JP2003119191A - Benzoazepine derivative, production method and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new benzoazepine derivative, and to provide a production method and a use thereof. SOLUTION: The compound represented by the formula R<1> is a substituent- having aromatic ring; R<2> is a lower alkyl, or the like; Y is an imino group which may be substituted; the rings A and B may further be substituted, respectively; W is W<1> -X<2> -W<2> [W<1> and W<2> are each S(O)m ((m) is 0, 1 or 2)]; X<2> is an alkylene which may be substituted, or the like} or its salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzazepine derivative, its production method and use.

[0002]

2. Description of the Related Art In recent years, an HIV (human immunodeficiency virus) protease inhibitor has been developed as a treatment for AIDS (acquired immunodeficiency syndrome), and it should be combined with two conventionally used HIV reverse transcriptase inhibitors. Although the treatment of AIDS has been remarkably advanced by this, it cannot be said to be sufficient for the eradication of AIDS, and the development of a new anti-AIDS drug based on another mechanism of action is desired. HI
CD4 as a receptor when V invades target cells
Has been known for a long time, but recently, as a second receptor for macrophage-directed HIV, CCR5,
Seven transmembrane G protein-coupled chemokine receptors called CXCR4 have been found as T cell-oriented second receptors, and it is considered that these chemokine receptors play an essential role in the establishment and transmission of HIV infection. Has been. In fact, humans who resisted HIV infection despite repeated exposure were
There is also a report that the CCR5 gene had a homozygous deletion mutation. Therefore, it is expected that the CCR5 antagonist will be a new anti-HIV drug, but to date, there are no examples in which the CCR5 antagonist has been developed as a therapeutic drug for AIDS. In addition, Japanese Patent Laid-Open No. 2001-058992 and Japanese Patent Laid-Open No. 2001-026586 describe CCR.
It has been described that a compound having a 5-antagonism is useful as a prophylactic / therapeutic agent for AIDS.
The structure is different from the compound of the present application.

[0003]

DISCLOSURE OF THE INVENTION In order to search for an anti-AIDS drug based on CCR5 antagonism, a CCR5 gene is cloned from a human tissue-derived cDNA library and ligated to an expression vector for animal cells to obtain animal cells. It is necessary to introduce and obtain a CCR5-expressing cell line. Then, using this transformed cell line, the natural ligand CC
A compound that strongly inhibits the binding of the chemokine RANTES to CCR5 must be screened, but the present situation is that few low-molecular compounds suitable for oral administration having this antagonistic effect have been reported. The present invention is a CCR
The present invention provides a novel alinide derivative which is useful as a prophylactic / therapeutic agent for HIV infection, particularly AIDS, based on its 5 antagonistic action, and which is suitable for oral administration, its production method and use.

[0004]

[Means for Solving the Problems] The present inventors have found that CCR5
As a result of extensive studies on compounds having an antagonistic effect, a benzazepine derivative represented by the following formula (I) or a salt thereof (hereinafter, may be abbreviated as compound (I)) was identified as C
C chemokine receptor (CCR) antagonism, particularly excellent CCR5 antagonism, and clinically desirable medicinal effects such as remarkable inhibition of HIV infection of human peripheral blood mononuclear cells, and oral administration The present invention was completed based on this finding that it has excellent absorbency.

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

[Chemical 6] [In the formula, ^{R 1} has the formula ^{R-Z 1 -X 1 -Z 2} - ( wherein, R
Represents a hydrogen atom or an optionally substituted hydrocarbon group, X ¹ represents an optionally substituted alkylene chain,
Z ¹ and Z ² each represent a hetero atom. 5) having a substituent represented by the formula (4) and optionally having a substituent 5
Or a 6-membered aromatic ring, the group represented by R may be bonded to the 5- or 6-membered aromatic ring to form a ring, R ² is a hydrogen atom, an optionally substituted lower alkyl group, Represents a lower alkoxy group which may be substituted or a halogen atom, Y represents an imino group which may be substituted, ring A and ring B each represent an aromatic ring which may be further substituted, and W is a formula —W ¹ —X ² —W ² — (W ¹ and W ² are each O, S (O) _m1 (m1 represents 0, 1 or 2), an optionally substituted imino group or a bond. , X ² is an optionally substituted alkylene group,
Represents an optionally substituted alkenylene group or a bond). ] The compound or its salt represented by these. (2) A prodrug of the compound described in (1) above; (3) A compound described in (1) above, wherein the 5- or 6-membered aromatic ring of R ¹ is benzene; (4) R may be halogenated. The compound according to (1) above, which is a lower alkyl group; (5) The compound according to (1) above, wherein X ¹ is-(CH ₂ ) _n- (n represents an integer of 1 to 4); The compound according to (1) above, wherein Z ¹ is -O-; (7) The compound according to (1) above, wherein Z ² is -O-; (8) Y is -N (R ^{5 '} )-(R. ^{5 ′} represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or an optionally substituted acyl group) (1) a compound according; (9) may be R 5 ^'is substituted C _1-4 alkyl, benzyl optionally substituted or substituted A compound of the above (8), which is an optionally substituted 5- or 6-membered aromatic heterocyclic group; (10) ring A, which may be substituted, benzene ring, which may be substituted, pyridine ring, substituted The compound according to (1) above, which is an optionally substituted pyridazine ring or an optionally substituted benzimidazole ring; (11) An imidazole ring substituted with an optionally substituted lower alkyl group or a substituted ring B The compound according to (1) above, which is a triazole ring substituted with an optionally substituted lower alkyl group; (12) One of W ¹ and W ² is O or S (O).
_m1 (m1 is 0, 1 or 2) or -N ^(R 3) -
(R ³ represents a hydrogen atom or an optionally substituted lower alkyl group), the other is a bond, and X ² is — (C
H ₂ ) _p − (p is an integer of 1 to 3) or W is —CH (OH) —; (13) Ring A is a benzene ring; B is an optionally substituted imidazole ring or an optionally substituted triazole ring, wherein one of W ¹ and W ² is S (O) _m1 (m1 is 0, 1 or 2) and the other is The compound according to (1) above, which is a bond and X ² is — (CH ₂ ) _p— (p is an integer of 1 to 3) or W is —CH (OH) —;

[Chemical 7] 15. The compound according to (1) above, which is: (15) The configuration of SO is (S) coordination.
(16) (-)-7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, (-)- 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4
-[[[1-Propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide, (-)-7-
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4-
Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-
4-carboxamide, (-)-1-isobutyl-7-
[4- (2-propoxyethoxy) phenyl] -N-
[4-[[[1-Propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-
1-benzazepine-4-carboxamide, (+)-7
-[4- (2-Butoxyethoxy) phenyl] -N-
[4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide or a salt thereof.
Compound described (17) formula

[Chemical 8] (Wherein each symbol has the same meaning as described in the above (1)), a salt thereof or a reactive derivative thereof, and a formula

[Chemical 9] (Wherein each symbol has the same meaning as described in (1) above), the compound or salt thereof is subjected to a condensation reaction.

[Chemical 10] (Wherein each symbol has the same meaning as described in (1) above), or a salt thereof; (18) a pharmaceutical composition containing the compound described in (1) above or a prodrug thereof; 19) The CC chemokine receptor antagonist as described above (1)
8) The composition according to (18) above, which is a CCR5 antagonist and / or CCR2 antagonist; (21) HIV infection, rheumatoid arthritis, autoimmune disease, allergic disease, imaginary Bloody brain cell disorder, myocardial infarction,
(18) The composition according to the above (18), which is a preventive / therapeutic agent for nephritis / nephropathy or arteriosclerosis; (22) The above (18), which is blood or a blood product for transfusion.
(23) A composition for preventing / treating graft-versus-host disease and / or rejection at the time of organ or bone marrow transplantation (23).
8) The composition as described above;

In the above formula (I), the "formula R represented by R ¹
—Z ¹ —X ¹ —Z ² — (In the formula, R represents a hydrogen atom or an optionally substituted hydrocarbon group, X ¹ represents an optionally substituted alkylene chain, and Z ¹ and Z ² Each represents a heteroatom), and has a substituent represented by "5 to 6-membered aromatic ring which may further have a substituent".
~ 6 membered aromatic ring "is a 6 membered aromatic hydrocarbon such as benzene, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole. 1-2 selected from nitrogen atom, sulfur atom and oxygen atom such as
Examples thereof include 5- to 6-membered aromatic heterocycles containing 1 to 4 heteroatoms, and the like. Among them, benzene, furan, thiophene, pyridine and the like are preferable, and benzene,
Furan or thiophene are more preferred, with benzene being especially preferred.

The "optionally substituted carbonization" represented by R
As the “hydrocarbon group” of the “hydrogen group”, for example, (1) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, hexyl, heptyl, octyl, nonyl, decyl
Such as C_1-10Alkyl, preferably lower
(C_1-6) Alkyl, more preferably lower (C_1
-4) Alkyl and the like); (2) cycloalkyl (eg, cyclopropyl, cyclo)
Robutyl, cyclopentyl, cyclohexyl, cyclohexyl
C such as petit_3-7Such as cycloalkyl
); (3) Alkenyl (eg, allyl, cloth)
2-, 2-pentenyl, 3-hexenyl and the like having 2 to 2 carbon atoms
10 alkenyl, preferably lower (C_2-6) Arche
Nil and the like); (4) cycloalkenyl (for example, 2-cyclopentenyl
2-cyclohexenyl, 2-cyclopentenylmethyl
And 3-cyclohexenylmethyl and the like having 3 to 7 carbon atoms.
Examples include chloralkenyl); (5) Alkynyl (eg, ethynyl, 1-propini
2, 2-propynyl, 1-butynyl, 2-pentynyl,
Alkynyl having 2 to 10 carbon atoms such as 3-hexynyl, preferably
More preferably lower (C_2-6) Alkynyl etc.
); (6) Aralkyl (eg, phenyl-C_1-4Archi
Such as benzyl, phenethyl, etc.
); (7) Aryl (eg, phenyl, naphthyl, etc. are listed.
); (8) cycloalkyl-alkyl (eg cyclopro
Pyrmethyl, cyclobutylmethyl, cyclopentylmethyl
, Cyclohexylmethyl, cycloheptylmethyl, etc.
C_3-7Cycloalkyl-C_1-4Alkyl etc.
And the like, and (1) Alki mentioned above.
Le, (2) cycloalkyl, (3) alkenyl, (4)
Cycloalkenyl, (5) alkynyl, (6) aralkyl
, (7) aryl and (8) cycloalkyl-ar
The substituent that the kill may have is halogen.
(Eg, fluorine, chlorine, bromine, iodine, etc.), nitro, silane
Ano, hydroxyl group, optionally substituted thiol group (eg,
Thiol, C_1-4Alkylthio, etc.), substituted
Optionally an amino group (eg, amino, mono C_1-4Alkyl
Amino, di C_1-4Alkylamino, tetrahydropyro
, Piperazine, piperidine, morpholine, thiomol
5- to 6-membered rings such as holin, pyrrole and imidazole
Amino), esterified or amidated
Good carboxyl group (eg, carboxyl, C_1-4Al
Coxycarbonyl, carbamoyl, mono C _1-4Archi
Lucarbamoyl, di-C_1-4Alkyl carbamoyl
Etc.), optionally halogenated C_1-4Alkyl
(Eg, trifluoromethyl, methyl, ethyl, etc.)
C which may be rogenated_1-4Alkoxy (eg,
Toxy, ethoxy, propoxy, butoxy, trifluor
Romethoxy, trifluoroethoxy, etc.), C_1-4A
Rukirenedioxy (eg, -O-CH_Two-O-, -OC
H _Two-CH_Two-O-, etc.), optionally substituted sul
Honamide [eg, an optionally substituted amino group (eg,
Amino, Mono C_1-4Alkylamino, di-C_1-4Al
Kiramino, tetrahydropyrrole, piperazine, pipette
Lysine, morpholine, thiomorpholine, pyrrole, imi
5-6 membered cyclic amino such as dazole) is -SO_Two
-Groups formed by bonding to-], formyl, C_2-4
Alkanoyl (eg, acetyl, propionyl, etc.), C
_1-4Alkylsulfonyl (eg, methanesulfonyl,
Tansulfonyl, etc.), optionally substituted heterocyclic group
Etc., and the number of substituents is preferably 1 to 3.
Good Here, “optionally substituted charcoal represented by R
A “optionally substituted” group as a substituent of “hydrogen group”
The “heterocyclic group” in the “cyclic group” means an aromatic heterocycle.
Or by removing one hydrogen atom from a non-aromatic heterocycle
Examples include groups formed. As the aromatic heterocycle
Is, for example, furan, thiophene, pyrrole, imidazo
, Pyrazole, thiazole, oxazole, isothiazole
Azole, isoxazole, tetrazole, pyridine,
Pyrazine, pyrimidine, pyridazine, triazole, o
Nitrogen atom such as oxadiazole and thiadiazole, sulfur
1 to 2 heteroatoms selected from atoms and oxygen atoms
Examples include 5- to 6-membered aromatic heterocycles containing 1 to 4
As the non-aromatic heterocycle, for example, tetrahydr
Rofuran, tetrahydrothiophene, dioxolane, di
Thiolane, oxathiolane, pyrrolidine, pyrroline, a
Midazolidine, imidazoline, pyrazolidine, pyrazoli
, Piperidine, piperazine, oxazine, oxadia
Gin, thiazine, thiadiazine, morpholine, thiomol
Nitrogen atoms such as holin, pyran and tetrahydropyran,
1-2 kinds of hetero selected from sulfur atom and oxygen atom
5- to 6-membered non-aromatic heterocycles containing 1 to 4 atoms and
And some or all of the aromatic heterocycles have saturated bonds.
Such as a non-aromatic heterocycle (preferably pyrazol
Thiol, thiazole, oxazole, tetrazole, etc.
Aromatic heterocycle). "Replaced
“Substituted” as a substituent of “optional hydrocarbon group”
The "heterocyclic group" in "heterocyclic group which may be present" may be substituted.
May have 1 to 3 substituents at any available position
Examples of such a substituent include halogen (eg, fluorine
Fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, water
Acid group, optionally substituted thiol group (eg, thiol
Le, C_1-4Alkylthio, etc.), may be substituted
Amino group (eg, amino, mono C_1-4Alkylami
No, the C_{1- Four}Alkylamino, tetrahydro pillow
Le, piperazine, piperidine, morpholine, thiomorpho
5- or 6-membered cyclic amides such as phosphorus, pyrrole and imidazole
Mino, etc.), esterified or amidated
A carboxyl group (eg, carboxyl, C_1-4Arco
Xycarbonyl, carbamoyl, mono C_1-4Alkyl
Carbamoyl, di-C_1-4Alkyl carbamoyl
Etc.), optionally halogenated C_1-4Alkyl
(Eg, trifluoromethyl, methyl, ethyl, etc.)
C which may be rogenated_1-4Alkoxy (eg,
Toxy, ethoxy, propoxy, butoxy, trifluor
Romethoxy, trifluoroethoxy, etc.), C_{1- Four}A
Rukirenedioxy (eg, -O-CH_Two-O-, -OC
H_Two-CH_Two-O-, etc.), optionally substituted sul
Honamide [eg, an optionally substituted amino group (eg,
Amino, Mono C_1-4Alkylamino, di-C_1-4Al
Kiramino, tetrahydropyrrole, piperazine, pipette
Lysine, morpholine, thiomorpholine, pyrrole, imi
5-6 membered cyclic amino such as dazole) is -SO_Two
-Groups formed by bonding to-], formyl, C_2-4
Alkanoyl (eg, acetyl, propionyl, etc.), C
_1-4Alkylsulfonyl (eg, methanesulfonyl,
Tansulfonyl, etc.) (preferably C_1-4Al
Kill). In addition, the formula R-Z¹-X¹−
Z^Two-(Wherein each symbol has the same meaning as described above)
Is a monovalent group (bonded to a 5- or 6-membered aromatic ring
Is not formed), R may be substituted.
Preferred alkyl group, which may be halogenated
Lower alkyl groups are more preferred, especially halogenated
May be C_1-4Alkyl groups are preferred.

X¹, Which may be substituted
As the “rubylene chain”, for example, even if it has a substituent,
Well, C which may be linear or branched_1-6Al
Examples thereof include xylene and the like.
The number of carbon atoms in the chain is preferably 1 to 4
X, especially¹As a straight line that may be substituted
Chain C_1-4Alkylene (preferably ethylene or
Propylene) is preferred. X¹"Replaced
"Alkylene chain" in "optional alkylene chain"
The substituent which may have has a straight-chain portion.
Any divalent chain that can bind to
Is, for example, a lower alkyl having 1 to 6 carbon atoms (eg, methyl
Ru, ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, etc.), low grade
(C_3-7) Cycloalkyl (eg, cyclopropyl, silane
Crobutyl, cyclopentyl, cyclohexyl, cyclo
Heptyl, etc., formyl, low grade (C_2-7) Arcano
Yl (eg, acetyl, propionyl, butyryl, etc.),
Phosphono group which may be esterified, esterified
Optionally substituted carboxyl group, hydroxyl group, oxo, etc.
And preferably lower alkyl having 1 to 6 carbon atoms.
(Preferably C_1-3Alkyl), hydroxyl, oxo
Which can be mentioned. The optionally esterified phospho
As a group, P (O) (OR^7a) (OR ^8a) [Where
R^7aAnd R^8aAre hydrogen and carbon atoms of 1 to 6 respectively.
Represents a alkyl group or a cycloalkyl group having 3 to 7 carbon atoms
And R^7aAnd R^8aAre bonded to each other to form a 5- to 7-membered ring
May be formed]. Up
R in the ceremony^7aAnd R^8aWith 1 to 6 carbon atoms
Alkyl groups include methyl, ethyl, propyl, iso
Propyl, butyl, isobutyl, sec-butyl, te
rt-butyl, pentyl, isopentyl, neopentyl
And hexyl and the like, and cycloalkyl having 3 to 7 carbon atoms.
Examples of alkyl include cyclopropyl, cyclobutyl, and
Examples include lopentyl, cyclohexyl, and cycloheptyl.
However, preferably, a lower chain-like C 1-6 lower alkyl group is used.
Rualkyl, more preferably lower alkyl having 1 to 3 carbon atoms
Is mentioned. R^7aAnd R^8aAs the same
May be different or different but is preferably the same
Yes. Also, R^7aAnd R ^8aAre bound together 5-7
When forming a member ring, R^7aAnd R^8aAnd are bound to each other
,-(CH_Two)_Two-,-(CH_Two)_Three-,-(CH_Two)_Four−
Linear C represented by_2-4Form an alkylene side chain
It The side chain may have a substituent, such as
Examples of the substituent include a hydroxyl group and halogen.
The ester of carboxyl group which may be esterified
As a rutile, a carboxyl group and an alkyl group having 1 to 6 carbon atoms
Group or a cycloalkyl group having 3 to 7 carbon atoms is bonded to
, Such as methoxycarbonyl, ethoxycarbonyl
L, propoxycarbonyl, isopropoxycarbony
L, butoxycarbonyl, isobutoxycarbonyl, s
ec-butoxycarbonyl, tert-butoxycarbo
Nyl, pentyloxycarbonyl, hexyloxycal
Bonyl etc. are mentioned. X¹Has been replaced as
Good C_1-4Alkylene, especially C_1-3Archi
C, which may be substituted with chloro, hydroxyl or oxo
_1-4Alkylene is preferred, especially the formula-(CH_Two)
_nA group represented by-(n represents an integer of 1 to 4) is preferable.
Yes.

Examples of the hetero atom represented by Z ¹ and Z ² include —O—, —S (O) _{m 2} — (m 2 is 0 to 2).
And an —N (R ⁴ )-(R ⁴ represents a hydrogen atom or an optionally substituted lower alkyl group), and the like, and Z ¹ is —O— or —S (O ) _m2-
(M2 represents an integer of 0 to 2) is preferable, and -O- is more preferable. Further, Z ² is -O- or -N.
(R ⁴ ) — (R ⁴ represents a hydrogen atom or an optionally substituted lower alkyl group) is preferable, and —O— is more preferable. The lower alkyl group which may be substituted represented by R ^4, similar to the illustrated "optionally substituted lower alkyl group" as the "hydrocarbon group which may be substituted" represented by R There are things.

[0010] represented by ^{R 1} 'wherein ^R-Z 1 ^-X 1 -Z
^2- (wherein each symbol has the same meaning as described above), and may further have a substituent.
Of 6-membered aromatic ring "," 5- to 6-membered ring "has the formula ^{R-Z 1} -X 1
Examples of the “substituent” which may be present in addition to the group represented by —Z ² — include a halogen atom, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, Optionally substituted hydroxyl group, optionally substituted thiol group (sulfur atom may be oxidized, may form optionally substituted sulfinyl group or optionally substituted sulfonyl group Good), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, an optionally substituted aromatic group and the like are used.

Examples of halogen as the substituent of R ¹ include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. The alkyl in the optionally substituted alkyl as the substituent of R ¹ is linear or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
C such as butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl
_1-10 alkyl, preferably lower (C _1-6 ) alkyl is mentioned. Examples of the substituent in the optionally substituted alkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and 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, morpholine, thiomorpholine, pyrrole, imidazole and other 5- or 6-membered cyclic amino), esterification or amidation Optionally carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl,
Carbamoyl, mono C _1-4 alkylcarbamoyl, diC _1-4 alkylcarbamoyl and the like), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
Trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (eg, 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 can be mentioned, and the number of substituents is 1 to 3.
Individuals are preferred. The cycloalkyl in the optionally substituted cycloalkyl as the substituent of R ¹ is
Examples thereof include C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the substituent in the optionally substituted cycloalkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group (eg,
Thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine) , A 5- or 6-membered cyclic amino such as pyrrole or imidazole), an optionally 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 (eg trifluoromethyl, methyl, ethyl etc.), optionally halogenated C _1-4 alkoxy (eg, Methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, Fluoro-ethoxy and the like), formyl,
C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like can be mentioned, and the number of substituents is preferably 1 to 3.

The substituent in the optionally substituted hydroxyl group as the substituent of R ¹ includes (1) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C _1-6 ) alkyl, etc.); (2) optionally substituted hetero atom Optionally contained cycloalkyl (for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro) Saturated 5- or 6-membered heterocyclic group containing 1-2 heteroatoms such as pyranyl and tetrahydrothiopyranyl (preferably tetrahydropyranyl and the like); and the like); (3) substituted Even There alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3-hexenyl, etc. alkenyl having 2 to 10 carbon atoms, preferably lower _{(C 2-6)} such as alkenyl and the like); (4) substituted Optionally cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl and the like cycloalkenyl having 3 to 7 carbon atoms); (5) optionally substituted aralkyl (eg, phenyl-C _1-4 alkyl (eg, benzyl, benzyl, (6) formyl or optionally substituted acyl (eg, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), carbon number 1)
To 4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and (7) substituents such as optionally substituted aryl (eg, phenyl, naphthyl, etc.), and the like, The above-mentioned (1) optionally substituted alkyl,
(2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) substituted The optionally substituted acyl and (7) the optionally substituted aryl may have a 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, imidazole and other 5- or 6-membered cyclic amino), esterification or amidation Optionally 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 (eg, trifluoromethyl, methyl, ethyl, etc.), halogenated Optionally C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc .; preferably optionally halogenated C _1-4 alkoxy), formyl, C _2-4 alkanoyl. (Eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), optionally substituted 5- or 6-membered aromatic heterocycle [eg, furan, thiophene, pyrrole, Imidazole, pyrazole, thiazole, oxazole, isothiazole, a Soxazole, tetrazole, pyridine,
1 to 1 selected from a nitrogen atom, a sulfur atom and an oxygen atom such as pyrazine, pyrimidine, pyridazine and triazole.
A 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms, etc .; a substituent which the heterocycle may have is halogen (eg, fluorine, chlorine, bromine, iodine, etc.). ), Nitro, cyano, hydroxyl group, thiol group, amino group, carboxyl group, and 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 can be mentioned, and the number of substituents is preferably 1 to 3. . ] Etc. are mentioned, and as the number of substituents, 1 to 3 are preferable.

[0013] Examples of the substituent in the optionally substituted thiol group as the substituent for R ^1, and the "R ¹
Examples of the “substituent in the optionally substituted hydroxyl group as the substituent” of the formula (1) include (1) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (2) optionally substituted cycloalkyl (eg, ,
C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like); (3) optionally substituted aralkyl (eg, phenyl-C _1-4 alkyl (eg, benzyl, benzyl, (Eg, phenethyl, etc.); (4) optionally substituted aryl (eg, phenyl, naphthyl, etc.) and the like are preferable, and the above-mentioned (1) optionally substituted alkyl, (2) substituted Optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) optionally substituted aryl include a halogen (eg, fluorine, chlorine, bromine, Iodine, etc.), nitro, cyano, hydroxyl group, optionally substituted thiol group (eg, thiol,
C _1-4 alkylthio etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole) , cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated carboxyl group which may be (for example, _{carboxyl, C 1 -4} alkoxycarbonyl, carbamoyl, mono _{C 1-4} alkylcarbamoyl, di-C _1-4 etc. alkylcarbamoyl), optionally _{C 1-4} alkyl (e.g. optionally halogenated, trifluoromethyl, methyl, ethyl, etc.), halogenated which may be _{C 1-4} alkoxy (e.g., methoxy, Ethoxy, propoxy, butoxy, trifluoromethoxy,
Trifluoroethoxy, etc.), _{formyl, C 2-4} alkanoyl (e.g., acetyl, propionyl, etc.), C
_1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like can be mentioned, and the number of substituents is preferably 1 to 3.

[0014] 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"
Examples thereof include an amino group which may have 1 or 2 substituents similar to the above, and among them, (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl). , Sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (2) optionally substituted cycloalkyl (eg, ,
C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like); (3) optionally substituted alkenyl (eg, 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) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl). Two
-Cyclopentenylmethyl, 2-cyclohexenylmethyl and the like cycloalkenyl having 3 to 7 carbon atoms, etc.); (5) formyl or optionally substituted acyl (e.g., alkanoyl having 2 to 4 carbon atoms (eg, Acetyl, propionyl, butyryl, isobutyryl, etc.), carbon number 1
To alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and (6) optionally substituted aryl (eg, phenyl, naphthyl, etc.) and the like,

The above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl,
(3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl, and (6) optionally substituted aryl have Examples of the substituent that may be substituted include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and an optionally substituted thiol group (eg,
Thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine) , A 5- or 6-membered cyclic amino such as pyrrole or imidazole), an optionally 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 (eg trifluoromethyl, methyl, ethyl etc.), optionally halogenated C _1-4 alkoxy (eg, Methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, Fluoro-ethoxy and the like), formyl,
C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like can be mentioned, and the number of substituents is preferably 1 to 3. Further, the optionally substituted amino group as the substituent of R ¹ is a cyclic amino group (for example, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole) in which the substituents of the amino groups are bonded to each other. , A 5- to 6-membered cyclic amino such as imidazole) may be formed. The cyclic amino group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group. (Eg, thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine) , 5- or 6-membered cyclic amino such as thiomorpholine, pyrrole, and imidazole), an optionally 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 (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, and the number of substituents is preferably 1 to 3.

R¹May be substituted as a substituent of
As an acyl group, (1) hydrogen, (2) optionally substituted alkyl (eg, methyl
Ru, ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, o
C such as cutyl, nonyl and decyl_1-10Alkyl, good
More preferably lower (C_1-6) Alkyl etc.
); (3) optionally substituted cycloalkyl (eg,
Cyclopropyl, cyclobutyl, cyclopentyl, shik
C such as lohexyl and cycloheptyl_3-7Cycloal
Such as kills); (4) optionally substituted alkenyl (for example, ari
Allyl, crotyl, 2-pentenyl, 3-hexeni
Alkenyl having 2 to 10 carbon atoms, such as ru, preferably lower
(C_2-6) Examples include alkenyl); (5) optionally substituted cycloalkenyl (eg,
For example, 2-cyclopentenyl, 2-cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl
And cycloalkenyl having 3 to 7 carbon atoms.
); (6) 5- to 6-membered monocyclic aromatic group which may be substituted
(For example, phenyl, a 5- or 6-membered aromatic heterocyclic group (eg,
For example, furyl, thienyl, pyrrolyl, imidazolyl, pyra.
Zolyl, thiazolyl, oxazolyl, isothiazolyl,
Isoxazolyl, tetrazolyl, pyridyl, pyrazyl,
Nitrogen such as pyrimidinyl, pyridazinyl, triazolyl
1 to 2 kinds of atoms, sulfur atoms and oxygen atoms
5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms
Groups, etc .; preferably pyridyl, thienyl, etc.)
)); (7) 5- or 6-membered optionally substituted monocyclic non-aromatic
Heterocyclic groups (eg, tetrahydrofuran, tetrahydro
Thiophene, dioxolane, dithiolane, oxathiola
, Pyrrolidine, pyrroline, imidazolidine, imidazo
Phosphorus, pyrazolidine, pyrazoline, piperidine, pipera
Gin, oxazine, oxadiazine, thiazine, thiadi
Azine, morpholine, thiomorpholine, pyran, tetra
Nitrogen, sulfur and oxygen atoms such as hydropyran
Contains 1 to 2 heteroatoms of 1 to 4 selected from
A hydrogen atom from a 5- or 6-membered monocyclic non-aromatic heterocycle
Groups formed by removal; preferably dioxola
Examples include nil and the like. ) Is a carbonyl group or
Bound to a sulfonyl group (eg acetyl, propioni
Le, butyryl, isobutyryl, valeryl, isovaleri
Le, pivaloyl, hexanoyl, heptanoyl, octa
Noyl, cyclobutanecarbonyl, cyclopentanecar
Bonyl, cyclohexane carbonyl, cycloheptane
Rubonyl, crotonyl, 2-cyclohexene carbononi
, Benzoyl, nicotinoyl, methanesulfonyl, d
Tansulfonyl and the like), and the
Optionally substituted alkyl, (3) optionally substituted
Cycloalkyl, (4) optionally substituted alkene
(5) optionally substituted cycloalkenyl,
(6) 5- to 6-membered monocyclic aromatic group which may be substituted
And (7) an optionally substituted 5- to 6-membered monocyclic non-ring
The substituent that the aromatic heterocyclic group may have is
Rogen (eg, fluorine, chlorine, bromine, iodine), nit
B, cyano, hydroxyl group, optionally substituted thiol group
(Eg thiol, C_1-4Alkylthio, etc.), substituted
Optionally substituted amino groups (eg amino, mono C_1-4A
Rukiruamino, di C _1-4Alkylamino, tetrahydr
Ropyrrole, piperazine, piperidine, morpholine, chi
5-6 members such as omorpholine, pyrrole, imidazole
Cyclic amino, etc.), esterified or amidated
Optional carboxyl group (eg, carboxyl, C
_1-4Alkoxycarbonyl, carbamoyl, mono C
_1-4Alkylcarbamoyl, di-C_1-4Alkylcal
Vamoyl, etc.), optionally halogenated C_1-4
Alkyl (eg trifluoromethyl, methyl, ethyl
Etc.), optionally halogenated C_1-4Alkoxy
(Eg methoxy, ethoxy, propoxy, butoxy,
Lifluoromethoxy, trifluoroethoxy, etc.), C
_1-4Alkylenedioxy (eg, -O-CH_Two-O-,
-O-CH_Two-CH_Two-O-), even if substituted
Good sulfonamides [eg optionally substituted amino]
Groups (eg amino, mono C_1-4Alkylamino, di-C
_1-4Alkylamino, tetrahydropyrrole, pipera
Gin, piperidine, morpholine, thiomorpholine, pyro
5-, 6-membered cyclic amino such as ole and imidazole)
Is -SO_TwoGroup formed by bonding to-], holmi
Le, C_2-4Alkanoyl (eg acetyl, propioni
, Etc., C_1-4Alkylsulfonyl (eg methans
(E.g., sulfonyl, ethanesulfonyl, etc.)
The number of substituents is preferably 1 to 3.

Examples of the optionally esterified carboxyl group as the substituent of R ¹ include (1) hydrogen and (2) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (3) optionally substituted cycloalkyl (eg, ,
And C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) optionally substituted alkenyl (eg, allyl, crotyl, 2-pentenyl, 3; -Alkenyl having 2 to 10 carbon atoms such as hexenyl, preferably lower (C _2-6 ) alkenyl and the like); (5) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) Two
-Cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., such as cycloalkenyl having 3 to 7 carbon atoms); (6) optionally substituted aryl (eg, phenyl, naphthyl, etc.) and the like are bonded to a carbonyloxy group. which was, preferably carboxyl, lower _{(C 1-6)} alkoxycarbonyl, aryloxycarbonyl (e.g.,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), and the like (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) An optionally substituted alkenyl,
(5) optionally substituted cycloalkenyl, and (6) optionally substituted aryl, may have a halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro , Cyano, a hydroxyl group, 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, morpholine, thiomorpholine, pyrrole, cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated Optionally 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 (eg, trifluoromethyl, methyl, ethyl, etc.), halogenated _May be 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, and the number of substituents is 1 to 3
Individuals are preferred. Further, as the optionally amidated carboxyl group as the substituent of R ¹ , the above-mentioned “R
And the like, which is similar to the "optionally substituted amino group as the substituent of ¹ " and the like, which may be substituted amino group, preferably carbamoyl, mono-C _1-6 alkylcarbamoyl, di a C _1-6 alkylcarbamoyl and the like.

The aromatic group in the optionally substituted aromatic group as the substituent of R ¹ is phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, A 5- or 6-membered homologous or heterocyclic aromatic group such as pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, benzofuran, indole, benzothiophene, benzoxazole, benzthiazole, indazole, benzimidazole, quinoline, isoquinoline,
Quinoxaline, phthalazine, quinazoline, cinnoline,
Examples include condensed heterocyclic aromatic groups such as imidazopyridine. Examples of the substituent of these aromatic groups include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group (eg,
Thiol, C _1-4 alkylthio, etc.), optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine) , pyrrole, cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated carboxyl group which may be (for example, _{carboxyl, C 1 -4} alkoxycarbonyl, carbamoyl, mono _{C 1-4} alkylcarbamoyl, di _{C 1-4} alkylcarbamoyl, etc.), optionally _{C 1-4} alkyl which may be halogenated (for example, trifluoromethyl, methyl, ethyl, etc.), halogenated which may be _{C 1-4} alkoxy (e.g., Methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, Lifluoroethoxy, etc.), formyl,
C _2-4 alkanoyl (e.g., acetyl, propionyl, _{etc.), C 1-4} alkylsulfonyl (e.g., methanesulfonyl, etc. ethanesulfonyl), and the like, the number of substituents, 1 to 3 are preferred. The substituents of R ¹ may be substituted at ^{1 to} 4 (preferably 1 to 2) the same or different and at any position of the ring.

Further, the group represented by R is a 5- or 6-membered aromatic ring.
When combined to form a ring, the formula R-Z¹-X¹-Z^Two
-(Wherein each symbol has the same meaning as defined above; R is a hydrogen atom)
Is preferably a group represented by
(C_1-6) Alkylenedioxy (eg, -O-CH_Two−
O-, -O-CH_Two-CH_Two-O-, -O-CH_Two-C
H_Two-CH_Two-O-), oxy-lower (C_1-6)
Rukirenamino (eg, -O-CH _Two-NH-, -OC
H_Two-CH_Two-NH-, etc., oxy-lower (C_1-6)
Alkylenethio (eg, -O-CH_Two-S-, -O-CH
_Two-CH_Two-S-), lower (C_1-6) Alkylene
Diamino (eg, -NH-CH_Two-NH-, -NH-CH
_Two-CH_Two-NH- etc., lower thia (C_1-6) Al
Xylene amino (eg, -S-CH_Two-NH-, -S-CH
_Two-CH_Two-NH-, etc.), etc. to form a divalent group.
It R¹"Formula R-Z¹-X¹-Z^Two− (Expression
Inside, each symbol has the same meaning as described above. ) Substituent
And a 6-membered fragrance which may further have a substituent
"5- to 6-membered ring" of "ring" has the formula R-Z¹-X¹-Z^Two−
As a "substituent" which may be present in addition to the group represented by
Is, inter alia, halogenated or lower (C_{1 -4}) Al
Coxylated lower (C_1-4) Alkyl
(Eg, methyl, ethyl, t-butyl, trifluoromethyl
, Methoxymethyl, ethoxymethyl, propoxymethyi
L, butoxymethyl, methoxyethyl, ethoxyethyl
, Propoxyethyl, butoxyethyl, etc.), halogen
Or lower (C_1-4) Even if it is alkoxylated
Good low (C_1-4) Alkoxy (eg methoxy, eth
Xy, propoxy, butoxy, t-butoxy, triflu
Oromethoxy, methoxymethoxy, ethoxymethoxy,
Propoxymethoxy, butoxymethoxy, methoxyeth
Xy, ethoxyethoxy, propoxyethoxy, butoki
Ciethoxy, methoxypropoxy, ethoxypropoxy
Ci, propoxy propoxy, butoxy propoxy
Etc.), halogen (eg, fluorine, chlorine, etc.), nitro,
Ano, 1-2 lower grades (C_1-4) Alkyl, formyl
Or lower (C_2-4) Even if substituted with alkanoyl
Good amino (eg amino, methylamino, dimethylamido)
No, formylamino, acetylamino, etc.), 5-6 members
Cyclic amino (eg, 1-pyrrolidinyl, 1-piperazini
L, 1-piperidinyl, 4-morpholino, 4-thiomol
Holino, 1-imidazolyl, 4-tetrahydropyranyl
Etc.) and the like. Also, R¹Is benzene
Where the formula R-Z¹-X¹-Z^TwoSubstitution of group represented by-
As the position, the para position is preferable, and the formula R-Z¹-X¹
-Z^TwoHas a "5- or 6-membered aromatic ring" in addition to the group represented by-
As the substitution position of the "substituent" which may be present, a meta position is
preferable.

In the above formula, examples of the "optionally substituted imino group" represented by Y include, for example, the formula -N (R ⁵ )-
[In the formula, R ⁵ represents a hydrogen atom or a substituent. ] The divalent group etc. which are represented by these are mentioned. R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted thiol group (sulfur atom is oxidized. Optionally, may form a sulfinyl group which may be substituted or a sulfonyl group which may be substituted), an amino group which may be substituted, which may be esterified or amidated A carboxyl group, an optionally substituted acyl group and the like are preferable, and a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5
Further, a 6-membered aromatic heterocyclic group, an optionally substituted acyl group and the like are more preferable. Preferred embodiments of R ⁵ include a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted acyl group and the like. , C _1-4
Alkyl, C _1-4 alkylsulfonyl, formyl, C
_2-5 alkanoyl and the like are more preferable, C _1-4 alkyl, formyl, C _2-5 alkanoyl and the like are further preferable, and propyl, cyclopropylmethyl or isobutyl is particularly preferable. Another preferred embodiment of R ⁵ is formula — (CH ₂ ) _k —R ⁶ [wherein, k represents 0 or 1, and R ⁶ is an optionally substituted 5- or 6-membered monocyclic aromatic group. Group (for example, “(6) exemplified in the section of the optionally substituted acyl group as the substituent of R ¹ ”)
Those similar to the "optionally substituted 5- to 6-membered monocyclic aromatic group"; preferably halogen, optionally halogenated C _1-4 alkyl, optionally halogenated C _{1 -4,} phenyl, pyrazolyl, thiazolyl, oxazolyl, tetrazolyl, etc., each of which may be substituted with alkoxy or the like). ] The group etc. which are represented by these are mentioned. As a specific example of "an optionally substituted hydrocarbon group" as R ⁵ are include those similar to the "optionally substituted hydrocarbon group" as R, as R ⁵ As a specific example of the “optionally substituted heterocyclic group”, the “optionally substituted heterocyclic group” as the substituent of the “optionally substituted hydrocarbon group” represented by R And the like, and examples thereof include "an optionally substituted hydroxyl group" as R ⁵ , "an optionally substituted thiol group", "an optionally substituted amino group", and "esterification or amide". Specific examples of the “optionally substituted carboxyl group” and the “optionally substituted acyl group” include “optionally substituted hydroxyl group” as the substituent of R ¹ and “substituted. Good thiol group "," even if substituted Good amino group ",
The same thing as the "carboxyl group which may be esterified or amidated" and the "acyl group which may be substituted" is mentioned.

In the above formula (I), the lower alkyl group of the “optionally substituted lower alkyl group” represented by R ² is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl. , Tert-
Examples include C _1-6 alkyl such as butyl, pentyl, isopentyl, neopentyl, and hexyl. In the above formula (I), the lower alkoxy group of the “optionally substituted lower alkoxy group” represented by R ² is C _1-6 such as methoxy, ethoxy, propoxy, butoxy and the like.
Examples include alkoxy. Examples of the substituent that the "optionally substituted lower alkyl group" and "optionally substituted lower alkoxy group" may have include halogen (eg, fluorine, chlorine, bromine, iodine). , Hydroxyl group, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoyl and the like. The lower alkyl contained in the mono (lower alkyl) amino and di (lower alkyl) amino is, for example,
The same as the lower alkyl group of the "optionally substituted lower alkyl group" for R ² above can be mentioned.
Examples of the lower alkanoyl include C _2-6 alkanoyl such as acetyl, propionyl, butyryl, isobutyryl and the like. In the above formula (I), the “halogen atom” represented by R ² is fluorine, chlorine, bromine,
Examples include iodine. Among them, R ² is preferably an optionally substituted lower C _1-6 alkyl group or a halogen atom, and particularly preferably an optionally substituted methyl group or a halogen atom.

"Aromatic ring" of "optionally further substituted aromatic ring" represented by ring A and ring B in the above formula (I)
Examples include 6-membered aromatic hydrocarbons such as benzene, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole. 5- to 6-membered aromatic heterocycle containing 1 to 2 heteroatoms of 1 to 4 selected from nitrogen atom, sulfur atom and oxygen atom or benzofuran, indole, benzothiophene, benzoxazole, benzthiazole , Indazole, benzimidazole,
Quinoline, isoquinoline, quinoxaline, phthalazine,
Examples thereof include condensed aromatic heterocycles such as quinazoline, cinnoline, and imidazopyridine. Among them, as the ring A, benzene, furan, thiophene, pyridine, pyridazine, benzimidazole and the like are preferable, and benzene,
Pyridine, pyridazine, benzimidazole and the like are more preferable, and benzene is particularly preferable. The ring B is preferably a nitrogen-containing aromatic heterocycle such as imidazole, triazole, tetrazole, pyridine and imidazopyridine, more preferably imidazole, triazole, pyridine and imidazopyridine, and particularly preferably imidazole and triazole. Examples of the “substituent” that the “aromatic ring” of the “optionally further substituted aromatic ring” represented by ring A and ring B may have:
Halogen atom, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyl group, optionally substituted thiol group (sulfur atom may be oxidized. , Optionally substituted sulfinyl group or optionally substituted sulfonyl group), optionally substituted amino group, optionally substituted acyl, optionally esterified A good carboxyl group, an aromatic group which may be substituted, and the like are used. Examples of halogen as the substituent include fluorine, chlorine, bromine, iodine and the like, with fluorine and chlorine being particularly preferable.

Alkyl in the optionally substituted alkyl as the "substituent" for ring A and ring B is
Straight chain or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,
_Examples thereof include C _1-10 alkyl such as isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably lower (C _1-6 ) alkyl. Examples of the substituent in the optionally substituted alkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group (eg, thiol, C _{1-). 4} alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc. 5
~ 6-membered cyclic amino, etc.), an optionally esterified or amidated carboxyl group (eg, carboxyl,
C _1-4 alkoxycarbonyl, carbamoyl, mono C
_{1- 4} alkylcarbamoyl, and _{di-C 1-4} alkylcarbamoyl), optionally _{C 1-4} which may be halogenated
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (eg, methoxymethoxy, methoxyethoxy, ethoxy). Ethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, 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. Examples of cycloalkyl in the optionally substituted cycloalkyl as the substituent of ring A and ring B include C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The substituent in the optionally substituted cycloalkyl includes halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group (eg, thiol,
C _1-4 alkylthio etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole) , A 5- or 6-membered cyclic amino such as imidazole), an optionally esterified or amidated carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, diC) _1-4 alkylcarbamoyl), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _{1 -4} alkoxy _{-C 1-4} alkoxy (e.g., methemoglobin Shimetokishi, methoxyethoxy, ethoxyethoxy, trifluoromethoxy ethoxy, etc. trifluoroethoxy ethoxy), _{formyl, C 2-4} alkanoyl (e.g., acetyl, propionyl, etc.), C
_1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like can be mentioned, and the number of substituents is preferably 1 to 3.

The substituent in the optionally substituted hydroxyl group as the substituent of ring A and ring B includes (1) optionally substituted alkyl (eg, 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 and the like); (2) cycloalkyl which may be substituted and may contain a hetero atom (eg, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; A saturated 5- or 6-membered heterocyclic group containing 2 to 2 heteroatoms (preferably tetrahydropyranyl, etc .; and the like); (3) optionally substituted alkenyl (eg, allyl) ), Crotyl, 2-penteny Al, alkenyl having 2 to 10 carbon atoms such as 3-hexenyl, preferably lower (C _2-6 ) alkenyl and the like); (4) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2 -Cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl and the like cycloalkenyl having 3 to 7 carbon atoms); (5) optionally substituted aralkyl (eg, phenyl-C _1-4 alkyl (eg, benzyl, benzyl, (6) formyl or optionally substituted acyl (eg, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), carbon number 1)
To 4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); and (7) substituents such as optionally substituted aryl (eg, phenyl, naphthyl, etc.), and the like, The above-mentioned (1) optionally substituted alkyl,
(2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) substituted The optionally substituted acyl and (7) the optionally substituted aryl may have a 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, imidazole and other 5- or 6-membered cyclic amino), esterification or amidation Optionally 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 (eg, trifluoromethyl, methyl, ethyl, etc.), halogenated Optionally C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc .; preferably optionally halogenated C _1-4 alkoxy), formyl, C _2-4 alkanoyl. (Eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), optionally substituted 5- or 6-membered aromatic heterocycle [eg, furan, thiophene, pyrrole, Imidazole, pyrazole, thiazole, oxazole, isothiazole, a Soxazole, tetrazole, pyridine,
1 to 1 selected from a nitrogen atom, a sulfur atom and an oxygen atom such as pyrazine, pyrimidine, pyridazine and triazole.
A 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms, etc .; a substituent which the heterocycle may have is halogen (eg, fluorine, chlorine, bromine, iodine, etc.). ), Nitro, cyano, hydroxyl group, thiol group, amino group, carboxyl group, and 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 can be mentioned, and the number of substituents is preferably 1 to 3. . ] Etc. are mentioned, and as the number of substituents, 1 to 3 are preferable.

