such a formulation. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

[0054] After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Example 1 (Preparation of Compound 1) 7- (4-morpholinophenyl) -1,1-dioxo-
DMF of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (177 mg, purity about 50%) and 1-hydroxybenzotriazole (HOBt) (90 mg)
(5 ml) solution at room temperature with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WS)
C) (127 mg) was added and the mixture was stirred for 1 hour. 4 in the reaction system
-[N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (107 mg) and triethylamine (0.12 ml) in DMF (5 ml)
And one fragment of 4-dimethylaminopyridine was added, and 6
Stir for 4 hours. After concentration under reduced pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 1) and recrystallization (ethanol / diethyl ether) to obtain N- [4- [N
-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-morpholinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 1 ) (31.
6 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.38-1.84 (4H, m), 2.23 (3
H, s), 2.58-2.80 (1H, m), 3.10-3.45 (8H, m), 3.61
(2H, s), 3.67-3.78 (2H, m), 3.83-3.94 (4H, m), 3.9
9-4.09 (2H, m), 7.00 (2H, d, J = 8.8 Hz), 7.19-7.38
(3H, m), 7.49-7.60 (4H, m), 7.62-7.71 (2H, m), 7.8
9-7.95 (1H, m), 8.19 (1H, d, J = 8.4 Hz) .IR (KBr) 3277, 1659, 1603, 1522, 1313, 1234, 1124,
928, 820 cm ^-1

Example 2 (Preparation of Compound 2) N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -7- (4-morpholinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (36 m
Concentrated hydrochloric acid (0.5 ml) was added to a solution of g) in ethanol / methanol (10/5 ml) at room temperature, followed by stirring for several minutes.
Insoluble materials were removed by filtration, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration. After washing with diethyl ether, N
-[4- [N-methyl-N- (tetrahydropyran-4
-Yl) aminomethyl] phenyl] -7- (4-morpholinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide dihydrochloride (Compound 2) (34 mg). Was. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.65-2.18 (4H, m), 2.60
(3H, s), 3.01-3.12 (2H, m), 3.16-3.51 (7H, m), 3.6
2-3.87 (6H, m), 3.93-4.07 (2H, m), 4.10-4.22 (1H,
m), 4.39-4.51 (1H, m), 7.08 (2H, d, J = 8.8 Hz), 7.5
3-7.58 (3H, m), 7.72 (2H, d, J = 8.8 Hz), 7.80-7.92
(3H, m), 8.02-8.10 (2H, m), 10.42 (1H, br s).

Example 3 (Preparation of Compound 3) 7- (4-methoxyphenyl) -1,1-dioxo-
Oxalyl chloride (0.2 ml) and 1 drop of DMF were added to a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) in THF (10 ml) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (20 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (107 mg) and triethylamine (0 .12 ml) and stirred at room temperature for 4 hours. The reaction was added to vigorously stirred water to stop the reaction, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 2) and recrystallization (ethanol) to give 7- (4-methoxyphenyl) -N- [4- [N- Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 3) (161.1 mg). ^{mp 247-249 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ1.68-1.83 (4H, m), 2.21 (3
H, s), 2.52-2.74 (1H, m), 3.16 (2H, d, J = 6.6 Hz),
3.31-3.44 (2H, m), 3.58 (2H, s), 3.69-3.76 (2H,
m), 3.87 (3H, s), 3.98-4.10 (2H, m), 7.02 (2H, d,
J = 8.8 Hz), 7.30-7.35 (3H, m), 7.52-7.57 (4H, m),
7.62-7.70 (2H, m), 7.91 (1H, br s), 8.20 (1H, d, J =
8.0 Hz) .IR (KBr) 3246, 1655, 1633, 1605, 1518, 1410, 1317,
1294, 1250, 1171, 1128, 825 cm ^-1 Elemental analysis C ₃₁ H ₃₄ N ₂ O ₅ S Calcd. C, 70.56; H, 6.97;
N, 7.26: Found.C, 70.43; H, 6.83; N, 7.22.

Example 4 (Preparation of Compound 4) 7- (4-ethoxyphenyl) -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (16.90 g) in THF (340 ml) and DMF
(2 ml) suspension at room temperature with thionyl chloride (3.62 m
l) was added and stirred for 2 hours. The reaction mixture was added at room temperature
[N-methyl-N- (tetrahydropyran-4-yl)
Aminomethyl] aniline dihydrochloride (15.21 g) and triethylamine (40 ml) in THF (150 m
l) The suspension was added dropwise over 1 hour and stirred for another 4 hours. The mixture was concentrated under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with water, ethyl acetate and diisopropyl ether to obtain crude crystals (21.90 g). Purified by recrystallization (THF / ethanol) to give 7- (4-ethoxyphenyl) -N- [4
-[N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (compound 4) (21.02 g) was obtained. mp 243-246 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.45 (3H, t, J = 7.0 Hz), 1.
67-1.80 (4H, m), 2.21 (3H, s), 2.55-2.72 (1H, m),
3.13-3.20 (2H, m), 3.28-3.44 (2H, m), 3.58 (2H, m
s), 3.69-3.76 (2H, m), 3.97-4.08 (2H, m), 4.10 (2
H, q, J = 7.0 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.31-7.35
(3H, m), 7.52-7.57 (4H, m), 7.63-7.70 (2H, m), 7.
89 (1H, br s), 8.20 (1H, d, J = 8.0 Hz) .IR (KBr) 3428, 1657, 1635, 1603, 1518, 1410, 1317,
. 1294, 1246, 1128, 827cm -1 elemental analysis _{C 32 H 36 N 2 O 5} S Calcd C, 68.55; H, 6.47;
N, 5.00: Found.C, 68.68; H, 6.50; N, 4.92.

Example 5 (Preparation of Compound 4) 7- (4-ethoxyphenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) in THF (10 ml) was added one drop of oxalyl chloride (0.18 ml) and DMF at room temperature, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (20 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (102 mg) and triethylamine (0 ml) were dissolved at 0 ° C. .12 ml) and stirred at room temperature for 4 hours. The reaction was added to vigorously stirred water to stop the reaction, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 2) and recrystallization (ethanol) to give 7- (4-ethoxyphenyl) -N- [4- [N- Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 4) (134 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ1.45 (3H, t, J = 7.0 Hz), 1.
67-1.80 (4H, m), 2.21 (3H, s), 2.55-2.72 (1H, m),
3.13-3.20 (2H, m), 3.28-3.44 (2H, m), 3.58 (2H, m
s), 3.69-3.76 (2H, m), 3.97-4.08 (2H, m), 4.10 (2
H, q, J = 7.0 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.31-7.35
(3H, m), 7.52-7.57 (4H, m), 7.63-7.70 (2H, m), 7.
89 (1H, br s), 8.20 (1H, d, J = 8.0 Hz) .IR (KBr) 3428, 1657, 1635, 1603, 1518, 1410, 1317,
. 1294, 1246, 1128, 827cm -1 elemental analysis _{C 32 H 36 N 2 O 5} S Calcd C, 68.55; H, 6.47;
N, 5.00: Found.C, 68.16; H, 6.52; N, 5.13.

Example 6 (Preparation of Compound 5) 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1 Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (2.5
To a solution of g) in THF (125 ml) was added 6N hydrochloric acid (1.5 ml) at room temperature, and the mixture was stirred for 0.5 hour. After concentration under reduced pressure, diethyl ether was added and colorless crystals were collected by filtration to give crude crystals (2.61 g). Recrystallization (9
0% ethanol) to give 7 as colorless crystals.
-(4-Ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin- 4-Carboxamide hydrochloride (compound 5) (2.33 g) was obtained. mp 255 ° C (dec.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (3 H, t, J = 7.0 Hz), 1.
53-1.86 (2H, m), 1.93-2.21 (2H, m), 2.48 (3H, br
s), 2.94-3.35 (5H, m), 3.70-3.76 (2H, m), 3.78-3.9
9 (3H, m), 4.10 (2H, q, J = 7.0 Hz), 4.16-4.35 (1H,
m), 7.00 (2H, d, J = 8..8 Hz), 7.57-7.70 (5H, m), 7.8
7-7.92 (1H, m), 8.00-8.08 (3H, m), 8.18 (1H, d, J =
8.4 Hz), 9.72-9.83 (1H, m). Elemental analysis C ₃₂ H ₃₇ N ₂ O ₅ SCl0.5H ₂ O Calcd. C, 63.40;
H, 6.32; N, 4.62; Cl, 5.85: Found.C, 63.36; H,
6.10; N, 4.49; Cl, 5.76.

Example 7 (Preparation of Compound 6) 7- (3,4-methylenedioxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
Oxalyl chloride (0.07 ml) and D in a solution of carboxylic acid (150 mg) in THF (10 ml) at room temperature
One drop of MF was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (20 ml),
-[N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (102 mg) and triethylamine (0.12 ml) were added, and the mixture was stirred at room temperature for 16 hours. The reaction was added to vigorously stirred water to stop the reaction, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 2) and recrystallization (ethanol),
7- (3,4-methylenedioxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1 as colorless crystals
-Dioxo-2,3-dihydro-1-benzothiepin-
4-Carboxamide (compound 6) (133 mg) was obtained. mp 245-248 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.66-1.83 (4
H, m), 2.21 (3H, s), 2.52
-2.74 (1H, m), 3.17 (2H,
t, J = 7.0 Hz), 3.29-3.45
(2H, m), 3.58 (2H, s),
70-3.76 (2H, m), 3.96-4.1
0 (2H, m), 6.05 (2H, s),
6.92 (1H, d, J = 8.8 Hz),
7.07-7.12 (2H, m), 7.31-
7.35 (3H, m), 7.52-7.67
(4H, m), 7.89 (1H, brs),
8.20 (1H, d, J = 8.0 Hz). IR (KBr) 3259, 1651, 159
7, 1512, 1477, 1319, 129
4, 1232, 1128, 1036, 930,
810 cm ^-1 elemental analysis _{C 31 H 32 N 2 O 6} S Calcd.
C, 66.41; H, 5.75; N,
5.00: Found. C, 66.34;
H, 5.75; N, 4.85.

Example 8 (Preparation of Compound 7) 7- (4-Chlorophenyl) -1,1-dioxo-2,
Oxalyl chloride (0.08 ml) and one drop of DMF were added to a solution of 3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) in THF (10 ml) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (104 mg) and triethylamine (0%) were dissolved at 0 ° C. .12 ml) in THF (5 ml) and stirred at room temperature for 19 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 2) and recrystallization (ethanol / diisopropyl ether) to give 7- (4-chlorophenyl)-as colorless crystals.
N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 7) (154.8 mg). mp 247-250 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.62-1.85 (4H, m), 2.21 (3
H, s), 2.52-2.73 (1H, m), 3.14-3.21 (2H, m), 3.29-
3.44 (2H, m), 3.57 (2H, s), 3.69-3.76 (2H, m), 3.9
7-4.10 (2H, m), 7.31-7.35 (3H, m), 7.45-7.56 (6H,
m), 7.63-7.72 (2H, m), 7.90 (1H, br s), 8.24 (1H,
d, J = 8.0 Hz) .IR (KBr) 3246, 1655, 1601, 1529, 1410, 1317, 1294,
1130, 818 cm ^-1 Elemental analysis C ₃₀ H ₃₁ N ₂ O ₄ SCl Calcd.C, 65.38; H, 5.67
; N, 5.08: Found. C, 65.54; H, 5.56; N, 4.98.

Example 9 (Preparation of Compound 8) 7- (4-Fluorophenyl) -1,1-dioxo-
Oxalyl chloride (0.08 ml) and one drop of DMF were added to a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) in THF (10 ml) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (109 mg) and triethylamine (0 mg) were dissolved at 0 ° C. .13 ml) in THF (5 ml) and stirred at room temperature for 24 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with 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 as colorless crystals.
-(4-Fluorophenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin- 4-Carboxamide (compound 8) (128.5 mg) was obtained. mp 219-221 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.52-1.83 (4H, m), 2.21 (3
H, s), 2.53-2.75 (1H, m), 3.14-3.21 (2H, m), 3.30-
3.45 (2H, m), 3.58 (2H, s), 3.71-3.78 (2H, m), 3.9
9-4.10 (2H, m), 7.15-7.24 (2H, m), 7.31-7.35 (3H, m
m), 7.52-7.70 (6H, m), 7.95 (1H, br s), 8.23 (1H,
d, J = 8.6 Hz). IR (KBr) 3273, 1655, 1601, 1516, 1410, 1311, 1128,
825 cm ^-1 Elemental analysis C ₃₀ H ₃₁ N ₂ O ₄ SF ・ 0.5H ₂ O Calcd.C, 66.28; H,
5.93; N, 5.15: Found.C, 66.56; H, 5.90; N,
5.13.

Example 10 (Preparation of Compound 9) 7- (4-Trifluoromethylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-
To a solution of the carboxylic acid (180 mg) in THF (10 ml) was added oxalyl chloride (0.8 ml) and D at room temperature.
One drop of MF was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (10 ml),
[N-methyl-N- (tetrahydropyran-4-yl)
The mixture was added dropwise to a solution of [aminomethyl] aniline (114 mg) and triethylamine (0.13 ml) in THF (5 ml), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction system, and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were purified by recrystallization (ethanol) to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- as colorless crystals.
(4-Trifluoromethylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 9) (208.9 mg) was obtained. ^{mp 270-272 ℃ 1 H-NMR (} 200MHz, DMSO-d 6) δ1.37-1.61 (2H, m), 1.63-
1.78 (2H, m), 2.10 (3H, s), 2.46-2.67 (1H, m), 3.0
7-3.13 (2H, m), 3.18-3.35 (2H, m), 3.52 (2H, s), 3.
75-3.96 (4H, m), 7.27 (2H, d, J = 8.5 Hz), 7.56 (1H,
s), 7.67 (2H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.4 H
z), 7.97-8.06 (3H, m), 8.14-8.18 (2H, m) .IR (KBr) 3245, 1654, 1636, 1601, 1529, 1410, 1325,
1294, 1173, 1130, 1072, 827 cm ^-1 Elemental analysis C ₃₁ H ₃₁ N ₂ O ₄ SF ₃ Calcd.C, 63.68; H, 5.34
N, 4.79: Found.C, 63.64; H, 5.30; N, 4.70.

Example 11 (Preparation of Compound 10) 7- (4-Ethylphenyl) -1,1-dioxo-2,
To a solution of 3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml) was added oxalyl chloride (0.09 ml) and one drop of DMF at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (128 mg) and triethylamine (0%) were dissolved at 0 ° C. .15 ml) in THF (5 ml).
After stirring at room temperature for 64 hours, water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were purified by recrystallization (ethanol) to give 7- (4) as pale yellow crystals.
-Ethylphenyl) -N- [4- [N-methyl-N-
(Tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 10) (1
73.6 mg). mp 257-260 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.29 (3H, t, J = 6.7 Hz), 1.
56-1.83 (4H, m), 2.21 (3H, s), 2.54-2.71 (1H, m),
2.72 (2H, q, J = 6.7 Hz), 3.17 (2H, t, J = 6.7 Hz), 3.
31-3.44 (2H, m), 3.58 (2H, s), 3.70-3.76 (2H, m),
3.98-4.11 (2H, m), 7.31-7.35 (5H, m), 7.54 (2H, d,
J = 8.0 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.66 (1H, s),
7.71 (1H, dd, J = 8.4 Hz), 7.92 (1H, br s), 8.21 (1
H, d, J = 8.4Hz) .IR (KBr) 3248, 1657, 1635, 1599, 1525, 1410, 1317,
1294, 1128, 824 cm ^-1 Elemental analysis C ₃₂ H ₃₆ N ₂ O ₄ S Calcd. C, 70.56; H, 6.66;
N, 5.14: Found.C, 70.30; H, 6.73; N, 5.29.

Example 12 (Production of Compound 11) A solution of 7- (4-isopropylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml). To the mixture was added oxalyl chloride (0.09 ml) and one drop of DMF at room temperature, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml), and 4- [N-
Methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (122 mg) and triethylamine (0.14 ml) were added dropwise to a solution of THF (5 ml).
Stirred at room temperature for 20 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with 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-isopropylphenyl) -N- [4-
[N-methyl-N- (tetrahydropyran-4-yl)
Aminomethyl] phenyl] -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxamide (Compound 11) (189.8 mg, 67%) was obtained. mp 240-247 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.30 (6H, d, J = 7.0 Hz), 1.
52-1.83 (4H, m), 2.21 (3H, s), 2.55-2.77 (1H, m),
2.90-3.04 (1H, m), 3.17 (2H, t, J = 6.6 Hz), 3.37 (2
H, dt, J = 2.8, 11.0 Hz), 3.58 (2H, s), 3.70-3.76 (2
H, m), 3.98-4.09 (2H, m), 7.31-7.38 (5H, m), 7.52-
7.58 (4H, m), 7.66-7.73 (2H, m), 7.98 (1H, br s),
8.21 (1H, d, J = 8.4 Hz) .IR (KBr) 3251, 1655, 1601, 1525, 1410, 1317, 1296,
1130, 821 cm ^-1 Elemental analysis C ₃₃ H ₃₈ N ₂ O ₄ S Calcd. C, 70.94; H, 6.86;
N, 5.01: Found.C, 70.89; H, 6.61; N, 7.75.

Example 13 (Preparation of Compound 12) 7- (4-tert-Butylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml) ) Solution
Oxalyl chloride (0.09 ml) and DMF at room temperature
Was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in tetrahydrofuran (15 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (119 mg) at 0 ° C.
And triethylamine (0.14 ml) in THF (5
ml) was added dropwise to the solution. After stirring at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were purified by recrystallization (ethanol) to give 7- (4-tert-butylphenyl)-as colorless crystals.
N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 12) (209.8 mg). mp 247-249 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.37 (9H, s), 1.52-1.83 (4
H, m), 2.21 (3H, s), 2.54-2.74 (1H, m), 3.13-3.20
(2H, m), 3.29-3.45 (2H, m), 3.58 (2H, s), 3.68-3.7
9 (2H, m), 3.98-4.10 (2H, m), 7.31-7.35 (3H, m),
7.46-7.60 (6H, m), 7.66 (1H, d, J = 1.8 Hz), 7.71 (1
H, dd, J = 8.0, 1.8 Hz), 7.99 (1H, br s), 8.21 (1H,
d, J = 8.0 Hz) .IR (KBr) 3278, 1655, 1599, 1512, 1313, 1300, 1130,
821 cm ^-1 Elemental analysis C ₃₄ H ₄₀ N ₂ O ₄ S ・ 0.2H ₂ O Calcd.C, 70.85; H,
7.07; N, 4.86: Found.C, 70.60; H, 6.91; N, 4.
78.

Example 14 (Preparation of Compound 13) 7- [4- (1-Pyrrolidinyl) phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-In a solution of carboxylic acid (75 mg) in DMF (5 ml),
At room temperature, thionyl chloride (0.1 ml) was added and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane (10 ml), and 4- [N-methyl-N
-(Tetrahydropyran-4-yl) aminomethyl] aniline (53 mg) and triethylamine (0.5 m
1) was added dropwise to a dichloromethane (5 ml) solution. After stirring at room temperature for 16 hours, water was added and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 2) to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] as yellow crystals. Phenyl]-
7- [4- (1-pyrrolidinyl) phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (Compound 13) (36.3 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.42-1.67 (4H, m), 1.89-
2.04 (4H, m), 2.10 (3H, s), 2.45-2.68 (1H, m), 2.9
8-3.10 (2H, m), 3.17-3.36 (6H, m), 3.52 (2H, s), 3.
69-3.81 (2H, m), 3.83-3.96 (2H, m), 6.65 (2H, d, J
= 8.6 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.52 (1H, s), 7.6
1-7.71 (4H, m), 7.76-7.84 (1H, m), 7.98-8.02 (2H,
m), 10.16 (1H, s) .IR (KBr) 3278, 1657, 1606, 1525, 1379, 1315, 1294,
1167, 1128, 812 cm ^-1

Example 15 (Preparation of Compound 14) 7- (4-Piperidinophenyl) -1,1-dioxo-
Thionyl chloride (0.1 ml) was added to a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg) in DMF (10 ml) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was diluted with dichloromethane (15 m
1) and dissolved at 0 ° C. in 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (125 mg) and triethylamine (0.5 ml).
Was added dropwise to a dichloromethane (5 ml) solution. 1 at room temperature
After stirring for 6 hours, the reaction was added to water and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 4) to give N- [4- [N-methyl-N-
(Tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-piperidinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-
Carboxamide (Compound 14) (39.5 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.39-1.77 (10H, m), 2.10
(3H, s), 2.46-2.70 (1H, m), 3.01-3.11 (2H, m), 3.
17-3.35 (6H, m), 3.52 (2H, s), 3.72-3.81 (2H, m),
3.83-3.97 (2H, m), 7.05 (2H, d, J = 8.8 Hz), 7.27 (2
H, d, J = 8.4 Hz), 7.53 (1H, s), 7.67 (2H, d, J = 8.4 H
z), 7.68 (2H, d, J = 8.8 Hz), 7.84 (1H, dd, J = 8.2, 2.
IR (KBr) 3280, 1657, 1603, 1522, 1315, 1292, 1238, 2 Hz), 8.01-8.05 (2H, m), 10.17 (1H, s).
1126, 818 cm ^-1

Example 16 (Preparation of Compound 15) 7- (4-morpholinophenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (200 mg) and 1-hydroxybenzotriazole (0.12 g) in DMF (5 ml),
At room temperature, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (0.18 g) was added, and the mixture was stirred for 1 hour. 4- [N- (4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] aniline (0.19 g) and triethylamine (0.2 m
1) DMF solution (3 ml) was added and stirred 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 brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 1) to obtain N- [4- [N- (4,4-ethylenedioxycyclohexyl)-] as yellow crystals. N-methylaminomethyl] phenyl] -7- (4-morpholinophenyl)-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 15) (119 m
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.51-1.75 (4H, m), 1.77-1.
91 (4H, m), 2.20 (3H, s), 2.44-2.65 (1H, m), 3.11-
3.20 (2H, m), 3.23-3.28 (4H, m), 3.57 (2H, s), 3.6
9-3.75 (2H, m), 3.87-3.91 (4H, m), 3.95 (4H, s),
7.00 (2H, d, J = 8.8 Hz), 7.30-7.35 (3H, m), 7.51-7.
58 (4H, m), 7.64 (1H, br s), 7.65-7.73 (1H, m), 7.8
8-7.93 (1H, m), 8.18 (1H, d, J = 7.6 Hz) .IR (KBr) 3346, 1653, 1608, 1520, 1410, 1310, 1238,
1165, 1126, 928, 819cm ^-1

Example 17 (Preparation of Compound 16) 7- (4-methoxyphenyl) -1,1-dioxo-
Oxalyl chloride (0.09 ml) and 1 drop of DMF were added to a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (170 mg) in THF (10 ml) at room temperature, followed by stirring for 1 hour. After concentration under reduced pressure, the residue was
F (15 ml) and dissolved at 0 ° C. in 4- [N- (4,4
-Ethylenedioxycyclohexyl) -N-methylaminomethyl] aniline (0.15 g) and triethylamine (0.14 ml) in THF (5 ml).
Stir at room temperature for 21 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 1) and recrystallization (ethanol / ethyl acetate) to obtain N- [4- [N- ( 4,4-
Ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -7- (4-methoxyphenyl)-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 16) (164.2)
mg). mp 222-228 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45-1.90 (8H, m), 2.20 (3
H, s), 2.45-2.63 (1H, m), 3.13-3.20 (2H, m), 3.56
(2H, s), 3.69-3.76 (2H, m), 3.88 (3H, s), 3.95 (4
H, s), 7.02 (2H, d, J = 8.6 Hz), 7.30-7.35 (3H, m),
7.52-7.70 (6H, m), 7.92 (1H, br s), 8.20 (1H, d, J
= 8.0 Hz) .IR (KBr) 3356, 1651, 1608, 1518, 1311, 1292, 1252,
1126, 824 cm ^-1 Elemental analysis C ₃₄ H ₃₈ N ₂ O ₆ S Calcd. C, 67.75; H, 6.35;
N, 4.65: Found.C, 67.48; H, 6.15; N, 4.47.

Example 18 (Production of compound 17) N- [4- [N- (4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -7-
(4-methoxyphenyl) -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxamide (112 mg) in THF (20 ml) at room temperature with 3N
Hydrochloric acid (1 ml) was added and stirred for 18 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. A colorless solid obtained by concentration under reduced pressure was purified by recrystallization (ethyl acetate / hexane) to give 7- (4-
Methoxyphenyl) -N- [4- [N-methyl-N-
(4-oxocyclohexyl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 17) (7
7.6 mg). mp 214-218 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.77-2.14 (4H, m), 2.24 (3
H, s), 2.26-2.58 (4H, m), 2.80-2.96 (1H, m), 3.13-
3.20 (2H, m), 3.61 (2H, s), 3.70-3.76 (2H, m), 3.8
7 (3H, s), 7.02 (2H, d, J = 8.8 Hz), 7.32-7.36 (3H,
m), 7.53-7.70 (6H, m), 7.97 (1H, br s), 8.20 (1H,
d, J = 8.4 Hz) .IR (KBr) 3280, 1713, 1657, 1603, 1518, 1313, 1296,
1252, 1128, 825 cm ^-1 Elemental analysis C ₃₂ H ₃₄ N ₂ O ₅ S ・ 0.5H ₂ O Calcd.C, 67.70; H,
6.21; N, 4.93: Found.C, 67.58; H, 5.97; N, 4.
66.

Example 19 (Preparation of Compound 18) 7- (4-ethoxyphenyl) -1,1-dioxo-
Oxalyl chloride (0.09 ml) and one drop of DMF were added to a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml) at room temperature, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the residue was
F (10 ml) and dissolved at 0 ° C. in 4- [N- (4,4
-Ethylenedioxycyclohexyl) -N-methylaminomethyl] aniline in THF, 0.153 g (0.553 mmol) and triethylamine (0.14 ml)
(5 ml) solution and stirred at room temperature for 16 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting crude crystals were recrystallized (ethanol /
Diisopropyl ether) to give 7- (4-ethoxyphenyl) -N- [4- [N-
(4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (compound 18) (187 mg) was obtained. mp 220-223 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.46 (3H, t, J = 7.0 Hz), 1.
51-1.92 (8H, m), 2.21 (3H, s), 2.46-2.64 (1H, m),
3.17 (2H, t, J = 7.0 Hz), 3.57 (2H, s), 3.73 (2H, t,
J = 7.0 Hz), 3.95 (4H, s), 4.10 (2H, q, J = 7.0 Hz),
7.01 (2H, d, J = 9.0 Hz), 7.28-7.38 (3H, m), 7.49-7.
59 (4H, m), 7.61-7.72 (2H, m), 7.87-7.94 (1H, m),
8.21 (1H, d, J = 8.2 Hz). IR (KBr) 3346, 1651, 1518, 1311, 1292, 1250, 1164,
1126, 822 cm ^-1 Elemental analysis C ₃₅ H ₄₀ N ₂ O ₆ S ・ 0.2H ₂ O Calcd.C, 67.76; H,
6.56; N, 4.52: Found.C, 67.66; H, 6.32; N, 4.
36.

Example 20 (Preparation of Compound 19) 7- (4-ethoxyphenyl) -N- [4- [N-
(4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxamide (140 mg) in THF (20 ml) was added 3N hydrochloric acid (1 ml) at room temperature, and the mixture was stirred for 40 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate.
The resulting colorless solid was concentrated under reduced pressure, and the resulting colorless solid was purified by recrystallization (ethyl acetate / hexane) to give 7-colorless crystals.
(4-ethoxyphenyl) -N- [4- [N-methyl-
N- (4-oxocyclohexyl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 19) (1
01.1 mg). mp 195 ° C (dec.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (3H, t, J = 7.0 Hz), 1.
83-2.17 (4H, m), 2.24 (3H, s), 2.26-2.59 (4H, m),
2.80-2.98 (1H, m), 3.13-3.20 (2H, m), 3.62 (2H,
s), 3.69-3.76 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 7.0
1 (2H, d, J = 8.8 Hz), 7.32-7.36 (3H, m), 7.52-7.70
(6H, m), 7.96 (1H, br s), 8.20 (1H, d, J = 8.4 Hz) .IR (KBr) 3278, 1713, 1657, 1603, 1520, 1313, 1298,
1248, 1128, 824 cm ^-1 Elemental analysis C ₃₃ H ₃₆ N ₂ O ₅ S ・ 1.0H ₂ O Calcd.C, 67.10; H,
6.48; N, 4.74: Found.C, 66.97; H, 6.09; N, 4.
72.

Example 21 (Preparation of Compound 20) 7- (3,4-Methylenedioxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzoxepin-
Oxalyl chloride (0.09 ml) and one drop of DMF were added to a solution of 4-carboxylic acid (180 mg) in THF (10 ml) at room temperature, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (15 ml).
[N- (4,4-ethylenedioxycyclohexyl)-
[N-methylaminomethyl] aniline (0.153 g) and triethylamine (0.14 ml) in THF (5 m
l) Added to the solution and stirred at room temperature for 15 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 1) and recrystallization (ethanol / diisopropyl ether) to obtain N- [4- [N- ( 4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -7-
(3,4-Methylenedioxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 20) (153.1 mg) was obtained. mp 214-215 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45-1.92 (8H, m), 2.20 (3
H, s), 2.43-2.62 (1H, m), 3.17 (2H, t, J = 7.0 Hz),
3.57 (2H, s), 3.69-3.76 (2H, m), 3.95 (4H, s), 6.0
4 (2H, s), 6.92 (1H, d, J = 8.6 Hz), 7.07-7.12 (2H,
m), 7.31-7.35 (3H, m), 7.51-7.66 (4H, m), 7.88 (1
H, br s), 8.19 (1H, d, J = 8.4 Hz) .IR (KBr) 3327, 1649, 1514, 1314, 1292, 1238, 1128,
1109, 930, 818 cm ^-1 Elemental analysis C ₃₄ H ₃₆ N ₂ O ₇ S ・ 0.1H ₂ O Calcd.C, 66.02; H,
5.90; N, 4.53: Found.C, 65.98; H, 5.78; N, 4.
twenty three.

Example 22 (Production of compound 21) N- [4- [N- (4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -7-
To a solution of (3,4-methylenedioxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (100 mg) in THF (10 ml) was added 3N hydrochloric acid (1 ml) at room temperature. Stir for 39 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The colorless solid obtained by concentration under reduced pressure was purified by recrystallization (ethyl acetate) to give 7-colorless crystals.
(3,4-methylenedioxyphenyl) -N- [4-
[N-Methyl-N- (4-oxocyclohexyl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 21) (56.8 mg) was obtained. . ^{mp 219-223 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ1.83-2.17 (4H, m), 2.24 (3
H, s), 2.29-2.59 (4H, m), 2.81-2.98 (1H, m), 3.16
(2H, t, J = 6.9 Hz), 3.61 (2H, s), 3.73 (2H, t, J = 6.
9 Hz), 6.05 (2H, s), 6.92 (1H, d, J = 8.4 Hz), 7.07-
7.12 (2H, m), 7.32-7.36 (3H, m), 7.54-7.59 (3H,
m), 7.64 (1H, dd, J = 8.0, 2.0 Hz), 7.98 (1H, br s),
8.19 (1H, d, J = 8.0 Hz). IR (KBr) 3280, 1716, 1659, 1599, 1510, 1479, 1410,
1317, 1292, 1234, 1128, 1041, 812 cm ^-1 Elemental analysis C ₃₂ H ₃₂ N ₂ O ₆ S ・ 0.5H ₂ O Calcd.C, 66.08; H,
5.72; N, 4.82: Found.C, 66.36; H, 5.73; N, 4.
78.

Example 23 (Preparation of Compound 22) 7- (4-Chlorophenyl) -1,1-dioxo-2,
Oxalyl chloride (0.13 ml) and one drop of DMF were added to a solution of 3-dihydro-1-benzothiepine-4-carboxylic acid (250 mg) in THF (10 ml) at room temperature, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the residue was concentrated in THF.
(15 ml) and dissolved at 0 ° C. in 4- [N- (4,4-
Ethylenedioxycyclohexyl) -N-methylaminomethyl] aniline (0.238 g) and a solution of triethylamine (0.2 ml) in THF (5 ml) were stirred at room temperature for 20 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography (ethanol / ethyl acetate 1:
2) and recrystallization (ethanol) to give 7- (4-chlorophenyl) -N- [4- [N-
(4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 22) (286.8 mg) was obtained. mp 224-228 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.44-1.90 (8H, m), 2.20 (3
H, s), 2.42-2.64 (1H, m), 3.12-3.23 (2H, m), 3.56
(2H, s), 3.70-3.77 (2H, m), 3.95 (4H, s), 7.31-7.3
5 (3H, m), 7.45-7.57 (6H, m), 7.63-7.73 (2H, m),
7.90 (1H, br s), 8.24 (1H, d, J = 8.4 Hz). IR (KBr) 3336, 1672, 1518, 1308, 1282, 1165, 1126,
1097, 820 cm ^-1 Elemental analysis C ₃₃ H ₃₅ N ₂ O ₅ SCl Calcd.C, 65.28; H, 5.81
; N, 4.61: Found. C, 65.18; H, 5.70; N, 4.60.

Example 24 (Preparation of Compound 23) 7- (4-Chlorophenyl) -N- [4- [N- (4
4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -1,1-dioxo-2,3-
A 3N solution of dihydro-1-benzothiepine-4-carboxamide (180 mg) in THF (15 ml) was added at room temperature.
Hydrochloric acid (1 ml) was added and stirred for 7 days. Saturated aqueous sodium hydrogen carbonate was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. A colorless solid obtained by concentration under reduced pressure was purified by recrystallization (ethyl acetate), and as colorless crystals, 7- (4-chlorophenyl) -N- [4- [N-methyl-N- (4-oxo) was obtained. Cyclohexyl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 23) (85.9 mg). mp 197-200 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.79-2.20 (4H, m), 2.25 (3
H, s), 2.29-2.62 (4H, m), 2.84-3.03 (1H, m), 3.18
(2H, t, J = 7.0 Hz), 3.63 (2H, s), 3.70-3.78 (2H,
m), 7.30-7.72 (11H, m), 7.84-8.02 (1H, m), 8.24 (1
H, d, J = 8.4 Hz) .IR (KBr) 3277, 1714, 1653, 1599, 1529, 1410, 1319,
1128, 820 cm ^-1 Elemental analysis C ₃₁ H ₃₁ N ₂ O ₄ SCl ・ 0.75H ₂ O Calcd. C, 64.57;
H, 5.68; N, 4.86: Found.C, 64.49; H, 5.40; N,
4.92.

Example 25 (Preparation of Compound 24) 7- (4-morpholinophenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (101 mg) in DMF (5 ml) at room temperature was added 1
-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (144 mg) was added, and the mixture was stirred for 2 hours. 3- [N- (4-aminobenzyl) -N-
Methylamino] ethyl propionate (133 mg) and triethylamine (0.1 ml) in DMF (5 m
l) and one fragment of 4-dimethylaminopyridine were added and stirred for 20 hours. After concentration under reduced pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography (ethanol / ethanol).
Purification by ethyl acetate (1: 9) and recrystallization (ethyl acetate / hexane) gave N- [4- [N
-(2-Ethoxycarbonylethyl) -N-methylaminomethyl] phenyl] -7- (4-morpholinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 24) (13
3.6 mg). mp 209-211 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.2 Hz), 2.
21 (3H, s), 2.49-2.55 (2H, m), 2.72-2.79 (2H, m),
3.10-3.20 (2H, m), 3.23-3.28 (4H, m), 3.51 (2H, m
s), 3.69-3.76 (2H, m), 3.87-3.92 (4H, m), 4.15 (2
H, q, J = 7.2 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.25-7.37
(3H, m), 7.53-7.58 (4H, m), 7.63-7.72 (2H, m), 7.
96 (1H, s), 8.19 (1H, d, J = 8.0 Hz) .IR (KBr) 3334, 1732, 1651, 1605, 1520, 1311, 1238,
1165, 1126, 930, 818cm- ¹ Elemental analysis C ₃₄ H ₃₉ N ₃ O ₆ S Calcd. C, 66.10; H, 6.36;
N, 6.80: Found.C, 65.84; H, 6.44; N, 6.81.

Example 26 (Preparation of Compound 25) 7- (4-trifluoromethoxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
Oxalyl chloride (0.08 ml) and one drop of DMF were added to a solution of carboxylic acid (180 mg) in THF (5 ml) at room temperature, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in DMF (4 ml) and
[N-methyl-N- (tetrahydropyran-4-yl)
The mixture was added dropwise to a solution of [aminomethyl] aniline (109 mg) and triethylamine (0.19 ml) in THF (5 ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol / ethyl acetate 1:
3) and recrystallization (ethanol) to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7 as colorless crystals.
-(4-trifluoromethoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-
Carboxamide (Compound 25) (137.0 mg) was obtained. mp 261-263 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.52-1.82 (4H, m), 2.21 (3
H, s), 2.52-2.74 (1H, m), 3.15-3.22 (2H, m), 3.31-
3.45 (2H, m), 3.58 (2H, s), 3.71-3.78 (2H, m), 3.9
8-4.12 (2H, m), 7.27-7.35 (5H, m), 7.55 (2H, d, J =
8.8 Hz), 7.61-7.65 (3H, m), 7.70 (1H, dd, J = 8.1,
1.8 Hz), 7.93 (1H, br s), 8.25 (1H, d, J = 8.1 Hz) .IR (KBr) 3242, 1657, 1633, 1601, 1518, 1412, 1317,
. 1294, 1265, 1215, 1169 , 1130 cm -1 elemental analysis _{C 31 H 31 N 2 O 5} SF 3 Calcd C, 61.99; H, 5.20
; N, 4.66: Found.C, 61.95; H, 5.01; N, 4.59.

Example 27 (Preparation of Compound 26) 7- (3,4-Dichlorophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml) To the solution was added thionyl chloride (0.08 ml) and one drop of DMF at room temperature and stirred for 1 hour. After the solvent was distilled off under reduced pressure, the residue was
Dissolved in HF (15 ml) and added dropwise at 0 ° C. to a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (114 mg) and triethylamine (0.2 ml) in THF (2 ml). did. After stirring at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 4) and recrystallization (ethanol) to give 7-colorless crystals.
(3,4-dichlorophenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin- 4-carboxamide (compound 2
6) (155.0 mg) was obtained. ^{mp 235-237 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ1.56-1.78 (4H, m), 2.21 (3
H, s), 2.55-2.73 (1H, m), 3.17 (2H, t, J = 6.6 Hz),
3.31-3.44 (2H, m), 3.57 (2H, s), 3.73 (2H, t, J = 6.
6 Hz), 3.98-4.10 (2H, m), 7.30-7.35 (3H, m), 7.43
(1H, dd, J = 8.4, 2.2 Hz), 7.52-7.69 (6H, m), 7.96 (1
H, br s), 8.25 (1H, d, J = 8.2 Hz) .IR (KBr) 3253, 1655, 1633, 1601, 1529, 1467, 1410,
1317, 1296, 1130, 818cm- ¹ Elemental analysis C ₃₀ H ₃₀ N ₂ O ₄ SCl ₂ Calcd.C, 61.54; H, 5.16
N, 4.78: Found.C, 61.71; H, 5.14; N, 4.77.

Example 28 (Preparation of Compound 27) 7- (4-Propylphenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg) in THF (5 ml) at room temperature was added 1 drop of thionyl chloride (0.09 ml) and 1 drop of DMF to obtain a solution.
Stirred for hours. After evaporating the solvent under reduced pressure, the residue was washed with THF.
(12 ml) and dissolved at 0 ° C. in 4- [N-methyl-N
-(Tetrahydropyran-4-yl) aminomethyl] aniline (122 mg, 0.55 mmol) and triethylamine (0.14 ml) were added dropwise to a solution of THF (2 ml). After stirring at room temperature for 4 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting pale yellow crystals were purified by recrystallization (ethanol) to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] as colorless crystals. -7- (4-
(Propylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 27) (195.0 mg) was obtained. mp 247-250 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.98 (3H, t, J = 7.3 Hz), 1.
56-1.83 (6H, m), 2.21 (3H, s), 2.52-2.74 (3H, m),
3.18 (2H, t, J = 6.6 Hz), 3.31-3.44 (2H, m), 3.58 (2
H, s), 3.70-3.76 (2H, m), 3.97-4.10 (2H, m), 7.28-
7.35 (5H, m), 7.52 (2H, d, J = 8.4 Hz), 7.55 (2H, d,
J = 8.4 Hz), 7.66-7.73 (2H, m), 7.94 (1H, br s), 8.
21 (1H, d, J = 8.0 Hz). IR (KBr) 3250, 1657, 1635, 1599, 1525, 1410, 1315,
1296, 1165, 1130 cm- ¹ Elemental analysis C ₃₃ H ₃₈ N ₂ O ₄ S Calcd. C, 70.94; H, 6.86;
N, 5.01: Found.C, 70.99; H, 6.51; N, 5.05.

Example 29 (Preparation of Compound 28) 7- (4-Isopropoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (400 mg) in THF (10 ml) Thionyl chloride (0.094 ml) and one drop of DMF were added to the solution at room temperature, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (10 ml), and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (260 mg) and triethylamine (0%) were dissolved at 0 ° C. .45 ml) in THF (2 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 brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting pale yellow crystals were purified by recrystallization (ethanol) to give 7- (4-isopropoxyphenyl) -N- [4- [N
-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 28) (367.1 mg). . mp 245-247 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.38 (6H, d, J = 5.8 Hz), 1.
59-1.84 (4H, m), 2.21 (3H, s), 2.54-2.76 (1H, m),
3.16 (2H, t, J = 7.0 Hz), 3.31-3.44 (2H, m), 3.58 (2
H, s), 3.69-3.76 (2H, m), 3.99-4.10 (2H, m), 4.56-
4.69 (1H, m), 6.99 (2H, d, J = 8.8 Hz), 7.31-7.35 (3
H, m), 7.53 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8
Hz), 7.62-7.69 (2H, m), 7.93 (1H, br s), 8.19 (1H,
d, J = 8.4Hz). IR (KBr) 3248, 1655, 1603, 1515, 1410, 1317, 1292,
1248, 1171, 1128, 825cm- ¹ Elemental analysis C ₃₃ H ₃₈ N ₂ O ₅ S Calcd. C, 68.96; H, 6.66;
N, 4.87: Found.C, 68.70; H, 6.34; N, 4.86.

Example 30 (Preparation of Compound 29) 7- (4-Propoxyphenyl) -1,1-dioxo-
To a suspension of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (170 mg) in THF (5 ml) was added at room temperature thionyl chloride (0.07 ml) and one drop of DMF, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was treated with TH.
F (10 ml) and dissolved at room temperature in 4- [N-methyl-
N- (tetrahydropyran-4-yl) aminomethyl]
Aniline (111 mg) and triethylamine (0.
18 ml) in THF (2 ml). After stirring at room temperature for 21 hours, water was added and extracted with ethyl acetate.
The organic layer was washed with 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 N- [4
-[N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 29)
(147.6 mg) was obtained. mp 244-247 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.06 (3H, t, J = 7.4 Hz), 1.
57-1.90 (6H, m), 2.21 (3H, s), 2.54-2.75 (1H, m),
3.13-3.20 (2H, m), 3.31-3.44 (2H, m), 3.58 (2H, m
s), 3.69-3.76 (2H, m), 3.98 (2H, t, J = 6.6 Hz), 3.9
9-4.11 (2H, m), 7.01 (2H, d, J = 8.8 Hz), 7.31-7.35
(3H, m), 7.52-7.56 (4H, m), 7.62 (1H, d, J = 1.8 Hz),
7.67 (1H, dd, J = 8.0, 1.8 Hz), 7.92 (1H, br s), 8.
19 (1H, d, J = 8.0 Hz) .IR (KBr) 3280, 1657, 1603, 1520, 1315, 1294, 1250,
1130, 822 cm ^-1 Elemental analysis C ₃₃ H ₃₈ N ₂ O ₅ S Calcd. C, 68.96; H, 6.66;
N, 4.87: Found.C, 68.72; H, 6.70; N, 4.88.

Example 31 (Preparation of Compound 30) 7- (4-Butoxyphenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (5 ml) at room temperature was added 1 drop of thionyl chloride (0.07 ml) and 1 drop of DMF to obtain a solution.
Stirred for hours. After evaporating the solvent under reduced pressure, the residue was washed with THF.
(10 ml), and dissolved at room temperature in 4- [N-methyl-N
-(Tetrahydropyran-4-yl) aminomethyl] aniline (114 mg) and triethylamine (0.2
ml) in THF (2 ml). After stirring at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was purified by column chromatography (ethanol / ethyl acetate 1: 4) and recrystallization (ethanol) to give 7- (4-butoxyphenyl) -N- [4- [N -Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 30) (13
8.6 mg). mp 233-236 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.00 (3H, t, J = 7.3 Hz), 1.
40-1.87 (8H, m), 2.21 (3H, s), 2.55-2.72 (1H, m),
3.16 (2H, t, J = 6.8 Hz), 3.31-3.42 (2H, m), 3.58 (2
H, s), 3.72 (2H, t, J = 6.8 Hz), 3.98-4.10 (2H, m),
4.02 (2H, t, J = 6.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.
30-7.35 (3H, m), 7.54 (2H, d, J = 8.8 Hz), 7.55 (2H,
d, J = 8.8 Hz), 7.62-7.69 (2H, m), 7.93 (1H, br s),
8.19 (1H, d, J = 8.0 Hz) IR (KBr) 3280, 1659, 1603, 1518, 1315, 1294, 1250,
1128, 825 cm ^-1 Elemental analysis C ₃₄ H ₄₀ N ₂ O ₅ S Calcd. C, 69.36; H, 6.85;
N, 4.76: Found.C, 69.20; H, 6.75; N, 4.94.

Example 32 (Production of Compound 31) 6- (4-methylphenyl) -1,1-dioxo-1,
2-dihydro-2H-thiochromene-3-carboxylic acid (1
WSC (163 mg, 0.85 mmol) was added to a suspension of HOBt (115 mg, 0.85 mmol) in acetonitrile (5 ml).
mmol) and stirred for 1 hour. 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (187 mg, 0.85 mmol) and triethylamine (0.16 ml, 1.13 mmol) in acetonitrile (1 ml) were added to the reaction mixture.
The solution was added and stirred for 15 hours. The residue obtained by distilling off the solvent was diluted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography,
From the ethyl acetate / ethanol (2: 1) elution part, 6- (4
-Methylphenyl) -N- (4-((N-methyl-N-
(Tetrahydropyran-4-ylaminomethyl) phenyl-1,1-dioxo-1,2-dihydro-2H-thiochromene-3-carboxamide (compound 31) (89.4 mg,
31%) as a brown powder. 197 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 7.96-8.02 (3H, m), 7.86 (1H,
s), 7.65-7.71 (4H, m), 7.25-7.38 (4H, m), 4.57 (2H,
s), 3.81-4.00 (2H, m), 3.54 (2H, s), 3.20-3.32 (2
H, m), 2.50-2.72 (1H, m), 2.39 (3H, s), 2.12 (3H,
s).

Example 33 (Preparation of Compound 32) 7- (4-Methylphenyl) -1,1-dioxo-2,
3-dihydro-1-benzothiepine-4-carboxylic acid
Oxalyl chloride (0.26 ml, 2.97 mmol) and DMF were added to a suspension of (325 mg, 0.991 mmol) in THF (10 ml) at 0 ° C.
(1 drop) and stirred at room temperature for 1.5 hours. After distilling off the solvent, a THF solution (8 ml) was prepared.
(N- (2-ethoxycarbonylethyl) -N-methyl) aminomethyl) aniline (257 mg, 1.09 mmol) and triethylamine (0.42 ml, 2.97 mmol) in THF
(2 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and N- (4-
(N- (2-ethoxycarbonylethyl) -N-methyl) aminomethyl) phenyl-7- (4-methylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 32) (310 m
g, 57%) and recrystallized from acetone / ethanol to give colorless crystals having a melting point of 180 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.20 (1H, d, J = 8.0), 7.98 (1H,
br s), 7.64-7.71 (2H, m), 7.47-7.57 (4H, m), 7.26-
7.36 (4H, m), 4.15 (2H, q, J = 7.4), 3.72 (2H, t, J =
6.7), 3.51 (2H, s), 3.16 (2H, t, J = 6.7), 2.76 (2H,
t, J = 7.0), 2.52 (2H, t, J = 7.0), 2.42 (3H, s), 2.21
(3H, s), 1.26 (3H, t, J = 7.4).

Example 34 (Production of Compound 33) 6- (4-Methylphenyl) -1,1-dioxo-1,
2-dihydro-2H-thiochromene-3-carboxylic acid
To a suspension of (115 mg, 0.494 mmol) in THF (5 ml) was added oxalyl chloride (0.13 ml, 1.48 mmol) and DMF (1 drop), and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was converted to a THF (5 ml) solution, and 4- (N-
(2-methoxyethyl) -N-methyl) aminomethylaniline (127 mg, 0.543 mmol) and triethylamine (0.2
(1 ml, 1.48 mmol) in THF (2 ml) was added and stirred for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and ethyl acetate / ethanol (4: 4).
1) N- (4- (N- (2-methoxyethyl) -N-methyl) aminomethyl) phenyl-6- (4
-Methylphenyl) -1,1-dioxo-1,2-dihydro-2H-thiochromene-3-carboxamide (Compound 33) (110 mg, 42%) was obtained as dark green crystals. 138 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, br s), 7.90 (2H, d, J
= 8.4), 7.56 (2H, dd, J = 8.0, 8.1), 7.32-7.48 (5H,
m), 7.17-7.22 (4H, m), 4.21 (2H, s), 3.44 (2H, s),
3.43 (2H, t, J = 5.6), 3.25 (3H, s), 2.51 (2H, t, J
= 5.6), 2.32 (3H, s), 2.17 (3H, s). Anal.Calcd for C ₂₈ H ₃₀ N ₂ O ₄ S ・ 0.5H ₂ O: C; 67.31, H;
6.25, N; 5.61. Found: C; 67.61, H; 5.98, N; 5.33.

Example 35 (Preparation of Compound 34) 7- (4-Methylphenyl) -N- (4-((N-methyl-N-tetrahydropyran-4-ylamino) methyl) phenyl-1,1-dioxo -2,3-dihydro-
1-benzothiepine-4-carboxamide (137 mg, 0.2
58 mmol) in DMF solution (2 ml) was added methyl iodide (0.02
ml, 0.284 mmol) and stirred for 16 hours. The powder obtained by distilling off the solvent is washed with hexane, and dimethyl chloride (N- (7- (4-methylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carbonyl-carbonyl) is obtained. 4-Aminobenzyl) -N- (tetrahydropyran-4-yl) ammonium (Compound 34) (164 m
g, 95%) as a brown powder. Melting point 170-171
° C. ¹ H-NMR (DMSO-d ₆ ) δ: 9.46 (1H, s), 8.04-8.11 (2H,
m), 7.84-7.86 (3H, m), 7.72 (2H, d, J = 8.4), 7.52-7.
61 (2H, m), 7.36 (2H, d, J = 7.4), 4.47 (2H, s), 4.00
-4.14 (2H, m), 3.83 (2H, t, J = 6.2), 3.50-3.71 (1H,
m), 2.88 (6H, s), 2.38 (3H, s), 2.10-2.22 (2H, m),
1.79-2.00 (2H, m). Anal.Calcd for C ₃₂ H ₃₇ IN ₂ O ₄ S ・ H ₂ O: C; 55.65, H; 5.
69, N; 4.06. Found: C; 55.65, H; 5.64, N; 4.17.

Example 36 (Preparation of Compound 35) 7- (4-Methylphenyl) -N- (4-((N-methyl-N- (3-pentyl) amino) methyl) phenyl-
DM of 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (119 mg, 0.321 mmol)
F solution (2 ml) in methyl iodide (0.025 mml, 0.353 mmo
l) was added and the mixture was stirred for 16 hours. The powder obtained by distilling off the solvent was washed with hexane, and dimethyl chloride (N- (1,1
-Dioxo-7- (4-methylphenyl) -2,3-dihydro-1-benzothiepine-4-carbonyl-4-aminobenzyl) -N- (3-pentyl) ammonium (compound 35) (114 mg, 95% ) Was obtained. Melting point 150-
151 ° C. ¹ H-NMR (CDCl ₃ ) δ: 9.48 (1H, br s), 8.22 (1H, br
s), 8.13 (2H, d, J = 8.0), 7.86-7.92 (2H, m), 7.45-
7.76 (4H, m), 7.24-7.29 (2H, m), 4.74 (2H, s), 3.76
(2H, t, J = 5.2), 3.20-3.37 (1H, m), 3.02 (2H, t, J
= 5.2), 2.98 (6H, s), 2.38 (3H, s), 1.50-1.80 (4H,
m), 1.08 (6H, t, J = 7.4). Anal.Calcd for C ₃₂ H ₃₉ IN ₂ O ₃ S ・ 1.5H ₂ O: C; 56.06, H;
6.17, N; 4.09.Found: C; 55.47, H; 5.90, N; 4.38.

Example 37 (Preparation of compound 36) 7- (4-Methylphenyl) -N- (4-((N-methyl-N-tetrahydropyran-4-yl) aminomethyl) phenyl) -2,3 -Dihydro-1-benzothiepine-4-carboxamide (0.2 g) in dichloromethane (50 ml) at -30 to -10 ° C at 70% mC
PBA (0.1 g) was added, and the mixture was stirred at −30 to −10 ° C. for 1 hour. After adding an aqueous solution of sodium thiosulfate, the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Residue is applied to silica gel column (methanol / dichloromethane)
And crude crystals were obtained. Recrystallized from ethyl acetate / hexane to give 7- (4-methylphenyl) -N- (4-
((N-methyl-N-tetrahydropyran-4-yl)
(Aminomethyl) phenyl) -1-oxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 36) (0.04 g) was obtained as colorless crystals. mp 191-192 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.65-1.80 (4H, m), 2.22 (3H, s),
2.41 (3H, s), 2.55-2.90 (2H, m), 3.10-3.25 (1H, m), 3.35
-3.50 (3H, m), 3.58 (2H, s), 3.81-3.95 (1H, m), 4.01-4.1
1 (2H, m), 7.25 (2H, d, J = 8.0Hz), 7.33 (2H, d, J = 8.5Hz),
7.45 (2H, d, J = 8.0Hz), 7.52 (1H, s), 7.61 (2H, d, J = 8.5H
z), 7.70 (1H, dd, J = 2.0,8.2Hz), 7.97 (1H, d, J = 8.0Hz),
8.26 (1H, s) .IR (KBr) ν: 2948, 2845, 1663cm ^-1 .

Example 38 (Preparation of compound 37) 7- (4-Methylphenyl) -1,1-dioxo-2,
3-Dihydro-1-benzothiepine-4-carboxylic acid (0.3 g) was suspended in dichloromethane (10 ml),
Under ice cooling, oxalyl chloride (0.25 ml) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, the residue was dissolved in tetrahydrofuran (20 ml), and tetrahydrofuran (25 ml) of 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.22 g) and triethylamine (0.38 ml) was used. ) The solution was added dropwise to the solution under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. Under reduced pressure,
The solvent was distilled off to obtain a crude crystal. Recrystallized from ethyl acetate / hexane to give 7- (4-methylphenyl) -N- (4-
((N-methyl-N-tetrahydropyran-4-yl)
Aminomethyl) phenyl) -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxamide (compound 39) (0.22 g) was obtained as pale yellow crystals. mp 234-235 ° C (dec.). ¹ H-NMR (δppm, CDCl ₃ ) 1.67-1.75 (4H, m), 2.21 (3H, s),
2.42 (3H, s), 2.57-2.70 (1H, m), 3.17 (2H, t, J = 6.8Hz),
3.37 (2H, dt, J = 2.6, 11.2Hz), 3.58 (2H, s), 3.73 (2H, t, J
= 6.8Hz), 4.01-4.11 (2H, m), 7.27-7.36 (4H, m), 7.49-7.
57 (4H, m), 7.65 (1H, s), 7.70 (1H, dd, J = 2.0,8.2Hz), 7.
94 (1H, s), 8.21 (1H, d, J = 8.2Hz) .IR (KBr) ν: 2946, 2845, 1667cm ^-1 .Anal.Calcd. For C ₃₁ H ₃₄ N ₂ O ₄ S: C, 70.16; H, 6.46; N,
5.28. Found C, 69.95; H, 6.22; N, 5.16.

Example 39 (Preparation of Compound 38) 7- (4-Methylphenyl) -1,1-dioxo-2,
Oxalyl chloride (0.2 ml) and dimethylformamide (catalytic amount) were added to a suspension of 3-dihydro-1-benzothiepine-4-carboxylic acid (0.25 g) in dichloromethane (8 ml) under ice-cooling. Stir for 2 hours. After evaporating the solvent, the residue was dissolved in tetrahydrofuran (15 ml), and 4-((N-methyl-N- (pentan-3-yl)) aminomethyl) aniline (0.17 g) and triethylamine (0.32 ml) in tetrahydrofuran ( 1
5 ml) was added dropwise to the solution under ice-cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude crystal. Recrystallization from ethyl acetate / hexane gave N- (4-((N-methyl-N- (pentane-3
-Yl)) aminomethyl) phenyl) -7- (4-methylphenyl) -1,1-dioxo-2,3-dihydro-
1-benzothiepine-4-carboxamide (compound 3
8) (0.13 g) was obtained as colorless crystals. mp 130-131 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 0.94 (6H, t, J = 7.3Hz), 1.27-1.58
(4H, m), 2.15 (3H, s), 2.28-2.38 (1H, m), 2.42 (3H, s),
3.17 (2H, t, J = 6.8Hz), 3.58 (2H, s), 3.72 (2H, t, J = 6.8H
z), 7.27-7.37 (4H, m), 7.49-7.56 (4H, m), 7.66-7.72 (2
H, m), 7.97 (1H, s), 8.21 (1H, d, J = 8.0Hz) .IR (KBr) ν: 2963, 2930, 1663cm ^-1 . Anal.Calcd. For C ₃₁ H ₃₆ N ₂ O ₃ S ・ 0.5H ₂ O: C, 70.83; H, 7.
09; N, 5.33. Found C, 70.77; H, 6.76; N, 5.45.

Example 40 (Preparation of compound 39) 7- (4-Methylphenyl) -1,1-dioxo-2,
3-Dihydro-1-benzothiepine-4-carboxylic acid (0.3 g) was suspended in dichloromethane (5 ml), and oxalyl chloride (0.25 ml) and dimethylformamide (catalytic amount) were added under ice-cooling. Stirred for hours. After evaporating the solvent, the residue was dissolved in tetrahydrofuran (20 ml), and N- (4-aminobenzyl) sarcosine methyl ester (0.21 g) and triethylamine (0.38 g) were added.
ml) in tetrahydrofuran (10 ml) under ice-cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (ethyl acetate / hexane) to obtain a crude crystal. Recrystallized from ethyl acetate / hexane, N-
(4-((N-methoxycarbonylmethyl-N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide ( Compound 39)
(0.22 g) as colorless crystals. mp 136-143 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 2.39 (3H, s), 2.43 (3H, s), 3.17
(2H, t, J = 6.6Hz), 3.27 (2H, s), 3.66 (2H, s), 3.69-3.76
(2H, m), 3.72 (3H, s), 7.28-7.37 (4H, m), 7.48-7.58 (4H,
m), 7.65 (1H, s), 7.70 (1H, dd, J = 1.6,8.4Hz), 7.93 (1H,
s), 8.21 (1H, d, J = 8.4Hz). IR (KBr) ν: 2932, 1744cm ^-1 .Anal.Calcd. for C ₂₉ H ₃₀ N ₂ O ₅ S: C, 67.16; H, 5.83; N,
5.40. Found C, 66.94; H, 5.94; N, 5.20.

Example 41 (Preparation of Compound 40) 7- (5-Methyl-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (166 mg) was added to THF ( 6.5 ml) and oxalyl chloride (0.087 m
l), DMF (one drop) was added, and the mixture was stirred at room temperature for 2 hours.
The solvent was removed under reduced pressure, and a THF solution of the obtained residue (6 m
l) is converted to 4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] aniline (135 mg) and a solution of triethylamine (0.2 ml) in THF (4 ml) were added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 13 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4- [N-methyl-N- ( Tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (5-methyl-2-thienyl)-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 40) (113 m
g) was obtained. mp 229-231 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.60-1.82 (4H, m),
2.21 (3H, s), 2.54 (3H, s), 2.65 (1H, m),
3.37 (2H, td, J = 11.4, 3.0 Hz), 3.57 (2H,
s), 3.70 (2H, m), 4.01-4.07 (2H, m), 6.79
(1H, dd, J = 3.6, 1.0Hz), 7.24-7, 34 (3H,
m), 7.53-7.64 (4H, m), 8.01 (1H, s), 8.11
(1H, d, J = 8.4Hz) IR (KBr) 1659, 1526, 1410, 1318, 1292, 1128, 806c
m ^-1

Example 42 (Preparation of compound 41) 7- (4-Methyl-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (400 mg) was added to THF ( Oxalyl chloride (0.21 ml), DMF
(One drop) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and a THF solution (6 ml) of the obtained residue was added to 4-
A solution of [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (352 mg) and triethylamine (0.5 ml) in THF (10 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Stirred. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4- [N-methyl-N-
(Tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-methyl-2-thienyl) -1,1
-Dioxo-2,3-dihydro-1-benzothiepin-
4-Carboxamide (Compound 41) (355 mg) was obtained. mp 232-234 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.57-1.83 (4H, m),
2.21 (3H, s), 2.54 (3H, s), 2.65 (1H, m),
3.13 (2H, t, J = 6.6 Hz), 3.38 (2H, td, J = 11.4,
2.8 Hz), 3.57 (2H, s), 3.70 (2H, t, J = 6.6H)
z), 4.00-4.08 (2H, m), 7.00 (1H, s), 7.23
−7.34 (3H, m), 7.53 − 7.64 (4H, m), 8.10 (2
H, d, J = 8.0 Hz) IR (KBr) 1643, 1518, 1408, 1319, 1294, 817cm ^-1

Example 43 (Preparation of Compound 42) 7- (5-Chloro-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (200 mg) was added to THF (200 mg). 8.0 ml), and oxalyl chloride (0.075 m
l), DMF (one drop) was added, and the mixture was stirred at room temperature for 2 hours.
The solvent was removed under reduced pressure, and a THF solution of the obtained residue (8 m
l) is converted to 4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] aniline (153 mg), a solution of triethylamine (0.20 ml) in THF (6 ml)
The mixture was added dropwise with stirring under ice-cooling and stirred at room temperature for 16 hours.
The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 3/1).
And recrystallized from ethanol to give 7- (5-chloro-2-thienyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl]- 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 42) (90
mg). mp 221-222 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.60-1.83 (4H, m),
2.22 (3H, s), 2.67 (1H, m), 3.14 (2H, m),
3.37 (2H, td, J = 11.4, 2.6 Hz), 3.59 (2H, s),
3.71 (2H, m), 4.00-4.08 (2H, m), 6.97 (1H,
d, J = 4.0 Hz), 7.22 (1H, J = 4.0 Hz), 7.33 (3H,
d, J = 8.8 Hz), 7.51-7.61 (4H, m), 8.00 (1H,
s), 8.14 (1H, d, J = 8.0 Hz) IR (KBr) 1655, 1528, 1410, 1318, 1294, 1130, 819c
. m ^-1 elemental analysis _{C 28 H 29 ClN 2 O 4} S 2 Calcd C, 60.36; H, 5.25
; N, 5.03: Found. C, 60.56; H, 5.37; N, 4.93

Example 44 (Preparation of Compound 43) 7-[(4-Methylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (133 mg) was added to THF (8 ml). ), Oxalyl chloride (0.065 ml), DM
F (one drop) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and a THF solution (6 ml) of the obtained residue was added to 4
-[N-methyl-N- (tetrahydropyran-4-yl)
A solution of [aminomethyl] aniline (100 mg) and triethylamine (0.15 ml) in THF (6 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4- [N-methyl-
N- (tetrahydropyran-4-yl) aminomethyl]
Phenyl] -7-[(4-methylthio) phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 43) (80 mg)
I got mp 249-252 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ (3H, t, J = 7.2 Hz), 1.
58−2.00 (4H, m), 2.32 (3H, s), 2.54 (3H,
s), 2.87 (1H, m), 3.16 (2H, t, J = 6.6 Hz), 3.
30 (2H, td, J = 11.4, 2.6 Hz), 3.74 (4H, m),
3.94-4.10 (2H, m), 7.27-7.81 (12H, m), 8.
20 (1H, d, J = 8.4Hz) IR (KBr) 1653, 1530, 1410, 1318, 1294, 1130, 812c
m ^-1

Example 45 (Preparation of Compound 44) 7-[(4-Ethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (130 mg) was added to THF (4 ml). ) And thionyl chloride (0.035 ml) and DMF (0.
02 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a THF solution (6 ml) of the obtained residue was added to 4
-[N-methyl-N- (tetrahydropyran-4-yl)
It was added dropwise to a THF solution (6 ml) of [aminomethyl] aniline (130 mg) and triethylamine (0.3 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 4 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1).
Recrystallized from ethanol to give 7-[(4-ethylthio) phenyl] -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1
-Dioxo-2,3-dihydro-1-benzothiepin-
4-Carboxamide (Compound 44) (82 mg) was obtained. mp 232-233 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.37 (3 H, t, J = 7.2 H
z), 1.58-1.82 (4H, m), 2.21 (3H, s), 2.66
(1H, m), 3.02 (2H, q, J = 7.2Hz), 3.16 (2H,
m), 3.37 (2H, td, J = 11.4, 2.6 Hz), 3.58 (2H,
s), 3.72 (2H, m), 4.00-4.08 (2H, m), 7.30
-7.70 (11H, m), 8.01 (1H, s), 8.20 (1H, d, J
= 8.0Hz) IR (KBr) 1655, 1522, 1410, 1315, 1294, 1130, 816c
m ^-1

Example 46 (Preparation of compound 45) 7-[(4-Ethylsulfonyl) phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxylic acid (250 mg) was dissolved in THF (10 ml) and thionyl chloride (0.054 ml), DM
F (one drop) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a THF solution (8 ml) of the obtained residue was added to 4
-[N-methyl-N- (tetrahydropyran-4-yl)
A solution of [aminomethyl] aniline (167 mg) and triethylamine (0.43 ml) in THF (8 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and 7-[(4-ethylsulfonyl) phenyl] -N -[4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 45) (105 m
g) was obtained. mp 210-211 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.32 (3 H, t, J = 7.2 H
z), 1.56-1.83 (4H, m), 2.21 (3H, s), 2.65
(1H, m), 3.16 (2H, q, J = 7.2Hz), 3.19 (2H,
m), 3.37 (2H, td, J = 11.4, 3.0 Hz), 3.58 (2H,
s), 3.74 (2H, m), 4.01-4.07 (2H, m), 7.33
(2H, d, J = 8.4Hz), 7.38 (1H, s), 7.55 (2H,
d, J = 8.4 Hz), 7.69-7.80 (4H, s), 7.99-8.05
(3H, m), 8.29 (2H, d, J = 8.0 Hz) IR (KBr) 1659, 1530, 1410, 1313, 1294, 1146, 747,
733cm ^-1

Example 47 (Preparation of Compound 46) 1,1-Dioxo-7-[(4-propylthio) phenyl] -2,3-dihydro-1-benzothiepine-4-carboxylic acid (400 mg) was added to THF (10 ml). )
Under stirring at room temperature, thionyl chloride (0.089 ml), DMF
(One drop) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a THF solution (8 ml) of the obtained residue was added to 4-
A solution of [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (280 mg) and triethylamine (0.57 ml) in THF (8.4 ml) was added dropwise with ice-cooling and stirring, and the mixture was stirred at room temperature. Stir for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4- [N-methyl-N
-(Tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1-dioxo-7-[(4-propylthio) phenyl] -2,3-dihydro-1-benzothiepine-4-carboxamide (compound 46) ( 298 mg)
I got mp 220-220 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (3 H, t, J = 7.2 H
z), 1.60-1.81 (6H, m), 2.21 (3H, s), 2.65
(1H, m), 2.97 (2H, t, J = 7.4 Hz), 3.17 (2H,
m), 3.37 (2H, td, J = 11.2, 2.8 Hz), 3.58 (2H,
s), 3.72 (2H, m), 4.00-4.09 (2H, m), 7.29
−7.70 (11H, m), 7.95 (1H, s), 8.21 (1H, d, J
= 8.0 Hz) Elemental analysis _{C 33 H 38 N 2 O 4} S 2 Calcd C, 67.09;. H, 6.48;
N, 4.74: Found.C, 67.15; H, 6.27; N, 4.98 R (KBr) 1660, 1516, 1410, 1314, 1294, 1130, 816cm
^-1

Example 48 (Production of compound 47) 7-[(4-Butylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (400 mg) was added to THF (10 ml). ), Thionyl chloride (0.086 ml) and DMF (one drop) were added under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a THF solution (8 ml) of the obtained residue was added to 4- [N-
Methyl-N- (tetrahydropyran-4-yl)] aniline (270 mg), triethylamine (0.55 m)
The mixture was dropped into a THF solution (8.1 ml) of 1) under ice-cooling and stirring, followed by stirring at room temperature for 2 hours. Add the reaction solution to water,
Extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and treated with 7-[(4-butylthio) phenyl] -N
-[4- [N-methyl-N- (tetrahydropyran-4-
Yl) aminomethyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (compound 47) (267 mg) was obtained. mp 207-209 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.0H)
z), 1.42-1.75 (8H, m), 2.21 (3H, s), 2.65
(1H, m), 2.99 (2H, t, J = 7.2Hz), 3.16 (2H,
m), 3.37 (2H, td, J = 11.2, 3.0 Hz), 3.57 (2H,
s), 3.72 (2H, m), 4.01-4.09 (2H, m), 7.30
−7.70 (11H, m), 7.96 (1H, s), 8.21 (1H, d, J
= 8.2Hz) IR (KBr) 1653, 1530, 1410, 1318, 1294, 1130, 816c
. m ^-1 elemental analysis _{C 34 H 40 N 2 O 4} S 2 Calcd C, 67.52; H, 6.67;
N, 4.63: Found.C, 67.66; H, 6.52; N, 4.87

Reference Example 1 7-bromo-2,3-dihydro-1-benzothiepin-
Acetic acid (30 m) of methyl 4-carboxylate (3.00 g)
1) Add 30% aqueous hydrogen peroxide (4.5 m
l) was added and the mixture was heated under reflux for 1 hour. The reaction mixture was added to the stirred water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diisopropyl ether, and as colorless crystals, methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (3.
06g). mp 162-164 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ3.11 (2H, t, J = 6.5 Hz), 3.
62 (2H, t, J = 6.5 Hz), 3.87 (3H, s), 7.64-7.76 (3H,
m), 8.03 (1H, d, J = 8.4 Hz) .IR (KBr) 1718, 1288, 1263, 1165, 1128, 1090, 797,
748 cm ^-1 Elemental analysis C ₁₂ H ₁₁ O ₄ SBr Calcd. C, 43.52; H, 3.35:
Found. C, 43.52; H, 3.18.

Reference Example 2 7-bromo-2,3-dihydro-1-benzothiepin-
Methyl 4-carboxylate (0.8 g) in THF (10 m
l) Add 70% 3-chloroperbenzoic acid (1.
45 g), and the mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 1 hour. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 1), and further recrystallized (ethyl acetate / hexane) to give 7-bromo-1,1-dioxo as pale yellow crystals. There was obtained methyl-2,3-dihydro-1-benzothiepine-4-carboxylate (827 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.11 (2H, t, J = 6.5 Hz), 3.
62 (2H, t, J = 6.5 Hz), 3.87 (3H, s), 7.64-7.76 (3H,
m), 8.03 (1H, d, J = 8.4 Hz) .IR (KBr) 1718, 1288, 1263, 1165, 1128, 1090, 797,
748 cm ^-1 Elemental analysis C ₁₂ H ₁₁ O ₄ SBr Calcd. C, 43.52; H, 3.35:
Found. C, 43.39; H, 3.38.

Reference Example 3 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.7 g), 4-morpholinophenylboric acid (481 mg) and potassium carbonate (0.59 g) in toluene / ethanol / water (20/2/2 ml) ) The mixture
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.12 g) was added to the reaction system, and the mixture was heated under reflux for 20 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated solid was purified by recrystallization (ethyl acetate / hexane) to give 7- (4-morpholinophenyl) -1,1-dioxo- as yellow crystals.
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (617.6 mg) was obtained. mp 215-217 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.10-3.17 (2H, m), 3.23-3.
28 (4H, m), 3.61-3.67 (2H, m), 3.87 (3H, s), 3.84-
3.95 (4H, m), 7.00 (2H, d, J = 8.8 Hz), 7.56 (2H, d,
J = 8.8 Hz), 7.66-7.74 (2H, m), 7.91 (1H, s), 8.18
(1H, d, J = 8.8 Hz). IR (KBr) 1705, 1605, 1520, 1309, 1290, 1238, 1165,
1126, 928, 816, 752 cm- ¹ Elemental analysis C ₂₂ H ₂₃ NO ₅ S Calcd. C, 63.90; H, 5.61;
N, 3.39: Found.C, 63.89; H, 5.74; N, 3.51.

Reference Example 4 7- (4-morpholinophenyl) -1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (550 mg) in ethanol / THF (15 m
1/15 ml) solution at room temperature was added with 1N aqueous sodium hydroxide solution (1.6 ml) and stirred for 18 hours. After 1N hydrochloric acid (1.6 ml) was added to the reaction system, the mixture was concentrated under reduced pressure.
The precipitated crystals were collected by filtration, and 2-propanol,
After washing with diethyl ether, 7- (4
-Morpholinophenyl) -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxylic acid (26
8.9 mg). The mother liquor was further concentrated and the resulting solid was collected by filtration (177 mg). (2nd crystal, purity about 50%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.89-3.02 (2H, m), 3.15-
3.26 (4H, m), 3.68-3.82 (6H, m), 7.06 (2H, d, J = 9.
0 Hz), 7.74 (2H, d, J = 9.0 Hz), 7.83-7.91 (2H, m),
7.99-8.08 (2H, m) .IR (KBr) 3408, 1711, 1678, 1605, 1520, 1290, 1236,
1167, 1124, 928, 820,746 cm- ¹ Elemental analysis C ₂₁ H ₂₁ NO ₅ S ・ 0.5H ₂ O Calcd.C, 61.75; H,
5.43; N, 3.43: Found.C, 61.60; H, 5.65; N, 3.5
0.

Reference Example 5 7- (4-morpholinophenyl) -1,1-dioxo-
A mixture of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (100 mg) and 6N hydrochloric acid (10 ml) was stirred at 70 ° C. for 4 hours. The mixture was concentrated under reduced pressure, 2-propanol was added to the residue, and the resulting solid was collected by filtration. After washing with 2-propanol and diethyl ether, 7- (4-morpholinophenyl) is obtained as a yellow powder.
-1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (89.3 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.89-3.02 (2H, m), 3.15-
3.26 (4H, m), 3.68-3.82 (4H, m), 7.06 (2H, d, J = 9.
0 Hz), 7.74 (2H, d, J = 9.0 Hz), 7.83-7.91 (2H, m),
7.99-8.08 (2H, m). Elemental analysis C ₂₁ H ₂₁ NO ₅ S ・ HCl Calcd. C, 57.86; H, 5.09
; N, 3.21: Found. C, 57.47; H, 5.12; N, 3.31.

Reference Example 6 7- (4-methoxyphenyl) -2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (0.60
g) in THF (10 ml) was added 70% 3-chloroperbenzoic acid (1.0 g) at 0 ° C., and the mixture was added at 0 ° C. for 30 minutes.
Stirred at room temperature for 2 hours. An aqueous solution of sodium thiosulfate was added to the reaction system, the mixture was stirred for several minutes, and extracted with dichloromethane.
The organic layer was washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting solid was purified by recrystallization (ethyl acetate / hexane) to give 7- (4-methoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine- as colorless crystals. Methyl 4-carboxylate (584.5 mg) was obtained. mp 191-193 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.11-3.17 (2
H, m), 3.61-3.68 (2H, m),
3.87 (3H, s), 3.88 (3H,
s), 7.02 (2H, d, J = 9.0 H)
z), 7.57 (2H, d, J = 9.0 H
z), 7.66-7.70 (2H, m), 7.
92 (1H, s), 8.20 (1H, d,
J = 8.6 Hz). IR (KBr) 1713, 1603, 151
6, 1437, 1286, 1248, 117
1, 1128, 1030, 820, 750, 6
06 cm ^-1 elemental analysis _{C 19 H 18 O 5 S Calcd} . C,
63.67; H, 5.06: Found.
C, 63.88; H, 5.14.

Reference Example 7 7- (4-methoxyphenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (463 mg) in 1,2-dimethoxyethane (30 ml), 6N hydrochloric acid (30 ml) was added, and
Heated to reflux for an hour. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with 2-propanol and hexane to obtain 7- (4-methoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (384 mg) as pale yellow crystals. Was. mp 250 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ2.91-3.01 (2H, m), 3.71-
3.78 (2H, m), 3.83 (3H, s), 7.08 (2H, d, J = 8.8 H
z), 7.80 (2H, d, J = 8.8 Hz), 7.84-7.91 (2H, m), 8.03
-8.07 (2H, m) .IR (KBr) 2978, 1682, 1608, 1520, 1292, 1255, 1165,
1130, 824 cm ^-1 Elemental analysis C ₁₈ H ₁₆ O ₅ S Calcd. C, 62.78; H, 4.68: F
ound. C, 62.51; H, 4.50.

Reference Example 8 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethoxyphenylboric acid (0.44 g) and potassium carbonate (0.67 g) in toluene / ethanol / water (20/2) / 2 ml) mixture
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system, and the mixture was heated under reflux for 16 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting solid was purified by recrystallization (ethyl acetate / hexane) to give 7- (4-ethoxyphenyl) -1,1-dioxo-2,3-dihydro-1- as pale yellow crystals.
Benzothiepine-4-carboxylate (739.5 m
g) was obtained. mp 173-175 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.46 (3H, t, J = 7.0 Hz), 3.
11-3.17 (2H, m), 3.61-3.68 (2H, m), 3.87 (3H, s),
4.10 (2H, q, J = 7.0 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.
55 (2H, d, J = 8.8 Hz), 7.64-7.72 (2H, m), 7.91 (1H,
s), 8.19 (1H, d, J = 8.4 Hz) .IR (KBr) 1713, 1608, 1518, 1292, 1250, 1225, 1167,
. 1132, 1038, 829, 757cm -1 elemental analysis _{C 20 H 20 O 5 S Calcd} C, 64.50; H, 5.41: F
ound. C, 64.21; H, 5.26.

Reference Example 9 7- (4-ethoxyphenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (40 ml) was added 6N hydrochloric acid (30 ml).
Heated to reflux for an hour. The mixture was concentrated under reduced pressure, 2-propanol was added, and the resulting crystals were collected by filtration. Crystals in THF
And concentrated by filtration, and the resulting crystals were collected by filtration to give 7- (4-ethoxyphenyl) as pale yellow crystals.
-1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (507.5 mg) was obtained. mp 278 ° C (dec.) ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.36 (3H, t, J = 7.0 Hz),
2.94-3.00 (2H, m), 3.71-3.78 (2H, m), 4.10 (2H, q,
J = 7.0 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.78 (2H, d, J
= 8.8 Hz), 7.83-7.92 (2H, m), 8.03-8.07 (2H, m) .IR (KBr) 3039, 1676, 1608, 1518, 1294, 1250, 1165,
1130, 827, 746 cm ^-1 Elemental analysis C ₁₉ H ₁₈ O ₅ S Calcd.C, 63.67; H, 5.06: F
ound. C, 63.73; H, 5.28.

Reference Example 10 7- (3,4-Methylenedioxyphenyl) -2,3-
A solution of methyl dihydro-1-benzothiepine-4-carboxylate (0.80 g) in THF (10 ml) was added at 0 ° C. for 7 hours.
0% 3-chloroperbenzoic acid (1.22 g) was added, and the mixture was added at 0 ° C.
For 15 minutes and at room temperature for 2 hours. An aqueous solution of sodium thiosulfate was added to the reaction system, the mixture was stirred for several minutes, and extracted with dichloromethane. Wash the organic layer with aqueous sodium bicarbonate and saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the resulting solid was purified by recrystallization (THF / isopropanol) to give 7- (3,4-methylenedioxyphenyl) -1,1-dioxo-2,3-dihydro-1 as colorless crystals.
Methyl benzothiepine-4-carboxylate (763.3
mg). mp 185-187 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.11-3.17 (2H, m), 3.61-3.
65 (2H, m), 3.87 (3H, s), 6.05 (2H, s), 6.92 (1H, d
d, J = 7.3, 1.1 Hz), 7.08-7.13 (2H, m), 7.62-7.66 (2
H, m), 7.90 (1H, br s), 8.20 (1H, d, J = 8.8 Hz) .IR (KBr) 1714, 1481, 1277, 1252, 1232, 1130, 1036,
804, 754 cm ^-1 elemental analysis C ₁₉ H ₁₆ O ₆ S Calcd. C, 61.28; H, 4.33: F
ound. C, 61.41; H, 4.56.

Reference Example 11 7- (3,4-Methylenedioxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-To a solution of methyl carboxylate (500 mg) in 1,2-dimethoxyethane (50 ml) was added 6N hydrochloric acid (30 ml), and the mixture was heated under reflux for 5 hours. The mixture was concentrated under reduced pressure, and the precipitate was collected by filtration. After washing with 2-propanol and diethyl ether, 7- (3,4-methylenedioxyphenyl) -1,1-dioxo-2,3- as pale yellow crystals.
Dihydro-1-benzothiepine-4-carboxylic acid (41
5.7 mg). mp 254 ° C. (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.97 (2H, t,
J = 6.6 Hz), 3.71-3.78 (2
H, m), 6.10 (2H, s), 7.05
(1H, d, J = 8.0 Hz), 7.34
(1H, dd, J = 8.0, 1.8 Hz),
7.50 (1H, d, J = 1.8 Hz),
7.82-7.90 (2H, m), 8.01-
8.06 (2H, m). IR (KBr) 3439, 1678, 147
9, 1290, 1234, 1128, 1038
cm ^-1 Elemental analysis _{C 18 H 14 O 6 S ·} 0.2H 2 O Ca
lcd. C, 59.73; H, 4.01:
Found. C, 59.82; H, 3.9
5.

Reference Example 12 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-chlorophenylboric acid (0.38 g) and potassium carbonate (0.59 g) in toluene / ethanol / water (20/2 / 2 ml) mixture
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.12 g) was added to the reaction system, and the mixture was heated under reflux for 20 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate / hexane 1: 1) and recrystallized (ethyl acetate / hexane)
And 7- (4-chlorophenyl) -1,1-dioxo-2,3-dihydro-1 as pale yellow crystals.
-Methyl benzothiepine-4-carboxylate (466 m
g) was obtained. mp 168-170 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.15 (2H, t, J = 6.2 Hz), 3.
62-3.68 (2H, m), 3.88 (3H, s), 7.44-7.57 (4H, m),
7.67-7.70 (2H, m), 7.91 (1H, s), 8.24 (1H, d, J = 8.
6 Hz). IR (KBr) 1720, 1296, 1275, 1248, 1223, 1194, 1165,
. 1132, 1090, 822, 752cm -1 elemental analysis _{C 18 H 15 O 4 SCl Calcd} C, 59.59; H, 4.17:
Found. C, 59.77; H, 4.14.

Reference Example 13 7- (4-Chlorophenyl) -1,1-dioxo-2,
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (0.95 g) in 1,2-dimethoxyethane (50
6N hydrochloric acid (30 ml) was added to the solution, and the mixture was stirred at 70 ° C. for 64 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with 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 and hexane to give 7- (4-chlorophenyl) -1,1- as pale yellow crystals.
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxylic acid (804.9 mg) was obtained. mp 288 ° C (dec.) ¹ H-NMR (200MHz, DMSO-d ₆ ) δ2.95-3.01 (2H, m), 3.73-
3.80 (2H, m), 7.59 (2H, d, J = 8.4 Hz), 7.85-7.96 (4
H, m), 8.10 (1H, d, J = 8.0 Hz), 8.14 (1H, s) .IR (KB
r) 2987, 1697, 1142, 1294, 1165, 1134, 1093, 818 c
. m ^-1 elemental analysis _{C 17 H 13 O 4 SCl Calcd} C, 58.54; H, 3.76:
Found. C, 58.55; H, 3.85.

Reference Example 14 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (1.0 g), 4-fluorophenylboric acid (0.465 g) and potassium carbonate (0.84 g) in toluene / ethanol / water (30/3) // 3ml) mixture was stirred at room temperature for 1 hour. To the reaction system was added tetrakistriphenylphosphine palladium (0.17 g), and 2
The mixture was refluxed for 0 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate / hexane 1: 1) and recrystallization (ethyl acetate / hexane 1: 1) to give 7- as pale yellow crystals.
(4-fluorophenyl) -1,1-dioxo-2,3
Methyl -dihydro-1-benzothiepine-4-carboxylate (656.3 mg) was obtained. ^{mp 180-183 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ3.12-3.19 (2H, m), 3.62-3.
69 (2H, m), 3.88 (3H, s), 7.15-7.24 (2H, m), 7.55-
7.70 (4H, m), 7.91 (1H, br s), 8.23 (1H, d, J = 9.2 H
z) .IR (KBr) 1718, 1692, 1514, 1279, 1242, 1201, 1161,
1130, 831, 752, 604,519 cm- ¹ Elemental analysis C ₁₈ H ₁₅ O ₄ SF Calcd. C, 62.42; H, 4.36: F
ound. C, 62.38; H, 4.40.

Reference Example 15 7- (4-Fluorophenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.55 g) in 1,2-dimethoxyethane (20 ml) was added 6N hydrochloric acid (10 ml), and
The mixture was refluxed for 9 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration.
Washing the crystals with diisopropyl ether and hexane,
7- (4-fluorophenyl)-as pale yellow crystals
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (490.7 mg) was obtained. mp 260 ° C (dec.) ¹ H-NMR (200MHz, DMSO-d ₆ ) δ2.98 (2H, t, J = 7.0 Hz),
3.76 (2H, d, J = 7.0 Hz), 7.32-7.40 (2H, m), 7.85-7.
94 (4H, m), 8.07-8.11 (2H, m) .IR (KBr) 2939, 1687, 1514, 1296, 1161, 1132, 824 c
. m ^-1 elemental analysis _{C 17 H 13 O 4 SF Calcd} C, 61.44; H, 3.94: F
ound. C, 61.20; H, 4.09.

Reference Example 16 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (1.00 g), 4-trifluoromethylphenylboronic acid (0.63 g) and potassium carbonate (0.84 g)
g) toluene / ethanol / water (30/3/3 ml)
The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.174 g) was added to the reaction system, and the mixture was heated under reflux for 16 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 2) to give 7- (4-trifluoromethylphenyl) as pale yellow crystals.
Methyl -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (704.7 mg) was obtained. ^{mp 168-170 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ3.13-3.20 (2H, m), 3.63-3.
70 (2H, m), 3.88 (3H, s), 7.67-7.80 (6H, m), 7.92
(1H, br s), 8.28 (1H, d, J = 8.4 Hz) .IR (KBr) 1714, 1325, 1248, 1169, 1130, 1070, 831,
750 cm ^-1 elemental analysis C ₁₉ H ₁₅ O ₄ SF ₃ Calcd. C, 57.57; H, 3.81:
Found. C, 57.62; H, 3.66.

Reference Example 17 7- (4-Trifluoromethylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-
To a solution of methyl carboxylate (600 mg) in 1,2-dimethoxyethane (40 ml) was added 6N hydrochloric acid (20 m 2) at room temperature.
l) was added and the mixture was heated under reflux for 22 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate / THF. The organic layer was washed with 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 hexane to give 7- (4-trifluoromethylphenyl) -1,1-dioxo-2,3-dihydro-1- as colorless crystals.
Benzothiepine-4-carboxylic acid (439.5 mg) was obtained. mp> 300 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ2.96-3.02 (2H, m), 3.75-
3.82 (2H, m), 7.87-8.17 (7H, m), 8.22 (1H, d, J = 1.
6 Hz). IR (KBr) 2985, 1695, 1325, 1294, 1171, 1132, 1117,
1072, 829 cm ^-1 Elemental analysis C ₁₈ H ₁₃ O ₄ SF ₃ Calcd. C, 56.54; H, 3.43:
Found. C, 56.43; H, 3.55.

Reference Example 18 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethylphenylboric acid (0.40 g) and potassium carbonate (0.67 g) in toluene / ethanol / water (30/3) / 3 ml) mixture
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system, and the mixture was heated under reflux for 15 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 1) to give 7- as pale yellow crystals.
(4-ethylphenyl) -1,1-dioxo-2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (732 mg) was obtained. mp 173-176 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.29 (3 H, t, J = 7.5 Hz), 2.
72 (2H, q, J = 7.5 Hz), 3.11-3.18 (2H, m), 3.62-3.68
(2H, m), 3.87 (3H, s), 7.33 (2H, d, J = 8.1 Hz), 7.5
4 (2H, d, J = 8.1 Hz), 7.66-7.74 (2H, m), 7.92 (1H,
br s), 8.21 (1H, d, J = 8.4 Hz) .IR (KBr) 1714, 1315, 1294, 1277, 1252, 1223, 1165,
1130, 825, 750 cm ^-1 Elemental analysis C ₂₀ H ₂₀ O ₄ S Calcd.C, 67.39; H, 5.66: Fo
und. C, 67.36; H, 5.63.

Reference Example 19 7- (4-Ethylphenyl) -1,1-dioxo-2,
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (20
ml) solution, 6N hydrochloric acid (10 ml) was added, and the mixture was heated under reflux for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 7 as pale yellow crystals.
-(4-ethylphenyl) -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxylic acid (5
01.2 mg). mp 260-265 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.29 (3H, t,
J = 7.6 Hz), 2.73 (2H, q,
J = 7.6 Hz), 3.17 (2H, t, J
= 6.6 Hz), 3.67 (2H, t, J =
6.6 Hz), 7.34 (2H, d, J =
8.4 Hz), 7.55 (2H, d, J =
8.4 Hz), 7.70-7.78 (2H,
m), 8.02 (1H, s), 8.24 (1
H, d, J = 8.8 Hz). IR (KBr) 2966, 1675, 129
0, 1163, 1128, 824, 744 c
m ^-1 elemental analysis _{C 19 H 18 O 4 S Calcd} . C,
H, 5.30: Found.
C, 66.47; H, 5.41.

Reference Example 20 7-bromo-2,3-dihydro-1 under an argon atmosphere
-Methyl benzothiepine-4-carboxylate (0.80
g), 4-isopropylphenylboric acid (0.44 g)
And a mixture of potassium carbonate (0.67 g) in toluene / ethanol / water (30/3/3 ml) was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system, and the mixture was heated under reflux for 20 hours. After cooling, the mixture was extracted with ethyl acetate and washed with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate / hexane 1: 1).
Separated and purified in 2), and as light yellow crystals, methyl 7- (4-isopropylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (7)
74.7 mg). mp 142-144 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.30 (6H, d, J = 6.6 Hz), 2.
90-3.06 (1H, m), 3.12-3.18 (2H, m), 3.62-3.68 (2H,
m), 3.87 (3H, s), 7.36 (2H, d, J = 8.2 Hz), 7.55 (2
H, d, J = 8.2 Hz), 7.69-7.73 (2H, m), 7.92 (1H, br
s), 8.22 (1H, d, J = 8.8 Hz) .IR (KBr) 1713, 1315, 1294, 1277, 1252, 1223, 1196,
1167, 1130, 825, 752cm- ¹ Elemental analysis C ₂₁ H ₂₂ O ₄ S Calcd.C, 68.08; H, 5.99: Fo
und. C, 68.04; H, 6.15.

Reference Example 21 A solution of methyl 7- (4-isopropylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (20 ml). To the mixture was added 6N hydrochloric acid (10 ml) at room temperature, and the mixture was heated under reflux for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 7- (4-isopropylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (555.2 mg) as colorless crystals. mp 282 ° C (dec.) ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.30 (6H, d, J = 7.0 Hz), 2.
92-3.05 (1H, m), 3.13-3.20 (2H, m), 3.63-3.70 (2H,
m), 7.36 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.2 H
z), 7.69-7.78 (2H, m), 8.01 (1H, br s), 8.24 (1H,
d, J = 8.8 Hz) .IR (KBr) 2962, 1676, 1294, 1167, 1132, 824, 748 cm
. ^-1 elemental analysis _{C 20 H 20 O 4 S ·} 0.2H 2 O Calcd C, 66.72; H, 5.
71: Found.C, 66.63; H, 5.79.

Reference Example 22 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-tert-butylphenylboronic acid (0.47 g) and potassium carbonate (0.67 g)
g) toluene / ethanol / water (30/3/3 ml)
The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system, and the mixture was heated under reflux for 16 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate / hexane 1: 1) and recrystallization (ethyl acetate / hexane).
Diisopropyl ether) to give 7- (4-tert-butylphenyl) -1,1 as colorless crystals.
-Dioxo-2,3-dihydro-1-benzothiepin-
Methyl 4-carboxylate (793.6 mg) was obtained. mp 170-172 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.38 (9H, s),
3.12-3.18 (2H, m), 3.62-
3.69 (2H, m), 3.88 (3H,
s), 7.49-7.59 (4H, m), 7.
70-7.74 (2H, m), 7.92 (1
H, brs), 8.22 (1H, d, J =
8.8 Hz). IR (KBr) 1713, 1319, 129
6, 1277, 1244, 1198, 116
^{9, 1128, 827, 752 cm} -1 elemental analysis _{C 22 H 24 O 4 S Calcd} . C,
H. 6.29: Found.
C, 68.67; H, 6.31.

Reference Example 23 Methyl 7- (4-tert-butylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) in 1,2-dimethoxyethane (20 ml) 6) Hydrochloric acid (10 ml) was added to the solution, and the mixture was stirred at 70 ° C. for 55 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 7- (4-tert-butylphenyl)-as pale yellow crystals.
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (362.7 mg) was obtained. ^{mp 289-291 ℃ 1 H-NMR (} 200MHz, DMSO-d 6) δ1.33 (9H, s), 2.94-3.01
(2H, m), 3.73-3.79 (2H, m), 7.54 (2H, d, J = 8.6 H
z), 7.76 (2H, d, J = 8.6 Hz), 7.89-7.93 (2H, m), 8.06
-8.11 (2H, m) .IR (KBr) 2962, 1689, 1292, 1165, 1132, 824, 748 cm
^-1 elemental analysis C ₂₁ H ₂₂ O ₄ S Calcd. C, 68.08; H, 5.99: Fo
und. C, 67.93; H, 5.69.

Reference Example 24 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4- (1-pyrrolidinyl) phenylboric acid (508 mg) and potassium carbonate (0.6 mg)
7g) of toluene / ethanol / water (30/3 / 3m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system.
Was added and heated under reflux for 17 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration.
The crystals were washed with diisopropyl ether to give 7- [4- (1-pyrrolidinyl) phenyl] -1,1 as yellow crystals.
Methyl 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (323 mg) was obtained. mp 227 ° C (dec.) ¹ H-NMR (200MHz, CDCl ₃ ) δ2.00-2.11 (4H, m), 3.09-3.
16 (2H, m), 3.29-3.41 (4H, m), 3.61-3.67 (2H, m),
3.87 (3H, s), 6.65 (2H, d, J = 8.8 Hz), 7.54 (2H, d,
J = 8.8 Hz), 7.65-7.69 (2H, m), 7.91 (1H, br s), 8.
15 (1H, d, J = 9.2Hz). IR (KBr) 1714, 1608, 1585, 1529, 1385, 1313, 1279,
1252, 1163, 1128, 808, 754 cm- ¹ Elemental analysis C ₂₂ H ₂₃ NO ₄ S Calcd. C, 66.48; H, 5.83;
N, 3.52: Found.C, 66.74; H, 5.82; N, 3.38.

Reference Example 25 7- [4- (1-Pyrrolidinyl) phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Methyl carboxylate (270mg) in 6N hydrochloric acid (30m
l) was added and the mixture was stirred at 70 ° C for 7 hours. Concentrate under reduced pressure,
The crystals formed after adding 2-propanol were collected by filtration. Washing the crystals with 2-propanol and hexane,
7- [4- (1-Pyrrolidinyl) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (204 mg) as yellow crystals
I got mp 283 ° C (dec.) ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.86-2.03 (4H, m), 2.95
(2H, t, J = 6.3 Hz), 3.23-3.36 (4H, m), 3.69-3.75 (2
H, m), 6.67 (2H, d, J = 8.7 Hz), 7.70 (2H, d, J = 8.7 H
z), 7.80-7.86 (2H, m), 7.97-8.01 (2H, m) .IR (KBr) 2883, 1701, 1389, 1319, 1288, 1196, 1171,
1128, 822 cm ^-1 Elemental analysis C ₂₁ H ₂₂ NO ₄ SCl ・ 0.5H ₂ O Calcd.C, 58.80; H,
5.40; N, 3.27: Found.C, 59.02; H, 5.27; N,
3.20.

Reference Example 26 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-piperidinophenylboric acid (0.55 g) and potassium carbonate (0.67 g) in toluene / ethanol / water (30 // 3/3 ml) mixture was stirred at room temperature for 1 hour. To the reaction system was added tetrakistriphenylphosphine palladium (0.14 g), and 1
The mixture was refluxed for 5 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were purified by recrystallization (ethyl acetate) to give 7- (4-piperidinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine- as yellow crystals. Methyl 4-carboxylate (0.85 g) was obtained. mp 202-204 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.59-1.80 (6H, m), 3.10-3.
16 (2H, m), 3.23-3.34 (4H, m), 3.61-3.67 (2H, m),
3.87 (3H, s), 7.01 (2H, d, J = 9.0 Hz), 7.54 (2H, d,
J = 9.0 Hz), 7.65-7.70 (2H, m), 7.91 (1H, br s), 8.
17 (1H, d, J = 8.8Hz) .IR (KBr) 1707, 1605, 1585, 1518, 1435, 1298, 1240,
. 1511, 1124, 816, 741cm -1 elemental analysis _{C 23 H 25 NO 4 S Calcd} C, 67.13; H, 6.12;
N, 3.40: Found.C, 67.12; H, 6.36; N, 3.52.

Reference Example 27 7- (4-Piperidinophenyl) -1,1-dioxo-
6N hydrochloric acid (60 ml) was added to methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg), and the mixture was stirred at 70 ° C. for 5 hours. After concentration under reduced pressure, ethanol was added to the residue. An 8N aqueous sodium hydroxide solution and a 1N aqueous sodium hydroxide solution were added until the pH reached 6-7. The mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration. After washing with water, 2-propanol, acetone and diisopropyl ether, 7- (4-piperidinophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (yellow powder) 549.
5 mg). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.45-1.60 (6H, m), 2.96
(2H, t, J = 6.7 Hz), 3.12-3.46 (4H, m), 3.69-3.75 (2
H, m), 7.03 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 H
z), 7.78-7.87 (2H, m), 7.99-8.03 (2H, m) .IR (KBr) 2937, 1680, 1605, 1587, 1520, 1292, 1240,
1128, 818, 744 cm ^-1

Reference Example 28 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-trifluoromethoxyphenylboric acid (0.55 g) and potassium carbonate (0.6
7g) of toluene / ethanol / water (30/3 / 3m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system.
Was added and heated under reflux for 20 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 2) to give 7- (4-trifluoromethoxyphenyl) -1,1-dioxo-2,3- as pale yellow crystals. Methyl dihydro-1-benzothiepine-4-carboxylate (638.5 mg)
I got ^{mp 142-143 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ3.13-3.19 (2H, m), 3.62-3.
69 (2H, m), 3.88 (3H, s), 7.35 (2H, d, J = 8.0 Hz),
7.60-7.73 (4H, m), 7.92 (1H, br s), 8.25 (1H, d, J
= 8.8 Hz) .IR (KBr) 1713, 1514, 1257, 1215, 1165, 1130, 837,
754 cm ^-1 elemental analysis C ₁₉ H ₁₅ O ₅ SF ₃ Calcd. C, 55.34; H, 3.67:
Found. C, 55.48; H, 3.63.

Reference Example 29 7- (4-Trifluoromethoxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-To a solution of methyl carboxylate (450 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (5 m
l) was added and the mixture was heated under reflux for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 7- (4-trifluoromethoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (390.3 mg) as colorless crystals. . mp 284-285 ° C ¹ H-NMR (200MHz, DMSO-d ₆ ) δ2.95-3.02 (2H, m), 3.74-
3.80 (2H, m), 7.52 (2H, d, J = 8.0 Hz), 7.89-7.99 (4
H, m), 8.09-8.16 (2H, m) .IR (KBr) 3047, 1693, 1269, 1215, 1165, 1132 cm ^-1 Elemental analysis C ₁₈ H ₁₃ O ₅ SF ₃ Calcd. 3.29:
Found. C, 54.22; H, 3.20.

Reference Example 30 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 3,4-dichlorophenylboric acid (0.54 g) and potassium carbonate (0.67 g) in toluene / ethanol / water (30 / g) 3/3 ml) mixture was stirred at room temperature for 1 hour. To the reaction system was added tetrakistriphenylphosphine palladium (0.14 g), and 1
The mixture was refluxed for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate / hexane 1: 2 → 1: 1) to give 7- (3,4-dichlorophenyl) -1,1-dioxo-2,3 as pale yellow crystals. -Methyl -dihydro-1-benzothiepine-4-carboxylate (631.3 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.13-3.19 (2H, m), 3.62-3.
69 (2H, m), 3.88 (3H, s), 7.45 (1H, dd, J = 8.2, 2.0
Hz), 7.58 (1H, d, J = 8.2 Hz), 7.66-7.71 (3H, m), 7.9
1 (1H, br s), 8.26 (1H, d, J = 8.2 Hz). IR (KBr) 1707, 1321, 1275, 1252, 1171, 1130, 750 c
m ^-1

Reference Example 31 Methyl 7- (3,4-dichlorophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (450 mg) in 1,2-dimethoxyethane (10 ml) 6N hydrochloric acid (10 ml) was added to the solution,
The mixture was heated under reflux for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration to give 7- (3,4-dichlorophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (395. 5 mg). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ2.94-3.02 (2H, m), 3.73-
3.80 (2H, m), 7.78 (1H, d, J = 8.4 Hz), 7.83-7.91 (2
H, m), 7.97-8.02 (1H, m), 8.10 (1H, d, J = 8.0Hz),
8.18 (1H, d, J = 2.2 Hz), 8.23-8.27 (1H, m) .IR (KBr) 2985, 1672, 1468, 1415, 1319, 1292, 1173,
1133, 820 cm ^-1

Reference Example 32 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-propylphenylboric acid (0.435 g) and potassium carbonate (0.67 g) in toluene / ethanol / water (25/2) .5 / 2.5ml)
The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system, and the mixture was heated under reflux for 18 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate.
After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, diisopropyl ether and hexane to give colorless crystals of methyl 7- (4-propylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylate (557. 2m
g) was obtained. mp 155-156 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.98 (3H, t,
J = 7.4 Hz), 1.63-1.77 (2H,
m), 2.66 (2H, t, J = 7.6H
z), 3.11-3.18 (2H, m),
61-3.68 (2H, m), 3.87 (3
H, s), 7.30 (2H, d, J = 8.4)
Hz), 7.54 (2H, d, J = 8.4)
Hz), 7.69-7.73 (2H, m),
7.92 (1H, brs), 8.22 (1
H, d, J = 8.8 Hz). IR (KBr) 1709, 1313, 129
0, 1248, 1165, 1130, 748
cm ^-1 Elemental analysis _{C 21 H 22 O 4 S Calcd} . C,
H. 5.99: Found.
C, 68.13; H, 5.89.

Reference Example 33 7- (4-Propylphenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (450 mg) in 1,2-dimethoxyethane (15 ml) was added 6N hydrochloric acid (7.5 ml),
The mixture was heated under reflux for 40 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. Purified by recrystallization (THF / diisopropyl ether), 7- (4-propylphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (433.6 m) as colorless crystals.
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.92 (3H, t, J = 7.3 Hz),
1.58-1.69 (2H, m), 2.58-2.66 (2H, m), 2.93-3.01 (2
H, m), 3.72-3.79 (2H, m), 7.34 (2H, d, J = 8.2Hz),
7.74 (2H, d, J = 8.2 Hz), 7.88-7.93 (2H, m), 8.06-8.
09 (2H, m) .IR (KBr) 3012, 1678, 1408, 1321, 1298, 1167, 1132
cm ^-1

Reference Example 34 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-isopropoxyphenylboric acid (0.48 g) and potassium carbonate (0.67 g)
Of toluene / ethanol / water (25 / 2.5 / 2.5m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.14 g) was added to the reaction system.
Was added and the mixture was refluxed for 13 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 2) to give 7- (4-isopropoxyphenyl) -1, colorless crystals.
Methyl 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (606.5 mg) was obtained. mp 140-142 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.38 (6H, d, J = 6.2 Hz), 3.
11-3.17 (2H, m), 3.61-3.68 (2H, m), 3.87 (3H, s),
4.57-4.69 (1H, m), 6.99 (2H, d, J = 9.0 Hz), 7.54 (2
H, d, J = 9.0 Hz), 7.66-7.70 (2H, m), 7.91 (1H, br
s), 8.19 (1H, d, J = 8.8 Hz) .IR (KBr) 1709, 1516, 1309, 1288, 1246, 1165, 1128,
829, 750 cm ^-1 Elemental analysis C ₂₁ H ₂₂ O ₅ S Calcd. C, 65.27; H, 5.74: Fo
und. C, 65.13; H, 5.83.

Reference Example 35 Methyl 7- (4-isopropoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (250 mg) 1,2-dimethoxyethane (10 ml) 6N hydrochloric acid (3 ml) was added to the solution,
Stirred at 0 ° C. for 18 hours. 1,2-Dimethoxyethane (10 ml) and 6N hydrochloric acid (5 ml) were added to the reaction system,
Stirred at 70 ° C. for a further 4 days. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 7- (4-isopropoxyphenyl) -1,1 as colorless crystals.
-Dioxo-2,3-dihydro-1-benzothiepin-
4-carboxylic acid (230.3 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.30 (6H, d, J = 5.8 Hz),
2.93-3.00 (2H, m), 3.71 (2H, m), 4.63-4.78 (1H,
m), 7.04 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.8Hz),
7.84-7.91 (2H, m), 8.03-8.07 (2H, m) .IR (KBr) 2977, 1676, 1608, 1513, 1292, 1246, 1165,
1130, 951, 829, 746 cm ^-1

Reference Example 36 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-propoxyphenylboric acid (0.38 g) and potassium carbonate (0.58 g) in toluene / ethanol / water (20/2) / 2 ml) mixture was stirred at room temperature for 1 hour. To the reaction system was added tetrakistriphenylphosphine palladium (0.12 g), and 1
The mixture was refluxed for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 2 → 1: 1) to give 7- (4-propoxyphenyl) -1,1-dioxo-2, 3-dihydro-1-benzothiepin-4-
Methyl carboxylate (616.4 mg) was obtained. mp 153-155 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.07 (3H, t, J = 7.5 Hz), 1.
76-1.93 (2H, m), 3.11-3.17 (2H, m), 3.61-3.68 (2H,
m), 3.87 (3H, s), 3.99 (2H, t, J = 6.6 Hz), 7.01 (2
H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.66-7.70
(2H, m), 7.91 (1H, br s), 8.20 (1H, d, J = 8.4 Hz) .IR (KBr) 1718, 1608, 1518, 1315, 1281, 1248, 1223,
1163, 1132, 831, 754cm- ¹ elemental analysis C ₂₁ H ₂₂ O ₅ S Calcd.C, 65.27; H, 5.74: Fo
und. C, 65.35; H, 5.63.

Reference Example 37 7- (4-Propoxyphenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (5 ml), and the mixture was heated under reflux for 2 days. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration. The crystals were washed with water, 2-propanol and diisopropyl ether to give 7- (4-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (346.1 mg) as colorless crystals. ) Got. mp 270-273 ° C ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.00 (3H, t, J = 7.5 Hz),
1.65-1.86 (2H, m), 2.93-3.00 (2H, m), 3.71-3.78 (2
H, m), 4.00 (2H, t, J = 6.6 Hz), 7.06 (2H, d, J = 8.7 H
z), 7.78 (2H, d, J = 8.7 Hz), 7.83-7.93 (2H, m), 8.0
3-8.07 (2H, m) ,. IR (KBr) 2972, 1676, 1608, 1518, 1292, 1250, 1163,
1128, 827, 746 cm ^-1 Elemental analysis C ₂₀ H ₂₀ O ₅ S Calcd.C, 64.50; H, 5.41: Fo
und. C, 64.34; H, 5.48.

Reference Example 38 Under an argon atmosphere, 7-bromo-1,1-dioxo-
Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-butoxyphenylboric acid (0.45 g) and potassium carbonate (0.58 g) in toluene / ethanol / water (20/2) / 2 ml) mixture
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (0.12 g) was added to the reaction system, and the mixture was heated under reflux for 20 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 1: 1) to give 7- as colorless crystals.
(4-butoxyphenyl) -1,1-dioxo-2,3
Methyl -dihydro-1-benzothiepine-4-carboxylate (672.6 mg) was obtained. mp 123-125 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.00 (3H, t, J = 7.1 Hz), 1.
45-1.62 (2H, m), 1.74-1.88 (2H, m), 3.11-3.18 (2H, m
m), 3.61-3.68 (2H, m), 3.87 (3H, s), 4.03 (2H, t,
J = 6.4 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J
= 8.8 Hz), 7.64-7.72 (2H, m), 7.91 (1H, br 2), 8.19
(1H, d, J = 8.8 Hz). IR (KBr) 1714, 1516, 1317, 1294, 1248, 1223, 1165,
1132, 824, 750 cm- ¹ Elemental analysis C ₂₂ H ₂₄ O ₅ S Calcd.C, 65.98; H, 6.04: Fo
und. C, 66.27; H, 5.78.

Reference Example 39 7- (4-Butoxyphenyl) -1,1-dioxo-
To a solution of methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (5 ml).
Heated to reflux for an hour. 1,2-Dimethoxyethane (5 ml) and 6N hydrochloric acid (2 ml) were added to the reaction system.
Heated to reflux for an hour. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with 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-butoxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxylic acid (388.9 mg) was obtained. mp 244-247 ° C ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.95 (3H, t, J = 7.1 Hz),
1.35-1.56 (2H, m), 1.64-1.81 (2H, m), 2.93-3.00 (2
H, m), 3.71-3.78 (2H, m), 4.04 (2H, t, J = 6.6Hz),
7.06 (2H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz), 7.
85-7.90 (2H, m), 8.03-8.07 (2H, m), .IR (KBr) 2958, 1676, 1608, 1518, 1408, 1292, 1252,
1163, 1128, 827, 746cm- ¹ Elemental analysis C ₂₁ H ₂₂ O ₅ S Calcd.C, 65.27; H, 5.74: Fo
und. C, 65.28; H, 5.70.