The substituent in the optionally substituted thiol group as the substituent of ring A and ring B is the above-mentioned "substituent in the optionally substituted hydroxyl group as the substituent of ring A and ring B". And the like, but among them (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (2) optionally substituted cycloalkyl (eg, ,
And C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) optionally substituted aralkyl (eg, phenyl-C _1-4 alkyl (eg, benzyl, benzyl, (Eg, phenethyl)); (4) optionally substituted aryl (eg, phenyl, naphthyl, etc.)) and the like, and (1) optionally substituted alkyl, (2) ) Optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) 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.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 5- to 6-membered cyclic amino such as imidazole), optionally esterified or amidated carboxyl group (eg, carboxyl, C _1
-4 alkoxycarbonyl, carbamoyl, mono C
_1-4 alkylcarbamoyl, and _{di-C 1-4} alkylcarbamoyl), optionally _{C 1-4} may be halogenated
Alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (eg, methoxymethoxy, methoxyethoxy, ethoxy). Ethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, 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.

Substituted as substituents on Ring A and Ring B
Examples of the substituent of the amino group which may be present include the above-mentioned “ring”.
Optionally substituted water as a substituent for A and ring B
Having 1 to 2 substituents similar to the “substituent in the acid group”
Examples of amino groups include
(1) optionally substituted alkyl (eg, methyl
Ru, ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, o
C such as cutyl, nonyl and decyl_1-10Alkyl, good
More preferably lower (C_{1- 6}) Alkyl etc.
); (2) optionally substituted cycloalkyl (eg,
Cyclopropyl, cyclobutyl, cyclopentyl, shik
C such as lohexyl and cycloheptyl_3-7Cycloal
Such as kills); (3) optionally substituted alkenyl (eg, ari
Allyl, crotyl, 2-pentenyl, 3-hexeni
Alkenyl having 2 to 10 carbon atoms, such as ru, preferably lower
(C_2-6) Examples include alkenyl); (4) optionally substituted cycloalkenyl (eg,
For example, 2-cyclopentenyl, 2-cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl
And cycloalkenyl having 3 to 7 carbon atoms.
); (5) Formyl or optionally substituted acyl (eg,
For example, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, pr
Ropionyl, butyryl, isobutyryl, etc.), carbon number 1
~ 4 alkylsulfonyl (eg, methanesulfonyl,
Tansulfonyl etc.) and the like); (6) optionally substituted aryl (eg, phenyl
And naphthyl) are preferable, and
(1) optionally substituted alkyl, (2) substitution
Optionally substituted cycloalkyl, (3) substituted
Optionally alkenyl, (4) optionally substituted shik
Alkenyl, (5) optionally substituted acyl,
And (6) optionally substituted aryl has
Examples of suitable substituents include halogen (eg, fluorine, chlorine,
Bromine, iodine, etc.), nitro, cyano, hydroxyl group, substituted
Optionally substituted thiol groups (eg thiol, C_1-4A
(Eg, rukylthio), optionally substituted amino group
(Eg amino, mono C_1-4Alkylamino, di-C
_1-4Alkylamino, tetrahydropyrrole, pipera
Gin, piperidine, morpholine, thiomorpholine, pyro
5- or 6-membered cyclic amino compounds such as diol and imidazole
Etc.), which may be esterified or amidated
Boxyl group (eg carboxyl, C_1-4Alkoxyca
Lubonyl, carbamoyl, mono C_1-4Alkyl carba
Moyle, The C_1-4Alkylcarbamoyl etc.), halo
C which may be genated_1-4Alkoxy (eg, met
Xy, ethoxy, propoxy, butoxy, trifluoro
Methoxy, trifluoroethoxy, etc.), halogenated
May be C_1-4Alkoxy-C_1-4Arcoki
Si (eg, methoxymethoxy, methoxyethoxy, etoki
Ciethoxy, trifluoromethoxyethoxy, triflu
Oroethoxyethoxy, etc.), formyl, C_2-4Al
Canoyl (eg, acetyl, propionyl, etc.), C
_1-4Alkylsulfonyl (eg, methanesulfonyl,
Tansulphonyl etc.) and the number of substituents
However, the number is preferably 1 to 3. In addition, the ring A and ring B
The optionally substituted amino group as a substituent is amino
The substituents on the groups are attached to each other to form a cyclic amino group (for example, the
Trahydropyrrole, piperazine, piperidine, morpho
Phosphorus, thiomorpholine, pyrrole, imidazole, etc.
Excluding one hydrogen atom from the ring-constituting nitrogen atom of a 5- or 6-membered ring
A cyclic amino group having a bond on the nitrogen atom.
May be formed. The cyclic amino group is a substituent
And the substituent may be halogen.
(Eg, fluorine, chlorine, bromine, iodine, etc.), nitro, silane
Ano, hydroxyl group, optionally substituted thiol group (eg,
Thiol, C_1-4Alkylthio, etc.), substituted
Optionally an amino group (eg, amino, mono C_1-4Alkyl
Amino, di C_1-4Alkylamino, tetrahydropyro
, Piperazine, piperidine, morpholine, thiomol
5- to 6-membered rings such as holin, pyrrole and imidazole
Amino), esterified or amidated
Good carboxyl group (eg, carboxyl, C_1-4Al
Coxycarbonyl, carbamoyl, mono C_1-4Archi
Lucarbamoyl, di-C_1-4Alkyl carbamoyl
Etc.), optionally halogenated C _1-4Alkoxy
(Eg methoxy, ethoxy, propoxy, butoxy,
Lifluoromethoxy, trifluoroethoxy, etc.)
C which may be rogenated_{1 -4}Alkoxy-C
_1-4Alkoxy (eg, methoxy methoxy, methoxy ether
Toxy, ethoxyethoxy, trifluoromethoxyeth
Xy, trifluoroethoxyethoxy, etc.), holmi
Le, C_2-4Alkanoyl (eg acetyl, propioni
, Etc., C_1-4Alkylsulfonyl (eg methans
(E.g., sulfonyl, ethanesulfonyl, etc.)
The number of substituents is preferably 1 to 3.

As the optionally substituted acyl as the substituents of the ring A and the ring B, (1) hydrogen and (2) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl) , Isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (3) optionally substituted cycloalkyl (eg, ,
And C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) optionally substituted alkenyl (eg, allyl, crotyl, 2-pentenyl, 3; -Alkenyl having 2 to 10 carbon atoms such as hexenyl, preferably lower (C _2-6 ) alkenyl and the like); (5) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) Two
-Cyclopentenylmethyl, 2-cyclohexenylmethyl and other cycloalkenyl having 3 to 7 carbon atoms); (6) optionally substituted 5- to 6-membered monocyclic aromatic group (eg, phenyl, Such as pyridyl) bonded to a carbonyl group or a sulfonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, Cycloheptane carbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl and the like), and (2) optionally substituted alkyl described above,
(3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5-6 membered Examples of the substituent that the monocyclic aromatic group may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group, and optionally substituted thiol group (eg, thiol , C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, Pyrrole, 5- or 6-membered cyclic amino such as imidazole), optionally 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 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), optionally halogenated C
_1-4 alkoxy _{-C 1-4} alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxy ethoxy, etc. trifluoroethoxy ethoxy), _{formyl, C 2-4} alkanoyl (e.g., 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 the optionally esterified carboxyl group as the substituent of ring A and ring B include (1) hydrogen and (2) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl). , Butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-10 alkyl such as isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferably lower (C _1-6 ) alkyl and the like); (3) optionally substituted cycloalkyl (eg, ,
And C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) optionally substituted alkenyl (eg, allyl, crotyl, 2-pentenyl, 3; -Alkenyl having 2 to 10 carbon atoms such as hexenyl, preferably lower (C _2-6 ) alkenyl and the like); (5) optionally substituted cycloalkenyl (eg, 2-cyclopentenyl, 2-cyclohexenyl) Two
-Cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., such as cycloalkenyl having 3 to 7 carbon atoms); (6) optionally substituted aryl (eg, phenyl, naphthyl, etc.) and the like are bonded to a carbonyloxy group. which was, preferably carboxyl, lower _{(C 1-6)} alkoxycarbonyl, aryloxycarbonyl (e.g.,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), and the like (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) An optionally substituted alkenyl,
(5) optionally substituted cycloalkenyl, and (6) optionally substituted aryl, may have a halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro , Cyano, a hydroxyl group, 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, morpholine, thiomorpholine, pyrrole, cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated Optionally carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl,
Carbamoyl, mono C _1-4 alkylcarbamoyl, diC _1-4 alkylcarbamoyl and the like), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
Trifluoroethoxy, etc.), optionally halogenated C _1-4 alkoxy-C _1-4 alkoxy (eg, 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 can be mentioned, and the number of substituents is 1 to 3.
Individuals are preferred.

Substituted as substituents on Ring A and Ring B
The aromatic group in the aromatic group which may be
Nyl, pyridyl, furyl, thienyl, pyrrolyl, imida
Zolyl, pyrazolyl, thiazolyl, oxazolyl, iso
Thiazolyl, isoxazolyl, tetrazolyl, pyrazini
5 such as le, pyrimidinyl, pyridazinyl, triazolyl, etc.
~ 6-membered homo or heterocyclic aromatic groups, benzofuran, a
Ndol, benzothiophene, benzoxazole,
Indazole, indazole, benzimidazole,
Quinoline, isoquinoline, quinoxaline, phthalazine,
Fused rings such as quinazoline, cinnoline, and imidazopyridine
Heterocyclic aromatic groups and the like can be mentioned. Of these aromatic groups
As the substituent, halogen (eg, fluorine, chlorine, bromine,
Iodine, etc.), nitro, cyano, hydroxyl, substituted
Thiol group (eg, thiol, C_1-4Alkyl
Thio), an optionally substituted amino group (eg, amino
No, Mono C_1-4Alkylamino, di-C_1-4Alkyl
Amino, tetrahydropyrrole, piperazine, piperidi
, Morpholine, thiomorpholine, pyrrole, imidazo
A 5- or 6-membered cyclic amino such as oleyl), esterified
Or an optionally amidated carboxyl group (eg,
Ruboxil, C_1-4Alkoxycarbonyl, carbamo
Il, Mono C_1-4Alkylcarbamoyl, di-C_1-4
Alkylcarbamoyl etc.), even if halogenated
Good C_1-4Alkyl (eg trifluoromethyl, methyl
, Ethyl, etc.), optionally halogenated C
_1-4Alkoxy (eg methoxy, ethoxy, propoxy
Ci, butoxy, trifluoromethoxy, trifluoroe
Toxy etc.), formyl, C_2-4Alkanoyl (eg,
Acetyl, propionyl, etc.), C_1-4Alkylsul
Fonyl (eg, methanesulfonyl, ethanesulfonyl, etc.
Etc., and the number of the substituents is 1 to 3
preferable. The substituents on the ring A and the ring B are respectively
1-4 (preferably 1-2) the same or different
It may be substituted at any position on the ring. Also, in ring A
In the indicated "aromatic ring which may be further substituted",
An incense ring or a ring B "which may be further substituted
“Aromatic ring” of “good aromatic ring” has two or more substituents
Of these, two of these substituents are bonded to each other.
In combination, for example, lower (C_1-6) Alkylene (eg,
Rimethylene, tetramethylene, etc.), lower (C_1-6)
Alkyleneoxy (eg, -CH_Two-O-CH_Two-, -O
-CH_Two-CH_Two-, -O-CH_Two-CH_Two-CH
_Two-, -O-CH_Two-CH_Two-CH_Two-CH_Two-, -O
-C (CH_Three) (CH_Three) -CH_Two-CH_Two-Etc.), Low grade
(C_1-6) Alkylenethio (eg, -CH_Two-S-CH
_Two-, -S-CH_Two-CH_Two-, -S-CH_Two-CH_Two
-CH_Two-, -S-CH_Two-CH_Two-CH_Two-CH
_Two-, -SC (CH_Three) (CH_Three) -CH_Two-CH_Two-N
Do), low grade (C_1-6) Alkylenedioxy (eg, -O
-CH_Two-O-, -O-CH_Two-CH_Two-O-, -O-
CH_Two-CH_Two-CH_Two-O-, etc.), low grade
(C_1-6) Alkylenedithio (eg, -S-CH_Two-S
-, -S-CH_Two-CH_Two-S-, -S-CH_Two-CH
_Two-CH_Two-S-, etc.), oxy-lower (C_1-6) Al
Xylene amino (eg, -O-CH _Two-NH-, -O-CH
_Two-CH_Two-NH-, etc., oxy-lower (C_1-6)
Rukirenthio (eg, -O-CH_Two-S-, -O-CH_Two
-CH_Two-S-), lower (C_1-6) Alkylene
Mino (eg, -NH-CH_Two-CH_Two-, -NH-CH_Two
-CH_Two-CH_Two-Etc.), Low grade (C_1-6) Arche
Ndiamino (eg, -NH-CH_Two-NH-, -NH-C
H_Two-CH_Two-NH- etc., lower thia (C_1-6)
Rukirenamino (eg, -S-CH_Two-NH-, -SC
H_Two-CH _Two-NH-, etc., lower (C_2-6) Arche
Nylene (eg, -CH_Two-CH = CH-, -CH_Two-CH
_Two-CH = CH-, -CH_Two-CH = CH-CH_Two-N
Do), low grade (C_4-6) Arcadienylene (eg, -CH
= CH-CH = CH-, etc.) and the like.
Yes. Further, two substituents of ring A are bonded to each other to form
Divalent group and two substituents of ring B are bonded to each other to form
The divalent group formed is represented by Ring A and Ring B
“Aromatic ring” of “optionally substituted aromatic ring” has
The same substituents as the “substituent” (halogen atom, ni
Toro, cyano, optionally substituted alkyl, substituted
Optionally substituted cycloalkyl, optionally substituted
Hydroxyl group, optionally substituted thiol group (sulfur atom is
Sulfi that may be oxidized or substituted
Forms an nyl group or an optionally substituted sulfonyl group
Optionally substituted), optionally substituted amino group,
Optionally substituted acyl, esterified or amidated
Optionally substituted carboxyl group, optionally substituted
1 to 3 aromatic groups). Ring A
And a ring B which represents an “optionally further substituted aroma”
As the “substituent” that the “aromatic ring” of the “ring” may have
Is, inter alia, a halogen atom, cyano, hydroxyl group, nit
Carbo, which may be esterified or amidated
Xyl group (eg, carboxyl, C_1-4Alkoxycar
Bonyl, carbamoyl, mono C_{1- Four}Alkyl carbamo
Il, the C_1-4Alkylcarbamoyl, pyrrolidinoca
Lubonyl, piperidinocarbonyl, morpholinocarboni
, Thiomorpholinocarbonyl, etc.), halogenated or
Is lower (C_1-4) Lower optionally optionally alkoxylated
(C_1-4) Alkyl (eg, methyl, ethyl, t-butyl
, Trifluoromethyl, methoxymethyl, ethoxymeth
Tyl, propoxymethyl, butoxymethyl, methoxye
Chill, ethoxyethyl, propoxyethyl, butoxy
Even if it is substituted with a hydroxyl group or a cyano group)
Good low (C_1-4) Alkyl (eg hydroxy C
_1-4Alkyl, cyano C_1-4Alkyl, etc.)
Carboxyl group which may be tellurized or amidated
Lower optionally substituted with (C_{1- Four}) Alkyl
(Eg carboxyl C_1-4Alkyl, C_1-4Arco
Xycarbonyl C_1-4Alkyl, carbamoyl C
_1-4Alkyl, mono C_1-4Alkylcarbamoyl C
_1-4Alkyl, di-C_1-4Alkylcarbamoyl C
_1-4Alkyl, pyrrolidinocarbonyl C_1-4Archi
Le, piperidino carbonyl C_1-4Alkyl, morpholi
Nocarbonyl C_1-4Alkyl, thiomorpholinocarbo
Nil C_1-4Alkyl, etc.), halogenated or lower
(C_1-4) Lower optionally optionally alkoxylated (C
_1-4) Alkoxy (eg methoxy, ethoxy, propo
Xy, butoxy, t-butoxy, trifluoromethoxy
Ci, methoxymethoxy, ethoxymethoxy, propoxy
Methoxy, butoxymethoxy, methoxyethoxy, eth
Xyethoxy, propoxyethoxy, butoxyethoxy
Ci, methoxypropoxy, ethoxypropoxy, propo
Xypropoxy, butoxypropoxy, etc.), halogen
(Eg, fluorine, chlorine, etc.), nitro, cyano, 1-2 pieces
Lower of (C_1-4) Alkyl, formyl or lower (C
_2-4) Amino optionally substituted with alkanoyl
(Eg amino, methylamino, dimethylamino, formy
Luamino, acetylamino, etc.), 5- to 6-membered cyclic amino
Group (eg, 1-pyrrolidinyl, 1-piperazinyl, 1-
Piperidinyl, 4-morpholino, 4-thiomorpholino,
1-imidazolyl, 4-tetrahydropyranyl, etc.)
Which can be mentioned. As the substituent of ring A, halo is most preferable.
Optionally low-grade (C_1-4) Alkyl is
In particular, the substituent of ring B is preferably a substituted group.
Optionally lower alkyl (C_1-4) Is more preferred
Good

In the above formula (I), the divalent group represented by W is, for example, the formula --W ¹ --X ² --W ^2- (W ¹ and W ²
Each _{O, S (O) m1 (} m1 is 0, 1 or 2), an optionally substituted imino group (-N ^(R 3)
-) Or a bond, and X ² represents an optionally substituted alkylene group, an optionally substituted alkenylene group, or a bond. ), The bonding position of W ¹ may be any position when ring A is, for example, a benzene ring, but is preferably in the para position. The substituent (R ³ ) of the optionally substituted imino group represented by W ¹ and W ² is a hydrogen atom, or an optionally substituted lower (C _1-6 ).
Alkyl [eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, isopentyl, neopentyl, hexyl, hydroxy C _1-6 alkyl (eg, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.),
C _1-6 alkyl halide (eg, trifluoromethyl, trifluoroethyl, etc.), C _1-6 alkyl cyanide (eg, cyanoethyl, cyanopropyl, etc.), carboxyl C which may be esterified or amidated
_{1- 6} alkyl, etc.], formyl, lower _{(C 2-5)} alkanoyl (e.g., acetyl, propionyl, butyryl), a lower _{(C 1-5)} alkylsulfonyl (methylsulfonyl, ethyl sulfonyl), and the like.
"An optionally substituted alkylene group" represented by X ²
The alkylene group, for example _{- (CH 2) k1 - (} k
1 is an integer of 1 to 4) and the like. Examples of the alkenylene group of the “optionally substituted alkenylene group” represented by X ² include — (CH
_{2) k2 - (CH = CH} ) - (CH 2) k3 -. (K2 and k3 are the same or different and 0, 1 or 2 provided that the sum of k2 and k3 is represented by 2 or less is) Alkenylene chains and the like. The alkylene group and alkenylene group represented by X ² may have a substituent at any position (preferably on a carbon atom), and such a substituent includes an alkylene chain and an alkenylene chain forming a straight chain portion. May be any as long as it can bind to, for example, lower (C _1-6 ) alkyl (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec
-Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower ( _C3-7 )
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 or amidated carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl, carbamoyl, mono C _1-4 alkyl) Carbamoyl, diC _1-4 alkylcarbamoyl and the like), hydroxyl group, oxo, hydroxyimino group, optionally substituted lower (C _1-6 ) alkoxyimino group and the like, preferably having 1 to 6 carbon atoms.
Lower alkyl (preferably C _1-3 alkyl), hydroxyl group, oxo, hydroxyimino group, (hydroxyl group, cyano group, optionally substituted with a polar group such as esterified or amidated carboxyl group) Good) Lower (C
_1-6 ) alkoxyimino groups and the like.

The phosphono group which may be esterified
As -P (O) (OR^7b) (OR^8b) [Wherein R
^7bAnd R^8bAre hydrogen and C1-C6 al, respectively.
A kill group or a cycloalkyl group having 3 to 7 carbon atoms,
R^7bAnd R^8bCombine with each other to form a 5- to 7-membered ring
May be used]. The above formula
Medium, R^7bAnd R^8bAl having 1 to 6 carbon atoms represented by
Kill groups include methyl, ethyl, propyl and isopro
Pill, butyl, isobutyl, sec-butyl, tert
-Butyl, pentyl, isopentyl, neopentyl,
Examples include xyl and the like, cycloalkyl having 3 to 7 carbon atoms.
As, cyclopropyl, cyclobutyl, cyclopen
Chill, cyclohexyl, cycloheptyl, etc.
However, it is preferable that a chain-like lower alkyl having 1 to 6 carbon atoms.
And more preferably lower alkyl having 1 to 3 carbon atoms.
You can R^7bAnd R^8bAre the same as
May be different, but are preferably the same.
Also, R^7bAnd R ^8bAre bonded to each other and have a 5 to 7 membered ring
To form R^7bAnd R^8bAnd combine with each other,
-(CH_Two)_Two-,-(CH_Two)_Three-,-(CH_Two)_Four-Table
Straight chain C _2-4Form an alkylene side chain. The
The side chain may have a substituent, for example, such a substituent
Examples thereof include a hydroxyl group and halogen. The es
With ester group of carboxyl group which may be tellurized
Include a carboxyl group and an alkyl group having 1 to 6 carbon atoms.
Or with a cycloalkyl group having 3 to 7 carbon atoms
, For example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl,
Toxycarbonyl, isobutoxycarbonyl, sec-
Butoxycarbonyl, tert-butoxycarbonyl,
Pentyloxycarbonyl, hexyloxycarbonyl
L, cyclopentyloxycarbonyl, cyclohexyl
Oxycarbonyl and the like can be mentioned. The amidated
As the amide of the carboxyl group, which may be
Sil group and alkylamino group having 1 to 6 carbon atoms, 3 to carbon atoms
7 cycloalkylamino group or 5-8 membered cyclic amine
(Eg, pyrrolidine, piperidine, morpholine, etc.)
Bound, eg carbamoyl, mono C_1-6Al
Kircarbamoyl, di-C_1-6Alkylcarbamoyl,
Cyclopentylaminocarbonyl, cyclohexylami
Nocarbonyl, pyrrolidinocarbonyl, piperidinocar
Bonyl, morpholinocarbonyl, thiomorpholinocarbo
Examples include nil and the like. As W, W¹And W^TwoNoi
One of the gaps is O, S (O)_m1(M1 is 0, 1 or
2) or -N (R^Three)-(R^ThreeIs a hydrogen atom or substitution
Optionally lower C_1-4Other)
X is the bond,^TwoIs-(CH_Two)_p-(P is not 1
And W is -CH (OH)-.
A divalent group is preferred and W¹And W^TwoEither one of
O, S (O)_m1(M1 is 0, 1 or 2) and the other is connected
It's a joint, X^TwoIs-(CH_Two)_p-(P is 1 to 3
An integer) or a divalent group in which W is —CH (OH) —
More preferred are groups, especially W¹Is connected to ring A
-SOCH_Two− Is preferable.

As the compound represented by the above formula (I),
Ring A is a benzene ring, Ring B is an optionally substituted imidazole ring or an optionally substituted triazole ring, and one of W ¹ and W ² is S (O).
In _m1 (m1 is 0, 1 or 2), the other is a bond, ^{X 2} is _{- (CH 2) p - (} p represents an integer of 1 to 3) or W is -CH (OH) - in Certain compounds according to claim 1 are preferred, among which

[Chemical 11] Are preferred, in which case the compounds in which the configuration of SO is (S) coordinated are preferred. Specific examples of the compound represented by the formula (I) include 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-
Trifluoromethylphenyl] -1-propyl-2,3
-Dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(4-propyl-
4H-1,2,4-triazol-3-yl) methoxy] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl]- 1-isobutyl-N- [3
-Methyl-4-[(4-propyl-4H-1,2,4-
Triazol-3-yl) methylthio] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [2- (4-propyl-4H-1,2 , 4-Triazol-3-yl) methylthiopyridin-5-yl] -2,3-dihydro-1H-
1-benzazepine-4-carboxamide, 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- [3- (4H-1,2,4-triazol-4-yl) propyl] phenyl] -2,3-dihydro-1H-1 -Benzazepine-4-carboxamide, 7
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(4-propyl-1H-1,
2,4-Triazol-5-3-yl) methylsulfinyl] pyridazin-3-yl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide, 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-cyclopropylimidazol-4-yl) methylsulfinyl] phenyl] -2,
3-dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) Methyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-
4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(S) -hydroxy (1
-Oxidopyridin-2-yl) methyl] phenyl]-
1- (1-methylpyrazol-5-ylmethyl) -2,
3-dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -N- [4- (4-methyl-4H-1,2,4-triazole-3- Ilthiomethyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -N- [4- (4-methyl-4H) −
1,2,4-Triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide, 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- (4
-Ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H)
-1,2,4-Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl- N- [4-
[2- (4-Propyl-4H-1,2,4-triazol-3-yl) ethyl] phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide, 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-(4H-1,2,4-triazol-4-ylethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide, 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [ 4- (2-Butoxyethoxy) phenyl] -N- [4-[[(4,6-dimethyl-2-pyrimidinyl) methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine -4-carboxamide, 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[3-Methoxy-4-[(3-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl -N- [4
-[[(1-Ethyl-tetrazol-5-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide, 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(2-methyl-3-pyridinyl) methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide, 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-pyridazinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-
[[(2-Methyl-3-pyridinyl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[[1- (2-Methoxyethyl) imidazol-5-yl] methyl] sulfinyl] phenyl] -2,
3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl]-
1-isobutyl-N- [2-[[(1-propylimidazol-5-yl) methyl] sulfinyl] benzimidazol-5-yl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3
-Methyl-4-[[(1-methylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, N-
[4-[[[1-Allylimidazol-2-yl] methyl] sulfinyl] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-
Dihydro-1-benzazepine-4-carboxamide,
7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclopropylimidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2- Butoxyethoxy) phenyl] -N- [4-[[[1-cyclopropylimidazol-2-yl] methyl] sulfinyl] phenyl]-
1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, 7- [4- (2-
Butoxyethoxy) phenyl] -1-propyl-N-
[4-[[[1-Propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-
1-benzazepine-4-carboxamide, 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-isopropylimidazole-5
-Yl] methyl] sulfanyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide,
(-)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide, (-)-7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, (−)-7- [4
-(2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide, (−)-1-isobutyl-7- [4-
(2-Propoxyethoxy) phenyl] -N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, (+)-7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[Hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-4
-Carboxamide and the like are preferred.

The salt of the compound represented by 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, Examples thereof include salts with organic acids and salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include 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. Suitable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Examples thereof include salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable 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 such as toluene sulfonic acid are included. Suitable examples of salts with basic amino acids include:
Examples thereof include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. The compound represented by the formula (I) of the present invention or a salt thereof may be a hydrate or a non-hydrate.
Further, when the compound represented by the formula (I) of the present invention or a salt thereof exists as a configurational isomer (configurational isomer), a diastereomer, a conformer or the like, if desired, it is known per se. Each can be isolated by the separation / purification means of. Further, when the compound represented by the formula (I) or a salt thereof is a racemate, the (S) form,
It can be separated into the (R) form, and each of the optically active forms and racemic forms is included in the present invention. The compound represented by formula (I) or a salt thereof used in the present invention [hereinafter, may be referred to as compound (I). ]
Is a compound which is converted into a compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, a compound which is enzymatically oxidized, reduced or hydrolyzed to be converted into the compound (I). , A compound which is converted to compound (I) by being hydrolyzed by gastric acid or the like. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) ,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,
tert-butylated compound); Compound (I)
A compound whose 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.); Compound (I) having a carboxyl group esterified or amidated (eg, compound (I) having a carboxyl group converted to ethyl ester) , Phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolene -4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound, etc.); and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is a compound which is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990 "Development of Pharmaceuticals" Vol. 7, Molecular Design, pages 163 to 198. May be The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

The present invention further provides a process for producing a compound represented by 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 Kaihei 8-73476) or a method analogous thereto. Further, for example, it can be manufactured according to the following method. The following formulas (II), (III),
(IV), (V), (VI), (VII), (VIII), (I ')
And a compound represented by (I ″) (hereinafter, abbreviated as compound (II), compound (III), compound (IV), compound (V),
The salt of compound (VI), compound (VII), compound (VIII), compound (I ′) and compound (I ″) may be the same as the salt with compound (I).
In each of the following reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group after the reaction, if necessary. As the amino-protecting group,
For example, C _1-6 alkylcarbonyl which may have a substituent (eg, acetyl, propionyl, etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl). Etc.), phenyloxycarbonyl (eg benzoxycarbonyl etc.), C _7-10 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), trityl, phthaloyl etc. are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), a nitro group, etc. are used. Is about 1 to 3. Examples of the protecting group for the carboxyl group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),
Phenyl, trityl, silyl and the like are used. Examples of these substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine, _{etc.), C 1-6} alkylcarbonyl (e.g., 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 hydroxyl-protecting group include, for example,
C which may have a substituent_1-6Alkyl (eg,
Methyl, ethyl, propyl, isopropyl, butyl, te
rt-butyl etc.), phenyl, C_7-10Aralkyl
(Eg, benzyl, etc.), C _1-6Alkyl Carboni
(Eg acetyl, propionyl, etc.), holmi
Lu, phenyloxycarbonyl, C_7-10Aralkyl
Oxycarbonyl (eg, benzyloxycarbonyl
Etc.), pyranyl, furanyl, silyl, etc.
It As these substituents, a halogen atom (for example,
Fluorine, chlorine, bromine, iodine, etc.), C_1-6Archi
Le, phenyl, C_7-10Aralkyl, nitro group, etc.
The number of substituents used is about 1 to 4. Well
In addition, the method of introducing and removing the protecting group is not
Knowledge or a method similar to it (eg, Protective
Groups in Organic Chemistry (J.F.
W. McOmie et al., Plenum Press Co.)
However, the removal method includes, for example, acid, base, reduction,
UV light, hydrazine, phenylhydrazine, N-methyl
Sodium dithiocarbamate, tetrabutylammoni
How to treat with umfluoride, palladium acetate, etc.
Used.

[Method A]

[Chemical 12] [Each symbol in the formula has the same meaning as described above] In this method, the anilide compound (I) can be produced by reacting the compound (II) with the compound (III). The condensation reaction of the compound (II) and the compound (III) is carried out by a usual peptide synthesis means. The peptide synthesizing means may be according to any known method, for example, M. Bodans
ky and MA Ondetti, Peptide Synthesis, Interscience, New York, 1966; FM Finn and K. Hofmann.
By The Proteins, Volume 2, H. Nen
rath, edited by RL Hill, Academic Press Ink. Nobuo Izumiya et al., "Basics and Experiments of 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, carbonyldiimidazole method, redox method, DCC / HONB method, etc., WSC method, diethyl cyanophosphate (DEPC ) And the like. That is, as the reactive derivative, for example, acid halide (eg, acid chloride, acid bromide, etc.), acid azide, acid anhydride, mixed acid anhydride (eg, mono C _1-6 alkyl carbonic acid mixed acid anhydride (eg, free acid). And monomethyl carbonic acid, monoethyl carbonic acid, monoisopropyl carbonic acid, monoisobutyl carbonic acid, mono tert-butyl carbonic acid, monobenzyl carbonic acid, mono (p-nitrobenzyl) carbonic acid, monoallyl carbonic acid, etc.), C _1-6 fat Group carboxylic acid mixed anhydrides (for example with free acid and acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc. Mixed acid anhydride), C _7-12 aromatic carboxylic acid mixed acid anhydride (for example, free acid and benzoic acid, p-toluic acid, p-c Mixed acid anhydride with lolobenzoic acid, etc.), mixed acid anhydride with organic sulfonic acid (for example, mixed acid anhydride with free acid and methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), etc. ), Active amide, active ester (eg, diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester, p-nitrophenyl ester, 2,4-
Reactive derivatives such as dinitrophenyl ester) and active thioester (eg, 2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc.) can be used. This condensation reaction can be carried out in a solvent. Examples of the solvent include anhydrous or hydrous N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, or an appropriate mixture thereof. In this condensation reaction, the compound (III) is usually used in an amount of about 1 to 2 mol per 1 mol of the compound (II). The reaction temperature is generally about -20 ° C to about 50 ° C, preferably about -10 ° C to about 3 ° C.
It is 0 ° C. The reaction time is about 1 to about 100 hours, preferably about 2 to about 40 hours. The compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method B]

[Chemical 13] V in the compound (IV) represents a halogen atom (chlorine, bromine, iodine, etc.), a sulfonyloxy group (methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), and other The symbols have the same meaning as described above. R ^a in the compound (I ′) represents hydrogen or a substituent which the above-mentioned optionally substituted imino group represented by W ¹ and W ² may have. A compound (I) having an oxy group, a thio group or an imino group in W ^2a such as the compound (I ′) can be produced by reacting the compound (IV) with the compound (V) having the ring B. it can. The compound (V) is usually used in an amount of about 1 to 3 mol per 1 mol of the compound (IV). In this reaction, triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. are used in an equivalent amount to about 3 times the molar amount as the base. As a result, the reaction can be smoothly proceeded by adding sodium iodide, potassium iodide or the like. This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2. -Dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or a mixed solvent thereof can be used. The reaction is about -10 ℃
To about 180 ° C for about 1 hour to about 40
Done on time. In addition, this reaction is preferably carried out under an atmosphere of an inert gas (eg, nitrogen, argon, etc.). [C method]

[Chemical 14] V'in the compound (VII) is a halogen atom (chlorine,
Bromine, iodine, etc.), sulfonyloxy group (methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), and R in compound (I ″)
^b represents hydrogen or a substituent which the above-mentioned optionally substituted imino group represented by W ¹ and W ² may have, and other symbols have the same meanings as described above. By reacting the compound (VI) with the compound (VII) having the ring B, for example, the compound (I ″) having an oxy group, a sulfinyl group or an imino group in W ^1a can be produced. The compound (VII) is usually used in an amount of about 1 to 3 mol per 1 mol of the compound (VI). In this reaction, triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. are used in an equivalent amount to about 3 times the molar amount as the base. As a result, the reaction can be smoothly proceeded by adding sodium iodide, potassium iodide or the like. This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2. -Dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or a mixed solvent thereof can be used. The reaction is about -10 ℃
To about 180 ° C for about 1 hour to about 40
Done on time. In addition, this reaction is preferably carried out under an atmosphere of an inert gas (eg, nitrogen, argon, etc.).

[D method]

[Chemical 15] Compound (VIII) [In the formula, V ″ represents a halogen atom (bromine, iodine, etc.), a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc.), and other symbols have the same meanings as described above. ] For example, Suzuki reaction [with aryl boric acid,
Palladium-catalyzed cross-condensation reactions with, for example, aryl halides or aryloxytrifluoromethanesulfonates; A. Suzuki et al., Synth. Commun. 1981.
11, 513], a compound (I) in which R ¹ represents a 5- or 6-membered aromatic group can be produced. The compound (I) can be obtained by using the arylboric acid in an amount of about equimolar to 1.5 times the amount of the compound (VIII). [Method E] W of compound (I) is, for example, -CO- or -S.
When having −, a method known per se, for example, Ojima,
I., ed., Catalytic Asymmetric Synthesis, 2000, Wil
The compound (I) having optically active —CH (OH) — or —SO— can be produced by the method described in ey-VCH (New York) or a method similar thereto.

The compound (I) thus obtained is separated by known means of separation and purification, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like. Compound (II) used as a starting material can be prepared by a known method (for example, JP-A-8-73476).
Etc.) or a method analogous thereto, for example, reaction formula I or reaction formula I
It can be produced by the method shown by I and the method shown in the reference example described below or a method similar thereto.

Reaction Formula I

[Chemical 16] [In the formula, R ⁹ represents a C _1-4 alkyl group, and R ^{5 ′} represents R 1.
^{5 has the} same meaning as the substituent represented by ⁵ , and the other symbols have the same meanings as described above. In this method, first, the compound represented by the formula (IX) is heated with polyphosphoric acid, or the compound (IX) is converted to an acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride or the like, The compound (X) is produced by cyclization by a usual Friedel-Crafts reaction. Then, the compound (X) in the presence of a base,
The keto ester (XI) is produced by reacting with a carbonic acid ester. Compound (XI) is converted to compound (XII) by catalytic hydrogenation or reduction reaction with sodium borohydride or the like. Compound (XII) is subjected to dehydration reaction according to a conventional method to give compound (XIII). The compound (XIII) can be subjected to an ester hydrolysis reaction to produce an unsaturated carboxylic acid (II). Reaction formula II

[Chemical 17] [In the formula, R ¹⁰ represents a C _1-4 alkyl group, and other symbols have the same meanings as described above. ] Compound (XIV) Dieckmann (type) condensation reaction (JPSchae
fer and J. J. Bloomfield, Org. Reactions, 1967, 1
Compound (XI) to compound (XIII) can be produced by subjecting the compound to 5, 1). Compound (XI) or Compound (XII
The unsaturated carboxylic acid compound (II) can be produced by sequentially reacting I) according to the method described in Reaction Formula I.

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 similar thereto, for example, by the method shown in Reaction Formula III and the method shown in the reference example described below or a method similar thereto. Reaction formula III

[Chemical 18] The reduction reaction of compound (XV) can be carried out by a method known per se. For example, reduction with a metal, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used.
That is, this reaction is carried out by treating compound (XV) with a reducing agent. Examples of the reducing agent include metals such as reduced iron and zinc dust, alkali metal borohydrides (eg, sodium borohydride, lithium borohydride, etc.), metal hydrogen complex compounds such as lithium aluminum hydride, sodium hydride, etc. Metal hydrides, organic tin compounds (hydrogen triphenyltin, etc.), nickel compounds, metals such as zinc compounds and metal salts, catalytic reducing agents using transition metal catalysts such as palladium, platinum, rhodium and hydrogen, and diborane. However, it is advantageously carried out by catalytic reduction using a transition metal catalyst such as palladium, platinum or rhodium and hydrogen, or reduction with a metal such as reduced iron. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,
2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N, N-dimethylformamide, acetic acid or a mixed solvent thereof, etc. It is appropriately selected and used according to the type of reducing agent. The reaction temperature is preferably about -20 ° C to about 150 ° C, particularly preferably about 0 ° C to about 100 ° C, and the reaction time is about 1 to about 24 hours. The compound (II) or (II
I) can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The above compound (I ') and compound (I ")
Including a compound represented by the formula (I) or a salt thereof (hereinafter, referred to as a compound represented by the formula (I) for short, the salt and the compound represented by the formula (I) and a salt thereof. Is used alone or in combination with a pharmaceutically acceptable carrier, for example, solid preparations such as tablets, capsules, granules, powders; or liquid preparations such as syrups and injections. It can be administered orally or parenterally. Parenteral administration forms include
Examples thereof include injections, infusions, suppositories, vaginal suppositories, etc. In particular, vaginal suppositories are useful for preventing HIV infection.
As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents and solubilizing agents in liquid formulations , A suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Suitable examples of excipients include
Examples thereof include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch,
Examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, and carboxymethyl starch sodium. Preferable examples of the solvent include water for injection, alcohol,
Examples include propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; and polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and other hydrophilic polymers. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. As a preferable example of the preservative,
Examples thereof include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like.

The compound of the formula (I) of the present invention or a salt thereof has excellent CC chemokine receptor antagonism, particularly CCR5 and / or CCR2 antagonism, especially
HIV in humans has a strong CCR5 antagonism
It can be used for the prevention and treatment of infectious diseases such as AIDS, and for the prevention and treatment of various other diseases. Further, the compound represented by the formula (I) of the present invention or a salt thereof has low toxicity and can be safely used. For example, the pharmaceutical composition containing the compound represented by the formula (I) of the present invention or a salt thereof can be used as a CCR5 antagonist, for example, an AIDS preventive / therapeutic agent and an AIDS disease progression inhibitor. A pharmaceutical composition containing the compound represented by formula (I) or a salt thereof of the present invention is a preventive / therapeutic agent for graft-versus-host disease and / or rejection reaction rheumatoid arthritis, autoimmune disease, allergic disease. It can be used as a prophylactic / therapeutic agent for various diseases such as ischemic brain cell injury, myocardial infarction, chronic nephritis, arteriosclerotic prophylactic / therapeutic agent and the like. The target disease of the preventive / therapeutic agent of the present invention includes, for example, graft rejection (rejection after transplantation, erythrocytosis after transplantation / hypertension / organ damage / vascular thickening, graft-versus-host disease, etc.), Arthritic bone diseases such as meningitis (rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, bone fracture, re-fracture, osteomalacia, bone Pecet's disease, ankylosing myelitis) , Destruction of joint tissue in knee osteoarthritis and similar diseases), autoimmune diseases (collagen disease, systemic lupus erythematosus, scleroderma, polyarteritis, myasthenia gravis, multiple sclerosis, etc.) , Allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, atopic dermatitis, bronchial asthma, etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease, gastritis, stomach)瘍, gastric cancer, gastric postoperative disorder, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, peptic ulcers, relay station ileitis,
, Etc.), inflammatory diseases (retinopathy, inflammation after surgery / trauma, remission of swelling, pharyngitis, cystitis, meningitis, inflammatory eye disease, etc.), respiratory diseases (cold syndrome, pneumonia, asthma, etc.) Pulmonary hypertension, pulmonary thrombosis / embolism, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, etc., infectious diseases (cytomegal virus, influenza virus, herpes virus) Virus infections such as Rickettsia infections, bacterial infections, sexually transmitted diseases, carinii pneumonia, Helicobacter pylori infections, systemic fungal infections, tuberculosis, invasive staphylococcal infections, acute viral encephalitis, acute bacterial meninges Inflammation, AIDS encephalopathy, sepsis, sepsis, severe sepsis, septic shock, endotoxic shock, toxin shock syndrome, etc.), cancer and associated cachexia, cancer Metastasis (bladder cancer, breast cancer, cervical cancer, ovarian cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, rectal cancer, colon cancer, multiple myeloma, malignant myeloma, prostate cancer, lung cancer, gastric cancer , Hodgkin's disease,
Malignant melanoma, malignant lymphoma, etc.), non-Hodgkin's lymphoma, non-small cell lung cancer, malignant melanoma, neurodegenerative disease (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, Diabetic neuropathy, Creutzfeldt-Jakob disease, etc.), mental disorders (depression, epilepsy, alcoholism, etc.), schizophrenia,
Venous insufficiency, central nervous system disorder (disorders such as cerebral hemorrhage and cerebral infarction and its aftereffects / complications, head trauma, spinal cord injury,
Cerebral edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, etc., central injury (head injury, spinal cord injury, whiplash, etc.), vascular dementia (multiple infarction dementia, Binswanger disease, Etc.), cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), recurrent cerebrovascular disorder and sequelae (neurologic symptoms, psychotic symptoms, Subjective symptoms, disturbance of activities of daily living, etc.), cerebrovascular dementia, hypofunction of the central nervous system after cerebrovascular obstruction, impairment or abnormality of cerebral circulation, autoregulation of renal circulation, impaired cerebral blood barrier, anxiety symptoms, unstable narrowing Acute coronary syndromes such as heart disease, unpleasant psychiatric conditions, amnesia, trigeminal neuralgia, otolaryngological diseases (Menuel syndrome, tinnitus, taste disorders, dizziness, imbalance, dysphagia, etc.), migraine, chronic pain, skin diseases (keloids) , Hemangiomas, Ichthyosis, etc.), arteriosclerosis obliterans,
Obstructive thrombotic vasculitis, peripheral arterial occlusion, post-ischemic reperfusion injury, Raynaud's disease, Buerger's disease, myocarditis, myocardial ischemia, myocardial infarction, heart failure progression after myocardial infarction, cardiomyopathy, cardiac hypertrophy, acute heart failure And chronic heart failure including congestive, angina, arrhythmia, tachycardia, abnormal blood pressure diurnal variation, abnormal blood / hemocyte component properties (enhanced platelet aggregation, abnormal red blood cell deformability, increased leukocyte adhesion, increased blood viscosity) , Erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelopathy, etc., arteriosclerosis including atherosclerosis (aneurysm, coronary atherosclerosis, cerebral arteriosclerosis) , Peripheral arteriosclerosis, etc.), revascularization / restenosis after bypass surgery, intervention (percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolysis) Thickened blood vessels Occlusion and organ damage, production and hyperactivity of vasoactive substances and thrombus-inducing substances (endothelin, thromboxane A2, etc.), and angiogenesis (abnormal angiogenesis in the formation of abnormal capillaries of the atherosclerotic lesion adventitia) ), Thrombosis, accelerated fat deposition, eye diseases (glaucoma,
Ocular hypertension), hypertension, tinnitus hypertension, dialysis hypotension, endothelial and organ disorders, endocrine diseases (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), nephritis, renal disease (nephritis, Glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis,
Organ damage including nephropathy due to irradiation, diabetic nephropathy,
Etc.), diabetic diseases (insulin-dependent diabetes mellitus, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.), impaired glucose tolerance, liver diseases (hepatitis including chronic, cirrhosis, etc.) , Interstitial liver disease, chronic pancreatitis, portal hypertension, obesity, male infertility, gynecological diseases (menopausal disorders, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, mammary gland disease, etc.), edema , Chronic fatigue syndrome, benign prostatic hyperplasia,
Behcet's disease, Hodgkin's disease, Lacquer infarction, consciousness disorder,
Psoriasis, diseases caused by environmental / occupational factors (radiation damage, damage caused by ultraviolet rays / infrared rays / laser rays, altitude sickness, etc.),
Examples include intermittent lameness.

A compound represented by the formula (I) of the present invention or
The pharmaceutical composition containing the salt depends on the type of target disease.
Although different, it may be used in combination with other drugs. Other
Examples of the drug include HDL-increasing drugs [squalene
Synthetic enzyme inhibitors, CETP inhibitors, LPL activators
Etc., a preventive / therapeutic agent for HIV infection [Zidovudine (zi
dovudine), didanosine, zalcitabine
(Zalcitabine), lamivudine (lamivudine), stub
Gin (stavudine), abacavir (abacavir), Adef
Adefovir, adifovir dipivoxil (ad
efovir dipivoxil), fozibuzin tidoxyl (fozi
vudine tidoxil) and other nucleic acid reverse transcriptase inhibitors, nevi
Nevirapine, delavirdin
e), efavirenz, and loviri
de), immunocal (immunocal), oltipraz (oltip
raz) and other non-nucleic acid reverse transcriptase inhibitors, saquinavir (s
aquinavir), ritonavir, indinavir
(Indinavir), nelfinavir (am)
Plenavir (amprenavir), Parinaville (palinavi)
r), lasinavir, lopinavir
r) and other protease inhibitors], NMG-CoA reduction
Enzyme inhibitors: cerivastatin, atorvastatin, pla
Vastatin, Simvastatin, Itavastatin, Rovas
Tatin, fluvastatin, (+)-3R, 5S-7-
[4- (4-fluorophenyl) -6-isopropyl-
2- (N-methyl-N-methanesulfonylamino) pyri
Midin-5-yl] -3,5-dihydroxy-6 (E)
-Atopic dermatitis drug such as heptenoic acid [Chromog
Sodium citrate, etc.], remedies for allergic rhinitis
Sodium lomoglycate, Chlorpheniramine maleate
Aminemazine tartrate, clemastine fumarate, hydrochloric acid
Homochlorcyclidine, terfenadine, mequitazine
DO], imipenem / cilastatin sodium, endoto
Toxin antagonist or antibody, oxidosqualene-lano
Sterol cyclase [eg decalin derivatives, aza
Decalin derivative and indane derivative], calcium
Anti-drugs (diltiazem etc.), glycerol, choline ester
Lase inhibitor (eg, Aricept (Donepezil), etc.)
Compounds that inhibit the absorption of resterol [eg, sitosterone
And neomycin], inhibit cholesterol biosynthesis
Compounds [eg, lovastatin, simvastatin, prava
HMG-CoA reductase inhibitors such as statins], cyclo
Oxygenase inhibitor [(Cox-I, Cox-II inhibitor
For example, celecoxib, rofecoxib, aspira
Salicylic acid derivatives such as phosphorus, diclofenac, India
Methacine, loxoprofen, etc.], signal transduction inhibition
Drugs, squalene epoxidase inhibitors [eg, NB-59
8 and related compounds, etc.], steroid drugs [dexamesazo
, Hexestrol, methimazole, betamethasone,
Triamcinolone, triamcinolone acetonide, full
Osinonide, fluocinolone acetonide, prednisolo
, Methylprednisolone, cortisone acetate, hydroco
Lutisone, fluorometholone, beclometa propionate
Zon, estriol, etc.], diacerine, nicotine
Acids, their derivatives and analogs [eg acipimox and
And Propcol], Niceroline, Nephrotic Syndrome
Drugs: Prednisolone (Predonin), Pred succinate
Nizolone sodium (predonin), methyl succinate
Rednizolone sodium (sol medrol), betta
Tazon (Linderon), Dipyridamole (Belsanthi
), Dilazeb hydrochloride (comelian), ticlopidine, cucumber
Antiplatelet drugs such as ropidogrel and FXa inhibitors
Coagulants, valpital anticonvulsants or anesthetics (fetus
Nobarbital, Mehobarbital, Metalbital
Etc.), Parkinson's disease drug (eg, L-dopa drug), His
Tamine receptor blockers (cimetidine, famotidine, etc.),
Hydantoin anticonvulsants (phenytoin, mefenitoi
, Etotoin, etc.), piroxicam, fibrates
[Eg clofibrate, benzafibrate, gem
Fiprozil, etc.], prostaglandins, megestro
Acetic acid, gastroduodenal ulcer treatment drug therapeutic agent: antacid
[Eg, histamine H2 antagonists (cimetidine, etc.), proto
Pump inhibitors (such as lansoprazole)], inflammatory
Mediator inhibitor, coronary vasodilator: Nifedipi
Infectious diseases such as
Therapeutic agent: [eg, antibiotics (cefatium hydrochloride, hydrochloric acid
Cefozopran, ampicillin, etc., chemotherapeutic agents (support
Rufa drug, synthetic antibacterial drug, antiviral drug, etc.), biological
Drug products (vaccines, blood products such as immunoglobulins)
Etc.], etc., liver drug: Glycyrrhizin preparation
[Eg, strong minophagen, etc.], liver hydrolyzate, SH compound
[Eg, glutathione, etc.], special amino acid preparations [eg, amino
Norevan, etc.], phospholipids [eg, polyenephosphatidyl]
Choline, etc., vitamins [eg, vitamin B ₁ , B _Two , B
₆ , B ₁₂ , C, etc.], corticosteroids [eg, dexame
Tazone, betamethasone, etc.], interferon [eg, a
Interferon α, β, etc.], hepatic encephalopathy therapeutic drug [eg, lac
Tulose, etc.], hemostasis used when the esophagus, gastric varices are ruptured
Agents [eg, vasopressin, somatostatin, etc.]
Anti-inflammatory drug, muscle relaxant [pridinol, tubocurarine,
Pancuronium, tolperisone hydrochloride, black carbamate
Luphenesin, baclofen, chlormezanone, mefe
Nesine, clozoxazone, eperisone, tizanidine
Thor, vasodilator [oxyfedrine, diltiazem,
Tolazoline, hexobenzin, bamethane, clonidine,
Methyldopa, Guanabenz, etc.], vasoconstrictor [dopami]
, Dopamine, denopamine, etc.], platelet aggregation inhibitor
(Ozagrel, etc.), anti-thrombogenic drug: anticoagulant
Antidote [eg, heparin sodium, heparin calcium,
Warfarin calcium (warfarin), Xa inhibition
Drugs], thrombolytic drugs [eg, tPA, urokinase], anti-blood
Platelets [eg aspirin, sulfinpyrazone (Anz
-Run), dipyridamole (persantin), ticlopi
Gin (panardine), cilostazol (pletal),
GPIIb / IIIa antagonist (leopro)], antidepressant
[Imipramine, clomipramine, noxiptiline, fu
Enerzine, Amitriptyline Hydrochloride, Nortriptyline Hydrochloride
Phosphorus, amoxapine, mianserin hydrochloride, maproti hydrochloride
Phosphorus, sulpiride, arboxamine maleate, sodium chloride
Razodon etc.], antiepileptic drugs [gabapentin, fe
Nitoin, ethosuximide, acetazolamide, chlordi
Azepoxide, trimetadione, carbamazepine, fe
Novalpital, primidone, sultium, parbroic acid
Sodium, clonazepam, diazepam, nitrazepam
Etc.], antiallergic drug [diphenhydramine, chlor
Pheniramine, triperenamine, methodilamine, kuremi
Zole, diphenylpyraline, methoxyphenamine,
Sodium lomoglycate, tranilast, lepirinas
To, amlexanox, ibudilast, ketotifen,
Terfenadine, mequitazine, acerastine, epinas
Chin, ozagrel hydrochloride, pranlukast hydrate, serato
Rodust, fexofenadine, ebastine, bushirami
, Oxatomide, strong neo-minophagen C, tiger
Nexamic acid, ketotifen fumarate, etc.], anticholinergics
(For example, ipratropium bromide, flutropium bromide
, Oxitropium bromide, etc.), anti-Parkinson drug
(Dopamine, levodopa, etc.), anti-rheumatic drug, anti-inflammatory drug
(For example, aspirin, acetaminophen, diclov
Enac sodium, ibuprofen, indomethacin,
Loxoprofen sodium, dexamethasone, etc.),
Anticoagulants and antiplatelets [sodium citrate, active
Protein C, tissue factor pathway inhibitor, antithrombi
III, dalteparin sodium, argatroban,
Gabexate, ozacrel sodium, icosapentaenoic acid
Ethyl, beraprost sodium, alprostadil,
Pentoxifylline, tisokinase, streptokiner
Zeze, hevalin, etc.], anticoagulant drug [dipyridamole
(Bersantine), Dilazep hydrochloride (Comelian), Ciro
Pidgin, Clovidogrel, Xa inhibitor], antibacterial drug [SA
Rufa drugs [sulfamethizole, sulfisoxazo
L, sulfamonomethoxine, sulfamethizole, sa
Razosulfapyridine, silver sulfadiazine, etc.],
Quinoline antibiotics [nalidixic acid, pipemidic acid trihydrate
Thing, enoxacin, norfloxacin, ofloxacin
, Tosufloxacin tosylate, ciprofloxa hydrochloride
, Lomefloxacin hydrochloride, sparfloxacin,
Loxacin, etc.], antituberculosis drug [isoniazide, tan
Butol (ethambutol hydrochloride), paraaminosalicyl
Acid (calcium para-aminosalicylate), pyrazinami
De, ethionamide, prothionamide, rifampicin,
Streptomycin sulfate, kanamycin sulfate, cyclo
Serine, etc., mycobacterial drug [diaphenyl sulfone,
Rifampicillin, etc.], antiviral drug [Idokusu]
Lysine, acyclovir, vitarabine, ganciclovir
Thor, anti-HIV drug [zidovudine, didanosine, zalsi
Tabine, Indinavir Sulfate Ethanol Additive, Ritonavi
Etc.], anti-spirochete drugs, antibiotics [tet hydrochloride
Lacycline, ampicillin, piperacillin, gentama
Isin, dibekacin, canendomycin, libidomic
, Tobramycin, amikacin, fradiomycin,
Sisomycin, tetracycline, oxytetracycline
Phosphorus, Lolitetracycline, Doxycycline, Anne
Picillin, Piperacillin, Ticarcillin, Cephaloti
, Cephapirin, cephaloridine, cefaclor, ce
Farexin, cefloxazine, cefadroxil, ce
Famandor, cefotiam, cefuroxime, cefo
Tiam, Cefotiam Hexetil, Cefuroxime Axe
Chill, cefdinir, cefditoren pivoxil, ceftazi
Jim, Cefpyramide, Cefthrozine, Cefmenoxime,
Cefpodoxime proxetil, cefpirom, cefazop
Orchid, cefepime, cefsulodin, cefmetazole, ce
Huminox, cefoxitin, cefuperazone, ratamo
Quinacef, Flomoxef, Cefazolin, Cefotaxi
, Cefoperazone, ceftizoxime, moxalacta
Mu, thienamycin, sulfazecin, aztreonam
Or their salts, griseofulvin, lancasidins
[Journal of Antibiotics (J. Ant
ibiotics), 38, 877-885 (1985)].
DO] cefixime, levofloxacin], antithrombotic agent
Rugatroban, etc.), antiprotozoal drug [metronidazole, tini
Dazole, diethylcarbamazine citrate, quinine hydrochloride
Ne, quinine sulfate, etc.], antineoplastic drug [6-O- (N-q
Loloacetylcarbamoyl) fumagillol, bleomay
Syn, methotrexate, actinomycin D, mite
Mycin C, daunorubicin, adriamycin, neo
Carzinostatin, cytosine arabinoside, fluoro
Racil, tetrahydrofuryl-5-fluorouracil,
Picibanil, lentinan, levamisole, bestatin
, Azimexone, glycyrrhizin, doxorubicin hydrochloride
, Aclarubicin hydrochloride, bleomycin hydrochloride, sodium sulfate
Puromycin, vincristine sulfate, vinplasti sulfate
, Irinotecan hydrochloride, cyclophosphamide, melf
Alan, busulfan, thiotepa, procarbazi hydrochloride
, Cisplatin, azathioprine, mercaptopuri
, Tegafur, carmofur, cytarabine, methyl te
Strosterone, testosterone propionate, enanthate
Acid testosterone, mepithiostane, fosfestro
, Chlormadinone acetate, leuprin acetate, buse acetate
Relin etc.], antifungal drug [polyethylene antibiotics
(Eg, amphotericin B, nystatin, trichomes)
, Griseofulvin, pyrrole nitrine, etc.
Cytosine antimetabolites (eg, flucytosine, imidazo
Derivative (eg, econazole, clotrimazole, nitric acid)
Miconazole, bifonazole, croconazole),
Riazole derivatives (eg fluconazole, itraconazo)
And azole compounds [2-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -4- [4- (2,2,3,3-the
Trafluoropropoxy) phenyl-3- (2H, 4
H) -1,2,4-Triazolone], thiocarbamine
Acid derivatives (eg trinaphthol), echinocandin
Derivatives (eg Caspofungin, FK-463, V-E
Quinocandin), etc.], antipsychotics [chlorproma hydrochloride]
Gin, prochlorperazine, trifluoperazine, thihydrochloride
Oridazine, Perphenazine maleate, Fenanthate
Luphenazine, prochlorperazine maleate, male
Levomepromazine acidate, promethazine hydrochloride, haloperide
, Promperidol, spiperone, reserpine, salt
Acid chlorcapramine, sulpiride, zotepine, etc.], anti
Ulcer drug [metaclopromide, histidine hydrochloride, lansop
Razol, metoclopramide, pirenzepine, cimetidi
, Ranitidine, famotidine, urogastrin, oki
Sesazein, proglumide, omeprazole, sucraral
Fert, sulpiride, cetraxate, gefarner
Todo, aldioxa, teprenone, prostaglandin
, Etc., antidiabetic agents (eg, pioglitazone, nafugu)
(Linide, voglibose, acarbose, etc.), antiobesity drugs
Anxiolytics such as mazindol and antirheumatic drugs
[Diazepam, lorazepam, oxazepam, chlordia
Zepoxide, medazepam, oxazolam, cloxazola
Mu, crotiazepam, promazepam, etizolam, full
Diazepam, hydroxyzine, etc.], antiarrhythmic drug: diso
Pyramide, lidocaine, quinidine sulfate, flecaini acetate
, Mexiletine hydrochloride, amiodarone hydrochloride, and β-blocking
Anti-asthma drugs such as abstinence drugs and Ca antagonists [isoprenari hydrochloride
, Salbutamol sulfate, procaterol hydrochloride,
Rubutaline, trimethoxynol hydrochloride, tulobtero hydrochloride
, Orciprenaline sulfate, fenoterot hydrobromide
, Ephedrine hydrochloride, iprotropium bromide, obromide bromide
Xytropium, flutropium bromide, theophylline,
Aminophylline, sodium cromoglycate, tranilla
Strike, repirinast, amlexanox, ibzilas
To, ketotifen, terfenadine, mequitazine, aze
Rustin, Epinastine, Ozagrel hydrochloride, Pranluka
Strike hydrate, seratrodast, dexamethasone, pred
Nizolone, hydrocortisone, beclopeta propionate
Dzone, fluticasone propionate, beclopropionate
Methazone, procaterol, etc.], hypothyroidism
Therapeutic agent [dry thyroid (threoid), levothyroxine
Thorium (Tyrazine S), Sodium liothyronidine
(Thyronine, thyronine); Nephrotic syndrome drug:
Prednisolone (predonin), prednisolo succinate
Sodium (predonin), methyl pred succinate
Nizolone sodium (sol medrol), betamethazo
(Linderon)], antihypertensive drug [sympathetic nerve suppressant]
[Α2 stimulants (eg clonidine, guanabenz, guan
Fascin, methyldopa, etc., ganglion blockers (eg, hex)
Sametonium, trimetaphan, etc.), presynaptic blockade
Agents (eg, Arthur Oxylone, Dimethylaminoreserpi
Nato, resinamine, reserpine, syrosingopine.
, Etc., neuron blockers (eg, betanidine, guanethidi)
, Etc.), α1 blockers (eg, bunazosin, doxazosi)
, Prazosin, terazosin, urapidil, etc.)
Abstinence (eg, purpranolol, nadolol, timoroh)
Le, nipradilol, bunitrolol, indenolow
Le, penbutolol, carteolol, carvedileo
Le, pindolol, acebutolol, atenolol, pi
Soprolol, metoprolol, labetalol, amos
Vasodilators such as larol and arotinolol)
[Calcium channel antagonists (eg, manidipine, Nika
Ludipine, Nilvadipine, Nisoldipine, Nitrendipi
, Benidipine, amlodipine, alanidipine, etc.),
Phthalazine derivatives (eg, budralazine, cadralazine,
(Ecarazine, hydralazine, todralazine, etc.)
, Etc., ACE inhibitors [alacepril, captopril,
Cilazapril, delapril, enalapril, lisinopril
Le, temocapril, trandolapril, quinapril, a
Midapril, Benazepril, Benridopril, etc.],
AII antagonists [Losartan, Candesartan, Valsal
Tan, Telmisartan, Irbesartan, Forasarta
Etc.], diuretics (such as those listed above)], high
Blood pressure medications: diuretics [eg, furosemide (Lasix),
Bumetanide (Renetron), Azosemide (Dyer
)], Antihypertensive drugs [eg, ACE inhibitors, (enamate maleate
Lapril (renipace) and Ca antagonists (manifold)
Dipine, amlodipine, etc.), α or β receptor blockers
Etc.], therapeutic drug for hyperlipidemia [HMG-CoA reductase inhibition
Drugs (eg, fluvastatin, cerivastatin, atorvas
Tatin, etc., fibrate drugs (eg, synfibra)
, Clofibrate aluminum, crinofibra
, Fenofibrate, etc.), anion exchange resin
(Eg, cholestyramide, etc.), nicotinic acid preparations (eg, nitric acid)
Komol, niceritrol, tocopherol nicotinate
Etc.), polyunsaturated fatty acid derivatives (eg, icosapentaenoic acid)
Ethyl, polyenphosphatidylcholine, melinamide
Etc.), plant sterols (eg gamma-oryzanol,
Soysterol, etc.), elastase, dextran sulphate
Sodium acid, squalene synthase inhibitor, CETP inhibitor
Harmful drug, 2-chloro-3 [4- (2-methyl-2-phenyl
Lepropoxy) phenyl] ethyl propionate [Chemica
Le And Pharmaceutical Bulletin (Ch
em. Pharm. Bull), 38, 2792-2796 (19)
90)], etc.], therapeutic agents for bone diseases: calcium preparations (eg,
Calcium carbonate, etc., calcitonin preparation, activated vitamin
D _Three Formulation (eg, alfacalcidol (alfalow
, Etc.), calcitriol (locartrol), etc.),
Sex hormones (eg, estrogen, estradiol)
Etc.), hormone preparations [eg, conjugated estrogens (prema
Phosphorus, etc.], ibriflavone preparations (such as Osten),
Vitamin K _Two , Vitamin K _Two Formulation [eg, menatetrenone
(Graquette), etc., bisphosphonic acid-based preparations (ETIDRO
Nate), prostaglandin E2, fluorine compound
(Eg, sodium fluoride, etc.), bone morphogenetic protein (BM
P), fibroblast growth factor (FGF), platelet-derived proliferation
Factor (PDGF), transforming growth factor (T
GF-β), insulin-like growth factors-1 and 2 (IG
F-1, -2), parathyroid hormone (PTH), Europe
JP Application Publication EP-A1-376197, EP-
A1-460488 gazette and EP-A1-7197.
82 (e.g., (2R, 4S)-(-)
-N- [4- (diethoxyphosphorylmethyl) phenyl
]]-1,2,4,5-Tetrahydro-4-methyl-
7,8-Methylenedioxy-5-oxo-3-benzothi
Fat-soluble vitamins such as epine-2-carboxamide)
Medicine [Vitamin A: Vitamin A ₁ , Vitamin A _Two And
And retinol palmitate, vitamins D: vitamins
D ₁ , D _Two , D _Three , D _Four And D ₅ , Vitamin Es:
α-tocopherol, β-tocopherol, γ-tocoph
, Δ-tocopherol, nicotinic acid dl-α-
Tocopherol, Vitamin Ks: Vitamin K ₁ ,
K _Two , K _Three And K _Four , Folic acid (vitamin M), etc.],
Vitamin derivatives [various derivatives of vitamins such as 5,
6-trans-cholecalciferol, 2,5-hydro
Xycolecalciferol, 1-α-hydroxycholeca
Vitamin D such as luciferol _Three Derivative, 5,6-to
Lance-Vitamin D such as ergocalciferol _Two Induction
Body etc.], disease-modifying anti-rheumatic drug and immunosuppressant drug
[For example, methotrexate, leflunomide, program
F, sulfasalazine, D-penicillamine, oral gold
Agent], pressor drug [dopamine, dobutamine, denopamine, di
Gitoxin, digoxin, methyldigoxin, lanatosi
C, G-strophanthin, etc.], cardioprotective agent: heart
Opener for ATP-K, Na-H exchange inhibitor, endoseri
Heart failure drugs, such as urotensin antagonists and urotensin antagonists
Cardiovascular drugs (eg, digitoxin, digoxin, methyldigoxi)
, Lanatoside C, proscillaridin, etc.), α, β
Drugs (eg, epinephrine, norepinephrine, isoproline)
Terenol, dopamine, docarpamine, dobutamine, de
Nopamine, etc.), phosphodiesterase inhibitors (eg,
Mullinone, milrinone, olprinone hydrochloride, etc.) Calci
Um channel sensitizers (eg pimobentan
Etc.), nitric acid drugs (eg, nitroglycerin, isosorbic acid nitrate)
Etc.), ACE inhibitors (for example, the above-mentioned ACE inhibitors
Etc.), diuretics (such as those listed above), carperiti
De, ubidekarenone, vesnarinone, aminophylline
Throat], neurotrophic factor, renal failure, remedy for nephropathy, biologics
[For example, a monoclonal antibody (eg, anti-TNF-α anti-
Body, anti-IL-12 antibody, anti-IL-6 antibody, anti-ICAM-
I antibody, anti-CD4 antibody, etc., soluble receptor (eg, acceptable)
Soluble TNF-α receptor, etc.), proteinaceous ligand
(IL-I receptor antagonist etc.)], bile acid formation
Compound resin [eg, cholestyramine, colestipol, etc.], gall
Drugs for the treatment of tract diseases: Bilary drugs [eg, dehydrocholic acid, etc.]
Central nervous system effects such as bile agents [eg, magnesium sulfate, etc.]
Drugs: anxiolytics, hypnotics, anesthetics, anticonvulsants, autonomic gods
Such as medications, anti-Parkinson's drugs and other neuropsychiatric drugs.
Throat, antitussive and analgesic [ephedrine hydrochloride, noscapi hydrochloride
, Codeine phosphate, dihydrocodeine phosphate, a hydrochloride
Soproterenol, ephedrine hydrochloride, methylef hydrochloride
Edrine, Noscapine hydrochloride, Alloclamide, Crofe
Ranol, picoperidamine, cloperastine, protox
Roll, isoproterenol, salbutamol, terb
Tallin, oxymethebanol, morphine hydrochloride, hydrogen bromide
Acid dextromethorphan, oxycodone hydrochloride, phosphoric acid
Dimemorphan, tipepidine hibenzate, citrate pen
Toxiverine, clofedanol hydrochloride, benzonate
, Guaifenesin, bromhexine hydrochloride, anhydrochloride
Broxol, acetyl cysteine, ethyl system
In, carbocysteine, etc., sedative [chlorp hydrochloride
Romazine, atropine sulfate, phenobarbital, val
Bitar, Amobarbital, Pentobarbital, Chi
Opental sodium, thiamylar sodium, d
Trazepam, estazolam, flurazapam, haloxazo
Rum, triazolam, flunitrazepam, bromvaleri
Lurea, chloral hydrate, triclofos sodium
, Etc., analgesics and anti-inflammatory agents [eg central analgesics
(Eg morphine, codeine, pentazocine, etc.)
Lloyds (eg, prednisolone, dexamethasone, beta
Methazone, etc., anti-inflammatory enzyme agent (eg, bromelain, lysochi)
, Proctase, etc.)], antidiabetic drug [sulfonyl]
Urea agents (eg, tolbutamide, chlorpropamide, glic)
Lopyramide, acetohexamide, tolazamide, gliben
Chlamide, glybuzole, etc.), biguanides (eg,
Metformin hydrochloride, pformin hydrochloride, etc.), α-glucose
Sidase inhibitors (eg voglibose, acarbose
, Etc., insulin sensitizers (eg, pioglitazone,
Troglitazone), insulin, glucagon, diabetes
Drugs for pathological complications (eg, epalrestat, thioctic acid)
Etc.), Actos, Rogiglitazone, Kinedac, Ben
Phil, Humarine, Euglecon, Grimicron,
Daonir, novolin, monotard, insulin,
Glucobai, Dimelin, Rustinone, Basilcon, Dare
Melin S, isdiphosphoric acid, etc.], brain function activator (eg, a
Debenone, vinpocetine, etc.), urological and male genital disease treatment
Remedy: [eg, prostatic hypertrophy treatment (tamsulosin hydrochloride,
Prazosin hydrochloride, chromemadinone acetate, etc.)
(Leuprorelin acetate, goserelin acetate, black acetate
Lumadinone, etc.)] and other non-steroidal anti-inflammatory drugs [a
Cetoaminophen, phenacetin, etenzamid, sul
Pilin, antipyrine, miglenin, aspirin, mef
Enamic acid, flufenamic acid, diclofenac sodium
, Loxoprofen sodium, phenylbutazone,
Indomethacin, ibuprofen, ketoprofen, ke
Toprofen, naproxen, oxaprozin, fururu
Piprofen, Fenbufen, Planoprofen, F
Loctaphenine, epirizole, tiaramid hydrochloride, monkey
Toprofen, gabexate mesylate, camos mesilate
Tat, ulinastatin, colchicine, probenedide,
Sulfinpyrazone, benzpromaron, allopurino
Ru, sodium sodium thiomalate, sodium hyaluronate
, Sodium salicylate, morphine hydrochloride, salicyl
Acid, atropine, scopolamine, morphine, pethidine,
Levorfinol, ketoprofen, naproxen,
Oxymorphone or its salt], frequent urination / urinary incontinence
Medical agent [flavoxate hydrochloride, etc.], unstable plug stable
Chemicals [MMP inhibitors, chymase inhibitors, etc.], Arrhythmia treatment
Remedies [sodium channel blockers (eg, quinidine,
Rocainamide, disopyramide, ajmaline, cibenzo
Phosphorus, lidocaine, diphenylhydantoin, mexile
Chin, Propafenone, Flecainide, Pilsikaini
, Phenytoin, etc.], β-blockers (eg, propranolo
, Alprenolol, pfetrol, oxpre
Nolol, Athenol, Aseptol, Metoprolo
Le, pisoprolol, pindolol, carteolol,
Arotyrol, etc.), potassium channel blockers (eg,
Amiodarone), calcium channel blocker
(Eg, verapamil, diltiazem, etc.)], gynecology
Disease remedies: [eg, menopausal remedies (combined estro
Gen, estradiol, testosterone enanthate,
Estradiol valerate, etc., breast cancer drug (citric acid
Tamoxifen, etc.), endometriosis / uterine fibroid treatment
(Leuprorelin acetate, danazol, etc.)], etc.
Drunk drug [a. Local anesthetics [cocaine hydrochloride, procayl hydrochloride
, Lidocaine, dibucaine hydrochloride, tetracaine hydrochloride,
Mepivacaine hydrochloride, bupivacaine hydrochloride, oxybup hydrochloride
Locaine, ethyl aminobenzoate, oxesazein]
, B. General anesthetics [inhalation anesthetics (eg ether,
Halothane, nitrous oxide, influrane, enflura
), Intravenous anesthetics (eg, ketamine hydrochloride, droperido
Lu, thiopental sodium, thiamylar natriu
, Pentobarbital), etc.]], anesthesia antagonist [Leva
Lorphan, nalorphine, naloxone or salt thereof
, Etc., chronic heart failure remedy: cardiotonic drug [eg, cardiac glycosides
Goxin, etc.), beta-receptor stimulants (denopamine and dopamine)
Catecholamines such as butamine) and PDE inhibitors
Etc.], diuretics [eg, furosemide (Lasix), spine
Lonolactone (Aldacton), Bumetamide (Renetro)
), Azosemide (Diaart), etc.], ACE inhibition
Drugs, eg enalapril maleate (renibase)
Etc., Ca antagonist [eg, amlodipine, manidipine, etc.
Etc. and β-receptor blockers, such as immunomodulators [Cyclos
Porin, Tacrolimus, Gusperimus, Azathiopuri
, Anti-lymph serum, dried sulfonated immunoglobulin, Eli
Sulopoietin, colony stimulating factor, interleukin
, Interferon, etc.], diuretics [thiazide series]
Diuretics (benthyl hydrochlorothiazide, cyclobench
Azide, ethiazide, hydrochlorothiazide, hydrof
Lumethiazide, methycrothiazide, penfluthiazide,
Polythiazide, trichlormethiazide, etc.), loop
Urine drugs (chlorthalidone, clofenamide, indapami)
De, Mefluzide, Methiclan, Sotrazone, Tribami
De, quinetazone, metolazone, furosemide, mefluside
Etc.), potassium-sparing diuretics (spironolactone,
Liamteren, etc.)], erectile dysfunction drugs (viagra, apo
Morphine, etc.) and the like.

These drugs may be administered separately or simultaneously.
It can be orally or parenterally administered by mixing it with a pharmaceutically acceptable carrier, excipient, binder, diluent, etc. to prepare a formulation. When the drugs are formulated separately, they can be administered separately by mixing them with a diluent or the like at the time of use.However, the individual formulations prepared separately can be administered simultaneously or with a time lag. Alternatively, they may be separately administered to the same subject. A kit product for administering separately formulated products by mixing them with a diluent or the like at the time of use (for example, an ampoule containing an individual drug in powder form and two or more drugs at the time of use are mixed and dissolved) Injectable kit containing diluent etc.), a kit product for administration of separately formulated individual preparations to the same subject simultaneously or separately with a time lag (for example, individual drugs) Put the tablets containing in the same or separate bags,
If necessary, a column for entering the drug administration time is provided, and 2
A tablet kit for administering one or more tablets at the same time or separately at different times) and the like are also included in the pharmaceutical composition of the present invention.

The dose of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration subject, age and weight of administration subject, symptoms, administration time, administration method, dosage form and the like. The dosage for a particular patient may depend on age, weight, general health, sex, diet, time of administration, mode of administration, excretion rate, the extent of the medical condition being treated by the patient, and other factors. It is decided in consideration of the factors. The dose when the above pharmaceutical composition is used as an AIDS preventive / therapeutic agent and an AIDS disease progression inhibitor depends on the patient's condition, body weight, and method of administration, but in the case of oral administration, per adult (body weight 50 kg) The active ingredient [compound represented by formula (I)] is about 5 to 1000 mg, preferably about 10 to 600 mg, and more preferably about 10 mg.
~ 300 mg, particularly preferably about 15-15
It is 0 mg and is administered once or in 2 to 3 divided doses per day. Graft-versus-host disease in transplanting organs such as heart, kidney, liver and bone marrow with the above-mentioned pharmaceutical composition, and / or
When used as a prophylactic / therapeutic agent for rejection, it is administered 3 days before transplantation and continuously administered even after transplantation. The daily dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient and the method of administration, but in the case of oral administration, the active ingredient per adult (body weight 50 kg) [represented by the formula (I) Compound], about 5 to 100
It is 0 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, which is administered once or in 2 to 3 divided doses per day. In this case, it may be used in combination with an agent for suppressing graft-versus-host disease and / or rejection at the time of transplanting another organ. Graft-versus-host disease at the time of organ transplantation and / or use in combination with the compound represented by the above formula (I) or a salt thereof
Or specific examples of the inhibitory agent for rejection include cyclosporine, tacrolimus, rapamycin, steroids,
Azathioprine, mycophenolate mofetil, mizoribine and the like can be mentioned. When these drugs are used in combination and one drug affects the metabolism of the other drug, the dose of each drug is adjusted appropriately,
Generally, the dose of each drug used as a single agent is used. When the compound represented by the above formula (I) or a salt thereof is used for a target disease other than an agent for suppressing graft-versus-host disease and / or rejection at the time of organ transplantation, the daily dose is the kind of the target disease. , The patient's condition and weight, the method of administration, but oral administration adult (body weight 50k
g) Active ingredient per person [compound represented by formula (I)]
About 5 to 1000 mg, preferably about 10 to 6
00 mg, more preferably about 10 to 300 mg
And particularly preferably about 15 to 150 mg, which is administered once per day or in 2 to 3 divided doses. When used in combination with another drug, the dose of the other drug is, for example, about 1/200 of the usual dose.
To 1/2 or more and about 2 to 3 times or less. Furthermore, when two or more drugs are used in combination and the dose of one drug affects the metabolism of the other drug, the dose of each drug is adjusted appropriately. The dose at the time of single agent administration of the drug is used.

Further, the compound represented by the above formula (I) or a salt thereof can be contained in or combined with blood for transfusion or blood products. Blood or blood products for transfusion are usually produced by mixing blood taken from multiple people, but in some cases, cells infected with HIV virus and cells not infected with HIV virus are mixed. Yes, in this case there is a risk of infecting uninfected cells. Incorporation of the compound represented by formula (I) of the present invention can prevent or suppress infection and growth of these viruses. In particular, when the blood product is stored, it is effective to mix the compound represented by the formula (I) in order to prevent or suppress virus infection and proliferation. Also,
When blood or blood products for transfusion that are contaminated with HIV virus are administered, the compound of formula (I) is mixed in the blood or blood products for transfusion so that the It can prevent the infection and proliferation of HIV in the body. For example, for the prevention of HIV infection during transfusion and use of blood products, adults (body weight 0k
When administered orally to g), it is usually used as a single dose of about 0.02 to 50 mg / kg, preferably 0.05 to 30 mg / kg, more preferably 0.1 to 50 mg / kg as a CCR antagonist.
The dose is about 1 to 10 mg / kg, and these doses are preferably administered about 1 to about 3 times a day. Of course, these dosage ranges can be adjusted on the unit basis necessary to divide the daily dose, but as noted above, the dosage will vary according to the nature and extent of the disease, age of the patient, weight, general health status, It will be decided in consideration of sex, diet, administration time, administration method, excretion rate, and other factors. The administration method in this case can be appropriately selected, and the HIV infection preventive agent of the present invention may be directly added to blood or a blood product to be transfused before transfusion or before use of a blood product. In that case, immediately before to 24 hours, preferably immediately before to 12
It is desirable to mix before the time, more preferably immediately before to 6 hours. When the HIV infection preventive agent of the present invention is administered separately from blood or a blood product to be transfused at the time of blood transfusion or use of a blood product, it is desirable to administer 1 hour before or at the same time as the use of the blood transfusion or blood product, and more preferably 1. It is desirable to continue the administration 1 to 3 times a day for 4 weeks.

Further, when the compound represented by the formula (I) or a salt thereof is used in combination with a reverse transcriptase inhibitor and / or a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor is For example, it is appropriately selected within the range of about 1/200 to 1/2 or more and about 2 to 3 times the usual dose. Typical doses of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as shown below. Zidovudine: 100 mg Didanosine: 125-200 mg Zalcitabine: 0.75 mg Lamivudine: 150 mg Stavudine: 30-40 mg Saquinavir: 600 mg Ritonavir: 600 mg Indinavir: 800 mg Nelfinavir: 750 mg Further, the compound represented by the formula (I) or its salt and reverse transcription. Specific embodiments when used in combination with an enzyme inhibitor and / or a rotease inhibitor are shown below. About 10 to 300 mg of the compound represented by formula (I) or a salt thereof is administered to an adult (body weight: 50 Kg) in the form of a combination with about 50 to 200 mg of zidovudine, to the same subject. Each individual drug may be administered simultaneously,
Also, the administration may be performed with a time lag within 12 hours. About 10 to 300 mg of the compound represented by the formula (I) or a salt thereof is administered to each adult (body weight: 50 kg) in the form of a combination with about 300 to 1200 mg of saquinavir, to the same subject. The individual drugs may be administered simultaneously, or may be administered with a time difference of 12 hours or less.

[0049]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 (Production of Compound 1) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g ) Was dissolved in ethanol (30 ml), sodium borohydride (0.08 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-
Methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 1) (0.26 g) was obtained as yellow crystals. mp 198-201 ℃ (dec.). ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.1 Hz), 1.34-
1.45 (2H, m), 1.57-1.65 (2H, m), 2.28 (3H, s), 2.9
7 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t, J =
6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.16 (2H, t, J
= 4.9 Hz), 4.61 (1H, br), 6.03-6.04 (1H, m), 6.69
-6.73 (3H, m), 6.95-7.17 (3H, m), 7.26-7.34 (2H,
m), 7.43-7.48 (5H, m), 7.63-7.67 (3H, m), 8.14 (1
H, d, J = 6.6 Hz) .IR (KBr) ν: 2926, 2843, 1651, 1601 cm ^-1 . Anal.calcd. For C ₃₆ H ₃₉ N ₃ O ₅・ 0.25H ₂ O: C, 72.28; H,
6.66; N, 7.02. FoundC, 71.99; H, 6.57; N, 6.91.

Example 2 (Production of Compound 2) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g), isobutyraldehyde (0 .15m
l) is dissolved in 1,2-dichloroethane (80 ml),
Under ice cooling, sodium triacetoxyborohydride (0.
27 g) was added and the mixture was stirred at room temperature overnight. Isobutyraldehyde (1 ml) and sodium triacetoxyborohydride (1.3 g) were added, and the mixture was stirred overnight at room temperature. The extract was washed with aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-isobutyl- 2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 2) (0.2 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-0.99 (9H, m), 1.22-1.45 (2
H, m), 1.54-1.65 (2H, m), 2.08 (1H, br), 2.28 (3H,
s), 2.93 (2H, t-like), 3.19 (2H, d, J = 7.4Hz), 3.
37 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2
H, t, J = 5.0Hz), 4.16 (2H, t, J = 5.0Hz), 6.05
(1H, s), 6.65 (1H, br), 6.72-6.73 (1H, m), 6.90-7.
06 (5H, m), 7.38-7.68 (10H, m), 8.16 (1H, d, J =
6.6 Hz) .IR (KBr) ν: 2957, 2934, 2870, 1653, 1607,
1514, 1499 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₇ N ₃ O ₅・ 0.5H ₂ O: C, 72.92; H,
7.34; N, 6.38.Found C, 72.81; H, 7.43; N, 6.38.

Example 3 (Production of Compound 3) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.4 g ) Was dissolved in ethanol (300 ml), sodium borohydride (0.11 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-
Oxidopyridin-2-yl) methyl] -3-methoxyphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 3) (0.35 g)
Was obtained as yellow crystals. mp 116-118 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.1 Hz), 1.26-
1.57 (4H, m), 2.96 (2H, t-like), 3.48 (2H, t-lik
e), 3.55 (2H, t, J = 6.6 Hz), 3.73-3.90 (5H, m),
4.16 (2H, t, J = 5.0 Hz), 4.61 (1H, br), 6.33 (1H,
d, J = 4.8 Hz), 6.67-6.73 (2H, m), 6.87-7.00 (4H,
m), 7.21-7.48 (7H, m), 7.63-7.75 (3H, m), 8.22-8.
26 (1H, m). IR (KBr) ν: 2934, 2872, 1651, 1609, 1499 cm ^-1 . Anal.calcd. For C ₃₆ H ₃₉ N ₃ O ₆・ 0.75H ₂ O: C, 69.38; H ,
6.55; N, 6.74. FoundC, 69.55; H, 6.66; N, 6.38.

Example 4 (Production of Compound 4) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), isobutyraldehyde (0 .22 ml)
Was dissolved in 1,2-dichloroethane (15 ml), and sodium triacetoxyborohydride (0.31
g) was added, and the mixture was stirred overnight at room temperature. It was poured into water, neutralized with an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl]]
-3-Methoxyphenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 4) (0.3 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.90-1.00 (9H, m), 1.26-1.65 (4
H, m), 2.00-2.15 (1H, m), 2.93 (2H, t-like), 3.20
(2H, d, J = 7.2 Hz), 3.38 (2H, t-like), 3.55 (2H,
t, J = 6.5 Hz), 3.74-3.83 (5H, m), 4.16 (2H, t, J
= 4.8 Hz), 6.33 (1H, d, J = 4.8 Hz), 6.69 (1H, d, J
= 4.8 Hz), 6.88-7.00 (5H, m), 7.21-7.26 (1H, m),
7.40-7.52 (6H, m), 7.63-7.68 (2H, m), 7.77 (1H,
s), 8.22-8.24 (1H, m) .IR (KBr) ν: 2959, 1653, 1605, 1499 cm ^-1 . Anal.calcd. for C ₄₀ H ₄₇ N ₃ O ₆・ 0.25H ₂ O: C, 71.67; H,
7.14; N, 6.27. FoundC, 71.51; H, 7.24; N, 6.17.

Example 5 (Production of Compound 5) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Chloro-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.24 g ) Was dissolved in ethanol (30 ml), sodium borohydride (0.065 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off and 7- [4- (2-butoxyethoxy) phenyl] -N- [3-chloro-4- [hydroxy (1-oxidepyridin-2-yl) methyl]
Phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 5) (0.3 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.29-
1.48 (2H, m), 1.54-1.72 (2H, m), 2.92 (2H, br), 3.
43 (2H, br), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t,
J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 4.60 (1H,
br), 6.39 (1H, s), 6.69 (1H, d, J = 8.4 Hz), 6.85-
6.98 (3H, m), 7.23-7.55 (9H, m), 7.60-8.00 (3H,
m), 8.26 (1H, br). IR (KBr) ν: 2934, 2872, 1692 cm ^-1 .

Example 6 (Production of Compound 6) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-chloro-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), isobutyraldehyde (0 .22 ml)
Was dissolved in 1,2-dichloroethane (30 ml), and sodium triacetoxyborohydride (0.31
g) was added, and the mixture was stirred overnight at room temperature. Isobutyraldehyde (0.22 ml) and sodium triacetoxyborohydride (0.31 g) were added, and the mixture was stirred overnight at room temperature.
The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate). The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -N- [3-chloro-4-.
[Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 6) (0.2 g) was obtained as yellow crystals. mp 105-107 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.85-0.99 (9H, m), 1.22-1.68 (4
H, m), 2.00-2.11 (1H, m), 2.92 (2H, t, J = 4.6 Hz),
3.19 (2H, d, J = 7.6 Hz), 3.37 (2H, t, J = 4.6 H
z), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.9
Hz), 4.16 (2H, t, J = 4.9 Hz), 6.39 (1H, d, J = 3.
7 Hz), 6.68 (1H, d, J = 3.7 Hz), 6.82-7.00 (4H,
m), 7.20-7.30 (1H, m), 7.38-7.51 (6H, m), 7.72 (1
H, s), 7.78 (1H, d, J = 8.8 Hz), 7.94 (1H, d, J =
2.2 Hz), 8.26-8.30 (1H, m). IR (KBr) ν: 2957, 2934, 2870, 1651, 1659, 1607, 1
588, 1499 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₄ ClN ₃ O ₅・ 0.25H ₂ O: C, 69.42;
H, 6.65; N, 6.23. Found C, 69.45; H, 6.52; N, 6.2
3.

Example 7 (Production of Compound 7) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-methylphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g ) Was dissolved in ethanol (200 ml), sodium borohydride (0.13 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-
Oxopyridin-2-yl) methyl] -3-methylphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 7) (0.64 g) was obtained as yellow crystals. mp 179-182 ℃ (dec.). ¹ H-NMR (δ, CDCl3) 0.93 (3H, t, J = 7.3 Hz), 1.22-
1.64 (4H, m), 2.21 (3H, s), 2.96 (2H, t, J = 4.4 H
z), 3.46 (2H, t, J = 4.4 Hz), 3.55 (2H, t, J = 6.6
Hz), 3.80 (2H, t, J = 4.9 Hz), 4.15 (2H, t, J = 4.
9 Hz), 4.63 (1H, br), 6.27 (2H, s), 6.68-6.76 (2H,
m), 6.97 (2H, d, J = 8.8 Hz), 7.16-7.33 (3H, m),
7.43-7.47 (4H, m), 7.56-7.60 (2H, m), 7.70 (1H,
s), 8.30 (1H, dd, J = 1.0, 5.8 Hz) .IR (KBr) ν: 2955, 2928, 2872, 1645, 1609, 1501 cm
^-1 . Anal.calcd. For C ₃₆ H ₃₉ N ₃ O ₅・ 0.5H ₂ O: C, 71.74; H,
6.69; N, 6.97. Found C, 71.75; H, 6.65; N, 6.81.