Reference Example 40 6- (4-methylphenyl) -1,2-dihydro-2H
-Ethyl thiochromene-3-carboxylate (1.03 g, 3.32
mmol) in dichloromethane (20 ml) at 0 ° C. was added with metachloroperbenzoic acid (1.73 g, 6.98 mmol).
And stirred at room temperature for 20 minutes. The reaction was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. After the organic layer was dried over magnesium sulfate, the colorless powder obtained by evaporating the solvent was washed with ethanol, and 6- (4-methylphenyl) -1,1-dioxo-1,2-dihydro-2 was obtained.
Ethyl H-thiochromene-3-carboxylate (0.95 g, 84
%). A part was recrystallized from ethyl acetate to give a melting point of 174.
Colorless scaly crystals at a temperature of ° C were obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.09 (1H, d, J = 8.0), 7.87 (1H,
s), 7.80 (1H, dd, J = 8.0, 1.8), 7.70 (1H, d, J = 1.
8), 7.41 (2H, d, J = 8.0), 7.31 (2H, d, J = 8.0), 4.35
(2H, q, J = 7.4), 4.29 (2H, d, J = 1.8), 2.43 (3H, s),
1.39 (3H, t, J = 7.4). Anal. Calcd for C ₁₉ H ₁₈ O ₄ S ・ 0.25H ₂ O: C; 65.78, H;
5.37. Found: C; 65.93, H; 5.26.

Reference Example 41 6- (4-methylphenyl) -1,1-dioxo-1,
Ethyl 2-dihydro-2H-thiochromene-3-carboxylate (0.90 g, 2.63 mmol) in tetrahydrofuran (10 m
l) and 1N sodium hydroxide (3 ml) were added dropwise to a solution of acetonitrile (10 ml) and stirred for 1 hour. The reaction solution was partitioned between diethyl ether and water, and the aqueous layer was adjusted to pH 3 with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off to obtain a crude carboxylic acid as a brown powder, which was washed with ethanol to give 6-
(4-methylphenyl) -1,1-dioxo-1,2-
Dihydro-2H-thiochromene-3-carboxylic acid (0.24
g, 29%) as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 7.95-7.99 (3H, m), 7.69 (2H, d,
J = 8.2), 7.35 (2H, d, J = 8.2), 4.45 (2H, s), 3.78 (3
H, s).

Reference Example 42 7- (4-Methylphenyl) -2,3-dihydro-1-
A solution of methyl benzothiepine-4-carboxylate (1.5 g) in dichloromethane (25 ml) was added with 70% mC under ice-cooling.
PBA (2.4 g) was added, and the mixture was stirred at room temperature for 1 hour. After adding an aqueous solution of sodium thiosulfate, the mixture was concentrated and extracted with ethyl acetate. The organic layer was treated with an aqueous solution of sodium hydrogen carbonate,
After washing with water and saturated saline, it was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 7- (4-methylphenyl) -1,1-dioxo-2,3-dihydro-1.
-Methyl benzothiepine-4-carboxylate (1.6 g)
Was obtained as colorless crystals. mp 203-204 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 2.43 (3H, s), 3.15 (2H, t, J = 6.6H
z), 3.65 (2H, t, J = 6.6Hz), 3.88 (3H, s), 7.31 (2H, d, J = 8.3
Hz), 7.52 (2H, d, J = 8.3Hz), 7.69-7.74 (2H, m), 7.92 (1H,
s), 8.22 (1H, d, J = 8.8Hz) .IR (KBr) ν: 2951, 1713cm ^-1 .Anal.Calcd. for C ₁₉ H ₁₈ O ₄ S: C, 66.65; H, 5.30. Found
C, 66.47; H, 5.33.

Reference Example 43 7- (4-Methylphenyl) -1,1-dioxo-2,
Methyl 3-dihydro-1-benzothiepine-4-carboxylate (1.6 g) was added to a 1N aqueous sodium hydroxide solution (50 g).
ml), methanol (200 ml) and diethyl ether (100 ml) were added and stirred overnight. After concentration, the mixture was extracted with water. The aqueous layer was washed with ethyl acetate, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. Organic layer with water,
After washing with saturated saline, drying using anhydrous magnesium sulfate, the solvent was distilled off, and 7- (4-methylphenyl) -1,
1-Dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (1.5 g; purity about 70%) was obtained as a colorless powder. ¹ H-NMR (δppm, CDCl ₃ ) 2.43 (3H, s), 3.14 (2H, t, J = 6.6H
z), 3.66 (2H, t, J = 6.6Hz), 7.26-7.33 (2H, m), 7.47-7.57
(2H, m), 7.70-7.74 (2H, m), 7.95 (1H, s), 8.21 (1H, d, J =
8.8Hz).

Reference Example 44 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (870 m
g) in toluene / ethanol / water (10/1 / 1.2)
ml), and 5-methyl-2-thienylboronic acid (530 mg) and potassium carbonate (1.02 g) were added.
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (152 mg) was added, and the mixture was stirred at 100 ° C. for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 3 /
Purified in 1), 7- (5-methyl-2-thienyl)-
Methyl 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (210 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.54 (3 H, d, J = 1.0 H)
z), 3.12 (2H, m), 3.63 (2H, m), 3.89 (3H,
s), 6.79 (1H, dd, J = 3.6, 1.0 Hz), 7.26 (1H,
d, J = 3.6 Hz), 7.61-7.66 (2H, m), 7.86 (1H,
s), 8.12 (1H, d, J = 8.8Hz)

Reference Example 45 Methyl 7- (5-methyl-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (210 mg) was added to 1,2-dimethoxyethane (210 mg). 10.5 ml), 6N hydrochloric acid (6.3 ml) was added, and the mixture was stirred at 100 ° C. for 14 hours. After cooling to room temperature,
Extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. 7-
(5-methyl-2-thienyl) -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (180 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.49 (3H, s), 2.93
(2H, m), 3.72 (2H, m), 6.89 (1H, d, J = 3.6H
z), 7.59 (1H, d, J = 3.6 Hz), 7.72-7.81 (2H,
m), 8.05 (1H, s), 7.98 (2H, d, J = 8.0Hz)

Reference Example 46 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (800 m
g) in toluene / ethanol / water (10/1 / 1.2 m
l) and dissolved in 4-methyl-2-thienyl boric acid (5
24 mg) and potassium carbonate (935 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (152 mg) was added, and the mixture was stirred at 100 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 7- (4-methyl-2-thienyl) -1,1-dioxo-2. Methyl 3,3-dihydro-1-benzothiepine-4-carboxylate (510 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.31 (3H, m), 3.09 (2
H, m), 3.63 (2H, t, J = 6.6 Hz), 3.87 (3H, s),
7.00 (1H, m), 7.27 (1H, m), 7.64-7.70 (2H,
m), 7.86 (1H, s), 8.13 (1H, d, J = 10.8 Hz)

Reference Example 47 Methyl 7- (4-methyl-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (510 mg) was treated with 1,2-dimethoxyethane (510 mg). 15.3 ml) and 6N hydrochloric acid (10.2 ml)
Was added and stirred at 100 ° C. for 15 hours. After cooling to room temperature, the organic solvent was removed under reduced pressure, ethyl acetate and aqueous potassium carbonate solution were added, and the mixture was extracted with water. Add 6N hydrochloric acid and adjust the pH to 4
-5 and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 7- (4-methyl-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (459 mg). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.51 (3H, s), 2.95
(2H, t, J = 6.6Hz), 3.74 (2H, t, J = 6.6Hz), 6.
91 (1H, d, J = 3.6 Hz), 7.61 (1H, d, J = 3.6 Hz),
7.73-7.94 (2H, m), 8.05 (1H, s), 8.00 (2H,
d, J = 8.4Hz)

Reference Example 48 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (750 m
g) in toluene / ethanol / water (10/1 / 1.2 m
l) and dissolved in 5-chloro-2-thienyl boric acid (7
After adding 36 mg) and potassium carbonate (1.0 g), the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (210 mg) and add 1 at 100 ° C.
Stir for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
Purification by 3/1) gave methyl 7- (5-chloro-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (350 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.13 (2H, m), 3.64 (2
H, t, m), 3.87 (3H, s), 3.88 (3H, s), 6.98
(1H, d, J = 4.2Hz), 7.44 (1H, d, J = 4.2Hz), 7.
60−7.64 (2H, m), 7.86 (1H.s), 8.17 (1H, d,
J = 8.6Hz)

Reference Example 49 Methyl 7- (5-chloro-2-thienyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (230 mg) was treated with 1,2-dimethoxyethane ( 11.5 ml), 6N hydrochloric acid (9.2 ml) was added, and the mixture was stirred at 100 ° C. for 16 hours. After cooling to room temperature,
Extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. Remove the solvent under reduced pressure and 7-
(5-chloro-2-thienyl) -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (200 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.96 (2H, m), 3.75
(2H, t, m), 7.25 (2H, d, J = 4.0 Hz), 7.70 (2
H, d, J = 4.0 Hz), 7.79-7.84 (2H, m), 8.03 (1
H, d, J = 8.4 Hz), 8.09 (1H, s)

Reference Example 50 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (900 m
g) was dissolved in toluene (21.7 ml), and tetrakistriphenylphosphine palladium (243 mg) was added, followed by stirring for 15 minutes. 4- (methylthio) phenylboronic acid (1.82 g), 2N sodium carbonate (2.7
ml) and methanol (5.4 ml), and the mixture was stirred at 75 ° C for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2).
/ 1) to give methyl 7-[(4-methylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (340 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.55 (3H, s), 2.97 (2
H, m), 3.75 (2H, m), 7.39 (2H, d, J = 8.6Hz),
7.79 (2H, d, J = 8.6Hz), 7.91 (2H, d, J = 8.6H)
z), 8.05 (1H, s), 8.10 (1H, d, J = 9.8Hz)

Reference Example 51 Methyl 7-[(4-methylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (330 mg) was added to 1,2-dimethoxyethane (10 ml). ), Dissolved in 6N hydrochloric acid (10 ml),
Stirred at 0 ° C. for 18 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and 7-[(4-methylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (133 m
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.54 (3H, s), 3.06
(2H, q, J = 7.4 Hz), 3.75 (2H, t, J = 6.4 Hz), 7.
43 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz),
7.89-7.95 (2H, m), 8.06-8.12 (2H, m)

Reference Example 52 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (1.16
g) in toluene / ethanol / water (10/1 / 1.2 m
l), 4- (ethylthio) phenyl boric acid (1.28 g) and potassium carbonate (1.45 g) were added,
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (243 mg) was added, and the mixture was stirred at 100 ° C for 20 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2).
/ 1) to give methyl 7-[(4-ethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (330 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.37 (3 H, t, J = 7.4 H
z), 3.02 (2H, q, J = 7.4 Hz), 3.15 (2H, m), 3.
65 (2H, m), 3.87 (3H, s), 7.40 (2H, m), 7.54
(2H, m), 7.71 (2H, m), 7.91 (1H.s), 8.22
(1H, d, J = 8.8Hz)

Reference Example 53 Methyl 7-[(4-ethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) was added to 1,2-dimethoxyethane (10 ml). ), Dissolved in 6N hydrochloric acid (10 ml),
Stirred at 0 ° C. for 14 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 7-[(4-ethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (135 m
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.28 (3 H, t, J = 7.4 H
z), 2.98 (2H, m), 3.06 (2H, q, J = 7.4 Hz),
75 (2H, m), 7.43 (2H, d, J = 8.4 Hz), 7.79 (2H,
d, J = 8.4 Hz), 7.89-7.95 (2H, m), 8.06-8.12
(2H, m)

Reference Example 54 Methyl 7-[(4-ethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylate (870 mg) was dissolved in THF (35 ml). Under ice-cooling and stirring, 70% m-chloroperbenzoic acid (1.1%
1 g) and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and 7-
Methyl [(4-ethylsulfonyl) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylate (880 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.33 (3 H, t, J = 7.4 H
z), 3.19 (2H, q, J = 7.4 Hz), 3.17 (2H, m),
67 (2H, m), 3.88 (3H, s), 7.72-7.83 (3H,
m), 7.93 (1H.s), 8.02-8.07 (3H, m), 8.30
(1H, d, J = 8.8Hz)

Reference Example 55 7-[(4-Ethyllsulfonyl) phenyl] -1,1
-Dioxo-2,3-dihydro-1-benzothiepin-
Methyl 4-carboxylate (870 mg) was dissolved in 1,2-dimethoxyethane (35 ml) and 6N hydrochloric acid (26 ml) and stirred at 100 ° C. for 12 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. 7-
[(4-Ethylsulfonyl) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (690 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.15 (3 H, t, J = 7.4 H
z), 3.00 (2H, m), 3.37 (2H, q, J = 7.4 Hz), 3.
79 (2H, m), 7.92 (2H, s), 8.00-8.18 (5H,
m), 8.25 (1H, s)

Reference Example 56 4-bromobenzenethiol (12.0 g) was added to DMF (9
6 ml) and potassium carbonate (11.4) at room temperature.
After adding g), 1-iodopropane (6.6 ml) was added dropwise and stirred for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue (14.1 g) was dissolved in THF (126 ml).
1.6N n-butyllithium / hexane (42ml)
Was removed and stirred for 1 hour. Trimethoxyborane (19
g) in THF (40 ml) was added dropwise, and the mixture was stirred for 30 minutes.
For a minute. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (propylthio) phenylboronic acid (6.0 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08 (2 H, t, J = 7.0 H
z), 1.60-1.82 (3H, m), 7.38 (2H, d, J = 8.2H
z), 8.10 (2H, d, J = 8.2Hz)

Reference Example 57 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (780 m
g) in toluene / ethanol / water (10/1 / 1.2 m
l), 4- (propylthio) phenyl boric acid (743 ng) and potassium carbonate (716 mg) were added,
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (136 mg) was added, and the mixture was stirred at 90 ° C for 14 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2).
/ 1) to give methyl 1,1-dioxo-7-[(4-propylthio) phenyl] -2,3-dihydro-1-benzothiepine-4-carboxylate (798 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (3 H, t, J = 7.2 H
z), 1.73 (2H, m), 2.97 (2H, t, J = 7.2 Hz), 3.
15 (2H, m), 3.65 (2H, m), 3.87 (3H, s), 7.37
−7.43 (2H, s), 7.49−7.55 (2H, m), 7.91 (1
H, s), 8.21 (1H, d, J = 8.4 Hz)

Reference Example 58 Methyl 1,1-dioxo-7-[(4-propylthio) phenyl] -2,3-dihydro-1-benzothiepine-4-carboxylate (770 mg) was added to 1,2-dimethoxyethane (23 ml). ), Dissolved in 6N hydrochloric acid (7.7 ml),
Stirred at 100 ° C. for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and 1,1-dioxo-7-[(4-propylthio) phenyl] -2,3
-Dihydro-1-benzothiepine-4-carboxylic acid (7
00 mg). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.00 (3 H, t, J = 7.4 H
z), 1.64 (2H, m), 2.99 (2H, m), 3.76 (2H, m)
m), 7.43 (2H, d, J = 8.6 Hz), 7.89 (1H, s), 7.
94 (1H, s), 8.10 (2H, m), 8.08 (2H, m)

Reference Example 59 4-bromobenzenethiol (12.0 g) was added to DMF (9
6 ml) and potassium carbonate (11.4) at room temperature.
After adding g), 1-iodobutane (13.9 g) was added dropwise and stirred for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue (14.3 g) was dissolved in THF (130 ml).
1.6N n-butyllithium / hexane (40 ml)
Was removed and stirred for 1 hour. Trimethoxyborane (1
A solution of 8.1 g) in THF (40 ml) was added dropwise, and the mixture was stirred for 30 minutes, then allowed to warm to room temperature, 10% sulfuric acid (70 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate,
After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (butylthio) phenylboronic acid (6.1 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.2H)
z), 1.40-1.60 (2H, m), 1.67-1.79 (2H, m),
3.12 (2H, t, J = 7.2 Hz), 7.63 (2H, d, J = 8.4)
z), 8.09 (2H, d, J = 8.4Hz)

Reference Example 60 7-bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (730 m
g) in toluene / ethanol / water (10/1 / 1.2 m
l), 4- (butylthio) phenyl boric acid (780 mg) and potassium carbonate (620 mg) were added,
The mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (127 mg) and add 1
Stir for 6 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
2/1) to give methyl 7-[(4-butylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (680 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3 H, t, J = 7.2 H
z), 1.43-1.74 (2H, m), 2.99 (2H, t, J = 7.4H
z), 3.15 (2H, m), 3.65 (2H, m), 3.87 (3H,
s), 7.38-7.43 (2H, m), 7.52-7.55 (2H,
m), 7.67-7.72 (2H, m), 7.91 (1H, s), 8.22
(1H, d, J = 11.2Hz)

Reference Example 61 Methyl 7-[(4-butylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (670 mg) was added to 1,2-dimethoxyethane (20 ml). ), Dissolved in 6N hydrochloric acid (6.7 ml)
Stirred at 00 ° C. for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and 7-[(4-butylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (620
mg). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.90 (3 H, t, J = 7.2 H
z), 1.14-1.65 (4H, m), 2.97 (2H, m), 3.04
(2H, t, J = 7.2Hz), 3.76 (2H, m), 7.43 (2H,
d, J = 8.4 Hz), 7.78 (2H, d, J = 8.4 Hz), 7.89-9
7.95 (2H, m), 8.10-8.14 (2H, m)

Reference Example 62 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (700 m
g) 1,2-dimethoxyethane (15 ml) and 6
The N hydrochloric acid solution was heated at reflux for 18 hours. After cooling to room temperature,
The solvent was distilled off under reduced pressure, and the resulting colorless crystals were collected by filtration. The crystals were washed with water, 2-propanol and diisopropyl ether to give 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (634 mg) as colorless crystals. ^{mp 290-300 ℃ 1 H-NMR (} 200MHz, DMSO-d 6) δ2.91-2.97 (2H, m), 3.73-
3.80 (2H, m), 7.73 (1H, s), 7.84 (1H, dd, J = 8.4,
2.0 Hz), 7.94 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 2.0
Hz) .IR (KBr) 3088, 1680, 1419, 1286, 1165, 1133, 1097,
793, 744 cm ^-1 Elemental analysis C ₁₁ H ₉ O ₄ SBr Calcd. C, 41.66; H, 2.86: F
ound. C, 41.82; H, 3.02. Reference Example 63 7-bromo-1,1-dioxo-2,3-dihydro-1
-T of benzothiepine-4-carboxylic acid (4.47 g)
To a suspension of HF (90 ml) was added thionyl chloride (1.
03 ml) and DMF (1 ml) were added and stirred for 1 hour. The reaction mixture was treated with 4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] aniline (3.41 g) and triethylamine (7.9 ml).
Was added dropwise to a THF (30 ml) solution at 0 ° C, and the mixture was further stirred for 3 hours. After concentration under reduced pressure, water was added and the precipitated colorless crystals were collected by filtration. The crystals are water, ethanol,
After washing with 2-propanol and diisopropyl ether, 7-bromo-N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (4.94 g) was obtained. mp 232-235 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.54-1.83 (4H, m), 2.21 (3
H, s), 2.54-2.73 (1H, m), 3.11-3.18 (2H, m), 3.30-
3.44 (2H, m), 3.58 (2H, s), 3.66-3.73 (2H, m), 3.99
-4.10 (2H, m), 7.19 (1H, s), 7.33 (2H, d, J = 8.3 H
z), 7.53 (2H, d, J = 8.3 Hz), 7.62-7.71 (2H, m), 7.88
(1H, br s), 8.04 (1H, d, J = 8.4 Hz) .IR (KBr) 3259, 1657, 1633, 1603, 1529, 1410, 1319,
1296, 1132 cm ^-1 Elemental analysis C ₂₄ H ₂₇ N ₂ O ₄ SBr Calcd. C, 55.49; H, 5.24
N, 5.39: Found. C, 55.56; H, 4.98; N, 5.22. Reference Example 64 DMF of 4-bromo-2-chlorophenol (10.81 g) and potassium carbonate (8.65 g) in DMF (100 m).
l) Ethyl iodide (4.17 ml) was added to the mixture at room temperature, and the mixture was stirred for 68 hours. Water was added to the reaction system, water was added, and the mixture was extracted with hexane. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-bromo-2-chloro-1-ethoxybenzene (12.28 g) as a pale yellow oil. To a solution of 4-bromo-2-chloro-1-ethoxybenzene (12.0 g) in diethyl ether (100 ml) was added dropwise a 1.6 M n-butyllithium hexane solution (35 ml) at -78 ° C, and the mixture was added for 1 hour. Stirred. Trimethyl boric acid (17
ml) in diethyl ether (20 ml) was added dropwise. The reaction system was warmed to room temperature and further stirred at room temperature for 2 hours. 10% sulfuric acid (100 ml) was added dropwise to the reaction system, and the mixture was further stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with hexane to give 3-colorless crystals.
Chloro-4-ethoxyphenylboric acid (4.44 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.53 (3H, t, J = 7.0 Hz), 4.
21 (2H, q, J = 7.0 Hz), 7.02 (1H, d, J = 8.2 Hz), 8.05
(1H, dd, J = 8.2, 1.8 Hz), 8.14 (1H, d, J = 1.8 Hz).

Reference Example 65 To a mixture of 4-bromo-2-fluorophenol (10 g) and potassium carbonate (8.7 g) in DMF (100 ml) was added ethyl iodide (4.2 ml) at room temperature, and the mixture was stirred for 68 hours. Water was added to the reaction system, and extracted with hexane.
The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-yellow oil.
Bromo-1-ethoxy-3-fluorobenzene (11.
46 g) were obtained. 4-Bromo-1-ethoxy-3-fluorobenzene (11.10 g) in diethyl ether (1
(00 ml), a 1.6 M n-butyllithium hexane solution (35 ml) was added dropwise at −78 ° C., and the mixture was stirred for 1 hour. A solution of trimethyl boric acid (17 ml) in diethyl ether (20 ml) was added dropwise to the reaction system. The reaction system was warmed to room temperature and further stirred at room temperature for 2 hours. 10% sulfuric acid (100 ml) was added dropwise to the reaction system, and the mixture was further stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with hexane to give 4-ethoxy-3 as colorless crystals.
-Fluorophenylboric acid (4.66 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ1.51 (3H, t, J = 7.0 Hz), 4.
20 (2H, q, J = 7.0 Hz), 7.06 (1H, dd, J = 8.0, 8.0 H
z), 7.82-7.93 (2H, m).

Reference Example 66 Boron tribromide (25 g) in dichloromethane (100 m
l) A solution of 3,4-dimethoxybromobenzene (10.0 g) in dichloromethane (20 ml) was added dropwise to the solution at 0 ° C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was added to ice / water to stop the reaction, and extracted with diethyl ether. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, 4-bromocatechol (8.43 g) was obtained as colorless crystals. Ethane iodide (7.5 ml) was added to a mixture of 4-bromocatechol (8.43 g) and potassium carbonate (15.4 g) in DMF (80 ml) at room temperature, followed by stirring for 15 hours. Water was added to the reaction system, and extracted with hexane. The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 4) to give 4-bromo-1,2-diethoxybenzene (10.06 g) as a yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ1.44 (3H, t, J = 7.0 Hz), 1.
45 (3H, t, J = 7.0 Hz), 4.06 (2H, q, J = 7.0 Hz), 4.07
(2H, q, J = 7.0 Hz), 6.74 (1H, d, J = 8.8 Hz), 6.97-
7.02 (2H, m) .IR (neat) 1585, 1500, 1477, 1396, 1252, 1219, 113
4, 1041, 845, 795 cm ^-1

Reference Example 67 DMF of 4-bromophenol (15 g), sodium iodide (13.0 g) and potassium carbonate (14.4 g)
(200 ml), 2-chloroethyl methyl ether (9 ml) was added to the mixture at room temperature, and the mixture was stirred at 80 ° C for 3 days. Water was added to the reaction system, and extracted with diethyl ether.
The organic layer was washed with water and brine, and dried over magnesium sulfate. Concentrate under reduced pressure to give 1- as an orange oil.
Bromo-4- (2-methoxyethoxy) benzene (1
7.44 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ3.45 (3H, s), 3.72-3.77 (2
H, m), 4.06-4.11 (2H, m), 6.81 (2H, d, J = 8.9 Hz),
7.37 (2H, d, J = 8.9 Hz) .IR (neat) 1587, 1489, 1454, 1284, 1246, 1128, 106
1, 824 cm ^-1

Reference Example 68 To a mixture of 1,4-benzodioxane (5.0 g) and sodium carbonate (5.9 g) in hexane (100 ml) was added, at room temperature, hexane (20 ml) of bromine (1.9 ml).
The solution was added dropwise over 1 hour. After the addition, the mixture was further stirred for 1 hour. After adding an aqueous solution of sodium thiosulfate to the reaction system,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dried over magnesium sulfate. Concentration under reduced pressure gave 6-bromo-2,3-dihydro-1,4-benzodioxin (7.48 g) as an orange oil. Under an argon atmosphere, a solution of 6-bromo-2,3-dihydro-1,4-benzodioxin (7.48 g) in THF (50 ml) was added,
At -78 ° C, a 1.6 M n-butyllithium hexane solution (20 ml) was added dropwise, and the mixture was stirred for 1 hour. A THF (12 ml) solution of trimethyl boric acid (12 ml) was added dropwise to the reaction system. The reaction system was slowly warmed to room temperature and further stirred at room temperature for 2 hours. 10% sulfuric acid (100
ml) was added dropwise, stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with diisopropyl ether to give colorless crystals of 2,3-dihydro-1,4.
-Benzodioxin-6-ylboric acid (2.02 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ4.24-4.37 (4H, m), 6.97 (1
(H, d, J = 8.4 Hz), 7.68-7.73 (2H, m).

Reference Example 69 2,3-Dihydrobenzofuran (11.06 g) and sodium carbonate (14.8 g) in hexane (100 m
l) To the mixture was added dropwise a solution of bromine (4.8 ml) in hexane (20 ml) at 0 ° C over 1.5 hours. After the dropwise addition, the mixture was further stirred at room temperature for 1 hour, and water was added, followed by extraction with hexane. The organic layer was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure to give 5 as gray crystals.
-Bromo-2,3-dihydrobenzofuran (17.64
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ3.20 (2H, t, J = 8.8 Hz), 4.
57 (2H, t, J = 8.8 Hz), 6.66 (1H, d, J = 8.4 Hz), 7.17
-7.30 (2H, m).

Reference Example 70 4-bromo-2-fluoroaniline (10.0 g), potassium carbonate (21.8 g) and sodium iodide (1 g)
To a mixture of 5.8 g) in DMF (100 ml) was added bis (2-chloroethyl) ether (7.53 g) at room temperature, and the mixture was stirred at 90 ° C for 4 days. Bis (2
-Chloroethyl) ether (1 ml) was added and 2 more
Stirred for days. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate / hexane 1: 1).
Separation and purification were performed in 5) to obtain an orange oil (9.19 g). The obtained oil was dissolved in THF (100 ml), and triethylamine (2.5 ml) was added.
Then, acetyl chloride (1.3 ml) was added thereto, followed by stirring for 1 hour.
Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was acetylated by silica gel column chromatography (ethyl acetate / hexane 1: 4) to remove 4- (4-bromo-3-) as a yellow oil.
Fluorophenyl) morpholine (6.89 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ3.03-3.08 (4H, m), 3.84-3.
89 (4H, m), 6.76-6.85 (1H, m), 7.16-7.26 (2H, m) .IR (neat) 1565, 1497, 1450, 1257, 1236, 1209, 111
9, 935, 866, 808 cm ^-1

Reference Example 71 6-Iodo-3,4-dihydro-2 under an argon atmosphere
To a solution of H-1-benzopyran (10.15 g) in diethyl ether (80 ml) was added dropwise a 1.6 M n-butyllithium hexane solution (27 ml) at −78 ° C.
Stirred for hours. Trimethyl boric acid (14ml)
Of diethyl ether (14 ml) was added dropwise. The reaction system was slowly warmed to room temperature and further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added dropwise to the reaction system, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
Hexane and diisopropyl ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with hexane to obtain 3,4-dihydro-2H-1-benzopyran-6-yl boric acid (2.00 g) as colorless crystals. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.97-2.15 (2H, m), 2.91 (2
H, t, J = 6.2 Hz), 4.27 (2H, t, J = 5.1 Hz), 6.90 (1H,
d, J = 8.2 Hz), 7.90 (1H, d, J = 1.4 Hz), 7.96 (1H, d
d, J = 8.2, 1.4 Hz).

Reference Example 72 To a solution of 7-bromo-3,4-dihydro-1-benzoxepin-5 (2H) -one (20.0 g) in trifluoroacetic acid (32 ml) at room temperature was added triethylsilane (29.
2 ml) and stirred for 2 hours. After concentration under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. After concentration under reduced pressure, distillation under reduced pressure (0.8 mmHg / 123 ° C) was performed to obtain a colorless oil. The resulting oil (13.1)
2 g) was dissolved in ethanol (200 ml), platinum oxide (0.4 g) was added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane → ethyl acetate / hexane 1:19) to give 7-bromo-2,3,4,5-tetrahydro- as a colorless oil.
1-benzoxepin (9.61 g) was obtained. Under an argon atmosphere, 7-bromo-2,3,4,5-tetrahydro-1-benzoxepin (9.61 g) in THF (50
ml) solution, a 1.6 M hexane solution of n-butyllithium (29 ml) was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. Trimethyl boric acid (14 ml) in THF was added to the reaction system.
(14 ml) solution was added dropwise. The reaction system was slowly warmed to room temperature and further stirred at room temperature for 2 hours. 1 for reaction system
N hydrochloric acid (100 ml) was added dropwise, and the mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with hexane to give colorless crystals of 2,3,4,5-tetrahydro-1-benzoxepin-7-yl boric acid (3.1
8 g) were obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.72-1.88 (2H, m), 1.93-2.
11 (2H, m), 2.91-3.04 (2H, m), 3.99-4.14 (2H, m),
7.10 (1H, d, J = 7.8 Hz), 7.99-8.04 (2H, m).

Reference Example 73 10.0 g of 5-bromo-2-hydroxyacetophenone
(46.5 mmol), a solution of acetone (17 ml) and pyrrolidine (3.9 ml) in toluene (100 ml) were heated under reflux for 4 hours. Add acetone (17
ml) and heated under reflux for 15 hours. After adding 1N hydrochloric acid (100 ml) to the reaction system, the mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 7) to give 6-bromo-2,2- as a yellow oil.
Dimethyl-2,3-dihydro-4H-1-benzopyran-4-one (7.57 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.46 (6H, s), 2.72 (2H,
s), 6.83 (1H, d, J = 8.8Hz), 7.54 (1H, dd, J = 8.8, 2.
6 Hz), 7.97 (1H, d, J = 2.6 Hz) .IR (neat) 1689, 1597, 1464, 1414, 1373, 1319, 128
2, 1225, 1167, 1132,1066, 926, 827cm ^-1

Reference Example 74 6-bromo-2,2-dimethyl-2,3-dihydro-4
Triethylsilane (10.4 ml) was added to a solution of H-1-benzopyran-4-one (7.57 g) in trifluoroacetic acid (21.4 ml) at room temperature, and the mixture was stirred for 4 days. Triethylsilane (7.1 ml) was added to the reaction system,
For 24 hours. A 12N aqueous solution of sodium hydroxide was added to the reaction system at 0 ° C. until it became alkaline, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane) to give 6-bromo-2,2- as a colorless oil.
Dimethyl-3,4-dihydro-2H-1-benzopyran (10.77 g) was obtained. Under an argon atmosphere, 6-bromo-2,2-dimethyl-3,4-dihydro-2H-1-
To a solution of benzopyran (10.77 g) in THF (50 ml) was added dropwise a 1.6 M n-butyllithium hexane solution (18 ml) at -78 ° C, and the mixture was stirred for 1 hour. To the reaction system was added trimethyl boric acid (7.5 ml) in THF (7.5 ml).
ml) solution was added dropwise. The reaction system was slowly warmed to room temperature and further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added dropwise to the reaction system, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 4 → 1: 2) to give colorless crystals.
2-Dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl boric acid (170 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.38 (6H, s), 1.87 (2H, t,
J = 6.9 Hz), 2.90 (2H, t, J = 6.9 Hz), 6.89 (1H, d, J
= 8.0 Hz), 7.94-7.98 (2H, m).

Reference Example 75 4-bromo-2-fluorophenol (10.07 g)
And potassium carbonate (9.5 g) in DMF (100 m
l) To the mixture was added 2-bromoethyl ethyl ether (6.0 ml) at room temperature, and the mixture was stirred for 18 hours. 2- in the reaction system
Bromoethyl ethyl ether (1.2 ml) was added and 5
Stirred at 5 ° C. for 5 hours. Water was added to the reaction system, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water and once with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-bromo-1- (2
-Ethoxyethoxy) -2-fluorobenzene (13.
79 g) were obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.24 (3H, t, J = 7.0 Hz), 3.
60 (2H, q, J = 7.0 Hz), 3.78-3.83 (2H, m), 4.14-4.19
(2H, m), 6.84-6.92 (1H, m), 7.15-7.27 (2H, m) .IR (neat) 1502, 1306, 1269, 1207, 1130, 1055, 866
cm ^-1

Reference Example 76 TH under magnesium atmosphere (1.34 g) in an argon atmosphere
To a suspension of F (30 ml) was added 4-bromo-1- (2
-Ethoxyethoxy) -2-fluorobenzene (13.
79 g) and the 1,2-dibromoethane (1 ml) T
An HF (50 ml) solution was added dropwise over 1 hour. After the dropwise addition, the mixture was stirred at 60 ° C. for 1 hour. The reaction was cooled to -78 ° C and trimethyl boric acid (17.6 ml) in THF (20 ml) was added.
ml) solution was added dropwise over 30 minutes. After the dropwise addition, the temperature was raised to room temperature, and the mixture was further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added to the reaction system, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 1 → 2: 1) to give 4- (2-ethoxyethoxy) -3-fluorophenylboric acid (1 .40 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.2 Hz), 3.
64 (2H, q, J = 7.2 Hz), 3.85-3.90 (2H, m), 4.26-4.31
(2H, m), 7.06-7.14 (1H, m), 7.82-7.94 (2H, m).

Reference Example 77 To a mixture of 3,4-dihydro-2H-1,5-benzodioxepin (8.86 g) and sodium carbonate (9.4 g) in hexane (100 ml) was added bromine (3.0 ml) at room temperature.
A solution of l) in hexane (30 ml) was added dropwise over 2.5 hours. After the addition, the mixture was further stirred for 24 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Concentrate under reduced pressure,
An orange oil was obtained. Obtained oil (13.39 g)
Of sodium acetate (4.1 ml) in a solution of acetic acid (50 ml).
g), and bromine (1.3 ml) in acetic acid (25 m
l) The solution was added dropwise over 1 hour. After the addition, the mixture was stirred 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 brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 4) to give 7-bromo-3,4-dihydro-2H-1,5-benzodioxepin as an orange oil. (13.17
g) was obtained. 7-bromo-3,4-dihydro-2H-
THF of 1,5-benzodioxepin (13.17 g)
To the (60 ml) solution, a 1.6 M n-butyllithium hexane solution (40 ml) was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. In the reaction system, trimethyl boric acid (19 ml) T
An HF (19 ml) solution was added dropwise over 1 hour. -78
After stirring at ℃ for 1 hour, the temperature was raised to room temperature, and further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added dropwise to the reaction system, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated pale yellow crystals were collected by filtration. The crystals were washed with hexane to obtain 3,4-dihydro-2H-1,5-benzodioxepin-7-ylboric acid (2.99 g) as pale yellow crystals. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.17-2.31 (2H, m), 4.26-4.
35 (4H, m), 7.06 (1H, d, J = 7.8 Hz), 7.76-7.80 (2H,
m).

Reference Example 78 4-Bromo-2-chlorophenol (15.92 g) and potassium carbonate (15.9 g) in DMF (100 m
l) To the mixture was added 2-bromoethyl ethyl ether (9.51 ml) at room temperature, and the mixture was stirred at 60 ° C for 18 hours. Water was added to the reaction system, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-bromo-2-chloro-1- (2-ethoxyethoxy) benzene (21.76 g) as a pale yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.24 (3H, t, J = 7.1 Hz), 3.
63 (2H, q, J = 7.1 Hz), 3.80-3.85 (2H, m), 4.13-4.18
(2H, m), 6.84 (1H, d, J = 8.8 Hz), 7.31 (1H, dd, J =
8.8, 2.6 Hz), 7.49 (1H, d, J = 2.6 Hz) .IR (neat) 1481, 1290, 1263, 1250, 1124, 1056, 802
cm ^-1

Reference Example 79 4-Bromo-2-chloro-1- (2-ethoxyethoxy) benzene (21.76 g) in diethyl ether / T
A 1.6 M n-butyllithium hexane solution (53 ml) was added dropwise to the HF (80/80 ml) solution at -78 ° C, and the mixture was stirred for 1 hour. Trimethyl boric acid (26
ml) in THF (26 ml) was added dropwise over 1 hour. After stirring at -78 ° C for 1 hour, the temperature was raised to room temperature, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added dropwise to the reaction system, and the mixture was further stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 3-chloro-4- (2-ethoxyethoxy) phenylboronic acid (10.24 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.0 Hz), 3.
68 (2H, q, J = 7.0 Hz), 3.88-3.93 (2H, m), 4.26-4.31
(2H, m), 7.06 (1H, d, J = 8.4 Hz), 8.06 (1H, dd, J =
8.4, 1.6 Hz), 8.15 (1H, d, J = 1.6 Hz).

Reference Example 80 A solution of 4-bromophenol (15.0 g), tetrahydropyran-4-ol (9.0 g) and triphenylphosphine (23.08 g) in THF (100 ml) was added at 0 ° C. with azodicarboxylic acid. Diethyl (40% toluene solution) (38.3 g) was added dropwise, and the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, diethyl ether was added, and the resulting crystals were removed by filtration. After concentration, the residue was dissolved in ethyl acetate, washed with a 1N aqueous solution of sodium hydroxide (x3) and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 4) to obtain 4- (4-bromophenyloxy) tetrahydropyran (15.94 g) as colorless crystals. TH of 4- (4-bromophenyloxy) tetrahydropyran (15.73 g)
A 1.6 M n-butyllithium hexane solution (42 ml) was added dropwise to the F (100 ml) solution at −78 ° C.
Stirred for hours. Trimethyl boric acid (20 ml)
(20 ml) was added dropwise over 1 hour. −
After stirring at 78 ° C. for 1 hour, the mixture was heated to room temperature, and further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added dropwise to the reaction system, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with ethyl acetate / hexane,
4- (Tetrahydropyran-4-yloxy) phenylboric acid (4.30 g) was obtained as colorless crystals. Furthermore, the mother liquor was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 1) to obtain 4- (tetrahydropyran-4-yloxy) phenylboronic acid (2.97 g) as colorless crystals. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.74-1.93 (2H, m), 1.98-2.
15 (2H, m), 3.55-3.68 (2H, m), 3.95-4.08 (2H, m),
4.56-4.70 (1H, m), 7.02 (2H, d, J = 8.6 Hz), 8.15 (2
(H, d, J = 8.6 Hz).

Reference Example 81 N-ethylaniline (10.0 g) in DMF (50 m
1) Add N-bromosuccinimide (14.
A solution of 69 g) in DMF (100 ml) was added dropwise. After stirring at room temperature for 19 hours, the reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 4-bromo-N-ethylaniline (17.08) as a pale yellow oil.
g) was obtained. 4-bromo-N-ethylaniline (17.
08g) in a solution of DMF (100 ml) at room temperature in potassium carbonate (17.1 g) and sodium iodide (12.4 g).
g) and 2-bromoethyl ethyl ether (10.2 m
l) was added and the mixture was stirred at 90 ° C for 24 hours. 2-Bromoethyl ethyl ether (5.0 ml), potassium carbonate (6.22 g), and sodium iodide (6.6) were further added to the reaction system.
4g) and stirred for 2 days. Further, 2-bromoethyl ethyl ether (10.0 ml), potassium carbonate (17.1 g), and sodium iodide (12.4 g) were added to the reaction system.
And stirred at 90 ° C. for 3 days. Add water to the reaction system,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 9) to give 4-bromo-N- (2-propoxyethyl) -N as a yellow oil.
-Ethyl aniline (18.11 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.14 (3H, t, J = 6.9 Hz), 1.
20 (3H, t, J = 7.0 Hz), 3.38 (2H, q, J = 7.0 Hz), 3.41
-3.59 (6H, m), 6.56 (2H, d, J = 9.2 Hz), 7.26 (2H,
d, J = 9.2 Hz) .IR (neat) 1591, 1498, 1394, 1373, 1352, 1267, 119
2, 1115, 806cm ^-1

Reference Example 82 TH under magnesium atmosphere (1.57 g) in an argon atmosphere
To a suspension of F (30 ml) was added a portion of iodine at room temperature, followed by 4-bromo-N- (2-propoxyethyl) -N-ethylaniline (16.82) at 40-50 ° C.
g) in THF (50 ml) was added dropwise over 1.5 hours. After the dropwise addition, the mixture was stirred at 50 ° C. for 2 hours. The reaction system is -7
Cool to 8 ° C and trimethyl boric acid (20 ml) in THF
(20 ml) solution was added dropwise. After dropping, raise the temperature to room temperature,
The mixture was further stirred at room temperature for 18 hours. Add 2N hydrochloric acid (1
00 ml) and stirred for 3 hours. An 8N aqueous sodium hydroxide solution was added to the reaction system until the pH became 7-8, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, hexane was added and collected by filtration of precipitated green crystals. The crystals were washed with diisopropyl ether and hexane to give green crystals.
[N- (2-ethoxyethyl) -N-ethylamino] phenylboric acid (1.21 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.09-1.28 (6H, m), 3.35-3.
70 (8H, m), 6.76 (2H, d, J = 8.8 Hz), 8.06 (2H, d, J
= 8.8 Hz).

Reference Example 83 N-methylaniline (10.0 g) in DMF (100 m
l) Add N-bromosuccinimide (16.
A solution of 6 g) in DMF (100 ml) was added dropwise. After stirring at room temperature for 20 hours, the reaction mixture was added to water and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 4-bromo-N-methylaniline (1
8.18 g) were obtained. To a solution of 4-bromo-N-methylaniline (18.18 g) in DMF (150 ml) was added potassium carbonate (25.8 g) and sodium iodide (2
8.0 g) and 2-bromoethyl ethyl ether (21
ml) and stirred at 90 ° C. for 4 days. 2-bromoethyl ethyl ether (10.0 ml) was added to the reaction system,
Potassium carbonate (20.0 g), sodium iodide (1
3.3 g) was added and the mixture was further stirred for 2 days. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. Under reduced pressure,
After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1:19), and further distilled under reduced pressure (0.7 mmHg, 131).
C.) 4-Bromo-N- (2-ethoxyethyl) -N-methylaniline (17.63 g) was obtained as a yellow oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (3H, t, J = 7.0 Hz), 2.
95 (3H, s), 3.43-3.60 (6H, m), 6.59 (2H, d, J = 9.2
Hz), 7.28 (2H, d, J = 9.2 Hz) .IR (neat) 1593, 1497, 1373, 1350, 1115, 806 cm ^-1

Reference Example 84 TH under magnesium atmosphere (1.83 g) in an argon atmosphere
To a suspension of F (30 ml) was added 1,2-dibromoethane (0.1 ml) at room temperature, followed by 4-bromo-N-
(2-ethoxyethyl) -N-methylaniline (17.
A solution of 63 g) in THF (30 ml) was added dropwise over 1 hour. After the dropwise addition, the mixture was stirred at 60 ° C. for 2 hours. The reaction system is -7
After cooling to 8 ° C, trimethyl boric acid (23.0 ml)
An HF (23 ml) solution was added dropwise. After stirring at 78 ° C. for 1 hour, the temperature was raised to room temperature, THF (50 ml) was added, and the mixture was further stirred at room temperature for 1 hour. 3N hydrochloric acid (5 ° C) was added to the reaction system at 0 ° C.
0 ml) and stirred at room temperature for 2.5 hours. A 2N aqueous sodium hydroxide solution was added to the reaction system until the pH became 7-8, extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, diisopropyl ether was added, and the collected green crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 4- [N- (2-ethoxyethyl) -N-methylamino] phenylboronic acid (8.51 g) as green crystals. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.21 (3H, t, J = 7.0 Hz), 3.
08 (3H, s), 3.51 (2H, q, J = 7.0 Hz), 3.59-3.68 (4H,
m), 6.79 (2H, d, J = 8.8 Hz), 8.08 (2H, d, J = 8.8 H
z).

Reference Example 85 2- (N-ethylanilino) ethanol (17.83)
g) in DMF (300 ml) was added at 0 ° C. with sodium hydride (60%, 4.74 g), and the mixture was added at 0 ° C. for 30 minutes.
Stirred at room temperature for 30 minutes. Propyl iodide (1
1.0 ml) and stirred at 50 ° C. for 19 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1:19) to obtain N-ethyl-N- (2-propoxyethyl) aniline (10.18 g) as a colorless oil. Was. N-ethyl-
N- (2-propoxyethyl) aniline (10.18
To a solution of g) in 50 ml of DMF, a solution of N-bromosuccinimide (7.45 g) in 50 ml of DMF was added over 40 minutes at room temperature, followed by stirring for 3 hours. The reaction system was further added with N-bromosuccinimide (0.2 g) in DMF (10 g).
ml) solution and stirred for 15 hours. The reaction mixture was added to water and extracted with diethyl ether. The organic layer was washed with water (2
Times) and washed with saturated saline, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was distilled under reduced pressure (0.7 mmHg, 134 ° C) to obtain 4-bromo-N-ethyl-N- (2-propoxyethyl) aniline (9 .49 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.4 Hz), 1.
14 (3H, t, J = 7.1 Hz), 1.50-1.67 (2H, m), 3.31-3.60
(8H, m), 6.56 (2H, d, J = 9.2 Hz), 7.26 (2H, d, J =
9.2 Hz) .IR (neat) 1591, 1498, 1356, 1267, 1192, 1113, 804
cm ^-1

Reference Example 86 TH in magnesium (0.89 g) under an argon atmosphere
To a suspension of F (30 ml) was added 1,2-dibromoethane (0.1 ml) at room temperature, followed by 4-bromo-N-ethyl-N- (2-propoxyethyl) aniline (9.49 g) at 60 ° C. ) In THF (40 ml) was added dropwise over 40 minutes. After the addition, the mixture was further stirred for 2 hours. The reaction system was cooled to −78 ° C., and a solution of trimethyl boric acid (11 ml) in THF (11 ml) was added dropwise over 1 hour. 78
After stirring at ℃ for 1 hour, the temperature was raised to room temperature, and further stirred at room temperature for 2 hours. 3N hydrochloric acid (25 ml) was added to the reaction system, and 2
Stirred for hours. A 2N aqueous sodium hydroxide solution was added to the reaction system until the pH became 7-8, extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to give 4- [N-ethyl-
N- (2-Propoxyethyl) amino] phenyl boric acid (0.7 g) was obtained. Further, the mother liquor was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 1) to give 4- [N-ethyl-N- as green crystals.
(2-Propoxyethyl) amino] phenyl boric acid (2.1 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.5 Hz), 1.
21 (3H, t, J = 7.0 Hz), 1.53-1.69 (2H, m), 3.39-3.62
(8H, m), 6.76 (2H, d, J = 9.0 Hz), 8.06 (2H, d, J =
8.0 Hz).

Reference Example 87 N-methylaniline (10.0 g) in DMF (100 m
l) Add N-bromosuccinimide (16.
A solution of 6 g) in DMF (100 ml) was added dropwise. After stirring at room temperature for 20 hours, the reaction mixture was added to water and extracted with diethyl ether. The organic layer was washed with water (3 times) and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 4-bromomethylaniline (1
7.93 g). 4-bromomethylaniline (1
To a solution of (7.93 g) in DMF (300 ml) were added potassium carbonate (52 g), sodium iodide (42 g) and 2-bromoethyl ethyl ether (35 ml) at room temperature, and the mixture was stirred at 90 ° C for 4 days. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water (3 times) and a saturated saline solution, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1:19), and further distilled under reduced pressure (0.5 mmHg, 124-127 ° C).
To give 4-bromo-N-methyl- as a yellow oil.
N- (2-propoxyethyl) aniline (17.95
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.3 Hz), 1.
46-1.65 (2H, m), 2.95 (3H, s), 3.37 (2H, t, J = 6.6
Hz), 3.45-3.59 (4H, m), 6.58 (2H, d, J = 9.2Hz), 7.2
8 (2H, d, J = 9.2 Hz) .IR (neat) 1593, 1502, 1373, 1352, 1117, 806cm ^-1

Reference Example 88 TH of magnesium (1.76 g) in an argon atmosphere
To a suspension of F (30 ml) was added 1,2-dibromoethane (0.1 ml) at room temperature, followed by 4-bromo-N-methyl-N- (2-propoxyethyl) aniline (17.
A solution of 95 g) in THF (30 ml) was added dropwise over 30 minutes. After the addition, the mixture was stirred at 60 ° C. for 1.5 hours. The reaction system was cooled to −78 ° C., and a solution of trimethyl boric acid (22 ml) in THF (22 ml) was added dropwise over 30 minutes. 7
After stirring at 8 ° C. for 1 hour, the mixture was heated to room temperature and stirred for 2 hours. 3N hydrochloric acid (50 ml) was added to the reaction system, and the mixture was stirred for 30 minutes. A 2N aqueous sodium hydroxide solution was added to the reaction system until the pH became 7-8, extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to give 4- [N-methyl-N-
(2-Propoxyethyl) amino] phenyl boric acid (5.18 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.5 Hz), 1.
49-1.68 (2H, m), 3.08 (3H, s), 3.41 (2H, t, J = 6.7
Hz), 3.55-3.67 (4H, m), 6.78 (2H, d, J = 8.7Hz), 8.0
8 (2H, d, J = 8.7 Hz).

Reference Example 89 D of 4-bromo-2-ethoxyphenol (8.0 g)
To a MF (50 ml) solution was added potassium carbonate (7.6 g) at room temperature.
5g), sodium iodide (6.64 g) and 2-chloroethyl propyl ether (5.6 ml) were added, and 90
Stirred at C for 24 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water, a 1N aqueous solution of sodium hydroxide and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 4).
4-bromo-2-ethoxy-1- as a yellow oil
(2-Propoxyethoxy) benzene (10.33 g)
I got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.5 Hz), 1.
43 (3H, t, J = 7.0 Hz), 1.53-1.72 (2H, m), 3.50 (2H,
t, J = 6.8 Hz), 3.79 (2H, t, J = 4.9 Hz), 4.05 (2H,
q, J = 7.0 Hz), 4.14 (2H, t, J = 4.9 Hz), 6.80 (1H, d,
J = 9.2 Hz), 6.98-7.02 (2H, m) .IR (neat) 1587, 1498, 1475, 1454, 1402, 1294, 125
4, 1219, 1137, 1041,934 cm ^-1

Reference Example 90 4-bromo-2-ethoxy-1- under an argon atmosphere
(2-Propoxyethoxy) benzene (10.25 g)
Was added dropwise to a THF / diethyl ether (30/30 ml) solution at 78 ° C., and a 1.6 M n-butyllithium hexane solution (23 ml) was added dropwise, followed by stirring at 78 ° C. for 1 hour.
A solution of 11 ml (98.1 mmol) of trimethylboric acid in THF (11 ml) was added to the reaction system over 1 hour.
After stirring at 78 ° C. for 1 hour, the mixture was heated to room temperature, and further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added to the reaction system, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with 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 hexane to give 3-ethoxy- as colorless crystals.
4- (2-propoxyethoxy) phenyl boric acid (3.
09g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.5 Hz), 1.
50 (3H, t, J = 6.9 Hz), 1.57-1.72 (2H, m), 3.55 (2H,
t, J = 6.8 Hz), 3.84-3.90 (2H, m), 4.17-4.29 (4H,
m), 7.04 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J = 1.4 H
z), 7.81 (1H, dd, J = 8.0, 1.4 Hz).

Reference Example 91 DMF of 4-bromo-2-chlorophenol (10 g)
(200 ml) solution at room temperature with potassium carbonate (9.995).
g), sodium iodide (7.95 g) and 2-chloroethylpropyl ether (6.7 ml), and the mixture was added at 90 ° C.
For 24 hours. Water was added to the reaction system, and extracted with hexane. The organic layer was washed with water, a 1N aqueous solution of sodium hydroxide and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 4-bromo-2-chloro-1- (2-propoxyethoxy) benzene (14.9) as a pale yellow oil.
1 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
54-1.70 (2H, m), 3.52 (2H, t, J = 6.6 Hz), 3.82 (2H,
t, J = 4.9 Hz), 4.16 (2H, t, J = 4.9 Hz), 6.85 (1H,
d, J = 8.8 Hz), 7.31 (1H, dd, J = 8.8, 2.4 Hz), 7.50
(1H, d, J = 2.4 Hz) .IR (neat) 1584, 1483, 1452, 1290, 1265, 1250, 112
8, 1086, 1066, 800cm ^-1

Reference Example 92 Under an argon atmosphere, 4-bromo-2-chloro-1- (2
-Propoxyethoxy) benzene (14.91 g) T
In a solution of HF / diethyl ether (40/40 ml), 7
A 1.6 M n-butyllithium hexane solution (33 ml) was added dropwise at 8 ° C, and the mixture was stirred at 78 ° C for 1 hour. To the reaction system was added trimethyl boric acid (16.1 ml) in THF (16 ml).
ml) solution was added over 1 hour. After stirring at 78 ° C. for 1 hour, the mixture was heated to room temperature, and further stirred at room temperature for 36 hours.
1N hydrochloric acid (100 ml) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane 1: 1 →
2: 1) to give 3-chloro-4 as colorless crystals.
-(2-propoxyethoxy) phenylboric acid (3.3
1 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.3 Hz), 1.
56-1.70 (2H, m), 3.57 (2H, t, J = 6.6 Hz), 3.89 (2H,
t, J = 5.0 Hz), 4.28 (2H, t, J = 5.0 Hz), 7.06 (1H,
d, J = 8.2 Hz), 8.05 (1H, dd, J = 8.2, 1.4 Hz), 8.14
(1H, d, J = 1.4 Hz).

Reference Example 93 To a solution of 4-bromo-2-methylphenol (10.46 g) in DMF (100 ml) was added potassium carbonate (1 ml) at room temperature.
1.5 g), sodium iodide (9.97 g) and 2-
Chloroethyl propyl ether (5.6 ml) was added,
Stirred at 90 ° C. for 7 days. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with water, a 1N aqueous solution of sodium hydroxide and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 9).
4-bromo-2-methyl-1- as a pale yellow oil
(2-Propoxyethoxy) benzene (11.7 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.6 Hz), 1.
52-1.71 (2H, m), 2.20 (3H, s), 3.50 (2H, t, J = 6.8
Hz), 3.79 (2H, t, J = 5.0 H), 4.09 (2H, t, J = 5.0 H)
z), 6.69 (1H, d, J = 9.2 Hz), 7.18-7.27 (2H, m) .IR (neat) 1491, 1454, 1296, 1248, 1190, 1132 cm ^-1

Reference Example 94 TH in magnesium (1.14 g) under an argon atmosphere
To a suspension of F (10 ml) was added 1,2-dibromoethane (0.05 ml) at room temperature.
Methyl-1- (2-propoxyethoxy) benzene (1
1.7 g) in THF (50 ml) was added dropwise over 20 minutes. After the addition, the mixture was stirred at 60 ° C. for 1.5 hours. The reaction system was cooled to -78 ° C and trimethyl boric acid (10.0m
A solution of l) in THF (10 ml) was added dropwise. 1 at 78 ° C
After stirring for an hour, the temperature was raised to room temperature, THF (50 ml) was added, and the mixture was further stirred at room temperature for 2 hours. 1N hydrochloric acid (100 ml) was added to the reaction system, and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, diisopropyl ether was added,
The precipitated green crystals were collected by filtration. The crystals were washed with hexane to give 3-methyl-4- (2-
(Propoxyethoxy) phenyl boric acid (5.44 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.5 Hz), 1.
56-1.75 (2H, m), 2.34 (3H, s), 3.55 (2H, t, J = 6.6
Hz), 3.86 (2H, t, J = 5.0), 4.22 (2H, t, J = 5.0), 6.9
4 (1H, d, J = 8.1 Hz), 7.97 (1H, s), 8.05 (1H, d, J =
8.1 Hz).