Example 8 (Production of compound 8) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-methylphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g), isobutyraldehyde (0 .46 ml)
Was dissolved in 1,2-dichloroethane (50 ml), and sodium triacetoxyborohydride (0.64) was added under ice cooling.
g) was added, and the mixture was stirred overnight at room temperature. Isobutyraldehyde (0.46 ml) and sodium triacetoxyborohydride (0.64 g) were added, and the mixture was stirred overnight at room temperature.
The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol / triethylamine).
Purified with 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-methylphenyl] -1-isobutyl-2, 3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 8) (0.6 g) was obtained as a pale yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-0.99 (9H, m), 1.26-1.68 (4
H, m), 2.04-2.14 (1H, m), 2.21 (3H, s), 2.93 (2H, t
-like), 3.19 (2H, d, J = 7.0 Hz), 3.36 (2H, t-lik
e), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0
Hz), 4.15 (2H, t, J = 5.0 Hz), 6.27 (2H, br), 6.73
(1H, dd, J = 2.4, 7.8 Hz), 6.90-6.99 (3H, m), 7.16
-7.30 (2H, m), 7.37-7.60 (7H, m), 7.72 (1H, s), 8.
30 (1H, d, J = 4.8 Hz) .IR (KBr) ν: 2957, 2932, 2870, 1645, 1607, 1520, 1
499 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₇ N ₃ O ₅・ 0.5H ₂ O: C, 72.92; H,
7.34; N, 6.38. Found C, 72.74; H, 7.47; N, 6.18.

Example 9 (Production of Compound 9) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl] -1
-Trifluoroacetyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (0.77g)
Was dissolved in ethanol (200 ml), sodium borohydride (0.12 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl] -2,3-dihydro-1H-1-benzo Azepine-4-carboxamide (Compound 9) (0.56 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.22-
1.57 (4H, m), 2.27 (3H, s), 2.96 (2H, t-like), 3.4
7 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.8
9 (5H, m), 4.16 (2H, t, J = 4.8 Hz), 4.61 (1H, b
r), 6.32 (1H, s), 6.68-6.76 (2H, m), 6.85-7.02 (5H,
m), 7.30-7.47 (5H, m), 7.62 (1H, d, J = 8.6 Hz),
7.73 (1H, s), 7.80 (1H, br), 8.12 (1H, d, J = 6.2
Hz) .IR (KBr) ν: 2936, 2868, 1647, 1607, 1507 cm ^-1 . Anal.calcd. For C ₃₇ H ₄₁ N ₃ O ₆・ 1.5H ₂ O: C, 68.29; H,
6.81; N, 6.46. Found C, 68.46; H, 6.52; N, 6.39.

Example 10 (Production of Compound 10) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and isobutyraldehyde (0.23 ml) were added to 1,2-dichloroethane (30 m).
It was dissolved in 1), sodium triacetoxyborohydride (0.85 g) was added under ice cooling, and the mixture was stirred at room temperature overnight.
The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methanol / triethylamine).
The crude crystal was obtained by purification. Recrystallize from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-methoxy. Phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (Compound 10)
(0.38 g) was obtained as yellow crystals. mp 174-176 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.89-1.00 (9H, m), 1.23-1.65 (4
H, m), 2.00-2.20 (1H, m), 2.27 (3H, s), 2.93 (2H, t
-like), 3.20 (2H, d, J = 6.8 Hz), 3.38 (2H, t-lik
e), 3.55 (2H, t, J = 6.5 Hz), 3.75-3.83 (5H, m),
4.16 (2H, t, J = 5.0 Hz), 6.32 (1H, d, J = 4.4 Hz),
6.74 (1H, s), 6.88-7.03 (6H, m), 7.39-7.52 (5H,
m), 7.62-7.70 (2H, m), 7.77 (1H, d, J = 1.8 Hz),
8.12 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 2957, 2911, 1605, 1499 cm ^-1 . Anal.calcd. For C ₄₁ H ₄₉ N ₃ O ₆ 0.5H ₂ O: C, 71.49 ; H, 7.
32; N, 6.10. Found C, 71.46; H, 7.18; N, 6.12.

Example 11 (Production of Compound 11) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Ethoxy-4- [hydroxy (4-methyl-1-
Oxidopyridin-2-yl) methyl] phenyl] -1
-Trifluoroacetyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (0.85g)
Was dissolved in ethanol (200 ml), sodium borohydride (0.13 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4-
(2-Butoxyethoxy) phenyl] -N- [3-ethoxy-4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzo Azepine-4-carboxamide (Compound 11) (0.66 g) was obtained as yellow crystals. mp 110-115 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.85-0.97 (6H, m), 1.23-1.65 (4
H, m), 2.28 (3H, s), 2.96 (2H, t-like), 3.47 (2H,
t-like), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J =
4.8 Hz), 4.02-4.18 (4H, m), 4.61 (1H, br), 6.27-
6.28 (1H, m), 6.70 (1H, d, J = 8.0 Hz), 6.85-7.03
(6H, m), 7.30-7.35 (2H, m), 7.43-7.47 (3H, m), 7.64
-7.72 (3H, m), 8.10 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 2936, 2870, 1651, 1609, 1499 cm ^-1 . Anal.calcd. For C ₃₈ H ₄₃ N ₃ O ₆・ 0.5H ₂ O: C, 70.57; H,
6.86; N, 6.50. Found C, 70.27; H, 7.00; N, 6.48.

Example 12 (Production of compound 12) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Ethoxy-4- [hydroxy (4-methyl-1-
Oxidopyridin-2-yl) methyl] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) and isobutyraldehyde (0.27 ml) were added to 1,2-dichloroethane (50 m).
It was dissolved in 1), sodium triacetoxyborohydride (1 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent:
Purification with ethyl acetate) gave crude crystals. Recrystallize from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -N- [3-ethoxy-4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl]. Phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 12) (0.53 g) was obtained as yellow crystals. mp 108-110 ° C. ¹ H-NMR (δ, CDCl ₃ ) 0.85-0.99 (12H, m), 1.23-1.65
(4H, m), 2.00-2.15 (1H, m), 2.28 (3H, s), 2.92 (2H,
t-like), 3.19 (2H, d, J = 7.4 Hz), 3.38 (2H, t-li
ke), 3.55 (2H, t, J = 6.5 Hz), 3.80 (2H, t, J = 5.
0 Hz), 4.02-4.18 (4H, m), 6.29 (1H, d, J = 5.6 Hz),
6.84-7.06 (7H, m), 7.38-7.53 (5H, m), 7.65-7.69
(2H, m), 7.75 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J
= 6.6 Hz). IR (KBr) ν: 2959, 2870, 1651, 1605, 1499 cm ^-1 . Anal.calcd. For C ₄₂ H ₅₁ N ₃ O ₆・ H ₂ O: C, 70.86; H, 7.5
0; N, 5.90. Found C, 71.25; H, 7.57; N, 6.00.

Example 13 (Production of Compound 13) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) and propionaldehyde (0.3 ml) were added to 1,2-dichloroethane (50 ml).
, Sodium triacetoxyborohydride (0.87 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. Evaporate the solvent,
The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), 7- [4- (2-butoxyethoxy) phenyl]
-N- [4- [hydroxy (1-oxidepyridine-2
-Yl) methyl] -3-trifluoromethylphenyl]
-1-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 13) (0.4
6 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.88-1.01 (6H, m), 1.28-1.78 (6
H, m), 2.89 (2H, t-like), 3.24-3.31 (4H, m), 3.54
(2H, t, J = 6.6 Hz), 3.79 (2H, t, J = 4.9 Hz), 4.1
3 (2H, t, J = 4.9 Hz), 6.43 (1H, s), 6.60-6.65 (2
H, m), 6.84-6.96 (3H, m), 7.12-7.27 (2H, m), 7.36-
7.44 (5H, m), 7.76-7.92 (2H, m), 8.05-8.06 (1H,
m), 8.21-8.24 (1H, m), 8.50 (1H, s). IR (KBr) ν: 2957, 2872, 1653, 1607 cm ^-1 . Anal.calcd. for C ₃₉ H ₄₂ F ₃ N ₃ O ₅・ 0.5H ₂ O: C, 67.03;
H, 6.20; N, 6.01.FoundC, 67.40; H, 6.36; N, 6.02.

Example 14 (Production of Compound 14 and Compound 15) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.4 g) was added to CHIRAL.
Optical resolution was performed using PAK AD 50 mm ID × 500 mm L and an elution solvent (hexane / ethanol). Fractions were concentrated to dryness, the residue was dissolved in ethanol and then 0.45μ
It filtered with the filter of m. The filtrate was concentrated, hexane was added to dryness, and (+)-7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] ] -3-Trifluoromethylphenyl] -1-propyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 14) (160 mg,> 99.9% ee), (−)-
7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 15) (160 m
g,> 99.9% ee). (+) Form: [α] _D = + 18.1 ° (c = 0.497)
%, Ethanol solution) (−) form: [α] _D = -18.5 ° (c = 0.500)
%, Ethanol solution)

Example 15 (Production of Compound 16) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (1
g) was dissolved in ethanol (100 ml), sodium borohydride (0.15 g) was added under ice cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[Hydroxy (4-methyl-1-oxidepyridine-2
-Yl) methyl] -3-trifluoromethylphenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
Carboxamide (Compound 16) (0.63 g) was obtained as yellow crystals. mp 124-128 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.1 Hz), 1.27-
1.68 (4H, m), 2.23 (3H, s), 2.98 (2H, t-like), 3.4
9 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2
H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.65
(1H, br), 6.38-6.43 (2H, m), 6.71 (1H, d, J = 8.6
Hz), 6.95-7.07 (4H, m), 7.31-7.54 (5H, m), 7.82-7.9
5 (3H, m), 8.04 (1H, s), 8.17 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 2934, 2847, 1653, 1609, 1499 cm ^-1 . Anal.calcd. For C ₃₇ H ₃₈ F ₃ N ₃ O ₅ H ₂ O: C, 65.38; H,
5.93; N, 6.18.Found C, 65.16; H, 5.81; N, 6.17.

Example 16 (Production of Compound 17) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g ) And propionaldehyde (0.16 ml) were added to 1,2-dichloroethane (25
ml), sodium triacetoxyborohydride (0.48 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain crude crystals. Recrystallize from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-tri. Fluoromethylphenyl] -1-propyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 17) (0.28 g) was obtained as yellow crystals. mp 103-105 ° C. ¹ H-NMR (δ, CDCl ₃ ) 0.88-1.04 (6H, m), 1.22-1.82 (6
H, m), 2.23 (3H, s), 2.94 (2H, t-like), 3.30-3.37
(4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J =
5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 6.37 (1H, d, J
= 2.2 Hz), 6.43 (1H, s), 6.89-7.06 (5H, m), 7.40-
7.52 (5H, m), 7.85-7.96 (3H, m), 8.05 (1H, s), 8.17
(1H, d, J = 6.6 Hz) .IR (KBr) ν: 2961, 2932, 2911, 1659, 1607, 1501 cm
^-1 . Anal.calcd. For C ₄₀ H ₄₄ F ₃ N ₃ O ₅ : C, 68.26; H, 6.30;
N, 5.97. Found C, 67.88; H, 6.27; N, 6.11.

Example 17 (Production of Compound 18 and Compound 19) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-propyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (0.11 g) was added to CHIRALPAK AD 50mm IDx500mm
Optical resolution was performed using L and an elution solvent (hexane / ethanol). Fractions were concentrated to dryness, the residue was dissolved in ethanol and then filtered through a 0.45 μm filter. The filtrate was concentrated, hexane was added to dryness, and (+)-7- [4- (2
-Butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl)
Methyl] -3-trifluoromethylphenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 18) (54 mg,> 9
9.9% ee), (-)-7- [4- (2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3.
-Trifluoromethylphenyl] -1-propyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 19) (53 mg,> 99.9% e)
e) was obtained. (+) Form: [α] _D = + 36.0 ° (c = 0.491)
%, Ethanol solution) (−) form: [α] _D = −30.5 ° (c = 0.118)
%, Ethanol solution)

Example 18 (Production of compound 20) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g ) And isobutyraldehyde (0.22 ml) were added to 1,2-dichloroethane (25
ml), sodium triacetoxyborohydride (0.48 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- [hydroxy (4-
Methyl-1-oxidepyridin-2-yl) methyl]-
3-Trifluoromethylphenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 20) (0.3 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-1.00 (9H, m), 1.22-1.68 (4
H, m), 2.05-2.12 (1H, m), 2.23 (3H, s), 2.95 (2H, t
-like), 3.20 (2H, d, J = 7.2 Hz), 3.38 (2H, t-lik
e), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.8)
Hz), 4.16 (2H, t, J = 4.8 Hz), 6.37 (1H, d, J = 2.
2 Hz), 6.44 (1H, s), 6.91-7.06 (5H, m), 7.40-7.51
(5H, m), 7.90-7.93 (3H, m), 8.06 (1H, s), 8.17 (1
H, d, J = 6.6 Hz) .IR (KBr) ν: 2957, 2870, 1651, 1607, 1520, 1499 cm
^-1 . Anal.calcd. For C ₄₁ H ₄₆ F ₃ N ₃ O ₅・ 0.5H ₂ O: C, 67.75;
H, 6.52; N, 5.78.FoundC, 67.93; H, 6.74; N, 5.67.

Example 19 (Production of Compound 21) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3- (2,2,2-trifluoroethoxy) phenyl] -1-trifluoroacetyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (1.7 g) was dissolved in ethanol (150 ml), sodium borohydride (0.24 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. The solvent was distilled off, water was added,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off and 7- [4- (2-butoxyethoxy) phenyl]
-N- [4- [hydroxy (1-oxidepyridine-2
-Yl) methyl] -3- (2,2,2-trifluoroethoxy) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 21) (1
g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.22-
1.68 (4H, m), 2.94 (2H, t-like), 3.47 (2H, t-lik
e), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0
Hz), 4.15 (2H, t, J = 5.0 Hz), 4.33-4.44 (2H, m),
4.63 (1H, br), 6.24 (1H, d, J = 6.6 Hz), 6.70 (1H,
d, J = 8.4 Hz), 6.89 (1H, dd, J = 1.8,8.4 Hz), 6.
95-7.01 (3H, m), 7.14-7.34 (5H, m), 7.42-7.47 (3H,
m), 7.75-7.79 (2H, m), 7.72 (1H, d, J = 1.8 Hz),
8.17-8.20 (1H, m). IR (KBr) ν: 3326, 2934, 1651, 1609, 1501 cm ^-1 . Anal.calcd. For C ₃₇ H ₃₈ F ₃ N ₃ O ₆・ 0.5H ₂ O: C , 64.71;
H, 5.72; N, 6.12. FoundC, 64.70; H, 5.79; N, 5.84.

Example 20 (Production of compound 22) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3- (2,2,2-trifluoroethoxy) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and propionaldehyde (0.27 ml) were dissolved in 1,2-dichloroethane (25 ml), sodium triacetoxyborohydride (0.78 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. . After neutralization with an aqueous solution of sodium hydrogen carbonate,
It was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3- (2,2,2-tri Fluoroethoxy) phenyl] -1-propyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 22) (0.49 g) was obtained as a pale yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-1.03 (6H, m), 1.22-1.81 (6
H, m), 2.91 (2H, t-like), 3.29-3.36 (4H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.1
6 (2H, t, J = 5.0 Hz), 4.33-4.45 (2H, m), 6.24 (1
H, d, J = 7.0 Hz), 6.85-7.03 (5H, m), 7.14-7.32 (3
H, m), 7.40-7.50 (5H, m), 7.70 (1H, s), 7.78 (1H,
d, J = 8.4 Hz), 7.88 (1H, s), 8.18-8.20 (1H, m). IR (KBr) ν: 2961, 2934, 2872, 1651, 1605, 1499 cm
^-1 . Anal.calcd. For C ₄₀ H ₄₄ F ₃ N ₃ O ₆・ 0.5H ₂ O: C, 65.92;
H, 6.22; N, 5.77.FoundC, 66.16; H, 6.00; N, 5.78.

Example 21 (Production of compound 23) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3- (2,2,2-trifluoroethoxy) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) and isobutyraldehyde (0.32 ml) were dissolved in 1,2-dichloroethane (15 ml), sodium triacetoxyborohydride (0.7 g) was added under ice cooling, and the mixture was stirred overnight at room temperature. .. After neutralization with an aqueous solution of sodium hydrogen carbonate,
It was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain crude crystals. Recrystallized from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- [hydroxy (1
-Oxidopyridin-2-yl) methyl] -3- (2,
2,2-Trifluoroethoxy) phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 23) (0.44 g) was obtained as yellow crystals. mp 118-123 ° C. ¹ H-NMR (δ, CDCl ₃ ) 0.86-0.99 (9H, m), 1.26-1.68 (4
H, m), 1.95-2.15 (1H, m), 2.91 (2H, t-like), 3.20
(2H, d, J = 6.8 Hz), 3.38 (2H, t-like), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.9 Hz), 4.16 (2
H, t, J = 4.9 Hz), 4.34-4.46 (2H, m), 6.25 (1H, d,
J = 7.0 Hz), 6.87-7.04 (5H, m), 7.19-7.30 (3H,
m), 7.40-7.51 (5H, m), 7.70 (1H, s), 7.79 (1H, d,
J = 8.0 Hz), 7.89 (1H, d, J = 2.2 Hz), 8.20 (1H, d,
J = 6.0 Hz). IR (KBr) ν: 2955, 2870, 1651, 1605, 1499 cm ^-1 . Anal.calcd. For C ₄₁ H ₄₆ F ₃ N ₃ O ₆ : C, 67.11; H, 6.32;
N, 5.73. Found C, 66.75; H, 6.35; N, 5.46.

Example 22 (Production of compound 24) 7- [4- (2-butoxyethoxy) phenyl] -N-
(4-Hydroxyphenyl) -1-propyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (0.62 g), 3-chloromethyl-4-methyl-
4H-1,2,4-triazole monohydrochloride (0.24
g), N, N-dimethylformamide (15 ml) was added to potassium carbonate (0.5 g), and at room temperature under a nitrogen atmosphere,
Stir overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), and 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4-[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy] phenyl] -1-propyl-2,3-dihydro-1H-1- Benzazepine-4-carboxamide (Compound 24) (0.48 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-1.06 (6H, m), 1.25-1.80 (6
H, m), 2.90 (2H, t-like), 3.25-3.38 (4H, m), 3.55
(2H, t, J = 6.6 Hz), 3.77 (3H, s), 3.80 (2H, t, J =
4.8 Hz), 4.15 (2H, t, J = 4.8 Hz), 5.29 (2H, s),
6.87-7.03 (5H, m), 7.40-7.58 (8H, m), 8.11 (1H, s) .IR (KBr) ν: 2957, 2930, 2872, 1501 cm ^-1 . Anal.calcd. For C ₃₆ H ₄₃ N ₅ O ₄・ 0.25H ₂ O: C, 70.39; H,
7.14; N, 11.40.FoundC, 70.35; H, 7.46; N, 11.46.

Example 23 (Production of Compound 25) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- (4-hydroxyphenyl) -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 2-chloromethyl-1-propylimidazole monohydrochloride (0.22 g), potassium carbonate (0.4 g) in N, N-dimethyl Formamide (15m
1) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to give crude crystals. Recrystallized from ethyl acetate-hexane to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(1-propylimidazole-2
-Yl) methoxy] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (Compound 25) (0.51 g) was obtained as pale yellow crystals. mp 118-120 ° C. ¹ H-NMR (δ, CDCl ₃ ) 0.89-0.98 (12H, m), 1.30-1.69
(4H, m), 1.77-1.88 (2H, m), 2.04-2.10 (1H, m), 2.91
(2H, t-like), 3.18 (2H, d, J = 7.2 Hz), 3.36 (2H,
t-like), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J
= 5.0 Hz), 3.97 (2H, t, J = 7.3 Hz), 4.16 (2H, t,
J = 5.0 Hz), 5.14 (2H, s), 6.89-7.04 (7H, m), 7.37
-7.51 (8H, m). IR (KBr) ν: 2957, 2934, 2870, 1647, 1605, 1499, 1
510 cm ^-1 . Anal.calcd. For C ₄₀ H ₅₀ N ₄ O ₄・ 0.25H ₂ O: C, 73.31; H,
7.77; N, 8.55. FoundC, 73.07; H, 7.67; N, 8.44.

Example 24 (Production of compound 26) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- (4-hydroxyphenyl) -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole monohydrochloride (0.22
g), N, N-dimethylformamide (10 ml) was added to potassium carbonate (0.4 g), and at room temperature under a nitrogen atmosphere,
Stir overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), and 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[(4-Propyl-4H-1,2,4-triazol-3-yl) methoxy] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 26) (0 0.47 g) was obtained as a pale yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.89-1.01 (12H, m), 1.23-1.56
(4H, m), 1.80-1.91 (2H, m), 2.00-2.18 (1H, m), 2.91
(2H, t-like), 3.18 (2H, d, J = 7.2 Hz), 3.36 (2H,
t-like), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J
= 5.0 Hz), 4.03 (2H, t, J = 7.3 Hz), 4.16 (2H, t,
J = 5.0 Hz), 5.28 (2H, s), 6.89-7.03 (5H, m), 7.38
-7.59 (8H, m), 8.15 (1H, s). IR (KBr) ν: 2957, 2868, 1647, 1605, 1507 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₄・ 0.25H ₂ O: C, 71.37; H,
7.60; N, 10.67.FoundC, 71.12; H, 7.58; N, 10.88.

Example 25 (Production of compound 27) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- (4-hydroxyphenyl) -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole monohydrochloride (0.1
5 g) and potassium carbonate (0.4 g), N, N-dimethylformamide (5 ml) was added, and under a nitrogen atmosphere at room temperature,
Stir overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), and 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl) methoxy] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 27) (0 0.31 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.85-1.00 (15H, m), 1.26-1.48
(2H, m), 1.54-1.68 (2H, m), 2.00-2.16 (2H, m), 2.91
(2H, t-like), 3.17 (2H, d, J = 7.2 Hz), 3.34 (2H,
t-like), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.86 (4H,
m), 4.13-4.17 (2H, m), 5.25 (2H, s), 6.88-7.01 (5
H, m), 7.36-7.56 (7H, m), 7.85 (1H, br), 8.09 (1H,
s) .IR (KBr) ν: 2950, 2880, 1650, 1600, 1507 cm ^-1 .

Example 26 (Production of compound 28) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (15 ml), and thionyl chloride (0.2 g) was added under ice cooling.
5 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (25 ml), and S- (4-aminophenyl) O-benzyl thiocarbonate (0.6 g) and triethylamine (1 ml) in tetrahydrofuran (15 ml) was added under ice cooling. Dropped. Stir overnight at room temperature under a nitrogen atmosphere, then add methanol (15 m
l) 1N aqueous sodium hydroxide solution (15 ml) was added, and the mixture was stirred for 30 minutes. 3-Chloromethyl-4-isobutyl-4H-1,2,4-triazole monohydrochloride (0.
53 g) was added, and the mixture was stirred at room temperature for 1 hour. It was concentrated and extracted with ethyl acetate. After washing the organic layer with water and saturated saline,
It was dried with anhydrous magnesium sulfate and the solvent was distilled off.
The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), 7- [4- (2-butoxyethoxy) phenyl]
-1-isobutyl-N- [4-[(4-isobutyl-4
H-1,2,4-triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 28) (0.6
g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.88-1.01 (15H, m), 1.17-1.68
(4H, m), 1.70-2.15 (2H, m), 2.91 (2H, t-like), 3.18
(2H, d, J = 7.0 Hz), 3.34 (2H, t-like), 3.55 (2H,
t, J = 6.6 Hz), 3.69 (2H, d, J = 7.2 Hz), 3.80 (2
H, t, J = 5.0 Hz), 4.07 (2H, s), 4.16 (2H, t, J =
5.0 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J
= 8.8 Hz), 7.28-7.46 (7H, m), 7.60 (2H, d, J = 8.
8 Hz), 7.94 (1H, s), 8.37 (1H, br). IR (KBr) ν: 2959, 2932, 2870, 1651, 1607, 1588, 1
497 cm ^-1 . Anal.calcd. For C ₄₀ H ₅₁ N ₅ O ₃ S ・ 0.75H ₂ O: C, 69.08;
H, 7.01; N, 10.07. Found C, 68.84; H, 7.80; N, 10.
39

Example 27 (Production of Compound 29) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(4-isobutyl-4H-
1,2,4-Triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) was dissolved in dichloromethane (20 ml). Cool to −78 ° C. and add 3-chloroperbenzoic acid (0.45 g) in dichloromethane (5 m
l) The solution was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[(4-isobutyl-4H-1,2,4-triazol-3-yl) methylsulfinyl] phenyl] -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 29) (0.3 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.83-1.09 (15H, m), 1.22-1.48
(2H, m), 1.54-1.65 (2H, m), 1.80-1.95 (1H, m), 1.95
-2.15 (1H, m), 2.95 (2H, t-like), 3.20 (2H, d, J =
6.6 Hz), 3.63 (2H, t-like), 3.55 (2H, t, J = 6.6 H
z), 3.74 (2H, d, J = 7.0 Hz), 3.80 (2H, t, J = 5.0
Hz), 4.03-4.22 (4H, m), 6.90-6.99 (3H, m), 7.15-
7.45 (7H, m), 7.84 (2H, d, J = 8.8 Hz), 8.02 (1H,
s), 8.51 (1H, br). IR (KBr) ν: 2959, 2932, 2872, 1661, 1588, 1518, 1
499 cm ^-1 .

Example 28 (Production of compound 30 and compound 31) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(4-isobutyl-4H-
1,2,4-triazol-3-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) in CH
IRALPAK AD 50mmIDx500mmL,
Optical resolution was performed using an elution solvent (hexane / ethanol). Fractions were concentrated to dryness, the residue was dissolved in ethanol,
It was filtered with a 0.45 μm filter. Concentrate the filtrate,
Hexane was added to dryness, and (+)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl) methylsulfinyl] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 30) (0.13 g,> 99.9)
% Ee), (-)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(4-
Isobutyl-4H-1,2,4-triazol-3-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 31) (0.12 g,> 99. 9% ee) was obtained. (+) Form: [α] _D = + 119.2 ° (c = 0.49)
2%, ethanol solution) (−) form: [α] _D = -114.1 ° (c = 0.49)
9%, ethanol solution)

Example 29 (Production of Compound 32) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.97 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.
25 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and S- (4-
Aminophenyl) O-benzyl thiocarbonate (0.6 g) and triethylamine (1 ml) were added dropwise to a tetrahydrofuran (10 ml) solution under ice cooling. Stir for 2.5 hours at room temperature under a nitrogen atmosphere, then add methanol (15
ml), 1N aqueous sodium hydroxide solution (15 ml) was added, and the mixture was stirred for 30 minutes. 3-Chloromethyl-4-isobutyl-4H-1,2,4-triazole monohydrochloride (0.
53 g) was added, and the mixture was stirred at room temperature for 2 hours. It was concentrated and extracted with ethyl acetate. After washing the organic layer with water and saturated saline,
It was dried with anhydrous magnesium sulfate and the solvent was distilled off.
The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine), 7- [4- (2-butoxyethoxy) phenyl]
-N- [4-[(4-isobutyl-4H-1,2,4-
Triazol-3-yl) methylthio] phenyl] -1
-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 32) (1.2 g)
Was obtained as pale yellow crystals. mp 130-132 ℃. ¹ H-NMR (δ, CDCl ₃ ) 0.85-1.03 (12H, m), 1.34-1.49
(2H, m), 1.54-1.80 (4H, m), 1.93-2.07 (1H, m), 2.91
(2H, t-like), 3.28-3.34 (4H, m), 3.55 (2H, t, J =
6.6 Hz), 3.68 (2H, d, J = 7.4 Hz), 3.80 (2H, t, J
= 5.0 Hz), 4.06 (2H, s), 4.16 (2H, t, J = 5.0 Hz),
6.87 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.8 H
z), 7.26-7.46 (7H, m), 7.60 (2H, d, J = 8.8 Hz),
7.94 (1H, s), 8.41 (1H, br). IR (KBr) ν: 2961, 2932, 2872, 1655, 1605, 1588, 1
499 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₃ S: C, 70.13; H, 7.39;
N, 10.49. Found C, 69.89; H, 7.52; N, 10.46.

Example 30 (Production of compound 33) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl) methylthio] phenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-
4-carboxamide (0.7 g) was added to dichloromethane (5
0 ml). After cooling to -78 ° C, a solution of 3-chloroperbenzoic acid (0.39g) in dichloromethane (5ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallized from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(4-isobutyl-4H-1,
2,4-Triazol-3-yl) methylsulfinyl] phenyl] -1-propyl-2,3-dihydro-1
H-1-benzazepine-4-carboxamide (Compound 33) (0.57 g) was obtained as yellow crystals. mp 186-190 ℃ (dec.). ¹ H-NMR (δ, CDCl ₃ ) 0.82 (6H, d, J = 6.6 Hz), 0.93
(3H, t, J = 7.1 Hz), 1.02 (3H, t, J = 7.3Hz), 1.30
-1.48 (2H, m), 1.54-1.89 (5H, m), 2.96 (2H, br), 3.
31-3.34 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.70 (2
H, d, J = 7.4 Hz), 3.80 (2H, t, J = 4.7 Hz), 3.95-
4.17 (4H, m), 6.89 (1H, d, J = 8.8 Hz), 6.95 (2H,
d, J = 8.8 Hz), 7.27-7.43 (7H, m), 7.86 (2H, d, J
= 8.8 Hz), 8.01 (1H, s), 8.68 (1H, br). IR (KBr) ν: 2961, 2930, 2872, 1661, 1607, 1590, 1
520, 1499 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₄ S: C, 68.49; H, 7.22;
N, 10.24. Found C, 68.17; H, 7.02; N, 10.17.

Example 31 (Production of compound 34 and compound 35) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl) methylsulfinyl] phenyl]-
1-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) was added to CHIR
Optical resolution was performed using ALPAK AD 50 mmID × 500 mmL, an elution solvent (hexane / isopropanol). Fractions were concentrated to dryness, the residue was dissolved in ethanol,
It was filtered with a 0.45 μm filter. Concentrate the filtrate,
Hexane was added to dryness, and (+)-7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(4-isobutyl-4H-1,2,4-triazol-3-yl). )
Methylsulfinyl] phenyl] -1-propyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 34) (0.12 g,> 99.9% e)
e), (-)-7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(4-isobutyl-4H-1,
2,4-Triazol-3-yl) methylsulfinyl] phenyl] -1-propyl-2,3-dihydro-1
H-1-Benzazepine-4-carboxamide (Compound 35) (0.12 g, 99.6% ee) was obtained. (+) Form: [α] _D = + 131.9 ° (c = 0.45)
(7%, ethanol solution) (-) form: [α] _D = -137.6 ° (c = 0.49)
3%, ethanol solution)

Example 32 (Production of compound 36) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.2 g) was added under ice cooling.
5 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and 4-
[(5,6-Dimethyl-1,2,4-triazine-3-
Il) methylthio] aniline (0.59 g) and triethylamine (1 ml) were added dropwise to a tetrahydrofuran (5 ml) solution under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere, and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
Hexane), 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(5,6-dimethyl-
1,2,4-Triazin-3-yl) methylthio] phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (Compound 36)
(0.46 g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.90-0.98 (9H, m), 1.29-1.49 (2
H, m), 1.54-1.69 (2H, m), 2.04-2.10 (1H, m), 2.47
(3H, s), 2.60 (3H, s), 2.90 (2H, t-like), 3.17 (2
H, d, J = 7.2 Hz), 3.34 (2H, t-like), 3.55 (2H, t,
J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.14 (2H,
t, J = 5.0 Hz), 4.33 (2H, s), 6.87-6.99 (3H, m), 7.
35-7.54 (9H, m), 7.85 (1H, br). IR (KBr) ν: 2959, 2867, 1653, 1607, 1586, 1499 cm
^-1 .

Example 33 (Production of Compound 37) 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[(5,6-Dimethyl-1,2,4-triazin-3-yl) methylthio] phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (0.
25 g) was dissolved in dichloromethane (100 ml).
It was cooled to -78 ° C and 3-chloroperbenzoic acid (0.14
A solution of g) in dichloromethane (3 ml) was added dropwise. -7
After stirring at 8 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine) to obtain crude crystals. Recrystallized from ethyl acetate-hexane to give 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[(5,6-Dimethyl-1,2,4-triazine-3
-Yl) methylsulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 37) (0.20 g) was obtained as yellow crystals. mp 178-183 ℃ (dec.). ¹ H-NMR (δ, CDCl ₃ ) 0.88-1.09 (9H, m), 1.22-1.69 (4
H, m), 2.00-2.15 (1H, m), 2.51 (3H, s), 2.67 (3H,
s), 2.93 (2H, t-like), 3.20 (2H, d, J = 7.2Hz), 3.
38 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2
H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.36
(1H, d, J = 12.6 Hz), 4.53 (1H, d, J = 12.6 Hz), 6.
91-7.00 (3H, m), 7.37-7.49 (5H, m), 7.61 (2H, d, J
= 8.4 Hz), 7.74-7.82 (3H, m). IR (KBr) ν: 2955, 2928, 2868, 1653, 1607, 1588, 1
518, 1499 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₄ S ・ 0.25H ₂ O: C, 68.49;
H, 7.22; N, 10.24.Found C, 68.17; H, 7.02; N, 10.
17.

Example 34 (Production of compound 38) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.9 g) was dissolved in tetrahydrofuran (15 ml), and thionyl chloride (0.
23 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), and 4-[(5
-Methyl-1,2,4-triazin-3-yl) methylthio] aniline (0.47 g) and triethylamine (0.86 ml) were added dropwise to a tetrahydrofuran (10 ml) solution under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere, and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
Hexane), 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(5-methyl-1,2,2,
4-triazin-3-yl) methylthio] phenyl]-
1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 38) (1.1
g) was obtained as a yellow amorphous. ¹ H-NMR (δ, CDCl ₃ ) 0.89-0.98 (9H, m), 1.34-1.45 (2
H, m), 1.54-1.72 (2H, m), 1.94-2.05 (1H, m), 2.51
(3H, s), 2.89 (2H, t-like), 3.17 (2H, d, J = 7.4 H
z), 3.33 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz),
3.80 (2H, t, J = 4.9 Hz), 4.14 (2H, t, J = 4.9 Hz),
4.36 (2H, s), 6.90 (1H, d, J = 9.6 Hz), 6.97 (2H,
d, J = 8.8 Hz), 7.34-7.55 (9H, m), 7.92 (1H, br),
8.93 (1H, s) .IR (KBr) ν: 2953, 2867, 1659 cm ^-1 .

Example 35 (Production of compound 39) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(5-methyl-1,2,4-triazine-3-
Il) methylthio] phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was added to dichloromethane (100 m).
It was suspended in 1) and cooled to -78 ° C. A solution of 3-chloroperbenzoic acid (0.38 g) in dichloromethane (7 ml) was added dropwise. After stirring at -78 ° C for 1.5 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to give crude crystals. Recrystallized from ethyl acetate-hexane to give 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[(5-Methyl-1,2,4-triazin-3-yl) methylsulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-
Carboxamide (Compound 39) (0.50 g) was obtained as yellow crystals. ¹ H-NMR (δ, CDCl ₃ ) 0.89-1.05 (9H, m), 1.27-1.49 (2
H, m), 1.54-1.68 (2H, m), 1.98-2.15 (1H, m), 2.56
(3H, s), 2.92 (2H, t-like), 3.20 (2H, d, J = 7.2 H
z), 3.37 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz),
3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz),
4.40 (1H, d, J = 12.6 Hz), 4.58 (1H, d, J = 12.6 H
z), 6.90-7.00 (3H, m), 7.39-7.49 (5H, m), 7.59 (2
H, d, J = 8.6 Hz), 7.76 (2H, d, J = 8.6 Hz), 7.81
(1H, s), 9.03 (1H, s). IR (KBr) ν: 2957, 2899, 1663, 1588, 1518, 1499 cm
^-1 .

Example 36 (Production of compound 40) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (3 g) was dissolved in tetrahydrofuran (15 ml), and thionyl chloride (0.8
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off to obtain acid chloride. 4-benzyl chloroformate (0.9 ml)
Mercapto-3-methylaniline (0.9 g), triethylamine (4.5 ml) in tetrahydrofuran (50
(ml) solution was added dropwise at -78 ° C and stirred for 1.5 hours. Then, the above acid chloride tetrahydrofuran (1
5 ml) solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour.
A 1N sodium hydroxide aqueous solution (40 ml) and methanol (40 ml) were added, and the mixture was stirred at room temperature for 30 minutes. 3-Chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (1.3 g) was added, and the mixture was stirred at room temperature overnight. It was concentrated and 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. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate) to obtain crude crystals. Recrystallized from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-
4-[(4-Propyl-4H-1,2,4-triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 40) (1. 9 g) was obtained as yellow crystals. mp 104-107 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.90-0.99 (12
H, m), 1.27-1.45 (2H, m), 1.49-1.65 (2H, m), 1.72-
1.85 (2H, m), 2.00-2.18 (1H, m), 2.33 (3H, s), 2.9
1 (2H, t-like), 3.18 (2H, d, J = 7.4 Hz), 3.35 (2
H, t-like), 3.56 (2H, t, J = 6.6 Hz), 3.78-3.91 (4
H, m), 4.05 (2H, s), 4.16 (2H, t, J = 4.9 Hz), 6.9
1 (1H, d, J = 9.2 Hz), 6.97 (2H, d, J = 8.4 Hz),
7.29-7.47 (7H, m), 7.57 (1H, s), 8.01 (1H, s), 8.0
7 (1H, br). IR (KBr) n: 2959, 2870,1659, 1607, 158
0, 1518, 1499 cm ^-1 . Anal.calcd. For C ₄₀ H ₅₁ N ₅ O ₃ S
0.25H ₂ O: C, 69.99; H, 7.56; N, 10.20.Found C, 69.9
8; H, 7.55; N, 10.00.

Example 37 (Production of compound 41) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (0.67 g) was suspended in dichloromethane (100 ml) and cooled to -78 ° C. A solution of 3-chloroperbenzoic acid (0.35 g) in dichloromethane (5 ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N-
[3-Methyl-4-[(4-propyl-4H-1,2,2
4-Triazol-3-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 41) (0.54 g)
Was obtained as a yellow amorphous solid. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-1.02 (12H, m), 1.22-1.75
(6H, m), 2.05-2.18 (1H, m), 2.29 (3H, s), 2.85-2.
98 (2H, m), 3.18-3.28 (2H, m), 3.30-3.40 (2H, m),
3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 3.89-3.95 (2H, m), 4.08-4.17 (2H, tm), 6.89-6.9
8 (3H, m), 7.31-7.65 (7H, m), 7.72 (1H, d, J = 8.4
Hz), 8.04 (1H, s), 8.46 (1H, br). IR (KBr) n: 2959, 2932, 2870, 1661, 1405, 1520, 14
99 cm ^-1 .

Example 38 (Production of Compound 42) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.14 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.
05 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and 4-
[(4-Propyl-4H-1,2,4-triazole-
3-yl) methylthio] -3-trifluoromethylaniline (0.1 g) and 4-dimethylaminopyridine (catalytic amount) in pyridine (5 ml) were added dropwise under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate) to obtain crude crystals. Recrystallized from ethyl acetate-hexane to give 7- [4- (2-butoxyethoxy) phenyl]
-1-isobutyl-N- [3-trifluoromethyl-4
-[(4-Propyl-4H-1,2,4-triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 42) (0.23 g ) Was obtained as yellow crystals. mp 131-133 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.84-1.01 (12H, m), 1.27-1.69
(6H, m), 2.00-2.15 (1H, m), 2.96 (2H, t-like), 3.
20 (2H, d, J = 7.0 Hz), 3.34 (2H, t-like), 3.56 (2
H, t, J = 6.6 Hz), 3.70 (2H, t, J = 7.6 Hz), 3.81
(2H, t, J = 5.0Hz), 3.86 (2H, s), 4.15 (2H, t, J =
5.0 Hz), 6.87-6.97 (3H, m), 7.11 (1H, s), 7.24 (1
H, s), 7.36-7.43 (4H, m), 7.84 (1H, dd, J = 2.2,
8.8 Hz), 7.90 (1H, s), 8.18 (1H, d, J = 2.2 Hz),
9.46 (1H, br). IR (KBr) n: 2963, 2934, 2870, 1661, 1607, 1518, 14
99 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₈ F ₃ N ₅ O ₃ S ・ 0.25H ₂ O: C, 64.89;
H, 6.66; N, 9.46.Found C, 64.70; H, 6.49; N, 9.6
Five.

Example 39 (Production of Compound 43) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-trifluoromethyl-4-
[(4-Propyl-4H-1,2,4-triazole-
3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.38 g) was dissolved in dichloromethane (50 ml) and cooled to -78 ° C. 3-chloroperbenzoic acid (0.
A solution of 14 g) in dichloromethane (5 ml) was added dropwise.
After stirring at -78 ° C for 2 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline.
Dry with anhydrous magnesium sulfate and evaporate the solvent to give 7
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3-trifluoromethyl-4-[(4
-Propyl-4H-1,2,4-triazol-3-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 43) (0.35 g) as yellow Obtained as crystals. mp 169-172 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.82 (3H, t, J = 7.3 Hz), 0.9
4 (3H, t, J = 7.2 Hz), 1.05 (6H, d, J = 6.6 Hz), 1.
31-1.72 (6H, m), 2.06-2.15 (1H, m), 2.85-3.52 (6H,
m), 3.56 (2H, t, J = 6.6 Hz), 3.60-3.78 (2H, m),
3.80 (2H, t, J = 4.8 Hz), 3.88 (2H, s), 4.14 (2H,
t, J = 4.8 Hz), 6.84-6.94 (4H, m), 7.08 (1H, s),
7.30-7.41 (4H, m), 7.92 (1H, s), 8.13 (1H, s), 8.2
8-8.32 (1H, m), 10.14 (1H, br). IR (KBr) n: 2961, 2934, 2870, 1663, 1599, 1539, 15
20, 1501 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₈ F ₃ N ₅ O ₄ S: C, 63.90; H, 6.43;
N, 9.31. Found C, 63.63; H, 6.31; N, 9.55.

Example 40 (Production of compound 44) 7- [4- (2-butoxyethoxy) phenyl] -2,
3-Dihydro-1-benzoxepin-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.14 ml), N, N- under ice cooling.
Dimethylformamide (catalytic amount) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off to obtain acid chloride. Benzyl chloroformate (0.18 ml) was combined with 4-mercapto-3-chloroaniline (0.2 g) and triethylamine (0.8 g).
7 ml) in tetrahydrofuran (10 ml)-
The mixture was added dropwise at 78 ° C and stirred for 1 hour. Then, a solution of the above acid chloride in tetrahydrofuran (10 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. 1N aqueous sodium hydroxide solution (8.5 ml) and methanol (10 ml) were added,
Stir for 30 minutes at room temperature. 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.2
5 g) was added and the mixture was stirred at room temperature overnight. It was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate),
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-chloro-4-[(4-propyl-4H-1,2,4-triazol-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (compound 44) (0.
37 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.82-1.00 (12H, m), 1.17-1.66
(6H, m), 2.04-2.15 (1H, m), 2.94 (2H, t-like), 3.
18 (2H, d, J = 7.6 Hz), 3.32 (2H, t-like), 3.56 (2
H, t, J = 6.5 Hz), 3.67 (2H, t, J = 7.7 Hz), 3.79-
3.83 (4H, m), 4.14 (2H, t, J = 5.0 Hz), 6.85-7.03
(4H, m), 7.17 (1H, s), 7.31-7.40 (4H, m), 7.53 (1H,
dd, J = 2.2, 8.4 Hz), 7.84 (1H, s), 8.06 (1H, d,
J = 2.2 Hz), 9.70 (1H, br). IR (KBr) n: 2957, 2934, 2868, 1653, 1607, 1580, 14
99 cm ^-1 .

Example 41 (Production of Compound 45) 7- [4- (2-propoxyethoxy) phenyl] -1
-Propyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.5 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.35 ml) was added and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (950 mg), triethylamine (2.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (18.3 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-propylimidazole hydrochloride (928 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 7- [4- (2-propoxyethoxy) phenyl] -1- as yellow crystals. Propyl-N-
[4-[[[1-Propylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (1.63
g) (Compound 45) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91-1.01 (9H, m), 1.53-
1.93 (6H, m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.
0 Hz), 3.28-3.36 (4H, m), 3.51 (2H, t, J = 6.6Hz),
3.81 (2H, t, J = 4.4 Hz), 3.93 (2H, t, J = 7.4 Hz), 3.
99 (2H, s), 4.16 (2H, t, J = 4.4 Hz), 6.70 (1H, s),
6.90 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.
25-7.30 (2H, m), 7.36-7.55 (8H, m), 7.63 (1H, s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 70.94; H,
7.28; N, 8.71; Found. C, 70.93; H, 7.22; N, 8.
69.