Example 49 (Production of compound 48) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0m), 2,4-dimethoxyphenylboric acid (116m
g) and a mixture of potassium carbonate (160 mg) in toluene / ethanol / water (6 / 0.6 / 0.6 ml) was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 7 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol /
After separation and purification with ethyl acetate (1: 3), the resulting crystals were recrystallized (ethanol) to give 7- (2,4) as colorless crystals.
-Dimethoxyphenyl) -N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 4
8) (216 mg) was obtained. mp 175-178 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.54-1.82 (4H, m), 2.20 (3
H, s), 2.55-2.74 (1H, m), 3.16 (2H, t, J = 6.7 Hz),
3.31-3.43 (2H, m), 3.57 (2H, s), 3.72 (2H, t, J = 6.7
Hz), 3.82 (3H, s), 3.87 (3H, s), 3.99-4.10 (2H,
m), 6.57-6.62 (2H, m), 7.23-7.34 (4H, m), 7.54 (2H,
d, J = 8.4 Hz), 7.62-7.66 (2H, m), 7.97 (1H, br s),
8.16 (1H, d, J = 8.2 Hz). IR (KBr) 3284, 1649, 1610, 1518, 1313, 1296, 1211,
1130 cm ^-1 Elemental analysis C ₃₂ H ₃₆ N ₂ O ₆ S ・ 0.2H ₂ O Calcd.C, 66.23; H,
6.32; N, 4.83: Found.C, 65.93; H, 6.33; N,
4.79.

Example 50 (Production of compound 49) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3-chloro-4-ethoxyphenylboric acid (127 mg) and potassium carbonate (160 mg) in a toluene / ethanol / water (10/1/1 ml) mixture.
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 30 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 4), and the resulting crystals were recrystallized (ethanol) to give 7-colorless crystals.
(3-chloro-4-ethoxyphenyl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 49) (38 mg) was obtained. mp 201-204 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.52 (3H, t, J = 7.0 Hz), 1.
63-1.85 (4H, m), 2.21 (3H, s), 2.56-2.74 (1H, m),
3.14-3.20 (2H, m), 3.31-3.44 (2H, m), 3.58 (2H, s),
3.70-3.76 (2H, m), 3.99-4.10 (2H, m), 4.18 (2H, m
q, J = 7.0 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.31-7.35 (3
H, m), 7.46 (1H, dd, J = 8.8, 2.2 Hz), 7.55 (2H, d, J
= 8.8 Hz), 7.61-7.68 (3H, m), 7.91 (1H, br s), 8.21
(1H, d, J = 8.0 Hz). IR (KBr) 3332, 1649, 1599, 1516, 1311, 1294, 1269,
1165, 1130, 820 cm- ¹ Elemental analysis C ₃₂ H ₃₅ N ₂ O ₅ SCl Calcd.C, 64.58; H, 5.93
; N, 4.71: Found. C, 64.53; H, 5.81; N, 4.70.

Example 51 (Production of compound 50) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), a mixture of 4-ethoxy-3-fluorophenylboric acid (117 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1/1 ml).
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 4), and the resulting crystals were recrystallized (ethanol) to give 7 as pale yellow crystals.
-(4-ethoxy-3-fluorophenyl) -N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 50) (137 mg) was obtained. mp 233-235 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.50 (3H, t, J = 6.9 Hz), 1.
64-1.84 (4H, m), 2.21 (3H, s), 2.56-2.72 (1H, m),
3.14-3.20 (2H, m), 3.31-3.44 (2H, m), 3.58 (2H, s),
3.70-3.76 (2H, m), 3.98-4.11 (2H, m), 4.18 (2H, m
q, J = 6.9 Hz), 7.02-7.11 (1H, m), 7.30-7.40 (5H, m),
7.55 (2H, d, J = 8.4 Hz), 7.60 (1H, d, J = 1.8 Hz), 7.
66 (1H, dd, J = 8.2, 1.8 Hz), 7.92 (1H, br s), 8.21
(1H, d, J = 8.2 Hz). IR (KBr) 3432, 1659, 1603, 1522, 1309, 1130 cm ^-1 Elemental analysis C ₃₂ H ₃₅ N ₂ O ₅ SF Calcd. C, 66.42; H, 6.10;
N, 4.84: Found.C, 66.16; H, 6.09; N, 4.83.

Example 52 (Production of compound 51) 4-Bromo-1,2-diethoxybenzene (9.74)
g) in THF (80 ml) at −78 ° C.
Was added dropwise and stirred for 1 hour. Trimethyl boric acid (1
4 ml) in THF (14 ml) was added dropwise. The reaction system was warmed to room temperature and further stirred at room temperature for 2 hours. 10% sulfuric acid (100 ml) was added dropwise to the reaction system, and the mixture was further stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with hexane to give 3,4-diethoxyphenylboric acid (5.22 g) as colorless crystals. Under an argon atmosphere, 7-bromo-N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (300 m
g), 3,4-diethoxyphenylboric acid (134 m
g) and a mixture of potassium carbonate (160 mg) in toluene / ethanol / water (10/1/1 ml) was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 7 hours. After cooling, the mixture was extracted with ethyl acetate and washed with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were recrystallized (ethanol) to give 7- (3,4-diethoxyphenyl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 51) (214 mg) was obtained. mp 224-226 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.49 (6H, t, J = 7.0 Hz), 1.
66-1.83 (4H, m), 2.21 (3H, s), 2.57-2.72 (1H, m),
3.17 (2H, t, J = 6.8 Hz), 3.31-3.44 (2H, m), 3.58 (2
H, s), 3.72 (2H, t, J = 6.8 Hz), 3.98-4.11 (2H, m),
4.16 (2H, q, J = 7.0 Hz), 4.18 (2H, q, J = 7.0 Hz), 6.
97 (1H, d, J = 8.0 Hz), 7.11-7.16 (2H, m), 7.31-7.35
(3H, m), 7.56 (2H, d, J = 8.4 Hz), 7.60-7.68 (2H,
m), 7.96 (1H, s), 8.18 (1H, d, J = 8.4 Hz) .IR (KBr) 3329, 1653, 1599, 1518, 1315, 1250, 1134,
810 cm ^-1 Elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S ・ 0.2H ₂ O Calcd.C, 67.13; H,
6.69; N, 4.60: Found.C, 67.01; H, 6.55; N,
4.48.

Example 53 (Production of compound 52) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1 under an argon atmosphere. -Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300
mg), 3,4-dimethoxyphenylboric acid (116 m
g) and a mixture of potassium carbonate (160 mg) in toluene / ethanol / water (10/1/1 ml) was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (40 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate and washed with saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were recrystallized (ethanol) to give colorless crystals.
-(3,4-dimethoxyphenyl) -N- [4-[[N
-Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 52) (112 mg) was obtained. mp 195-197 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.67-1.84 (4H, m), 2.21 (3
H, s), 2.56-2.74 (1H, m), 3.14-3.21 (2H, m), 3.31-
3.44 (2H, m), 3.58 (2H, s), 3.69-3.76 (2H, m), 3.95
(3H, s), 3.97 (3H, s), 3.99-4.11 (2H, m), 6.98 (1
H, d, J = 8.2 Hz), 7.10 (1H, d, J = 2.0 Hz), 7.18 (1H,
(dd, J = 8.2, 2.0 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.37
(1H, s), 7.55 (2H, d, J = 8.4 Hz), 7.62 (1H, d, J = 2.
0 Hz), 7.68 (1H, dd, J = 8.4, 2.0 Hz), 7.95 (1H, s),
8.20 (1H, d, J = 8.4 Hz) .IR (KBr) 3327, 1668, 1595, 1520, 1311, 1257, 1136
cm ^-1 elemental analysis C ₃₂ H ₃₆ N ₂ O ₆ S ・ 0.2H ₂ O Calcd.C, 66.23; H,
6.32; N, 4.82: Found.C, 66.19; H, 6.52; N,
4.73.

Example 54 (Production of compound 53) 1-Bromo-4- (2-methoxyethoxy) benzene (17.0 g) in diethyl ether / THF (150 /
To the solution (50 ml), a 1.6 M n-butyllithium hexane solution (50 ml) was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. A THF (25 ml) solution of trimethyl boric acid (24.8 ml) was added dropwise to the reaction system. The reaction system was warmed to room temperature and further stirred at room temperature for 2 hours. 10% for reaction system
Sulfuric acid (100 ml) was added dropwise, and after stirring for another 30 minutes,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 1) to give colorless crystals.
-(2-methoxyethoxy) phenylboric acid (7.17
g) was obtained. Under an argon atmosphere, 7-bromo-N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4- (2-methoxyethoxy)
Phenyl boric acid (124 mg) and potassium carbonate (16
0 mg) of toluene / ethanol / water (10/1/1 m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (40 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate.
After concentration under reduced pressure, the resulting crystals were recrystallized (ethanol) to give 7- [4- (2-methoxyethoxy) phenyl] -N- [4-[[N-methyl-N- (tetrahydro Pyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 53) (24)
6 mg). mp 227-231 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.64-1.84 (4H, m), 2.21 (3
H, s), 2.55-2.74 (1H, m), 3.13-3.19 (2H, m), 3.32-
3.44 (2H, m), 3.47 (3H, s), 3.58 (2H, s), 3.69-3.81
(4H, m), 3.99-4.09 (2H, m), 4.16-4.21 (2H, m), 7.
04 (2H, d, J = 8.8 Hz), 7.30-7.35 (3H, m), 7.52-7.56
(4H, m), 7.62-7.69 (2H, m), 7.92 (1H, s), 8.19 (1
H, d, J = 8.4 Hz) .IR (KBr) 3246, 1655, 1605, 1518, 1410, 1315, 1294,
1254, 1167, 1128, 825 cm- ¹ Elemental analysis C ₃₃ H ₃₈ N ₂ O ₆ S Calcd. C, 67.10; H, 6.48;
N, 4.74: Found.C, 66.85; H, 6.40; N, 4.62.

Example 55 (Production of compound 54) 4-Bromo-N, N-diethylaniline (17.0 g)
Was added dropwise to a THF (150 ml) solution at -78 ° C and a 1.6 M n-butyllithium hexane solution (51 ml) was added dropwise, followed by stirring for 1 hour. Trimethyl boric acid (25m
A solution of l) in THF (25 ml) was added dropwise. The reaction system was warmed to room temperature and further stirred at room temperature for 2 hours. 1N Hydrochloric acid (200 ml) was added dropwise to the reaction system, and after stirring for 1 hour, saturated aqueous sodium hydrogen carbonate was added until the pH reached 7. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain colorless crystals of 4-diethylaminophenylboric acid (2.47 g). The mother liquor was further concentrated and the resulting gray crystals were collected by filtration. The crystals were washed with hexane to give 4-diethylaminophenylboric acid (4.00 g). Under an argon atmosphere, 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (300 mg), 4-diethylaminophenylboric acid (123 mg) and potassium carbonate (16 mg).
0 mg) of toluene / ethanol / water (10/1/1 m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 7 hours. After cooling, ethyl acetate / TH
Extracted with F (1: 1), washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were recrystallized (ethanol) to give 7- (4-diethylaminophenyl) -N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 5
4) (198 mg) was obtained. mp 240-246 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.21 (6H, t, J = 6.9 Hz), 1.
65-1.82 (4H, m), 2.21 (3H, s), 2.56-2.75 (1H, m),
3.15 (2H, t, J = 7.0 Hz), 3.31-3.50 (6H, m), 3.58 (2
H, s), 3.68-3.74 (2H, m), 3.98-4.08 (2H, m), 6.75
(2H, d, J = 9.2Hz), 7.31-7.35 (3H, m), 7.49-7.67 (6
H, m), 7.93 (1H, br s), 8.14 (1H, d, J = 8.2 Hz) .IR (KBr) 3292, 1657, 1606, 1527, 1408, 1315, 1296,
1271, 1128, 812 cm ^-1 Elemental analysis C ₃₄ H ₄₁ N ₃ O ₄ S ・ 0.5H ₂ O Calcd.C, 68.42; H,
7.09; N, 7.04: Found.C, 68.39; H, 7.11; N,
7.02.

Example 56 (Production of compound 55) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 2,3-dihydro-1,4-benzodioxin-6-ylboric acid (114 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1).
/ 1 ml) mixture was stirred at room temperature for 1 hour. In the reaction system, tetrakistriphenylphosphine palladium (33 m
g) was added and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 2), and the resulting crystals were recrystallized (ethanol) to give 7- (2,3-dihydro- as colorless crystals. 1,4-benzodioxin-6-yl) -N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 5
5) (257 mg) was obtained. mp 248-251 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.66-1.84 (4H, m), 2.21 (3
H, s), 2.57-2.74 (1H, m), 3.17 (2H, t, J = 6.9 Hz),
3.31-3.43 (2H, m), 3.58 (2H, s), 3.73 (2H, t, J = 6.9
Hz), 3.99-4.10 (2H, m), 4.32 (4H, s), 6.98 (1H,
d, J = 8.6 Hz), 7.08-7.13 (2H, m), 7.31-7.35 (3H, m),
7.55 (2H, d, J = 8.4 Hz), 7.61-7.68 (2H, m), 7.90 (1
H, s), 8.19 (1H, d, J = -8.4 Hz) .IR (KBr) 3246, 1653, 1599, 1514, 1410, 1317, 1290,
. 1246, 1128, 1068, 816 cm -1 elemental analysis _{C 32 H 34 N 2 O 6} S Calcd C, 66.88; H, 5.96;
N, 4.87: Found.C, 66.70; H, 6.15; N, 4.74.

Example 57 (Preparation of Compound 56) A solution of 5-bromo-2,3-dihydrobenzofuran (17.64 g) in THF (150 ml) was added to a solution of 1.6 M n-butyl at -78 ° C in an argon atmosphere. A hexane solution of lithium (60 ml) was added dropwise, and the mixture was stirred for 1 hour. In the reaction system, THF (30 ml) of trimethyl boric acid (30 ml) was added.
The solution was added dropwise. The reaction system was slowly warmed to room temperature,
The mixture was further stirred at room temperature for 2 hours. 10% sulfuric acid (1
00 ml), and the mixture was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated colorless crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 2,3-dihydrobenzofuran-5-ylboric acid (8.28 g) as colorless crystals. Under an argon atmosphere, 7-bromo-N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 m
g), a mixture of 2,3-dihydrobenzofuran-5-ylboric acid (104 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1/1 ml).
Stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystals were recrystallized (ethanol) to give 7- as pale yellow crystals.
(2,3-dihydrobenzofuran-5-yl) -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 56) (246 mg). mp 214-216 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.57-1.84 (4H, m), 2.21 (3
H, s), 2.54-2.76 (1H, m), 3.13-3.20 (2H, m), 3.29
(2H, t, J = 8.6 Hz), 3.13-3.44 (2H, m), 3.58 (2H, s),
3.69-3.76 (2H, m), 4.00-4.09 (2H, m), 4.66 (2H, m
t, J = 8.6 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.31-7.40 (4
H, m), 7.45 (1H, s), 7.55 (2H, d, J = 8.4 Hz), 7.60
(1H, d, J = 1.6 Hz), 7.65 (1H, dd, J = 8.4, 1.6 Hz),
7.94 (1H, s), 8.18 (1H, d, J = 8.4 Hz) .IR (KBr) 3265, 1653, 1632, 1597, 1527, 1410, 1317,
1294, 1234, 1128, 818 cm ^-1 Elemental analysis C ₃₂ H ₃₄ N ₂ O ₅ S ・ 0.2H ₂ O Calcd.C, 68.35; H,
6.17; N, 4.98: Found.C, 68.24; H, 6.21; N,
4.80.

Example 58 (Production of compound 57) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (50
0 mg), 4-methoxycarbonylphenylboric acid (1
A mixture of 91 mg) and potassium carbonate (266 mg) in toluene / ethanol / water (10/1/1 ml) was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (56 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol /
Separation and purification with ethyl acetate 1: 2 → 1: 1), recrystallization of the resulting crystals (ethanol), and 7-colorless crystals.
(4-methoxycarbonylphenyl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (290 mg) was obtained. mp 269-273 ° C (dec.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.66-1.83 (4H, m), 2.21 (3
H, s), 2.56-2.72 (1H, m), 3.15-3.22 (2H, m), 3.31-
3.44 (2H, m), 3.57 (2H, s), 3.70-3.77 (2H, m), 3.96
(3H, s), 3.98-4.10 (2H, m), 7.32 (2H, d, J = 8.4 H
z), 7.37 (1H, s), 7.54 (2H, d, J = 8.4 Hz), 7.64-7.68
(3H, m), 7.74 (1H, dd, J = 8.0, 2.0Hz), 7.95 (1H,
s), 8.16 (2H, d, J = 8.4 Hz), 8.26 (1H, d, J = 8.0 H
z) .IR (KBr) 3280, 1722, 1657, 1603, 1524, 1410, 1317,
. 1290, 1130, 1109, 816 cm -1 elemental analysis _{C 32 H 34 N 2 O 6} S Calcd C, 66.88; H, 5.96;
N, 4.87: Found.C, 66.65; H, 5.83; N, 5.03.

Example 59 (Production of compound 58) 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (2.
To a solution of 5g) in THF (200ml) was added methanesulfonic acid (0.29ml) at room temperature and stirred for 0.5h. After adding 2-propanol, the mixture was concentrated under reduced pressure. The resulting crystals were dissolved in 2-propanol at 90 ° C., and then cooled to room temperature. The mixture was further cooled to 0 ° C., and the precipitated crystals were collected by filtration. The crystals are washed with diethyl ether to give 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1 as colorless crystals. ,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide methanesulfonate (compound 5
8) (2.56 g) was obtained. mp 161-166 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (3H, t, J = 7.0 Hz), 1.
76-2.16 (4H, m), 2.56-2.65 (3H, m), 2.78 (3H, s),
3.04-3.14 (2H, m), 3.20-3.52 (3H, m), 3.72-3.85 (2
H, m), 3.90-4.05 (3H, m), 4.09 (2H, q, J = 7.0 Hz),
4.21-4.33 (1H, m), 7.00 (2H, d, J = 8.8 Hz), 7.46 (2
H, d, J = 8.8 Hz), 7.59-7.68 (3H, m), 7.78-7.88 (4H,
m), 8.15 (1H, d, J = 8.4 Hz), 9.33 (1H, s) .IR (KBr) 3427, 1664, 1605, 1520, 1294, 1248, 1217,
1165, 1126, 1039, 825 cm ^-1 Elemental analysis C ₃₃ H ₄₀ N ₂ O ₈ S ₂・ 0.5H ₂ O Calcd.C, 59.53;
H, 6.21; N, 4.21: Found.C, 59.28; H, 6.04; N,
4.39.

Example 60 (Preparation of Compound 59) 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (50
Citric acid (171.1 mg) was added to a solution of 0 mg) in THF (37.5 ml) at room temperature, followed by stirring for 1 hour. After concentration under reduced pressure, ethanol was added and the resulting crystals were collected by filtration. Purified by recrystallization (water / ethanol 1:10), 7- (4-ethoxyphenyl) as colorless crystals.
-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide.1 / 2 citrate (Compound 59)
(413 mg) was obtained. mp 241-245 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.36 (3H, t, J = 7.0 Hz),
1.50-1.73 (2H, m), 1.76-1.90 (2H, m), 2.30 (3H, m
s), 2.58 (1H, s), 2.61 (1H, s), 2.82-3.03 (1H, m),
3.05-3.11 (2H, m), 3.22-3.51 (2H, m), 3.73-3.87
(4H, m), 3.89-4.01 (2H, m), 4.10 (2H, q, J = 7.0 H
z), 7.08 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz),
7.54 (1H, s), 7.74 (2H, d, J = 8.8 Hz), 7.76 (2H,
d, J = 8.8 Hz), 7.87 (1H, dd, J = 8.2, 1.8 Hz), 8.04-8.
09 (2H, m), 10.26 (1H, s) .IR (KBr) 3336, 1726, 1664, 1603, 1522, 1317, 1292,
1248, 1168, 1128, 827 cm ^-1 Elemental analysis C ₃₅ H ₄₀ N ₂ O _8.5 S ・ 1.5H ₂ O Calcd.C, 61.48;
H, 6.34; N, 4.10: Found.C, 61.50; H, 6.11; N,
4.09.

Example 61 (Preparation of Compound 60) 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg) in THF (22.5 ml) at room temperature.
(+)-Tartaric acid (80 mg) was added, and the mixture was stirred at 60 ° C for 2 hours. After concentration under reduced pressure, ethanol was added, and the crystals were further concentrated and collected by filtration. The crystals were washed with ethanol to give colorless crystals of 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide.1 / 2L-(+)-tartrate (Compound 60) (259 mg) was obtained. mp 245-247 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.36 (3H, t, J = 7.0 Hz),
1.43-1.66 (2H, m), 1.69-1.82 (2H, m), 2.17 (3H, m
s), 2.60-2.80 (1H, m), 3.04-3.11 (2H, m), 3.17-3.3
3 (2H, m), 3.62 (2H, s), 3.75-3.82 (2H, m), 3.87-
3.98 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 4.14 (1H,
s), 7.07 (2H, d, J = 8.9 Hz), 7.30 (2H, d, J = 8.5 Hz),
7.54 (1H, s), 7.69 (2H, d, J = 8.5 Hz), 7.76 (2H,
d, J = 8.9 Hz), 7.87 (1H, dd, J = 8.4, 1.8 Hz), 8.04 (1
H, d, J = 1.8 Hz), 8.07 (1H, d, J = 8.4 Hz), 10.21 (1
H, s) .IR (KBr) 3263, 1659, 1633, 1605, 1518, 1412, 1317,
1294, 1248, 1128, 825 cm ^-1 Elemental analysis C ₃₄ H ₃₉ N ₂ O ₈ S Calcd. C, 64.23; H, 6.18;
N, 4.41: Found.C, 64.21; H, 6.19; N, 4.63.

Example 62 (Production of Compound 61) Under argon atmosphere, 4- (4-bromo-3-fluorophenyl) morpholine (6.89 g) in THF (50 m
l) To the solution was added dropwise a 1.6 M n-butyllithium hexane solution (18.2 ml) at -78 ° C, and the mixture was stirred for 1 hour. The reaction system was charged with TH of trimethyl boric acid (9.0 ml).
The F (9 ml) solution was added dropwise. The reaction system was slowly warmed to room temperature and further stirred at room temperature for 2 hours. 1 for reaction system
N hydrochloric acid (100 ml) was added dropwise and stirred for 30 minutes. An 8N aqueous sodium hydroxide solution was added to the reaction system until the pH reached 7, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated gray crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 3
-Fluoro-4-morpholinophenylboric acid (0.65
g) was obtained. Under an argon atmosphere, 7-bromo-N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-fluoro-4-morpholinophenylboronic acid (156 mg) and potassium carbonate (16 mg)
0 mg) of toluene / ethanol / water (10/1/1 m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate and washed with saturated saline. Heat the extract to 70 ° C,
After dissolving the crystals, it was dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were purified by recrystallization (ethanol) and 7- (3-fluoro-4-morpholinophenyl) -N was obtained as yellow crystals.
-[4-[[N-methyl-N- (tetrahydropyran-
4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 61) (149 mg). mp 275-277 ° C (dec.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.64-1.85 (4H, m), 2.22 (3
H, s), 2.54-2.77 (1H, m), 3.15-3.19 (6H, m), 3.28-
3.44 (2H, m), 3.59 (2H, s), 3.70-3.78 (2H, m), 3.88
-3.92 (4H, m), 3.98-4.10 (2H, m), 6.98-7.07 (1H,
m), 7.24-7.38 (5H, m), 7.55 (2H, d, J = 8.4 Hz), 7.62
-7.69 (2H, m), 7.90 (1H, s), 8.21 (1H, d, J = 8.0 H
z) .IR (KBr) 3253, 1657, 1601, 1520, 1315, 1296, 1126
cm- ¹ elemental analysis C ₃₄ H ₃₈ N ₃ O ₅ SF ・ 0.6H ₂ O Calcd. C, 64.76;
H, 6.27; N, 6.66: Found.C, 64.54; H, 6.21; N,
6.75.

Example 63 (Production of compound 62) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere.
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3,4-dihydro-2H-1-benzopyran-6-ylboric acid (113 mg) and potassium carbonate (1 mg).
60 mg) of toluene / ethanol / water (10/1/1
ml) The mixture was stirred at room temperature for 1 hour. 33 mg of tetrakistriphenylphosphine palladium in the reaction system
(0.029 mmol), and the mixture was refluxed for 6 hours.
After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were purified by recrystallization (ethanol) to give 7- (3,4-dihydro-2H-1-benzopyran-6-yl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 62) (149 mg) was obtained. mp 245-249 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.67-1.83 (4H, m), 1.99-2.
11 (2H, m), 2.21 (3H, s), 2.52-2.75 (1H, m), 2.84-
2.90 (2H, m), 3.10-3.21 (2H, m), 3.31-3.44 (2H, m),
3.58 (2H, s), 3.69-3.74 (2H, m), 3.98-4.09 (2H,
m), 4.22-4.27 (2H, m), 6.90 (1H, d, J = 8.4 Hz), 7.31
-7.36 (5H, m), 7.55 (2H, d, J = 8.4 Hz), 7.62-7.69
(2H, m), 7.90 (1H, s), 8.18 (1H, d, J = 8.2 Hz) .IR (KBr) 3250, 1653, 1632, 1597, 1529, 1510, 1410,
1317, 1294, 1128 cm ^-1 Elemental analysis C ₃₃ H ₃₆ N ₂ O ₅ S Calcd. C, 69.21; H, 6.34;
N, 4.89: Found.C, 68.81; H, 6.46; N, 4.83.

Example 64 (Production of compound 63) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 2,3,4,5-tetrahydro-1-benzoxepin-7-ylboric acid (122 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (1
0/1/1 ml) mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 7 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol / ethyl acetate 1: 1).
The resulting crystals are recrystallized (ethanol) to give N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -7- (2,3,4,5-tetrahydro-1-
Benzoxepin-7-yl) -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 63) (231 mg) was obtained. mp 238-242 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.68-1.86 (6H, m), 1.94-2.
08 (2H, m), 2.22 (3H, s), 2.55-2.76 (1H, m), 2.87-
2.92 (2H, m), 3.17 (2H, t, J = 6.8 Hz), 3.31-3.44 (2
H, m), 3.59 (2H, s), 3.73 (2H, t, J = 6.8 Hz), 3.97-
4.11 (4H, m), 7.10 (1H, d, J = 9.0 Hz), 7.31-7.39 (5
H, m), 7.55 (2H, d, J = 8.6 Hz), 7.63 (1H, d, J = 1.8 H
z), 7.68 (1H, dd, J = 8.2, 1.8 Hz), 7.93 (1H, s), 8.
20 (1H, d, J = 8.2 Hz) .IR (KBr) 3235, 1657, 1635, 1601, 1529, 1510, 1483,
1410, 1316, 1292, 1244, 1125cm- ¹ Elemental analysis C ₃₄ H ₃₈ N ₂ O ₅ S Calcd. C, 69.60; H, 6.53;
N, 4.77: Found.C, 69.31; H, 6.53; N, 5.01.

Example 65 (Production of compound 64) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 2,2-dimethyl-3,4-dihydro-2H
A mixture of -1-benzopyran-6-ylboric acid (131 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1/1 ml) was stirred at room temperature for 1 hour. 33 mg (0.029 mmol) of tetrakistriphenylphosphine palladium was added to the reaction system, and 6.5.
Heated to reflux for an hour. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. Purification by recrystallization (ethanol) gave 7- (2,2) as colorless crystals.
2-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl) -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (Compound 64)
(117 mg) was obtained. mp 222-226 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.37 (6H, s), 1.64-1.82 (4
H, m), 1.86 (2H, t, J = 6.6 Hz), 2.21 (3H, s), 2.55-
2.75 (1H, m), 2.82-2.88 (2H, m), 3.16 (2H, t, J = 6.6
Hz), 3.31-3.44 (2H, m), 3.58 (2H, s), 3.68-3.75
(2H, m), 3.98-4.11 (2H, m), 6.89 (1H, d, J = 8.8 H
z), 7.30-7.37 (5H, m), 7.55 (2H, d, J = 8.4 Hz), 7.6
1-7.67 (2H, m), 7.93 (1H, s), 8.17 (1H, d, J = 8.0 H
z) .IR (KBr) 3245, 1653, 1605, 1532, 1514, 1410, 1318,
1302, 1122, 820 cm ^-1 Elemental analysis C ₃₅ H ₄₀ N ₂ O ₅ S ・ 0.2H ₂ O Calcd.C, 69.56; H,
6.74; N, 4.64: Found.C, 69.35; H, 6.78; N,
4.76.

Example 66 (Production of compound 65) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 4- (2-ethoxyethoxy) -3-fluorophenylboric acid (145 mg) and potassium carbonate (1
60 mg) of toluene / ethanol / water (10/1/1
ml) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system.
Was added and heated under reflux for 7 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystals were recrystallized (ethanol) to give 7- [4- (2-ethoxy) as colorless crystals. Ethoxy) -3-
Fluorophenyl] -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (compound 65)
(244 mg). mp 212-214 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.25 (3H, t, J = 7.2 Hz), 1.
68-1.82 (4H, m), 2.21 (3H, s), 2.54-2.76 (1H, m),
3.14-3.21 (2H, m), 3.30-3.44 (2H, m), 3.58 (2H, s),
3.63 (2H, q, J = 7.2 Hz), 3.70-3.76 (2H, m), 3.85
(2H, t, J = 4.9Hz), 3.98-4.10 (2H, m), 4.26 (2H, t,
J = 4.7 Hz), 7.06-7.15 (1H, m), 7.27-7.39 (5H, m),
7.55 (2H, d, J = 8.8 Hz), 7.61-7.67 (2H, m), 7.91 (1
H, s), 8.21 (1H, d, J = 8.0 Hz) .IR (KBr) 3243, 1651, 1630, 1599, 1526, 1410, 1318,
1294, 1281, 1128 cm ^-1 Elemental analysis C ₃₄ H ₃₉ N ₂ O ₆ SF Calcd. C, 65.57; H, 6.31;
N, 4.50: Found.C, 65.28; H, 6.18; N, 4.50.

Example 67 (Preparation of compound 66) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3,4-dihydro-2H-1,5-benzodioxepin-7-ylboric acid (123 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (1
0/1/1 ml) mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol / ethyl acetate 1: 3).
The resulting crystals are recrystallized (ethanol) to give 7- (3,4-dihydro-2H-) as colorless crystals.
1,5-benzodioxepin-7-yl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 66) (194 mg) was obtained. mp 242-245 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.66-1.83 (4H, m), 2.21 (3
H, s), 2.18-2.29 (2H, m), 2.55-2.72 (1H, m), 3.13-
3.20 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.68
-3.75 (2H, m), 3.98-4.09 (2H, m), 4.26-4.31 (4H,
m), 7.06 (1H, d, J = 8.4 Hz), 7.17 (1H, dd, J = 8.8, 2.
2 Hz), 7.23 (1H, d, J = 2.2 Hz), 7.30-7.35 (3H, m),
7.54 (2H, d, J = 8.4 Hz), 7.60-7.67 (2H, m), 7.83 (1
H, s), 8.19 (1H, d, J = 8.4 Hz) .IR (KBr) 3248, 1651, 1632, 1601, 1532, 1510, 1410,
1317, 1298, 1267, 1125 cm ^-1 Elemental analysis C ₃₃ H ₃₆ N ₂ O ₆ S Calcd. C, 67.33; H, 6.16;
N, 4.76: Found.C, 66.96; H, 6.32; N, 4.74.

Example 68 (Production of compound 67) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3-chloro-4- (2-ethoxyethoxy)
Phenyl boric acid (156 mg) and potassium carbonate (16
0 mg) of toluene / ethanol / water (10/1/1 m
l) The mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3).
After recrystallization (ethanol), 7-colorless crystals were obtained.
[3-chloro-4- (2-ethoxyethoxy) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 67) (269 mg) was obtained. mp 203-205 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.1 Hz), 1.
68-1.82 (4H, m), 2.21 (3H, s), 2.55-2.76 (1H, m),
3.14-3.21 (2H, m), 3.31-3.44 (2H, m), 3.58 (2H, s),
3.66 (2H, q, J = 7.1 Hz), 3.69-3.76 (2H, m), 3.85-
3.90 (2H, m), 3.99-4.10 (2H, m), 4.23-4.28 (2H, m),
7.07 (1H, d, J = 8.8 Hz), 7.31-7.35 (3H, m), 7.45 (1
H, dd, J = 8.8, 2.2 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.6
1-7.68 (3H, m), 7.78 (1H, s), 8.21 (1H.d.J = 8.2 H
z) .IR (KBr) 3250, 1651, 1632, 1601, 1527, 1510, 1482,
1410, 1318, 1294, 1273, 11300 cm- ¹ Elemental analysis C ₃₄ H ₃₉ N ₂ O ₆ SCl Calcd.C, 63.89; H, 6.15
; N, 4.38: Found. C, 63.73; H, 6.19; N, 4.39.

Example 69 (Production of compound 68) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 4- (tetrahydropyran-4-yloxy) phenylboric acid (141 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1).
/ 1 ml) mixture was stirred at room temperature for 1 hour. In the reaction system, tetrakistriphenylphosphine palladium (33 m
g) was added and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystals were recrystallized (ethanol) to give N- [4-[[N- Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
-7- [4- (Tetrahydropyran-4-yloxy)
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 68)
(274 mg) was obtained. ^{mp 227-229 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ1.63-1.92 (6H, m), 1.99-2.
15 (2H, m), 2.21 (3H, s), 2.55-2.76 (1H, m), 3.13-
3.21 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.59
-3.75 (4H, m), 3.95-4.11 (4H, m), 4.50-4.63 (1H,
m), 7.03 (2H, d, J = 8.8 Hz), 7.31-7.35 (3H, m), 7.52
-7.56 (4H, m), 7.62-7.68 (2H, m), 7.79 (1H, s), 8.
20 (1H, d, J = 8.0 Hz). IR (KBr) 3243, 1655, 1638, 1603, 1518, 1410, 1316,
1292, 1250, 1130 cm ^-1 Elemental analysis C ₃₅ H ₄₀ N ₂ O ₆ S Calcd. C, 68.16; H, 6.54;
N, 4.54: Found.C, 67.95; H, 6.57; N, 4.56.

Example 70 (Production of compound 69) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 4- [N- (2-ethoxyethyl) -N-ethylamino] phenylboronic acid (410 mg) and potassium carbonate (400 mg) in toluene / ethanol / water (1
0/1/1 ml) mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (50 mg) was added to the reaction system, and the mixture was heated under reflux for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol / ethyl acetate 1: 3).
The resulting crystals are recrystallized (ethanol) to give 7- [4- [N- (2-ethoxyethyl) -N-ethylamino] phenyl] -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 69) (260 mg) was obtained. mp 194-197 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.21 (3H, t, J = 7.0 Hz), 1.
22 (3H, t, J = 7.0 Hz), 1.68-1.83 (4H, m), 2.21 (3H,
s), 2.52-2.73 (1H, m), 3.15 (2H, t, J = 6.8Hz), 3.3
1-3.64 (12H, m), 3.71 (2H, t, J = 6.8 Hz), 3.98-4.10
(2H, m), 6.77 (2H, d, J = 9.2 Hz), 7.30-7.34 (3H,
m), 7.47-7.66 (6H, m), 7.90 (1H, s), 8.13 (1H, d, J
= 8.4 Hz) .IR (KBr) 3281, 1655, 1637, 1607, 1591, 1526, 1412,
1318, 1294, 1128, 810 cm ^-1 Elemental analysis C ₃₆ H ₄₅ N ₃ O ₅ S ・ 0.3H ₂ O Calcd.C, 67.86; H,
7.21; N, 6.59: Found.C, 67.74; H, 6.91; N,
6.67.

Example 71 (Production of compound 70) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 4- [N- (2-ethoxyethyl) -N-methylamino] phenylboronic acid (168 mg) and potassium carbonate (176 mg) in toluene / ethanol / water (1
0/1/1 ml) mixture was stirred at room temperature for 1 hour. Tetrakistriphenylphosphine palladium (33 mg) was added to the reaction system, and the mixture was heated under reflux for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethanol / ethyl acetate 1: 3).
The resulting crystals are recrystallized (ethanol) to give 7- [4- [N- (2-ethoxyethyl) -N-methylamino] phenyl] -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 70) (235 mg) was obtained. mp 190-192 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.20 (3H, t, J = 7.0 Hz), 1.
67-1.84 (4H, m), 2.21 (3H, s), 2.55-2.75 (1H, m),
3.06 (3H, s), 3.15 (2H, t, J = 6.6 Hz), 3.31-3.44 (2
H, m), 3.46-3.63 (8H, m), 3.68-3.74 (2H, m), 3.99-
4.09 (2H, m), 6.80 (2H, d, J = 9.0 Hz), 7.30-7.35 (3
H, m), 7.49-7.67 (6H, m), 7.87 (1H, s), 8.14 (1H,
d, J = 8.0 Hz) .IR (KBr) 3275, 1655, 1636, 1609, 1591, 1526, 1508,
1318, 1292, 1128, 810 cm- ¹ Elemental analysis C ₃₅ H ₄₃ N ₃ O ₅ S Calcd.C, 68.04; H, 7.02;
N, 6.80: Found.C, 67.68; H, 6.72; N, 6.89.

Example 72 (Production of compound 71) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (20
0 mg), 4- [N-ethyl-N- (2-propoxyethyl) amino] phenylboronic acid (290 mg) and potassium carbonate (266 mg) in toluene / ethanol / water (10/1/1 ml) were mixed at room temperature with 1 part. Stirred for hours. Tetrakistriphenylphosphine palladium (40 mg) was added to the reaction system, and the mixture was refluxed for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystals were recrystallized (ethanol) to give 7- [4- [N- Ethyl-N- (2-propoxyethyl) amino] phenyl]
-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (Compound 71) (89 mg) was obtained. mp 172-175 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
21 (3H, t, J = 7.0 Hz), 1.53-1.83 (6H, m), 2.21 (3H,
s), 2.55-2.74 (1H, m), 3.12-3.19 (2H, m), 3.31-3.6
3 (12H, m), 3.68-3.74 (2H, m), 3.99-4.11 (2H, m),
6.77 (2H, d, J = 9.0 Hz), 7.30-7.35 (3H, m), 7.48-7.6
9 (6H, m), 7.88 (1H, s), 8.14 (1H, d, J = 8.2 Hz) .IR (KBr) 3281, 1655, 1607, 1590, 1524, 1410, 1318,
1294, 1128, 810 cm- ¹ Elemental analysis C ₃₇ H ₄₇ N ₃ O ₅ S Calcd. C, 68.81; H, 7.33;
N, 6.51: Found.C, 68.77; H, 7.25; N, 6.60.

Example 73 (Production of compound 72) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 4- [N-methyl-N- (2-propoxyethyl) amino] phenylboronic acid (205 mg) and potassium carbonate (176 mg) in toluene / ethanol / water (10/1/1 ml) were mixed at room temperature with 1 part. Stirred for hours. Tetrakistriphenylphosphine palladium (40 mg) was added to the reaction system, and the mixture was refluxed for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 4), and the resulting crystals were recrystallized (ethanol) to give 7- [4- [N- Methyl-N- (2-propoxyethyl) amino] phenyl]
-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (Compound 72) (210 mg) was obtained. mp 193-194 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.4 Hz), 1.
53-1.83 (6H, m), 2.21 (3H, s), 2.53-2.76 (1H, m),
3.07 (3H, s), 3.16 (2H, t, J = 6.8 Hz), 3.31-3.44 (4
H, m), 3.58-3.62 (6H, m), 3.68-3.75 (2H, m), 3.99-
4.12 (2H, m), 6.80 (2H, d, J = 9.0 Hz), 7.31-7.35 (3
H, m), 7.50-7.57 (4H, m), 7.61 (1H, d, J = 1.7 Hz),
7.66 (1H, dd, J = 8.3, 1.7 Hz), 7.87 (1H, s), 8.15
(1H, d, J = 8.3 Hz). IR (KBr) 3281, 1655, 1638, 1609, 1591, 1526, 1410,
1318, 1294, 1128, 810 cm- ¹ Elemental analysis C ₃₆ H ₄₅ N ₃ O ₅ S Calcd. C, 68.43; H, 7.18;
N, 6.65: Found.C, 68.50; H, 7.18; N, 6.79.

Example 74 (Production of compound 73) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3-ethoxy-4- (2-propoxyethoxy) phenylboronic acid (171 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1).
/ 1 ml) mixture was stirred at room temperature for 1 hour. In the reaction system, tetrakistriphenylphosphine palladium (33 m
g) was added and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystals were recrystallized (ethanol) to give 7- [3-ethoxy-4- as colorless crystals. (2-propoxyethoxy) phenyl] -N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 7
3) (237 mg) was obtained. mp 171-172 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.3 Hz), 1.
47 (3H, t, J = 7.0 Hz), 1.58-1.83 (6H, m), 2.21 (3H,
s), 2.56-2.73 (1H, m), 3.14-3.21 (2H, m), 3.30-3.4
5 (2H, m), 3.52 (2H, t, J = 6.8 Hz), 3.58 (2H, s),
3.68-3.75 (2H, m), 3.85 (2H, t, J = 4.9 Hz), 3.99-4.1
0 (2H, m), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, t, J =
4.9 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.10-7.15 (2H,
m), 7.31-7.35 (3H, m), 7.55 (2H, d, J = 8.4 Hz), 7.5
9 (1H, d, J = 2.0 Hz), 7.64 (1H, dd, J = 8.0, 2.0 Hz),
7.86 (1H, s), 8.18 (1H, d, J = 8.0 Hz). IR (KBr) 3324, 1651, 1595, 1520, 1316, 1291, 1254,
1128, 810 cm ^-1 Elemental analysis C ₃₇ H ₄₆ N ₂ O ₇ S Calcd. C, 67.04; H, 6.99;
N, 4.23: Found.C, 66.75; H, 7.02; N, 4.22.

Example 75 (Production of compound 74) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3-chloro-4- (2-propoxyethoxy) phenylboronic acid (164 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1).
/ 1 ml) mixture was stirred at room temperature for 1 hour. In the reaction system, tetrakistriphenylphosphine palladium (33 m
g) was added and the mixture was heated under reflux for 6 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The resulting crystals were concentrated under reduced pressure and collected by filtration.
Further, recrystallization (ethanol) was performed to obtain 7- [3-chloro-4- (2-propoxyethoxy) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-) as colorless crystals. Yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 74) (255 m
g) was obtained. mp 183-184 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4 Hz), 1.
54-1.82 (6H, m), 2.21 (3H, s), 2.55-2.72 (1H, m),
3.14-3.20 (2H, m), 3.31-3.44 (2H, m), 3.55 (2H, t,
J = 6.8 Hz), 3.57 (2H, s), 3.69-3.75 (2H, m), 3.87
(2H, t, J = 4.9Hz), 3.99-4.09 (2H, m), 4.26 (2H, t,
J = 4.9 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.30-7.35 (3H,
m), 7.45 (1H, dd, J = 8.6, 2.4 Hz), 7.54 (2H, d, J =
8.4 Hz), 7.60-7.67 (3H, m), 7.82 (1H, s), 8.20 (1H,
d, J = 8.0 Hz) .IR (KBr) 3241, 1651, 1634, 1601, 1507, 1410, 1318,
1294, 1130 cm ^-1 Elemental analysis C ₃₅ H ₄₁ N ₂ O ₆ SCl Calcd.C, 64.35; H, 6.33
; N, 4.29: Found.C, 64.24; H, 6.38; N, 4.25.

Example 76 (Production of compound 75) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] under an argon atmosphere
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg), 3-methyl-4- (2-propoxyethoxy) phenylboronic acid (151 mg) and potassium carbonate (160 mg) in toluene / ethanol / water (10/1).
/ 1 ml) mixture was stirred at room temperature for 1 hour. In the reaction system, tetrakistriphenylphosphine palladium (33 m
g) was added and the mixture was heated under reflux for 8 hours. After cooling, the mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethanol / ethyl acetate 1: 3), and the resulting crystal was recrystallized (ethanol) to give 7- [3-methyl-4-colorless crystal. (2-propoxyethoxy) phenyl] -N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 75)
(261 mg). mp 192-195 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.3 Hz), 1.
56-1.83 (6H, m), 2.21 (3H, s), 2.31 (3H, s), 2.54-
2.74 (1H, m), 3.16 (2H, t, J = 6.6 Hz), 3.30-3.45 (2
H, m), 3.53 (2H, t, J = 6.6 Hz), 3.57 (2H, s), 3.72
(2H, t, J = 6.6Hz), 3.82-3.87 (2H, m), 3.98-4.09 (2
H, m), 4.16-4.21 (2H, m), 6.93 (1H, d, J = 9.2 Hz),
7.30-7.43 (5H, m), 7.54 (2H, d, J = 8.4 Hz), 7.62-7.
68 (2H, m), 7.85 (1H, s), 8.18 (1H, d, J = 8.4 Hz) .IR (KBr) 3279, 1661, 1603, 1534, 1514, 1313, 1291,
1254, 1132 cm ^-1 Elemental analysis C ₃₆ H ₄₄ N ₂ O ₆ S Calcd. C, 68.33; H, 7.01;
N, 4.43: Found.C, 68.30; H, 6.92; N, 4.45.

Example 77 (Production of compound 76) N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- (4-
(Propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (1
7.6g) in THF (1160ml) at room temperature.
N hydrochloric acid (10 ml) was added and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration. The crystals were washed with THF and diisopropyl ether to obtain colorless crystals. Purification by recrystallization (ethanol / water) gave N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- (4-
(Propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide hydrochloride (Compound 76) (13.2 g) was obtained. mp 259-273 ° C (dec.) ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.00 (3H, t, J = 7.3 Hz),
1.67-1.91 (4H, m), 1.94-2.16 (2H, m), 2.57-2.59 (3
H, m), 3.01-3.12 (2H, m), 3.21-3.51 (3H, m), 3.76-
3.83 (2H, m), 3.97-4.19 (5H, m), 4.37-4.48 (1H,
m), 7.08 (2H, d, J = 8.8 Hz), 7.56-7.60 (3H, m), 7.74
-7.90 (5H, m), 8.05-8.09 (2H, m), 10.23-10.39 (1H,
m), 10.44 (1H, s) .IR (KBr) 3218, 1669, 1595, 1522, 1319, 1294, 1258,
1168, 1132, 831 cm- ¹ Elemental analysis C ₃₃ H ₃₉ N ₂ O ₅ SCl Calcd.C, 64.85; H, 6.43
; N, 4.58; Cl, 5.80: Found. C, 64.84; H, 6.50;
N, 4.34; Cl, 5.61

Example 78 (Preparation of Compound 77) 7- (4-ethoxyphenyl) -1,1-dioxo-
To a suspension of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg) in THF (5 ml) was added 1 drop of thionyl chloride (0.05 ml) and DMF at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was treated with TH.
F (10 ml) and dissolved at room temperature in 4-[[N- (3-
Ethoxypropyl) -N-methylamino] methyl] aniline dihydrochloride (181 mg) and triethylamine (0.39 ml) were added dropwise to a suspension of THF (2 ml).
Stir for 4 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethanol / ethyl acetate 1: 2) and recrystallization (ethanol) to give 7- (4-ethoxyphenyl) -N- [4-
[[N- (3-ethoxypropyl) -N-methylamino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 77) (161 mg) was obtained. mp 197-198 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.19 (3H, t, J = 7.0 Hz), 1.
45 (3H, t, J = 7.0 Hz), 1.73-1.88 (2H, m), 2.19 (3H,
s), 2.45 (2H, t, J = 7.4 Hz), 3.16 (2H, t, J = 6.8 H
z), 3.42-3.52 (6H, m), 3.71 (2H, t, J = 6.8 Hz), 4.1
0 (2H, q, J = 7.0Hz), 7.00 (2H, d, J = 8.8 Hz), 7.29-
7.34 (3H, m), 7.53 (2H, d, J = 8.8 Hz), 7.54 (2H, d,
J = 8.4 Hz), 7.60 (1H, d, J = 1.8 Hz), 7.65 (1H, dd, J
= 8.0, 1.8 Hz), 7.95 (1H, br s), 8.18 (1H, d, J = 8.0
Hz). IR (KBr) 3338, 1651, 1606, 1518, 1311, 1292, 1252,
1165, 1128, 820 cm- ¹ Elemental analysis C ₃₂ H ₃₈ N ₂ O ₅ S Calcd. C, 68.30; H, 6.81;
N, 4.98: Found.C, 68.20; H, 6.75; N, 4.93.