Example 42 (Production of Compounds 46 and 47) 7- [4- (2-propoxyethoxy) phenyl] -1
-Propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl] phenyl]-
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (579 mg) in dichloromethane (15 ml) at -78 ° C. . After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-propoxyethoxy) phenyl] -1-propyl as a yellow amorphous substance. -N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (693 mg) (Compound 46), 7- [4- (2-propoxyethoxy) phenyl] -1-propyl-N- [4- [[[1-Propylimidazol-5-yl] methyl] sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-
Carboxamide (48 mg) (Compound 47) was obtained. Compound 46 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.03 (9H, m), 1.56-
1.81 (6H, m), 2.90-2.95 (2H, m), 3.30-3.40 (4H,
m), 3.51 (2H, t, J = 6.6 Hz), 3.74-3.84 (4H, m), 4.02
(1H, d, J = 13.2 Hz), 4.07-4.19 (3H, m), 6.57 (1H,
s), 6.91 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz),
7.37-7.51 (8H, m), 7.74 (2H, d, J = 8.8Hz), 7.87 (1
H, s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 69.22; H,
7.11; N, 8.50; Found. C, 69.03; H, 6.97; N, 8.
47. Compound 47 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.03 (9H, m), 1.59-
1.81 (6H, m), 2.85-2.95 (2H, m), 3.25-3.40 (4H,
m), 3.51 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.4Hz),
3.95 (2H, t, J = 7.6 Hz), 4.16 (2H, t, J = 4.4 Hz),
4.32 (2H, s), 6.53 (1H, s), 6.90 (1H, d, J = 8.8 Hz),
6.98 (2H, d, J = 8.8 Hz), 7.40-7.50 (6H, m), 7.60 (2
H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.8 Hz), 8.02 (1H,
s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₅ S Calcd. C, 68.03; H, 6.91;
N, 8.35; Found. C, 67.73; H, 6.85; N, 8.13.

Example 43 (Production of compound 48) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (600 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.13 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). 4 this solution
-[(1-Methylimidazol-2-yl) thio] aniline (365 mg), triethylamine (1.3 ml)
Was added dropwise to a THF (15 ml) solution at 0 ° C. under a nitrogen atmosphere. After the dropping, return to room temperature and under a nitrogen atmosphere,
After stirring overnight, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, basic silica gel column chromatography (hexane-ethyl acetate = 1: 1).
Separated and purified in 4) to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[1-methylimidazol-2-yl]
Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (716 mg) (Compound 48) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.98 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.75 (2H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.2 Hz), 3.30
-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.63 (3H,
s), 3.80 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 H
z), 6.91 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 H
z), 7.05 (1H, d, J = 1.4 Hz), 7.16-7.21 (3H, m), 7.3
7-7.53 (7H, m), 7.64 (1H, s). Elemental analysis C ₃₇ H ₄₄ N ₄ O ₃ S Calcd. C, 71.12; H, 7.10;
N, 8.97; Found. C, 70.81; H, 7.07; N, 8.89.

Example 44 (Production of compound 49) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.
26 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and 4- [2-
(4-Propyl-4H-1,2,4-triazole-3
-Yl) Ethylthio] aniline (0.6 g) was added dropwise to a pyridine (10 ml) solution under ice cooling. The mixture was stirred overnight at room temperature and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- [2- (4-propyl-4H-1,2,4
-Triazol-3-yl) ethylthio] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 49) (1.49 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-0.98
(12H, m), 1.33-1.45 (2H, m), 1.54-1.77 (4H, m), 1.
98-2.58 (1H, m), 2.91-2.98 (4H, m), 3.17 (2H, d, J
= 7.2 Hz), 3.32-3.40 (4H, m), 3.55 (2H, t, J = 6.6
Hz), 3.71 (2H, t, J = 7.3 Hz), 3.80 (2H, t, J = 4.
7 Hz), 4.15 (2H, t, J = 4.7 Hz), 6.88-6.99 (3H, m),
7.34-7.47 (7H, m), 7.61 (2H, d, J = 8.8 Hz), 8.00
(1H, s), 8.04 (1H, s). IR (KBr) n: 2959, 2930, 2870, 1659, 1588, 1499 cm
^-1 .

Example 45 (Production of compound 50) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- [2- (4-propyl-4H-
1,2,4-Triazol-3-yl) ethylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.1 g) was dissolved in dichloromethane (40 ml) and the temperature was adjusted to −78 ° C. Cooled. 3-chloroperbenzoic acid (0.6 g) in dichloromethane (10 m
l) The solution was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- [2
-(4-Propyl-4H-1,2,4-triazole-
3-yl) ethylsulfinyl] phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 50) (0.94 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.86-0.99 (12H, m), 1.30-1.45
(2H, m), 1.58-1.77 (4H, m), 1.95-2.15 (1H, m), 2.
87-3.05 (3H, m), 3.10-3.35 (4H, m), 3.37 (2H, t-li
ke), 3.45-3.65 (3H, m), 3.78-3.83 (4H, m), 4.14-4.
18 (2H, m), 6.90-7.00 (3H, m), 7.39-7.48 (5H, m),
7.61 (2H, d, J = 8.6 Hz), 7.83 (2H, d, J = 8.6 Hz),
8.02 (1H, s), 8.15 (1H, br). IR (KBr) n: 2961, 2932, 2872, 1661, 1590, 1518, 14
99 cm ^-1 .

Example 46 (Production of Compound 51) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.7 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.1 g) was added under ice cooling.
8 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (20 ml), and 4- [2-
(4-Propyl-4H-1,2,4-triazole-3
-Yl) Ethylthio] aniline (0.43 g) was added dropwise to a pyridine (10 ml) solution under ice cooling. The mixture was stirred overnight at room temperature and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4-
(2-Butoxyethoxy) phenyl] -1-propyl-
N- [4- [2- (4-propyl-4H-1,2,4-
Triazol-3-yl) ethylthio] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 51) (0.9 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.88-1.03 (9H, m), 1.30-1.45
(2H, m), 1.54-1.81 (6H, m), 2.91-3.02 (4H, m), 3.2
8-3.43 (6H, m), 3.55 (2H, t, J = 6.6 Hz), 3.72-3.8
3 (4H, m), 4.16 (2H, t, J = 4.9 Hz), 6.90 (1H, d,
J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.36-7.48
(7H, m), 7.57 (2H, d, J = 8.8 Hz), 7.67 (1H, br),
8.03 (1H, s) .IR (KBr) n: 2963, 2934, 2876, 1655, 1499 cm ^-1 .

Example 47 (Production of compound 52) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4- [2- (4-propyl-4H-
1,2,4-Triazol-3-yl) ethylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml) and the temperature was adjusted to -78 ° C. Cooled. 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 m
l) The solution was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4- [2- [2-
(4-Propyl-4H-1,2,4-triazole-3
-Yl) ethylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 52) (0.43 g) was obtained as pale yellow crystals. mp 93-101 ° C. ¹ H-NMR (dppm, CDCl ₃ ) 0.91-1.02 (9H, m), 1.36-1.43
(2H, m), 1.56-1.66 (2H, m), 1.72-1.80 (4H, m), 2.9
1-2.99 (3H, m), 3.19-3.37 (6H, m), 3.53-3.57 (3H,
m), 3.79-3.86 (4H, m), 4.16 (2H, t, J = 5.9 Hz),
6.90 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.7 Hz),
7.40-7.49 (5H, m), 7.62 (2H, d, J = 9.0 Hz), 7.81
(2H, d, J = 8.7 Hz), 7.93 (1H, br), 8.04 (1H, s) .IR (KBr) n: 2963, 2932, 2870, 1661, 1590, 1520, 14
99 cm ^-1 . Anal.calcd.for C ₃₉ H ₄₉ N ₅ O ₄ S ・ 0.25H ₂ O: C, 68.04; H,
7.25; N, 10.17. FoundC, 67.82; H, 7.24; N, 10.13.

Example 48 (Production of compound 53) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.79 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.
2 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), and 5-amino-
2- (4-Propyl-4H-1,2,4-triazol-3-yl) methylthiopyridine (0.45 g) was added dropwise to a pyridine (10 ml) solution under ice cooling. The mixture was stirred overnight at room temperature and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [2- (4-propyl-4H-1,2,4-triazol-3-yl) methylthiopyridin-5-yl] -2,3- Dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 53) (1.1 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.84-1.22 (12H, m), 1.54-1.85
(4H, m), 2.03-2.14 (1H, m), 2.92 (2H, t-like), 3.
18 (2H, d, J = 7.4 Hz), 3.34 (2H, t-like), 3.55 (2
H, t, J = 6.6 Hz), 3.78-3.90 (4H, m), 4.13-4.17 (2
H, m), 4.54 (2H, s), 6.88-6.99 (3H, m), 7.18 (1H,
d, J = 8.8 Hz), 7.36-7.46 (5H, m), 7.93 (1H, dd, J
= 2.6, 8.4 Hz), 7.98 (1H, s), 8.58 (1H, br), 8.75
(1H, s) .IR (KBr) n: 2959, 2932, 2870, 1659, 1499
cm ^-1 .

Example 49 (Production of compound 54) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [2- (4-propyl-4H-1,
2,4-Triazol-3-yl) methylthiopyridin-5-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 g) was dissolved in dichloromethane (50 ml), and the temperature was -78 ° C. Cooled to. Three
A solution of chloroperbenzoic acid (0.31 g) in dichloromethane (5 ml) was added dropwise. After stirring at -78 ° C for 2 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer is an aqueous sodium hydrogen carbonate solution,
It was washed with water and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [2
-(4-Propyl-4H-1,2,4-triazole-
3-yl) methylsulfinylpyridin-5-yl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 54) (0.70 g) was obtained as yellow crystals. mp 135-138 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.77 (3H, t, J = 7.6 Hz), 0.9
3 (3H, t, J = 7.1 Hz), 1.06 (6H, d, J = 6.2 Hz), 1.
34-1.68 (6H, m), 2.05-2.25 (1H, m), 2.85-3.40 (5H,
m), 3.45-3.75 (3H, m), 3.55 (2H, t, J = 6.6 Hz),
3.80 (2H, t, J = 5.0 Hz), 3.82-4.07 (2H, m), 4.14
(2H, t, J = 5.0 Hz), 6.85-6.94 (4H, m), 7.24-7.40
(5H, m), 7.92 (1H, s), 8.00 (1H, d, J = 8.4 Hz),
9.61 (1H, s), 10.17 (1H, br). IR (KBr) n: 2959, 2934, 2870, 1667, 1607, 1574, 15
18, 1499 cm ^-1 . Anal.calcd.for C ₃₈ H ₄₈ N ₆ O ₄ S: C, 66.64; H, 7.06;
N, 12.27.Found C, 66.33; H, 6.88; N, 12.21.

Example 50 (Production of compound 55 and compound 56) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [2- (4-propyl-4H-1,
2,4-Triazol-3-yl) methylsulfinylpyridin-5-yl] -2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (0.39 g) was optically resolved using CHIRALPAK AD (ethanol / isopropyl alcohol) to give (+)-7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [2- (4-propyl-4H-1,2,4-triazol-3-yl) methylsulfinylpyridine-5
-Yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 55) (0.18 g,
99.9% ee), (-)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [2-
(4-Propyl-4H-1,2,4-triazole-3
-Yl) methylsulfinylpyridin-5-yl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 56) (0.18 g, 99.8%)
ee) was obtained. (+)-Body: [α] _D = + 235.0 ° (C = 0.50)
(0%, ethanol solution) (-)-form: [α] _D = -238.9 ° (C = 0.49)
3%, ethanol solution)

Example 51 (Production of compound 57) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.76 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.2
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), and 5-amino-2 was used.
-(4-Propyl-4H-1,2,4-triazole-
A solution of 3-yl) methylthiopyridine (0.45 g) in pyridine (10 ml) was added dropwise under ice cooling. The mixture was stirred overnight at room temperature and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4-
(2-Butoxyethoxy) phenyl] -1-propyl-
N- [2- (4-propyl-4H-1,2,4-triazol-3-yl) methylthiopyridin-5-yl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 57) (1.1 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.86-1.02 (9H, m), 1.30-1.45
(2H, m), 1.54-1.80 (6H, m), 2.91 (2H, t-like), 3.2
8-3.35 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.9
1 (4H, m), 4.15 (2H, t, J = 4.8 Hz), 4.56 (2H, s),
6.18 (1H, d, J = 9.2 Hz), 6.97 (2H, d, J = 8.8 H
z), 7.19 (1H, d, J = 8.4 Hz), 7.38-7.46 (5H, m), 7.
92 (1H, dd, J = 2.6, 8.8 Hz), 8.00 (1H, br), 8.72
(1H, d, J = 2.4 Hz) .IR (KBr) n: 2961, 2934, 2872, 1659, 1501 cm ^-1 .

Example 52 (Production of compound 58) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [2- (4-propyl-4H-1,2,2
4-triazol-3-yl) methylthiopyridin-5
-Yl] -2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.60 g) was dissolved in dichloromethane (50 ml) and cooled to -78 ° C. 3-chloroperbenzoic acid (0.27 g) in dichloromethane (5 m
l) The solution was added dropwise. After stirring at -78 ° C for 1.5 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer is an aqueous sodium hydrogen carbonate solution,
It was washed with water and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [2-
(4-Propyl-4H-1,2,4-triazole-3
-Yl) methylsulfinylpyridin-5-yl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 58) (0.50 g) was obtained as yellow crystals. ¹ H-NMR (dppm, CDCl ₃ ) 0.78 (3H, t, J = 7.3 Hz), 0.9
3 (3H, t, J = 7.3 Hz), 1.06 (3H, t, J = 7.4 Hz), 1.
30-1.88 (10H, m), 2.90-3.71 (8H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.79 (2H, t, J = 5.0 Hz), 3.90 (1H,
d, J = 14.2 Hz), 4.03 (1H, d, J = 14.2 Hz), 4.13 (2
H, t, J = 5.0 Hz), 6.86-6.94 (4H, m), 7.25-7.46 (5
H, m), 7.93 (1H, s), 7.99 (1H, dd, J = 2.0, 8.8 H
z), 9.60 (1H, d, J = 2.0 Hz), (1H, s), 10.06 (1H,
s) .IR (KBr) n: 2959, 2932, 2872, 1669, 1607, 1518, 14
99 cm ^-1 . Anal.calcd. For C ₃₇ H ₄₆ N ₆ O ₄ S: C, 66.24; H, 6.91;
N, 12.53. Found C, 66.06; H, 6.96; N, 12.29.

Example 53 (Production of compound 59, compound 60) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [2- (4-propyl-4H-1,2,2
4-triazol-3-yl) methylsulfinylpyridin-5-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.39 g) in CH
Optical resolution was performed using IRALPAK AD (ethanol / isopropyl alcohol), and (+)-7- [4- (2
-Butoxyethoxy) phenyl] -1-propyl-N-
[2- (4-Propyl-4H-1,2,4-triazol-3-yl) methylsulfinylpyridin-5-yl] -2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 59) (0.16 g,> 9
9.9% ee), (-)-7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [2- (4-
Propyl-4H-1,2,4-triazol-3-yl) methylsulfinylpyridin-5-yl] -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 60) (0.16 g, 99.4% ee)
Got (+)-Body: [α] _D = + 245.5 ° (C = 0.47)
3%, ethanol solution) (-)-form: [α] _D = -254.6 ° (C = 0.49)
1%, ethanol solution)

Example 54 (Production of Compound 61) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (5 ml) and thionyl chloride (0.13
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and 4- [2- (1
-Propylimidazol-2-yl) ethyl] aniline (0.27 g) and triethylamine (0.82 ml) were added dropwise to a tetrahydrofuran (5 ml) solution under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. Add water,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue is subjected to silica gel column chromatography (elution solvent: triethylamine / methanol / ethyl acetate),
Purify by basic silica gel column chromatography (elution solvent: ethyl acetate / hexane) to obtain 7- [4- (2
-Butoxyethoxy) phenyl] -1-propyl-N-
[4- [2- (1-propylimidazol-2-yl)
Ethyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 61)
(0.36 g) was obtained as a pale yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-1.03 (9H, m), 1.30-1.45
(2H, m), 1.54-1.81 (6H, m), 2.87-2.95 (4H, m), 3.0
5-3.13 (2H, m), 3.28-3.32 (4H, m), 3.55 (2H, t, J
= 6.6 Hz), 3.67 (2H, t, J = 7.1Hz), 3.80 (2H, t,
J = 5.0 Hz), 4.14 (2H, t, J = 5.0 Hz), 6.80 (1H,
s), 6.90 (1H, d, J = 8.8Hz), 6.95-7.01 (3H, m), 7.1
6 (2H, d, J = 8.4 Hz), 7.38-7.54 (8H, m). IR (KBr) n: 2961, 2938, 2870, 1655, 1605, 1516 cm
^-1 .

Example 55 (Production of compound 62) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.52 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.1
3 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), and 4- [N-methyl-N-[(1-propylimidazol-2-yl) was used.
Methyl] amino] aniline (0.3 g), triethylamine (0.86 ml) in tetrahydrofuran (10 m
l) The solution was added dropwise under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4
-[N-methyl-N-[(1-propylimidazole-
2-yl) methyl] amino] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 62) (0.51 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.83-1.02 (9H, m), 1.34-1.45
(2H, m), 1.54-1.80 (6H, m), 2.81 (3H, s), 2.85-2.9
5 (2H, m), 3.27-3.35 (4H, m), 3.55 (2H, t, J = 6.6
Hz), 3.78-3.87 (4H, m), 4.13-4.15 (2H, m), 4.46 (2
H, s), 6.86-6.99 (7H, m), 7.37-7.55 (8H, m) .IR (KBr) n: 2959, 2872, 1651, 1607, 1520, 1499 cm
^-1 .

Example 56 (Production of compound 63) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.
13 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (25 ml), and 4- [3-
(4H-1,2,4-triazol-4-yl) propyl] aniline (0.23 g) and 4-dimethylaminopyridine (catalytic amount) in pyridine (10 ml) were added dropwise under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: triethylamine /
Purified with methanol / ethyl acetate), 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4- [3- (4H-1,2,4-triazole-4-
Il) propyl] phenyl] -2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (Compound 6
3) (0.51 g) was obtained as yellow crystals. mp 165-167 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.89-0.99 (9H, m), 1.26-1.65
(4H, m), 2.05-2.19 (3H, m), 2.64 (2H, t, J = 7.1 H
z), 2.92 (2H, t-like), 3.19 (2H, d, J = 7.2Hz), 3.
37 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2
H, t, J = 5.1 Hz), 3.99 (2H, t, J = 7.2 Hz), 4.16
(2H, t, J = 5.1 Hz), 6.90-7.00 (3H, m), 7.13 (2H,
d, J = 8.4 Hz), 7.39-7.61 (7H, m), 8.14 (2H, s) .IR (KBr) n: 2953, 1651, 1607, 1516, 1499 cm ^-1 . Anal.calcd. for C ₃₈ H ₄₇ N ₅ O ₃ : C, 73.40; H, 7.62; N,
11.26. Found C, 73.10; H, 7.47; N, 11.28.

Example 57 (Production of Compound 64) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (7.5 ml), and thionyl chloride (0.
15 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (20 ml), and 4- [3-
(4H-1,2,4-triazol-4-yl) propyl] aniline (0.24 g) and 4-dimethylaminopyridine (catalytic amount) in a pyridine (5 ml) solution were added dropwise under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4
-[3- (4H-1,2,4-triazol-4-yl) propyl] phenyl] -2,3-dihydro-1H-
1-Benzazepine-4-carboxamide (Compound 6
4) (0.53 g) was obtained as pale yellow crystals. mp 191-194 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.90-1.03 (6H, m), 1.30-1.48
(2H, m), 1.54-1.81 (4H, m), 2.09-2.23 (2H, m), 2.6
4 (2H, t, J = 7.4 Hz), 2.92 (2H, t-like), 3.29-3.3
5 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t,
J = 5.0 Hz), 4.00 (2H, t, J = 7.2 Hz), 4.16 (2H,
t, J = 5.0 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.98 (2
H, d, J = 8.8 Hz), 7.38-7.57 (8H, m), 8.14 (2H,
s) .IR (KBr) n: 2959, 1653, 1605, 1516, 1501 cm ^-1 . Anal.calcd. for C ₃₇ H ₄₅ N ₅ O ₃ : C, 73.12; H, 7.46; N,
11.52. Found C, 72.76; H, 7.53; N, 11.33.

Example 58 (Preparation of compound 65) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.61 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.
15 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (25 ml), and 4-[(4
-Propyl-1H-1,2,4-triazol-5-on-3-yl) methylthio] aniline (0.35 g) was added dropwise to a pyridine (10 ml) solution under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), 7
-[4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(4-propyl-1H-1,
2,4-Triazol-5-one-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 65) (0.6
9 g) was obtained as pale yellow crystals. mp 98-101 ° C. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-0.99 (12H, m), 1.22-1.48
(2H, m), 1.54-1.82 (4H, m), 1.95-2.15 (1H, m), 2.
88 (2H, t-like), 3.16 (2H, d, J = 7.2 Hz), 3.32 (2
H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.67-3.85 (6
H, m), 4.15 (2H, t, J = 5.0 Hz), 6.87-6.98 (3H,
m), 7.31-7.46 (7H, m), 7.57 (2H, d, J = 8.8 Hz), 7.
83 (1H, s), 9.31 (1H, s). IR (KBr) n: 2959, 2934, 2868, 1703, 1499 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₄ S: C, 68.49; H, 7.22;
N, 10.24. Found C, 68.21; H, 7.17; N, 10.10.

Example 59 (Preparation of compound 66) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(4-propyl-1H-1,
2,4-triazol-5-on-3-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxami (0.50 g) was dissolved in dichloromethane (30 ml) and -78 was added. Cooled to ° C. Three
A solution of chloroperbenzoic acid (0.22g) in dichloromethane (5ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer is an aqueous sodium hydrogen carbonate solution,
It was washed with water and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4
-[(4-Propyl-1H-1,2,4-triazol-5-on-3-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 66) (0.45 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-1.04 (12H, m), 1.22-1.70
(6H, m), 2.00-2.15 (1H, m), 2.90 (2H, t-like), 3.
18 (2H, d, J = 7.2 Hz), 3.35 (2H, t-like), 3.52-3.
61 (4H, m), 3.80 (2H, t-like), 3.97 (2H, s), 4.15
(2H, t, J = 4.9Hz), 6.89-6.99 (3H, m), 7.36-7.52
(7H, m), 7.29 (2H, d, J = 8.8 Hz), 8.03 (1H, s),
9.53 (1H, s) .IR (KBr) n: 2959, 2936, 2874, 1705 cm ^-1 . Anal.calcd. For C ₃₉ H ₄₉ N ₅ O ₅ S ・ 0.25H ₂ O: C, 66.50; H,
7.08; N, 9.94.FoundC, 66.18; H, 6.93; N, 9.93.

Example 60 (Production of Compound 67) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.95 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.
23 ml), N, N-dimethylformamide (catalytic amount)
Was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and 3-amino-6-[(4-propyl-1H-1,2,4-triazol-3-yl) methylthio] pyridazine (0.5
2 g) was added dropwise to a solution of pyridine (20 ml) under ice cooling. The mixture was stirred overnight at room temperature and the solvent was distilled off. Water was added and the mixture was extracted with ethyl acetate. The organic layer is a 1N aqueous citric acid solution,
The extract 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 (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(4-propyl-
1H-1,2,4-triazol-3-yl) methylthio] pyridazin-3-yl] -2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (Compound 6
7) (0.22g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.86-0.99 (12H, m), 1.34-1.46
(2H, m), 1.57-1.66 (2H, m), 1.79-1.89 (2H, m), 2.
05-2.11 (1H, m), 2.93 (2H, t-like), 3.21 (2H, d, J
= 7.2 Hz), 3.39 (2H, t-like), 3.56 (2H, t, J = 6.
6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.04 (2H, t, J =
7.2 Hz), 4.17 (2H, t, J = 5.0 Hz), 4.78 (2H, s),
6.93 (1H, d, J = 8.7 Hz), 6.99 (2H, d, J = 9.0 H
z), 7.41-7.49 (4H, m), 7.53 (1H, d, J = 2.1 Hz),
7.60 (1H, s), 8.12 (1H, s), 8.46 (1H, d, J = 9.6 H
z), 8.60 (1H, s) .IR (KBr) n: 2957, 2934, 2872, 1663, 1605, 1499 cm
^-1 .

Example 61 (Production of compound 68) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[(4-propyl-1H-1,
2,4-Triazol-3-yl) methylthio] pyridazin-3-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.18 g) was dissolved in dichloromethane (20 ml) and -78 was added. Cooled to ° C. A solution of 3-chloroperbenzoic acid (0.08 g) in dichloromethane (5 ml) was added dropwise. After stirring at -78 ° C for 2 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography (elution solvent: triethylamine /
Purified with methanol / ethyl acetate), 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[6-[(4-Propyl-1H-1,2,4-triazol-3-yl) methylsulfinyl] pyridazine-3
-Yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 68) (0.14 g)
Was obtained as a yellow amorphous solid. ¹ H-NMR (dppm, CDCl3) 0.86-1.08 (12H, m), 1.29-1.48
(2H, m), 1.54-1.67 (2H, m), 1.72-1.90 (2H, m), 2.
04-2.15 (1H, m), 2.94 (2H, br), 3.19 (2H, d, J = 7.
4 Hz), 3.37 (2H, br), 3.54 (2H, t, J = 6.5 Hz), 3.
80 (2H, t, J = 4.8 Hz), 3.95-4.18 (4H, m), 4.44 (1
H, d, J = 14.2 Hz), 4.66 (1H, d, J = 14.2 Hz), 6.89
-7.00 (3H, m), 7.34-7.51 (4H, m), 7.67 (2H, d, J
= 9.6 Hz), 8.14 (1H, s), 8.67 (1H, d, J = 9.0 H
z), 9.62 (1H, s) .IR (KBr) n: 2950, 2872, 1671 cm ^-1 .

Example 62 (Production of compound 69) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.92 g) was dissolved in tetrahydrofuran (10 ml), and thionyl chloride (0.22 ml) and N, N-dimethylformamide were dissolved under ice cooling. (Catalyst amount) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (10 ml),
3-Amino-6-[(3-propylimidazol-4-
It was added dropwise to a solution of (yl) methylthio] pyridazine (0.5 g) in pyridine (15 ml) under ice cooling. The mixture was stirred overnight at room temperature and the solvent was distilled off. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue (elution solvent: methanol / ethyl acetate / triethylamine)
And purified with 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(3-propylimidazol-4-yl) methylthio] pyridazine-3-.
Il] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 69) (0.3 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.91-0.99 (12H, m), 1.34-1.46
(2H, m), 1.56-1.66 (2H, m), 1.78-1.87 (2H, m), 2.
05-2.11 (1H, m), 2.94 (2H, t, J = 4.5 Hz), 3.20 (2
H, d, J = 7.5 Hz), 3.39 (2H, t, J = 4.5 Hz), 3.55
(2H, t, J = 6.8Hz), 3.81 (2H, t, J = 5.0Hz), 3.93
(2H, t, J = 7.2 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.5
8 (2H, s), 6.91-7.04 (4H, m), 7.31 (1H, d, J = 9.
5 Hz), 7.41-7.53 (5H, m), 7.62 (1H, s), 8.42 (1H,
d, J = 9.5 Hz), 8.78 (1H, br). IR (KBr) n: 2959, 2870, 1661, 1499 cm ^-1 .

Example 63 (Production of compound 70) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[(3-propylimidazol-4-yl) methylthio] pyridazin-3-yl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was added to dichloromethane (10 m).
It was dissolved in 1) and cooled to -78 ° C. A solution of 3-chloroperbenzoic acid (0.38 g) in dichloromethane (5 ml) was added dropwise. After stirring at -78 ° C for 4 hours, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate.
The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(3-propylimidazole -4-yl) Methylsulfinyl] pyridazin-3-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 70)
(0.14 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.89-1.00 (12H, m), 1.34-1.44
(2H, m), 1.54-1.81 (4H, m), 2.05-2.13 (1H, m), 2.
96 (2H, t-like), 3.21 (2H, d, J = 7.4 Hz), 3.40 (2
H, t-like), 3.55 (2H, t, J = 6.5 Hz), 3.80 (2H, t,
J = 5.0 Hz), 3.88-4.01 (2H, m), 4.17 (2H, t, J =
5.0 Hz), 4.23 (1H, d, J = 7.4 Hz), 4.50 (1H, d, J
= 7.4 Hz), 6.52 (1H, d, J = 0.6 Hz), 6.91-7.02 (3
H, m), 7.41-7.53 (5H, m), 7.63 (1H, s), 7.72 (1
H, d, J = 9.5 Hz), 8.69 (1H, d, J = 9.5 Hz), 9.37
(1H, br). IR (KBr) n: 2961, 2930, 2870, 1667, 1607, 1559, 14
99 cm ^-1 .

Example 64 (Preparation of compound 71) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.6 g) was dissolved in tetrahydrofuran (5 ml) and thionyl chloride (0.1 g) was added under ice cooling.
5 ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (5 ml), and S was added under ice cooling.
-(4-Aminophenyl) -o-benzylthiocarbonate (0.36 g) and triethylamine (1 ml) were added dropwise to a solution of tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 4 hours, and a 1N sodium hydroxide aqueous solution (7 m
1) and methanol (7 ml) were added, and the mixture was stirred at room temperature for 1 hour. Then, 4-chloromethyl-3-methylimidazole hydrochloride (0.24 g) was added, and the mixture was stirred at room temperature overnight.
After concentration, it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate / triethylamine), and 7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-N- [4-[(3-methylimidazol-4-yl) methylthio] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 71) (0.61 g) was obtained as a pale yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.89-0.99 (9H, m), 1.33-1.48
(2H, m), 1.54-1.68 (2H, m), 2.00-2.10 (1H, m), 2.9
1 (2H, t-like), 3.19 (2H, d, J = 7.2 Hz), 3.35 (2
H, t-like), 3.55 (2H, t, J = 6.8 Hz), 3.65 (3H,
s), 3.80 (2H, t, J = 4.8 Hz), 3.99 (2H, s), 4.16 (2
H, t, J = 4.9 Hz), 6.71 (1H, s), 6.89-7.00 (3H,
m), 7.25-7.29 (2H, m), 7.40-7.56 (8H, m), 7.65 (1
H, br). IR (KBr) n: 2955, 2867, 1655, 1605, 1586, 1499 cm
^-1 .

Example 65 (Production of compound 72) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-methylimidazole-
4-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) was dissolved in dichloromethane (5 ml),
Cooled to -78 ° C. 3-chloroperbenzoic acid (0.31
A solution of g) in dichloromethane (5 ml) was added dropwise. -7
After stirring at 8 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate),
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-methylimidazole-
4-yl) methylsulfinyl] phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 72) (0.36 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.89-0.99 (9H, m), 1.30-1.48
(2H, m), 1.54-1.68 (2H, m), 2.05-2.15 (1H, m), 2.9
3 (2H, t-like), 3.19 (2H, d, J = 7.0 Hz), 3.36 (2
H, t-like), 3.44 (3H, s), 3.55 (2H, t, J = 6.6 H
z), 3.80 (2H, t, J = 5.0 Hz), 3.95 (1H, d, J = 7.2
Hz), 4.14-4.17 (3H, m), 6.60 (1H, s), 6.92 (1H, d,
J = 8.4 Hz), 6.97 (2H, d, J = 8.4 Hz), 7.30-7.47
(8H, m), 7.77 (2H, d, J = 8.8 Hz), 8.28 (1H, br). IR (KBr) n: 2955, 2930, 2870, 1663, 1605, 1588, 14
99 cm ^-1 .

Example 66 (Production of Compound 73) 7- [4- (2-Butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.25
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and S- was added under ice cooling.
(4-Aminophenyl) -o-benzylthiocarbonate (0.6 g) and triethylamine (1 ml) were added dropwise to a solution of tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 4 hours, and a 1N sodium hydroxide aqueous solution (12.5 m
1), methanol (25 ml) and tetrahydrofuran (15 ml) were added, and the mixture was stirred at room temperature for 4 hours. Then 4
-Chloromethyl-3-cyclopropylimidazole hydrochloride (0.57 g) was added, and the mixture was stirred at room temperature overnight. After concentration, it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate / triethylamine), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-cyclopropyl Imidazol-4-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 73) (0.34 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.90-1.06 (13H, m), 1.30-1.45
(2H, m), 1.54-1.68 (2H, m), 2.05-2.10 (1H, m), 2.
91 (2H, t-like), 3.19 (2H, d, J = 7.6 Hz), 3.21-3.
34 (1H, m), 3.36 (2H, t-like), 3.55 (2H, t, J = 6.
6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.07-4.18 (4H, m),
6.67 (1H, s), 6.92 (1H, d, J = 8.8Hz), 6.98 (2H,
d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.38-7.
57 (8H, m), 7.72 (1H, br). IR (KBr) n: 2957, 2928, 2870, 1657, 1605, 1588, 14
97 cm ^-1 .

Example 67 (Production of compound 74) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-cyclopropylimidazol-4-yl) methylthio] phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (0.3g) was dissolved in dichloromethane (10ml) and cooled to -78 ° C. 3-chloroperbenzoic acid (0.
A solution of 17 g) in dichloromethane (5 ml) was added dropwise.
After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline.
It was dried with anhydrous magnesium sulfate and the solvent was distilled off.
The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), 7- [4- (2-butoxyethoxy) phenyl]
-1-Isobutyl-N- [4-[(3-cyclopropylimidazol-4-yl) methylsulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 74) (0.22 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-1.07 (13H, m), 1.33-1.46
(2H, m), 1.56-1.66 (2H, m), 1.98-2.11 (1H, m), 2.
93-3.00 (3H, m), 3.19 (2H, d, J = 6.9 Hz), 3.36 (2
H, s), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J =
4.8 Hz), 4.09-4.26 (4H, m), 6.57 (1H, s), 6.92 (1
H, d, J = 8.7 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.37-
7.48 (8H, m), 7.77 (2H, d, J = 8.1 Hz), 8.06 (1H,
br). IR (KBr) n: 2959, 2930, 2870, 1663, 1607, 1588, 15
18, 1499 cm ^-1 .

Example 68 (Production of compound 75) 7- [4- (2-butoxyethoxy) phenyl] -1-
Formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg), 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml)
1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (0.20 g) was added to the solution at room temperature, and the mixture was stirred for 1 hour. In the reaction system, (S)-(4-aminophenyl)-(2-pyridyl) methanol (150 m
g) and triethylamine (0.28 ml) in DMF
(10 ml) was added dropwise to the solution. After stirring at room temperature for 4 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate), and recrystallized from ethyl acetate-diisopropyl ether to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-formyl-
N- [4-[(S) -Hydroxy (2-pyridyl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 75) (247)
mg) was obtained. mp 130-134 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
30-1.48 (2H, m), 1.53-1.68 (2H, m), 3.02 (2H, t, J
= 5.5 Hz), 3.56 (2H, t, J = 6.4 Hz), 3.82 (2H, t, J = 5.
0 Hz), 3.91 (2H, t, J = 5.5 Hz), 4.18 (2H, t, J = 5.0
Hz), 5.32 (1H, d, J = 4.1 Hz), 5.75 (1H, d, J = 4.1 H
z), 7.02 (2H, d, J = 8.4 Hz), 7.12-7.24 (3H, m), 7.36
-7.67 (11H, m), 8.54 (1H, s), 8.56-8.59 (1H, m). IR (KBr) 3343, 1664, 1601, 1597, 1514, 1497, 1360,
1314, 1248, 1190, 824cm ^-1 Elemental analysis C ₃₆ H ₃₇ N ₃ O ₅ Calcd. C, 73.08; H, 6.30;
N, 7.10: Found. C, 72.72; H, 6.27; N, 7.04.

Example 69 (Production of compound 76) 7- [4- (2-butoxyethoxy) phenyl] -1-
Formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg), 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml)
1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (0.20 g) was added to the solution at room temperature, and the mixture was stirred for 0.5 hours. In the reaction system, (R)-(4-aminophenyl)-(2-pyridyl) methanol (150
mg) and triethylamine (0.28 ml) in DMF
(10 ml) was added dropwise to the solution. After stirring at room temperature for 3 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate), and recrystallized from ethyl acetate-diisopropyl ether to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-formyl-
N- [4-[(R) -Hydroxy (2-pyridyl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 76) (15
4.5 mg) was obtained. mp 110-112 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
30-1.48 (2H, m), 1.53-1.68 (2H, m), 3.02 (2H, t, J
= 5.5 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 5.
0 Hz), 3.91 (2H, t, J = 5.5 Hz), 4.18 (2H, t, J = 5.0
Hz), 5.32 (1H, d, J = 4.4 Hz), 5.75 (1H, d, J = 4.4 H
z), 7.02 (2H, d, J = 8.4 Hz), 7.12-7.24 (3H, m), 7.36
-7.67 (11H, m), 8.54 (1H, s), 8.56-8.59 (1H, m). IR (KBr) 3357, 1663, 1601, 1597, 1514, 1497, 1360,
1314, 1248, 1190, 822cm ^-1 Elemental analysis C ₃₆ H ₃₇ N ₃ O ₅・ 0.25H ₂ O Calcd. C, 72.52; H,
6.34; N, 7.05: Found. C, 72.45; H, 6.35; N, 7.
Ten.

Example 70 (Production of compound 77) 7- [4- (2-butoxyethoxy) phenyl] -1-
Formyl-N- [4-[(S) -hydroxy (2-pyridyl) methyl] phenyl] -2,3-dihydro-1H-
1-benzazepine-4-carboxamide (225.3
mg) in dichloromethane (20 ml) at 0 ° C.
-Chloroperbenzoic acid (70%, 113 mg) was added, and the mixture was stirred at room temperature for 20 hours. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2- Butoxyethoxy) phenyl] -1-formyl-N- [4-
[(S) -Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (Compound 77)
(125.5 mg) was obtained. mp 120-125 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
28-1.47 (2H, m), 1.53-1.68 (2H, m), 3.03 (2H, t, J
= 5.5 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 5.
0 Hz), 3.93 (2H, t, J = 5.5 Hz), 4.18 (2H, t, J = 5.0
Hz), 6.07 (1H, d, J = 4.8 Hz), 6.43 (1H, d, J = 4.8 H
z), 6.91-7.01 (1H, m), 7.03 (2H, d, J = 8.8 Hz), 7.1
6-7.28 (2H, m), 7.46-7.79 (10H, m), 8.25-8.29 (1H,
m), 8.55 (1H, s) .IR (KBr) 3248, 1665, 1607, 1518, 1499, 1314, 1246,
1186 cm ^-1 Elemental analysis C ₃₆ H ₃₇ N ₃ O ₆ 1.0H ₂ O Calcd. C, 69.10; H, 6.
28; N, 6.72: Found.C, 68.78; H, 6.20; N, 6.78.

Example 71 (Production of compound 78) 7- [4- (2-butoxyethoxy) phenyl] -1-
Formyl-N- [4-[(R) -hydroxy (2-pyridyl) methyl] phenyl] -2,3-dihydro-1H-
1-benzazepine-4-carboxamide (130m
g) in dichloromethane (20 ml) at 0 ° C.
Chloroperbenzoic acid (70%, 65 mg) was added, and the mixture was stirred at room temperature for 18 hours. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4),
Recrystallization (ethyl acetate-diisopropyl ether)
To give 7- [4- (2-butoxyethoxy) phenyl] -1-formyl-N- [4-
[(R) -Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (Compound 78)
(68.2 mg) was obtained. mp 104-106 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
28-1.47 (2H, m), 1.53-1.68 (2H, m), 3.03 (2H, t, J
= 5.5 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.
0 Hz), 3.91 (2H, t, J = 5.5 Hz), 4.17 (2H, t, J = 5.0
Hz), 6.06 (1H, d, J = 4.2 Hz), 6.39 (1H, d, J = 4.2 H
z), 6.91-7.01 (1H, m), 7.03 (2H, d, J = 8.8 Hz), 7.1
6-7.28 (2H, m), 7.44-7.67 (9H, m), 7.75 (1H, s),
8.23-8.27 (1H, m), 8.53 (1H, s). IR (KBr) 3263, 1667, 1607, 1518, 1497, 1316, 1248,
1188 cm ^-1 Elemental analysis C ₃₆ H ₃₇ N ₃ O ₆ 1.0H ₂ O Calcd. C, 69.10; H, 6.
28; N, 6.72: Found.C, 69.31; H, 6.17; N, 6.85.

Example 72 (Production of compound 79) 7- [4- (2-butoxyethoxy) phenyl] -2,
3-Dihydro-1H-1-benzazepine-4-carboxylic acid (463 mg), triethylamine (0.51 m
To a solution of 1) in acetonitrile (25 ml) was added trifluoroacetic anhydride (0.43 ml) at 0 ° C, and the mixture was stirred for 1 hour. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue and 1-hydroxybenzotriazole (0.33 g) in DMF (10 ml) were added to 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (0.46 g) at room temperature. Was added and stirred for 1 hour. (S)-(4-aminophenyl)-(2-pyridyl) methanol (267 mg) in the reaction system.
And triethylamine (0.67 ml) DMF (5 m
l) Dropped into the solution. After stirring at room temperature for 20 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate), and recrystallized from ethyl acetate-hexane to give pale yellow crystals 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[(S) -Hydroxy (2-pyridyl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 79) (316 mg) was obtained. mp 100-102 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 1.
32-1.48 (2H, m), 1.51-1.66 (2H, m), 2.86-3.27 (3H,
m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 4.9 H
z), 4.18 (2H, t, J = 4.9 Hz), 4.74-4.89 (1H, m), 5.3
4 (1H, d, J = 3.0 Hz), 5.75 (1H, d, J = 3.0 Hz), 7.03
(2H, d, J = 8.8 Hz), 7.13-7.27 (3H, m), 7.30-7.42 (4
H, m), 7.51-7.69 (7H, m), 8.5-8.62 (1H, m) .IR (KBr) 3356, 1694, 1653, 1595, 1520, 1499, 1314,
1208, 1179, 1155, 826cm ^-1 Elemental analysis C ₃₇ H ₃₆ N ₃ O ₅ F ₃・ 0.25H ₂ O Calcd. C, 66.91;
H, 5.54; N, 6.33: Found. C, 66.93; H, 5.60; N,
6.32.

Example 73 (Preparation of compound 80) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (2-pyridyl) methyl]
Phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (285 mg) in dichloromethane (10 ml),
3-Chloroperbenzoic acid (70%, 127 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 20 hours. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4), and recrystallized (ethanol-diisopropyl ether) to give 7- [4- (2
-Butoxyethoxy) phenyl] -N- [4-[(S)
-Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (Compound 80) (220.9 mg) was obtained. . mp 107-110 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
29-1.48 (2H, m), 1.51-1.67 (2H, m), 2.86-3.34 (3H,
m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 4.9 H
z), 4.18 (2H, t, J = 4.9 Hz), 4.76-4.91 (1H, m), 6.0
7 (1H, d, J = 3.8 Hz), 6.41 (1H, d, J = 3.8 Hz), 6.91-
7.05 (3H, m), 7.20-7.38 (4H, m), 7.45-7.67 (9H,
m), 8.24-8.28 (1H, m). IR (KBr) 3044, 1696, 1650, 1607, 1499, 1435, 1316,
1252, 1206, 1181, 1155, 825 cm ^-1 Elemental analysis C ₃₇ H ₃₆ N ₃ O ₆ F ₃ 0.5H ₂ O Calcd. C, 64.90; H,
5.45; N, 6.14: Found. C, 64.97; H, 5.37; N, 6.
Ten.

Example 74 (Production of compound 81) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (2-pyridyl) methyl]
Phenyl] -1-propyl-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (300m
Thionyl chloride (0.13 ml) and DMF (1 drop) were added to a THF (10 ml) solution of g) at room temperature, and the mixture was stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (15 ml) was added to a solution of (S)-(4-aminophenyl)-(2-pyridyl) methanol (156 mg) and triethylamine (0.59 ml) in THF (5 ml) at 0 ° C. It was dripped at. After stirring at room temperature for 18 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → 4: 1) to give 7- [4- (2-butoxyethoxy) phenyl] -N-as a yellow amorphous substance. [4-[(S) -Hydroxy (2-pyridyl) methyl] phenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 81) (316 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
99 (3H, t, J = 7.3 Hz), 1.29-1.47 (2H, m), 1.50-1.82
(4H, m), 2.86-2.95 (2H, m), 3.25-3.39 (4H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16
(2H, t, J = 5.0 Hz), 5.27-5.37 (1H, m), 5.74 (1H, br
s), 6.89 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 H
z), 7.12-7.26 (2H, m), 7.34-7.67 (11H, m), 8.56-8.
58 (1H, m). IR (KBr) 3350, 1651, 1607, 1516, 1499, 1314, 1242,
1179 cm ^-1 Elemental analysis C ₃₈ H ₄₃ N ₃ O ₄ 0.25H ₂ O Calcd. C, 74.79; H,
7.18; N, 6.89: Found.C, 74.82; H, 7.29; N, 6.9
3.

Example 75 (Production of compound 82) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
-Trifluoroacetyl-1H-1-benzazepine 4
-Carboxamide (180 mg) in ethanol (30 m
l) Sodium borohydride (10.0
mg) was added and the mixture was stirred for 2 hours. Sodium borohydride (10.0 mg) was further added to the reaction system, and the mixture was stirred for 2 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-] as a yellow amorphous substance. [(S) -Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 82) (141.4 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
28-1.48 (2H, m), 1.51-1.68 (2H, m), 2.89-3.01 (2H,
m), 3.41-3.51 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.
80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 6.07
(1H, br s), 6.31-6.45 (1H, m), 6.71 (1H, d, J = 8.0
Hz), 6.92-6.99 (3H, m), 7.20-7.36 (5H, m), 7.39-
7.52 (4H, m), 7.62-7.66 (3H, m), 8.24-8.28 (1H,
m). IR (KBr) 3293, 1651, 1609, 1499, 1435, 1408, 1316,
1246, 1181, 820 cm ^-1 Elemental analysis C ₃₅ H ₃₇ N ₃ O ₅ 1.5H ₂ O Calcd. C, 69.27; H, 6.
65; N, 6.93: Found.C, 69.05; H, 6.31; N, 6.67.