Reference Example 95 4-bromobenzenethiol (10.0 g) was added to DMF
(100 ml), and potassium carbonate (9.
After adding 5 g), 1-iodopentane (8.3 ml).
Was added dropwise and stirred for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in THF (112 ml).
1.6M n-butyllithium / hexane (32.9m
1) was removed and stirred for 1 hour. A solution of trimethoxyborane (14.9 g) in THF (30 ml) was added dropwise, and 3
After stirring for 0 minutes, the mixture was naturally warmed to room temperature, and 10% sulfuric acid (6%
1 ml) and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (pentylthio) phenyl boric acid (5.6 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.0 Hz), 1.2
3-1.52 (4H, m), 1.65-1.81 (2H, m), 3.01 (2H, t, J = 7.4
Hz), 7.38 (2H, d, J = 8.4Hz), 8.10 (2H, d, J = 8.4Hz)

Example 79 (Production of compound 78) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
To 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene /
Add ethanol / water (10/1/1, 6.0 ml),
4- (pentylthio) phenyl boric acid (182 mg),
After adding potassium carbonate (181 mg), the mixture was added at room temperature for 30 minutes.
For a minute. Tetrakistriphenylphosphine palladium (34 mg) was added, and the mixture was stirred at 100 ° C for 12 hours. After cooling to room temperature, the mixture was added to water, and ethyl acetate / THF was added.
, And the extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4-[[N-methyl -N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
This gave 161 mg of -7- (4-pentylthiophenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 78). mp 204-206 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.0 Hz), 1.
23-1.49 (4H, m), 1.62-1.76 (6H, m), 2.21 (3H, s), 2.
65 (1H, m), 2.98 (2H, t, J = 7.4Hz), 3.12-3.20 (2H,
m), 3.31-3.43 (2H, m), 3.57 (2H, s), 3.68-3.75 (2H,
m), 4.00-4.08 (2H, m), 7.29-7.41 (5H, m), 7.48-7.68
(6H, m), 8.00 (1H, s), 8.20 (1H, d, J = 8.0Hz) IR (KBr) 3252, 2951, 1653, 1597, 1526, 1410, 1317,
1294, 1130, 814cm- ¹ elemental analysis C ₃₅ H ₄₂ N ₂ O ₄ S ₂ Calcd.C, 67.93; H, 6.84;
N, 4.53: Found.C, 67.84; H, 6.84; N, 4.52

Reference Example 96 4-bromobenzenethiol (10.1 g) was added to DMF
(100 ml), and potassium carbonate (9.
After adding 6 g), 1-iodohexane (9.5 ml).
Was added dropwise and stirred for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 1-bromo-4-
(Hexylthio) benzene (14.2 g) was obtained. 1-
Bromo-4- (hexylthio) benzene (14.1 g)
Was dissolved in THF (127 ml) and the mixture was dissolved in 1.6 M at -78 ° C.
n-Butyllithium / hexane (35.5 ml) was removed and stirred for 1 hour. Trimethoxyborane (16.1
g) in THF (32 ml) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, and 10% sulfuric acid (70.5 m
l) was added and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (hexylthio) phenyl boric acid (6.6 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 6.4 Hz), 1.
26-1.76 (8H, m), 3.01 (2H, t, J = 7.37 (2H, d, J = 8.0H
z), 8.09 (2H, d, J = 8.0Hz)

Example 80 (Preparation of compound 79) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 12 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (320 mg),
4- (hexylthio) phenyl boric acid (199 mg),
After adding potassium carbonate (187 mg), the mixture was added at room temperature for 30 minutes.
For a minute. Tetrakistriphenylphosphine palladium (36 mg) was added, and the mixture was stirred at 100 ° C for 14 hours. After cooling to room temperature, the mixture was added to water, and ethyl acetate / THF was added.
, And the extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and 7- (4-hexylthiophenyl) -N − [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 79) (298 mg) was obtained. mp 205-207 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90 (3 H, t, J = 6.4 Hz), 1.3
0-1.50 (4H, m), 1.62-1.76 (6H, m), 2.20 (3H, s), 3.31
-3.44 (2H, m), 3.56 (2H, s), 3.66-3.74 (2H, m), 4.00-
4.08 (2H, m), 7.28-7.40 (5H, m), 7.46-7.66 (6H, m),
8.04 (1H, s), 8.18 (1H, d, J = 8.0Hz) IR (KBr) 3275, 2951, 1655, 1597, 1526, 1410, 1318,
1294, 1130, 814cm- ¹ Elemental analysis C ₃₆ H ₄₄ N ₂ O ₄ S ₂ Calcd.C, 68.32; H, 7.01;
N, 4.43: Found.C, 68.35; H, 7.13; N, 4.47

Reference Example 97 4-Bromobenzyl alcohol (19.8 g) was added to THF.
(200 ml), and after adding 65% sodium hydride (3.6 g) under ice-cooling, the mixture was stirred at room temperature for 30 minutes.
Iodomethane (8.0 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to obtain 1-bromo-4- (methoxymethyl) benzene (14.8 g). . 1-bromo-4- (methoxymethyl) benzene (12.8 g) was added to T
Dissolved in HF (110 ml), and 1.6 M n-
Butyl lithium / hexane (42.4 ml) was removed,
Stir for 1 hour. T of trimethoxyborane (19.2 g)
HF solution (38.4 ml) was added dropwise, and after stirring for 30 minutes,
The temperature was naturally raised to room temperature, 5% sulfuric acid (124 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (methoxymethyl) phenyl boric acid (6.3 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ3.09 (3H, s), 4.41 (2H,
s), 7.27 (2H, d, J = 8.0Hz), 7.77 (2H, d, J = 8.0Hz)

Example 81 (Production of compound 80) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 6 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (220 mg), and 4
After adding-(methoxymethyl) phenyl boric acid (86 mg) and potassium carbonate (123 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (19 mg) was added, and the mixture was stirred at 90 ° C. for 9 hours.
After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol).
= 3/1) and recrystallized with ethanol.
7- (4-methoxymethylphenyl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 80) (99 mg) was obtained. mp 227-229 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.60-1.82 (4H, m), 2.21 (3
H, s), 2.66 (1H, m), 3.13-3.22 (2H, m), 3.30-3.45
(2H, m), 3.44 (3H, s), 3.69-3.78 (2H, m), 4.00-4.08
(2H, m), 4.53 (2H, s), 7.26-7.38 (3H, m), 7.44-7.74
(8H, m), 7.92 (1H, s), 8.23 (1H, d, J = 8.0 Hz) IR (KBr) 3239, 29198, 2840,,
1655, 1601, 1530, 1412,
1318, 1294, 1130,816cm ^-1 elemental analysis _{C 32 H 36 N 2 O 5} S Calcd.
C, 68.55; H, 6.47; N,
5.00: Found. C, 68.37;
H, 6.38; N, 5.05

Reference Example 98 4-Bromophenethyl alcohol (10 g) was added to THF
(100 ml), and after adding 65% sodium hydride (1.7 g) under ice-cooling, the mixture was stirred at room temperature for 30 minutes.
Iodomethane (3.7 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 1-bromo-4- (2-
Methoxyethyl) benzene (8.3 g) was obtained. 1-bromo-4- (2-methoxyethyl) benzene (8.2
g) was dissolved in THF (100 ml) and at -78 ° C.
6M n-butyllithium / hexane (26.0 ml) was removed and stirred for 1 hour. Trimethoxyborane (11.
8 g) of a THF solution (12 ml) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, and 10% sulfuric acid (40 ml).
Was added and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (2-methoxyethyl) phenylboronic acid (3.7 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.98 (2 H, t, J = 6.8 Hz), 3.3
8 (3H, s), 3.67 (2H, t, J = 6.8Hz), 7.37 (2H, d, J = 7.6H
z), 8.16 (2H, d, J = 7.6Hz)

Example 82 (Production of compound 81) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 16.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (420 mg), and 4- (2-methoxyethyl) was added. ) Phenyl boric acid (21
6 mg) and potassium carbonate (245 mg), and the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (47 mg) and add 1 at 100 ° C.
Stirred for 0 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and 7- [4- (2-methoxyethyl) phenyl]. -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 81) (99 mg) was obtained. mp 216-219 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.61-1.83 (4H, m), 2.21 (3
H, s), 2.65 (1H, m), 3.13-3.20 (2H, m), 3.30-3.43 (2
H, m), 3.38 (3H, s), 3.58 (2H, m), 3.66 (2H, s), 3.65
-3.76 (2H, m), 3.98-4.08 (2H, m), 7.30-7.38 (6H, m),
7.51-7.57 (4H, m), 7.98 (1H, s), 8.20 (1H, d, J = 8.2H
z) IR (KBr) 3293, 2944, 1667, 1597, 1522, 1408, 1314,
. 1294, 1130, 735cm ^-1 elemental analysis _{C 33 H 38 N 2 O 5} S Calcd C, 68.96; H, 6.66;
N, 4.87: Found.C, 68.85; H, 6.62; N, 4.83

Reference Example 99 7- (4-ethoxyphenyl) -2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (960 m
g) in THF (19.2 ml), methanol (9.6 m).
l) 1N sodium hydroxide (3.4 ml) was added, and the mixture was stirred at room temperature for 3 hours. The organic solvent was removed under reduced pressure, ethyl acetate was added, and the mixture was extracted with water. 6N hydrochloric acid (2 ml) was added, and the mixture was extracted with ethyl acetate / THF. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and 7- (4-ethoxyphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (850 m
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.35 (3 H, t, J = 7.0 Hz),
2.85-2.92 (2H, m), 3.14-3.20 (2H, m), 4.07 (2H, q, J =
7.0Hz), 7.00 (2H, d, J = 8.6Hz), 7.48 (2H, s), 7.65 (2
H, d, J = 8.6Hz), 7.79 (2H, d, J = 9.6Hz)

Reference Example 100 7- (4-ethoxyphenyl) -2,3-dihydro-1
-Benzothiepin-4-carboxylic acid (510 mg)
It was dissolved in HF (15.3 ml), and thionyl chloride (0.11 ml) and DMF (one drop) were added under ice-cooling.
Stirred for hours. 4-[[N-methyl-N- (tetrahydropyranyl-4-yl) amino] methyl] aniline (3
89 mg), TH in triethylamine (0.87 ml)
The reaction solution was added dropwise to the F solution (15.3 ml), and
Stirred for hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) to give 7- (4-ethoxyphenyl) -N- [4-[[N-methyl -N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,
3-Dihydro-1-benzothiepine-4-carboxamide (512 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.44 (3H, t, J = 7.0 Hz), 1.6
3-1.86 (4H, m), 2.21 (3H, s), 2.67 (1H, m), 3.02-3.09
(2H, m), 3.24-3.44 (4H, m), 3.59 (2H, m), 4.00-4.10
(2H, m), 4.08 (2H, q, J = 7.0Hz), 6.93-7.00 (2H, m),
7.29-7.58 (10H, m), 7.79 (1H, s)

Reference Example 101 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
Methyl] phenyl] -2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) in THF
(15 ml), and a solution of metachloroperbenzoic acid (140 mg) in THF (15 ml) was added dropwise at -78 ° C. After stirring at -78 ° C for 30 minutes, the mixture was added to a saturated aqueous solution of sodium thiosulfate. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1 → 2/1, 1% triethylamine) to give 7- (4-ethoxyphenyl) -N- [4-
[[N-methyl-N-oxide- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,3-
Dihydro-1-benzothiepine-4-carboxamide (140 mg) was obtained. mp 122-126 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.44 (3H, t, J = 7.0 Hz), 1.
80-2.01 (4H, m), 3.25 (3H, s), 3.03-3.10 (2H, m), 3.2
1-3.40 (4H, m), 3.74 (1H, m), 3.98-4.10 (2H, m), 4.07
(2H, q, J = 7.0 Hz), 4.34 (2H, s), 6.96 (2H, d, J = 8.
6Hz), 7.29-7.55 (8H, m), 7.73 (2H, d, J = 8.6Hz), 8.8
7 (1H, s)

Example 83 (Production of compound 82) 7- (4-Ethylthiophenyl) -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxylic acid (260 mg) was dissolved in THF (5.2 ml), and thionyl chloride (0.06 ml) and DMF (one drop) were dissolved at room temperature.
Was added and stirred at room temperature for 1 hour. 4-[[N- (3-
The reaction solution was added dropwise to a THF solution (5.2 ml) of ethoxypropyl) -N-methylamino] methyl] aniline (0.58 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- (4-ethylthiophenyl) -N -[4-[[N- (3-ethoxypropyl)-
[N-methylamino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 82) (115 mg) was obtained. mp 176-179 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.20 (3 H, t, J = 7.0 Hz), 1.
37 (3H, t, J = 7.4 Hz), 1.58-1.78 (2H, m), 2.20 (3H,
s), 2.47 (3H, t, J = 7.4Hz), 3.02 (2H, q, J = 7.4H)
z), 3.13-3.21 (2H, m), 3.42-3.53 (2H, m), 3.69-3.76
(2H, m), 7.29-7.71 (11H, m), 7.97 (1H, s), 8.21 (1H,
d, J = 8.0Hz) IR (KBr) 3349, 2974, 1669, 1593, 1520, 1406, 1308,
. 1128, 816cm ^-1 elemental analysis _{C 32 H 38 N 2 O 4} S 2 Calcd C, 66.41; H, 6.62;
N, 4.84: Found.C, 66.55; H, 6.64; N, 4.94

Example 84 (Production of compound 83) 7- (4-Ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
[Methyl] phenyl] -2,3-dihydro-1-benzothiepine-4-carboxamide (199 mg) was dissolved in methylene chloride (6 ml), and meta-chloroperbenzoic acid (93 mg) was added at -30 ° C. After stirring for 30 minutes, the mixture was added to a saturated aqueous solution of sodium thiosulfate. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / methanol = 3/1 → 2 / 1,1).
% Triethylamine) and purified by 7- (4-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
-1-Oxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 83) (28 mg) was obtained. mp 192-195 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (3 H, t, J = 7.0 Hz), 1.
66-2.10 (4H, m), 2.26 (3H, s), 2.60-2.92 (3H, m), 3.1
0-3.21 (2H, m), 3.31-3.44 (2H, m), 3.65 (2H, s), 3.81
-3.95 (2H, m), 4.02-4.10 (2H, m), 4.08 (2H, q, J = 7.0
Hz), 6.95 (2H, d, J = 8.8Hz), 7.34 to 7.71 (9H, m), 7.95
(1H, d, J = 8.2Hz), 8.33 to 8.36 (1H, m) IR (KBr) 3247, 2944, 1659, 1607, 1518, 1248, 1020,
814cm ^-1

Reference Example 102 4-Bromophenol (10 g) was added to DMF (80 ml).
And potassium carbonate (16.0 g) was added at room temperature, and then 2-chloroethyl ethyl ether (8.3 m) was added.
l) and sodium iodide (9.53 g),
For 5 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with 1N sodium hydroxide and saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1).
1-Bromo-4- (2-ethoxyethoxy) benzene (10.7 g) was obtained. 1-Bromo-4- (2-ethoxyethoxy) benzene (10.3 g) was added to THF (100
ml), and 1.6M n-butyllithium / hexane (29.1 ml) was removed at -78 ° C and stirred for 1 hour. Trimethoxyborane (13.2 g) in THF (13
ml) The solution was added dropwise, and after stirring for 30 minutes, the temperature was naturally raised to room temperature. 10% sulfuric acid (50 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (2-ethoxyethoxy) phenyl boric acid (2.52 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.13 (3 H, t, J = 7.0 Hz),
3.50 (2H, q, J = 7.0Hz), 3.66-3.71 (2H, m), 4.06-4.11
(2H, m), 6.89 (2H, d, J = 8.4Hz), 7.14 (2H, d, J = 8.4H
z)

Example 85 (Preparation of compound 84) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo- Toluene / ethanol / water (10/1/1, 13.6 ml) was added to 2,3-dihydro-1-benzothiepine-4-carboxamide (350 mg).
Was added, 4- (2-ethoxyethoxy) phenyl boric acid (226 mg) and potassium carbonate (205 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (40 mg), and add 100 ° C.
For 9 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- [4- (2-ethoxyethoxy) phenyl ] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide ( Compound 84) (31
2 mg). mp 215-217 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (3 H, t, J = 7.0 Hz), 1.6
0-1.81 (4H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13-3.21
(2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.63 (2H,
q, J = 7.0 Hz), 3.67-3.75 (2H, m), 3.83 (2H, t, J = 5.0
Hz), 3.98-4.09 (2H, m), 4.19 (2H, t, J = 5.0Hz), 7.24
(2H, d, J = 8.8Hz), 7.30 (1H, s), 7.35 (1H, s), 7.51-
7.69 (6H, m), 7.81 (1H, s), 8.19 (1H, d, J = 8.4Hz) IR (KBr) 3243, 2948, 1655, 1607, 1520, 1412, 1294,
1254, 1130, 824cm- ¹ Elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S Calcd. C, 67.53; H, 6.67;
N, 4.63: Found.C, 67.55; H, 6.58; N, 4.71

Reference Example 103 4-Bromophenol (15 g) was added to DMF (120 m
l), potassium carbonate (21.6 g) was added at room temperature, and then 2-chloroethyl methyl sulfide (10 m
l) and sodium iodide (15.6 g),
For 16 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1-
Bromo-4- (2-methylthioethoxy) benzene (4.0 g) was obtained. 1-Bromo-4- (2-methylthioethoxy) benzene (3.9 g) was dissolved in THF (58 ml), and 1.6 M n-butyllithium / hexane (10 ml) was removed at -78 ° C. Stirred for hours. A solution of trimethoxyborane (4.6 g) in THF (9.3 ml) was added dropwise, and the mixture was stirred for 30 minutes.
0% sulfuric acid (20 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether,
-(2-methylthioethoxy) phenylboronic acid (1.3
9 g) were obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.25 (3 H, s), 2.93 (2 H, t,
J = 6.8Hz), 4.25 (2H, t, J = 6.8Hz), 7.01 (2H, d, J = 8.8H
z), 8.16 (2H, d, J = 8.8Hz)

Example 86 (Production of compound 85) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 14.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (360 mg), and 4- (2-methylthioethoxy) was added. ) After adding phenylboric acid (241 mg) and potassium carbonate (216 mg), the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (41 mg), and add 100 ° C.
For 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- [4- (2-methylthioethoxy) Phenyl] -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (compound 85)
(30 mg) was obtained. mp 222-224 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.66-1.76 (4H, m), 2.21 (3
H, s), 2.24 (3H, s), 2.65 (1H, m), 2.92 (2H, t, J = 6.6
Hz), 3.12-3.20 (2H, m), 3.37 (2H, m), 3.57 (2H, s),
3.68-3.75 (2H, m), 3.87-4.01 (2H, m), 4.22 (2H, t, J
= 6.6Hz), 7.02 (2H, d, J = 8.8Hz), 7.30-7.35 (2H,
m), 7.51-7.67 (7H, m), 7.97 (1H, s), 8.18 (1H, d, J =
8.0Hz) IR (KBr) 3291, 2959, 1655, 1603, 1520, 1412, 1294,
1252, 1130, 824cm ^-1

Reference Example 104 4-Bromophenol (51.0 g) was added to DMF (255).
ml) and potassium carbonate (81.5 g) at room temperature
After addition of chloromethyl methyl ether (44.8 m
l) was added dropwise and stirred for 2 hours. Add the reaction solution to water,
Extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1-bromo-
4- (Methoxymethoxy) benzene (61.4 g) was obtained. 1-Bromo-4- (methoxymethoxy) benzene (30 g) was dissolved in ether (240 ml), and -78 was added.
1.6 M n-butyllithium / hexane at 90 ° C (90.
7 ml) was removed and stirred for 1 hour. A solution of trimethoxyborane (43.1 g) in THF (43 ml) was added dropwise,
After stirring for 30 minutes, the temperature was naturally raised to room temperature, and water (150 m
l) was added and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, the solvent was removed under reduced pressure, and the obtained residue was stirred in methanol / water (2/1, 1000 ml) for 3 days.
The methanol was removed under reduced pressure, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (methoxymethoxy) phenyl boric acid (2.4 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ3.51 (3H, s), 5.26 (2H,
s), 7.14 (2H, d, J = 8.4Hz), 8.15 (2H, d, J = 8.4Hz)

Example 87 (Preparation of Compound 86) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg), and 4- (methoxymethoxy) phenyl was added. Boric acid (262
mg) and potassium carbonate (292 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (56 mg) was added, and the mixture was stirred at 100 ° C for 9 hours. After cooling to room temperature, the mixture was added to water, and ethyl acetate /
The mixture was extracted with THF, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethyl acetate).
(Ethanol = 3/1) and purified by 7- (4-methoxymethoxyphenyl) -N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 86)
(340 mg). mp 227-229 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.63-1.76 (4H, m), 2.21 (3
H, s), 2.66 (1H, m), 3.12-3.20 (2H, m), 3.31-3.43 (2
H, m), 3.51 (3H, s), 3.58 (2H, s), 3.68-3.76 (2H,
m), 4.00-4.09 (2H, m), 5.24 (2H, s), 7.16 (2H, d, J =
8.8Hz), 7.30-7.36 (2H, m), 7.51-7.68 (7H, m), 8.01 (1
H, s), 8.19 (1H, d, J = 8.2Hz) IR (KBr) 3260, 2953, 1655, 1601, 1518, 1410, 1315,
1294, 1238, 1130, 997, 826cm ^-1

Reference Example 105 4-bromophenol (13 g) was added to toluene (104 m
l) and dissolved in ice-cooled 65% sodium hydride (6.0%).
After adding g), the mixture was stirred at room temperature for 30 minutes. Under ice cooling 2-
Chloroethyl-N, N-dimethylammonium chloride (14.1 g) was added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate.
After washing with 1N sodium hydroxide and saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give N- [2- (4
-Bromophenoxy) -N, N-dimethylamine (1
1.3 g) were obtained. N- [2- (4-bromophenoxy) -N, N-dimethylamine (11.2 g) was added to THF.
(100 ml), and 1.6 M n-butyllithium / hexane (31.5 ml) was removed at -78 ° C and stirred for 1 hour. TH of trimethoxyborane (14.3 g)
A solution of F (10 ml) was added dropwise, and the mixture was stirred for 30 minutes, then allowed to warm to room temperature, water (56 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- [2- (dimethylamino) ethoxy] phenyl boric acid (1.5 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.43 (6 H, s), 2.89 (2 H,
m), 4.20 (2H, m), 6.88 (2H, d, J = 8.2z), 8.09 (2H, d,
J = 7.2Hz)

Example 88 (Preparation of Compound 87) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg), and 4-[(2-dimethyl After adding (amino) ethoxy] phenylboric acid (321 mg) and potassium carbonate (292 mg), the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (56 mg) and add 1
The mixture was stirred at 00 ° C for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1).
After recrystallization from ethanol, 7- [4- (2-dimethylamino) ethoxyphenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 87) (190 mg) was obtained. mp 227-229 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.62-1.87 (4H, m), 2.21 (3
H, s), 2.37 (6H, s), 2.65 (1H, m), 2.78 (2H, t, J = 5.8
Hz), 3.11-3.20 (2H, m), 3.32-3.44 (2H, m), 3.58 (2H, m
s), 3.68-3.76 (2H, m), 4.00-4.10 (2H, m), 4.13 (2H, m
t, J = 5.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.30-7.35 (2
H, m), 7.51-7.69 (7H, m), 7.96 (1H, s), 8.19 (1H, d,
J = 8.4Hz) IR (KBr) 3245, 2946, 1655, 1607, 1520, 1412, 1318,
1294, 1254, 1130, 824cm ^-1

Reference Example 106 4-Bromophenol (12 g) was dissolved in 4-methyl-2-pentanone (96 ml), and potassium carbonate (24 g) and 4- [2- (chloroethyl)] morpholine hydrochloride (at room temperature). After adding 16.9 g), the mixture was heated under reflux for 18 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was collected by filtration to obtain 4- [2- (4-bromophenoxy) ethyl] morpholine (16.9 g). 4- [2- (4-bromophenoxy) ethyl] morpholine (16.5 g) was added to T
Dissolved in HF (100 ml) and 1.6M n-
Butyl lithium / hexane (31.5 ml) was removed,
Stir for 1 hour. A solution of trimethoxyborane (14.3 g) in THF (10 ml) was added dropwise, and the mixture was stirred for 30 minutes.
The temperature was naturally raised to room temperature, water (56 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was washed with hexane / isopropyl ether, and 4- [2- (4-morpholino) ethoxy] was obtained.
Phenyl boric acid (1.5 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.38-2.62 (4H, m), 3.56-
3.65 (6H, m), 4.10 (2H, t, J = 6.2Hz), 6.93 (2H, d, J =
9.2Hz), 7.24-7.32 (2H, m)

Example 89 (Preparation of compound 88) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg), and 4- [2- (4 After adding (morpholino) ethoxy] phenylboric acid (386 mg) and potassium carbonate (292 mg), the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (56 mg) and add 1
The mixture was stirred at 00 ° C for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1).
After recrystallization from ethanol, N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4- [2- (4-morpholino)
[Ethoxy] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 88) (190 mg) was obtained. mp 203-206 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.63-1.84 (4H, m), 2.23 (3
H, s), 2.60 (4H, t, J = 4.8 Hz), 2.71 (1H, m), 2.84 (2
H, t, J = 5.6Hz), 3.16-3.19 (2H, m), 3.29-3.41 (2H,
m), 3.62 (2H, s), 3.66-3.77 (6H, m), 3.98-4.19 (2H,
m), 4.17 (2H, t, J = 5.6Hz), 7.01 (2H, d, J = 8.8Hz),
7.32-7.41 (3H, m), 7.50-7.66 (7H, m), 8.14-8.19 (2H, m
m) IR (KBr) 3293, 2951, 1667, 1607, 1518, 1408, 1292,
1250, 1130, 826cm- ¹ Elemental analysis C ₃₆ H ₄₃ N ₃ O ₆ S Calcd. C, 66.95; H, 6.71;
N, 6.51: Found.C, 66.08; H, 6.71; N, 6.54

Example 90 (Production of compound 89) 7- (4-Methoxymethoxyphenyl) -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (650 mg) was added to THF / acetone (1 / 1,6).
0 ml), and 1N sulfuric acid (4.4 ml) was added.
The mixture was stirred at 5 ° C for 14 hours. After cooling to room temperature, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, the solvent was removed under reduced pressure, and the obtained residue was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was recrystallized with ethanol.
(4-hydroxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino]
[Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 89) (530 mg). mp 232-234 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.49-1.75 (4H, m), 2.11
(3H, s), 2.59 (1H, m), 3.03-3.11 (2H, m), 3.20-3.33
(2H, m), 3.53 (2H, s), 3.73-3.83 (2H, m), 3.86-3.98
(2H, m), 6.90 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz)
Hz), 7.52 (1H, s), 7.63-7.69 (4H, m), 7.82 (1H, d, J
= 10.4Hz), 8.05 (2H, d, J = 8.0Hz), 10.17 (1H, s) IR (KBr) 3223, 1655, 1599, 1524, 1410, 1318, 1128,
826cm ^-1

Example 91 (Production of compound 90) 7- (4-Hydroxyphenyl) -N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (320 mg) was dissolved in DMF (4.8 ml), potassium carbonate (96 mg) was added, and the mixture was stirred at room temperature for 30 minutes. t-Butyl bromoacetate (0.093 ml) was added, and the mixture was stirred at room temperature for 4 hours. It was added to water and extracted with ethyl acetate / THF. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- [4- (t-butoxycarbonylmethoxy). ) Phenyl] -N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 90)
(274 mg) was obtained. mp 209-211 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.51 (9 H, s), 1.64-2.05 (4
H, m), 2.23 (3H, s), 2.66 (1H, m), 3.12-3.23 (2H,
m), 3.27-3.44 (2H, m), 3.58 (2H, s), 3.65-3.76 (2H,
m), 3.99-4.12 (2H, m), 4.58 (2H, s), 7.00 (2H, d, J =
8.8Hz), 7.29 (1H, s), 7.35 (2H, d, J = 8.8Hz), 7.50-
7.68 (6H, m), 8.18 (1H, d, J = 8.0 Hz), 8.47 (1H, s) IR (KBr) 3241, 2949, 1752, 1655, 1601, 1522, 1410,
1292, 1130, 831cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₇ S Calcd. C, 66.22; H, 6.67;
N, 4.41: Found.C, 66.27; H, 6.59; N, 4.36

Example 92 (Production of compound 91) 7- [4- (t-Butoxycarbonylmethoxy) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] Methyl] phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (160 mg) was dissolved in methylene chloride (6.4 ml), and trifluoroacetic acid (6.4 m) was dissolved.
l) was added and the mixture was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure, the resulting residue was dissolved in ethanol / water, neutralized with saturated aqueous sodium hydrogen carbonate, and 1N hydrochloric acid was added, and the precipitate was collected by filtration. After washing with water and a small amount of ethanol,
-[4-[[4-[[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] anilino] carbonyl] -1,1-dioxo-2,3-dihydro-1-
Benzothiepin-7-yl] phenoxy] acetic acid.hydrochloride (Compound 91) (70 mg) was obtained. mp 172-175 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.67-2.12 (4H, m), 2.23
(4H, s), 3.03-3.13 (2H, m), 3.20-3.55 (4H, m), 3.74-
3.85 (2H, m), 3.95-4.07 (2H, m), 4.77 (2H, s), 7.07 (2H
H, d, J = 8.6 Hz), 7.54 (d, J = 8.6 Hz), 7.58 (1H, s),
7.73-7.92 (5H, m), 8.05-8.12 (2H, m) IR (KBr) 1671,1593,1518,1414,1289,1128,816cm
^-1

Reference Example 107 4-Bromobenzonitrile (25.1 g) was added to THF (3
00 ml), and 1.6 M n-butyllithium / hexane (94.8 ml) was removed at -100 ° C.
For a minute. Trimethoxyborane (26.5 g) was added dropwise, and the temperature was raised to room temperature over 6 hours. 15% hydrochloric acid (50
ml) and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed twice with water, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether,
4- (Cyanophenyl) boric acid (12.5 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ7.77 (2H, d, J = 7.8 Hz),
7.94 (2H, d, J = 8.4Hz), 8.40 (2H, br)

Example 93 (Preparation of compound 92) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/5/2, 21.6 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg), and 4-cyanophenylboric acid (147 mg) was added. ) And potassium carbonate (147 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (46 mg) was added, and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 3/1).
And recrystallized from ethanol to give 7- (4-cyanophenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1 , 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 92) (90
mg). mp 233-236 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.60-1.83 (4H, m), 2.21 (3
H, s), 2.66 (1H, m), 3.15-3.22 (2H, m), 3.32-3.42 (2
H, m), 3.58 (2H, s), 3.70-3.78 (2H, m), 7.30-7.37 (4
H, m), 7.55 (2H, d, J = 8.4 Hz), 7.68-7.83 (5H, m), 7.
95 (1H, s), 8.29 (1H, d, J = 8.0 Hz) IR (KBr) 3245, 2951, 2228, 1665, 1597, 1526, 140
8, 1314, 1294, 1132, 828, 733cm ^-1

Reference Example 108 5-Bromosalicylaldehyde (18.6 g) was added to DMF.
(150 ml), and potassium carbonate (1
After adding 6.6 g), iodoethane (17.3 ml) was added.
Was added and stirred at 90 ° C. for 3 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 5-bromo-2-ethoxybenzaldehyde (1
7.2 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.48 (3 H, t, J = 7.2 Hz),
3.13-3.20 (2H, m), 4.14 (2H, q, J = 7.0Hz), 6.87 (1H, m
d, J = 8.8 Hz), 7.60 (1H, d, J = 8.8, 2.6 Hz), 7.91 (1
H, d, J = 2.6 Hz), 10.41 (1H, s)

Reference Example 109 5-Bromo-2-ethoxybenzaldehyde (17.1)
g) was dissolved in formic acid (85.5 ml), hydroxylamine hydrochloride (7.8 g) was added, and the mixture was heated under reflux for 7 hours.
After cooling to room temperature, the solvent was removed under reduced pressure, and the obtained residue was washed with water and dried to obtain 5-bromo-2-ethoxybenzonitrile (15.8 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.48 (3H, t, J = 7.0 Hz), 4.
14 (2H, q, J = 7.0Hz), 6.85 (1H, d, J = 8.8Hz), 7.57-
7.66 (2H, m) IR (KBr) 2984, 2230, 1591, 1489, 1393, 1314, 1284,
1134, 1038, 810cm ^-1

Reference Example 110 5-bromo-2-ethoxybenzonitrile (15.8)
g) in THF (180 ml) and
1.6 M n-butyllithium / hexane (48 ml) was removed and stirred for 30 minutes. Trimethoxyborane (14.
After stirring for 20 minutes, the temperature was raised to room temperature over 5 hours, 4N hydrochloric acid (50 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed twice with water, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to give 3-cyano-
4-Ethoxyphenyl boric acid (6.0 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.38 (3 H, t, J = 7.0 Hz),
4.22 (2H, q, J = 7.0Hz), 7.20 (1H, d, J = 9.2Hz), 8.00
-8.05 (1H, m), 8.18 (1H, s)

Example 94 (Production of compound 93) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) to give 3-cyano-4-ethoxy. Phenyl boric acid (205
mg) and potassium carbonate (251 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (48 mg) was added, and the mixture was heated under reflux for 18 hours. After cooling to room temperature, the mixture was added to water, and ethyl acetate / THF was added.
, Washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- (4-cyano-3-ethoxyphenyl). -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (209 mg). mp 244-247 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.41 (3 H, t, J = 7.0 Hz),
1.45-1.73 (4H, m), 2.10 (3H, s), 2.59 (1H, m), 3.05-
3.12 (2H, m), 3.21-3.30 (2H, m), 3.52 (2H, s), 3.74-
3.84 (2H, m), 3.84-3.94 (2H, m), 4.28 (2H, q, J = 7.0
Hz), 7.26 (2H, d, J = 8.4Hz), 7.39 (2H, d, J = 9.2H
z), 7.53 (1H, s), 7.67 (2H, d, J = 8.4Hz), 7.92-7.97
(2H, m), 8.06-8.25 (3H, m)

Reference Example 111 5-Bromosalicylaldehyde (20 g) was added to DMF (1
60 ml) and potassium carbonate (17.9) at room temperature.
g), followed by 1-bromopropane (10.8 ml)
Was added and stirred at 90 ° C. for 3 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain 5-bromo-2-propoxybenzaldehyde (21.9 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.07 (3 H, t, J = 7.4 Hz), 1.
80-1.95 (2H, m), 4.03 (2H, t, J = 6.4Hz), 6.88 (1H,
d, J = 9.0Hz), 7.60 (1H, dd, J = 8.8, 2.6Hz), 7.91 (1
H, d, J = 2.6 Hz), 10.43 (1H, s)

Reference Example 112 5-Bromo-2-propoxybenzaldehyde (21.
8 g) was dissolved in formic acid (110 ml), hydroxylamine hydrochloride (9.4 g) was added, and the mixture was heated under reflux for 7 hours.
After cooling to room temperature, the solvent was removed under reduced pressure.
In addition to N potassium hydroxide, the mixture was extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 8/1).
To obtain 5-bromo-2-propoxybenzonitrile (15.8 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ1-07 (3H, t, J = 7.4 Hz), 1.
80-1.95 (2H, m), 4.02 (2H, t, J = 6.4Hz), 6.85 (1H,
d, J = 8.8Hz), 7.57-7.65 (2H, m) IR (KBr) 2969, 2230, 1591, 1489, 1391, 1285, 1132,
972, 812cm ^-1

Reference Example 113 5-bromo-2-propoxybenzonitrile (15.3)
g) in THF (180 ml) and
1.6 M n-butyllithium / hexane (44 ml) was removed. Trimethoxyborane (13.2 g) was added dropwise, and after stirring for 20 minutes, the temperature was raised to room temperature over 5 hours,
4N hydrochloric acid (50 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 3-cyano-4-propoxyphenyl boric acid (7.0 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.01 (3 H, t, J = 7.4 Hz),
1.70-1.85 (2H, m), 4.11 (2H, t, J = 6.4Hz), 7.21 (1H,
d, J = 9.2Hz), 8.01-8.06 (2H, m), 8.19 (2H, br)

Example 95 (Production of compound 94) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 13.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) to give 3-cyano-4-propoxy. Phenyl boric acid (20
After adding 5 mg) and potassium carbonate (234 mg), the mixture was stirred at room temperature for 30 minutes. Palladium acetate (8.6m
g), tris (2-methylphenyl) phosphine (2
(2.4 mg) and heated under reflux for 18 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 3 /
Purified in 1) and recrystallized in ethanol, 7- (4-
Cyano-3-propoxyphenyl) -N- [4-[[N
-Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 94) (243 mg) was obtained. mp 201-203 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.11 (3 H, t, J = 7.4 Hz), 1.
65-1.78 (4H, m), 1.86-2.00 (2H, m), 2.21 (3H, s), 2.6
5 (1H, m), 3.14-3.22 (2H, m), 3.30-3.44 (2H, m), 3.57
(2H, s), 3.69-3-77 (2H, m), 4.00-4.10 (2H, m), 4.11
(2H, t, J = 6.6Hz), 7.08 (1H, d, J = 9.0Hz), 7.30-7.3
7 (3H, m), 7.53-7.63 (4H, m), 7.71-7.77 (2H, m), 8.03
(1H, s), 8.22 (1H, d, J = 8.4Hz) IR (KBr) 3301, 2944, 2228, 1667, 1607, 1510, 1408,
1314, 1291, 1128, 819, 735cm- ¹ Elemental analysis C ₃₄ H ₃₇ N ₃ O ₅ S Calcd. C, 68.09; H, 6.22;
N, 7.01: Found.C, 67.83; H, 6.20; N, 6.89

Example 96 (Production of compound 95) 7- (4-Hydroxyphenyl) -N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (131 mg) was dissolved in DMF (1.6 ml), potassium carbonate (41 mg) was added, and after stirring for 50 minutes, iodoacetamide (50 mg) was added, and the mixture was added at room temperature for 20 hours. Stirred. The reaction solution was added to water, extracted with ethyl acetate / THF, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol.
7- (4-carbamoylmethoxyphenyl) -N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 95) (52 mg) was obtained. mp 240-243 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.45-1.78 (4H, m), 2.21
(3H, s), 2.60 (1H, m), 3.01-3.13 (2H, m), 3.21-3.35
(2H, m), 3.53 (2H, s), 3.74-3.80 (2H, m), 3.86-3.9
5 (2H, m), 4.51 (2H, m), 7.10 (2H, d, J = 8.8Hz), 7.27
(2H, d, J = 8.8Hz), 7.40-7.93 (8H, m), 8.05 (1H, s),
8.22 (1H, d, J = 8.4Hz) IR (KBr) 3320, 2951, 1669, 1597, 1518, 1408, 1291,
1130, 816cm ^-1

Reference Example 114 Morpholine (9.0 g) was dissolved in DMF (108 ml), and triethylamine (24 ml) and 4-bromobenzyl bromide (21.5 g) were added at room temperature.
Stirred at C for 16 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 4-
(4-Bromobenzyl) morpholine (17.2 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.38-2.45 (4H, m), 3.44 (2
H, s), 3.67-3.73 (4H, m), 7.21 (2H, d, J = 8.4Hz), 7.
44 (2H, d, J = 8.4Hz)

Reference Example 115 4- (4-bromobenzyl) morpholine (19.3 g)
Was dissolved in THF (174 ml) and the solution was dissolved in 1.6 M at -78 ° C.
n-Butyl lithium / hexane (52 ml) was removed,
Stir for 30 minutes. A THF solution (22 ml) of trimethoxyborane (21.8 g) was added dropwise, and the mixture was stirred for 30 minutes.
The temperature was raised naturally to room temperature. Water (73 ml) was added and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (4-morpholinomethyl) phenyl boric acid (5.7 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ2.36-2.59 (4H, m), 3.48-3.
81 (6H, m), 7.25-7.44 (2H, m), 7.93-8.10 (2H, m)

Example 97 (Preparation of Compound 96) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 18 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (560 mg),
4- (4-morpholinomethyl) phenyl boric acid (285
mg) and potassium carbonate (327 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (62.2 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol.
-[4-[[N-methyl-N- (tetrahydropyran-
4-yl) amino] methyl] phenyl] -7- [4-
(4-morpholinomethyl) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 96) (377 mg) was obtained. mp 211-213 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.65-1.82 (4H, m), 2.21 (3
H, s), 2.45-2.51 (2H, m), 2.65 (1H, m), 3.13-3.21 (2
H, m), 3.31-3.45 (2H, m), 3.56 (2H, s), 3.58 (2H,
s), 3.71-3.77 (2H, m), 3.98-4.10 (2H, m), 7.30-7.37
(3H, m), 7.43-7.59 (6H, m), 7.66-7.74 (2H, m), 7.91
(1H, s), 8.22 (1H, d, J = 8.2Hz) IR (KBr) 3254, 2948, 1667, 1597, 1514, 1408, 1314,
1294, 1130, 866, 735cm- ¹ Elemental analysis C ₃₅ H ₄₁ N ₃ O ₅ S Calcd. C, 68.27; H, 6.71;
N, 6.82: Found.C, 68.10; H, 6.74; N, 6.75

Reference Example 116 7-bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (5.0 g) in toluene / ethanol / water (10/1 / 1,188 m
l), 4- (2-ethoxyethoxy) phenylboronic acid (4.1 g) and potassium carbonate (4.6 g) were added, and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (0.7 g) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 7- [4- (2-ethoxyethoxy) phenyl] -1,1-dioxo. Methyl 2,3-dihydro-1-benzothiepine-4-carboxylate (4.6 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (3 H, t, J = 7.0 Hz), 3.
10-3.18 (2H, m), 3.58-3.87 (2H, m), 3.66 (2H, q, J =
7.0Hz), 3.87 (3H, s), 4.16-4.22 (2H, m), 7.04 (2H, d
d, J = 6.6, 1.8 Hz), 7.55 (2H, dd, J = 6.6, 1.8 Hz), 7.
64-7.70 (2H, m), 7.91 (1H, s), 8.19 (1H, d, J = 8.8H
z) IR (KBr) 2920, 1709, 1604, 1518, 1294, 1252, 1130,
828, 752m- ¹ Elemental analysis C ₂₂ H ₂₄ O ₆ S Calcd. C, 63.44; H, 5.81: Fo
und. C, 63.27; H, 5.74

Reference Example 117 7- [4- (2-ethoxyethoxy) phenyl] -1,
Methyl 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4.35 g) in 1,2-dimethoxyethane (87 ml), 6N hydrochloric acid (43.5 ml)
Was added and heated at 100 ° C. for 16 hours under reflux. It was cooled to room temperature and extracted with ethyl acetate. After washing with saturated saline,
It was dried over magnesium sulfate. Remove the solvent under reduced pressure,
7- [4- (2-ethoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.7 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.44 (3H, t, J = 7.0 Hz),
2.91-3.04 (2H, m), 3.52 (2H, q, J = 7.0Hz), 3.70-3.77
(4H, m), 4.13-4.19 (2H, m), 7.09 (2H, d, J = 8.8Hz),
7.78 (2H, d, J = 8.8 Hz), 7.85 to 7.92 (2H, m), 8.03 (1H,
s), 8.18 (1H, s) IR (KBr) 2978, 1684, 1606, 1518, 1412, 1292, 1252,
1165, 1128, 829cm ^-1 Elemental analysis C ₂₁ H ₂₂ O ₆ S Calcd. C, 62.67; H, 5.51: Fo
und. C, 62.75; H, 5.60

Example 98 (Preparation of Compound 84) 7- [4- (2-Ethoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.6 g) was dissolved in THF (72 ml), and thionyl chloride (0.93 ml), DM under ice cooling.
F (three drops) was added, and the mixture was stirred at room temperature for 30 minutes. 4-
The reaction solution was added dropwise to a solution of [[N-methyl-N- (tetrahydropyranyl-4-yl) amino] methyl] aniline (2.23 g) and triethylamine (5.0 ml) in THF (67 ml), and the mixture was stirred at room temperature. Stir for 1 hour. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- [4- (2-ethoxyethoxy) phenyl ] -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (compound 84)
(2.4 g) was obtained. mp 215-217 ° C elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S Calcd. C, 67.53; H, 6.67;
N, 4.63: Found.C, 67.24; H, 6.62; N, 4.34

Reference Example 118 4-bromophenol (20 g) was added to DMF (120 m
l), potassium carbonate (24 g) and sodium iodide (19.1 g) were added, and then 2-chloroethylpropyl ether (19 ml) was added dropwise, followed by stirring at 80 ° C for 16 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1-bromo-4-.
(2-Propoxyethoxy) benzene (23.1 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3 H, t, J = 7.2 Hz), 1.5
5-1.71 (2H, m), 3.48 (2H, t, J = 6.8Hz), 3.74-3.79 (2
H, m), 4.05-4.10 (2H, m), 6.77-6.83 (2H, m), 7.33-7.
38 (2H, m)

Reference Example 119 To a solution of magnesium (2.17 g) in THF (43 ml) was added 1,2-dibromoethane (3 drops), and the mixture was heated under reflux to obtain 1-bromo-4- (2-propoxyethoxy) benzene. (22 g) in THF (176 ml) was slowly added dropwise. After stirring for 15 minutes, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (13.2 g) in THF (13 ml) was added dropwise, and after stirring for 1 hour, the temperature was raised to room temperature over 6 hours. After stirring at room temperature for 8 hours, 5% sulfuric acid (75 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether and hexane / ethyl acetate in this order to obtain 4- (2-propoxyethoxy) phenyl boric acid (8.6 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.87 (3 H, t, J = 7.4 Hz),
1.44-1.62 (2H, m), 3.41 (2H, t, J = 6.6Hz), 3.67-3.72
(2H, m), 4.07-4.12 (2H, m), 6.89 (2H, d, J = 8.8Hz),
7.73 (2H, d, J = 8.8Hz)

Example 99 (Preparation of compound 97) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg), and 4- (2-propoxyethoxy) was added. ) After adding phenylboric acid (207 mg) and potassium carbonate (234 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (36 mg) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethyl acetate).
Purified with ethanol = 3/1), recrystallized from ethanol, and N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7
-[4- (2-propoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 97) (218 mg) was obtained. mp 195-197 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3 H, t, J = 7.2 Hz), 1.
60-1.80 (6H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13-3.2
0 (2H, m), 3.31-3.44 (2H, m), 3.52 (2H, t, J = 6.8H
z), 3.57 (2H, s), 3.68-3.75 (2H, m), 3.82 (2H, t, J =
4.8Hz), 4.10-4.20 (2H, m), 4.19 (2H, t, J = 4.8Hz),
7.04 (2H, d, J = 8.8Hz), 7.30-7.35 (3H, m), 7.51-7.68
(6H, m), 7.83 (1H, s), 8.19 (1H, d, J = 8.0Hz) IR (KBr) 3270, 2942, 1665, 1607, 1518, 1311, 1292,
1252, 1130, 826, 667cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.87; H, 6.98; N, 4.45

Reference Example 120 4-Bromophenol (25 g) was added to DMF (150 m
l), and potassium carbonate (30 g) was added.
-Bromoethanol (23.5 g) was added dropwise at 90 ° C.
For 6 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 2- (4-bromophenoxy) -1-ethanol (15.9 g). Was. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.24 (1 H, br), 3.91 to 3.91 (2
H, m), 4.02-4.07 (2H, m), 6.77-6.83 (2H, m), 7.33-7.
38 (2H, m)

Reference Example 121 2- (4-bromophenoxy) -1-ethanol (1
5.7 g) was dissolved in DMF (150 ml), 65% sodium hydride (4.3 g) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. Iodobutane (17.3 g) was added dropwise, and after stirring for 2 hours, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-bromo-4- (2-butoxyethoxy) benzene (12.6 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.4 Hz), 1.2
7-1.65 (4H, m), 3.53 (2H, t, J = 6.6Hz), 3.74-3.79 (2
H, m), 4.05-4.11 (2H, m), 6.81 (2H, d, J = 9.0Hz), 7.
36 (2H, d, J = 9.0Hz)

Reference Example 122 1,2-Dibromoethane (3 drops) was added to a solution of magnesium (1.14 g) in THF (23 ml), and the mixture was heated under reflux with 1-bromo-4- (2-butoxyethoxy) benzene. (12.2 g) in THF (98 ml) was slowly added dropwise. After stirring for 15 minutes, the mixture was cooled to −78 ° C., and trimethoxyborane (6.9 g) was added dropwise.
The temperature was raised to room temperature over time. After stirring at room temperature for 6 hours,
5% sulfuric acid (75 ml) was added and stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether and hexane / ethyl acetate in this order to obtain 4- (2-butoxyethoxy) phenylboronic acid (6.0 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.2 Hz),
1.25-1.58 (2H, m), 3.45 (2H, t, J = 6.6Hz), 3.64-3.76
(2H, m), 4.03-4.16 (2H, m), 6.87-6.96 (2H, m), 7.14
(1H, d, J = 8.4Hz), 7.81 (1H, d, J = 8.4Hz)

Example 100 (Preparation of Compound 98) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg), and 4- (2-butoxyethoxy) was added. ) Phenyl boric acid (2
21 mg) and potassium carbonate (234 mg),
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (36 mg) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol).
= 3/1) and recrystallized from ethanol to give 7
-[4- (2-butoxyethoxy) phenyl] -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 98) (330 mg). mp 194-196 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3 H, t, J = 7.2 Hz), 1.
33-1.55 (2H, m), 1.57-1.77 (6H, m), 2.21 (3H, s), 2.6
5 (1H, m), 3.16 (2H, t, J = 6.4Hz), 3.31-3.44 (2H,
m), 3.52-3.59 (2H, m), 3.57 (2H, s), 3.67-3.74 (2H,
m), 3.79-3.84 (2H, m), 3.98-4.08 (2H, m), 4.18 (2H,
t, J = 4.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.30-7.35 (3
H, m), 7.50-7.66 (6H, m), 7.88 (1H, s), 8.18 (1H, d,
J = 8.0Hz) IR (KBr) 3300, 2935, 2853, 1667, 1607, 1518, 1312,
1292, 1251, 1130, 826cm- ¹ Elemental analysis C ₃₆ H ₄₄ N ₂ O ₆ S Calcd. C, 68.33; H, 7.01;
N, 4.43: Found.C, 68.33; H, 6.85; N, 4.39

Reference Example 123 3-ethoxypropanol (10 g) was added to THF (100
ml), and triethylamine (14.
5 ml), methanesulfonyl chloride (6.8 ml)
Was added and stirred at room temperature for 2 hours. The reaction solution was added to water, extracted with THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was stirred under ice-cooling with 4-bromophenol (20.8
g), potassium carbonate (18.2 g) in DMF (130 m
l) The solution was added dropwise and stirred at 90 ° C for 60 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 10).
/ 1) to give 1-bromo-4- (3-ethoxypropoxy) benzene (10.8 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.20 (3 H, t, J = 7.0 Hz), 1.9
8-2.08 (2H, m), 3.49 (2H, q, J = 7.0Hz), 3.58 (2H, d, J
= 6.0Hz), 4.03 (2H, d, J = 6.4Hz), 6.79 (2H, d, J = 9.
0Hz), 7.36 (2H, d, J = 9.0Hz)

Reference Example 124 1,2-Dibromoethane (3 drops) was added to a solution of magnesium (1.03 g) in THF (21 ml), and 1-bromo-4- (3-ethoxypropoxy) benzene was added under reflux with heating. (10.5 g) in THF (84 ml) was slowly added dropwise. After stirring for 15 minutes, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (6.3 g) in THF (6 ml) was added dropwise, and after stirring for 1 hour, the temperature was raised to room temperature over 6 hours. After stirring at room temperature for 8 hours, 5% sulfuric acid (42 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (3-ethoxypropoxy) phenyl boric acid (5.94 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.11 (3 H, t, J = 7.0 Hz),
1.89-1.98 (2H, m), 3.42 (2H, q, J = 7.0Hz), 3.50 (2H, m
t, J = 6.2 Hz), 4.02 (2H, t, J = 6.2 Hz), 6.84-6.93 (2
H, m), 7.69-7.81 (2H, m)

Example 101 (Preparation of compound 99) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg), and 4- (3-ethoxypropoxy) was added. ) After adding phenylboric acid (207 mg) and potassium carbonate (234 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (36 mg) was added, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and treated with 7- [4- (3-ethoxypropoxy) phenyl. ]
-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (Compound 99) (140 mg) was obtained. mp 214-215 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.21 (3 H, t, J = 7.0 Hz), 1.
69-1.77 (4H, m), 2.05-2.13 (2H, m), 2.21 (3H, s), 2.6
5 (1H, m), 3.16 (2H, t, J = 6.6Hz), 3.31-3.44 (2H,
m), 3.51 (2H, q, J = 7.0 Hz), 3.57 (2H, s), 3.62 (2H,
t, J = 6.2Hz), 3.67-3.75 (2H, m), 3.98-4.16 (4H, m),
7.01 (2H, d, J = 8.8Hz), 7.29-7.35 (3H, m), 7.50-7.67
(6H, m), 7.86 (1H, s), 8.18 (1H, d, J = 8.0Hz) IR (KBr) 3274, 2953, 1665, 1601, 1520, 1316, 1292,
1250, 1130, 824cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.67; H, 6.77; N, 4.54

Reference Example 125 4-Bromobenzyl alcohol (10.1 g) was added to DMF
(65 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
Iodoethane (12.6 g) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to obtain 1-bromo-4- (ethoxymethyl) benzene (10.1 g). . ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.24 (3 H, t, J = 7.0 Hz), 2.5
3 (2H, q, J = 7.0 Hz), 4.45 (2H, s), 7.22 (2H, d, J = 8.
6Hz), 7.46 (2H, d, J = 8.6Hz)

Reference Example 126 1-bromo-4- (ethoxymethyl) benzene (9.8
g) was dissolved in THF / ether (4/1, 100 ml), 1.6 M n-butyllithium / hexane (31.3 ml) was removed at -78 ° C, and the mixture was stirred for 1 hour. Trimethoxyborane (11.8 g) was added dropwise, and the mixture was stirred for 30 minutes, then allowed to warm to room temperature, 5% sulfuric acid (39 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (ethoxymethyl) phenylboronic acid (3.05 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.15 (3 H, t, J = 7.0 Hz),
3.48 (2H, q, J = 7.0 Hz), 4.45 (2H, s), 7.27 (2H, d, J =
8.0Hz), 7.76 (2H, d, J = 8.0Hz)

Example 102 (Production of compound 100) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 4- (ethoxymethyl) phenyl was added. Boric acid (125m
g) and potassium carbonate (175 mg) were added, followed by stirring at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (26.6 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol).
= 3/1) and recrystallized from ethanol to give 7-
[4- (ethoxymethyl) phenyl] -N- [4-
[[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 100) (245 mg) was obtained. mp 221-224 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.28 (3 H, t, J = 7.0 Hz), 1.
65-1.77 (4H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13-3.2
1 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.60 (2H,
q, J = 7.0Hz), 4.00-4.09 (2H, m), 4.57 (2H, s), 7.29-
7.37 (3H, m), 7.44-7.68 (8H, m), 7.88 (1H, s), 8.19 (1
H, d, J = 8.0Hz) IR (KBr) 3274, 2949, 1655, 1526, 1410, 1315, 1294,
1130, 814cm- ¹ elemental analysis C ₃₃ H ₃₈ N ₂ O ₅ S Calcd. C, 68.96; H, 6.66;
N, 4.87: Found.C, 68.72; H, 6.65; N, 4.86

Reference Example 127 4-Bromobenzyl alcohol (15 g) was added to DMF (1
20 ml), 65% sodium hydride (3.0 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. 2-bromoethyl ethyl ether (11.4 g) at room temperature
Was added dropwise and stirred at room temperature for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline,
It was dried over magnesium sulfate. Remove the solvent under reduced pressure,
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1-
Bromo-4-[(2-ethoxyethoxy) methyl] benzene (9.0 g) was obtained. 1-bromo-4- [2-ethoxyethoxy) methyl)] benzene (8.7 g) was added to TH
F (104 ml), and 1.6 M n-butyllithium / hexane (23 ml) was removed at -78 ° C and stirred for 1 hour. Trimethoxyborane (8.7 g) was added dropwise,
After stirring for 30 minutes, the mixture was allowed to naturally warm to room temperature, and 5% sulfuric acid (3
5 ml) and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 4-[(2-ethoxyethoxy) methyl] phenylboronic acid (2.1 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.25 (3 H, t, J = 7.0 Hz), 3.5
7 (2H, q, J = 7.0Hz), 3.58-3.67 (2H, m), 4.68 (2H, s),
7.50 (2H, d, J = 8.0Hz), 8.22 (2H, d, J = 8.0Hz)

Example 103 (Preparation of Compound 101) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 25.5 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg), and 4-[(2-ethoxy) was added. After adding (ethoxy) methyl] phenylboronic acid (260 mg) and potassium carbonate (234 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (35.5 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and treated with 7- [4-[(2-ethoxyethoxy). ) Methyl] phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin- 4-carboxamide (compound 1
01) (282 mg). mp 184-186 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.24 (3 H, t, J = 7.0 Hz), 1.
63-1.79 (4H, m), 2.20 (3H, s), 2.64 (1H, m), 3.12-3.2
0 (2H, m), 3.30-3.44 (2H, m), 3.50-3.61 (4H, m), 3.62
-3.73 (2H, m), 3.66 (2H, s), 3.98-4.09 (2H, m), 4.64
(2H, s), 7.30-7.37 (3H, m), 7.45-7.72 (9H, m), 7.85
(1H, s), 8.22 (1H, d, J = 8.0Hz) IR (KBr) 3300, 2926, 1667, 1597, 1526, 1408, 1313,
1294, 1130, 815cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.69; H, 6.90; N, 4.53

Reference Example 128 4-Bromophenol (25 g) was added to DMF (150 m
l), and potassium carbonate (30 g) was added.
-Bromopropanol (26.1 g) was added dropwise.
Stirred at 0 ° C. for 20 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 3-
(4-bromophenoxy) -1-propanol (20.
6 g) were obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.76 (1 H, br), 1.97-2.09 (2
H, m), 3.80-3.91 (2H, m), 4.08 (2H, t, J = 6.0Hz), 6.7
6-6.81 (2H, m), 7.33-7.40 (2H, m).

Reference Example 129 3- (4-bromophenoxy) -1-propanol (1
0.0g) was dissolved in DMF (100 ml), 65% sodium hydride (2.4 g) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. Iodoethane (3.8 ml) was added dropwise, and after stirring for 3 hours, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-bromo-4- (3-methoxypropoxy) benzene (8.6 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.4 Hz), 1.2
7-1.65 (4H, m), 3.53 (2H, t, J = 6.6Hz), 3.74-3.79 (2
H, m), 4.05-4.11 (2H, m), 6.81 (2H, d, J = 9.0Hz), 7.
36 (2H, d, J = 9.0Hz)

Reference Example 130 THF (17.7 ml) of magnesium (0.89 g)
Iodine (catalytic amount) was added to the solution, and 1-bromo-4- (3-methoxypropoxy) benzene (8.
A solution of 5 g) in THF (68 ml) was slowly added dropwise. After stirring for 1 hour, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (5.4 g) in THF (10.8 ml) was added dropwise, and the mixture was stirred for 1 hour. The temperature was raised to room temperature over 6 hours, stirred at room temperature for 8 hours, and added with 5% sulfuric acid (34 ml).
Stir for 5 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was treated with hexane /
It wash | cleaned in order of isopropyl ether and hexane / ethyl acetate, and obtained 4- (3-methoxypropoxy) phenyl boric acid (4.0g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3H, t, J = 7.2 Hz),
1.25-1.58 (2H, m), 3.45 (2H, t, J = 6.6Hz), 3.64-3.76
(2H, m), 4.03-4.16 (2H, m), 6.87-6.96 (2H, m), 7.14
(1H, d, J = 8.4Hz), 7.81 (1H, d, J = 8.4Hz)

Example 104 (Preparation of Compound 102) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 4- (3-methoxypropoxy) was added. ) After adding phenylboric acid (145 mg) and potassium carbonate (175 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was refluxed for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and 7- [4- (3-methoxypropoxy) phenyl ]
-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carboxamide (Compound 102) (190 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.63-1.82 (4H, m), 2.03-2.
15 (2H, m), 2.20 (3H, s), 2.64 (1H, m), 3.11-3.19 (2
H, m), 3.31-3.44 (2H, m), 3.37 (3H, s), 3.55 (2H,
s), 3.53-3.58 (2H, m), 3.60-3.73 (2H, m), 4.01-4.13
(2H, m), 4.12 (2H, t, J = 6.2Hz), 7.01 (2H, d, J = 8.4
Hz), 7.26-7.35 (3H, m), 7.48-7.64 (6H, m), 7.94 (1H,
s), 8.16 (1H, d, J = 8.0Hz) IR (KBr) 3270, 2949, 1667, 1607, 1518, 1408, 1311,
1292, 1252, 1130, 826cm- ¹ Elemental analysis C ₃₄ H ₄₀ N ₂ O ₆ S Calcd. C, 67.53; H, 6.67;
N, 4.63: Found.C, 67.39; H, 6.38; N, 4.71

Reference Example 131 3- (4-bromophenoxy) -1-propanol (1
0.0g) was dissolved in DMF (100 ml), 65% sodium hydride (2.4 g) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. Bromopropane (5.5 ml) was added dropwise, and after stirring for 3 hours, 65% sodium hydride (0.8%) was added.
g) was added and the mixture was stirred at 70 ° C. for 1 hour. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give 1-bromo-4- (3-propoxypropoxy) benzene (6.7 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.4 Hz), 1.2
7-1.65 (4H, m), 3.53 (2H, t, J = 6.6Hz), 3.74-3.79 (2
H, m), 4.05-4.11 (2H, m), 6.81 (2H, d, J = 9.0Hz), 7.
36 (2H, d, J = 9.0Hz)

Reference Example 132 THF (12.5 ml) of magnesium (0.63 g)
Iodine (catalytic amount) was added to the solution, and a solution of 1-bromo-4- (3-propoxypropoxy) benzene (6.7 g) in THF (53.6 ml) was slowly added dropwise under heating and reflux. After stirring for 1 hour, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (3.8 g) in THF (7.6 ml) was added dropwise, and the mixture was stirred for 1 hour. The mixture was heated to room temperature over 6 hours, stirred at room temperature for 8 hours, added with 5% sulfuric acid (27 ml), and stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (3-propoxypropoxy) phenyl boric acid (2.0 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.2 Hz),
1.25-1.58 (2H, m), 3.45 (2H, t, J = 6.6Hz), 3.64-3.76
(2H, m), 4.03-4.16 (2H, m), 6.87-6.96 (2H, m), 7.14
(1H, d, J = 8.4Hz), 7.81 (1H, d, J = 8.4Hz)

Example 105 (Preparation of Compound 103) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 4- (3-propoxypropoxy) was added. ) After adding phenylboric acid (165 mg) and potassium carbonate (175 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was refluxed for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate / THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4-[[N-methyl- N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
-7- [4- (3-propoxypropoxy) phenyl]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 103) (245)
mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.2 Hz), 1.
54-1.92 (6H, m), 2.04-2.13 (2H, m), 2.20 (3H, s), 2.6
4 (1H, m), 3.11-3.18 (2H, m), 3.31-3.43 (2H, m), 3.4
1 (2H, t, J = 6.6Hz), 3.56 (2H, s), 3.58-3.72 (4H,
m), 4.00-4.11 (2H, m), 4.13 (2H, t, J = 6.2Hz), 7.01
(2H, d, J = 8.8Hz), 7.26-7.35 (3H, m), 7.48-7.63 (6
H, m), 7.98 (1H, s), 8.15 (1H, d, J = 8.0 Hz) IR (KBr) 3274, 2955, 165
5, 1601, 1520, 1410, 131
6, 1292, 1252, 1130, 822c
m ^-1 elemental analysis _{C 36 H 44 N 2 O 6} S Calcd.
C, 68.33; H, 7.01; N,
4.43: Found. C, 68.34;
H, 6.82; N, 4.48

Reference Example 133 7-Bromo-1,1-dioxo-2,3-dihydro-1
-Methyl benzothiepine-4-carboxylate (6.5 g)
To toluene / ethanol / water (10/1 / 1,188m
l), 4- (2-propoxyethoxy) phenyl boric acid (5.3 g) and potassium carbonate (6.0 g) were added, and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (0.9 g) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 7- [4- (2-propoxyethoxy) phenyl] -1,1-dioxo. −2,3-
Methyl dihydro-1-benzothiepine-4-carboxylate (6.5 g) was obtained. mp 105-107 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3 H, t, J = 7.4 Hz), 1.
56-1.76 (2H, m), 3.11-3.17 (2H, m), 3.52 (2H, t, J =
6.8Hz), 3.60-3.68 (2H, m), 3.80-3.85 (2H, m), 3.87 (3H
H, s), 4.16-4.21 (2H, m), 7.04 (2H, d, J = 8.4Hz), 7.
53-7.58 (2H, m), 7.65-7.70 (2H, m), 7.91 (1H, s), 8.2
0 (1H, d, J = 8.8Hz) IR (KBr) 2920, 1709, 1604, 1518, 1294, 1252, 1130,
828, 752m- ¹ Elemental analysis C ₂₃ H ₂₆ O ₆ S Calcd. C, 64.17; H, 6.09: Fo
und. C, 64.20; H, 5.91

Reference Example 134 7- [4- (2-Propoxyethoxy) phenyl]-
Methyl 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g) in 1,2-dimethoxyethane (130 ml), 6N hydrochloric acid (65 ml)
Was added and heated at 100 ° C. for 18 hours under reflux. It was cooled to room temperature and extracted with ethyl acetate. After washing with saturated saline,
It was dried over magnesium sulfate. Remove the solvent under reduced pressure,
7- [4- (2-propoxyethoxy) phenyl]-
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (5.0 g) was obtained. mp 176-179 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.4 Hz),
1.44-1.62 (2H, m), 2.93-3.00 (2H, m), 3.43 (2H, t, J
= 6.6Hz), 3.70-3.81 (4H, m), 4.14-4.19 (2H, m), 7.08
(2H, d, J = 8.8Hz), 7.78 (2H, d, J = 8.8Hz), 7.86-7.9
0 (2H, m), 8.05 (2H, m) IR (KBr) 2978, 1684, 1606, 1518, 1412, 1292, 1252,
1165, 1128, 829cm ^-1 Elemental analysis C ₂₂ H ₂₄ O ₆ S Calcd.C, 63.44; H, 5.81: Fo
und. C, 63.38; H, 5.66

Example 106 (Production of Compound 97) 7- [4- (2-Propoxyethoxy) phenyl]-
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (4.9 g) was added to THF (98 m
l) and thionyl chloride (1.3 ml) under ice-cooling.
DMF (three drops) was added, and the mixture was stirred at room temperature for 30 minutes. 4-
The reaction solution was added dropwise to a solution of [[N-methyl-N- (tetrahydropyranyl-4-yl) amino] methyl] aniline (2.93 g) and triethylamine (6.6 ml) in THF (88 ml), and the mixture was added at room temperature. Stir for 1 hour. The reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4- (2-propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 9
7) (2.9 g) was obtained. mp 195-197 ° C elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.84; H, 6.82; N, 4.59

Reference Example 135 4-Bromophenol (7.5 g) was added to DMF (75 m
l) and potassium carbonate (7.2 g) and sodium iodide (6.5 g) were added at room temperature.
5-chloromethylthiophene (6.5 g) was added dropwise and 9
Stirred at 0 ° C. for 6 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give a residue.
-Bromophenyl (5-chloro-2-thienyl) methyl ether (8.2 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 5.07 (2H, s), 6.79-6.87 (4
H, m), 7.34 to 7.42 (2H, m)

Reference Example 136 4-Bromophenyl (5-chloro-2-thienyl) methyl ether (8.1 g) was dissolved in THF (97 ml), and 1.6 M n-butyllithium / hexane (-78 ° C.) was dissolved at -78 ° C. 8.3 ml) was removed and stirred for 1 hour. A solution of trimethoxyborane (5.5 g) in THF (5.5 ml) was added dropwise, and the mixture was stirred for 30 minutes.
Sulfuric acid (32 ml) was added and stirred for 15 minutes. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was washed with hexane / isopropyl ether, and 4-[(5-chloro-2-thienyl) methoxy] phenylborate (4.
2 g) were obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 5.24 (2 H, s), 6.86 (2 H,
d, J = 8.4Hz), 7.01-7.11 (2H, m), 7.74 (2H, d, J = 8.4H
z)

Example 107 (Preparation of Compound 104) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1, 19.2 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 4-[(5-chloro- -2-thienyl) methoxy] phenylboric acid (186 mg), potassium carbonate (175 m
After adding g), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated and refluxed at 100 ° C. for 8 hours. After cooling to room temperature,
The mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 5/2), and then recrystallized from ethanol to give 7- [4-[(5
-Chloro-2-thienyl) methoxy] phenyl] -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 104) (137 mg). mp 207-210 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.60-1.82 (4H, m), 2.20 () 3
H, s), 2.65 (1H, m), 3.15 (2H, t, J = 6.2Hz), 3.31-3.
44 (2H, m), 3.57 (2H, s), 3.65-3.73 (2H, m), 3.98-4.0
9 (2H, m), 5.17 (2H, s), 6.83 (1H, d, J = 3.8Hz), 6.91
(1H, d, J = 3.6Hz), 7.05 (2H, d, 8.8Hz), 7.29-7.54 (3
H, m), 7.48-7.64 (6H, m), 7.98 (1H, s), 8.16 (1H, d,
J = 8.0Hz) IR (KBr) 2949, 2845, 1663, 1607, 1514, 1454, 1408,
1292, 1242, 1157, 1130, 1009, 814cm ^-1

Reference Example 137 4-Bromobenzenethiol (12 g) was added to DMF (96
ml) and potassium carbonate (12.3) at room temperature.
g), sodium iodide (10.5 g) and then 2
-Chloroethylpropyl ether (9.6 ml) was added dropwise, and the mixture was stirred at 90 ° C for 14 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried with magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1-bromo-4- (2-propoxyethylthio).
Benzene (16.9 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.91 (3 H, t, J = 7.4 Hz), 1.5
0-1.66 (2H, m), 3.09 (2H, t, J = 6.6Hz), 3.39 (2H, t, J
= 7.0Hz), 3.60 (2H, t, J = 7.0Hz), 7.20-7.26 (2H, m),
7.37-7.42 (2H, m)

Reference Example 138 Iodine (catalytic amount) was added to a solution of magnesium (1.53 g) in THF (23 ml), and the mixture was heated under reflux with 1-bromo-4- (2-propoxyethylthio) benzene (16.
A solution of 5 g) in THF (132 ml) was slowly added dropwise. After stirring for 30 minutes, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (9.3 g) in THF (9.3 ml) was added dropwise, and the mixture was stirred for 1 hour. The mixture was heated to room temperature over 8 hours, stirred at room temperature for 6 hours, and added with 3N hydrochloric acid (66 ml).
Stir for 5 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was treated with hexane /
After washing with isopropyl ether, 4- (2-propoxyethylthio) phenyl boric acid (6.5 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.86 (3 H, t, J = 7.2 Hz),
1.41-1.57 (2H, m), 3.15 (2H, t, J = 6.6Hz), 3.35 (2H, m
t, J = 6.6 Hz), 3.56 (2H, t, J = 6.6 Hz), 7.27 (2H, d, J =
8.0Hz), 7.71 (2H, d, J = 8.0Hz), 7.99 (2H, br)

Example 108 (Preparation of Compound 105) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.8 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg), and 4- (2-propoxyethyl) was added. After thio) phenylboronic acid (172 mg) and potassium carbonate (181 mg) were added, the mixture was stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (28 mg), and add 100 ° C.
And refluxed for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 5/2), recrystallized from ethanol, and N- [4-[[N-methyl -N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4- (2-propoxyethylthio) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4 -Carboxamide (compound 1
05) (220 mg). mp 198-200 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.92 (3 H, t, J = 7.4 Hz), 1.5
4-1.82 (6H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13-3.22
(4H, m), 3.31-3.43 (2H, m), 3.47 (2H, t, J = 7.0H
z), 3.57 (2H, s), 3.67 (2H, t, J = 7.0Hz), 3.65-3.72
(2H, m), 4.01-4.09 (2H, m), 7.30-7.35 (2H, m), 7.42-
7.57 (7H, m), 7.63-7.71 (2H, m), 7.87 (1H, s), 8.22 (1
H, d, J = 8.4Hz) IR (KBr) 2959, 2847, 1655, 1597, 1528, 1410, 1316,
1294, 1130, 816cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₄ S ₂ Calcd.C, 66.22; H, 6.67;
N, 4.41: Found.C, 66.03; H, 6.72; N, 4.41

Reference Example 139 2- (4-bromophenoxy) -1-ethanol (1
9.5 g) was dissolved in DMF (166 ml), 65% sodium hydride (5.3 g) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 1.5 hours. Iodopentane (17.7m
l) was added dropwise, and after stirring for 2 hours, the reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane / hexane).
Purified with ethyl acetate = 10/1) to give 1-bromo-4-
(2-pentyloxyethoxy) benzene (12.0
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90 (3 H, t, J = 6.6 Hz), 1.2
5-1.37 (4H, m), 1.57-1.68 (2H, m), 3.52 (2H, t, J = 6.6
Hz), 3.74-3.79 (2H, m), 4.05-4.11 (2H, m), 6.78-6.83
(2H, m), 7.33-7.39 (2H, m)

Reference Example 140 To a solution of magnesium (0.91 g) in THF (14 ml) was added iodine (catalyst amount), and the mixture was heated under reflux with 1-bromo-4- (2-pentyloxyethoxy) benzene (1).
A solution of 1.8 g) in THF (94 ml) was slowly added dropwise. After stirring for 30 minutes, the mixture was cooled to -78 ° C, trimethoxyborane (5.7 g) was added dropwise, and the temperature was raised to room temperature over 8 hours. After stirring at room temperature for 6 hours, 5% sulfuric acid (47 ml)
Was added and stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether and hexane / ethyl acetate in this order to give 4- (2-pentyloxyethoxy).
Phenyl boric acid (5.6 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.86 (3 H, t, J = 6.6 Hz),
1.22-1.59 (6H, m), 3.44 (2H, t, J = 6.6Hz), 3.66-3.71
(2H, m), 4.05-4.13 (2H, m), 6.88 (2H, d, J = 8.6Hz),
7.72 (2H, d, J = 8.6Hz), 7.82 (2H, br)

Example 109 (Preparation of Compound 106) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.8 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg), and 4- (2-pentyloxy) was added. After adding (ethoxy) phenylboric acid (180 mg) and potassium carbonate (181 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (28 mg) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 5/2), recrystallized from ethanol, and N- [4-[[N-methyl- N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7-
[4- (2-pentyloxyethoxy) phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 106) (188 m
g) was obtained. mp 188-189 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90 (3 H, t, J = 6.6 Hz), 1.
38-1.40 (4H, m), 1.56-1.77 (6H, m), 2.20 (3H, s), 2.6
4 (1H, m), 3.10-3.19 (2H, m), 3.30-3.44 (2H, m), 3.55
(2H, t, J = 6.6Hz), 3.56 (2H, s), 3.65-3.73 (2H, m),
3.79-3.85 (2H, m), 3.98-4.10 (2H, m), 4.15-4.21 (2H, m
m), 7.00-7.06 (2H, m), 7.29-7.34 (2H, m), 7.47-7.66
(7H, m), 7.95 (1H, s), 8.17 (1H, d, J = 8.4Hz) IR (KBr) 2938, 2853, 1667, 1607, 1516, 1408, 1312,
1292, 1251, 1130, 826cm- ¹ Elemental analysis C ₃₆ H ₄₄ N ₂ O ₆ S Calcd. C, 68.70; H, 7.17;
N, 4.33: Found.C, 68.64; H, 7.03; N, 4.31

Reference Example 141 2- (4-bromophenoxy) -1-ethanol (1
9.5 g) was dissolved in DMF (195 ml), 65% sodium hydride (5.3 g) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. Iodohexane (19.9 ml) was added dropwise, and after stirring for 2 hours, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1-bromo-4- (2-hexyloxyethoxy) benzene (16.2 g). I got ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.89 (3 H, t, J = 6.6 Hz), 1.2
5-1.43 (6H, m), 3.52 (2H, t, J = 6.6Hz), 3.74-3.79 (2
H, m), 4.05-4.11 (2H, m), 6.78-6-84 (2H, m), 7.34-7.
39 (2H, m)

Reference Example 142 To a solution of magnesium (1.19 g) in THF (14 ml) was added iodine (catalytic amount), and the mixture was refluxed with heating under the conditions of 1-bromo-4- (2-hexyloxyethoxy) benzene (1).
A solution of 6.0 g) in THF (102 ml) was slowly added dropwise. After stirring for 15 minutes, the mixture was cooled to -78 ° C, a solution of trimethoxyborane (7.2 g) in THF (14 ml) was added dropwise, and the temperature was raised to room temperature over 8 hours. After stirring at room temperature for 6 hours, 5% sulfuric acid (64 ml) was added, and the mixture was stirred for 15 minutes.
The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (2-hexyloxyethoxy) phenyl boric acid (6.7 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.86 (3 H, t, J = 6.6 Hz),
1.18-1.59 (8H, m), 3.44 (2H, t, J = 6.6Hz), 3.66-3.71
(2H, m), 4.04-4.12 (2H, m), 6.88 (2H, d, J = 8.4Hz),
7.73 (2H, d, J = 8.4Hz)

Example 110 (Production of Compound 107) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (10/1/1, 19.8 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg), and 4- (2-hexyloxy) was added. After adding (ethoxy) phenylboronic acid (190 mg) and potassium carbonate (181 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (28 mg) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 5/2) and recrystallized from ethanol to give 7- [4- (2-hexyloxyethoxy). ) Phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 107) (200 mg)
I got mp 180-182 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.89 (3 H, t, J = 7.2 Hz), 1.
21-1.46 (6H, m), 1.57-1.82 (6H, m), 2.21 (3H, s), 2.6
4 (1H, m), 3.16 (2H, t, J = 6.6Hz), 3.31-3.43 (2H,
m), 3.51-3.70 (2H, m), 3.57 (2H, s), 3.67-3.75 (2H,
m), 3.98-4.09 (2H, m), 4.15-4.21 (2H, t, J = 4.8Hz),
7.03 (2H, d, J = 8.8Hz), 7.30-7.35 (3H, m), 7.50-7.66
(6H, m), 7.89 (1H, s), 8.18 (1H, d, J = 8.4Hz) IR (KBr) 3245, 2953, 2855, 1651, 1605, 1518, 1412,
1316, 1294, 1252, 1130, 826cm ^-1

Example 111 (Production of compound 108) 7- (4-Hydroxyphenyl) -N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (380 mg) was dissolved in DMF (3.8 ml), potassium carbonate (252 mg) was added, and the mixture was stirred for 30 minutes.
-Chloromethylpyridine hydrochloride (130 mg) was added,
Stirred at room temperature for 6 hours. The reaction solution was added to water, extracted with ethyl acetate / THF, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and 7- [4- (2-pyridylmethoxy) phenyl ] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 108) (10 m
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.46-1.74 (4H, m), 2.10
(3H, s), 2.59 (1H, m), 3.02-3.14 (2H, m), 3.19-3.37
(2H, m), 3.52 (2H, s), 3.72-3.83 (2H, m), 3.88-3.94
(2H, m), 5.26 (2H, s), 6.90 (1H, d, J = 8.4Hz), 7.16
7.39 (5H, m), 7.53-7.89 (8H, m), 8.40-8.09 (2H, m),
8.57-8.62 (1H, m), 10.17 (1H, s)

Reference Example 143 3-Bromophenol (10 g) was added to DMF (100 m
l), potassium carbonate (10.4 g) and bromopropane (6.0 ml) were added, and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1-bromo-3-propoxybenzene (1
1.2 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ1-03 (3H, t, J = 7.2 Hz), 1.7
2-1.86 (2H, m), 3.89 (2H, t, J = 6.6Hz), 6.79-6.85 (1
H, m), 7.03-7.17 (3H, m)

Reference Example 144 1-Bromo-3-propoxybenzene (11.0 g) was dissolved in THF (110 ml), and the solution was dissolved in 1.6 M at -78 ° C.
n-Butyllithium / hexane (35.2 ml) was removed and stirred for 1 hour. Trimethoxyborane (10.6g)
(10.6 ml) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, 2N hydrochloric acid (44 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate,
After washing with saturated saline, it was dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 3-propoxyphenylboric acid (4.5 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.99 (3 H, t, J = 7.4 Hz),
1.65-1.81 (2H, m), 3.91 (2H, t, J = 6.6Hz), 6.90-6.95
(1H, m), 7.18 (3H, m), 7.99 (2H, br)

Example 112 (Preparation of Compound 109) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 3-propoxyphenylboronic acid (125 mg) was added. ) And potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 5/2), recrystallized from ethanol, and N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- (3-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 109 ) (2
82 mg). mp 219-221 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.07 (3 H, t, J = 7.2 Hz), 1.
63-1.90 (6H, m), 2.21 (3H, s), 2.64 (1H, m), 3.13-3.2
1 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.67-3.75
(2H, m), 3.95-4.09 (2H, m), 6.98 (1H, dd, J = 8.2, 2.
6Hz), 7.10-7.17 (2H, m), 7.29-7.43 (4H, m), 7.54 (2H, m)
H, d, J = 8.4 Hz), 7.64 to 7.71 (2H, m), 7.88 (1H, s), 8.
20 (1H, d, J = 8.4Hz) IR (KBr) 3357, 2946, 2841, 1649, 1631, 1595, 1510,
. 1406, 1321, 1294, 1217 , 1134, 785cm -1 elemental analysis _{C 33 H 38 N 2 O 5} S Calcd C, 68.96; H, 6.66;
N, 4.87: Found.C, 68.77; H, 6.85; N, 4.88

Reference Example 145 3-Bromophenol (14 g) was added to DMF (140 m
1), potassium carbonate (15.7 g) and sodium iodide (12.1 g) were added, and then 2-chloroethylpropyl ether (12.3 ml) was added, followed by stirring at 90 ° C. for 18 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 1-bromo-3- (2-propoxyethoxy) benzene (11.1 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3 H, t, J = 7.2 Hz), 1.5
6-1.72 (2H, m), 3.49 (2H, t, J = 6.6Hz), 3.74-3.80 (2
H, m), 4.07-4.12 (2H, m), 6.81-6.89 (1H, m), 7.03-7.
18 (3H, m)

Reference Example 146 To a solution of magnesium (0.99 g) in THF (9.9 ml) was added 1,2-dibromoethane (catalytic amount), and 1-bromo-3- (2-propoxyethoxy) was added at room temperature. A solution of benzene (10.5 g) in THF (84 ml) was slowly added dropwise. After stirring at 60 ° C. for 1 hour, the mixture was cooled to −78 ° C., a THF solution (17 ml) of trimethoxyborane (8.5 g) was added dropwise, and the temperature was raised to room temperature over 8 hours. After stirring at room temperature for 12 hours, 2N hydrochloric acid (42 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether and hexane / ethyl acetate to obtain 3- (2-propoxyethoxy) phenyl boric acid (3.5 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.2 Hz),
1.46-1.63 (2H, m), 3.42 (2H, t, J = 6.6Hz), 3.67-3.73
(2H, m), 4.05-4.10 (2H, m), 6.93-6.98 (2H, m), 7.19-
7.37 (2H, m), 8.00 (2H, br)

Example 113 (Production of compound 110) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 3- (propoxyethoxy) phenyl was added. Boric acid (15
After adding 5 mg) and potassium carbonate (176 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 5).
/ 2), recrystallized from ethanol,
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -7- [3- (2
-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 110) (154 mg). mp 166-167 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3 H, t, J = 7.4 Hz), 1.
57-1.83 (6H, m), 2.21 (3H, s), 2.64 (1H, m), 3.18 (2
H, t, J = 6.6 Hz), 3.31-3.45 (2H, m), 3.51 (2H, t, J =
6.6Hz), 3.57 (2H, s), 3.68-3.75 (2H, m), 3.79-3.85 (2
H, m), 4.01-4.16 (2H, m), 4.17-4.23 (2H, m), 6.97-7.
03 (1H, m), 7.15-7.19 (2H, m), 7.30-7.44 (4H, m), 7.5
5 (2H, d, J = 8.8Hz), 7.64-7.72 (2H, m), 7.84 (1H,
s), 8.21 (1H, d, J = 8.2Hz) IR (KBr) 2942, 2849, 1667, 1597, 1522, 1408, 1312,
1292, 1130cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.78; H, 6.76; N, 4.50

Reference Example 147 2-isopropoxyethanol (15 g) was added to THF (1
50 ml), and triethylamine (30.1 ml) and methanesulfonyl chloride (1
(4.6 ml) and stirred at room temperature for 1 hour. The reaction solution was added to water, extracted with THF, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was stirred under ice-cooling with 4-bromophenol (20.7 g) and potassium carbonate (21.5 g) in DM.
F (207 ml) solution was added dropwise, and the mixture was stirred at 70 ° C. for 16 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1-bromo-4- (2-
Isopropoxyethoxy) benzene (16.4 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (3H, s), 1.21 (3H,
s), 3.60-3.75 (1H, m), 4.04-4.09 (2H, m), 6.80 (2H,
d, J = 9.2 Hz), 7.36 (2H, d, J = 9.2 Hz)

Reference Example 148 To a solution of magnesium (1.58 g) in THF (24 ml) was added 1,2-dibromoethane (catalytic amount), and the mixture was heated under reflux to obtain 1-bromo-4- (2-isopropoxyethoxy). A solution of benzene (10 g) in THF (80 ml) was slowly added dropwise. After stirring at 50 ° C for 1 hour, -78 ° C
And trimethoxyborane (6.4 g) in THF
(9.6 ml) was added dropwise, and after stirring for 1 hour, the temperature was raised to room temperature. After stirring at room temperature for 8 hours, 2N hydrochloric acid (40 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 4- (2-isopropoxyethoxy) phenyl boric acid (1.3 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.09 (3 H, s), 1.12 (3 H,
s), 3.55-3.71 (3H, m), 4.03-4.09 (2H, m), 6.88 (2H,
d, J = 8.8Hz), 7.72 (2H, d, J = 8.8Hz)

Example 114 (Production of Compound 111) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 4- (2-isopropoxy) was added. After adding (ethoxy) phenylboronic acid (153 mg) and potassium carbonate (176 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- [4- (2-isopropoxyethoxy). ) Phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 111) (159 m
g) was obtained. mp 214-215 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.20 (3H, s), 1.23 (3H,
s), 1.62-1.77 (4H, m), 2.21 (3H, s), 2.67 (1H, m), 3.
16 (2H, t, J = 6.6Hz), 3.31-3.44 (2H, m), 3.57 (2H,
s), 3.64-3.74 (3H, m), 3.81 (2H, m), 4.00-4.18 (2H,
m), 4.17 (2H, t, J = 4.8Hz), 7.03 (2H, d, J = 8.8Hz),
7.30-7.34 (3H, m), 7.50-7.67 (6H, m), 7.86 (1H, s),
8.18 (1H, d, J = 8.2Hz) IR (KBr) 3274, 2953, 1665, 1601, 1520, 1316, 1292,
1250, 1130, 824cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.67; H, 6.77; N, 4.54

Example 115 (Preparation of compound 112) N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4-
(2-propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (17.3 g) was dissolved in THF (850 ml), and 4N hydrochloric acid / ethyl acetate was added at room temperature. (14 ml) was added and stirred for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was washed with ethyl acetate / acetone and recrystallized from ethanol to give N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) Amino] methyl] phenyl] -7- [4- (2-propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide hydrochloride (compound 11
2) (11.2 g) was obtained. mp 213-215 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.4 Hz),
1.05-1.63 (2H, m), 1.70-2.21 (4H, m), 2.58 (3H, s),
2.50-2.60 (2H, m), 3.05-3.12 (2H, m), 3.23-3.49 (4H, m
m), 3.43 (2H, t, J = 6.6 Hz), 3.72-3.82 (2H, m), 3.94
4.03 (2H, m), 4.17 (2H, s), 4.38-4.49 (2H, m), 7.10
(2H, d, J = 8.8Hz), 7.58-7.62 (2H, m), 7.76 (2H, d, J
= 8.8Hz), 7.83-7.90 (4H, m), 8.07 (2H, d, J = 8.2Hz),
10.47 (1H, s), 10.62 (1H, br) .IR (KBr) 2961, 2870, 1667, 1597, 1520, 1412, 1321,
1292, 1248, 1132, 828cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S ・ HCl Calcd.C, 64.16; H, 6.
61; N, 4.28: Found.C, 63.97; H, 6.55; N, 4.18

Reference Example 149 2-Bromophenol (12 g) was added to DMF (120 m
l), potassium carbonate (12.5 g) was added, and bromopropane (7.2 ml) was added.
Stirred for hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 1).
2/1) to obtain 1-bromo-2-propoxybenzene (10.5 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08 (3 H, t, J = 7.4 Hz), 1.7
8-1.94 (2H, m), 3.98 (2H, t, J = 6.6Hz), 6.77-6.91 (2
H, m), 7.19-7.29 (1H, m), 7.19-7.29 (1H, dd, J = 7.
6, 1.8Hz)

Reference Example 150 1-Bromo-2-propoxybenzene (10.1 g) was dissolved in THF (101 ml), and 1.6 M was added at -78 ° C.
n-Butyllithium / hexane (32.3 ml) was removed and stirred for 1 hour. A THF solution (9.8 ml) of trimethoxyborane (9.8 g) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, 2N hydrochloric acid (40 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2-propoxyphenylboric acid (5.3 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.00 (3 H, t, J = 7.2 Hz),
1.70-1.83 (2H, m), 4.00 (2H, t, J = 6.6Hz), 6.89-7.00
(2H, m), 7.33-7.42 (1H, m), 7.60 (2H, dd, J = 7.2, 2.
0Hz), 7.68 (2H, s)

Example 116 (Preparation of Compound 113) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.8 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 2-propoxyphenylboric acid (125 mg) was added. ) And potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated and refluxed at 100 ° C. for 8 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 3).
/ 1), recrystallized from ethanol,
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -7- (2-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 113) (46 mg). mp 190-192 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.97 (3 H, t, J = 7.2 Hz), 1.
62-1.81 (4H, m), 2.20 (3H, s), 2.64 (1H, m), 3.18 (2
(H, t, J = 7.0Hz), 3.31-3.43 (2H, m), 3.57 (2H, s), 3.
69-3-76 (2H, m), 3.96 (2H, t, J = 7.0Hz), 3.99-4.09 (2
H, m), 6.97-7.09 (2H, m), 7.30-7.42 (5H, m), 7.51-7.
56 (2H, m), 7.60-7.75 (2H, m), 7.81 (1H, s), 8.21 (1
H, d, J = 8.0 Hz) IR (KBr) 2938, 2920, 1667, 1599, 1529, 15166, 140
8, 1312, 1294, 1130, 754cm- ¹ Elemental analysis C ₃₆ H ₄₄ N ₂ O ₆ S Calcd. C, 68.70; H, 7.17;
N, 4.33: Found.C, 68.64; H, 7.03; N, 4.31

Reference Example 151 2-Bromophenol (12 g) was added to DMF (120 m
1), potassium carbonate (14.4 g) and sodium iodide (10.4 g) were added, and then 2-bromoethylpropyl ether (10.4 ml) was added, followed by stirring at 90 ° C. for 16 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 1-bromo-2- (2-propoxyethoxy) benzene (14.4 g). Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3 H, t, J = 7.4 Hz), 1.5
6-1.73 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.82-3.87 (2
H, m), 4.15-4.21 (2H, m), 6.79-6.96 (2H, m), 7.20-7.
29 (1H, m), 7.53 (1H, dd, J = 7.6, 1.6Hz)

Reference Example 152 To a solution of magnesium (1.39 g) in THF (14 ml) was added 1,2-dibromoethane (catalytic amount), and 1-bromo-2- (2-propoxyethoxy) benzene (at room temperature). A solution of 14.1 g) in THF (113 ml) was slowly added dropwise. After stirring at 60 ° C. for 1 hour, the mixture was cooled to −78 ° C. and trimethoxyborane (8.5 g) in THF (8.
5 ml) solution was added dropwise, and the temperature was spontaneously raised to room temperature. After stirring at room temperature for 12 hours, 2N hydrochloric acid (56 ml) was added to the mixture for 15 hours.
For a minute. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2- (2-propoxyethoxy) phenyl boric acid (12.2 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.89 (3 H, t, J = 7.2 Hz),
1.50-1.62 (2H, m), 3.43 (2H, t, J = 6.6Hz), 3.71-3.76
(2H, m), 4.15-4.20 (2H, m), 6.92-7.04 (2H, m), 7.35
7.44 (1H, m), 7.63-7.70 (3H, m)

Example 117 (Production of compound 114) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 2- (propoxyethoxy) phenyl was added. Boric acid (15
After adding 5 mg) and potassium carbonate (176 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 3).
/ 1), recrystallized from ethanol,
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -7- [2- (2
-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 114) (230 mg). mp 164-166 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.85 (3 H, t, J = 7.4 Hz), 1.
50-1.82 (6H, m), 2.20 (3H, s), 2.64 (1H, m), 3.19 (2
H, t, J = 6.2Hz), 3.32-3.42 (2H, m), 3.40 (2H, t, J =
6.6Hz), 3.57 (2H, s), 3.69-3.78 (4H, m), 4.00-4.19 (2
H, m), 4.16 (2H, t, J = 6.6Hz), 7.02 (1H, d, J = 8.4H
z), 7.09 (1H, d, J = 8.2Hz), 7.29-7.34 (6H, m), 7. (53
(2H, d, J = 8.4Hz), 7.74 to 7.80 (2H, m), 8.18 (1H,
d, J = 8.2Hz) IR (KBr) 2938, 2847, 1667, 1599, 1516, 1408, 1312,
1294, 1130, 754cm- ¹ Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S Calcd. C, 67.94; H, 6.84;
N, 4.53: Found.C, 67.90; H, 6.89; N, 4.46

Reference Example 153 3-Bromophenol (12 g) was added to DMF (120 m
1), potassium carbonate (12.5 g) was added, and then 2-bromoethyl ethyl ether (9.1 ml) was added, followed by stirring at 70 ° C. for 16 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 1-bromo-3- (2-ethoxyethoxy) benzene (12.1).
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.24 (3 H, t, J = 6.8 Hz), 3.6
0 (2H, q, J = 6.8 Hz), 3.75-3.80 (2H, m), 4.07-4.12 (2
H, m), 6.83-6.89 (1H, m), 7.05-7.14 (2H, m)

Reference Example 154 Magnesium (1.25 g) in THF (12.5 ml)
1,2-Dibromoethane (catalytic amount) was added to the solution, and a solution of 1-bromo-3- (2-ethoxyethoxy) benzene (12 g) in THF (96 ml) was slowly added dropwise at room temperature. After stirring at 60 ° C. for 1 hour, the mixture was cooled to −78 ° C., and trimethoxyborane (7.6 g) in THF (7.6 g) was added.
ml) The solution was added dropwise, and the temperature was naturally raised to room temperature. After stirring at room temperature for 12 hours, 2N hydrochloric acid (48 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 3- (2-ethoxyethoxy) phenyl boric acid (7.4 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.24 (3 H, t, J = 6.8 Hz),
3.51 (2H, t, J = 6.8Hz), 3.67-3.72 (2H, m), 4.04-4.10
(2H, m), 6.92-6.98 (1H, m), 7.19-7.28 (1H, m), 7.33
7.37 (2H, m), 8.00 (2H, br)

Example 118 (Preparation of Compound 115) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) to give 3- (2-ethoxyethoxy). ) Phenyl boric acid (1
45 mg) and potassium carbonate (176 mg)
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol).
= 3/1) and recrystallized from ethanol to give 7
-[3- (2-ethoxyethoxy) phenyl] -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 115) (152 mg). mp 180-182 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (3 H, t, J = 7.0 Hz), 1.
58-1.82 (4H, m), 2.21 (3H, s), 2.65 (1H, m), 3.17 (2
H, t, J = 6.6 Hz), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.
61 (2H, q, J = 7.0Hz), 3.71-3.75 (2H, m), 3.83 (2H,
t, J = 4.8 Hz), 3.98-4.10 (2H, m), 4.20 (2H, t, J = 4.8
Hz), 6.97-7.03 (1H, m), 7.14-7.19 (2H, m), 7.30-7.44
(5H, m), 7.55 (2H, d, J = 8.4Hz), 7.64-7.71 (2H, m),
7.95 (1H, s), 8.21 (1H, d, J = 8.4Hz) IR (KBr) 2945, 2845, 1667, 1595, 1526, 1408, 1312,
1221, 1130cm ^-1

Example 119 (Production of Compound 116) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 3-chlorophenylboric acid (108 mg) was added. After adding potassium carbonate (176 mg), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and treated with 7- (3-chlorophenyl) -N- [ 4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 116) (64 m
g) was obtained. mp 221-224 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.58-1.81 (4H, m), 2.21 (3
H, s), 2.65 (1H, m), 3.15-3.22 (2H, m), 3.30-3.45 (2
H, m), 3.57 (2H, s), 3.69-3.77 (2H, m), 4.00-4.10 (2
H, m), 7.30-7.71 (11H, m), 7.82 (1H, s), 8.25 (1H,
d, J = 8.0Hz) IR (KBr) 2951, 2845, 1653, 1595, 1410, 1315, 1294,
1221, 1130cm ^-1

Reference Example 155 3-Bromophenol (12 g) was added to DMF (96 ml).
And potassium carbonate (12.5 g) was added.
-Bromoethyl ethyl ether (6.7 ml) was added,
Stirred at room temperature for 16 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to obtain 1-bromo-3-ethoxybenzene (11.6 g). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.40 (3 H, t, J = 7.0 Hz), 4.0
0 (2H, q, J = 7.0Hz), 6.78-6.84 (1H, m), 7.02-7.16 (3
H, m)

Reference Example 156 1-Bromo-3-ethoxybenzene (11.5 g) was added to T
Dissolved in HF (115 ml) and 1.6M n at -78 ° C.
-Butyllithium / hexane (39.3 ml) was removed and stirred for 1 hour. Trimethoxyborane (11.9 g)
(11.9 ml) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, 2N hydrochloric acid (46 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate,
After washing with saturated saline, it was dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 3-ethoxyphenylboric acid (7.1 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.33 (3 H, t, J = 7.0 Hz),
4.01 (2H, q, J = 7.0Hz), 6.90-6.96 (1H, m), 7.18-7.47
(3H, m), 7.74 (2H, br)

Example 120 (Preparation of Compound 117) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 3-ethoxyphenylboric acid (115 mg) was added. ) And potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1) and recrystallized from ethanol to give 7- (3-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 117) (180 m
g) was obtained. mp 192-195 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (3 H, t, J = 7.0 Hz), 1.
66-1.79 (4H, m), 2.21 (3H, s), 2.64 (1H, m), 3.18 (2
H, t, J = 6.6 Hz), 3.30-3.44 (2H, m), 3.57 (2H, s), 3.
69-3.76 (2H, m), 3.99-4.10 (2H, m), 4.11 (2H, q, J =
7.0Hz), 6.94-7.00 (1H, m), 7.10-7.19 (1H, m), 7.30-
7.44 (4H, m), 7.54 (2H, d, J = 8.4Hz), 7.65-7.73 (2H,
m), 7.83 (1H, s), 8.22 (1H, d, J = 8.4Hz) IR (KBr) 2945, 1669, 1597, 1526, 1408, 1312, 1223,
1130cm ^-1

Reference Example 157 2-Bromophenol (12 g) was added to DMF (120 m
1), potassium carbonate (12.5 g) was added, and then 2-bromoethyl ethyl ether (9.1 ml) was added, followed by stirring at 70 ° C. for 4 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 1-bromo-2- (2-ethoxyethoxy) benzene (14.8).
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.24 (3 H, t, J = 7.0 Hz), 3.6
6 (2H, q, J = 7.0 Hz), 3.82-3.88 (2H, m), 4.15-4.20 (2
H, m), 6.79-6.95 (1H, m), 7.20-7.29 (1H, m), 7.53 (1
H, dd, J = 7.8, 1.4Hz)

Reference Example 158 Magnesium (1.46 g) in THF (14.6 ml)
1,2-Dibromoethane (catalytic amount) was added to the solution, and a solution of 1-bromo-2- (2-ethoxyethoxy) benzene (14 g) in THF (112 ml) was slowly added dropwise at room temperature. After stirring at 60 ° C. for 1 hour, the mixture was cooled to −78 ° C., and trimethoxyborane (8.9 g) in THF (8.9 g) was added.
ml) The solution was added dropwise, and the temperature was naturally raised to room temperature. 2N hydrochloric acid (56 ml) was added and stirred for 15 minutes. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2- (2-ethoxyethoxy) phenyl boric acid (6.3 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.15 (3 H, t, J = 7.0 Hz),
3.53 (2H, q, J = 7.0Hz), 3.70-3.76 (2H, m), 4.14-4.20
(2H, m), 6.93-7.04 (2H, m), 7.35-7.44 (1H, m), 7.62-
7.70 (3H, m)

Example 121 (Production of compound 118) 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 2- (2-ethoxyethoxy) was added. ) Phenyl boric acid (1
45 mg) and potassium carbonate (176 mg)
The mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol).
= 3/1) and recrystallized from ethanol to give 7
-[2- (2-ethoxyethoxy) phenyl] -N-
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 118) (245 mg). ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.16 (3 H, t, J = 7.0 Hz), 1.
63-1.78 (4H, m), 2.20 (3H, s), 2.64 (1H, m), 3.18 (2
H, t, J = 6.6 Hz), 3.30-3.43 (2H, m), 3.51 (2H, q, J =
7.0Hz), 3.56 (2H, s), 3.68-3.75 (2H, m), 3.98-4.07 (2
H, m), 4.13-4.19 (2H, m), 6.99-7.11 (2H, m), 7.28-7.
42 (5H, m), 7.52 (2H, d, J = 8.4Hz), 7.74-7.79 (2H,
m), 7.86 (1H, s), 8.17 (1H, d, J = 8.8Hz) IR (KBr) 3347, 2944, 2845, 1642, 1597, 1510, 1410,
1290, 1132, 747cm ^-1

Reference Example 159 2-Bromophenol (12 g) was added to DMF (120 m
1), potassium carbonate (12.5 g) was added, and then iodoethane (6.7 ml) was added, followed by stirring at room temperature for 1 hour. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 12).
/ 1) to give 1-bromo-2-ethoxybenzene (12.2 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ1.47 (3H, t, J = 7.0Hz), 4.1
0 (2H, q, J = 7.0Hz), 6.76-6.90 (2H, m), 7.19-7.29 (1
H, m), 7.50-7.56 (1H, m)

Reference Example 160 1-Bromo-2-ethoxybenzene (12.0 g) was added to T
Dissolved in HF (120 ml) and 1.6M at -78 ° C
n-Butyllithium / hexane (41.0 ml) was removed and stirred for 1 hour. Trimethoxyborane (12.4 g)
Then, a THF solution (12.4 ml) was added dropwise, and the mixture was stirred for 30 minutes, allowed to warm to room temperature, 2N hydrochloric acid (48 ml) was added, and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate,
After washing with saturated saline, it was dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2-ethoxyphenylboric acid (7.1 g). ¹ H-NMR (200MHz, DMSO-d ₆ ) δ1.37 (3H, t, J = 7.0Hz),
4.09 (2H, q, J = 7.0Hz), 6.89-6.99 (1H, m), 7.33-7.42
(1H, dd, J = 7.2, 1.6Hz), 7.66 (2H, s)

Example 122 (Production of compound 119) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo- Toluene / ethanol / water (20/1/1, 13.9 ml) was added to 2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg).
And 2-ethoxyphenyl boric acid (115 mg),
After adding potassium carbonate (176 mg), the mixture was added at room temperature for 30 minutes.
For a minute. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 3/1), recrystallized from ethanol, and treated with 7- (2-ethoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 119) ( 1
45 mg). mp 171-173 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.36 (3 H, t, J = 7.0 Hz), 1.
63-1.77 (4H, m), 2.20 (3H, s), 2.64 (1H, m), 3.18 (2H,
t, J = 6.6Hz), 3.30-3.44 (2H, m), 3.57 (2H, s), 3.68-
3.76 (2H, m), 4.00-4.10 (2H, m), 4.08 (2H, q, J = 7.0H
z), 6.98-7.09 (2H, m), 7.30-7.52 (5H, m), 7.54 (2H,
d, J = 8.4Hz), 7.66 (1H, s), 7.72 (1H, dd, J = 8.0, 1.4H
z), 7.88 (1H, s), 8.18 (1H, d, J = 8.0Hz) IR (KBr) 3270, 2944, 1645, 1599, 1514, 1410, 1319,
1292, 1130, 748cm ^-1

Reference Example 161 1-bromo-3-trifluoromethylbenzene (15.
0 g) was dissolved in THF (150 ml), and 1.6 M n-butyllithium / hexane (45.8 m) was added at -78 ° C.
1) was removed and stirred for 1 hour. A THF solution (13.9 ml) of trimethoxyborane (13.9 g) was added dropwise, and 3
After stirring for 0 minutes, the mixture was naturally warmed to room temperature, and was then added with 2N hydrochloric acid (60%).
ml) and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 3-trifluoromethylphenyl boric acid (5.7 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ7.53-7.80 (3H, m), 8.06-
8.21 (1H, m), 8.13 (2H, s)

Example 123 (Preparation of compound 120) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo- Toluene / ethanol / water (20/1/1, 13.9 ml) was added to 2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg).
And 3-trifluoromethylphenyl boric acid (13
1 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol = 4).
/ 1), recrystallized from ethanol,
[4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino) methyl] phenyl] -7- (3-trifluoromethylphenyl) -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxamide (Compound 120) (148 mg) was obtained. mp 236-238 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.62-1.81 (4H, m), 2.20 (3
H, s), 2.65 (1H, m), 3.19 (2H, t, J = 6.6Hz), 3.31-3.
43 (2H, m), 3.57 (2H, s), 3.70-3.78 (2H, m), 3.98-4.1
0 (2H, m), 7.30-7.38 (3H, m), 7.52-7.87 (9H, m), 8.27
(1H, d, J = 8.0Hz) IR (KBr) 2942, 1648, 1599, 1530, 1412, 1318, 1294,
1130, 801 cm ^-1 elemental analysis C ₃₁ H ₃₁ F ₃ N ₂ O ₄ S Calcd.C, 63.68; H, 5.34
; N, 4.79: Found. C, 63.51; H, 5.42; N, 4.70

Reference Example 162 4-Bromo-3-methylphenol (12 g) was added to DMF.
(120 ml), and potassium carbonate (11.5
g) and sodium iodide (9.6 g).
Chloroethyl propyl ether (9.7 ml) was added dropwise, and the mixture was stirred at 90 ° C. for 10 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 4-bromo-3-methyl-1- (2-propoxyethoxy) benzene (11 .0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 1.5
4-1.71 (2H, m), 2.25 (3H, s), 3.48 (2H, t, J = 6.6Hz),
3.73-3.79 (2H, m), 4.05-4.10 (2H, m), 6.63 (1H, dd, J =
8.8, 2.8Hz), 6.82 (1H, d, J = 2.8Hz), 7.38 (1H, d, J =
(8.8Hz)

Reference Example 163 To a solution of magnesium (0.98 g) in THF (9.8 ml) was added 1,2-dibromoethane (3 drops), and the mixture was refluxed with heating to obtain 4-bromo-3-methyl-1- ( 2-propoxyethoxy) benzene (10.5 g) in THF (84 m
l) The solution was slowly added dropwise. After stirring for 15 minutes, -78
° C and trimethoxyborane (6.0 g) in THF
(6.0 ml) was added dropwise, and the temperature was naturally raised to room temperature. After stirring at room temperature for 6 hours, 2N hydrochloric acid (42 ml) was added to the mixture for 15 hours.
For a minute. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2,3-dimethyl-4- (2-propoxyethoxy) phenylboronic acid (3.8 g). ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (3H, t, J = 7.2Hz),
1.42-1.61 (2H, m), 2.63 (3H, s), 3.41 (2H, t, J = 6.6H
z), 3.66-3.72 (2H, m), 4.03-4.10 (2H, m), 6.65-6.74
(2H, m), 7.82 (1H, d, J = 9.2Hz)

Example 124 (Production of compound 121) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino) methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 2-methyl-4- ( 2-propoxyethoxy) phenyl boric acid (165 mg), potassium carbonate (176 m
After adding g), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 14 hours. The reaction solution was cooled to room temperature, added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 4/1).
Recrystallization from ethanol gave 7- [2-methyl-4-
(2-propoxyethoxy) phenyl] -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino) methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 121) (184 mg) was obtained. mp 149-151 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3 H, t, J = 7.4 Hz), 1.5
6-1.82 (6H, m), 2.20 (3H, s), 2.64 (1H, m), 3.18 (2H,
t, J = 6.4Hz), 3.30-3.43 (2H, m), 3.51 (2H, t, J = 6.4H
z), 3.56 (2H, s), 3.68−3.75 (2H, m), 3.78−3.83 (2H,
m), 3.99−4.18 (2H, m), 6.79-6.87 (2H, m), 7.11 (1H,
d, J = 8.2Hz), 7.28-7.55 (7H, m), 7.91 (1H, s), 8.18
(1H, d, J = 8.2Hz) IR (KBr) 3374, 2953, 1659, 1609, 1505, 1406, 1290,
1242, 1127cm ^-1 elemental analysis C ₃₆ H ₄₄ N ₂ O ₆ S Calcd. C, 68.33; H, 7.01;
N, 4.43: Found.C, 68.18; H, 6.93; N, 4.53

Reference Example 164 4-bromo-2,3-dimethylphenol (8.2 g)
Was dissolved in DMF (82 ml) and potassium carbonate (7.3) was added.
g) and sodium iodide (6.1 g).
Chloroethyl propyl ether (6.2 ml) was added dropwise, and the mixture was stirred at 90 ° C for 10 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 4-bromo-2,3-dimethyl-1- (2-propoxyethoxy) benzene. (7.5 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4Hz), 1.5
5-1.70 (2H, m), 2.20 (3H, s), 2.36 (3H, s), 3.50 (2H,
t, J = 6.6Hz), 3.75-3.81 (2H, m), 4.03-4.10 (2H, m), 6.
60 (1H, d, J = 8.8Hz), 7.21 (1H, d, J = 8.4Hz)

Reference Example 165 To a solution of magnesium (0.62 g) in THF (9.3 ml) was added 1,2-dibromoethane (3 drops), and the mixture was heated under reflux to obtain 4-bromo-2,3-dimethyl-1. -(2-Propoxyethoxy) benzene (7.0 g) in THF (56
ml) solution was slowly added dropwise. After stirring for 15 minutes, -7
Cool to 8 ° C. and add trimethoxyborane (3.8 g) in TH
F (3.8 ml) was added dropwise, and the temperature was spontaneously raised to room temperature. After stirring at room temperature for 6 hours, 2N hydrochloric acid (28 ml) was added to the mixture for 1 hour.
Stir for 5 minutes. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to obtain 2,3-dimethyl-4- (2-propoxyethoxy) phenylboronic acid (3.8 g). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.89 (3 H, t, J = 7.2 Hz),
1.46-1.61 (2H, m), 2.08 (3H, s), 2.31 (3H, s), 3.44 (2
H, t, 6.6Hz), 3.68-3.74 (2H, m), 4.02-4.07 (2H, m),
6.72 (1H, d, J = 8.4Hz), 7.22 (1H, d, J = 8.2Hz), 7.75 (2
H, br)

Example 125 (Preparation of compound 122) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino) methyl] phenyl]
Toluene / ethanol / water (20/1/1, 13.9 ml) was added to -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), and 3-trifluoromethylphenylboronic acid was added. (174m
g) and potassium carbonate (176 mg) were added, followed by stirring at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (27 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethanol =
Purified in 4/1), recrystallized in ethanol, and
[2,3-dimethyl-4- (2-propoxyethoxy)
Phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino) methyl] phenyl]
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 122) (211 m
g) was obtained. mp 158-159 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4 Hz), 1.5
5-1.83 (6H, m), 2.16 (3H, s), 2.20 (3H, s), 2.24 (3H,
s), 2.64 (1H, m), 3.19 (2H, t, J = 6.4Hz), 3.30-3.43 (2
H, m), 3.53 (2H, t, J = 6.6Hz), 3.57 (2H, s), 3.69-3.
76 (2H, m), 3.84 (2H, t, J = 4.8Hz), 3.97−4.09 (2H,
m), 4.16 (2H, t, J = 4.8Hz), 6.80 (1H, d, J = 8.4Hz), 7.0
0 (1H, d, J = 8.4Hz), 7.28-7.38 (5H, m), 7.43 (1H, dd,
J = 8.0, 1.4Hz), 7.53 (1H, d, J = 8.4Hz), 7.87 (1H, s),
8.18 (1H, d, J = 8.0Hz) IR (KBr) 3331, 2942, 1651, 1593, 1518, 1408, 1289,
1130, 1096, 820cm- ¹ Elemental analysis C ₃₇ H ₄₆ N ₂ O ₆ S Calcd. C, 68.70; H, 7.17;
N, 4.33: Found.C, 68.70; H, 7.19; N, 4.09

Reference Example 166 A mixture of triphenylphosphine (33 g) and 2-bromoethylethyl ether (25 g) was heated and stirred at 140 ° C. for 1 hour. After cooling, the precipitated crystals (51.5
g) was collected by filtration and washed with acetone and diethyl ether. The obtained crystals (27 g) and p-bromobenzaldehyde (8 g) were combined with DMSO (25 ml) and THF (500
ml), potassium t-butoxide (7.3 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was poured into ice water, concentrated, and extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / diethyl ether) to obtain a colorless oil (5.6 g). Dissolve in ethyl acetate (150 ml) and add 5% palladium on carbon (0.
Using 6 g), catalytic reduction was carried out at room temperature for 4 hours. The catalyst was removed by filtration, and the solvent in the filtrate was distilled off. The residue was purified by distillation under reduced pressure to obtain 1-bromo-4- (3-ethoxypropyl) benzene (3.3 g) as a colorless oil. bp 104-111 ° C / 3mmHg. ¹ H-NMR (δppm, CDCl ₃ ) 1.21 (3H, t, J = 6.9Hz), 1.79-1.
93 (2H, m), 2.65 (2H, t, J = 7.7Hz), 3.37-3.52 (4H, m),
7.07 (2H, d, J = 8.4Hz), 7.39 (2H, d, J = 8.4Hz).

Reference Example 167 Magnesium (0.37 g) was suspended in THF (5 ml), and dibromoethane (catalytic amount) was added under a nitrogen atmosphere.
Then, a solution of 1-bromo-4- (3-ethoxypropyl) benzene (3.4 g) in THF (30 ml) was added dropwise. After heating and stirring at 50 ° C for 1.5 hours, dry ice /
After cooling with acetone, trimethoxyborane (3.1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes and concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to obtain 4- (3-ethoxypropyl) phenyl boric acid (1.2 g) as a pale yellow oil. ¹ H-NMR (δppm, CDCl ₃ ) 1.23 (3H, t, J = 7.0Hz), 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 = 7.6Hz).

Reference Example 168 A solution of 4-bromo-2,6-dimethylphenol (20 g) in DMF (100 ml) was added dropwise to a suspension of 60% sodium hydride (4.4 g) in DMF (50 ml) under ice-cooling. did. After stirring at room temperature for 2 hours under a nitrogen atmosphere, bromoethyl ethyl ether (12.3 ml) and sodium iodide (16.4 g) were added, and the mixture was heated and stirred at 75 ° C. overnight.
Poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, and dried using anhydrous magnesium sulfate.
The solvent was distilled off. The residue was purified by distillation under reduced pressure to obtain 5-bromo-2- (2-ethoxyethoxy) -1,3-dimethylbenzene (24.1 g) as a colorless oil. ¹ H-NMR (δppm, CDCl ₃ ) 1.25 (3H, t, J = 7.0Hz), 2.26 (6
H, s), 3.60 (2H, q, J = 7.0Hz), 3.72-3.77 (2H, m), 3.8
8-3.93 (2H, m), 7.13 (2H, s).

Reference Example 169 Magnesium (2.36 g) was suspended in THF (100 ml), dibromoethane (catalytic amount) was added under a nitrogen atmosphere, and then 5-bromo-2- (2-ethoxyethoxy) -1 was added. Of 3,3-dimethylbenzene (24.1 g)
F (100 ml) solution was added dropwise. After heating and stirring at 55 ° C. for 2.5 hours, the mixture was cooled with dry ice / acetone, trimethoxyborane (19.8 ml) was added dropwise, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes and concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off to obtain 4- (2-ethoxyethoxy) -3,5-dimethylphenylboric acid (8.4 g) as colorless crystals. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.16 (3H, t, J = 7.2Hz), 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 170 4-bromo-2-ethoxyphenol (8 g), 1-bromopropane (4 ml), sodium iodide (5.5)
g), potassium carbonate (10.2 g) in DMF (100 m
l) The suspension was heated and stirred under a nitrogen atmosphere at 75 ° C overnight. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure to obtain 1-bromo-3-ethoxy-4-propoxybenzene (8.5 g) as a pale yellow oil. bp 109-113 ° C / 2mmHg. ¹ H-NMR (δppm, CDCl ₃ ) 1.03 (3H, t, J = 7.5Hz), 1.44 (3
H, t, J = 7.0Hz), 1.77-1.89 (2H, m), 3.90-4.11 (4H,
m), 6.74 (1H, d, J = 9.2Hz), 6.96-7.02 (2H, m).