Example 76 (Production of compound 83) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (120
mg) and 1,2-dichloroethane (10 ml) solution of propionaldehyde (0.15 ml), sodium triacetoxyborohydride (0.13 g) was added at room temperature, and the mixture was stirred for 20 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(S ) -Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 83) (1
(55.4 mg) was obtained. mp 87-89 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
00 (3H, t, J = 7.0 Hz), 1.29-1.48 (2H, m), 1.53-1.82
(4H, m), 2.86-2.96 (2H, m), 3.25-3.40 (4H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16
(2H, t, J = 5.0 Hz), 6.06 (1H, br s), 6.35-6.45 (1H,
m), 6.88-7.00 (4H, m), 7.23-7.28 (2H, m), 7.38-7.
51 (7H, m), 7.62-7.67 (3H, m), 8.24-8.28 (1H, m) .IR (KBr) 3296, 1651, 1607, 1516, 1499, 1313, 1242,
1181, 814 cm ^-1 Elemental analysis C ₃₈ H ₄₃ N ₃ O ₅ 0.5H ₂ O Calcd. C, 72.36; H, 7.
03; N, 6.66: Found.C, 72.07; H, 7.01; N, 6.51.

Example 77 (Preparation of compound 84) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (14
2.6 mg), 1,2-dichloroethane (10 ml) of cyclopropane carboxaldehyde (0.17 g)
Sodium triacetoxyborohydride (0.13 g) was added to the solution at room temperature, and the mixture was stirred for 64 hours. Cyclopropanecarboxaldehyde (0.1 g) and sodium triacetoxyborohydride (0.13 g) were added to the reaction system.
Was added and the mixture was further stirred for 4 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallization (ethyl acetate-diisopropyl ether) were performed to obtain 7- [4- (2-butoxyethoxy) as yellow crystals. Phenyl] -1-cyclopropylmethyl-N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 84) (120.7 mg) was obtained. mp 85-88 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.24-0.35 (2H, m), 0.60-0.
70 (2H, m), 0.93 (3H, t, J = 7.1 Hz), 1.02-1.22 (1H,
m), 1.30-1.46 (2H, m), 1.53-1.66 (2H, m), 2.91-3.0
2 (2H, m), 3.26 (2H, d, J = 6.2 Hz), 3.43-3.50 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 6.04-6.09 (1H, m), 6.3
6-6.46 (1H, m), 6.91-7.00 (4H, m), 7.24-7.28 (2H,
m), 7.39-7.52 (7H, m), 7.63-7.67 (3H, m), 8.25-8.2
9 (1H, m). IR (KBr) 3270, 1653, 1605, 1516, 1499, 1244, 1181,
837 cm ^-1 Elemental analysis C ₃₉ H ₄₃ N ₃ O ₅ 1.0H ₂ O Calcd. C, 71.87; H, 6.
96; N, 6.45: Found.C, 72.10; H, 6.93; N, 6.50.

Example 78 (Production of compound 85) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), 1,2 of isobutyraldehyde (0.15 g)
-To the dichloroethane (10 ml) solution was added sodium triacetoxyborohydride (0.22 g) at room temperature and 4
It was stirred for a day. Isobutyraldehyde (0.
15 g) and sodium triacetoxyborohydride (0.22 g) were added, and the mixture was further stirred for 5 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) was performed as a yellow amorphous substance 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[(S) -hydroxy (1-oxidepyridine-2-
Il) methyl] phenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 85) (155.2 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.27-1.47 (2H, m), 1.53-1.68
(2H, m), 1.98-2.18 (1H, m), 2.89-2.98 (2H, m), 3.19
(2H, d, J = 7.4 Hz), 3.32-3.42 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 6.07 (1H, d, J = 4.1 Hz), 6.42 (1H, d, J
= 4.1 Hz), 6.90-7.00 (4H, m), 7.23-7.28 (2H, m), 7.
38-7.52 (7H, m), 7.63-7.68 (3H, m), 8.24-8.28 (1H,
m). IR (KBr) 3230, 1653, 1605, 1516, 1499, 1240, 1181,
839 cm ^-1 Elemental analysis C ₃₉ H ₄₅ N ₃ O ₅ 0.75H ₂ O Calcd. C, 72.14; H,
7.22; N, 6.47: Found.C, 72.22; H, 7.29; N, 6.5
7.

Example 79 (Production of compound 86) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), 2-formyl thiazole (0.24 g) 1,
Sodium triacetoxyborohydride (0.22 g) was added to a solution of 2-dichloroethane (10 ml) at room temperature, and the mixture was stirred for 4 days. 2-Formyl thiazole (0.24 g), sodium triacetoxyborohydride (0.22 g) and acetic acid (1 drop) were added to the reaction system, and the mixture was further stirred for 24 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4 → 1: 3) and further recrystallization (ethyl acetate) were performed to obtain 7- [4- (2-butoxyethoxy) as yellow crystals. ) Phenyl]
-N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1- (thiazol-2-ylmethyl) -2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 86)
(113.6 mg) was obtained. mp 164-165 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
29-1.47 (2H, m), 1.54-1.68 (2H, m), 2.90-2.99 (2H,
m), 3.43-3.50 (2H, m), 3.55 (2H, t, J = 6.8 Hz), 3.
80 (2H, t, J = 5.0 Hz), 4.15 (2H, t, J = 5.0 Hz), 4.87
(2H, s), 6.06 (1H, d, J = 4.4 Hz), 6.42 (1H, d, J =
4.4 Hz), 6.92-7.03 (4H, m), 7.23-7.27 (2H, m), 7.3
2 (1H, d, J = 3.2 Hz), 7.37-7.54 (7H, m), 7.65 (2H,
d, J = 8.4 Hz), 7.76 (1H, s), 7.79 (1H, d, J = 3.2 H
z), 8.23-8.27 (1H, m) .IR (KBr) 3263, 1634, 1595, 1537, 1499, 1435, 1406,
1318, 1244, 1188, 1126, 814 cm ^-1 Elemental analysis C ₃₉ H ₄₀ N ₄ O ₅ S Calcd. C, 69.21; H, 5.96;
N, 8.28: Found. C, 68.93; H, 5.84; N, 8.20.

Example 80 (Preparation of compound 87) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), 4-formyl-1-methylpyrazole (0.4
g) in 1,2-dichloroethane (10 ml) at room temperature with sodium triacetoxyborohydride (0.22).
g) and acetic acid (1 drop) were added and stirred for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 3 → 1: 2) and further recrystallization (ethyl acetate-diisopropyl ether) were performed to obtain 7- [4- (2 -Butoxyethoxy) phenyl]
-N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1- (1-methylpyrazol-4-ylmethyl) -2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 87) (96.1 mg) was obtained. mp 94-97 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
32-1.46 (2H, m), 1.51-1.68 (2H, m), 2.80-2.89 (2H,
m), 3.29-3.39 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.
81 (2H, t, J = 5.0 Hz), 3.90 (3H, s), 4.16 (2H, t, J
= 5.0 Hz), 4.44 (2H, s), 6.07 (1H, d, J = 4.4 Hz), 6.
43 (1H, d, J = 4.4 Hz), 6.91-7.00 (4H, m), 7.24-7.28
(2H, m), 7.32 (1H, s), 7.38-7.63 (8H, m), 7.62-7.
67 (3H, m), 8.24-8.28 (1H, m). IR (KBr) 3274, 1653, 1605, 1516, 1499, 1433, 1404,
1316, 1240, 1184, 1123, 818 cm ^-1 Elemental analysis C ₄₀ H ₄₃ N ₅ O ₅ 0.75H ₂ O Calcd. C, 69.90; H,
6.53; N, 10.19: Found. C, 69.98; H, 6.77; N,
9.90.

Example 81 (Production of compound 88) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), thiophene-3-carboxaldehyde (0.5
g) in 1,2-dichloroethane (10 ml) at room temperature with sodium triacetoxyborohydride (0.22).
g) and acetic acid (1 drop) were added and stirred for 20 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallization (ethyl acetate-
Diisopropyl ether) to give 7 as yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl]-(3-thienylmethyl) -2,3-dihydro-1-1H-1-benzazepine-4-carboxamide (Compound 88) (171.4m)
g) was obtained. mp 110-112 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
29-1.48 (2H, m), 1.54-1.68 (2H, m), 2.90-2.90 (2H, m)
m), 3.31-3.42 (2H, m), 3.55 (2H, t, J = 6.8 Hz), 3.
80 (2H, t, J = 4.9 Hz), 4.16 (2H, t, J = 4.9 Hz), 4.58
(2H, s), 6.07 (1H, d, J = 4.2 Hz), 6.42 (1H, d, J =
4.2 Hz), 6.91-7.07 (5H, m), 7.12-7.18 (1H, m), 7.2
3-7.27 (2H, m), 7.34-7.49 (7H, m), 7.54 (1H, d, J =
2.2 Hz), 7.63-7.68 (3H, m), 8.24-8.28 (1H, m). IR (KBr) 3262, 1636, 1595, 1499, 1435, 1406, 1316,
1242, 1186, 1128, 810cm ^-1 Elemental analysis C ₄₀ H ₄₁ N ₃ O ₅ S0.25H ₂ O Calcd. C, 70.62; H,
6.15; N, 6.18: Found. C, 70.61; H, 6.22; N, 6.
twenty one.

Example 82 (Preparation of compound 89) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), 5-formyl-1-methylpyrazole (0.2
3 g) in a solution of 1,2-dichloroethane (10 ml),
Sodium triacetoxyborohydride (0.2
2 g) and acetic acid (1 drop) were added and the mixture was stirred for 5 days. In the reaction system, 5-formyl-1-methylpyrazole (0.23
g) and sodium triacetoxyborohydride (0.22 g) and acetic acid (1 drop), and a further 24
Stir for hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 3) and recrystallization (ethyl acetate) were performed to obtain yellow crystals of 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[(S) -hydroxy (1-oxidepyridine-2-
Iyl) methyl] phenyl] -1- (1-methylpyrazol-5-ylmethyl) -2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 89)
(140.1 mg) was obtained. mp 109-111 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
30-1.48 (2H, m), 1.52-1.68 (2H, m), 2.62-2.70 (2H,
m), 3.29-3.39 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.
78-3.83 (5H, m), 4.17 (2H, t, J = 5.0 Hz), 4.55 (2H,
s), 6.07 (1H, d, J = 4.3 Hz), 6.25 (1H, d, J = 1.8 H
z), 6.43 (1H, d, J = 4.3 Hz), 6.91-7.02 (4H, m), 7.2
4-7.28 (2H, m), 7.42-7.67 (11H, m), 8.25-8.28 (1H,
m). IR (KBr) 3260, 1636, 1597, 1499, 1437, 1406, 1318,
1246, 1188, 1128, 810cm ^-1 Elemental analysis C ₄₀ H ₄₃ N ₅ O ₅ 1.0H ₂ O Calcd. C, 69.44; H, 6.
56; N, 10.12: Found.C, 69.34; H, 6.72; N, 10.0
7.

Example 83 (Production of compound 90) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg) and 1,2-dichloroethane (10 ml) solution of benzaldehyde (0.22 g), sodium triacetoxyborohydride (0.22 g) and acetic acid (1 drop) were added at room temperature, and the mixture was stirred for 24 hours. Benzaldehyde (0.22 g) and sodium triacetoxyborohydride (0.22 g) were added to the reaction system, and the mixture was further stirred for 24 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallization (ethyl acetate-diisopropyl ether) were performed, and 1-benzyl-7- [4- (2 as yellow crystals were obtained. -Butoxyethoxy) phenyl] -N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 90) (168.0 mg)
Got mp 89-93 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
28-1.48 (2H, m), 1.51-1.67 (2H, m), 2.81-2.89 (2H,
m), 3.32-3.42 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.
80 (2H, t, J = 4.9 Hz), 4.16 (2H, t, J = 4.9 Hz), 4.62
(2H, s), 6.07 (1H, d, J = 4.3 Hz), 6.41 (1H, d, J =
4.9 Hz), 6.88-7.06 (4H, m), 7.24-7.67 (17H, m), 8.
25-8.28 (1H, m). IR (KBr) 3275, 1653, 1603, 1499, 1454, 1433, 1406,
1314, 1244, 1184, 1123, 812 cm ^-1 Elemental analysis C ₄₂ H ₄₃ N ₃ O ₅ 1.0H ₂ O Calcd. C, 73.34; H, 6.
59; N, 6.11: Found.C, 73.70; H, 6.66; N, 5.99.

Example 84 (Production of compound 91) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg) and 2-furaldehyde (0.2 g) in 1,2-dichloroethane (10 ml) solution, sodium triacetoxyborohydride (0.22 g) and acetic acid (1 drop) were added at room temperature, and the mixture was stirred for 20 hours. 2-Furaldehyde (0.2 g) and sodium triacetoxyborohydride (0.22 g) were added to the reaction system, and the mixture was further stirred for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallization (ethyl acetate-diisopropyl ether) were performed to obtain 7- [4- (2-butoxyethoxy) as yellow crystals. Phenyl] -1- (2-furyl) -N- [4-[(S) -hydroxy (1-oxidepyridin-2-yl) methyl]
Phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 91) (150.0
mg) was obtained. mp 117-119 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
29-1.48 (2H, m), 1.54-1.68 (2H, m), 2.81-2.88 (2H,
m), 3.31-3.41 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.
80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.51
(2H, s), 6.06 (1H, d, J = 4.4 Hz), 6.30 (1H, d, J =
3.6 Hz), 6.37-6.42 (2H, m), 6.91-7.06 (3H, m), 7.0
8 (1H, d, J = 8.4 Hz), 7.23-7.27 (2H, m), 7.40-7.53
(8H, m), 7.64 (2H, d, J = 8.4 Hz), 7.68 (1H, s), 8.2
3-8.27 (1H, m). IR (KBr) 3281, 1644, 1597, 1499, 1435, 1408, 1316,
1244, 1186, 1123, 812cm ^-1 Elemental analysis C ₄₀ H ₄₁ N ₃ O ₆ 0.25H ₂ O Calcd. C, 72.32; H,
6.30; N, 6.33: Found.C, 72.36; H, 6.33; N, 6.1
0.

Example 85 (Preparation of compound 92) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (200
mg), 5-formyl-3-methylisothiazole (0.44 g) in 1,2-dichloroethane (10 ml)
Sodium triacetoxyborohydride (0.22 g) and acetic acid (1 drop) were added to the solution at room temperature, and the mixture was stirred for 24 hours. Sodium triacetoxyborohydride (0.22 g) was added to the reaction system, and the mixture was further stirred for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, separation and purification by column chromatography (ethanol: ethyl acetate 1: 4) and recrystallization (ethyl acetate-
Diisopropyl ether) to give 7 as yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -1-
(3-Methyl-isothiazol-5-ylmethyl) -N
-[4-[(S) -Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 92) (154.0 mg) was obtained. mp 93-96 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
29-1.47 (2H, m), 1.52-1.68 (2H, m), 2.49 (3H, s),
2.88-2.98 (2H, m), 3.35-3.45 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.81 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J
= 4.8 Hz), 4.79 (2H, s), 6.07 (1H, d, J = 4.4 Hz), 6.
43 (1H, d, J = 4.4 Hz), 6.91-7.01 (5H, m), 7.24-7.28
(2H, m), 7.39-7.49 (6H, m), 7.52-7.58 (1H, m), 7.
63-7.68 (3H, m), 8.25-8.29 (1H, m). IR (KBr) 3314, 1655, 1605, 1514, 1499, 1433, 1406,
1314, 1244, 1182, 1120, 814 cm ^-1 Elemental analysis C ₄₀ H ₄₂ N ₄ O ₅ S1.0H ₂ O Calcd. C, 67.77; H,
6.26; N, 7.90: Found.C, 67.73; H, 6.12; N, 7.9
0.

Example 86 (Production of compound 93) 7- [4- (2-butoxyethoxy) phenyl] -1-
Methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.50 g) in THF
(10 ml) solution, at room temperature, thionyl chloride (0.12 m
1) and DMF (1 drop) were added and stirred for 2 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added at 0 ° C. to (S)-(+)-(4-aminophenyl) (2-pyridyl) methanol (0.24 g) and triethylamine (0.6 ml). It was added dropwise to a THF (5 ml) solution and stirred at room temperature for 18 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, recrystallization (ethyl acetate-
Diisopropyl ether) to give 7 as colorless crystals.
-[4- (2-Butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (2-pyridyl) methyl]
Phenyl] -1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 93) (542.7 mg) was obtained. mp 158-160 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
32-1.45 (2H, m), 1.52-1.67 (2H, m), 2.88 (3H, s),
3.05-3.15 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2
H, t, J = 4.9 Hz), 3.88-3.94 (2H, m), 4.17 (2H, t, J
= 4.9 Hz), 5.29-5.36 (1H, m), 5.72-5.79 (1H, m), 7.
01 (2H, d, J = 8.8 Hz), 7.12-7.26 (2H, m), 7.39 (2H,
d, J = 8.8 Hz), 7.48-7.68 (10H, m), 8.56-8.59 (1H,
m) .IR (KBr) 3362, 1651, 1597, 1518, 1493, 1341, 1242,
1154, 966, 822 cm ^-1 Elemental analysis C ₃₆ H ₃₉ N ₃ O ₆ S Calcd. C, 67.37; H, 6.13;
N, 6.55: Found. C, 67.21; H, 5.85; N, 6.67.

Example 87 (Production of compound 94) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(S) -hydroxy (2-pyridyl) methyl]
Phenyl] -1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) in dichloromethane (10 ml),
3-Chloroperbenzoic acid (70%, 0.21 g) was added 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, the mixture was stirred for several minutes, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4), and recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4-[(S)-
Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 94) (292.1 mg) was obtained. mp 118-120 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
29-1.46 (2H, m), 1.51-1.68 (2H, m), 2.90 (3H, s),
3.08-3.19 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2
H, t, J = 4.9 Hz), 3.86-3.96 (2H, m), 4.18 (2H, t, J
= 4.9 Hz), 6.03-6.09 (1H, m), 6.38-6.45 (1H, m), 6.
94-7.00 (1H, m), 7.02 (2H, d, J = 8.6 Hz), 7.25-7.29
(2H, m), 7.46-7.57 (6H, m), 7.63-7.72 (5H, m), 8.
25-8.28 (1H, m). IR (KBr) 3250, 1657, 1607, 1518, 1493, 1341, 1246,
1154, 1103, 1061, 966, 824 cm ^-1 Elemental analysis C ₃₆ H ₃₉ N ₃ O ₇ S0.75H ₂ O Calcd. C, 64.41; H,
6.08; N, 6.26: Found. C, 64.39; H, 6.22; N, 6.
05.

Example 88 (Preparation of compound 95) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
To a solution of 0.5 g (1.05 mmol) of benzazepine-4-carboxylic acid and 1-hydroxybenzotriazole (0.35 g) in DMF (10 ml) at room temperature was added.
-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide / hydrochloride (0.50 g) was added, and the mixture was stirred for 1 hr. To the reaction system, (4-aminophenyl) (6-methylpyridin-2-yl) methanol (0.29 g), a solution of triethylamine (0.60 ml) in DMF (5 ml) and 4-dimethylaminopyridine (1 piece) were added. Addition was continued for 20 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1: 1 → 2: 1).
Separation and purification with a light yellow amorphous substance, 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (6-methylpyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (Compound 95) (378.9 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
29-1.48 (2H, m), 1.52-1.70 (2H, m), 2.60 (3H, s),
2.88-3.26 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2
H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 4.74-4.89
(1H, m), 5.64-5.76 (2H, m), 6.89 (1H, d, J = 7.6 H
z), 7.00-7.07 (3H, m), 7.30-7.65 (12H, m) .IR (KBr) 3343, 1692, 1597, 1518, 1497, 1460, 1406,
1314, 1250, 1208, 1179, 1155, 828 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₅ F ₃ 0.25H ₂ O Calcd. C, 67.29; H,
5.72; N, 6.20: Found. C, 67.25; H, 5.58; N,
6.35.

Example 89 (Preparation of compound 96) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (6-methylpyridin-2-yl)
Methyl] phenyl] -1-trifluoroacetyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (340 mg) in dichloromethane (10 ml)
To the solution at 0 ° C., 3-chloroperbenzoic acid (70%, 0.1%
5 g) was added and the mixture was stirred at room temperature for 20 hours. Aqueous sodium thiosulfate solution was added to the reaction system and stirred for several minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1:19) and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4- [hydroxy (6-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 96) (262 mg) was obtained. mp 170-173 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.2 Hz), 1.
29-1.48 (2H, m), 1.54-1.68 (2H, m), 2.57 (3H, s),
2.93-3.27 (3H, m), 3.56 (2H, t, J = 6.8 Hz), 3.82 (2
H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 4.76-4.91
(1H, m), 6.06 (1H, d, J = 4.6 Hz), 6.68 (1H, d, J =
4.6 Hz), 6.78-6.84 (1H, m), 7.03 (2H, d, J = 8.8 H
z), 7.13-7.36 (3H, m), 7.46-7.66 (10H, m). IR (KBr) 3296, 1694, 1647, 1597, 1530, 1497, 1316,
1248, 1206, 1179, 1154, 847, 828 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₆ F ₃ Calcd. C, 66.17; H, 5.55;
N, 6.09: Found. C, 65.97; H, 5.48; N, 6.10.

Example 90 (Production of compound 97) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-N- [4- [hydroxy (6-
Methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (230 mg) in ethanol (20 ml) at room temperature was added sodium borohydride (63 mg). ) Was added and stirred for 3 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline,
It was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol: ethyl acetate 1:
4) was separated and purified, and recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[Hydroxy (6-methyl-1-oxidepyridine-2
-Yl) methyl] phenyl] -2,3-dihydro-1H
-1-benzazepine-4-carboxamide (compound 9
7) (120.5 mg) was obtained. mp 175-177 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
28-1.44 (2H, m), 1.48-1.68 (2H, m), 2.56 (3H, s),
2.92-3.01 (2H, m), 3.41-3.49 (2H, m), 3.55 (2H, t,
J = 6.8 Hz), 3.80 (2H, t, t, J = 5.0 Hz), 4.16 (2H,
t, J = 5.0 Hz), 4.46-4.72 (1H, m), 6.06 (1H, s), 6.7
0 (1H, d, J = 8.4 Hz), 6.78-6.84 (1H, m), 6.97 (2H,
d, J = 8.8 Hz), 7.11-7.18 (1H, m), 7.20-7.34 (3H,
m), 7.43-7.47 (5H, m), 7.61-7.65 (3H, m) .IR (KBr) 3283, 1661, 1645, 1599, 1499, 1321, 1248,
1181, 826 cm ^-1 Elemental analysis C ₃₆ H ₃₉ N ₃ O ₅ 1.0H ₂ O Calcd. C, 70.68; H, 6.
76; N, 6.87: Found.C, 70.53; H, 6.15; N, 6.93.

Example 91 (Production of compound 98) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (6-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (1
To a solution of 54 mg) and isobutyraldehyde (0.12 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.17 g) and acetic acid (1 drop) at room temperature, and the mixture was stirred for 24 hours. In the reaction system,
Further, isobutyraldehyde (0.12 g) and sodium triacetoxyborohydride (0.17 g) were added, and the mixture was further stirred for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the product was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) using basic silica gel, and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4 as yellow crystals. -(2-butoxyethoxy) phenyl]-
N- [4- [hydroxy (6-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4
-Carboxamide (Compound 98) (122.3 mg) was obtained. mp 114-116 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.30-1.46 (2H, m), 1.50-1.71
(2H, m), 1.98-2.16 (1H, m), 2.57 (3H, s), 2.88-2.9
7 (2H, m), 3.19 (2H, d, J = 6.6 Hz), 3.33-3.43 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 6.07 (1H, s), 6.77-6.8
4 (1H, m), 6.91-7.00 (3H, m), 7.15 (1H, t, J = 7.7 H
z), 7.37-7.51 (8H, m), 7.63-7.70 (3H, m) .IR (KBr) 3282, 1641, 1598, 1499, 1315, 1246, 1182,
1065, 838, 815 cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₅ Calcd. C, 73.93; H, 7.29;
N, 6.47: Found. C, 73.83; H, 7.21; N, 6.45.

Example 92 (Production of compound 99) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g) and 1
DM of hydroxybenzotriazole (0.28 g)
F (10 ml) solution at room temperature in 1-ethyl-3- (3 '
-Dimethylaminopropyl) carbodiimide / hydrochloride (0.40 g) was added and stirred for 1 hour. In the reaction system (4
-Aminophenyl) (3-methylpyridin-2-yl)
Methanol (0.27 g), triethylamine (0.6
A solution of 0 ml of DMF (5 ml) and 4-dimethylaminopyridine (1 piece) were added, and the mixture was stirred for 3 days.
Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 3 → 1: 2 → 1: 1),
7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (3-methylpyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2, as a colorless amorphous substance 3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 99) (31
9.2 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 1.
30-1.48 (2H, m), 1.51-1.68 (2H, m), 2.09 (3H, s),
2.87-3.34 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2
H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 4.75-4.88
(1H, m), 5.73 (1H, d, J = 5.9 Hz), 6.06 (1H, d, J =
5.9 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.17-7.35 (5H,
m), 7.42-7.43 (1H, m), 7.47-7.54 (6H, m), 7.62-7.6
6 (1H, m), 8.45-8.50 (1H, m) .IR (KBr) 3314, 1693, 1607, 1520, 1497, 1414, 1314,
1250, 1206, 1179, 1155, 1042, 828 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₅ F ₃ 0.25H ₂ O Calcd. C, 67.29; H,
5.72; N, 6.20: Found. C, 67.13; H, 5.56; N,
6.05.

Example 93 (Production of compound 100) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-N- [4- [hydroxy (3-
Methylpyridin-2-yl) methyl] phenyl] -2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (291 mg) in dichloromethane (10 ml)
To the solution at 0 ° C. 3-chloroperbenzoic acid (70%, 128
mg) was added and the mixture was stirred at room temperature for 20 hours. Aqueous sodium thiosulfate solution was added to the reaction system and stirred for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol: ethyl acetate 1:
9) was separated and purified, and recrystallized (ethyl acetate-diisopropyl ether) to give 7- as pale yellow crystals.
[4- (2-butoxyethoxy) phenyl] -N- [4
-[Hydroxy (3-methyl-1-oxidepyridine-
2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 100) (210.9 m
g) was obtained. mp 109-112 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
29-1.48 (2H, m), 1.55-1.68 (2H, m), 2.46 (3H, s),
2.88-3.30 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2
H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 4.72-4.88
(1H, m), 6.03 (1H, d, J = 10.2 Hz), 7.02 (2H, d, J =
8.8 Hz), 7.15-7.64 (13H, m), 7.90-8.02 (1H, m), 8.0
8-8.11 (1H, m). IR (KBr) 3284, 1696, 1609, 1520, 1499, 1248, 1206,
1181, 1155, 1061, 1040, 828 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₆ F ₃ 1.0H ₂ O Calcd. C, 64.49; H,
5.70; N, 5.94: Found. C, 64.75; H, 5.42; N, 5.
75.

Example 94 (Production of compound 101) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (3-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (180 mg) in ethanol Sodium borohydride (49 mg) was added to the (10 ml) solution at room temperature, and the mixture was stirred for 2 hours. Sodium borohydride (49 mg) was further added to the reaction system, and the mixture was stirred for 2 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4), and recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2-butoxy) as yellow crystals. Ethoxy) phenyl] -N- [4- [hydroxy (3-methyl-1-
Oxidopyridin-2-yl) methyl] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 101) (86.1 mg) was obtained. mp 101-104 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
28-1.47 (2H, m), 1.52-1.89 (2H, m), 2.46 (3H, s),
2.90-2.97 (2H, m), 3.39-3.49 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.15 (2H, t, J
= 4.9 Hz), 4.52-4.64 (1H, m), 6.03 (1H, d, J = 11.2 H
z), 6.69 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.8 Hz),
7.15-7.58 (12H, m), 8.00 (1H, d, J = 11.2 Hz), 8.08
-8.11 (1H, m). IR (KBr) 3295, 1651, 1609, 1499, 1454, 1316, 1246,
1179, 1121, 1040, 824cm ^-1 Elemental analysis C ₃₆ H ₃₉ N ₃ O ₅ 1.0H ₂ O Calcd. C, 70.68; H, 6.
76; N, 6.87: Found.C, 70.72; H, 6.43; N, 6.86.

Example 95 (Production of compound 102) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (3-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (7
To a solution of 0 mg) and isobutyraldehyde (0.09 ml) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (64 mg) and acetic acid (1 drop) at room temperature, and the mixture was stirred for 18 hours. Isobutyraldehyde (0.09 ml) and sodium triacetoxyborohydride (64 mg) were added to the reaction system, and 2
Stir for 4 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (as a yellow amorphous substance. 3-Methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 102)
(28.5 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30-1.48 (2H, m), 1.50-1.70
(2H, m), 1.96-2.17 (1H, m), 2.46 (3H, s), 2.84-2.9
5 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.29-3.40 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 6.03 (1H, d, J = 10.8 H
z), 6.91 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 9.2 H
z), 7.15-7.24 (2H, m), 7.38-7.58 (10H, m), 8.01 (1
H, d, J = 10.8 Hz), 8.08-8.11 (1H, m). IR (KBr) 3295, 1657, 1607, 1514, 1499, 1454, 1244,
1181, 1117, 1061, 816cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₅ 1.25H ₂ O Calcd. C, 71.46; H,
7.42; N, 6.25: Found.C, 71.50; H, 7.32; N, 6.0
0.

Example 96 (Production of compound 103) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g), 1-hydroxybenzotriazole (0.28 g), (4-aminophenyl) (5-methylpyridin-2-yl) methanol (0.29 g) and triethylamine (0. 6
0 ml) in DMF (10 ml) was added with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (0.40 g) and 4-dimethylaminopyridine (1 piece) at room temperature and stirred for 3 days. did. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 2: 1) and recrystallized to give 7- [4- (2-butoxyethoxy) as pale yellow crystals. Phenyl] -N- [4- [hydroxy (5-methylpyridin-2-yl) methyl] phenyl]
-1-Trifluoroacetyl-2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (Compound 1
03) (529.9 mg). mp 110-113 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
28-1.48 (2H, m), 1.53-1.68 (2H, m), 2.33 (3H, s),
2.85-3.31 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2
H, t, J = 4.8 Hz), 4.18 (2H, t, J = 4.8 Hz), 4.74-4.89
(1H, m), 5.31 (1H, d, J = 4.2 Hz), 5.71 (1H, d, J =
4.2 Hz), 7.01-7.05 (3H, m), 7.31-7.57 (11H, m), 7.
62-7.67 (1H, m), 8.36-8.42 (1H, m). IR (KBr) 3364, 1692, 1651, 1609, 1518, 1499, 1314,
1250, 1208, 1181, 1154, 828 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₅ F ₃ Calcd. C, 67.74; H, 5.69;
N, 6.24: Found. C, 67.43; H, 5.76; N, 6.01.

Example 97 (Compound 104) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxide-5-methylpyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane. 3-Chloroperbenzoic acid (70%, 0.21 g) was added to the (15 ml) solution at 0 ° C, and the mixture was stirred at room temperature for 18 hours. Aqueous sodium thiosulfate solution was added to the reaction system and stirred for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2-butoxy) as colorless crystals. Ethoxy) phenyl] -N- [4- [hydroxy (5-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 104)
(386.8 mg) was obtained. mp 201-204 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.2 Hz), 1.
30-1.49 (2H, m), 1.54-1.70 (2H, m), 2.32 (3H, s),
2.89-3.35 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2
H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 4.78-4.97
(1H, m), 6.03 (1H, d, J = 4.2 Hz), 6.52 (1H, d, J =
4.2 Hz), 6.81 (1H, d, J = 8.2 Hz), 7.01-7.10 (3H,
m), 7.26-7.36 (1H, m), 7.44-7.66 (10H, m), 8.11 (1
H, s). IR (KBr) 3248, 1686, 1647, 1609, 1597, 1314, 1250,
1209, 1181, 1157, 1144, 826 cm ^-1 Elemental analysis C ₃₈ H ₃₈ N ₃ O ₆ F ₃ Calcd. C, 66.17; H, 5.55;
N, 6.09: Found. C, 66.11; H, 5.40; N, 6.21.

Example 98 (Production of compound 105) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (5-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (320 mg) in ethanol Sodium borohydride (88 mg) was added to the (10 ml) solution at room temperature, and the mixture was stirred for 2 hours. Sodium borohydride (88 mg) was added to the reaction system, and the mixture was stirred for 1 hour.
Sodium borohydride (88 mg) was further added, and 13
After stirring for an hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4), and recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2-butoxyethoxy) as yellow crystals. ) Phenyl] -N- [4- [hydroxy (5-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 105) (256.8 mg) was obtained. mp 119-121 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
29-1.46 (2H, m), 1.53-1.70 (2H, m), 2.30 (3H, s),
2.90-3.01 (2H, m), 3.21-3.50 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.15 (2H, t, J
= 4.9 Hz), 4.56-4.65 (1H, m), 6.03 (1H, br s), 6.45
-6.54 (1H, m), 6.70 (1H, d, J = 8.0 Hz), 6.79 (1H, d,
J = 8.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 6.99-7.07 (1H,
m), 7.29-7.33 (2H, m), 7.41-7.47 (5H, m), 7.64 (2
H, d, J = 8.4 Hz), 7.74 (1H, s), 8.10 (1H, s). IR (KBr) 3252, 1647, 1599, 1499, 1318, 1250, 1181,
1123, 822 cm ^-1 Elemental analysis C ₃₆ H ₃₉ N ₃ O ₅ 0.5H ₂ O Calcd. C, 71.74; H, 6.
69; N, 6.97: Found.C, 71.76; H, 6.98; N, 6.91.

Example 99 (Production of Compound 106) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (5-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (1
To a solution of 80 mg) and isobutyraldehyde (0.17 ml) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.19 g) and acetic acid (1 drop) at room temperature, and the mixture was stirred for 16 hours. Isobutyraldehyde (0.17 ml) and sodium triacetoxyborohydride (0.19 g) were further added to the reaction system, and the mixture was further stirred for 24 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (as a yellow amorphous substance. 5
-Methyl-1-oxidepyridin-2-yl) methyl]
Phenyl] -1-isobutyl-2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (Compound 1
06) (130.6 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.30-1.46 (2H, m), 1.52-1.68
(2H, m), 1.98-2.16 (1H, m), 2.31 (3H, s), 2.89-2.9
7 (2H, m), 3.19 (2H, d ,, J = 7.0 Hz), 3.31-3.42 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 6.03 (1H, s), 6.79 (1H,
d, J = 8.0 Hz), 6.90-7.08 (4H, m), 7.38-7.52 (7H,
m), 7.64 (2H, d, J = 8.4 Hz), 7.65 (1H, s), 8.11 (1
H, s) .IR (KBr) 3250, 1647, 1607, 1499, 1314, 1244, 1182,
1119, 1065, 1049, 818cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₅ 0.5H ₂ O Calcd. C, 71.94; H, 7.
40; N, 6.29: Found.C, 71.90; H, 7.53; N, 6.13.

Example 100 (Production of compound 107) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g), 1-hydroxybenzotriazole (0.28 g), (4-aminophenyl) (5-chloropyridin-2-yl) methanol (0.32 g) and triethylamine (0. 6
0 ml) in DMF (10 ml) was added with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (0.40 g) and 4-dimethylaminopyridine (1 piece) at room temperature and stirred for 24 hours. did. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1), and further column chromatography using basic silica gel (ethyl acetate: hexane 1: 1 → 2: 1 → 3: 1). ) And purified by recrystallization (ethyl acetate-diisopropyl ether) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (5-chloropyridine- 2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 106) (365.8)
mg) was obtained. mp 144-146 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 1.
29-1.47 (2H, m), 1.54-1.68 (2H, m), 2.90-3.25 (3H,
m), 3.56 (2H, t, J = 6.8 Hz), 3.82 (2H, t, J = 4.9 H
z), 4.18 (2H, t, J = 4.9 Hz), 4.75-4.89 (2H, m), 5.7
5 (1H, d, J = 4.0 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.14
(1H, d, J = 8.4 Hz), 7.32-7.43 (4H, m), 7.50-7.65 (8
H, m), 8.53 (1H, d, J = 2.6 Hz). IR (KBr) 3343, 1694, 1651, 1595, 1518, 1497, 1312,
1244, 1213, 1182, 1152, 1111, 828 cm ^-1 Elemental analysis C ₃₇ H ₃₅ N ₃ O ₅ ClF ₃ Calcd. C, 64.02; H, 5.08
; N, 6.05: Found. C, 64.02; H, 5.20; N, 6.03.

Example 101 (Production of Compound 108) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (5-chloropyridin-2-yl)
Methyl] phenyl] -1-trifluoroacetyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (682 mg) in dichloromethane (15 ml)
The solution was added with 3-chloroperbenzoic acid (70%, 0.2%) at 0 ° C.
9 g) was added, and the mixture was stirred at room temperature for 24 hours. Further, 3-chloroperbenzoic acid (70%, 0.29 g) was added, and the mixture was stirred at room temperature for 18 hours, then an aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as colorless crystals.
[4- [Hydroxy (5-chloro-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 108) ( 233.8
mg) was obtained. mp 200-203 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 1.
34-1.45 (2H, m), 1.52-1.67 (2H, m), 2.86-3.34 (3H,
m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 4.8 H
z), 4.18 (2H, t, J = 4.8 Hz), 4.78-4.92 (1H, m), 5.7
5 (1H, d, J = 4.2 Hz), 6.05 (1H, d, J = 4.2 Hz), 6.91
(1H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.22-7.
37 (2H, m), 7.43-7.67 (10H, m), 8.16 (1H, d, J = 1.6
Hz). IR (KBr) 3279, 1688, 1651, 1597, 1497, 1408, 1314,
1252, 1211, 1181, 1142, 924, 828 cm ^-1 Elemental analysis C ₃₇ H ₃₅ N ₃ O ₆ ClF ₃ Calcd. C, 62.58; H, 4.97
; N, 5.92: Found. C, 62.36; H, 5.01; N, 5.89.

Example 102 (Production of Compound 109) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (5-chloro-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.20 g) Sodium borohydride (50 mg) was added to the ethanol (30 ml) solution of the above at room temperature, and the mixture was stirred for 2.5 hours. Sodium borohydride (50 mg) was added to the reaction system, and the mixture was stirred for 2.5 hours. Sodium borohydride (50 mg) was further added, and the mixture was stirred for 1 hour. Further, sodium borohydride (50 mg) was added, the mixture was stirred for 13 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 4: 1 → ethyl acetate) to give 7- as a yellow amorphous substance.
[4- (2-butoxyethoxy) phenyl] -N- [4
-[Hydroxy (5-chloro-1-oxidepyridine-
2-yl) methyl] phenyl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (Compound 109) (53 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
34-1.49 (2H, m), 1.51-1.68 (2H, m), 2.91-3.00 (2H,
m), 3.42-3.50 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.
80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.45
-4.69 (1H, m), 5.71-5.78 (1H, m), 6.02-6.06 (1H,
m), 6.71 (1H, d, J = 8.4 Hz), 6.88 (1H, d, J = 8.4 H
z), 6.98 (2H, d, J = 8.8 Hz), 7.17-7.22 (1H, m), 7.2
8-7.36 (2H, m), 7.42-7.48 (5H, m), 7.50-7.67 (2H,
m), 8.30 (1H, d, J = 1.8 Hz).

Example 103 (Production of compound 110) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (5-chloro-1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (4
0 mg), isobutyraldehyde (0.1 ml) 1,
Sodium triacetoxyborohydride (60 mg) and acetic acid (1 drop) were added to a 2-dichloroethane (5 ml) solution at room temperature, and the mixture was stirred for 14 hours. Sodium triacetoxyborohydride (40 mg) was further added to the reaction system, and the mixture was stirred for 6 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, recrystallization (ethyl acetate-diisopropyl ether) was performed to obtain 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[Hydroxy (5-chloro-1-oxidepyridine-
2-yl) methyl] phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 110) (26.6 mg) was obtained. mp 137-139 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.29-1.46 (2H, m), 1.52-1.68
(2H, m), 1.94-2.17 (1H, m), 2.86-2.99 (2H, m), 3.19
(2H, d, J = 7.4 Hz), 3.31-3.41 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.16 (2H, t,
J = 4.9 Hz), 5.76 (1H, d, J = 3.9 Hz), 6.04 (1H, d, J
= 3.9 Hz), 6.87-6.94 (2H, m), 6.98 (2H, d, J = 8.8 H
z), 7.20-7.26 (1H, m), 7.35-7.52 (7H, m), 7.63-7.6
7 (3H, m), 8.29 (1H, d, J = 1.8 Hz). IR (KBr) 3290, 1644, 1597, 1499, 1318, 1244, 1182,
924, 813 cm ^-1

Example 104 (Production of compound 111) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g) and 1
-Hydroxybenzotriazole (0.30 g), (4
-Aminophenyl) (3-propoxypyridin-2-yl) methanol (0.30 g) in DMF (10 ml) at room temperature, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (0 0.40 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (1 piece) were added and stirred for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate:
Separated and purified with hexane 1: 1) to give 7 as pale yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -N-
[4- [Hydroxy (3-propoxypyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 111) (528.7 mg) was obtained. mp 154-157 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.6 Hz), 0.
99 (3H, t, J = 7.4 Hz), 1.31-1.48 (2H, m), 1.51-1.66
(2H, m), 1.71-1.83 (2H, m), 2.83-3.26 (3H, m), 3.56
(2H, t, J = 6.6 Hz), 3.79-3.89 (2H, m), 4.18 (2H,
t, J = 4.8 Hz), 4.74-4.95 (1H, m), 5.59 (1H, d, J = 6.
6 Hz), 5.93 (1H, d, J = 6.6 Hz), 7.02 (2H, d, J = 8.8
Hz), 7.08-7.24 (2H, m), 7.29-7.41 (4H, m), 7.46-7.
58 (6H, m), 7.64 (1H, br s), 8.16-8.18 (1H, m). IR (KBr) 3324, 1698, 1671, 1609, 1522, 1499, 1453,
1406, 1316, 1281, 1250, 1208, 1179, 1144, 1042, 8
28 cm ^-1 Elemental analysis C ₄₀ H ₄₂ N ₃ O ₆ F ₃ Calcd. C, 66.93; H, 5.90;
N, 5.85: Found. C, 66.72; H, 6.09; N, 5.80.

Example 105 (Preparation of compound 112) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (3-propoxypyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (10 m
l) The solution was added with 3-chloroperbenzoic acid (70%,
0.2 g) was added and the mixture was stirred at room temperature for 30 hours. Aqueous sodium thiosulfate solution was added to the reaction system and stirred for several minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 9), and as colorless crystals, 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy ( 1
-Oxide-3-propoxypyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 112) (370 mg) was obtained. mp 144-146 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
09 (3H, t, J = 7.3 Hz), 1.31-1.47 (2H, m), 1.51-1.67
(2H, m), 1.82-1.97 (2H, m), 2.86-3.24 (3H, m), 3.56
(2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 3.93-
4.13 (2H, m), 4.18 (2H, t, J = 5.0 Hz), 4.72-4.89 (1
H, m), 6.36 (1H, d, J = 11.0 Hz), 6.95 (1H, d, J = 7.6
Hz), 7.02 (2H, d, J = 8.8 Hz), 7.12-7.19 (1H, m), 7.
28-7.41 (2H, m), 7.45-7.64 (9H, m), 7.81-7.84 (1H,
m), 7.90-7.96 (1H, m) .IR (KBr) 3318, 1694, 1674, 1599, 1532, 1514, 1499,
1319, 1291, 1250, 1181, 1146, 1074, 1042, 826 cm
^-1 Elemental analysis C ₄₀ H ₄₂ N ₃ O ₇ F ₃ Calcd. C, 65.47; H, 5.77;
N, 5.73: Found. C, 65.23; H, 5.60; N, 5.51.

Example 106 (Production of compound 113) 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-N- [4- [hydroxy (1-
A solution of oxide-3-propoxypyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (330 mg) in ethanol (20 ml) was added at room temperature to sodium borohydride (85 mg). ) Was added and stirred for 2 hours. Sodium borohydride (85 mg) was further added to the reaction system, and the mixture was stirred for 2 hours. Furthermore, sodium borohydride (85
mg) was added and the mixture was stirred for 2 hours. Sodium borohydride (85 mg) was further added to the reaction system, and after stirring for 14 hours,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was recrystallized (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as yellow crystals.
[4- [Hydroxy (1-oxide-3-propoxypyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 113) (230.7 mg) was obtained. It was mp 148-149 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
09 (3H, t, J = 7.3 Hz), 1.28-1.49 (2H, m), 1.52-1.67
(2H, m), 1.81-2.00 (2H, m), 2.88-2.97 (2H, m), 3.41
-3.52 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, t, J = 4.9 Hz), 3.95-4.10 (2H, m), 4.15 (2H, t, J
= 4.9 Hz), 4.48-4.67 (1H, m), 6.31-6.41 (1H, m), 6.
92-6.99 (3H, m), 7.11-7.19 (1H, m), 7.26-7.33 (3H,
m), 7.43-7.47 (3H, m), 7.50-7.56 (4H, m), 7.82 (1
H, m, J = 6.6 Hz), 7.84-8.02 (1H, m). IR (KBr) 3308, 1657, 1601, 1507, 1498, 1317, 1244,
1181, 1040, 831 cm ^-1 Elemental analysis C ₃₈ H ₄₃ N ₃ O ₆ Calcd. C, 71.56; H, 6.80;
N, 6.59: Found. C, 71.37; H, 6.82; N, 6.42.