Reference Example 171 Magnesium (0.88 g) was suspended in THF (5 ml), and dibromoethane (catalytic amount) was added under a nitrogen atmosphere.
Next, a solution of 1-bromo-3-ethoxy-4-propoxybenzene (8.5 g) in THF (30 ml) was added dropwise. After heating and stirring at 50 ° C. for 1 hour, the mixture was cooled with dry ice / acetone, trimethoxyborane (7.4 ml) was added dropwise, and the mixture was stirred at room temperature overnight. Add 1N hydrochloric acid, and add
After stirring for minutes, the mixture was concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off to obtain 3-ethoxy-4-propoxyphenyl boric acid (4.7 g) as colorless crystals. ¹ H-NMR (δppm, DMSO-d ₆ ) 0.98 (3H, t, J = 7.5Hz), 1.32
(3H, t, J = 6.9Hz), 1.67-1.78 (2H, m), 3.89-4.06 (4H,
m), 6.90 (1H, d, J = 8.4Hz), 7.32-7.37 (2H, m), 7.82 (2
H, s).

Reference Example 172 DMF of 4-bromo-2-ethoxyphenol (8 g), bromoethyl ethyl ether (5 ml), sodium iodide (5.5 g), and potassium carbonate (10.2 g)
(100 ml) The suspension was heated and stirred at 90 ° C. overnight under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure to give 1-bromo-3-ethoxy-4- (2
-Ethoxyethoxy) benzene (8.1 g) was obtained as a yellow oil. bp 131-134 ° C / 2mmHg. ¹ H-NMR (δppm, CDCl ₃ ) 1.23 (3H, t, J = 7.2Hz), 1.44 (3
H, t, J = 7.0Hz), 3.61 (2H, q, J = 7.0Hz), 3.79 (2H, t,
J = 5.2Hz), 4.00-4.16 (4H, m), 6.80 (1H, d, J = 8.8Hz),
6.96-7.02 (2H, m).

Reference Example 173 Magnesium (0.79 g) was suspended in THF (5 ml), and dibromoethane (catalytic amount) was added under a nitrogen atmosphere.
Then, 1-bromo-3-ethoxy-4- (2-ethoxyethoxy) benzene (8.1 g) in THF (30 m
l) The solution was added dropwise. After heating and stirring at 50 ° C. for 1 hour, the mixture was cooled with dry ice / acetone, trimethoxyborane (6.6 ml) was added dropwise, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes and concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off to obtain 3-ethoxy-4- (2-ethoxyethoxy) phenylborate (2.1 g) as pale red crystals. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.13 (3H, t, J = 6.9Hz), 1.32
(3H, t, J = 6.9Hz), 3.52 (2H, q, J = 6.9Hz), 3.67-3.72
(2H, m), 3.97-4.10 (4H, m), 6.92 (1H, d, J = 7.8Hz),
7.32-7.39 (2H, m), 7.84 (2H, s).

Reference Example 174 4-bromocatechol (9.7 g), chloroethyl ethyl ether (13.3 ml), sodium iodide (1
5.4 g) and potassium carbonate (21.3 g) in DMF (1
The suspension was heated and stirred at 85 ° C. overnight under a nitrogen atmosphere. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure to obtain 1-bromo-3,4-bis (2-ethoxyethoxy) benzene (12.7 g) as an orange oil. bp 154-161 ° C / 1.5mmHg. ¹ H-NMR (δppm, CDCl ₃ ) 1.23 (6H, t, J = 7.2Hz), 3.60 (4
H, q, J = 7.2Hz), 3.76-3.82 (4H, m), 4.10-4.16 (4H,
m), 6.79 (1H, d, J = 8.0Hz), 7.02 (1H, dd, J = 2.2, 8.0H
z), 7.04 (1H, s).

Reference Example 175 Magnesium (1.0 g) was suspended in THF (10 ml), and dibromoethane (catalytic amount) was added under a nitrogen atmosphere.
Next, a solution of 1-bromo-3,4-bis (2-ethoxyethoxy) benzene (12.7 g) in THF (80 ml) was added dropwise. After heating and stirring at 50 ° C. for 1 hour, the mixture was cooled with dry ice / acetone, and trimethoxyborane (8.5 m
After l) was added dropwise, the mixture was stirred at room temperature overnight. Add 1N hydrochloric acid,
After stirring at room temperature for 30 minutes, the mixture was concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to give 3,4-
Bis (2-ethoxyethoxy) phenylborate (1.6
5g) were obtained as colorless crystals. ¹ H-NMR (δppm, DMSO-d ₆ ) 1.07-1.17 (6H, m), 3.44-3.58
(4H, m), 3.67-3.71 (4H, m), 4.01-4.11 (4H, m), 6.93 (1
(H, d, J = 8.0Hz), 7.34-7.41 (2H, m), 7.85 (2H, s).

Example 126 (Preparation of compound 123) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g), 4
-(3-ethoxypropyl) phenylboric acid (0.18
g) A mixture of a 1M aqueous potassium carbonate solution (1.3 ml), ethanol (1.3 ml), and toluene (25 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0.03
g) was added and the mixture was refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline.
Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallized from ethanol, 7- [4- (3-ethoxypropyl) phenyl] -N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (compound 123) (0.25 g) was obtained as colorless crystals. mp 217-219 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.23 (3H, t, J = 7.0Hz), 1.60-1.
86 (4H, m), 1.87-2.01 (2H, m), 2.21 (3H, s), 2.59-2.73
(1H, m), 2.77 (2H, t, J = 7.9Hz), 3.18 (2H, t, J = 6.7H
z), 3.33-3.55 (6H, m), 3.57 (2H, s), 3.72 (2H, t, J =
6.7Hz), 4.01-4.07 (2H, m), 7.31-7.35 (4H, m), 7.51-
7.56 (4H, m), 7.66 (1H, s), 7.70 (1H, d, J = 8.2Hz), 7.
80 (1H, s), 8.21 (1H, d, J = 8.2Hz) IR (KBr) ν:.... 2946, 2853, 1657, 1597, 1518cm -1 Anal calcd for C 35 H 42 N 2 O 5 S: C, 69.74; H, 7.02;
N, 4.65. Found C, 69.47; H, 7.26; N, 4.61.

Example 127 (Preparation of compound 124) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g), 4
A mixture of-(2-ethoxyethoxy) -3,5-dimethylphenylboric acid (0.16 g), 1 M aqueous potassium carbonate solution (1.3 ml), ethanol (1.3 ml), and toluene (25 ml) was added at room temperature under an argon atmosphere. At 30
Stirred for minutes. Tetrakis (triphenylphosphine)
Palladium (0.03 g) was added, and the mixture was refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off. The precipitated crude crystals were collected by filtration and washed with ethyl acetate / hexane. Recrystallized from ethanol, 7-
[4- (2-ethoxyethoxy) -3,5-dimethylphenyl] -N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1 , 1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 124)
(0.32 g) as colorless crystals. mp 211-212 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.27 (3H, t, J = 7.0 Hz), 1.59-1.
77 (4H, m), 2.21 (3H, s), 2.37 (6H, s), 2.58-2.70 (1
H, m), 3.17 (2H, t, J = 6.6Hz), 3.37 (2H, dt, J = 3.0, 1
1.0Hz), 3.57 (2H, s), 3.61-3.82 (6H, m), 3.97-4.06 (4
H, m), 7.25-7.35 (4H, m), 7.54 (2H, d, J = 8.4Hz), 7.6
3 (1H, s), 7.66 (1H, dd, J = 1.8, 9.8Hz), 7.79 (1H, s),
8.19 (1H, d, J = 8.0Hz). IR (KBr) ν: 2928, 2841, 1669, 1597, 1520cm ^-1 . Anal.calcd. For C ₃₆ H ₄₄ N ₂ O ₆ S: C, 68.33; H , 7.01;
N, 4.43. Found C, 68.23; H, 6.95; N, 4.38.

Example 128 (Preparation of compound 125) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g), 3
-Ethoxy-4-propoxyphenyl boric acid (0.16
g) A mixture of a 1M aqueous potassium carbonate solution (1.3 ml), ethanol (1.3 ml), and toluene (25 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0.03
g) was added and the mixture was refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline.
Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallization from ethanol gave 7- (3-ethoxy-
4-propoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 125) (0.16 g) was obtained as colorless crystals. mp 203-205 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.07 (3H, t, J = 7.5Hz), 1.48 (3
(H, t, J = 6.7Hz), 1.64-1.94 (6H, m), 2.21 (3H, s), 2.
60-2.71 (1H, m), 3.17 (2H, t, J = 6.7Hz), 3.37 (2H, dt,
J = 2.4, 10.9Hz), 3.58 (2H, s), 3.71 (2H, t, J = 6.7H
z), 3.74-4.22 (6H, m), 6.97 (1H, d, J = 8.0Hz), 7.11-
7.18 (2H, m), 7.31-7.35 (3H, m), 7.52-7.64 (4H, m),
7.94 (1H, s), 8.16 (1H, d, J = 8.0Hz) IR (KBr) ν:.... 2940, 2845, 1669, 1595, 1516cm -1 Anal calcd for C 35 H 42 N 2 O 6 S ・ 0.2H ₂ O: C, 67.54; H,
6.87; N, 4.50. Found C, 67.44; H, 6.67; N, 4.50.

Example 129 (Preparation of compound 126) 7-bromo-N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g), 3
-Ethoxy-4- (2-ethoxyethoxy) phenylborate (0.18 g), 1 M aqueous potassium carbonate solution (1.3
ml), ethanol (1.3 ml), toluene (25 m
The mixture of 1) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0.03 g) was added, and the mixture was refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallization from ethanol gave 7- [3
-Ethoxy-4- (2-ethoxyethoxy) phenyl]
-N- [4-[[N-methyl-N- (tetrahydro-2
H-pyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 126) (0.26
g) was obtained as colorless crystals. mp 164-168 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.24 (3H, t, J = 7.0Hz), 1.47 (3
(H, t, J = 7.0Hz), 1.61-1.75 (4H, m), 2.21 (3H, s), 2.
59-2.75 (1H, m), 3.17 (2H, t, J = 6.9Hz), 3.38 (2H, dt,
J = 3.6, 11.2Hz), 3.57 (2H, s), 3.61-3.74 (4H, m), 3.
85 (2H, t, J = 4.9Hz), 4.01-4.23 (6H, m), 6.98-7.14 (3
H, m), 7.30-7.35 (3H, m), 7.53-7.65 (4H, m), 7.88 (1
. H, s), 8.17 ( 1H, d, J = 8.0Hz) IR (KBr) ν:... 2946, 2843, 1661, 1599, 1518cm -1 Anal calcd for C 36 H 44 N 2 O 7 S: C, 66.64; H, 6.84;
N, 4.32. Found C, 66.44; H, 6.99; N, 4.19.

Example 130 (Production of compound 127) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g),
3,4-bis (2-ethoxyethoxy) phenyl boric acid (0.23 g), 1 M aqueous potassium carbonate solution (1.3 m
l), ethanol (1.3 ml), toluene (25 m
The mixture of 1) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0.03 g) was added, and the mixture was refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallized from ethanol, 7-
[3,4-bis (2-ethoxyethoxy) phenyl]-
N- [4-[[N-methyl-N- (tetrahydro-2H
-Pyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 127) (0.3
g) was obtained as colorless crystals. mp 150-151 ° C. ¹ H-NMR (δppm, CDCl ₃ ) 1.22 (3H, t, J = 7.0Hz), 1.23 (3
(H, t, J = 6.9Hz), 1.64-1.75 (4H, m), 2.21 (3H, s), 2.
59-2.70 (1H, m), 3.18 (2H, t, J = 6.4Hz), 3.38 (2H, dt,
J = 2.6, 11.1Hz), 3.55-3.73 (8H, m), 3.79-3.84 (4H,
m), 4.01-4.08 (2H, m), 4.19-4.27 (4H, m), 6.99 (1H, d,
J = 8.0Hz), 7.11-7.19 (2H, m), 7.30-7.34 (3H, m), 7.5
5-7.63 (4H, m), 7.99 (1H, s), 8.16 (1H, d, J = 8.0Hz) .IR (KBr) ν: 2975, 2960, 2880, 1665, 1597, 1516c
m ^-1 . Anal.calcd. for C ₃₈ H ₄₈ N ₂ O ₈ S: C, 65.87; H, 6.98;
N, 4.04. Found C, 65.65; H, 6.90; N, 4.16.

Reference Example 176 p-Bromophenol (10.0 g), 3-methoxy-
3-methylbutanol (8.2 g), triphenylphosphine (18.2 g) in tetrahydrofuran (60 m
1) Diethyl azodicarbonate (40% toluene solution, 12.1 g) was added to the solution at 0 ° C under a nitrogen atmosphere.
It was added dropwise over a period of minutes. After returning to room temperature and stirring for 16 hours, the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and insolubles were filtered off. The filtrate was washed with a 1N aqueous sodium hydroxide solution, further washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 5) to give 4-bromo- (3-methoxy-3-methyl) butoxybenzene (15.4 g) as a yellow oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.23 (6H, s), 1.98 (2H,
t, J = 7.4 Hz), 3.21 (3H, s), 4.02 (2H, t, J = 6.0 Hz),
6.78 (2H, dd, J = 8.0, 2.2 Hz), 7.36 (2H, dd, J = 9.2,
2.2 Hz).

Reference Example 177 Magnesium (1.39 g), 1,2-dibromoethane (0.15 ml), dry tetrahydrofuran (50 m
l) to a mixture of 4-bromo- (3-methoxy-3-methyl) butoxybenzene (1) under an argon atmosphere.
5.0 g) in dry tetrahydrofuran (100 ml) was added dropwise over 1 hour. After dropping, at 60 ° C 1
After heating for an hour, at -78 ° C trimethyl borate (11.5 g) in dry tetrahydrofuran (20 ml)
The solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, and then added with 3N hydrochloric acid at 0 ° C. and stirred for 30 minutes. After extracting twice with ethyl acetate, the organic layer was washed twice with saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid was washed with hexane (20 ml) and dried under vacuum to obtain 4- (3-methoxy-3-methyl) butoxyphenylboric acid (5.7 g) as a colorless solid. The filtrate washed with hexane is separated and purified by silica gel column chromatography to give 4- (3-methoxy-3-methyl).
Butoxyphenylboric acid (0.8 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.17 (6H, s), 1.91 (2
H, t, J = 7.0 Hz), 3.12 (3H, s), 4.04 (2H, t, J = 7.4
Hz), 6.88 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 H
z), 7.83 (2H, s).

Reference Example 178 o-Cresol (6.0 g) in dichloromethane (120
ml) and methanol (80 ml), tetrabutylammonium tribromide (27.0 g) was added little by little as a solid. After stirring for 1 hour, the mixture was concentrated under reduced pressure, added with water, and extracted four times with ether. The organic layer was washed twice with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was dried under vacuum to obtain 4-bromo-2-methylphenol (9.3 g) as a colorless solid. ¹ H-NMR (200 MHz, CDCl ₃ ) δ2.22 (3H, s), 4.96 (1H,
s), 6.65 (1H, d, J = 8.4 Hz), 7.15 (1H, dd, J = 8.4,
1.8 Hz), 7.24 (1H, d, J = 1.8 Hz).

Reference Example 179 DM of 4-bromo-2-methylphenol (9.3 g)
After adding potassium carbonate (9.62 g) to the F (50 ml) solution, 2-bromoethyl ethyl ether (7.99) was added.
g) was added dropwise. After completion of the dropwise addition, the mixture was heated at 70 ° C. for 3 days, and then 2-bromoethyl ethyl ether (1.52 g)
Was added dropwise and heated at 70 ° C. for an additional 4.5 hours. After cooling, water was added, and the mixture was extracted with ether. The organic layer was washed with a 1N aqueous sodium hydroxide solution, washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was distilled under reduced pressure (3 mmHg, 170 ° C.) to give 4-bromo-2-methyl- (2-ethoxyethoxy) benzene (10.6 g) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.24 (3H, t, J = 6.0 Hz),
2.21 (3H, s), 3.61 (2H, q, J = 6.2 Hz), 3.79 (2H, t,
J = 3.4 Hz), 4.09 (2H, t, J = 4.6 Hz), 6.69 (1H, d, J =
9.0 Hz), 7.20-7.26 (2H, m).

Reference Example 180 Magnesium (966 mg), 1,2-dibromoethane (0.1 ml), dry tetrahydrofuran (35 ml)
Was added under an argon atmosphere to a mixture of 4-bromo-2-methyl- (2-ethoxyethoxy) benzene (10.0 g).
Of tetrahydrofuran (70 ml) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was heated at 70 ° C. for 1 hour and 20 minutes. Then, a solution of trimethyl borate (8.0 g) in dry tetrahydrofuran (15 ml) was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours, and added with 1N hydrochloric acid (200 ml) at 0 ° C.
For a minute. After extraction twice with ethyl acetate, the organic layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Hexane (40m
l) and vacuum dried to give 4- (2) as a colorless solid.
-Ethoxyethoxy) -3-methylphenylboric acid (3.5 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.13 (3H, t, J = 7.0 H
z), 2.14 (3H, s), 3.51 (2H, q, J = 7.2 Hz), 3.71 (2
H, t, J = 4.4 Hz), 4.09 (2H, t, J = 4.6 Hz), 6.87 (1H,
d, J = 8.0 Hz), 7.50-7.61 (2H, m), 7.75 (2H, s).

Reference Example 181 3-chloro-2,2-dimethylpropanol (5.0
g), camphorsulfonic acid (57m) was added to a solution of 2,3-dihydropyran (4.12g) in ethyl acetate (20ml).
g) was added and the mixture was stirred for 19 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 0.1N aqueous sodium hydroxide solution, further washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was distilled under reduced pressure (2 mmHg, 108 ° C.) to obtain 2- (3-chloro-2,2-dimethylpropoxy) tetrahydropyran (6.07 g) as a colorless oil. . ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.01 (6H, d, J = 4.8 Hz),
1.43-1.90 (6H, m), 3.15 (1H, d, J = 9.2 Hz), 3.42-3.5
9 (4H, m), 3.80-3.91 (1H, m), 4.60 (1H, t, J = 2.8 H
z).

Reference Example 182 After washing sodium hydride (60% oil, 1.34 g) with hexane three times, DMF (50 ml) was added, and a solution of p-bromophenol (4.82 g) in DMF (50 ml) was added. It was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then a solution of 2- (3-chloro-2,2-dimethylpropoxy) tetrahydropyran (4.8 g) in DMF (30 ml) was added dropwise at 0 ° C. Sodium iodide (4.9 g) was added, and the mixture was heated and stirred at 165 ° C. for 3 days.
After cooling, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane 1:10) to give 4-bromo- [2,2- as a colorless oil.
Dimethyl-3- (2-tetrahydropyranoxy) propoxy] benzene (7.37 g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.03 (6H, d, J = 2.6 Hz),
1.45-1.79 (6H, m), 3.20 (1H, d, J = 9.4 Hz), 3.43-3.5
2 (1H, m), 3.62 (1H, d, J = 9.2 Hz), 3.66-3.82 (3H,
m), 4.55 (1H, t, J = 3.0Hz), 6.79 (2H, dd, J = 8.8, 2.
2 Hz), 7.35 (2H, dd, J = 9.2, 2.2 Hz).

Reference Example 183 4-bromo- [2,2-dimethyl-3- (2-tetrahydropyranoxy) propoxy] benzene (7.37 g)
After adding p-toluenesulfonic acid (205 mg) to a methanol (80 ml) solution and stirring at room temperature for 15.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane 1: 5) to give 4-bromo- (2,2-dimethyl-3-hydroxy) propoxybenzene (4.80) as colorless crystals.
g) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.02 (6H, s), 1.74 (1H,
t, J = 4.8 Hz), 3.54 (2H, d, J = 5.8 Hz), 3.73 (2H, s),
6.79 (2H, dd, J = 8.8, 2.2 Hz), 7.37 (2H, dd, J = 9.2,
2.2 Hz). Elemental analysis C ₁₁ H ₁₅ O ₂ Br Calcd. C, 50.98; H, 5.83: Fo
und. C, 50.93; H, 6.01.

Reference Example 184 After washing sodium hydride (60% oil, 1.28 g) with hexane three times, DMF (40 ml) was added, and 4-bromo- (2,2-dimethyl-3-) was added at 0 ° C. A solution of (hydroxy) butoxybenzene (4.5 g) in DMF (50 ml) was added dropwise under a nitrogen atmosphere. After dropping, return to room temperature
Stirred for 0 minutes. Then, a solution of iodoethane (7.82 g) in DMF (80 ml) was added dropwise at 0 ° C.
After returning to room temperature and stirring for 16 hours, water was added to the reaction solution and extracted with hexane. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane 1: 5) to give 4-bromo- (2,2-dimethyl-3-ethoxy) propoxybenzene (7.37 g) as a colorless oil. Was. ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.00 (6H, s), 1.14 (3H,
t, J = 7.0 Hz), 3.25 (2H, s), 3.44 (2H, q, J = 7.4 Hz),
3.69 (2H, s), 6.79 (2H, dd, J = 9.0, 2.2 Hz), 7.35
(2H, dd, J = 9.2, 2.2 Hz).

Reference Example 185 Magnesium (262 mg), 1,2-dibromoethane (0.05 ml), dry tetrahydrofuran (25 m
l) to a mixture of 4-bromo- (2,2-
Dimethyl-3-ethoxy) propoxybenzene (3.0
g) in dry tetrahydrofuran (25 ml)
Dropped over minutes. After completion of the dropwise addition, the mixture was heated at 70 ° C. for 3 hours. -78 ° C and trimethyl borate (2.17
A solution of g) in dry tetrahydrofuran (10 ml) was added dropwise. After completion of the dropwise addition, the temperature was raised, and the mixture was stirred at room temperature for 19 hours. Then, 1N hydrochloric acid (50 ml) was added at 0 ° C.
After stirring for 0 minutes, the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane 1: 1) to give 4- (2,2-dimethyl-3) as a colorless solid.
-Ethoxy) propoxyphenylboric acid (505 mg)
I got ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.96 (6H, s), 1.07 (3
H, t, J = 7.0 Hz), 3.23 (2H, s), 3.40 (2H, q, J = 7.0
Hz), 3.71 (2H, s), 6.88 (2H, t, J = 7.5 Hz), 7.69 (2
H, t, J = 7.6 Hz), 7.80 (2H, s).

Reference Example 186 4-bromo-3-chlorophenol (10.0 g), 3
Ethoxypropanol (6.0 g), triphenylphosphine (15.2 g) in tetrahydrofuran (50 g).
ml) solution at 0 ° C. under a nitrogen atmosphere was added dropwise with diethyl azodicarbonate (40% toluene solution, 25.2 g) over 15 minutes. Then, after stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and insolubles were filtered off. The filtrate was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / hexane 1: 5),
Further, distillation under reduced pressure (1.5 mmHg, 190 ° C.) gave 4-bromo-3-chloro- (3-ethoxypropoxy) benzene (11.2 g) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.19 (3H, t, J = 7.0 Hz),
2.08 (2H, m), 3.50 (2H, q, J = 7.4 Hz), 3.62 (2H, t,
J = 6.2 Hz), 4.11 (2H, t, J = 3.6 Hz), 6.82 (1H, d, J =
8.8 Hz), 7.31 (1H, dd, J = 8.4, 2.2 Hz), 7.49 (1H,
d, J = 2.2 Hz).

Reference Example 187 Magnesium (853 mg), 1,2-dibromoethane (0.2 ml), dry tetrahydrofuran (35 ml)
To a mixture of 4-bromo-3-chloro- (3-ethoxypropoxy) benzene (10.0
g) in 50 ml of dry tetrahydrofuran (70 ml).
Dropped over minutes. After completion of the dropwise addition, the mixture was heated at 65 ° C. for 2.5 hours, then set at −78 ° C. and trimethyl borate (7.0).
A solution of 8 g) in dry tetrahydrofuran (15 ml) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 19 hours. 0
At 1 ° C., 1N hydrochloric acid (50 ml) was added, and the mixture was stirred for 30 minutes, and then extracted three times with ethyl acetate. The organic layer was washed twice with a saturated saline solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane (35 ml) to obtain 3-chloro-4- (3-ethoxypropoxy) phenylboronic acid (5.65 g) as a colorless solid. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.10 (3H, t, J = 7.0 H
z), 1.97 (2H, m), 3.43 (2H, q, J = 7.0 Hz), 3.53 (2
H, t, J = 6.2 Hz), 4.12 (2H, t, J = 6.2 Hz), 7.10 (1H,
d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.0, 1.6 Hz), 7.79
(1H, d, J = 1.4 Hz), 8.03 (2H, s).

Example 131 (Production of compound 128) 4- (3-Methoxy-3-methyl) butoxyphenylboric acid (119 mg), 7-bromo-N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (200 mg), potassium carbonate (138 mg) in toluene (10 ml), ethanol (1 ml), water (1 ml)
And stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (31 mg) was added, and the mixture was added at 100 ° C under argon atmosphere for 8 hours.
Heated for hours. After allowing to cool, add saturated saline, and add ethyl acetate.
Extracted twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol 3: 1) and recrystallized from ethanol (19 ml) to give 7- [4- (3-methoxy-3-methyl) butoxyphenyl as colorless crystals. ] -N- [4-[[N-methyl-
N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 1
28) (136 mg). mp204.5-205.5 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (6H, s), 1.75 (4
H, br), 2.04 (2H, t, J = 6.8 Hz), 2.21 (3H, s), 3.17
(2H, t, J = 7.2 Hz), 3.24 (3H, s), 3.37 (2H, dt, J = 1
1.0, 2.2 Hz), 3.58 (2H, s), 3.73 (2H, t, J = 7.4 H
z), 4.02-4.17 (4H, m), 7.01 (2H, d, J = 8.8 Hz), 7.3
1-7.35 (3H, m), 7.52-7.57 (4H, m), 7.63-7.70 (2H,
m), 8.20 (1H, d, J = 8.4 Hz). Elemental analysis C ₃₆ H ₂₇ N ₂ O ₄ S Calcd. C, 68.33; H, 7.01;
N, 4.43: Found.C, 68.03; H, 6.78; N, 4.33.

Example 132 (Production of compound 129) 4- (2-Ethoxyethoxy) -3-methylphenylboric acid (119 mg), 7-bromo-N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (212 mg), potassium carbonate (147 mg) in toluene (10 ml), ethanol (1 ml), water (1 ml)
And stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (33 mg) was added, and the mixture was added at 100 ° C. under argon atmosphere for 8 hours.
Heated for hours. After allowing to cool, saturated saline was added, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 7:
Separated and purified in 1), and recrystallized from ethanol (22.5 ml) to give 7- [4- (2-ethoxyethoxy) -3-methyl-phenyl] -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 129) (131 mg) was obtained. mp 212-213 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.26 (3H, t, J = 6.4 Hz),
1.75 (4H, br), 2.21 (3H, s), 2.31 (3H, s), 2.65 (1
H, br), 3.16 (2H, t, J = 7.0 Hz), 3.38 (2H, dt, J = 9.
0, 3.0 Hz), 3.57-3.75 (6H, m), 3.85 (2H, t, J = 4.4
Hz), 4.04 (2H, d, J = 11.2 Hz), 4.19 (2H, t, J = 5.2 H
z), 6.92 (2H, d, J = 9.2 Hz), 7.26-7.39 (4H, m), 7.54
(2H, d, J = 8.8 Hz), 7.62-7.68 (2H, m), 7.87 (1H,
s), 8.18 (1H, d, J = 8.2 Hz). Elemental analysis C ₃₅ H ₄₂ N ₂ O ₆ S ・ 0.1H ₂ O Calcd. C, 67.94; H,
6.84; N, 4.53: Found.C, 67.45; H, 6.63; N,
4.53.

Example 133 (Production of compound 130) 4- (3-ethoxy-2,2-dimethyl) propoxyphenylboronic acid (189 mg), 7-bromo-N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg) were suspended in toluene (15 ml), ethanol (1.5 ml), and water (1.5 ml), and the suspension was performed under an argon atmosphere. Stir for 30 minutes. Then, tetrakistriphenylphosphine palladium (47 mg) was added, and under an argon atmosphere,
Heated at 100 ° C. for 8 hours. After allowing to cool, saturated saline was added, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol 8: 1), and ethanol (22.5 ml)
To give colorless crystals, 7- [4- (3-ethoxy-2,2-dimethylpropoxy) phenyl] -N
-[4-[[N-methyl-N- (tetrahydropyran-
4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 130) (175 mg) was obtained. mp209-210 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.04 (6H, s), 1.16 (3H,
t, J = 7.2 Hz), 1.76 (4H, br), 2.21 (3H, s), 3.17 (2
H, t, J = 6.2 Hz), 3.20 (2H, s), 3.38-3.51 (4H, m),
3.58 (2H, s), 3.69-3.79 (4H, m), 4.04 (2H, d, J = 1
1.4 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.31-7.35 (3H, m),
7.52-7.70 (6H, m), 7.85 (1H, s), 8.20 (1H, d, J =
8.0 Hz). Elemental analysis C ₃₇ H ₄₆ N ₂ O ₆ S Calcd. C, 68.70; H, 7.17;
N, 4.33: Found.C, 68.83; H, 7.25; N, 4.36.

Example 134 (Production of compound 131) 3-Chloro-4- (3-ethoxypropoxy) phenylboric acid (194 mg), 7-bromo-N- [4-[[N
-Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (300 mg), potassium carbonate (208 mg) in toluene (15 ml), ethanol (1.5 ml), water (1.
5 ml) and stirred under an argon atmosphere for 30 minutes. Then, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was added under an argon atmosphere.
Heated at ° C. for 8 hours. After allowing to cool, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: ethanol 8:
Separated and purified in 1), and recrystallized from ethanol (23 ml) to give 7- [3-chloro-4- (3-
Ethoxypropoxy) phenyl] -N- [4-[[N-
Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 131) (229 mg) was obtained. mp 182-183 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ1.21 (3H, t, J = 6.8 Hz),
1.75 (4H, m), 2.14 (2H, m), 2.21 (3H, s), 2.65 (1H,
m), 3.17 (2H, t, J = 7.0 Hz), 3.31-3.76 (10H, m),
4.04 (2H, d, J = 11.4 Hz), 4.21 (2H, t, J = 6.6 Hz),
7.05 (1H, d, J = 8.4 Hz), 7.31-7.35 (3H, m), 7.43-7.
68 (6H, m), 7.88 (1H, s), 8.21 (1H, d, J = 8.0 Hz).

Reference Example 188 4-Bromo-3-chlorophenol (9.8 g) was added to DMF.
(98 ml) and potassium carbonate (9.8 at room temperature).
g), sodium iodide (7.8 g) and 2-chloroethylpropyl ether (7.8 ml) were added in this order. 90
After stirring at ℃ for 16 hours, the reaction solution was cooled to room temperature and added to water. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1-bromo-2-chloro-4- (2-propoxyethoxy) benzene (8 .8 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 1.5
5-1.70 (2H, m), 3.48 (2H, t, J = 6.6Hz), 3.76 (2H, t, J
= 4.4Hz), 4.08 (2H, t, J = 4.4Hz), 6.72 (1H, dd, J = 8.8,
3.04), 7.04 (1H, d, J = 3.0 Hz), 7.46 (1H, d, J = 9.2 Hz) Reference Example 189 1-bromo-2-chloro-4- (2-propoxyethoxy) benzene (7. 0 g) in THF (70 ml)
At −78 ° C., 1.6 M n-butyllithium / hexane (17.3 ml) was removed and stirred for 1 hour. Trimethoxyborane (7.8 g) was added dropwise, and the mixture was stirred for 30 minutes.
The temperature was raised naturally to room temperature. 2N hydrochloric acid (28 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 2-chloro-4- (2-propoxyethoxy).
Phenyl boric acid (1.70 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.86 (3H, t, J = 7.2Hz),
1.43-1.58 (2H, m), 3.40 (2H, t, 6.6Hz), 3.65-3.71 (2
H, m), 4.08-4.15 (2H, m), 6.84-6.95 (1H, m), 7.38 (1
H, d, J = 8.0Hz), 7.84 (1H, d, J = 8.4Hz), 8.08 (2H, br)

Example 135 (Preparation of Compound 132) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
To 1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.40 g) was added toluene /
Ethanol / water (10/1/1, 19.2 ml) was added, and 2-chloro-4- (2-propoxyethoxy) phenylborate (0.24 g) and potassium carbonate (0.24 g) were added.
After adding g), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (45 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the reaction solution was added to water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 4/1).
After recrystallization from ethanol, 7- [2-chloro-4- (2-
Propoxyethyl) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin- 4-carboxamide (compound 1
32) (206 mg). mp 150-152 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz), 1.5
5-1.82 (6H, m), 2.20 (3H, s), 2.64 (1H, m), 3.15-3.22
(2H, m), 3.30-3.44 (2H, m), 3.51 (2H, t, J = 6.6Hz),
3.56 (2H, s), 3.72 (2H, t, J = 6.6Hz), 3.75-3.84 (2H,
m), 3.98-4.08 (2H, m), 4.17 (2H, t, J = 4.8Hz), 6.94 (1
H, dd, J = 8.8, 2.6Hz), 7.08 (1H, d, J = 2.4Hz), 7.21-
7.33 (4H, m), 7.50-7.60 (4H, m), 7.83 (1H, s), 8.20 (1
(H, d, J = 8.0Hz) IR (KBr) 3349, 2959, 1651, 1603, 1516, 1408, 1289,
1128, 1060, 822cm- ¹ Elemental analysis C ₃₅ H ₄₁ FN ₂ O ₆ S Calcd.C, 64.35; H, 6.33; N, 4.29: Found.C, 64.17; H, 6.24; N, 4.22

Reference Example 190 4-Bromo-3-fluorophenol (9.0 g) was added to DM
F (90 ml), and potassium carbonate (9.
8 g), sodium iodide (7.8 g) and 2-chloroethylpropyl ether (7.7 ml) in this order. 9
After stirring at 0 ° C. for 16 hours, the mixture was cooled to room temperature, and the reaction solution was added to water. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1-
Bromo-2-fluoro-4- (2-propoxyethoxy) benzene (8.8 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 1.5
4-1.73 (2H, m), 3.48 (2H, t, J = 6.6Hz), 3.74-3.81 (2H,
m), 4.06-4.13 (2H, m), 6.69-6.76 (1H, m), 7.37 (1H,
d, J = 8.0Hz), 7.69 (1H, d, J = 7.2Hz)

Reference Example 191 1-bromo-2-fluoro-4- (2-propoxyethoxy) benzene (8.0 g) was dissolved in THF (96 ml), and 1.6M n-butyllithium was added at -78 ° C. Hexane (19.8 ml) was removed and stirred for 1 hour. Trimethoxyborane (9.0 g) was added dropwise, and after stirring for 30 minutes, the temperature was naturally raised to room temperature. 2N hydrochloric acid (32 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was extracted with ethyl acetate,
After washing with saturated saline, it was dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/1).
To obtain 2-fluoro-4- (2-propoxyethoxy) phenylboronic acid (1.17 g). ^{1 H-NMR (200MHz, DMSO} -d 6) δ0.87 (3H, t, J = 7.2Hz),
1.46-1.60 (2H, m), 3.37-3.45 (2H, m), 3.66-3.72 (2H, m
m), 4.08-4.13 (2H, m), 6.70-6.77 (2H, m), 7.50 (1H,
d, J = 8.0Hz), 7.89 (2H, br)

Example 136 (Production of compound 133) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.35 g) was added to toluene /
Ethanol / water (10/1/1, 16.3 ml) was added, and 2-fluoro-4- (2-propoxyethoxy) phenylborate (0.20 g) and potassium carbonate (0.20 g) were added.
After adding g), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (31 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. After washing with saturated saline, it was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 4/1).
Recrystallization from ethanol gave 7- [2-fluoro-4- (2
-Propoxyethyl) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine -4-Carboxamide (Compound 133) (105 mg) was obtained. mp 172-174 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz), 1.5
8-1.76 (6H, m), 2.21 (3H, s), 2.65 (1H, m), 3.17 (2H,
t, J = 6.6Hz), 3.32-3.44 (2H, m), 3.51 (2H, t, J = 6.6H
z), 3.57 (2H, s), 3.72 (2H, t, J = 6.2Hz), 3.79-3.84 (2
H, m), 3.98-4.08 (2H, m), 4.17 (2H, t, J = 4.4Hz), 6.7
5-6.87 (2H, m), 7.30-7.40 (4H, m), 7.51-7.67 (4H, m),
7.85 (1H, s), 8.20 (1H, d, J = 8.6Hz) IR (KBr) 3345, 2940, 1651, 1620, 1520, 1410, 131
6, 1288, 1127, 816cm- ¹ Elemental analysis C ₃₅ H ₄₁ ClN ₂ O ₆ S ・ 0.3H ₂ O Calcd.C, 65.46; H, 6.53; N, 4.36: Found.C, 65.44; H, 6.38; N , 4.31

Example 137 (Preparation of compound 134) N- [4-[[N-methyl-N- (tetrahydropyran-4
-Yl) amino] methyl] phenyl] -7- [4- (2
-Propoxyethoxy) phenyl)]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (1.0 g) was dissolved in THF (30 ml), and L
-After adding tartaric acid (0.36 mg), the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the obtained residue was recrystallized from ethanol to give N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4- (2-propoxyethoxy) phenyl)]-1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide L-tartrate (compound 134) (1.7 g) was obtained. mp 116-119 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3 H, t, J = 7.2 Hz),
1.42-1.81 (6H, m), 2.22 (3H, s), 2.79 (1H, m), 3.22-
3.30 (2H, m), 3.39-3.46 (2H, m), 3.69-3.82 (6H, m),
3.70 (2H, s), 3.89-3.97 (2H, m), 4.17 (2H, s), 4.14-
4.19 (2H, m), 7.10 (2H, d, J = 8.8Hz), 7.33 (2H, d, J =
8.4Hz), 7.55 (1H, s), 7.69-7.89 (5H, m), 8.05-8.09 (2
H, m), 10.22 (1H, s) IR (KBr) 3247, 2965, 1663, 1607, 1518, 1416, 129
2, 1252, 1128, 826cm- ¹ Elemental analysis C ₃₉ H ₄₈ N ₂ O ₁₂ S ・ 0.2H ₂ O Calcd.C, 60.64; H, 6.32; N, 3.63: Found.C, 60.59; H, 6.12; N , 3.64

Reference Example 192 5-Bromo-2-methyl-1,3-benzoxazole (9.4 g) was dissolved in THF (94 ml). 30.5m
1) was removed and stirred for 1 hour. A THF solution (9.2 ml) of trimethoxyborane (9.2 ml) was added dropwise, and 3
After stirring for 0 minutes, the temperature was naturally raised to room temperature. Water (37.6
ml) and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / isopropyl ether to give 2-methyl-
1,3-benzoxazol-5-yl boric acid (5.5
g) was obtained. ^{1 H-NMR (200MHz, DMSO} -d 6) δ2.17 (3H, s), 6.88-6.93
(1H, m), 7.14-7.40 (1H, m), 7.48-7.56 (1H, m), 10.24
(2H, br)

Example 138 (Preparation of Compound 135) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.35 g) was added to toluene /
After adding ethanol / water (10/1/1, 16.3 ml), 2-methyl-1,3-benzoxazol-5-yl boric acid (0.14 g) and potassium carbonate (0.23 g) were added. And stirred at room temperature for 30 minutes. Add tetrakistriphenylphosphine palladium (31 mg) and add 1
The mixture was heated under reflux for 4 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / ethyl acetate).
Purified with ethanol = 4/1) and recrystallized with ethanol to give 7- (2-methyl-1,3-benzoxazole-
5-yl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 135) (110 m
g) was obtained. mp 236-240 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ1.42-1.76 (4H, m), 2.10
(3H, s), 2.50 (3H, s), 3.06 (2H, t, J = 6.6Hz), 3.20-
3.32 (2H, m), 3.52 (2H, s), 3.75-3.83 (2H, m), 3.85-
3.94 (2H, m), 7.27 (2H, d, J = 8.2Hz), 7.38 (1H, s), 7.
65 (2H, d, J = 8.4Hz), 7.79-7.85 (1H, d, J = 8.4Hz), 10.1
5 (1H, s) IR (KBr) 3256, 2953, 2836, 1655, 1634, 1534, 1412,
1319, 1130, 885, 822cm ^-1

Reference Example 193 5-Bromo-2- (hydroxymethyl) -1-benzofuran (5.7 g) was dissolved in THF (57 ml), and 60% sodium hydride (1.4 g) was added at 0 ° C. And stirred at room temperature for 1 hour. At 0 ° C., 1-bromopropane (3.
1 ml) and stirred at 65 ° C. for 16 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 8 /
Purification was performed in 1) to obtain 5-bromo-2- (propoxymethyl) -1-benzofuran (5.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.2Hz), 1.5
6-1.72 (2H, m), 3.50 (2H, t, J = 6.6Hz), 4.59 (2H, s),
6.63 (1H, S), 7.35-7.36 (2H, m), 7.66-7.68 (1H, m)

Reference Example 194 5-Bromo-2- (propoxymethyl) -1-benzofuran (4.8 g) was dissolved in THF (48 ml).
At 1.6M n-butyllithium / hexane (12.3
ml) was removed and stirred for 1 hour. Trimethoxyborane (5.6 g) was added dropwise, and the mixture was stirred for 30 minutes, then allowed to warm to room temperature and stirred for 12 hours. 2N hydrochloric acid (19.2 ml)
Was added and stirred for 15 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2 /
Purification was performed in 1) to obtain 2- (propoxymethyl) -1-benzofuran-5-yl boric acid (0.22 g). ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.84 (3H, t, J = 7.0Hz),
1.40-1.55 (2H, m), 3.30-3.36 (2H, m), 3.31 (2H, s),
4.37-4.41 (1H, m), 6.80 (1H, s), 7.47 (1H, d, J = 8.2H
z), 7.72 (1H, d, J = 8.4Hz), 7.95 (2H, br)

Example 139 (Production of compound 136) 7-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.41 g) was added to toluene /
Ethanol / water (10/1/1, 19.2 ml) was added, and 2- (propoxymethyl) -1-benzofuran-5 was added.
-Ill boric acid (0.22 g), potassium carbonate (0.24 g)
After adding g), the mixture was stirred at room temperature for 30 minutes. Tetrakistriphenylphosphine palladium (45 mg) was added, and the mixture was heated under reflux for 14 hours. After cooling to room temperature, the mixture was added to water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 4/1), recrystallized from ethanol, and N- [4-[[N-methyl-N -(Tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [2- (propoxymethyl) -1-benzofuran-5-yl] -1,1-dioxo-2,3-dihydro-1-benzothiepine -4-Carboxamide (Compound 136) (184 mg) was obtained. mp 204-206 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.92 (3H, t, J = 7.2 Hz),
1.30-1.43 (2H, m), 1.55-1.77 (4H, m), 2.20 (3H, s),
2.64 (1H, m), 3.17 (2H, t, J = 6.2Hz), 3.30-3.54 (4H,
m), 3.57 (2H, s), 3.98-4.09 (2H, m), 4.39 (1H, t, J = 6.
6Hz), 6.68 (1H, s), 7.29-7.37 (3H, m), 7.43-7.59 (4H,
m), 7.66-7.74 (3H, m), 8.02 (1H, s), 8.21 (1H, d, J =
8.0Hz) IR (KBr) 3254, 2948, 1655, 1599, 1530, 1410, 1316,
1128, 806cm ^-1

Reference Example 195 D of 4-bromo-2-methylphenol (14.2 g)
After potassium carbonate (14.7 g) was added to the MF (75 ml) solution, bromopropane (9.33 g) was added dropwise.
After completion of the dropwise addition, the mixture was heated at 70 ° C. for 3 hours. After allowing to cool, water was added and extracted with hexane. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-bromo-2-methyl-propoxybenzene (10.
6 g) were obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.04 (t, 3H, J = 7.4 Hz),
1.73-1.90 (m, 2H), 2.19 (s, 3H), 3.89 (t, 2H, J =
6.2 Hz), 6.66 (dd, 1H, J = 7.4, 1.8 Hz), 7.19-7.24
(m, 2H).

Reference Example 196 Magnesium (1.09 g), 1,2-dibromoethane (0.2 ml), dry tetrahydrofuran (35 ml)
To a mixture of 4-bromo-2 under an argon atmosphere.
A solution of -methylphenol (10.0 g) in dry tetrahydrofuran (70 ml) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was heated at 65 ° C. for 1 hour and 45 minutes. Then-
At 78 ° C., a solution of trimethyl borate (9.07 g) in dry tetrahydrofuran (15 ml) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 16 hours while gradually returning to room temperature. Then, 1N hydrochloric acid (200 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. The mixture was extracted twice with ethyl acetate, and the organic layer was washed twice with saturated saline. Then, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane (35 ml) and dried in vacuo to give a colorless solid.
-Methyl-4-propoxyphenylboric acid (1.32
g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.00 (t, 3H, J = 7.4 H
z), 1.66-1.83 (m, 2H), 2.14 (s, 3H), 3.94 (t, 2H, J
= 6.6 Hz), 6.85 (d, 1H, J = 8.0 Hz), 7.52-7.61 (m, 2
H), 7.75 (s, 2H).

Reference Example 197 Bromoacetaldehyde dimethyl acetal (12.2 g) was added to a suspension of 4-propoxyphenol (10.0 g) and potassium carbonate (10.0 g) in DMF (50 ml), and the mixture was refluxed for 14 hours. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with a 1N aqueous sodium hydroxide solution, further washed with a saturated saline solution, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 4- (2,2-dimethoxy) ethoxy-propoxybenzene (12.2 g) as a yellow oil. . ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.02 (t, 3H, J = 7.4 Hz),
1.69-1.83 (m, 2H), 3.45 (s, 6H), 3.86 (t, 2H, J =
6.6 Hz), 3.96 (d, 2H, J = 5.6 Hz), 4.70 (t, 1H, J = 5.2
Hz), 6.78-6.89 (m, 4H).

Reference Example 198 To a suspension of polyphosphoric acid (5.2 g) in toluene (120 ml) was added 4- (2,2-dimethoxy) ethoxy-propoxybenzene (5.0 g), and the mixture was heated at 100 ° C. overnight.
After allowing to cool, water was added, and the mixture was separated. The organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-propoxybenzofuran (1.7 g) as a brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.05 (t, 3H, J = 7.4 Hz),
1.74-1.92 (m, 2H), 3.95 (t, 2H, J = 6.6 Hz), 6.69
(dd, 1H, J = 2.2, 0.8 Hz), 6.90 (dd, 1H, J = 9.2,2.6 H
z), 7.05 (d, 1H, J = 2.6 Hz), 7.37 (d, 1H, J = 9.4 H
z), 7.58 (d, 1H, J = 2.2 Hz).

Reference Example 199 A solution of 5-propoxybenzofuran (1.50 g) in dry tetrahydrofuran (15 ml) was added at 0 ° C. under an argon atmosphere to an n-butyllithium hexane solution (1.6 M, 1.5 M).
6.4 ml) in dry tetrahydrofuran solution (15 m
l) was added dropwise. After stirring for 2 hours, trimethyl borate (2.65 g) in dry tetrahydrofuran (1
5 ml) The solution was added dropwise, and the mixture was stirred overnight while gradually returning to room temperature. At 0 ° C., 1N hydrochloric acid was added to the reaction solution, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5-propoxybenzofuran-2-ylboric acid (0.62 g) as a red solid. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.06 (t, 3H, J = 7.4 H
z), 1.75-1.92 (m, 2H), 3.95 (t, 2H, J = 6.6 Hz), 5.27
(br, 2H), 6.98 (dd, 1H, J = 9.2, 3.0 Hz), 7.07 (d,
1H, J = 2.6 Hz), 7.30 (d, 1H, J = 0.8 Hz), 7.39 (d, 1
(H, J = 8.8 Hz).

Reference Example 200 Bromoacetaldehyde dimethyl acetal (40.1 g) was added to a suspension of 4-methoxyphenol (26.7 g) and potassium carbonate (32.8 g) in DMF (150 ml), and the mixture was refluxed for 2.5 hours. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with a 1N aqueous sodium hydroxide solution, further washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-methoxy- (2,2-dimethoxy) ethoxybenzene (40.4 g) as a dark brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.45 (s, 6H), 3.77 (s,
3H), 3.96 (d, 2H, J = 5.2 Hz), 4.70 (t, 1H, J = 5.2 H
z), 6.79-6.90 (m, 4H).

Reference Example 201 To a suspension of polyphosphoric acid (38.3 g) in toluene (400 ml) was added 4-methoxy- (2,2-dimethoxy) ethoxybenzene (38.0 g), and the mixture was heated at 100 ° C. overnight. After allowing to cool, water was added for liquid separation, and the organic layer was washed with a 1N aqueous sodium hydroxide solution. Then, it was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-methoxybenzofuran (6.5 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.85 (s, 3H), 6.71-7.00
(m, 2H), 7.06 (d, 1H, J = 2.2 Hz), 7.39 (d, 1H, J = 9.
8 Hz), 7.59 (d, 1H, J = 2.2 Hz).

Reference Example 202 Collidine (2) of 5-methoxybenzofuran (3.6 g)
(0 ml), lithium iodide (6.5 g) was added to the solution, and the mixture was refluxed overnight under an argon atmosphere. After cooling, the mixture was acidified with 1N hydrochloric acid (pH = 4) and extracted three times with ethyl acetate. The organic layer was washed twice with 1N hydrochloric acid, further washed with water and saturated saline, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-hydroxybenzofuran (1.6 g) as a yellow oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 6.61 (dd, 1H, J = 2.2, 0.
6 Hz), 6.82 (dd, 1H, J = 8.8, 2.6 Hz), 7.01 (d, 1H,
J = 2.6 Hz), 7.34 (d, 1H, J = 8.8 Hz), 7.58 (d, 1H, J =
2.2 Hz).

Reference Example 203 DMF of 5-hydroxybenzofuran (1.90 g)
After adding potassium carbonate (5.09 g) and sodium iodide (5.52 g) to the (30 ml) solution, 2-chloroethylpropyl ether (3.47 g) was added, and the mixture was added at 95 ° C. for 3 days under a nitrogen atmosphere. Heated. After cooling, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and saturated saline, and then dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-propoxyethoxybenzofuran (1.22 g) as a yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.8 Hz),
1.56-1.74 (m, 2H), 3.51 (t, 2H, J = 6.4 Hz), 3.81
(t, 2H, J = 5.2 Hz), 4.16 (t, 2H, J = 4.6 Hz), 6.70 (d
d, 1H, J = 2.2, 1.2 Hz), 6.94 (dd, 1H, J = 9.0, 2.6 H
z), 7.09 (d, 1H, J = 2.2 Hz), 7.38 (d, 1H, J = 8.8 H
z), 7.59 (d, 1H, J = 2.2 Hz).

Reference Example 204 A solution of 5-propoxyethoxybenzofuran (1.20 g) in dry tetrahydrofuran (10 ml) was added to a solution of n-butyllithium hexane (1.
6M, 4.5 ml) was added dropwise. After stirring for 1 hour -7
A solution of trimethyl borate (1.54 g) in dry tetrahydrofuran (15 ml) was added dropwise at 8 ° C., and the mixture was stirred overnight while gradually returning to room temperature. At 0 ° C., 1N hydrochloric acid was added to the reaction solution, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was washed with hexane to obtain 5-propoxyethoxybenzobenzofuran-2-ylboric acid (0.82 g) as a pale red solid. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (t, 3H, J = 7.4 H
z), 1.45-1.59 (m, 2H), 3.44 (t, 2H, J = 6.6 Hz), 3.71
(t, 2H, J = 4.4 Hz), 4.11 (t, 2H, J = 4.4 Hz), 6.94 (d
d, 1H, J = 9.2, 2.6 Hz), 7.19 (d, 1H, J = 2.4 Hz), 7.3
8 (s, 1H), 7.45 (d, 1H, J = 9.2 Hz), 8.51 (s, 2H).

Reference Example 205 2-hydroxy-4-methoxybenzaldehyde (2
0.0g) and a suspension of potassium carbonate (20.0 g) in 2-butanone (80 ml) were added to diethyl bromomalonate (3 ml).
9.3 g) and refluxed for 7 hours under a nitrogen atmosphere. After allowing to cool, water was added, then acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained dark brown oil was suspended in a solution of potassium hydroxide (20.0 g) in ethanol (200 ml) and refluxed for 1 hour. After allowing to cool, water was added, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was washed with hexane to obtain 6-methoxybenzofuran-2-carboxylic acid (11.8 g) as a yellow solid. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.89 (s, 3H), 6.91-7.00
(m, 1H), 7.07 (br, 1H), 7.47-7.62 (m, 2H).

Reference Example 206 6-methoxybenzofuran-2-carboxylic acid (22.2)
g), a suspension of copper powder (3.7 g) in quinoline (200 ml) was refluxed under a nitrogen atmosphere for 2 hours. After allowing to cool, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed six times with 2N hydrochloric acid, and further washed with water and saturated saline. Dry over magnesium sulfate and evaporate the solvent under reduced pressure to give 6-methoxybenzofuran (17.1 g) as a dark brown oil.
I got ¹ H-NMR (200 MHz, CDCl ₃ ) δ 3.86 (s, 3H), 6.69 (dd,
1H, J = 2.2, 1.2 Hz), 6.88 (dd, 1H, J = 8.4, 2.2 Hz),
7.04 (br, 1H), 7.45 (d, 1H, J = 6.6 Hz), 7.53 (d, 1
(H, J = 1.4 Hz).

Reference Example 207 Lithium iodide (30.5 g) was added to a solution of 6-methoxybenzofuran (16.9 g) in collidine (200 ml), and the mixture was refluxed for one day under an argon atmosphere. 1N after cooling
Hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed 5 times with 2N hydrochloric acid, further washed with water and saturated saline, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 6-hydroxybenzofuran (2.9 g) as a dark brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 5.04 (s, 1H), 6.69 (dd,
1H, J = 2.6, 1.0 Hz), 6.79 (dd, 1H, J = 8.4, 2.2 Hz),
7.00 (d, 1H, J = 2.0 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.
52 (d, 1H, J = 2.2 Hz).

Reference Example 208 DMF of 6-hydroxybenzofuran (1.30 g)
After adding potassium carbonate (1.88 g) to the (15 ml) solution, bromopropane (1.44 g) was added dropwise under a nitrogen atmosphere. After stirring overnight, water was added and extracted twice with ethyl acetate. The organic layer was washed three times with water, further washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-propoxybenzofuran (0.93 g) as a yellow oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (t, 3H, J = 7.4 Hz),
1.75-1.93 (m, 2H), 3.96 (t, 2H, J = 6.6 Hz), 6.69
(d, 1H, J = 2.2 Hz), 6.88 (dd, 1H, J = 8.4, 2.0 Hz),
7.03 (d, 1H, J = 2.2 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.
52 (d, 1H, J = 2.2 Hz).

Reference Example 209 An n-butyllithium hexane solution (1.6) was added to a solution of 6-propoxybenzofuran (0.83 g) in dry tetrahydrofuran (12 ml) at 0 ° C. under an argon atmosphere.
M, 4.7 ml) was added dropwise. After stirring for 1 hour -78
At 0 ° C., a solution of trimethyl borate (1.47 g) in dry tetrahydrofuran (15 ml) was added dropwise, and the mixture was stirred overnight while gradually returning to room temperature. After adding 1N hydrochloric acid to the reaction solution at 0 ° C. and stirring for 30 minutes, the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane to obtain 6-propoxybenzofuran-2-ylboric acid (0.56 g) as a light red solid. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.00 (t, 3H, J = 7.8 H
z), 1.71-1.81 (m, 2H), 3.97 (t, 2H, J = 6.6 Hz), 6.85
(dt, 1H, J = 8.4, 2.2 Hz), 7.10 (s, 1H), 7.37 (s, 1
H), 7.53 (d, 1H, J = 8.4 Hz), 8.41 (s, 2H).