Example 107 (Production of compound 114) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxide-3-propoxypyridin-2-yl) methyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (190 mg), isobutyraldehyde (0.27 m
l) in 1,2-dichloroethane (10 ml) at room temperature with sodium triacetoxyborohydride (0.19).
g) and acetic acid (1 drop) were added and stirred for 15 hours. The reaction system was further charged with isobutyraldehyde (0.27 ml) and sodium triacetoxyborohydride (0.19 ml).
g) was added and stirred for 6 hours. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4) to give 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxide-3-propoxypyridin-2-yl) methyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4- Carboxamide (Compound 114) (143.3 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.09 (3H, t, J = 7.3 Hz), 1.32-
1.72 (4H, m), 1.81-2.13 (3H, m), 2.84-2.93 (2H, m),
3.18 (2H, d, J = 7.8 Hz), 3.30-3.38 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 3.98-4.
11 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.36 (1H, s),
6.89-7.00 (4H, m), 7.12-7.19 (1H, m), 7.37-7.60 (1
1H, m), 7.81-7.84 (1H, m). IR (KBr) 3301, 1653, 1607, 1514, 1499, 1468, 1314,
1244, 1181, 1073, 818cm ^-1 Elemental analysis C ₄₂ H ₅₁ N ₃ O ₆ 1.0H ₂ O Calcd. C, 70.86; H, 7.
50; N, 5.90: Found.C, 70.87; H, 7.33; N, 5.80.

Example 108 (Production of Compound 115) 7- [4- (2-butoxyethoxy) phenyl] -N-
A solution of (4-hydroxymethylphenyl) -2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) was added at room temperature to thionyl chloride (0.1 ml) and Pyridine (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, triethylamine (2.0 ml) and 2-mercapto-1,3,4-thiadiazole (0.12 g) were added to an ethanol (20 ml) solution of the residue, and the mixture was stirred at 50 ° C for 2 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 2 → 1: 1) and further recrystallized (ethyl acetate-hexane) to give 7- [4- ( 2-Butoxyethoxy) phenyl] -N- [4- (1,3,4-thiadiazole-
2-ylthiomethyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 115) (373.1 mg) was obtained. mp 77-79 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30-1.46 (2H, m), 1.52-1.68
(2H, m), 1.96-2.11 (1H, m), 2.86-2.97 (2H, m), 3.19
(2H, d, J = 7.4 Hz), 3.30-3.41 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.58 (2H, s), 6.92 (1H, d, J = 8.8 Hz),
6.98 (2H, d, J = 8.8 Hz), 7.34-7.61 (10H, m), 9.00
(1H, s) HH. IR (KBr) 3299, 1640, 1605, 1595, 1516, 1499, 1408,
1368, 1316, 1246, 1181, 1123, 1061, 816 cm ^-1 Elemental analysis C ₃₆ H ₄₂ N ₄ O ₃ S ₂ Calcd. C, 67.26; H, 6.59;
N, 8.72: Found. C, 67.07; H, 6.37; N, 8.53.

Example 109 (Production of compound 116) 7- [4- (2-butoxyethoxy) phenyl] -N-
A solution of (4-hydroxymethylphenyl) -2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) was added at room temperature to thionyl chloride (0.1 ml) and Pyridine (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in DMF (10 ml) was added with potassium carbonate (0.51).
g) and 5-methyl-2-mercapto-1,3,4-
Add oxadiazole potassium salt (0.18 g) and add 5
Stirred at 0 ° C. for 1 hour. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1), and recrystallized (ethyl acetate-hexane).
7- [4- (2-butoxyethoxy) as yellow crystals
Phenyl] -N- [4- (5-methyl-1,3,4-oxadiazol-2-ylthiomethyl) phenyl] -1
-Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 116) (46
9.8 mg) was obtained. mp 107-109 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.54-1.67
(2H, m), 1.97-2.16 (1H, m), 2.49 (3H, s), 2.85-2.9
5 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.33-3.37 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.15 (2H, t, J = 5.0 Hz), 4.43 (2H, s), 6.91 (1
H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.37-7.50
(7H, m), 7.57 (2H, d, J = 8.4 Hz), 7.63 (1H, s) .IR (KBr) 3345, 1645, 1605, 1591, 1518, 1499, 1487,
1246, 1161, 808 cm ^-1 Elemental analysis C ₃₇ H ₄₄ N ₄ O ₄ S Calcd. C, 69.35; H, 6.92;
N, 8.74: Found. C, 69.12; H, 6.84; N, 8.93.

Example 110 (Production of Compound 117) 7- [4- (2-butoxyethoxy) phenyl] -N-
A solution of (4-hydroxymethylphenyl) -2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) was added at room temperature to thionyl chloride (0.1 ml) and Pyridine (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, triethylamine (2.0 ml) and 2-mercapto-4-methyl- were added to a solution of the residue in ethanol (20 ml).
1,2,4-triazole (0.14 g) was added, and 50
The mixture was stirred at 0 ° C for 16 hours. 1,8-Diazabicyclo [5,4,0] -7-undecene (1.0 ml) was added to the reaction system, and the mixture was further stirred at 60 ° C. for 4 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethanol: ethyl acetate 1:10) to give 7- [4- (2-butoxyethoxy) phenyl as a yellow amorphous substance. ] -N- [4- (4-methyl-4H
-1,2,4-Triazol-3-ylthiomethyl) phenyl] -1-isobutyl-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (Compound 11
7) (312.9 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, = 6.6 Hz), 1.31-1.46 (2H, m), 1.51-1.66
(2H, m), 1.93-2.15 (1H, m), 2.85-2.94 (2H, m), 3.1
8 (2H, d, J = 7.2 Hz), 3.30-3.38 (5H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.34 (2H, s), 6.91 (1H, d, J = 8.8 Hz),
6.97 (2H, d, J = 8.8 Hz), 7.22-7.26 (2H, m), 7.37-7.
54 (7H, m), 7.62 (1H, s), 8.08 (1H, s). IR (KBr) 3275, 1655, 1605, 1516, 1499, 1408, 1316,
1244, 1181, 1123, 1065, 835, 816 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃ S0.5H ₂ O Calcd. C, 68.49; H,
7.15; N, 10.79: Found. C, 68.45; H, 7.22; N, 1
0.68.

Example 111 (Production of Compound 118) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Methyl-4H-1,2,4-triazol-3-ylthiomethyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.26 g) in dichloromethane (10 m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.26 g) in dichloromethane (10 ml) was added, and the mixture was stirred at -10 to -15 ° C for 1.5 hours. An aqueous magnesium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, 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-ish as yellow crystals.
[4- (2-butoxyethoxy) phenyl] -N- [4
-(4-Methyl-4H-1,2,4-triazole-3
-Ylsulfinylmethyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4
-Carboxamide (Compound 118) (73.8 mg) was obtained. mp 87-89 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.26-1.45 (2H, m), 1.48-1.67
(2H, m), 1.98-2.12 (1H, m), 2.85-2.96 (2H, m), 3.19
(2H, d, J = 7.0 Hz), 3.30-3.43 (5H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.37 (1H, d, J = 13.4 Hz), 4.65 (1H, d, J
= 13.4 Hz), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J =
8.8 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.34-7.64 (8H, m),
8.05 (1H, s). IR (KBr) 3267, 1655, 1607, 1516, 1499, 1410, 1314,
1246, 1182, 1125, 1063, 820 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₄ S1.0H ₂ O Calcd. C, 65.95; H,
7.03; N, 10.39: Found. C, 65.55; H, 6.79; N, 1
0.34.

Example 112 (Preparation of compound 119) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (1,3,4-thiadiazol-2-ylthiomethyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (4
To a solution of 80 mg) in dichloromethane (20 ml), -7
A solution of 3-chloroperbenzoic acid (70%, 0.28 g) in dichloromethane (10 ml) was added dropwise at 8 ° C. -10 ° C
After stirring for 4 hours, an aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 1: 2 → 1: 1) to give 7 as yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -N-
[4- (1,3,4-thiadiazol-2-ylsulfinylmethyl) phenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 119) (33 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30-1.49 (2H, m), 1.53-1.68
(2H, m), 1.98-2.13 (1H, m), 2.85-2.96 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.30-3.38 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.31 (1H, d, J = 13.2 Hz), 4.54 (1H, d, J
= 13.2 Hz), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J =
8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.35-7.56 (7H, m),
7.62 (1H, s), 9.21 (1H, s). IR (KBr) 3306, 1653, 1607, 1516, 1499, 1410, 1316,
1244, 1182, 1117, 1071, 820 cm ^-1 Elemental analysis C ₃₆ H ₄₂ N ₄ O ₄ S ₂ 0.5H ₂ O Calcd. C, 64.74; H,
6.49; N, 8.39: Found. C, 64.75; H, 6.48; N, 8.
50.

Example 113 (Production of compound 120) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[[(1-Isopropylimidazol-2-yl) methyl] sulfanyl] aniline (515 mg), triethylamine (5.8 ml) in tetrahydrofuran (15 m)
l) Added to the solution at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 1 hour, 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 solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3 → ethyl acetate) and recrystallized from ethanol-hexane to give 7- [as yellow crystals. 4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[(1-Isopropylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (41
7 mg) (compound 120) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.45 (8H, m), 1.55-1.70 (2H, m), 1.95-2.10 (1H,
m), 2.90 (2H, t, J = 4.8 Hz), 3.18 (2H, d, J = 7.0Hz),
3.35 (2H, t, J = 4.8 Hz), 3.56 (2H, t, J = 7.0 Hz),
3.80 (2H, t, J = 4.4Hz), 4.13-4.18 (4H, m), 4.40-4.6
0 (1H, m), 6.89-7.00 (5H, m), 7.32-7.55 (9H, m), 7.
75 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.55; H,
7.58; N, 8.34; Found. C, 71.32; H, 7.52; N, 8.
17.

Example 114 (Compound 121, Compound 12)
Production of 2) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-isopropylimidazol-2-yl) methyl] sulfanyl] phenyl]
2,2-Dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml)
A solution of 70% 3-chloroperbenzoic acid (111 mg) in dichloromethane (10 ml) was added dropwise to the solution at -78 ° C. After completion of dropping, the mixture was stirred at -10 ° C to -25 ° C for 1 hour. Aqueous sodium thiosulfate solution was added and the temperature was returned to room temperature.
After stirring for a minute, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl as a yellow amorphous substance. ] -1-isobutyl-N- [4-[[(1
-Isopropylimidazol-2-yl) methyl] sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (89.0 mg) (Compound 121), recrystallized from hexane-ethyl acetate to give a yellow color. 7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-isopropylimidazol-2-yl) methyl] sulfanyl] as crystals
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (29 mg) (Compound 122) was obtained Compound 121 ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.22-
1.49 (8H, m), 1.54-1.75 (2H, m), 2.00-2.20 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.6 Hz), 3.30
-3.40 (2H, m), 3.55 (2H, t, J = 7.6 Hz), 3.80 (2H,
t, J = 4.4 Hz), 4.10-4.30 (4H, m), 4.40-4.50 (1H,
m), 6.90-7.02 (5H, m), 7.38-7.48 (7H, m), 7.73 (2H,
d, J = 8.8 Hz), 7.88 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S ・ 0.3H ₂ O Calcd. C, 69.80; H,
7.41; N, 8.14; Found.C, 69.56; H, 7.18; N, 7.9
1. Compound 122 ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-1.02 (9H, m), 1.34-
1.65 (10H, m), 2.00-2.20 (1H, m), 2.90-3.00 (2H,
m), 3.21 (2H, d, J = 7.4 Hz), 3.30-3.40 (2H, m), 3.5
5 (2H, t, J = 7.0 Hz), 3.80 (2H, t, J = 5.2 Hz), 4.15
(2H, t, J = 5.2 Hz), 4.42 (2H, s), 4.60-4.70 (1H,
m), 6.89-7.03 (5H, m), 7.31-7.38 (5H, m), 7.55 (2H,
d, J = 8.8 Hz), 7.74 (2H, d, J = 8.8 Hz), 8.52 (1H,
s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₅ S ・ 0.5H ₂ O Calcd. C, 67.86; H,
7.26; N, 7.91; Found.C, 67.61; H, 7.07; N, 7.7
6.

Example 115 (Production of compound 123) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred for 1 hour. It concentrated under pressure reduction and the acid chloride was obtained. Also, 4-aminothiophenol (0.29 g) and triethylamine (1.6 ml)
Benzyl chlorocarbonate (0.35 ml) was added to a THF (10 ml) solution of the above at 0 ° C., and the mixture was stirred at 0 ° C. for 0.5 hours and at room temperature for 0.5 hours. Acid chloride T previously adjusted at 0 ° C
An HF (20 ml) solution was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue THF-methanol (30-30
ml) solution at room temperature with 1N aqueous sodium hydroxide solution (10
ml) was added and stirred for 0.5 hours. 5-Chloromethyl-1-methyl-1H-1,2,4-triazole.hydrochloride (0.39 g) was added to the reaction system, and the mixture was stirred for 16 hours.
After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate:
Hexane 1: 1 → 3: 2 → 2: 1) was used for separation and purification, and as a yellow amorphous substance, 7- [4- (2-butoxyethoxy) phenyl] -N- [4- (1-methyl-1H-). 1,
2,4-triazol-5-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 123)
(639 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30-1.48 (2H, m), 1.51-1.68
(2H, m), 1.98-2.16 (1H, m), 2.85-2.95 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.33-3.78 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.74 (3H, s), 3.80 (2H, t, J = 5.0 H
z), 4.12 (2H, s), 4.16 (2H, t, J = 5.0 Hz), 6.92 (1
H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.31-7.49
(7H, m), 7.55 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.
76 (1H, s). IR (KBr) 3300, 1651, 1607, 1586, 1497, 1395, 1312,
1285, 1244, 1181, 1119, 822 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃ S0.5H ₂ O Calcd. C, 68.49; H,
7.15; N, 10.79: Found. C, 68.62; H, 7.14; N, 1
1.00.

Example 116 (Production of compound 124) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (1-Methyl-1H-1,2,4-triazol-5-ylmethylthio) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (565 mg) in dichloromethane (10 m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.32 g) in dichloromethane (10 ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 19 → 1: 9) and further recrystallized (ethyl acetate-hexane) to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
(1-Methyl-1H-1,2,4-triazole-5-
Ilmethylsulfinyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-
A carboxamide (Compound 124) (515 mg) was obtained. mp 135-138 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.35-1.47 (2H, m), 1.52-1.68
(2H, m), 1.96-2.17 (1H, m), 2.87-2.97 (2H, m), 3.20
(2H, d, J = 7.4 Hz), 3.32-3.41 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.76 (3H, s), 3.81 (2H, t, J = 4.9 H
z), 4.16 (2H, t, J = 4.9 Hz), 4.19 (1H, d, J = 13.6 H
z), 4.28 (1H, d, J = 13.6 Hz), 6.91-7.01 (3H, m), 7.
36-7.52 (7H, m), 7.74 (1H, br s), 7.78 (2H, d, J = 8.
8 Hz), 7.83 (1H, s) .IR (KBr) 3382, 1655, 1613, 1591, 1520, 1497, 1393,
1318, 1246, 1184, 1121, 1036, 820 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₄ S Calcd. C, 67.76; H, 6.92;
N, 10.68: Found. C, 67.52; H, 6.76; N, 10.43.

Example 117 (Production of compound 125) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) at room temperature was thionyl chloride (0.26 ml) and DM.
F (1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a THF (30 ml) solution of the residue was added to a THF (5 ml) solution of S- (4-aminophenyl) O-benzyl thiocarbonate (0.64 g) and triethylamine (1.3 ml).
Dropwise at ° C. After stirring at room temperature for 2 hours, methanol (50
ml) and 1N aqueous sodium hydroxide solution (15 ml)
Was added and stirred for 0.5 hour. 3-Chloromethyl-1-methyl-1H-1,2,4-triazole.hydrochloride (0.44 g) was added to the reaction system and the mixture was stirred for 1 hour. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance.
-1-Isobutyl-N- [4- (1-methyl-1H-
1,2,4-Triazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4
-Carboxamide (Compound 125) (1.00 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.32-1.50 (2H, m), 1.53-1.69
(2H, m), 1.96-2.15 (1H, m), 2.85-2.95 (2H, m), 3.18
(2H, d, J = 7.0 Hz), 3.33-3.38 (2H, m), 3.55 (1H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 3.86 (3H,
s), 4.13-4.18 (4H, m), 6.92 (1H, d, J = 8.8 Hz), 6.9
8 (2H, d, J = 8.8 Hz), 7.38-7.55 (10H, m), 7.94 (1H,
s), H. IR (KBr) 3300, 1653, 1605, 1586, 1499, 1312, 1285,
1244, 1181, 1123, 820cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃ S0.5H ₂ O Calcd. C, 68.49; H,
7.15; N, 10.79: Found. C, 68.18; H, 6.85; N, 1
1.09.

Example 118 (Compound 126, Compound 12)
Production of 7) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (1-methyl-1H-1,2,2
4-triazol-3-ylmethylthio) phenyl]-
A solution of 2,3-dihydro-1H-benzazepine-4-carboxamide (0.8 g) in dichloromethane (20 ml) was added to 3-chloroperbenzoic acid (70%, 0.
46 g) in dichloromethane (10 ml) was added dropwise,
The mixture was stirred at -78 ° C for 0.5 hours. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 5 → 1: 3) and further recrystallized (ethyl acetate-hexane) to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (1-methyl-1H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl]-
2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 126) (678.9 mg) was obtained.
At the same time, 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- (1-methyl-1)
H-1,2,4-triazol-3-ylmethylsulfonyl) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 127) (22.
2 mg) was obtained. Compound 126 mp 112-114 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3 H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.30-1.44 (2H, m), 1.50-1.66
(2H, m), 1.96-2.15 (1H, m), 2.86-2.97 (2H, m), 3.20
(2H, d, J = 7.0 Hz), 3.32-3.41 (2H, m), 3.55 (1H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.8 Hz), 3.89 (3H,
s), 4.09 (1H, d, J = 13.2 Hz), 4.16 (2H, t, J = 4.8 H
z), 4.28 (1H, d, J = 13.2 Hz), 6.93 (1H, d, J = 8.4 H
z), 6.98 (2H, d, J = 9.2 Hz), 7.36-7.50 (5H, m), 7.58
(2H, d, J = 8.8 Hz), 7.69 (1H, s), 7.75 (2H, d, J = 8.
8 Hz), 7.97 (1H, s), H. IR (KBr) 3104, 1661, 1607, 1590, 1518, 1499, 1314,
1246, 1179, 1125, 1046, 835 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₄ S0.25H ₂ O Calcd. C, 67.30; H,
6.94; N, 10.61: Found. C, 67.16; H, 6.89; N, 1
0.61. Compound 127 mp 205-208 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.28-1.46 (2H, m), 1.52-1.68
(2H, m), 1.96-2.13 (1H, m), 2.86-2.96 (2H, m), 3.20
(2H, d, J = 7.0 Hz), 3.31-3.42 (2H, m), 3.55 (1H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 3.89 (3H,
s), 4.16 (2H, t, J = 4.8 Hz), 4.52 (2H, s), 6.91-7.0
0 (3H, m), 7.39-7.50 (5H, m), 7.77-7.81 (5H, m),
7.95 (1H, s), H. IR (KBr) 3240, 1672, 1609, 1590, 1520, 1501, 1402,
1318, 1240, 1182, 1146, 808 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₅ S0.5H ₂ O Calcd. C, 65.27; H,
6.81; N, 10.29: Found. C, 65.17; H, 6.72; N, 1
0.16.

Example 119 (Production of compound 128) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thioni chloride (0.21 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to 4- (1,2,2).
4-Oxadiazol-3-ylmethylthio) aniline (0.43 g) and triethylamine (1.6 ml)
Was added dropwise to a THF (2 ml) solution at 0 ° C. 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 saturated saline 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) and further recrystallized (ethanol) to give 7- [4 as yellow crystals.
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (1,2,4-oxadiazole-3-
Ilmethylthio) phenyl] -2,3-dihydro-1H
-Benzazepine-4-carboxamide (compound 12
8) (855.7 mg) was obtained. mp 112-115 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.28-1.48 (2H, m), 1.54-1.68
(2H, m), 1.94-2.18 (1H, m), 2.84-2.95 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.33-3.38 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.13-4.18 (4
H, m), 6.92 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8
Hz), 7.38-7.58 (10H, m), 8.67 (1H, s), H. IR (KBr) 3337, 1647, 1605, 1584, 1551, 1501, 1397,
1337, 1310, 1240, 1109, 828, 810 cm ^-1 Elemental analysis C ₃₆ H ₄₂ N ₄ O ₄ S Calcd. C, 68.98; H, 6.75;
N, 8.94: Found. C, 68.95; H, 6.94; N, 8.97.

Example 120 (Production of compound 129) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (1,2,4-oxadiazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (0.
To a solution of 60 g) in dichloromethane (15 ml), -78
A solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (5 ml) was added dropwise at C, and the mixture was stirred at -78 C for 1 hour. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 4: 1), and recrystallized (ethyl acetate-hexane).
7- [4- (2-butoxyethoxy) as yellow crystals
Phenyl] -1-isobutyl-N- [4- (1,2,4
-Oxadiazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-benzazepine-
4-carboxamide (Compound 129) (534.9m
g) was obtained. mp 142-144 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.34-1.49 (2H, m), 1.54-1.71
(2H, m), 1.96-2.16 (1H, m), 2.86-2.95 (2H, m), 3.20
(2H, d, J = 7.2 Hz), 3.31-3.41 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.21 (1H, d, J = 13.2 Hz), 4.32 (1H, d, J
= 13.2 Hz), 6.91-7.00 (3H, m), 7.39-7.50 (5H, m),
7.59 (2H, d, J = 8.8 Hz), 7.77-7.81 (3H, m), 8.71 (1
H, s), H. IR (KBr) 3222, 1649, 1607, 1588, 1499, 1397, 1343,
1314, 1246, 1181, 1128, 1047, 828, 808 cm ^-1 Elemental analysis C ₃₆ H ₄₂ N ₄ O ₅ S Calcd. C, 67.26; H, 6.59;
N, 8.72: Found. C, 67.24; H, 6.60; N, 8.66.

Example 121 (Production of compound 130) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.50 g) in THF (10 m
l) Thionyl chloride (0.13 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred for 1 hour. It concentrated under pressure reduction and the acid chloride was obtained. Separately, 4-aminothiophenol (0.16 g) and triethylamine (0.70
ml) in THF (10 ml), benzyl chlorocarbonate (0.19 ml) was added at −78 ° C.
The mixture was stirred for 0.5 minutes at 0 ° C. for 0.5 hours and at room temperature for 0.5 hours.
A solution of the acid chloride prepared above in THF (10 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hr. Add water to the reaction system,
It was extracted with ethyl acetate. The organic layer was washed with saturated saline,
It was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1: 4).
→ Separation and purification in 1: 3) yielded a yellow amorphous substance. THF-methanol (1 of the obtained compound (0.54 g)
0-10 ml) solution was added with 1N aqueous sodium hydroxide solution (32 ml) at room temperature and stirred for 1 hour. 3-in the reaction system
Chloromethyl-4-methyl-4H-1,2,4-triazole.hydrochloride (0.15 g) was added, and the mixture was stirred for 0.5 hr. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate → ethanol: ethyl acetate 1: 10 → 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance. -N- [4- (4-methyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 130) (352.8 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.51-1.68
(2H, m), 1.97-2.18 (1H, m), 2.86-2.96 (2H, m), 3.19
(2H, d, J = 6.6 Hz), 3.28-3.39 (2H, m), 3.56 (2H,
t, J = 6.6 Hz), 3.60 (3H, s), 3.81 (2H, t, J = 5.0 H
z), 4.11 (2H, s), 4.16 (2H, t, J = 5.0 Hz), 6.89-7.0
0 (3H, m), 7.29-7.43 (6H, m), 7.46 (2H, d, J = 8.4 H
z), 7.57 (2H, d, J = 8.4 Hz), 7.97 (1H, s), 806 (1H,
br s) .IR (KBr) 3282, 1655, 1607, 1586, 1499, 1312, 1242,
1181, 1123, 820 cm ^-1

Example 122 (Production of compound 131) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Methyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.30 g) in dichloromethane (10 m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.17 g) in dichloromethane (10 ml) was added dropwise. After stirring at −78 ° C. for 0.5 hour, an aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes.
After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4 → 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl]-as yellow crystals.
N- [4- (4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 131) (204m
g) was obtained. mp 103-105 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
01 (6H, d, J = 6.2 Hz), 1.29-1.47 (2H, m), 1.53-1.72
(2H, m), 1.96-2.17 (1H, m), 2.89-3.01 (2H, m), 3.22
(2H, d, J = 7.8 Hz), 3.30-3.40 (2H, m), 3.53-3.61
(5H, m), 3.81 (2H, t, J = 4.9 Hz), 3.96 (1H, d, J = 1
4.0 Hz), 4.11 (1H, d, J = 14.0 Hz), 4.16 (2H, t, J = 4.
9 Hz), 6.89-6.99 (3H, m), 7.16-7.22 (2H, m), 7.34-
7.48 (5H, m), 7.85 (2H, d, J = 8.4 Hz), 8.00 (1H, s),
8.64 (1H, br s). IR (KBr) 3298, 1655, 1607, 1588, 1520, 1499, 1314,
1246, 1181, 1125, 1090, 1047, 833 cm ^-1

Example 123 (Production of Compound 132) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.26 ml) and D
MF (1 drop) was added and stirred for 1 hour. It concentrated under pressure reduction and the acid chloride was obtained. In addition, 4-aminothiophenol (0.
30 g) and triethylamine (2.0 ml) TH
Benzyl chlorocarbonate (0.36 ml) was added to the F (5 ml) solution at -78 ° C, and the mixture was stirred at -78 ° C for 20 minutes and at 0 ° C for 20 minutes. TH of acid chloride previously adjusted at 0 ° C
The F (20 ml) solution was added dropwise, and the mixture was stirred at room temperature for 2 hours.
Methanol (50 ml) and 1N aqueous sodium hydroxide solution (15 ml) were added to the reaction system, and the mixture was stirred for 20 minutes.
3-chloromethyl-4-methyl-4H-1, in the reaction system
2,4-triazole hydrochloride (0.41 g) was added,
Stir for 0.5 hours. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 10 → 1: 4) to give 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4- (4-methyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-propyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 132) (836.4 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
00 (3H, t, J = 7.3 Hz), 1.30-1.46 (2H, m), 1.51-1.82
(4H, m), 2.85-2.96 (2H, m), 3.24-3.38 (4H, m), 3.56
(2H, t, J = 6.6 Hz), 3.57 (3H, s), 3.81 (2H, t, J =
4.9 Hz), 4.07 (2H, s), 4.16 (2H, t, J = 4.9 Hz), 6.8
8 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 9.2 Hz), 7.31-
7.47 (7H, m), 7.58 (2H, d, J = 8.8 Hz), 7.94 (1H,
s), 8.26 (1H, s). IR (KBr) 3268, 1655, 1605, 1586, 1499, 1397, 1310,
1242, 1179, 1119, 816cm ^-1

Example 124 (Production of compound 133) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Methyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-propyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.70 mg) in dichloromethane (20
ml) solution at 3-78 ° C with 3-chloroperbenzoic acid (70
%, 0.41 g) in dichloromethane (5 ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography using basic silica gel (ethanol: ethyl acetate → 1: 9), and recrystallized (ethyl acetate-hexane) to give 7- [as yellow crystals. 4- (2-butoxyethoxy) phenyl] -N- [4- (4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl]
-1-Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 133) (61
3.2 mg) was obtained. mp 101-103 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
03 (3H, t, J = 7.3 Hz), 1.30-1.46 (2H, m), 1.52-1.88
(4H, m), 2.89-3.00 (2H, m), 3.28-3.41 (4H, m), 3.48
(3H, s), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J =
4.8 Hz), 3.87 (1H, d, J = 14.0 Hz), 4.04 (1H, d, J = 1
4.0 Hz), 4.13 (2H, t, J = 4.8 Hz), 6.89 (1H, d, J = 8.6
Hz), 6.96 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.4 H
z), 7.30-7.43 (5H, m), 7.86 (2H, d, J = 8.8 Hz), 7.9
6 (1H, s), 8.88 (1H, br s). IR (KBr) 3262, 1653, 1590, 1520, 1501, 1316, 1246,
1179, 1123, 1051, 835cm ^-1

Example 125 (Production of compound 134) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) at room temperature was thionyl chloride (0.26 ml) and DM.
F (1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (35 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.59 g) and triethylamine (2.0 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 18 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (15
ml) was added and the mixture was stirred for 0.5 hours. 3-Chloromethyl-4-ethyl-4H-1,2,4-triazole.hydrochloride (0.46 g) was added to the reaction system, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 9 → 1: 5) to give 7- [4- (2-butoxyethoxy) phenyl] -N-as a yellow amorphous substance. [4- (4-Ethyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-
4-Carboxamide (Compound 134) (1.14 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.31-1.46 (5H, m), 1.55-1.67
(2H, m), 1.97-2.17 (1H, m), 2.85-2.95 (2H, m), 3.18
(2H, d, J = 7.4 Hz), 3.27-3.36 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 3.92 (2H, q,
J = 7.5 Hz), 4.06 (2H, s), 4.16 (2H, t, J = 5.0 Hz),
6.89 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.
26-7.41 (5H, m), 7.43 (2H, d, J = 8.8 Hz), 7.60 (2H,
d, J = 8.8 Hz), 8.00 (1H, s), 8.43 (1H, s) .IR (KBr) 3264, 1659, 1605, 1588, 1514, 1499, 1244,
1182, 1125, 818 cm ^-1 Elemental analysis C ₃₈ H ₄₇ N ₅ O ₃ S0.25H ₂ O Calcd. C, 69.32; H,
7.27; N, 10.64: Found. C, 69.28; H, 7.49; N, 1
0.50.

Example 126 (Production of compound 135) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Ethyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (0.94 g) in dichloromethane (20 ml)
To the solution at -78 ° C 3-chloroperbenzoic acid (70%,
A solution of 0.53 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 9), and recrystallized (ethyl acetate) to give 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- (4
-Ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 135) (858.7 mg) was obtained. mp 102-104 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
99 (6H, d, J = 6.6 Hz), 1.30-1.48 (5H, m), 1.51-1.68
(2H, m), 1.96-2.19 (1H, m), 2.89-2.99 (2H, m), 3.21
(2H, d, J = 6.6 Hz), 3.32-3.42 (2H, m), 3.56 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.8 Hz), 3.93-4.26 (6
H, m), 6.90-7.00 (3H, m), 7.37-7.46 (7H, m), 7.81
(2H, d, J = 8.8 Hz), 8.09-8.17 (2H, m). IR (KBr) 3218, 1655, 1605, 1590, 1520, 1499, 1314,
1244, 1181, 1090, 1053, 835 cm ^-1 Elemental analysis C ₃₈ H ₄₇ N ₅ O ₄ S0.5H ₂ O Calcd. C, 67.23; H,
7.13; N, 10.32: Found. C, 66.91; H, 7.06; N, 1
0.03.

Example 127 (Production of compound 136) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (1.0 g) in THF (10 ml) was added thionyl chloride (0.26 ml) and DMF at room temperature.
(1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (35 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.62 g) and triethylamine (2.0 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 16 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (1
5 ml) was added and stirred for 0.5 hours. 3-Chloromethyl-4-ethyl-4H-1,2,4-triazole.hydrochloride (0.47 g) was added to the reaction system and the mixture was stirred for 2 hours. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 9 → 1: 5) to give 7- [4- (2-butoxyethoxy) phenyl] -N-as a yellow amorphous substance. [4- (4-Ethyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4
-Carboxamide (Compound 136) (1.15 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
00 (3H, t, J = 7.3 Hz), 1.26-1.47 (5H, m), 1.52-1.82
(4H, m), 2.85-2.96 (2H, m), 3.27-3.37 (4H, m), 3.56
(2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 3.92
(2H, q, J = 7.4 Hz), 4.05 (2H, s), 4.16 (2H, t, J = 5.
0 Hz), 6.87 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.8
Hz), 7.27-7.32 (4H, m), 7.36-7.46 (3H, m), 7.60 (2
H, d, J = 8.4 Hz), 8.00 (1H, s), 8.45 (1H, br s) .IR (KBr) 3223, 1657, 1605, 1588, 1499, 1310, 1240,
1181, 1121, 816 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃ S0.5H ₂ O Calcd. C, 68.49; H,
7.15; N, 10.79: Found. C, 68.52; H, 7.20; N, 1
1.14.

Example 128 (Production of compound 137) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Ethyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-propyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (0.93 g) in dichloromethane (20 ml)
To the solution at -78 ° C 3-chloroperbenzoic acid (70%,
A solution of 0.54 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 5 → 1: 3 → 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl as a yellow amorphous substance. ] -N- [4- (4-Ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl]
-1-Propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 137) (694.
7 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
02 (3H, t, J = 7.3 Hz), 1.29-1.50 (5H, m), 1.53-1.86
(4H, m), 2.92-2.99 (2H, m), 3.25-3.40 (4H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 3.87-
4.01 (3H, m), 4.08-4.17 (3H, m), 6.89 (1H, d, J = 8.
8 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.23-7.43 (7H, m),
7.85 (2H, d, J = 8.8 Hz), 8.08 (1H, s), 8.62 (1H, br
s) .IR (KBr) 3104, 1661, 1607, 1588, 1518, 1499, 1397,
1314, 1244, 1179, 1123, 1090, 833 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₄ SH ₂ O Calcd. C, 65.95; H, 7.03
; N, 10.39: Found. C, 65.78; H, 7.10; N, 10.5
2.

Example 129 (Production of compound 138) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) at room temperature was thionyl chloride (0.26 ml) and DM.
F (1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.64 g) and triethylamine (1.3 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 2 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (15
ml) was added and the mixture was stirred for 0.5 hours. 3-Chloromethyl-4-propyl-4H-1,2,4-triazole.hydrochloride (0.51 g) was added to the reaction system, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol:
It was separated and purified with ethyl acetate 1: 9 → 1: 5) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- (4-propyl-) as a yellow amorphous substance.
Synthesis of 4H-1,2,4-triazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 138) (9
87 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-2.99 (12H, m), 1.29-
1.49 (2H, m), 1.53-1.85 (4H, m), 1.96-2.17 (1H, m),
2.86-2.96 (2H, m), 3.18 (2H, d, J = 7.0 Hz), 3.28-3.
38 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.79-3.86 (4H,
m), 4.06 (2H, s), 4.16 (2H, t, J = 4.9 Hz), 6.90 (1
H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.31-7.46
(7H, m), 7.60 (2H, d, J = 8.8 Hz), 7.97 (1H, s), 8.
42 (1H, br s), H. IR (KBr) 3264, 1659, 1607, 1588, 1497, 1397, 1312,
1242, 1181, 1123, 816cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₃ S0.5H ₂ O Calcd. C, 69.20; H,
7.45; N, 10.35: Found. C, 69.12; H, 7.58; N, 1
0.41.

Example 130 (Production of compound 139) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (4-propyl-4H-1,
2,4-Triazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-
Carboxamide (826 mg) in dichloromethane (20
ml) solution at 3-78 ° C with 3-chloroperbenzoic acid (70
%, 0.46 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography using basic silica gel (ethanol: ethyl acetate 1: 5 → 1: 3) to give 7- [4- (2-butoxyethoxy) as a yellow amorphous substance. ) Phenyl] -1-isobutyl-N- [4-
(4-Propyl-4H-1,2,4-triazole-3
-Ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 139) (628.7 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.3 Hz), 0.
93 (3H, t, J = 7.1 Hz), 1.01 (6H, d, J = 6.6 Hz), 1.28-
1.47 (2H, m), 1.51-1.78 (4H, m), 1.95-2.18 (1H, m),
2.90-3.01 (2H, m), 3.21 (2H, d, J = 7.2 Hz), 3.31-
3.41 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.76-3.86 (4
H, m), 3.97 (1H, d, J = 14.2 Hz), 4.11 (1H, d, J = 14.2
Hz), 4.15 (2H, t, J = 4.9 Hz), 6.91 (1H, d, J = 8.8 H
z), 6.96 (2H, d, J = 8.4 Hz), 7.27-7.43 (7H, m), 7.85
(2H, d, J = 8.8 Hz), 8.04 (1H, s), 8.70 (1H, br s),
H. IR (KBr) 3282, 1661, 1607, 1588, 1518, 1499, 1397,
1314, 1244, 1181, 1125, 1051, 835 cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₄ S0.5H ₂ O Calcd. C, 67.60; H,
7.27; N, 10.11: Found. C, 67.25; H, 7.28; N,
9.82.

Example 131 (Production of compound 140) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (1.0 g) in THF (10 ml) was added thionyl chloride (0.26 ml) and DMF at room temperature.
(1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.64 g) and triethylamine (2.0 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 2 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (15
ml) was added and the mixture was stirred for 0.5 hours. 3-Chloromethyl-4-propyl-4H-1,2,4-triazole.hydrochloride (0.50 g) was added to the reaction system, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol:
Separation and purification with ethyl acetate 1: 9 → 1: 5) gave 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4) as a yellow amorphous substance.
H-1,2,4-triazol-3-ylmethylthio)
Phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 140) (1.00 g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.03 (9H, m), 1.28-1.
47 (2H, m), 1.51-1.88 (6H, m), 2.85-2.96 (2H, m),
3.23-3.36 (4H, m), 3.56 (2H, t, J = 6.6 Hz), 3.77-3.
84 (4H, m), 4.04 (2H, s), 4.16 (2H, t, J = 4.8 Hz),
6.87 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.
26-7.45 (7H, m), 7.60 (2H, d, J = 8.8 Hz), 7.96 (1H,
s), 8.52 (1H, s), H. IR (KBr) 3280, 1655, 1607, 1588, 1499, 1456, 1397,
1310, 1287, 1242, 1181, 1121, 818 cm ^-1 Elemental analysis C ₃₈ H ₄₇ N ₅ O ₃ S Calcd. C, 68.85; H, 7.30;
N, 10.56: Found. C, 68.54; H, 7.41; N, 10.70.

Example 132 (Production of compound 141) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4- (4-propyl-4H-1,2,2
4-triazol-3-ylmethylthio) phenyl]-
2,3-Dihydro-1H-benzazepine-4-carboxamide (843.7 mg) in dichloromethane (20 m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.48 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 5 → 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl]-as a yellow amorphous substance.
1-propyl-N- [4- (4-propyl-4H-1,
2,4-triazol-3-ylmethylsulfinyl)
Phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 141) (490.8 m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.2 Hz), 0.
93 (3H, t, J = 7.4 Hz), 1.02 (3H, d, J = 7.3 Hz), 1.27-
1.48 (2H, m), 1.51-1.86 (6H, m), 2.89-3.00 (2H, m),
3.28-3.41 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-
3.89 (4H, m), 4.00 (1H, d, J = 14.4 Hz), 4.12-4.19
(3H, m), 6.90 (1H, d, J = 8.4 Hz), 6.96 (2H, d, J = 9.2
Hz), 7.27-7.44 (7H, m), 7.84 (2H, d, J = 8.4 Hz),
8.06 (1H, s), 8.54 (1H, br s), H.IR (KBr) 3284, 1661, 1607, 1588, 1518, 1499, 1397,
1314, 1244, 1179, 1088, 1051, 835 cm ^-1 Elemental analysis C ₃₈ H ₄₇ N ₅ O ₄ S Calcd. C, 66.35; H, 7.18;
N, 10.18: Found. C, 65.95; H, 7.23; N, 10.53.

Example 133 (Production of Compound 142) 7- [4- (2-Butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) at room temperature was thionyl chloride (0.26 ml) and DM.
F (1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.59 g) and triethylamine (2.0 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 18 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (15
ml) was added and the mixture was stirred for 0.5 hours. 4-n-Butyl-3-chloromethyl-4H-1,2,4-triazole.hydrochloride (0.51 g) was added to the reaction system, and the mixture was stirred for 2 hours.
After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol:
Separated and purified with ethyl acetate 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl]-as a yellow amorphous substance.
N- [4- (4-n-Butyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4
-Carboxamide (Compound 142) (1.34 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.22-
1.48 (4H, m), 1.52-1.83 (4H, m), 1.98-2.18 (1H, m),
2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.6 Hz), 3.29-3.
39 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J
= 4.8 Hz), 3.89 (2H, t. J = 7.5 Hz), 4.09 (2H, s), 4.1
6 (2H, t, J = 4.8 Hz), 6.88-6.99 (3H, m), 7.29-7.47
(7H, m), 7.58 (2H, d, J = 8.8 Hz), 8.00 (1H, s), 8.2
1 (1H, s). IR (KBr) 3227, 1653, 1605, 1588, 1518, 1497, 1312,
1242, 1181, 1121, 820cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₃ S0.5H ₂ O Calcd. C, 69.53; H,
7.59; N, 10.14: Found. C, 69.29; H, 7.57; N, 1
0.41.

Example 134 (Production of compound 143) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-n-Butyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.01 g) Dichloromethane (20m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.55 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, 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 recrystallized (ethyl acetate) to give 7- [4- (2- Butoxyethoxy) phenyl] -N- [4- (4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-isobutyl-2,3
-Dihydro-1H-benzazepine-4-carboxamide (Compound 143) (794.5 mg) was obtained. mp 178-180 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ0.88-1.07 (12H, m), 1.20-
1.69 (8H, m), 1.99-2.19 (1H, m), 2.91-2.99 (2H, m),
3.20 (2H, d, J = 7.0 Hz), 3.31-3.40 (2H, m), 3.55 (2
H, t, J = 6.6 Hz), 3.78-3.93 (4H, m), 4.03 (1H, d, J
= 14.0 Hz), 4.12-4.18 (3H, m), 6.90-6.99 (3H, m),
7.27-7.45 (7H, m), 7.83 (2H, d, J = 8.8Hz), 8.06 (1
H, s), 8.46 (1H, s). IR (KBr) 3297, 1653, 1607, 1588, 1520, 1499, 1397,
1310, 1240, 1181, 1028, 833 cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₄ S0.25H ₂ O Calcd. C, 68.39; H,
7.39; N, 9.97: Found. C, 68.22; H, 7.34; N, 1
0.04.

Example 135 (Preparation of compound 144) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (1.0 g) in THF (10 ml) was added thionyl chloride (0.26 ml) and DMF at room temperature.
(1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added dropwise to a solution of S- (4-aminophenyl) O-benzyl carbonate (0.61 g) and triethylamine (2.0 ml) in THF (5 ml) at 0 ° C. did. After stirring at room temperature for 64 hours, methanol (50 ml) and a 1N aqueous sodium hydroxide solution (1
5 ml) was added and stirred for 0.5 hours. 4-n- in the reaction system
Butyl-3-chloromethyl-4H-1,2,4-triazole.hydrochloride (0.52 g) was added, and the mixture was stirred for 2 hours. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 9 → 1: 5) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as a yellow amorphous substance. [4- (4-n-butyl-4H-
1,2,4-Triazol-3-ylmethylthio) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 144)
(1.23 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.03 (9H, m), 1.23-1.
45 (4H, m), 1.53-1.82 (6H, m), 2.87-2.96 (2H, m),
3.25-3.36 (4H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2
H, t, J = 5.0 Hz), 3.87 (2H, t, J = 7.3 Hz), 4.08 (2H,
s), 4.16 (2H, t. J = 5.0 Hz), 6.88 (1H, d, J = 8.6 H
z), 6.97 (2H, d, J = 8.4 Hz), 7.26-7.46 (7H, m), 7.5
9 (2H, d, J = 8.4 Hz), 7.98 (1H, s), 8.32 (1H, br
s) .IR (KBr) 3218, 1655, 1605, 1587, 1499, 1397, 1310,
1242, 1179, 1119, 833cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₃ S0.75H ₂ O Calcd. C, 68.74; H,
7.47; N, 10.28: Found. C, 68.79; H, 7.15; N, 1
0.68.

Example 136 (Production of compound 145) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-n-Butyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.00 g) Dichloromethane (20m
l) To the solution at -78 ° C 3-chloroperbenzoic acid (70
%, 0.55 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 5 → 1: 4), and recrystallized (ethyl acetate) to give 7- [4- (2- Butoxyethoxy) phenyl] -N- [4- (4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-propyl-2,3-
Dihydro-1H-benzazepine-4-carboxamide (Compound 145) (614.2 mg) was obtained. mp 157-160 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86-0.97 (6H, m), 1.02 (3
H, t, J = 7.3 Hz), 1.18-1.84 (10H, m), 2.89-2.99 (2
H, m), 3.26-3.40 (4H, m), 3.55 (2H, t, J = 6.6Hz),
3.78-3.97 (5H, m), 4.06-4.17 (3H, m), 6.89 (1H, d,
J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.24-7.42 (7H,
m), 7.85 (2H, d, J = 8.8 Hz), 8.03 (1H, s), 8.73 (1H,
s). IR (KBr) 3295, 1655, 1607, 1588, 1518, 1499, 1318,
1242, 1181, 1028, 835cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₄ S0.5H ₂ O Calcd. C, 67.60; H,
7.27; N, 10.11: Found. C, 67.46; H, 7.03; N, 1
0.33.