Reference Example 210 DMF of 6-hydroxybenzofuran (1.38 g)
(40 ml) solution, potassium carbonate (3.70 g) and sodium iodide (4.01 g) were added, and then 2-chloroethylpropyl ether (2.52 g) was added thereto. Heated. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed four times with a 1N aqueous sodium hydroxide solution, three times with water, and then with a saturated saline solution. Drying over magnesium sulfate and evaporation of the solvent under reduced pressure gave 6-propoxyethoxybenzofuran (1.50 g) as a yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.4 Hz),
1.56-1.74 (m, 2H), 3.51 (t, 2H, J = 6.6 Hz), 3.81
(t, 2H, J = 4.4 Hz), 4.17 (t, 2H, J = 4.4 Hz), 6.69
(d, 1H, J = 2.2 Hz), 6.91 (dd, 1H, J = 8.6, 2.2 Hz),
7.06 (d, 1H, J = 2.2 Hz), 7.44 (d, 1H, J = 8.6 Hz), 7.
53 (d, 1H, J = 2.2 Hz).

Reference Example 211 A solution of 6-propoxyethoxybenzofuran (1.34 g) in dry tetrahydrofuran (15 ml) was added to a solution of n-butyllithium hexane (1.
6M, 5.7 ml) was added dropwise. After stirring for 1 hour -7
A solution of trimethyl borate (1.90 g) in dry tetrahydrofuran (15 ml) was added dropwise at 8 ° C., and the mixture was stirred overnight while gradually returning to room temperature. At 0 ° C., 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes, and then extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-propoxyethoxybenzofuran-2-ylboric acid (0.27 g) as a brown solid. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (t, 3H, J = 7.0 H
z), 1.45-1.59 (m, 2H), 3.43 (t, 2H, J = 6.6 Hz), 3.70
(t, 2H, J = 4.6 Hz), 4.17 (t, 2H, J = 5.2 Hz), 6.82
(d, 1H, J = 2.2 Hz), 6.98 (d, 1H, J = 8.8 Hz), 7.55
(d, 1H, J = 8.2 Hz), 7.83 (d, 1H, J = 2.2 Hz), 8.04 (s,
2H).

Reference Example 212 o-Vaniline (25.0 g), potassium carbonate (28.4 g)
To a suspension of g) in 2-butanone (100 ml) was added diethyl bromomalonate (49.1 g), and the mixture was refluxed for 7 hours under a nitrogen atmosphere. After allowing to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained red oil was suspended in a solution of potassium hydroxide (17.5 g) in ethanol (175 ml) and refluxed for 2 hours. After allowing to cool and adding water, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate.
Extracted times. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-methoxybenzofuran-2-carboxylic acid (11.8 g) as a yellow solid. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 3.96 (s, 3H), 7.09 (d
d, 1H, J = 7.4, 1.4 Hz), 7.26 (t, 1H, J = 7.8 Hz), 7.33
(dd, 1H, J = 6.2, 1.8 Hz), 7.64 (s, 1H).

Reference Example 213 7-methoxybenzofuran-2-carboxylic acid (11.0
4g), copper powder (1.83g) quinoline (200ml)
The suspension was refluxed under a nitrogen atmosphere for 2 hours. After cooling 2
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed eight times with 2N hydrochloric acid, further washed with water and saturated saline, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 7-methoxybenzofuran (8.19 g) as a dark brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 4.02 (s, 3H), 6.77 (d,
1H, J = 1.8 Hz), 6.81 (dd, 1H, J = 6.8, 2.2 Hz), 7.16
(t, 1H, J = 7.8 Hz), 7.21 (d, 1H, J = 5.6 Hz), 7.63
(d, 1H, J = 2.2 Hz).

Reference Example 214 Collidine (8) of 7-methoxybenzofuran (8.0 g)
0 ml) solution, lithium iodide (14.5 g) was added, and the mixture was refluxed for 1 day under an argon atmosphere. After allowing to cool, 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with 1N hydrochloric acid, further washed with water and saturated saline, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 7-hydroxybenzofuran (7.0 g) as a dark brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 5.45 (br, 1H), 6.78 (d,
1H, J = 2.2 Hz), 6.84 (dd, 1H, J = 7.0, 1.4 Hz), 7.09
(d, 1H, J = 7.4 Hz), 7.17 (dd, 1H, J = 7.8, 1.8Hz),
7.61 (d, 1H, J = 2.2 Hz).

Reference Example 215 DMF of 7-hydroxybenzofuran (2.60 g)
After adding potassium carbonate (3.75 g) to the (30 ml) solution, bromopropane (2.87 g) was added dropwise under a nitrogen atmosphere. After stirring overnight, water was added and extracted with ethyl acetate. The organic layer was washed three times with water, further washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-propoxybenzofuran (2.73 g) as a brown oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.09 (t, 3H, J = 7.6 Hz),
1.84-2.01 (m, 2H), 4.15 (t, 2H, J = 7.0 Hz), 6.76
(d, 1H, J = 2.2 Hz), 6.80 (dd, 1H, J = 7.0, 1.8 Hz),
7.09-7.21 (m, 2H), 7.62 (d, 1H, J = 2.2 Hz).

Reference Example 216 An n-butyllithium hexane solution (1.6 g) was added to a solution of 7-propoxybenzofuran (2.4 g) in dry tetrahydrofuran (20 ml) at 0 ° C. under an argon atmosphere.
M, 15.4 ml) was added dropwise. After stirring for 1 hour -7
A solution of trimethyl borate (5.0 g) in dry tetrahydrofuran (30 ml) was added dropwise at 8 ° C., and the mixture was stirred overnight while gradually returning to room temperature. At 0 ° C., 1N hydrochloric acid was added to the reaction solution, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with hexane to give 7-propoxybenzofuran as a pale red solid.
2-Ilboric acid (1.5 g) was obtained. ¹ H-NMR (200 MHz, CDCL ₃ ) δ 1.10 (t, 3H, J = 7.4 Hz),
1.85-2.02 (m, 2H), 4.15 (t, 2H, J = 6.6 Hz), 5.23
(br, 2H), 6.85 (dd, 1H, J = 7.8, 1.6 Hz), 7.15 (t, 1
H, J = 7.8 Hz), 7.22 (dd, 1H, J = 8.0, 1.2 Hz), 7.37
(s, 1H).

Reference Example 217 7-Hydroxybenzofuran (2.60 g) in DMF
(70 ml) solution, potassium carbonate (6.97 g) and sodium iodide (7.55 g) were added, and then 2-chloroethylpropyl ether (4.76 g) was added thereto. Heated. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water, then with a saturated saline solution, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 7-propoxyethoxybenzofuran (3.76) as a brown oil.
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (t, 3H, J = 7.6 Hz),
1.55-1.73 (m, 2H), 3.53 (t, 2H, J = 6.6 Hz), 3.88
(t, 2H, J = 4.8 Hz), 4.37 (t, 2H, J = 5.2 Hz), 6.76
(d, 1H, J = 2.0 Hz), 6.84 (dd, 1H, J = 7.4, 1.4 Hz),
7.13 (t, 1H, J = 6.6 Hz), 7.21 (dd, 1H, J = 7.6, 1.6 H
z), 7.62 (d, 1H, J = 2.2 Hz).

Reference Example 218 A solution of 7-propoxyethoxybenzofuran (3.4 g) in dry tetrahydrofuran (30 ml) was added at 0 ° C. under an argon atmosphere to an n-butyllithium hexane solution (1.6 g).
M, 14.5 ml) was added dropwise. After stirring for 30 minutes -7
A solution of trimethyl borate (4.8 g) in dry tetrahydrofuran (30 ml) was added dropwise at 8 ° C., and the mixture was stirred overnight while gradually returning to room temperature. At 0 ° C., 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes, and then extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7-propoxyethoxybenzofuran-2-ylboric acid (0.8 g) as a brown oil. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.87 (t, 3H, J = 7.4 H
z), 1.45-1.62 (m, 2H), 3.44 (t, 2H, J = 6.6 Hz), 3.78
(t, 2H, J = 4.4 Hz), 4.29 (t, 2H, J = 4.8 Hz), 6.93
(d, 1H, J = 6.6 Hz), 7.11 (t, 1H, J = 7.6 Hz), 7.23
(d, 1H, J = 7.6 Hz), 7.43 (s, 1H), 8.53 (s, 2H).

Example 140 (Production of compound 137) 3-Methyl-4-propoxyphenylboronic acid (219m
g), 7-bromo-N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (450 mg),
Potassium carbonate (312 mg) in toluene (23 ml),
The suspension was suspended in ethanol (2.3 ml) and water (2.3 ml) and stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (70 m
g) was added and heated at 100 ° C. for 8 hours under an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol (125 ml) to give colorless crystals.
-(3-methyl-4-propoxyphenyl) -N- [4
-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 137) (242 mg) was obtained. mp 230.5-231.5 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08 (t, 3H, J = 7.4 Hz),
1.70-1.92 (m, 6H), 2.21 (s, 3H), 2.30 (s, 3H), 2.
64 (br, 1H), 3.16 (t, 2H, J = 7.2 Hz), 3.38 (dt, 2H,
J = 8.6, 1.8 Hz), 3.58 (s, 2H), 3.73 (t, 2H, J = 7.2
Hz), 3.96-4.07 (m, 4H), 6.91 (d, 1H, J = 9.2 Hz), 7.
30-7.39 (m, 5H), 7.55 (d, 2H, J = 8.0 Hz), 7.63 (s,
1H), 7.67 (d, 1H, J = 8.0 Hz), 7.93 (s, 1H), 8.18
(d, 1H, J = 8.0 Hz). Elemental analysis C ₃₄ H ₄₀ N ₂ O ₅ S Calcd. C, 69.36; H, 6.85; N, 4.76: Found.C, 69.13; H, 6.78; N, 4.64.

Example 141 (Production of compound 138) Benzofuran-2-ylboric acid (122 mg), 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl ] Phenyl] -1,
1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg) were suspended in toluene (15 ml), ethanol (1.5 ml), and water (1.5 ml). The mixture was stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (47 mg) was added,
The mixture was heated at 100 ° C. for 8 hours under an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol (120 ml) to give 7- (benzofuran-2) as colorless crystals.
-Yl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 138) (188 m
g) was obtained. mp 234.0-235.0 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.75 (br, 4H), 2.22 (s,
3H), 2.66 (br, 1H), 3.18 (t, 2H, J = 6.6 Hz), 3.39
(t, 2H, J = 8.6 Hz), 3.59 (s, 2H), 3.74 (t, 2H, J = 5.
8 Hz), 4.47 (d, 2H, J = 8.8 Hz), 7.21 (s, 1H), 7.28
-7.41 (m, 5H), 7.54-7.66 (m, 4H), 7.92-7.96 (m, 3
H), 8.23 (d, 1H, J = 8.8 Hz).

Example 142 (Preparation of compound 139) 5-Propoxy-benzofuran-2-ylboric acid (16
5 mg), 7-bromo-N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (300 m
g) and potassium carbonate (208 mg) in toluene (15 m
l), ethanol (1.5 ml) and water (1.5 ml), and the mixture was stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was added at 100 ° C. under argon atmosphere for 8 hours.
Heated for hours. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol (750 ml) to give N- [4-[[N-methyl-N- (Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-7- (5-propoxybenzofuran-2-yl) -2,3-dihydro-1-benzothiepin-4-carboxamide (Compound 139) ) (115 mg). mp 241.0-242.0 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.07 (t, 3H, J = 7.2 Hz),
1.67-1.90 (m, 6H), 2.21 (s, 3H), 2.67 (br, 1H),
3.18 (t, 2H, J = 7.4 Hz), 3.38 (dd, 2H, J = 10.6,2.6 H
z), 3.58 (s, 2H), 3.73 (t, 2H, J = 7.0 Hz), 3.97 (t,
2H, J = 7.0 Hz), 4.04 (d, 2H, J = 12.8 Hz), 6.98 (dd,
1H, J = 8.6, 2.6 Hz), 7.06-7.13 (m, 2H), 7.32-7.60
(m, 3H), 7.42 (d, 1H, J = 8.6 Hz), 7.56 (d, 2H, J = 8.
8 Hz), 7.89-7.94 (m, 3H), 8.22 (d, 1H, J = 8.4 Hz). Elemental analysis C ₃₅ H ₃₈ N ₂ O ₆ S Calcd. C, 68.38; H, 6.23; N, 4.56: Found. C, 68.02; H, 6.26; N, 4.56.

Example 143 (Preparation of compound 140) 5-Propoxyethoxy-benzofuran-2-ylboric acid (198 mg), 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4- Il) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg) and potassium carbonate (208 mg) in toluene (1
5 ml), ethanol (1.5 ml), water (1.5 m
l) and stirred under an argon atmosphere for 30 minutes.
Next, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was heated at 100 ° C. for 8 hours under an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol to obtain N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
7- (5-Propoxyethoxybenzofuran-2-yl) -2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 140) (200 mg) was obtained. mp 227.0-228.0 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (t, 3H, J = 7.2 Hz),
1.58-1.80 (m, 6H), 2.22 (s, 3H), 2.65 (br, 1H),
3.18 (t, 2H, J = 6.8 Hz), 3.39 (dd, 2H, J = 10.6,2.6 H
z), 3.52 (t, 2H, J = 6.6 Hz), 3.58 (s, 2H), 3.73 (t,
2H, J = 6.8 Hz), 3.82 (t, 2H, J = 5.6 Hz), 4.04 (d, 2
H, J = 10.8 Hz), 4.18 (t, 2H, J = 4.8 Hz), 7.01 (dd, 1
H, J = 9.2, 2.6 Hz), 7.11 (d, 2H, J = 7.4 Hz), 7.32-7.
36 (m, 3H), 7.42 (d, 1H, J = 9.2 Hz), 7.56 (d, 2H, J
= 8.4 Hz), 7.90-7.94 (m, 3H), 8.22 (d, 1H, J = 8.4 H
z). Elemental analysis C ₃₇ H ₄₂ N ₂ O ₇ S Calcd. C, 67.45; H, 6.43; N, 4.25: Found. C, 67.14; H, 6.35; N, 4.25.

Example 144 (Preparation of Compound 141) 6-Propoxy-benzofuran-2-yl boric acid (16
5 mg), 7-bromo-N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (300 m
g) and potassium carbonate (208 mg) in toluene (15 m
l), ethanol (1.5 ml) and water (1.5 ml), and the mixture was stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was heated at 100 ° C under argon atmosphere for 1 hour.
Heated for 0 hours. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol (40 ml) to give N- [4-[[N-methyl-N- (Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-7- (6-propoxybenzofuran-2-yl) -2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 141) ) (192 mg). mp 215.0-216.0 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08 (t, 3H, J = 7.8 Hz),
1.72-1.77 (m, 4H), 1.81-1.92 (m, 2H), 2.21 (s, 3
H), 2.65 (br, 1H), 3.16 (t, 2H, J = 6.2 Hz), 3.38 (d
t, 2H, J = 10.8, 2.4 Hz), 3.58 (s, 2H), 3.73 (t, 2H,
J = 7.2 Hz), 3.96-4.07 (m, 4H), 6.92 (dd, 1H, J = 8.
8, 2.2 Hz), 7.04 (s, 1H), 7.11 (s, 1H), 7.31-7.35
(m, 3H), 7.48 (d, 1H, J = 8.4 Hz), 7.58 (d, 2H, J = 8.
6 Hz), 7.83-7.86 (m, 2H), 8.18 (d, 1H, J = 8.8 Hz),
8.25 (s, 1H), elemental analysis C ₃₅ H ₃₈ N ₂ O ₆ S Calcd.C, 68.38; H, 6.23; N, 4.56: Found.C, 68.17; H, 6.38; N, 4.50.

Example 145 (Preparation of compound 142) 6-Propoxyethoxy-benzofuran-2-ylboric acid (250 mg), 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4- Il) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg) and potassium carbonate (262 mg) in toluene (1
5 ml), ethanol (1.5 ml), water (1.5 m
l) and stirred under an argon atmosphere for 30 minutes.
Next, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was heated at 100 ° C. for 1 day under an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography to give N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-7- (6-propoxyethoxybenzofuran-2-yl) -2,3-dihydro-
1-benzothiepine-4-carboxamide (compound 14
2) (200 mg) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.86 (t, 3
H, J = 7.2 Hz), 1.51-1.80
(M, 6H), 2.21 (s, 3H), 2.
65 (br, 1H), 3.20 (t, 2H,
J = 6.6 Hz), 3.31-3.44 (m,
4H), 3.58 (s, 2H), 3.68-
3.78 (m, 4H), 4.03 (d, 2
H, J = 11.4 Hz), 4.19 (t, 2
H, J = 4.8 Hz), 6.77 (d, 1
H, J = 2.2 Hz), 7.04 (d, 1
H, J = 8.4 Hz), 7.30-7.34
(M, 3H), 7.52-7.57 (m, 4
H), 7.92-7.98 (m, 3H), 8.
24 (d, 1H, J = 8.0 Hz). Elemental analysis _{C 37 H 42 N 2 O 7} S · 0.4H 2 O Calcd. C, 66.72; H, 6.35
N, 4.21: Found. C, 66.42; H, 6.49
N, 4.01.

Example 146 (Preparation of compound 143) 7-Propoxy-benzofuran-2-yl boric acid (16
5 mg), 7-bromo-N- [4-[[N-methyl-N
-(Tetrahydropyran-4-yl) amino] methyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1
-Benzothiepine-4-carboxamide (300 m
g) and potassium carbonate (208 mg) in toluene (15 m
l), ethanol (1.5 ml) and water (1.5 ml), and the mixture was stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was added at 100 ° C. under argon atmosphere for 8 hours.
Heated for hours. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol to obtain N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-
7- (7-propoxybenzofuran-2-yl) -2,
3-Dihydro-1-benzothiepine-4-carboxamide (Compound 143) (213 mg) was obtained. mp 246.5-247.5 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.12 (t, 3H, J = 7.4 Hz),
1.76 (br, 4H), 1.90-2.01 (m, 2H), 2.21 (s, 3H),
2.65 (br, 1H), 3.17 (t, 2H, J = 7.8 Hz), 3.38 (dt, 2
H, J = 11.8, 3.4 Hz), 3.58 (s, 2H), 3.74 (t, 2H, J =
7.2 Hz), 4.05 (d, 2H, J = 11.0 Hz), 4.19 (t, 2H, J = 6.
6 Hz), 6.87 (dd, 1H, J = 6.6, 2.6 Hz), 7.14-7.24 (m,
3H), 7.32-7.55 (m, 3H), 7.57 (d, 2H, J = 8.4 Hz),
7.94-7.99 (m, 3H), 8.22 (d, 1H, J = 8.8 Hz). Elemental analysis C ₃₅ H ₃₈ N ₂ O ₆ S Calcd. C, 68.38; H, 6.23; N, 4.56: Found. C, 68.18; H, 6.18; N, 4.60.

Example 147 (Preparation of compound 144) 7-propoxyethoxy-benzofuran-2-ylboric acid (229 mg), 7-bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4- Il) amino]
Methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (30
0 mg) and potassium carbonate (240 mg) in toluene (1
5 ml), ethanol (1.5 ml), water (1.5 m
l) and stirred under an argon atmosphere for 30 minutes.
Next, tetrakistriphenylphosphine palladium (47 mg) was added, and the mixture was heated at 100 ° C. for 8 hours under an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, recrystallized from ethanol (40 ml), and N- [4-[[N
-Methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-7- (7
-Propoxyethoxybenzofuran-2-yl) -2,
3-Dihydro-1-benzothiepine-4-carboxamide (Compound 144) (154 mg) was obtained. mp 178.5-179.5 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.8 Hz),
1.56-1.80 (m, 6H), 2.21 (s, 3H), 2.65 (br, 1H),
3.17 (t, 2H, J = 6.2 Hz), 3.38 (dt, 2H, J = 10.6,3.0 H
z), 3.54 (t, 2H, J = 7.0 Hz), 3.57 (s, 2H), 3.73 (t,
2H, J = 7.0 Hz), 3.91 (t, 2H, J = 4.6 Hz), 4.03 (d, 2
H, J = 7.6 Hz), 4.41 (t, 2H, J = 5.2 Hz), 6.91 (dt, 1H,
J = 7.2, 1.8 Hz), 7.13-7.21 (m, 3H), 7.33 (d, 2H, J
= 8.8 Hz), 7.38 (s, 1H), 7.58 (d, 2H, J = 8.4 Hz), 7.9
1-7.95 (m, 2H), 8.09 (s, 1H), 8.21 (d, 1H, J = 8.8 H
z). Elemental analysis C ₃₇ H ₄₂ N ₂ O ₇ S Calcd. C, 67.45; H, 6.43; N, 4.25: Found. C, 67.26; H, 6.31; N, 4.25.

Example 148 (Preparation of compound 145) Benzothiophen-2-ylboric acid (134 mg), 7
-Bromo-N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl]-
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg) are suspended in toluene (15 ml), ethanol (1.5 ml), and water (1.5 ml). And stirred for 30 minutes under an argon atmosphere. Then, tetrakistriphenylphosphine palladium (47 mg) was added,
Heated at 100 ° C. for 1 day in an argon atmosphere. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was separated and purified by silica gel column chromatography, and recrystallized from ethanol to give 7- (benzothiophen-2-yl) -N- [4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 145) (27 mg) was obtained. mp 270.0-271.0 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.75 (br, 4H), 2.21 (s,
3H), 2.65 (br, 1H), 3.18 (t, 2H, J = 6.6 Hz), 3.38
(dt, 2H, J = 11.8, 3.0 Hz), 3.58 (s, 2H), 3.74 (t, 2
H, J = 7.4 Hz), 4.05 (d, 2H, J = 13.4 Hz), 7.32-7.42
(m, 5H), 7.56 (d, 2H, J = 8.2 Hz), 7.69 (s, 1H), 7.76
-7.90 (m, 4H), 7.98 (s, 1H), 8.21 (d, 1H, J = 8.4 H
z). Elemental analysis C ₃₂ H ₃₂ N ₂ O ₄ S ₂・ 0.1H ₂ O Calcd. C, 66.90; H, 5.65; N, 4.88: Found.C, 66.67; H, 5.60; N, 4.91.

Example 149 (Production of compound 146) N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -7- [4- (2
-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.80 g) in ethanol (50 ml) at room temperature was treated with methanesulfonic acid (84 μl). The mixture was stirred for 1 hour. After concentration under reduced pressure, the residue was crystallized from 2-propanol to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- [4- as colorless crystals. (2-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide.methanesulfonate (Compound 146) (0.78 g) was obtained. mp 178-181 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.5 Hz), 1.
56-2.15 (6H, m), 2.59 (3H, s), 2.77 (3H, s), 3.09
(2H, t, J = 6.8 Hz), 3.21-3.55 (5H, m), 3.74-3.84 (4
H, m), 3.88-4.09 (3H, m), 4.13-4.32 (3H, m), 7.03
(2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.59-7.
67 (3H, m), 7.80-7.92 (4H, m), 8.14 (1H, d, J = 8.4
Hz), 9.43 (1H, s), 10.46 (1H, m) .IR (KBr) 3273, 1644, 1607, 1520, 1416, 1318, 1292,
1250, 1246, 1194, 1165 cm- ¹ Elemental analysis C ₃₆ H ₄₆ N ₂ O ₉ S ₂・ 0.25H ₂ O Calcd.C, 60.11; H, 6.52; N, 3.89: Found.C, 59.93; H, 6.48 ; N, 3.85.

Example 150 (Production of Compound 147) N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -7- [4- (2
-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (1.10 g) in THF (40 ml).
Benzenesulfonic acid (313 mg) was added at room temperature, and the mixture was stirred for 1 hour. After concentration under reduced pressure, 2-propanol was added.
After concentration under reduced pressure, crystallization from 2-propanol gave crude crystals. Purified by recrystallization (2-propanol), N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl]-as colorless crystals.
7- [4- (2-propoxyethoxy) phenyl]-
1,1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide.benzenesulfonate (compound 147) (1.19 g) was obtained. mp 187-189 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.87 (3H, t, J = 7.5 Hz),
1.44-1.63 (2H, m), 1.65-1.90 (2H, m), 1.95-2.08 (2
H, m), 2.62 (3H, s), 3.02-3.15 (2H, m), 3.25-3.60
(5H, m), 3.69-3.86 (4H, m), 3.94-4.22 (5H, m), 4.4
7 (1H, d, J = 12.0Hz), 7.10 (2H, d, J = 8.8 Hz), 7.29-
7.34 (3H, m), 7.49-7.62 (5H, m), 7.74-7.91 (5H,
m), 8.05-8.09 (2H, m), 10.39 (1H, s) .IR (KBr) 3239, 1665, 1642, 1605, 1518, 1318, 1292,
1167, 1121, 1017 cm ^-1 Elemental analysis C ₄₁ H ₄₈ N ₂ O ₉ S Calcd.C, 63.38; H, 6.23; N, 3.61: Found.C, 63.14; H, 6.20; N, 3.72.

Example 151 (Production of compound 148) N- [4- [N-methyl-N- (tetrahydropyran-
4-yl) aminomethyl] phenyl] -7- [4- (2
-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (1.10 g) in acetone (150 ml) at room temperature with 47% sulfuric acid (0.27 ml). The mixture was stirred for 0.5 hour. The mixture was concentrated under reduced pressure, 2-propanol was added to the residue, and the mixture was concentrated again. 2-Propanol was added to the residue and the resulting solid was collected by filtration. Under heating, the solid was dissolved in 2-propanol. The powder formed on cooling was collected by filtration and N- [4- [N
-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- [4- (2-propoxyethoxy) phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4 -Carboxamide sulfate (Compound 148) (1.21 g) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.88 (3H, t,
J = 7.5 Hz), 1.44-1.62 (2
H, m), 1.64-2.11 (4H, m),
2.62 (3H, brs), 3.02-3.
15 (2H, m), 3.24-3.57 (5
H, m), 3.67-3.87 (4H, m),
3.95-4.23 (5H, m), 4.38-
4.58 (1H, m), 7.10 (2H,
d, J = 9.2 Hz), 7.49-7.56
(3H, m), 7.74-7.91 (5H,
m), 8.05-8.09 (2H, m), 1
0.38 (1H, s). IR (KBr) 3274, 1663, 160
6, 1518, 1414, 1292, 125
2, 1127 ^{cm -1} elemental analysis _{C 35 H 44 N 2 O 10} S 2 · 0.5H 2 O Calcd. C, 57.91; H, 6.25
N, 3.86: Found. C, 57.95; H, 6.22
N, 4.01.

Example 152 (Production of compound 149) 7- (4-Butoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1,1 -Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 m
To a solution of g) in DMF (7 ml) was added methane iodide (63 μl) at room temperature, and the mixture was stirred for 18 hours. After concentration under reduced pressure,
Ethyl acetate was added and the resulting crystals were collected by filtration. Recrystallized from ethanol to give pale yellow crystals
-[4-[[7- (4-butoxyphenyl) -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4
-Carbonyl] amino] benzyl] -N, N-dimethyltetrahydro-2H-pyran-4-aminium (Compound 149) (290 mg) was obtained. mp 186-190 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 0.95 (3H, t, J = 7.3 Hz),
1.36-1.55 (2H, m), 1.66-2.00 (4H, m), 2.09-2.55 (2
H, m), 2.88 (6H, s), 3.01-3.16 (2H, m), 3.23-3.66
(3H, m), 3.77-3.84 (2H, m), 4.00-4.15 (4H, m), 4.4
7 (2H, s), 7.09 (2H, d, J = 8.8 Hz), 7.55-7.59 (3H,
m), 7.76 (2H, d, J = 8.8 Hz), 7.86-7.91 (3H, m), 8.06
-8.10 (2H, m), 10.44 (1H, s) .IR (KBr) 3220, 1669, 1607, 1593, 1518, 1474, 1410,
1314, 1285, 1246, 1128 cm- ¹ Elemental analysis C ₃₅ H ₄₃ N ₂ O ₅ SI ・ 0.5H ₂ O Calcd.C, 56.83; H, 6.00; N, 3.79: Found.C, 56.58; H, 6.13; N, 3.63.

Reference Example 219 (4-Aminophenyl)-(2-pyridyl) methanol (0.93 g) was fractionated using CHIRALCEL OD (hexane / ethanol 8: 2), and (+)-(4-
Aminophenyl)-(2-pyridyl) methanol (0.
41 g, 99.6% ee), (-)-(4-aminophenyl)-(2-pyridyl) methanol (0.43 g, 9
9.4% ee) was obtained. (+)-(4-Aminophenyl)-(2-pyridyl) methanol [α] _D = + 43.4 ° (−)-(4-aminophenyl)-(2-pyridyl) methanol [α] _D = −43 0.6 °

Example 153 (Preparation of compound 150) 7- [4- (2-Butoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (300 mg) in THF (10 ml).
Add thionyl chloride (0.1 ml) and DMF at room temperature
(1 drop) was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (20 ml), and (+)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.
58 ml) in THF (5 ml). After stirring at room temperature for 40 hours, water was added and extracted with ethyl acetate.
The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate) to give 7- [4-
(2-butoxyethoxy) phenyl] -N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -1,1
-Dioxo-2,3-dihydro-1-benzothiepin-
4-Carboxamide (Compound 150) (273 mg) was obtained. mp 173-174 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 7.1 Hz), 1.30-1.46 (2H,
m), 1.52-1.66 (2H, m),
3.11-3.18 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.68−
3.75 (2H, m), 3.79-3.84 (2
H, m), 4.16-4.20 (2H, m),
5.32 (1H, d, J = 4.4 Hz),
5.75 (1H, d, J = 4.4 Hz),
7.04 (2H, d, J = 8.8 Hz),
7.12-7.28 (2H, m), 7.34
(1H, s), 7.39 (2H, d, J =
8.6 Hz), 7.52-7.69 (7H,
m), 7.96 (1H, s), 8.19 (1
H, d, J = 8.4 Hz), 8.56-8.59
(1H, m). IR (KBr) 3403, 3339, 164
9, 1609, 1595, 1518, 131
^{4, 1289, 1252, 1128 cm} -1 elemental analysis _{C 35 H 36 N 2 O 6} S Calcd. C, 68.61; H, 5.92
N, 4.57: Found. C, 68.60; H, 5.98
N, 4.53.

Example 154 (Production of compound 151) 7- [4- (2-Butoxyethoxy) phenyl] -N-
[4- [hydroxy (2-pyridyl) methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 150) (2
30 mg) in dichloromethane (10 ml) at 0 ° C.
Then, 3-chloroperbenzoic acid (70%, 0.12 g) was added thereto, followed by stirring at room temperature for 24 hours. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol / ethyl acetate 1: 9 → 1:
Separated and purified in 4), and 7- [4- (2-
(Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide (Compound 151) ) (1
87 mg). mp 125-128 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
30-1.46 (2H, m), 1.54-1.68 (2H, m), 3.14-3.20 (2H, m
m), 3.56 (2H, t, J = 6.6 Hz), 3.68-3.75 (2H, m), 3.7
9-3.84 (2H, m), 4.16-4.21 (2H, m), 6.07 (1H, d, J =
4.6 Hz), 6.38 (1H, d, J = 4.6 Hz), 6.94-7.01 (1H,
m), 7.04 (2H, d, J = 9.2 Hz), 7.24-7.28 (1H, m), 7.3
7 (1H, s), 7.44-7.56 (5H, m), 7.62-7.69 (4H, m),
8.06 (1H, s), 8.18 (1H, d, J = 8.0 Hz), 8.24-8.28 (1
H, m) .IR (KBr) 3351, 3118, 1665, 1605, 1518, 1310, 1291,
1252, 1167, 1130 cm- ¹ Elemental analysis C ₃₅ H ₃₆ N ₂ O ₇ S ・ 1.0H ₂ O Calcd.C, 65.00; H, 5.92; N, 4.33: Found.C, 65.02; H, 5.90; N, 4.16.

Example 155 (Preparation of Compound 152) 7- [4- (2-Butoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (300 mg) in THF (10 ml).
Add thionyl chloride (0.1 ml) and DMF at room temperature
(1 drop) was added and stirred for 1 hour. After distilling off the solvent under reduced pressure, the residue was dissolved in THF (20 ml), and (-)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.
(58 ml) in a THF (3 ml) solution. After stirring at room temperature for 64 hours, water was added and extracted with ethyl acetate.
The organic layer was washed with 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 ethyl acetate to give 7-colorless crystals.
[4- (2-butoxyethoxy) phenyl] -N- [4
-[Hydroxy (2-pyridyl) methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 152) (201 m
g) was obtained. mp 171-173 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
30-1.46 (2H, m), 1.52-1.72 (2H, m), 3.11-3.17 (2H, m
m), 3.56 (2H, t, J = 6.8 Hz), 3.68-3.75 (2H, m), 3.7
9-3.84 (2H, m), 4.16-4.20 (2H, m), 5.34 (1H, br
s), 5.75 (1H, brs), 7.03 (2H, d, J = 8.8 Hz), 7.12-
7.28 (2H, m), 7.33 (1H, s), 7.38 (2H, d, J = 8.4 H
z), 7.52-7.69 (7H, m), 8.02 (1H, s), 8.18 (1H, d,
J = 8.2 Hz), 8.56-8.58 (1H, m) .IR (KBr) 3448, 3339, 1649, 1609, 1595, 1518, 1312,
1289, 1252, 1128 cm- ¹ Elemental analysis C ₃₅ H ₃₆ N ₂ O ₆ S ・ 0.25H ₂ O Calcd.C, 68.11; H, 5.96; N, 4.54: Found.C, 68.09; H, 5.84; N, 4.50.

Example 156 (Preparation of compound 153) 7- [4- (2-Butoxyethoxy) phenyl] -N-
[4- [hydroxy (2-pyridyl) methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 152) (1
57 mg) in dichloromethane (10 ml) at 0 ° C.
Then, 3-chloroperbenzoic acid (70%, 98 mg) was added.
Stirred at room temperature for 2 days. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol / ethyl acetate 1: 9 → 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [ 4- [hydroxy (1-
Oxidepyridin-2-yl) methyl] phenyl]-
1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 153) (67 m
g) was obtained. ^{mp 104-107 ℃ 1 H-NMR (} 200MHz, CDCl 3) δ0.93 (3H, t, J = 7.1 Hz), 1.
30-1.46 (2H, m), 1.54-1.68 (2H, m), 3.14-3.20 (2H, m
m), 3.56 (2H, t, J = 6.6 Hz), 3.68-3.75 (2H, m), 3.7
9-3.84 (2H, m), 4.16-4.21 (2H, m), 6.06 (1H, s),
6.94-7.01 (1H, m), 7.04 (2H, d, J = 8.8 Hz), 7.24-7.
28 (1H, m), 7.37 (1H, s), 7.44-7.56 (5H, m), 7.62-
7.69 (4H, m), 8.13 (1H, s), 8.18 (1H, d, J = 8.0 H
z), 8.24-8.28 (1H, m) .IR (KBr) 3368, 3210, 1663, 1607, 1518, 1310, 1292,
1252, 1128 cm ^-1 Elemental analysis C ₃₅ H ₃₆ N ₂ O ₇ S ・ 1.0H ₂ O Calcd.C, 65.00; H, 5.92; N, 4.33: Found.C, 65.06; H, 5.81; N, 4.28.

Example 157 (Preparation of compound 154) 7- [4- (2-Butoxyethoxy) phenyl] -1,
1-Dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg) in THF (10 ml).
The solution was added at room temperature with thionyl chloride (0.067 ml) and D
MF (1 drop) was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml),
With 1- (4-aminobenzyl) phospholinane-1-oxide (154 mg) and triethylamine (0.33
ml) in THF / DMF (5/5 ml) solution. After stirring at room temperature for 20 hours, water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol / ethyl acetate 1: 3 → 1: 2).
And recrystallized (ethanol / 2-propanol) to give 7- [4- (2-butoxyethoxy) phenyl] -N- (4-pentamethylenephosphorylmethylphenyl) -1, as colorless crystals. 1-dioxo-
2,3-Dihydro-1-benzothiepine-4-carboxamide (Compound 154) (114 mg) was obtained. mp 222-224 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
34-1.76 (12H, m), 1.82-2.11 (2H, m), 3.13 (2H, d,
J = 13.2 Hz), 3.17-3.23 (2H, m), 3.58 (2H, t, J = 6.6 H
z), 3.67-3.74 (2H, m), 3.80-3.84 (2H, m), 4.16-4.2
1 (2H, m), 7.04 (2H, d, J = 8.4 Hz), 7.21-7.26 (2H,
m), 7.46 (1H, s), 7.53-7.69 (6H, m), 8.20 (1H, d, J
= 8.0 Hz), 8.76-8.90 (1H, m) .IR (KBr) 3185, 1661, 1597, 1516, 1252, 1159, 1130
cm- ¹ elemental analysis C ₃₅ H ₄₂ NO ₆ SP Calcd.C, 66.12; H, 6.66; N, 2.20: Found.C, 65.81; H, 6.58; N, 2.38.

Reference Example 220 4-bromo-1,2-dihydroxybenzene (9.0
g), 1-bromopropane (9.1 ml), potassium carbonate (19.7 g) and sodium iodide (15.0 g) were suspended in acetone (100 ml) and refluxed overnight. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure, and 4-bromo-1,2-dipropoxybenzene (1
1.2 g) were obtained as a colorless oil. bp _0.8 = 114-118 ° C. ¹ H NMR (CDCl ₃ ) δ 1.03 (3H, t, J = 7.3 Hz), 1.04
(3H, t, J = 7.4 Hz), 1.73-1.93 (4H, m), 3.92 (2H,
t, J = 6.8 Hz), 3.93 (2H, t, J = 6.6 Hz), 6.74 (1
H, d, J = 9.0 Hz), 6.96-7.01 (2H, m) .IR (neat) ν 2965, 2938, 2878, 1586, 1503, 1470 cm
^-1 .

Reference Example 221 Magnesium (1.1 g) was suspended in THF (5 ml), and dibromoethane (catalytic amount) was added under a nitrogen atmosphere.
Next, a solution of 4-bromo-1,2-dipropoxybenzene (11.2 g) in THF (30 ml) was added dropwise.
After heating and stirring at 50 ° C. for 1 hour, the mixture was cooled with dry ice / acetone, trimethoxyborane (9.2 ml) was added dropwise, and the mixture was stirred at room temperature overnight. Add 1N hydrochloric acid, and add
After stirring for minutes, the mixture was concentrated. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off to obtain 3,4-dipropoxyphenyl boric acid (7.1 g) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ 0.95-1.04 (6H, m), 1.63-1.77 (4
H, m), 3.87-3.95 (4H, m), 6.90 (1H, d, J = 8.0 H
z), 7.32-7.39 (2H, m), 7.82 (1H, s).

Example 158 (Preparation of compound 155) 7-Bromo-N- (4-((N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -1,1 -Dioxo-2,3-dihydro-1-
Benzothiepine-4-carboxamide (0.3 g),
3,4-dipropoxyphenyl boric acid (0.17 g),
A mixture of a 1M aqueous potassium carbonate solution (1.3 ml), ethanol (1.3 ml), and toluene (25 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium (0.03 g)
And refluxed for 6 hours under an argon atmosphere. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate /
(Methanol / triethylamine) to obtain crude crystals. Recrystallized from ethanol to give 7- (3,4-dipropoxyphenyl) -N- (4-((N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -1 , 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 1
55) (0.27 g) as colorless crystals. mp 206-208 ° C. ¹ H NMR (CDCl ₃ ) δ 1.07 (6H, t, J = 7.5 Hz), 1.63-
1.97 (8H, m), 2.21 (3H, s), 2.59-2.67 (1H, m), 3.17
(2H, t, J = 6.7 Hz), 3.38 (2H, dt, J = 3.2,22.0 H
z), 3.58 (2H, s), 3.71 (2H, t, J = 6.7 Hz), 3.99-
4.08 (6H, m), 6.97 (1H, d, J = 8.2 Hz), 7.11-7.17
(2H, m), 7.31-7.35 (3H, m), 7.53-7.66 (4H, m), 7.8
5 (1H, s), 8.18 (1H, d, J = 8.2 Hz). IR (KBr) ν 3330, 2963, 1667, 1597, 1520 cm -1. Anal. Calcd. For C 36 H 44 N 2 O 6 S: C, 68.33; H, 7.01;
N, 4.43. Found C, 68.25; H, 7.06; N, 4.32.

Example 159 (Preparation of compound 156) 7- (4- (2-Butoxyethoxy) phenyl) -1,
1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxylic acid (0.4 g), 2- (4-aminobenzyl) -1,3,2-dioxaphosphorinane-2-oxide (0. 22g) and 1-hydroxybenzotriazole (0.13 g) were dissolved in DMF (8 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.36 g) and triethylamine (0.4
ml) was added. The mixture was stirred overnight at room temperature under a nitrogen atmosphere.
The mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Drying was performed using anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude crystal. Recrystallized from ethanol,
2- (4- (7- (4- (2-butoxyethoxy) phenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carbonylamino) benzyl)-
1,3,2-Dioxaphosphorinane-2-oxide (Compound 156) (0.40 g) was obtained as colorless crystals. mp 222-223 ° C. ¹ H NMR (CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.21-
1.48 (2H, m), 1.55-1.69 (2H, m), 1.70-1.90 (2H, m),
3.12-3.18 (2H, m), 3.24 (2H, d, J = 21.2 Hz), 3.5
6 (2H, t, J = 6.6 Hz), 3.69-3.75 (2H, m), 3.82 (2
H, t, J = 5.0 Hz), 4.02-4.21 (4H, m), 4.33-4.47 (2
H, m), 7.04 (2H, d, J = 8.8 Hz), 7.23-7.28 (1H,
m), 7.43 (1H, s), 7.52-7.68 (6H, m), 8.18 (1H, d,
J = 8.6 Hz), 8.44 (1H, br) .IR (KBr) ν 2957, 2922, 1657, 1607, 1597, 1537, 15
18 cm ^-1 . Anal.calcd. For C ₃₃ H ₃₈ NO ₈ PS: C, 61.96; H, 5.99;
N, 2.19. Found C, 61.63; H, 6.25; N, 2.07.

Example 160 (Production of Compound 157) 7- (4-Propoxyphenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (205 mg) in THF (10 ml) was added thionyl chloride (0.08 ml) and DMF (one drop) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (15 ml) and (+)-(4-
Aminophenyl)-(2-pyridyl) methanol (12
1 mg) and triethylamine (0.46 ml)
It was added dropwise to the HF (5 ml) solution. After stirring at room temperature for 40 hours, water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate).
And purified as N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -7- (4-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepin- as colorless crystals. 4-Carboxamide (Compound 157) (220 mg) was obtained. mp 208-210 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.5 Hz), 1.
75-1.92 (2H, m), 3.11-3.18 (2H, m), 3.68-3.75 (2H, m
m), 3.98 (2H, t, J = 6.6 Hz), 5.33 (1H, d, J = 4.0 H
z), 5.75 (1H, d, J = 4.0 Hz), 7.00 (2H, d, J = 8.8 H
z), 7.12-7.28 (2H, m), 7.34 (1H, s), 7.39 (2H, d, J
= 8.6 Hz), 7.52-7.69 (7H, m), 7.89 (1H, s), 8.19 (1
(H, d, J = 8.0 Hz), 8.54-8.60 (1H, m).

Example 161 (Preparation of compound 158) N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -7- (4-propoxyphenyl) -1,1-dioxo-2,3-dihydro- 1-benzothiepine-4-
To a solution of carboxamide (Compound 157) (180 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 96 mg) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol / ethyl acetate 1: 9 → 1: 4), further crystallized from ethanol / diisopropyl ether to give N- [4- [hydroxy (1- Oxidopyridin-2-yl) methyl] phenyl] -7- (4-propoxyphenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 158) (99 mg). . mp 184-186 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.07 (3H, t, J = 7.6 Hz), 1.
76-1.94 (2H, m), 3.14-3.20 (2H, m), 3.69-3.76 (2H, m
m), 3.99 (2H, t, J = 6.6 Hz), 6.07 (1H, d, J = 4.4 H
z), 6.40 (1H, d, J = 4.4 Hz), 6.94-7.03 (3H, m), 7.2
4-7.29 (2H, m), 7.38 (1H, s), 7.47 (2H, d, J = 8.8 H
z), 7.54 (2H, d, J = 9.2 Hz), 7.63-7.70 (4H, m), 8.0
4 (1H, s), 8.19 (1H, d, J = 8.0 Hz), 8.25-8.28 (1H,
m).

Example 162 (Preparation of compound 159) 7- (4-Butoxyphenyl) -1,1-dioxo-
To a solution of 2,3-dihydro-1-benzothiepine-4-carboxylic acid (240 mg) in THF (10 ml) was added thionyl chloride (0.09 ml) and DMF (one drop) at room temperature, followed by stirring for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (20 ml) and (+)-(4-
Aminophenyl)-(2-pyridyl) methanol (13
7 mg) and triethylamine (0.5 ml) in TH
It was added dropwise to the F (5 ml) solution. After stirring at room temperature for 20 hours, water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (ethyl acetate) to give 7- (4-butoxyphenyl) -N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -1 as colorless crystals. , 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (compound 1
59) (253 mg). mp 142-145 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.00 (3H, t, J = 7.1 Hz), 1.
42-1.64 (2H, m), 1.71-1.89 (2H, m), 3.15 (2H, t, J
= 6.8 Hz), 3.72 (2H, t, J = 6.8 Hz), 4.02 (2H, t, J = 6.
5 Hz), 5.34 (1H, d, J = 3.7 Hz), 5.75 (1H, d, J = 3.7
Hz), 7.00 (2H, d, J = 8.8 Hz), 7.12-7.29 (2H, m), 7.3
4 (1H, s), 7.39 (2H, d, J = 8.8 Hz), 7.52-7.69 (7H,
m), 7.94 (1H, s), 8.18 (1H, d, J = 8.0 Hz), 8.55-8.6
1 (1H, m).

Example 163 (Preparation of compound 160) 7- (4-Butoxyphenyl) -N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -1,1-dioxo-2,3-dihydro- To a solution of 1-benzothiepine-4-carboxamide (compound 160) (200 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 104 mg) at 0 ° C, and the mixture was stirred at room temperature for 20 hours. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol / ethyl acetate 1: 9 → 1: 4), and further crystallized from ethanol / diisopropyl ether.
7- (4-butoxyphenyl) -N as pale yellow crystals
-[4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide (Compound 163) (125 mg) was obtained. mp 133-136 ° C ¹ H-NMR (200MHz, CDCl ₃ ) δ1.00 (3H, t, J = 7.3 Hz), 1.
42-1.65 (2H, m), 1.72-1.86 (2H, m), 3.13-3.20 (2H, m
m), 3.69-3.75 (2H, m), 4.03 (2H, t, J = 6.4 Hz), 6.
07 (1H, d, J = 4.4 Hz), 6.39 (1H, d, J = 4.4 Hz), 6.93
-7.05 (3H, m), 7.24-7.29 (2H, m), 7.38 (1H, s), 7.
46 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.62
-7.69 (4H, m), 8.09 (1H, s), 8.18 (1H, d, J = 8.0 H
z), 8.24-8.28 (1H, m).

[0436] SEQ ID NOs in the sequence listing in the present specification indicate the following sequences. [SEQ ID NO: 1] This shows the base sequence of the primer used in Reference Example 1. [SEQ ID NO: 2] This shows the base sequence of the primer used in Reference Example 1.

[0437]

[Sequence List] [SEQUENCE LISTING] <110> Takeda Chemical Industries, Ltd. <120> Anilide Derivative, Production and Use Thereof <130> A99280 <150> JP 10-363404 <151> 1998-12-21 <150> JP 11-170212 <151> 1999-06-16 <160> 2 <210> 1 <211> 34 <212> DNA <213> Artificial Sequence <220><223><400> 1 CAGGATCCGA TGGATTATCA AGTGTCAAGT CCAA 3
4 <210> 2 <211> 34 <212> DNA <213> Artificial Sequence <220><223><400> 2 TCTAGATCAC AAGCCCCACAG ATATTTCTG CTC
C 34

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 31/18 A61P 31/18 37/04 37/04 43/00 111 43/00 111 C07D 409/12 C07D 409/12 409/14 409/14 C07F 9/6553 C07F 9/6553 (72) Inventor Nori Nishimura 586, Higashihiratsuka, Higashihiratsuka, Tsukuba, Ibaraki Pref. 4C063 AA01 AA03 BB01 BB08 BB09 CC95 CC96 DD12 DD52 DD76 DD78 EE01 4C086 AA01 AA02 AA03 AA04 BB01 BC07 BC17 BC70 BC73 DA35 DA36 GA02 GA04 GA07 GA08 GA09 GA12 MA01 MA02 MA03 MA04 NA14 ZC20 ZC41 ZC55 ZC75 4H050 AA01 AA02 AA03 AB20 AC50

Claims (31)

[Claims] (1) Formula (1) [Wherein, R ¹ represents a 5- or 6-membered ring which may be substituted, Ring A represents a 6- or 7-membered ring which may be substituted, and Ring B represents a benzene ring which may be substituted. , N represents 1 or 2, Z represents a bond or a divalent group, and R ² represents (1) an amino group which may be substituted and a nitrogen atom of which may be quaternized ammonium, 2) a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and a nitrogen atom may be quaternary ammonium-modified, and (3) a sulfur atom Or a group bonded through the formula (4): (In the formula, k represents 0 or 1, when k is 0, the phosphorus atom may form a phosphonium salt, and R ⁵ and R ⁶ may each be an optionally substituted hydrocarbon group, A hydroxyl group or an amino group which may be substituted, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom.) 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 optionally substituted benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran. 4. The compound according to claim 1, wherein R ¹ is benzene which may be substituted. (5) ring A is of the formula: (Wherein, Y is _{- (CH 2) m - (} m is 1 or 2), - CH = CH- or an -N = CH-) having a skeleton represented by, any substitutable The compound according to claim 1, which is a 6- to 7-membered ring which may have a substituent at the position. 6. The compound according to claim 5, wherein Y is — (CH ₂ ) _m — (m represents 1 or 2). 7. The compound according to claim 5, wherein Y is — (CH ₂ ) ₂ —. 8. The ring B is substituted with a substituent selected from a halogen atom, a C _1-4 alkyl group optionally substituted with a halogen atom and a C _1-4 alkoxy group optionally substituted with a halogen atom. 2. The compound according to claim 1, which is benzene which may be added. 9. The compound according to claim 1, wherein n is 2. 10. The compound according to claim 1, wherein Z is an optionally substituted C _1-3 alkylene. 11. Z is _{-Z '- (CH 2) n} ' - (Z ' is -C
H (OH) -, - C (O) - or -CH ₂ - indicates,
The compound according to claim 1, wherein n 'is a divalent group having a skeleton represented by the following formula (1) and optionally having a substituent on a methylene group. 12. The compound according to claim 1, wherein Z is methylene. 13. A nitrogen-containing heterocyclic ring wherein R ² is (1) an optionally substituted amino group, (2) an optionally substituted amino group, which may contain a sulfur atom or an oxygen atom as a ring-constituting atom. A group, (3) a group bonded via a sulfur atom, or (4) a compound represented by the formula: (In the formula, k represents 0 or 1, R ⁵ and R ⁶ each represent an optionally substituted hydrocarbon group or an optionally substituted amino group, and R ⁵ and R ⁶ are bonded to each other. (A cyclic group may be formed together with an adjacent phosphorus atom). 14. A nitrogen-containing heterocyclic ring wherein R ² is (1) an optionally substituted amino group, or (2) an optionally substituted amino group which may contain a sulfur atom or an oxygen atom as a ring-constituting atom. Group or formula (3) (Wherein, R ⁵ and R ⁶ each represent an optionally substituted hydrocarbon group, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom). The compound according to claim 1, which is a group to be formed. 15. A group in which R ² is a group represented by the formula —NRR ′, wherein
R and R ′ each represent an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic group). 16. R is an optionally substituted chain hydrocarbon group, and R ′ is an optionally substituted alicyclic hydrocarbon group or an optionally substituted alicyclic heterocyclic group. 16. The compound according to claim 15, wherein 17. R is an optionally substituted C _1-6 alkyl group, and R ′ is an optionally substituted C _3-8 cycloalkyl group or an optionally substituted saturated heterocyclic group. The compound according to claim 15, which is 18. The method according to claim 17, wherein R ′ is cyclohexyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrothiopyranyl which may be substituted or piperidyl which may be substituted. Compound. 19. N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-propoxyphenyl) -1,1-dioxo-2,3- Dihydro-1-benzothiepine
-4-carboxamide, 7- (4-butoxyphenyl) -N- [4- [N-
Methyl-N- (tetrahydropyran-4-yl) aminomethyl]
Phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- [4- [N-methyl-N- (2-propoxyethyl) amino] phenyl] -N- [4 -[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-
Dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- [4- (2-ethoxyethoxy) phenyl] -N- [4-
[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N- [4-[[ N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -7- [4
-(2-Propoxyethoxy) phenyl] -1,1-dioxo-2,3-
Dihydro-1-benzothiepine-4-carboxamide, 7- [4-
(2-butoxyethoxy) phenyl] -N- [4-[[N-methyl-N-
(Tetrahydropyran-4-yl) amino] methyl] phenyl]
-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7- [4- (2-ethoxyethoxy) -3,5-dimethylphenyl] -N- [4-[[N- Methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3
-Dihydro-1-benzothiepine-4-carboxamide, 7- [2-
Chloro-4- (2-propoxyethyl) phenyl] -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -1,1-dioxo-2,3 -Dihydro-1-benzothiepine
-4-carboxamide, 7- (3-methyl-4-propoxyphenyl) -N- [4-[[N-methyl-N- (tetrahydropyran-4-yl)
Amino] methyl] phenyl] -1,1-dioxo-2,3-dihydro-
1-benzothiepine-4-carboxamide and 7- (3,4-dipropoxyphenyl) -N- (4-((N-methyl-N- (tetrahydro-
A compound selected from 2H-pyran-4-yl) amino) methyl) phenyl) -1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide or a salt thereof. 20. The formula (Wherein each symbol is as defined in claim 1), a salt thereof or a reactive derivative thereof and a compound represented by the formula: (Wherein B and Z have the same meanings as in claim 1; R ² ′ may be each protected or (1) substituted and optionally substituted with a quaternary ammonium amino group; A group (2) a nitrogen-containing heterocyclic group which may be substituted, may contain a sulfur atom or an oxygen atom as a ring-constituting atom, and a nitrogen atom may be quaternary ammonium-modified, (3) A group bonded through a sulfur atom or (4)
Formula 8 (In the formula, k represents 0 or 1, when k is 0, the phosphorus atom may form a phosphonium salt, and R ⁵ and R ⁶ may each be an optionally substituted hydrocarbon group, Represents an optionally substituted hydroxyl group or an optionally substituted amino group, and R ⁵ and R ⁶ may be bonded to each other to form a cyclic group together with an adjacent phosphorus atom). Wherein the compound represented by the formula (I) or a salt thereof is subjected to a condensation reaction and, if desired, to a deprotection reaction, an oxidation / reduction reaction and / or a quaternization reaction. (Wherein each symbol is as defined in claim 1) or a method for producing a salt thereof. 21. The formula: (Wherein, R ¹ represents a 5- or 6-membered ring which may be substituted) or a salt thereof. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 23. The composition according to claim 22, which is a CCR antagonist. 24. The composition according to claim 22, which is a CCR5 antagonist. (25) The composition according to the above (22), which is an agent for preventing or treating HIV infection. 26. A prophylactic / therapeutic agent for AIDS.
2. The composition according to 2. (27) the composition according to the above (22), which is an AIDS disease progression inhibitor; 28. The composition according to claim 25, further comprising a protease inhibitor and / or a reverse transcriptase inhibitor. 29. The composition according to claim 28, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz or abacavir. 30. The composition according to claim 28, wherein the protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir or nelfinavir. (31) Use of the compound or a salt thereof according to (1) and a protease inhibitor and / or a reverse transcriptase inhibitor for the prevention and treatment of HIV infection.