Example 137 (Preparation of compound 146) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.21 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added to S- (4-aminophenyl) O-benzyl carbonate (0.48 g).
And triethylamine (1.5 ml) in THF (5 m
l) The solution was added dropwise at 0 ° C. After stirring at room temperature for 2 hours, methanol (50 ml) and 1N aqueous sodium hydroxide solution (9 ml) were added, and the mixture was stirred for 0.5 hour. 3-chloromethyl-5-ethylthio-4-isobutyl-4H- was added to the reaction system.
1,2,4-triazole hydrochloride (0.54 g) was added, and the mixture was stirred for 2 hours. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 2: 1) to give 7- [4- (2-butoxyethoxy) phenyl] -N-as a yellow amorphous substance. [4- (5-Ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -1-isobutyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 146) (845.4 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (6H, d, J = 7.0 Hz), 0.
93 (3H, t, J = 7.1 Hz), 0.97 (6H, d, J = 6.6 Hz), 1.26-
1.44 (5H, m), 1.54-1.68 (2H, m), 1.94-2.16 (2H, m),
2.84-2.95 (2H, m), 3.18 (2H, d, J = 7.0 Hz), 3.21
(2H, q, J = 7.4 Hz), 3.28-3.38 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.74 (2H, d, J = 8.0 Hz), 3.80 (2H, t, J
= 5.0 Hz), 4.12 (2H, s), 4.16 (2H, t, J = 5.0 Hz), 6.
90 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.31
-7.47 (7H, m), 7.56 (2H, d, J = 8.4 Hz), 7.93 (1H,
s) .IR (KBr) 3083, 1659, 1607, 1588, 1499, 1468, 1397,
1312, 1242, 1181, 1125, 831 cm ^-1 Elemental analysis C ₄₂ H ₅₅ N ₅ O ₃ S ₂ 0.25H ₂ O Calcd. C, 67.57; H,
7.49; N, 9.38: Found. C, 67.37; H, 7.50; N,
9.30.

Example 138 (Preparation of compound 147) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (5-ethylthio-4-isobutyl-4H-1,
2,4-Triazol-3-ylmethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (697 mg) in dichloromethane (15 ml) at −78 ° C. was treated with 3-chloroperoxide. A solution of benzoic acid (70%, 0.35 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 4: 1 → 9: 1 → ethyl acetate →
Separated and purified with ethanol: ethyl acetate 1:19) to obtain 7- [4- (2-butoxyethoxy) phenyl] -N- [4- (5-ethylthio-4-isobutyl-4H-1) as a yellow amorphous substance. , 2,4-Triazol-3-ylmethylsulfinyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 147) (574.6 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.84-1.00 (15H, m), 1.28-
1.48 (5H, m), 1.52-1.68 (2H, m), 1.84-2.18 (2H, m),
2.89-2.98 (2H, m), 3.16-3.31 (4H, m), 3.34-3.41
(2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.66-3.84 (4H,
m), 4.08-4.28 (4H, m), 6.91-7.00 (3H, m), 7.35-7.52
(7H, m), 7.79 (2H, d, J = 8.8 Hz), 7.92 (1H, s) .IR (KBr) 3268, 1663, 1607, 1588, 1518, 1499, 1468,
1397, 1312, 1244, 1179, 1125, 1090, 835 cm ^-1 Elemental analysis C ₄₂ H ₅₅ N ₅ O ₄ S ₂ 0.5H ₂ O Calcd. C, 65.76; H,
7.36; N, 9.13: Found. C, 65.85; H, 7.47; N, 9.
19.

Example 139 (Production of compound 148) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.21 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added to S- (4-aminophenyl) O-benzyl carbonate (0.48 g).
And triethylamine (1.5 ml) in THF (5 m
l) The solution was added dropwise at 0 ° C. After stirring at room temperature for 4 hours, methanol (50 ml) and 1N aqueous sodium hydroxide solution (12 ml) were added, and the mixture was stirred for 0.5 hour. 3-in the reaction system
Chloromethyl-5-methylthio-4-propyl-4H-
1,2,4-triazole hydrochloride (0.47 g) was added, and the mixture was stirred for 1 hour. After concentration under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate) to give 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4- (5-methylthio-4-propyl-4H-1,
2,4-Triazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-
Carboxamide (Compound 148) (931 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.25-
1.48 (2H, m), 1.52-1.81 (4H, m), 1.94-2.17 (1H, m),
2.68 (3H, s), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.
4 Hz), 3.29-3.39 (2H, m), 3.55 (2H, t, J = 6.6 Hz),
3.78-3.86 (4H, m), 4.11 (2H, s), 4.16 (2H, t, J = 4.9
Hz), 6.91 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 H
z), 7.32-7.47 (7H, m), 7.57 (2H, d, J = 8.8 Hz), 7.9
7 (1H, s) .IR (KBr) 3270, 1659, 1607, 1588, 1499, 1470, 1397,
1312, 1244, 1181, 1125, 816 cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₃ S ₂ 0.25H ₂ O Calcd. C, 66.87; H,
7.22; N, 9.75: Found. C, 66.82; H, 7.11; N,
9.82.

Example 140 (Production of compound 149) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (0. 80 g) in dichloromethane (10 ml) at -78 ° C with 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (10 ml).
(ml) solution was added dropwise, and the mixture was stirred at -78 ° C for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), and recrystallized (ethyl acetate-hexane) to give yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl]- 2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 149)
(617.6 mg) was obtained. mp 150-152 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.3 Hz), 0.
93 (3H, t, J = 7.3 Hz), 0.99 (6H, d, J = 6.6 Hz), 1.29-
1.45 (2H, m), 1.48-1.73 (4H, m), 1.96-2.19 (1H, m),
2.70 (3H, s), 2.89-3.01 (2H, m), 3.20 (2H, d, J =
7.0 Hz), 3.31-3.43 (2H, m), 3.55 (2H, t, J = 6.6 H
z), 3.78-3.89 (4H, m), 4.02 (1H, d, J = 13.8 Hz), 4.
13-4.20 (3H, m), 6.89-6.99 (3H, m), 7.36-7.47 (7H,
m), 7.83 (2H, d, J = 8.8 Hz), 8.22 (1H, s) .IR (KBr) 3164, 1659, 1603, 1590, 1518, 1499, 1476,
1395, 1312, 1242, 1179, 1125, 1053, 833 cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₄ S ₂ Calcd. C, 65.81; H, 7.04;
N, 9.59: Found. C, 65.64; H, 7.00; N, 9.52.

Example 141 (Production of Compound 150) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml)
Thionyl chloride (0.075 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (10 ml) was added to 4- [methyl (4-propyl-4H-1,2,4-triazole-3].
A solution of -ylmethyl) amino] aniline (0.18 g) in pyridine (2 ml) was added dropwise at 0 ° C. After stirring at room temperature for 18 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate) and further recrystallized (ethyl acetate-hexane) to give 7- [4- (2-butoxyethoxy) as yellow crystals. Phenyl]
-1-Isobutyl-N- [4- [methyl (4-propyl-4H-1,2,4-triazol-3-ylmethyl)
Amino] phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 150) (21
0.4 mg) was obtained. mp 134-136 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.84-0.98 (12H, m), 1.31-
1.46 (2H, m), 1.52-1.86 (4H, m), 1.95-2.13 (1H, m),
2.84 (3H, s), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.
2 Hz), 3.28-3.38 (2H, m), 3.55 (2H, t, J = 6.5 Hz),
3.78-3.90 (4H, m), 4.10-4.17 (2H, m), 4.56 (2H, s),
6.88-7.00 (5H, m), 7.36-7.54 (7H, m), 7.62-7.81
(1H, m), 8.10 (1H, s). IR (KBr) 3287, 1655, 1605, 1518, 1499, 1248, 1186,
1121, 1067, 820 cm ^-1 Elemental analysis C ₄₀ H ₅₂ N ₆ O ₃ Calcd. C, 72.26; H, 7.88;
N, 12.64: Found. C, 71.96; H, 7.89; N, 12.49.

Example 142 (Production of Compound 151) 7- [4- (2-Butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (0.30 g) in THF (10 ml) was added thionyl chloride (0.077 ml) and D at room temperature.
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (10 ml) was added to 4- [methyl (4-propyl-4H-1,2,4-triazole-3].
A solution of -ylmethyl) amino] aniline (0.19 g) in pyridine (7 ml) was added dropwise at 0 ° C. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 4), and recrystallized (ethyl acetate-hexane) to give 7- [4- (2-butoxyethoxy) as yellow crystals. ) Phenyl]
-N- [4- [methyl (4-propyl-4H-1,2,2
4-triazol-3-ylmethyl) amino] phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 151) (24
0.2 mg) was obtained. mp 131-133 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.3 Hz), 0.
93 (3H, t, J = 7.1 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.28-
1.47 (2H, m), 1.52-1.80 (6H, m), 2.85 (3H, s), 2.86
-2.95 (2H, m), 3.26-3.38 (4H, m), 3.55 (2H, t, J =
6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 3.89 (2H, t, J = 7.
3 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.59 (2H, s), 6.88-
7.00 (5H, m), 7.34-7.52 (8H, m), 8.11 (1H, s) .IR (KBr) 3303, 1640, 1605, 1518, 1501, 1306, 1246,
119, 1175, 1128, 833,821 cm ^-1 Elemental analysis C ₃₉ H ₅₀ N ₆ O ₃ 0.25H ₂ O Calcd. C, 71.48; H,
7.77; N, 12.82: Found. C, 71.51; H, 7.74; N, 1
2.54.

Example 143 (Preparation of compound 152) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml)
Thionyl chloride (0.075 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to 4- [2- (4
-Propyl-4H-1,2,4-triazol-3-yl) ethyl] aniline (0.17 g) and pyridine (2 ml) in THF (7 ml) was added dropwise at 0 ° C.
After stirring at room temperature for 64 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol: ethyl acetate 1: 9 → 1: 4).
Separation and purification with a yellow amorphous substance 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4- [2- (4-Propyl-4H-1,2,4-triazol-3-yl) ethyl] phenyl] -2,3-
Dihydro-1H-benzazepine-4-carboxamide (Compound 152) (219.5 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86-0.98 (12H, m), 1.33-
1.48 (2H, m), 1.51-1.79 (2H, m), 1.96-2.15 (1H, m),
2.82-3.03 (4H, m), 3.05-3.22 (4H, m), 3.27-3.41
(2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.63 (2H, t, J = 7.
2 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.15 (2H, t, J = 4.9 H
z), 6.91 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz),
7.16 (2H, d, J = 8.4 Hz), 7.37-7.55 (7H, m), 7.65-
7.86 (1H, m), 8.03 (1H, s) .IR (KBr) 3090, 1655, 1605, 1516, 1499, 1246, 1182,
1123, 1067, 820 cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₃ 0.5H ₂ O Calcd. C, 72.92; H,
7.95; N, 10.63: Found. C, 72.88; H, 7.78; N, 1
0.56.

Example 144 (Production of Compound 153) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (0.30 g) in THF (10 ml) was added thionyl chloride (0.077 ml) and D at room temperature.
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (10 ml) was added to 4- [2- (4
-Propyl-4H-1,2,4-triazol-3-yl) ethyl] aniline (0.18g) in pyridine (7m
l) The solution was added dropwise at 0 ° C. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate →
Separated and purified with ethanol: ethyl acetate 1: 9 → 1: 4) to obtain 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [4- [2- ( 4-
Propyl-4H-1,2,4-triazol-3-yl) ethyl] phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 153) (378.3 mg) was obtained. . ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2 Hz), 0.
93 (3H, t, J = 7.4 Hz), 0.99 (3H, t, J = 7.4 Hz), 1.28-
1.48 (2H, m), 1.54-1.81 (6H, m), 2.86-3.03 (4H, m),
3.10-3.22 (2H, m), 3.24-3.39 (4H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.65 (2H, t, J = 7.3 Hz), 3.80 (2H, t,
J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 6.90 (1H, d, J
= 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J =
8.8 Hz), 7.35-7.54 (7H, m), 7.62 (1H, s), 8.03 (1
H, s) .IR (KBr) 3260, 1655, 1605, 1516, 1499, 1454, 1408,
1316, 1244, 1179, 1123, 1067, 818 cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₃ 0.5H ₂ O Calcd. C, 72.64; H, 7.
82; N, 10.86: Found.C, 72.70; H, 7.74; N, 10.7
Four.

Example 145 (Production of Compound 154) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.20 ml) and D
MF (1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to a solution of 4- [2- (4-aminophenylthio) ethyl] -4H-1,2,4-triazole (0.44 g) in pyridine (20 ml). 0
Dropwise at ° C. After stirring at room temperature for 2 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate → ethanol: ethyl acetate 1: 4 → 1: 3) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance. -N
-[4- (4H-1,2,4-triazol-4-ylethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 154) (1.06 g) was obtained. It was ¹ H-NMR (200MHz, CDCl ₆ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.28-1.48 (2H, m), 1.51-1.67
(2H, m), 1.92-2.18 (1H, m), 2.86-2.96 (2H, m), 3.15
-3.22 (4H, m), 3.31-3.41 (2H, m), 3.55 (2H, t, J =
6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.10-4.19 (4H,
m), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 H
z), 7.35-7.50 (7H, m), 7.61 (2H, d, J = 8.4 Hz), 7.7
3 (1H, s), 8.15 (2H, s). IR (KBr) 3092, 1659, 1607, 1497, 1456, 1395, 1310,
1285, 1242, 1182, 1123, 1071, 818 cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃ S0.25H ₂ O Calcd. C, 68.97; H,
7.12; N, 10.87: Found. C, 68.94; H, 7.12; N, 1
1.03.

Example 146 (Production of Compound 155) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4H-1,2,4-triazol-4-ylethylthio) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (20 ml). ,
3-chloroperbenzoic acid (70%, 0.37 at -78 ° C)
A solution of g) in dichloromethane (10 ml) was added dropwise, and -7
Stirred at 8 ° C. for 1 hour. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 20 → 1: 19) and further recrystallized (ethyl acetate) to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
(4H-1,2,4-triazol-4-ylethylsulfinyl) phenyl] -1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 155) (681.4 mg) was obtained. mp 168-170 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4 Hz), 0.
97 (6H, d, J = 6.2 Hz), 1.25-1.48 (2H, m), 1.53-1.68
(2H, m), 1.95-2.19 (1H, m), 2.86-2.95 (2H, m), 2.97
-3.41 (6H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 4.9 Hz), 4.15 (2H, t, J = 4.9 Hz), 4.22-4.37 (1
H, m), 4.47-4.61 (1H, m), 6.90-6.99 (3H, m), 7.38-
7.57 (7H, m), 7.83 (2H, d, J = 8.6 Hz), 8.06 (1H,
s), 8.17 (2H, s) .IR (KBr) 3225, 1663, 1605, 1590, 1534, 1501, 1316,
1246, 1182, 1040, 828cm ^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₄ S Calcd. C, 67.76; H, 6.92;
N, 10.68: Found. C, 67.49; H, 6.89; N, 10.51.

Example 147 (Preparation of compound 156) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (1.0 g) in THF (10 ml) was added thionyl chloride (0.26 ml) and DMF at room temperature.
(1 drop) was added and stirred for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added to a solution of 4- [2- (4-aminophenylthio) ethyl] -4H-1,2,4-triazole (0.57 g) in pyridine (20 ml). It was added dropwise at 0 ° C. After stirring at room temperature for 18 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate → ethanol: ethyl acetate 1: 5 → 1: 3), and recrystallized (ethyl acetate-hexane) to give 7- [as yellow crystals. 4-
(2-Butoxyethoxy) phenyl] -N- [4- (4
H-1,2,4-triazol-4-ylethylthio)
Phenyl] -1-propyl-2,3-dihydro-1H-
Benzazepine-4-carboxamide (Compound 156)
(1.34 g) was obtained. mp 114-115 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
00 (3H, t, J = 7.4 Hz), 1.31-1.45 (2H, m), 1.52-1.84
(4H, m), 2.87-2.96 (2H, m), 3.20 (2H, t, J = 6.6 H
z), 3.26-3.40 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.8
1 (2H, t, J = 5.0 Hz), 4.14 (4H, m), 6.91 (1H, d, J =
8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.36-7.49 (7H,
m), 7.57-7.62 (3H, m), 8.16 (2H, s) .IR (KBr) 3243, 1647, 1609, 1591, 1526, 1501, 1397,
1319, 1275, 1246, 1182, 1123, 808 cm ^-1 Elemental analysis C ₃₆ H ₄₃ N ₅ O ₃ S0.5H ₂ O Calcd. C, 68.11; H,
6.99; N, 11.03: Found. C, 67.98; H, 7.07; N, 1
0.95.

Example 148 (Production of Compound 157) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4H-1,2,4-triazol-4-ylethylthio) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.
0 g) in dichloromethane (20 ml) at -78 ° C.
A solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 20 → 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl as a yellow amorphous substance. ]-
N- [4- (4H-1,2,4-triazol-4-ylethylsulfinyl) phenyl] -1-propyl-
2,3-Dihydro-1H-benzazepine-4-carboxamide (Compound 157) (0.90 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0 Hz), 0.
99 (3H, t, J = 7.2 Hz), 1.29-1.47 (2H, m), 1.52-1.86
(4H, m), 2.84-2.95 (2H, m), 2.98-3.39 (6H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.15
(2H, t, J = 4.9 Hz), 4.21-4.36 (1H, m), 4.46-4.61 (1
H, m), 6.90 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz
Hz), 7.39-7.55 (7H, m), 7.82 (2H, d, J = 8.8 Hz), 8.
09 (1H, s), 8.16 (2H, s). IR (KBr) 3112, 1661, 1607, 1588, 1516, 1499, 1397,
1312, 1242, 1181, 1046, 836 cm ^-1 Elemental analysis C ₃₆ H ₄₃ N ₅ O ₄ S0.5H ₂ O Calcd. C, 66.44; H,
6.81; N, 10.76: Found. C, 66.34; H, 6.80; N, 1
0.62.

Example 149 (Production of compound 158) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.50 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.13 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to 3-[(4-aminobenzyl) methylamino] -4-propyl-4H-.
A solution of 1,2,4-triazole (0.34 g) in pyridine (10 ml) was added dropwise at 0 ° C. After stirring at room temperature for 18 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate →
Separated and purified with ethanol: ethyl acetate 1: 4) to give 7- [4- (2-butoxyethoxy) as a yellow amorphous substance.
Phenyl] -1-isobutyl-N- [4- [methyl (4
-N-propyl-4H-1,2,4-triazole-3
-Yl) aminomethyl] phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 158) (243 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.29-
1.50 (2H, m), 1.52-1.68 (2H, m), 1.71-1.90 (2H, m),
1.97-2.18 (1H, m), 2.77 (3H, s), 2.87-2.96 (2H,
m), 3.19 (2H, d, J = 7.4 Hz), 3.30-3.42 (2H, m), 3.5
5 (2H, d, J = 6.6 Hz), 3.71-3.83 (4H, m), 4.16 (2H,
t, J = 4.9 Hz), 4.24 (2H, s), 6.92 (1H, d, J = 8.8 H
z), 6.98 (2H, d, J = 8.8 Hz), 7.27-7.50 (7H, m), 7.5
8 (2H, d, J = 8.6 Hz), 7.66 (1H, s), 7.93 (1H, s). IR (KBr) 3163, 1657, 1603, 1516, 1499, 1406, 1314,
1244, 1181, 1119, 816cm ^-1 Elemental analysis C ₄₀ H ₅₂ N ₆ O ₃ 0.25H ₂ O Calcd. C, 71.77; H,
7.91; N, 12.55: Found. C, 71.66; H, 7.91; N, 1
2.37.

Example 150 (Production of compound 159) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (0.48 g) in THF (10 ml) at room temperature was thionyl chloride (0.12 ml) and DM.
F (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure,
A solution of the residue in THF (20 ml) was added to 3-[(4-aminobenzyl) methylamino] -4-propyl-4H-1,
2,4-triazole (0.31 g) in pyridine (10
ml) solution at 0 ° C. After stirring for 16 hours at room temperature,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was separated and purified by column chromatography (ethyl acetate → ethanol: ethyl acetate 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [methyl (as a yellow amorphous substance. 4-n-propyl-4H-
1,2,4-triazol-3-yl) aminomethyl]
Phenyl] -1-propyl-2,3-dihydro-1H-
Benzazepine-4-carboxamide (Compound 159)
(120 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.03 (9H, m), 1.31-1.
49 (2H, m), 1.51-1.85 (6H, m), 2.77 (3H, s), 2.86-
2.97 (2H, m), 3.25-3.39 (4H, m), 3.55 (2H, t, J = 6.
6 Hz), 3.72-3.83 (4H, m), 4.16 (2H, t, J = 4.9 Hz),
4.24 (2H, s), 6.90 (1H, d, J = 8.4 Hz), 6.98 (2H, d,
J = 8.8 Hz), 7.29-7.55 (7H, m), 7.57 (2H, d, J = 8.6
Hz), 7.62 (1H, s), 7.94 (1H, s). IR (KBr) 3036, 1657, 1605, 1516, 1499, 1454, 1406,
1314, 1244, 1177, 818cm ^-1 Elemental analysis C ₃₉ H ₅₀ N ₆ O ₃ 0.25H ₂ O Calcd. C, 71.48; H,
7.77; N, 12.82: Found. C, 71.29; H, 7.63; N, 1
2.53.

Example 151 (Production of Compound 160) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[1-methylimidazole-
2-yl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (600
mg) in dichloromethane (15 ml) solution 70% 3-
Chloroperbenzoic acid (355 mg) in dichloromethane (1
5 ml) solution was added dropwise at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate) to give 7- [4 as a yellow amorphous substance.
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[1-methylimidazol-2-yl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (246 mg)
(Compound 160) was obtained ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.98 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.75 (2H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.2 Hz), 3.30
-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.63 (3H,
s), 3.80 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 H
z), 6.91 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 H
z), 7.05 (1H, d, J = 1.4 Hz), 7.16-7.21 (3H, m), 7.3
7-7.53 (7H, m), 7.64 (1H, s). Elemental analysis C ₃₇ H ₄₄ N ₄ O ₄ S Calcd. C, 71.12; H, 7.10;
N, 8.97; Found. C, 70.81; H, 7.07; N, 8.89.

Example 152 (Production of Compound 161) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (400 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.09 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). 4 this solution
-[(4-Methyl-1,2,4-triazol-3-yl) thio] aniline (189 mg) in pyridine (15 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under a nitrogen atmosphere for 1.5 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by basic silica gel column chromatography (hexane-ethyl acetate = 1: 3) to give 7- [4- (2-butoxyethoxy) phenyl] -1- as a yellow amorphous substance. Isobutyl-N- [4-
[(4-Methyl-1,2,4-triazol-3-yl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (376 mg)
(Compound 161) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.45 (2H, m), 1.50-1.70 (2H, m), 1.95-2.15 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.2 Hz), 3.30
-3.45 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.66 (3H,
s), 3.81 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 H
z), 6.93 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.6 H
z), 7.39-7.53 (5H, m), 7.67-7.76 (3H, m), 7.90 (1
H, s), 8.00 (2H, d, J = 8.8 Hz). Elemental analysis C ₃₆ H ₄₃ N ₅ O ₃ S ・ 0.25H ₂ O Calcd. C, 68.86; H,
6.95; N, 8.68; Found. C, 68.82; H, 6.98; N, 8.
55.

Example 153 (Preparation of compound 162) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.20 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to 3- (4) at 0 ° C.
-Aminophenylthiomethyl) -2-methylimidazo [1,2-a] pyridine (0.54 g) in pyridine (7
ml) solution. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N- [4- (2-methylimidazo [1,2-a] pyridin-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-
4-Carboxamide (Compound 162) (1.03 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
96 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.52-1.69
(2H, m), 1.94-2.17 (4H, m), 2.84-2.95 (2H, m), 3.18
(2H, d, J = 7.2 Hz), 3.32-3.37 (2H, m), 3.56 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.25 (2H, s), 6.81-6.85 (1H, m), 6.90
(1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.12-7.
23 (3H, m), 7.36-7.55 (8H, m), 7.83 (1H, s), 8.00-
8.06 (1H, m). IR (KBr) 3032, 1655, 1607, 1586, 1499, 1397, 1350,
1285, 1242, 1179, 912, 818, 743 cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₃ S0.5H ₂ O Calcd. C, 72.28; H,
7.08; N, 8.03: Found.C, 72.45; H, 7.58; N, 7.9
Five.

Example 154 (Preparation of compound 163) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (2-methylimidazo [1,2
-A] pyridin-3-ylmethylthio) phenyl]-
2,3-Dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml)
To the solution at -78 ° C 3-chloroperbenzoic acid (70%,
A solution of 0.43 g) in dichloromethane (10 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate / hexane 3: 1 → ethyl acetate) and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [as yellow crystals. 4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (2-methylimidazo [1,2-a] pyridin-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H -Benzazepine-4-carboxamide (Compound 163) (456.
5 mg) was obtained. mp 130-133 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.49 (2H, m), 1.53-1.68
(2H, m), 1.90 (3H, s), 1.95-2.18 (1H, m), 2.84-2.9
6 (2H, m), 3.19 (2H, d, J = 7.0 Hz), 3.30-3.40 (2H,
m), 3.56 (2H, d, J = 6.8 Hz), 3.81 (2H, t, J = 4.9 H
z), 4.16 (2H, t, J = 4.9 Hz), 4.27 (1H, d, J = 14.1 H
z), 4.45 (1H, d, J = 14.1 Hz), 6.72-6.79 (1H, m), 6.
91 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.12
-7.21 (1H, m), 7.31 (1H, s), 7.38-7.50 (7H, m), 7.
71 (2H, d, H = 8.8 Hz), 8.04 (1H, s), 8.07-8.11 (1H,
m) .IR (KBr) 3032, 1661, 1607, 1588, 1518, 1499, 1
3797, 1350, 1312, 1244, 1179, 912, 747 cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₄ S0.5H ₂ O Calcd. C, 70.66; H,
6.92; N, 7.85: Found.C, 70.79; H, 6.87; N, 7.7
8.

Example 155 (Production of compound 164) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-benzazepine-
To a solution of 4-carboxylic acid (0.80 g) in THF (10 ml) was added thionyl chloride (0.21 ml) and DM at room temperature.
F (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure,
A solution of the residue in THF (20 ml) was added to 3- (4-aminophenylthiomethyl) -2-methylimidazo [1,2] at 0 ° C.
Pyridine (7 ml) of 2-a] pyridine (0.56 g)
Dropped into the solution. After stirring at room temperature for 3 days, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance.
-N- [4- (2-methylimidazo [1,2-a] pyridin-3-ylmethylthio) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 164) ( 1.17 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
99 (3H, t, J = 7.5 Hz), 1.28-1.48 (2H, m), 1.53-1.84
(4H, m), 2.07 (3H, s), 2.84-2.93 (2H, m), 3.25-3.3
6 (4H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J =
4.7 Hz), 4.16 (2H, t, J = 4.7 Hz), 4.26 (2H, s), 6.8
1-6.95 (2H, m), 6.97 (2H, d, J = 8.8 Hz), 7.13-7.23
(3H, m), 7.39-7.54 (8H, m), 7.72 (1H, s), 8.03-8.0
7 (1H, m) .IR (KBr) 3077, 1659, 1607, 1586, 1499, 1397, 1352,
1308, 1242, 1177, 1119, 818, 737 cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₃ S0.5H ₂ O Calcd. C, 72.00; H,
6.93; N, 8.19: Found.C, 72.18; H, 6.89; N, 8.0
3.

Example 156 (Production of compound 165) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (2-Methylimidazo [1,2-a] pyridine-
3-ylmethylthio) phenyl] -1-propyl-2,
A solution of 3-dihydro-1H-benzazepine-4-carboxamide (0.96 g) in dichloromethane (10 ml) was added at -78 ° C to 3-chloroperbenzoic acid (70%, 0.5%).
A solution of 2 g) in dichloromethane (10 ml) was added dropwise.
After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 3:
Separation and purification with 1 → ethyl acetate) and recrystallization (ethyl acetate-diisopropyl ether) gave 7- [4- (2-butoxyethoxy) phenyl]-as yellow crystals.
N- [4- (2-Methylimidazo [1,2-a] pyridin-3-ylmethylsulfinyl) phenyl] -1-propyl-2,3-dihydro-1H-benzazepine-4
-Carboxamide (Compound 165) (663.1 mg)
Got mp 134-137 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
00 (3H, t, J = 7.3 Hz), 1.28-1.49 (2H, m), 1.51-1.84
(4H, m), 1.94 (3H, s), 2.86-2.96 (2H, m), 3.27-3.3
9 (4H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J =
5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.30 (1H, d, J = 1
4.4 Hz), 4.47 (1H, d, J = 14.4 Hz), 6.73-6.79 (1H,
m), 6.90 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 H
z), 7.13-7.21 (1H, m), 7.30 (2H, d, J = 8.8 Hz), 7.40
-7.53 (1H, m), 7.69 (2H, d, J = 8.8Hz), 7.73-7.79 (1
H, m), 8.09 (1H, d, J = 7.0 Hz), IR (KBr) 3228, 1661, 1607, 1588, 1518, 1499, 1312,
1244, 1179, 1042, 833cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₄ S0.5H ₂ O Calcd. C, 70.36; H,
6.77; N, 8.00: Found.C, 70.63; H, 6.96; N, 8.0
6.

Example 157 (Production of compound 166) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.20 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added to 3- (4) at 0 ° C.
-Aminophenylthiomethyl) imidazo [1,2-a]
Pyridine (0.51 g) was added dropwise to a pyridine (7 ml) solution. After stirring at room temperature for 18 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1: 1 →
2: 1 → ethyl acetate), and purified to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance.
-1-Isobutyl-N- [4- (imidazo [1,2-
a] pyridin-3-ylmethylthio) phenyl] -2,
3-Dihydro-1H-benzazepine-4-carboxamide (Compound 166) (0.98 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30-1.47 (2H, m), 1.55-1.76
(2H, m), 1.96-2.17 (1H, m), 2.84-2.96 (2H, m), 3.18
(2H, d, J = 7.4 Hz), 3.32-3.37 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.32 (2H, s), 6.86-6.93 (2H, m), 6.97
(2H, d, J = 8.8 Hz), 7.18-7.29 (5H, m), 7.37-7.52 (6
H, m), 7.58-7.64 (1H, m), 7.72 (1H, s), 8.13-8.17
(1H, m). IR (KBr) 3165, 1657, 1607, 1588, 1499, 1310, 1242,
1181, 1128, 741 cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₃ S0.25H ₂ O Calcd. C, 72.48; H,
6.90; N, 8.25: Found. C, 72.36; H, 6.98; N, 8.
31.

Example 158 (Preparation of compound 167) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (imidazo [1,2-a] pyridin-3-ylmethylthio) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml). To
3-chloroperbenzoic acid (70%, 0.44
A solution of g) in dichloromethane (10 ml) was added dropwise. −
After stirring at 78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 3: 1).
→ Ethyl acetate) to separate and purify to give 7- [4- (2-butoxyethoxy) phenyl] -1- as a yellow amorphous substance.
Isobutyl-N- [4- (imidazo [1,2-a] pyridin-3-ylmethylsulfinyl) phenyl] -2,
3-Dihydro-1H-benzazepine-4-carboxamide (Compound 167) (642 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.52-1.74
(2H, m), 1.96-2.15 (1H, m), 2.88-2.98 (2H, m), 3.20
(2H, d, J = 7.8 Hz), 3.30-3.42 (2H, m), 3.56 (2H,
d, J = 6.6 Hz), 3.81 (2H, t, J = 4.9 Hz), 4.16 (2H, t,
J = 4.9 Hz), 4.29 (1H, d, J = 14.3 Hz), 4.48 (1H, d, J
= 14.3 Hz), 6.76-6.85 (1H, m), 6.92 (1H, d, J = 8.8 H
z), 6.98 (2H, d, J = 8.8 Hz), 7.13-7.23 (2H, m), 7.32
-7.48 (7H, m), 7.56-7.60 (1H, m), 7.71 (2H, d, H = 8.
8 Hz), 7.92 (1H, s), 8.15-8.18 (1H, m). IR (KBr) 3088, 1661, 1607, 1588, 1518, 1499, 1397,
1312, 1244, 1179, 1123, 833 cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₄ S0.5H ₂ O Calcd. C, 70.36; H,
6.77; N, 8.00: Found.C, 70.1; H, 6.80; N, 7.9
Four.

Example 159 (Production of compound 168) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) at room temperature was thionyl chloride (0.25 ml) and DM.
F (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure,
A solution of the residue in THF (20 ml) was added dropwise to a solution of 5- (4-aminophenylthio) imidazo [1,2-a] pyridine (0.61 g) in pyridine (7 ml) at 0 ° C.
After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate) to give 7- [4- as a yellow amorphous substance.
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (imidazo [1,2-a] pyridine-5-
Ilthio) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 168)
(1.27 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
96 (6H, d, J = 6.6 Hz), 1.30-1.48 (2H, m), 1.51-1.69
(2H, m), 1.94-2.13 (1H, m), 2.86-2.96 (2H, m), 3.18
(2H, d, J = 7.0 Hz), 3.30-3.40 (2H, m), 3.55 (2H,
d, J = 6.8 Hz), 3.80 (2H, t, J = 4.9 Hz), 4.16 (2H, t,
J = 4.9 Hz), 6.89-7.00 (4H, m), 7.12-7.20 (1H, m),
7.31-7.49 (7H, m), 7.58-7.68 (6H, m). IR (KBr) 3223, 1655, 1609, 1588, 1499, 1397, 1310,
1289, 1244, 1179, 1121, 820 cm ^-1 Elemental analysis C ₄₀ H ₄₄ N ₄ O ₃ S0.25H ₂ O Calcd. C, 72.20; H,
6.74; N, 8.42: Found. C, 72.14; H, 6.67; N, 8.
35.

Example 160 (Production of compound 169) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (imidazo [1,2-a] pyridin-5-ylthio) phenyl] -2,3-dihydro-
1H-benzazepine-4-carboxamide (1.0
To a solution of g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.56 g) in dichloromethane (10 ml) at -78 ° C. After stirring at -20 ° C for 5 hours, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate,
The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 → 3: 1) to give 7- [4- (2-butoxyethoxy) phenyl]-as yellow crystals. 1-isobutyl-N- [4-
(Imidazo [1,2-a] pyridin-5-ylsulfinyl) phenyl] -2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 169) (259
mg) was obtained. mp 162-164 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
96 (6H, d, J = 6.6 Hz), 1.28-1.50 (2H, m), 1.52-1.70
(2H, m), 1.94-2.15 (1H, m), 2.84-2.93 (2H, m), 3.18
(2H, d, J = 7.4 Hz), 3.28-3.39 (2H, m), 3.55 (2H,
d, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.15 (2H, t,
J = 5.0 Hz), 6.91 (1H, d, J = 8.8 Hz), 6.97 (2H, d, J
= 8.6 Hz), 7.31-7.53 (7H, m), 7.63-7.83 (8H, m). IR (KBr) 3297, 1672, 1609, 1593, 1534, 1497, 1393,
1321, 1289, 1246, 1184, 1140, 138, 820 cm ^-1 Elemental analysis C ₄₀ H ₄₄ N ₄ O ₄ S Calcd. C, 70.98; H, 6.55;
N, 8.28: Found. C, 70.72; H, 6.26; N, 8.30.

Example 161 (Production of Compound 170) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml)
To the solution at room temperature thionyl chloride (0.20 ml) and D
MF (1 drop) was added and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (25 ml) was added to 5- (4
-Aminophenylthio) -2-methylimidazo [1,2
-A] Pyridine (0.52 g) in pyridine (10 ml)
Dropped into the solution. After stirring at room temperature for 3 days, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1- as yellow crystals.
Isobutyl-N- [4- (2-methylimidazo [1,2
-A] pyridin-5-ylthio) phenyl] -2,3-
Dihydro-1H-benzazepine-4-carboxamide (Compound 170) (574 mg) was obtained. mp 164-166 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.27-1.46 (2H, m), 1.51-1.67
(2H, m), 1.96-2.14 (1H, m), 2.43 (3H, s), 2.85-2.9
4 (2H, m), 3.19 (2H, d, J = 7.2 Hz), 3.30-3.40 (2H,
m), 3.55 (2H, d, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 6.87-6.94 (2H, m), 6.9
7 (2H, d, J = 8.8 Hz), 7.07-7.15 (1H, m), 7.30 (2H,
d, J = 8.8 Hz), 7.38-7.62 (10H, m). IR (KBr) 3274, 1638, 1607, 1586, 1499, 1397, 1314,
1244, 1181, 1121, 814cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₃ S Calcd. C, 72.97; H, 6.87;
N, 8.30: Found. C, 72.73; H, 6.96; N, 8.37.

Example 162 (Production of Compound 171) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (2-methylimidazo [1,2
-A] pyridin-5-ylthio) phenyl] -2,3-
To a solution of dihydro-1H-benzazepine-4-carboxamide (0.50 g) in dichloromethane (10 ml),
3-chloroperbenzoic acid (70%, 0.27
A solution of g) in dichloromethane (10 ml) was added dropwise. −
After stirring at 20 ° C. for 18 hours, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for several minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 1:
Separation and purification by 1 → 2: 1) to obtain 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (2-methylimidazo [1,2-a] pyridin-5-ylsulfinyl) phenyl] -2,3-
Dihydro-1H-benzazepine-4-carboxamide (Compound 171) (110.5 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
96 (6H, d, J = 6.6 Hz), 1.38-1.48 (2H, m), 1.51-1.67
(2H, m), 1.93-2.14 (1H, m), 2.40 (3H, s), 2.83-2.9
2 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.30-3.40 (2H,
), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz),
4.15 (2H, t, J = 5.0 Hz), 6.91 (1H, d, J = 9.2 Hz), 6.
97 (2H, d, J = 8.8 Hz), 7.26-7.34 (1H, m), 7.35-7.47
(6H, m), 7.58-7.78 (7H, m), IR (KBr) 3300, 1671, 1609, 1591, 1532, 1499, 1318,
1246, 1184, 1121, 1042, 808 cm ^-1 Elemental analysis C ₄₁ H ₄₆ N ₄ O ₄ S0.25H ₂ O Calcd. C, 70.81; H,
6.74; N, 8.06: Found. C, 70.75; H, 6.53; N, 7.
73.

Example 163 (Compound 172, Compound 17)
Production of 3) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-Methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 133) was added to CHIRALP
AK AD (50 mm ID x 500 mm L, hexane:
Optical resolution using (ethanol), and (+)-7- [4-
(2-Butoxyethoxy) phenyl] -N- [4- (4
-Methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-propyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 172) (141 mg, 99.9% e)
e) and (-)-7- [4- (2-butoxyethoxy) phenyl] -N- [4- (4-methyl-4H-1,
2,4-triazol-3-ylmethylsulfinyl)
Phenyl] -1-propyl-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (compound 17
3) (142 mg, 99.9% ee) was obtained. Compound 172 [α] _D = + 137.5 ° (C = 0.504, ethanol solution) Compound 173 [α] _D = −137.9 ° (C = 0.504, ethanol solution)

Example 164 (Compound 174, Compound 17)
Production of 5) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4- (4-propyl-4H-1,
2,4-triazol-3-ylmethylsulfinyl)
Phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 139) (387m
g) CHIRALPAK AD (50mmIDx50
Optical resolution was performed using 0 mmL, hexane: ethanol, and (+)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- (4-propyl-).
4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 174)
(170 mg, 99.9% ee) and (-)-7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- (4-propyl-4H-1,2,4
-Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 175) (171 mg, 9
9.9% ee) was obtained. Compound 174 [α] _D = + 146.6 ° (C = 0.498, ethanol solution) Compound 175 [α] _D = -147.0 ° (C = 0.506, ethanol solution)

Example 165 (Compound 176, Compound 17)
Production of 7) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4- (4-propyl-4H-1,2,
4-triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 141) was added to CHIRAL.
Optical resolution was performed using PAK AD (50 mm ID x 500 mm L, hexane: ethanol), and (+)-7-
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4-
Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-
4-carboxamide (Compound 176) (6.61 g, 9
9.9% ee) and (-)-7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-
(4-propyl-4H-1,2,4-triazole-3
-Ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 177) (6.85 g, 99.8% ee) was obtained. Compound 176 [α] _D = + 141.8 ° (C = 0.495, ethanol solution) Compound 177 [α] _D = −140.8 ° (C = 0.504, ethanol solution)

Example 166 (Compound 178, Compound 17)
Production of 9) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (4-n-Butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 143) in CHIR
Optical resolution was performed using ALPAK AD (50 mm ID x 500 mm L, hexane: ethanol), and (+)-7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-(4-n-Butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 178) (220 mg,
99.9% ee) and (-)-7- [4- (2-butoxyethoxy) phenyl] -N- [4- (4-n-butyl-4H-1,2,4-triazol-3-yl) Methylsulfinyl) phenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 179) (200 mg, 99.8% ee)
Got Compound 178 [α] _D = + 133.1 ° (C = 0.504, ethanol solution) Compound 179 [α] _D = −132.4 ° (C = 0.5005, ethanol solution)

Example 167 (Preparation of compound 180) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
Dissolve carboxylic acid (1.0 g) in THF (20 ml) and add DMF (2 drops) followed by thionyl chloride (0.3 g).
4 ml) and stirred at room temperature for 1 hour.
[(2-Pyridinylsulfanyl) methyl] aniline (0.56 g) and triethylamine (1.97 ml) in THF (20 ml) were added dropwise under ice-cooling to room temperature to 2
Stir for hours. 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 obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-propyl-
N- [4-[(2-pyridinylsulfanyl) methyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (Compound 180) (0.56 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.8Hz), 0.9
8 (3H, t, J = 7.4Hz), 1.33-1.45 (2H, m), 1.54-1.80 (4H,
m), 2.89 (2H, m), 3.26-3.34 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.77-3.83 (2H, m), 4.12-4.18 (2H, m), 4.41 (2
H, s), 6.88 (1H, d, J = 8.4Hz), 6.94-7.02 (2H, m), 6.97
(2H, d, J = 8.8Hz), 7.15 (1H, d, J = 8.0Hz), 7.35-7.56
(10H, m), 8.45 (1H, d, J = 5.2Hz) IR (KBr) 3339, 2959, 1642, 1607, 1497, 1412, 1250,
1127, 924, 829cm ^-1

Example 168 (Production of compound 181) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[(2-pyridinylsulfanyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.30 g) was dissolved in methylene chloride (15 ml), M-Chloroperbenzoic acid (83 mg) was added at -30 ° C, and the mixture was stirred at 0 ° C for 1 hr. The reaction solution was added to a saturated aqueous sodium thiosulfate solution,
It was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl].
-1-Propyl-N- [4-[(2-pyridinylsulfinyl) methyl] phenyl] -2,3-dihydro-1-
Benzazepine-4-carboxamide (Compound 181)
(97 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (3H, t, J = 7.4Hz), 1.33-1.45 (2H, m), 1.55-1.76 (4H,
m), 2.89 (2H, m), 3.26-3.34 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.78 (2H, t, J = 4.8Hz), 4.05 (1H, d, J = 13.2H
z), 4.12-4.18 (2H, m), 4.34 (1H, d, J = 13.2Hz), 6.86-
6.89 (5H, m), 7.32-7.59 (9H, m), 7.70-7.76 (2H, m),
8.64-8.68 (1H, m) IR (KBr) 2955, 1655, 1607, 1499, 1246, 1181, 1125,
1038 cm ^-1

Example 169 (Production of Compound 182) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
Dissolve carboxylic acid (1.0 g) in THF (20 ml) and add DMF (2 drops) followed by thionyl chloride (0.3 g).
4 ml) and stirred at room temperature for 1 hour.
(2-pyridinylsulfanyl) aniline (0.53
g) and triethylamine (1.97 ml) were added dropwise to a THF solution (20 ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-
(2-Pyridinylsulfanyl) phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 182) (0.57 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 1.0
0 (3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.57-1.77 (4H,
m), 2.93 (2H, m), 3.28-3.36 (4H, m), 3.51-3.59 (2H,
m), 3.80 (2H, t, J = 4.8Hz), 4.13-4.18 (2H, m), 6.85 (1
H, d, J = 8.0Hz), 6.90 (2H, t, J = 8.8Hz), 6.95-7.00 (3H,
m), 7.40-7.50 (6H, m), 7.58 (2H, d, J = 8.8Hz), 7.66-
7.71 (10H, m), 8.40-8.43 (1H, m) IR (KBr) 3283, 2957, 1651, 1607, 1499, 1242, 1177,
1127, 833, 733cm ^-1

Example 170 (Production of compound 183) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4- (2-pyridinylsulfanyl)
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (0.15 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (95 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 15 min. m-
Chloroperbenzoic acid (95 mg) was added, and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-Propyl-N- [4- (2-pyridinylsulfinyl) phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 183) (30 mg)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.6Hz), 0.9
6 (3H, t, J = 7.6Hz), 1.33-1.44 (2H, m), 1.43-1.82 (4H,
m), 2.85 (2H, m), 3.23-3.31 (2H, m), 3.54 (2H, t, J =
6.6Hz), 3.76-3.82 (2H, m), 3.76-3.82 (2H, m), 4.13 (2
H, t, J = 6.6Hz), 6.86 (1H, d, J = 8.8Hz), 6.93 (2H, d, J
= 8.8Hz), 7.24-8.09 (13H, m), 8.52 (1H, d, J = 4.0Hz) IR (KBr) 3268, 2957, 1663, 1588, 1499, 1244, 1123,
1036, 824, 735cm ^-1

Example 171 (Production of Compound 184) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (two drops) was added, oxalyl chloride (0.40 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue was dissolved in THF (2
0 ml) was added dropwise to a THF solution (16.2 ml) of 4-[(2-pyridinylsulfanyl) methyl] aniline (0.54 g) and triethylamine (1.91 ml) under ice cooling, and the mixture was cooled to 1 at room temperature. Stir for hours. 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 obtained residue was washed with hexane / ethyl acetate,
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyridinylsulfanyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 184)
(0.65 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, t, J = 6.6Hz), 1.33-1.44 (2H, m), 1.54-1.69 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.32-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 4.6Hz), 4.41 (2H, s), 6.91 (1H, d, J = 8.8H
z), 6.95-7.02 (3H, m), 7.15 (1H, d, J = 8.0Hz), 7.36-7.
54 (11H, m), 8.44-8.47 (1H, m) Elemental analysis C ₃₉ H ₄₅ N ₃ O ₃ S Cald. C, 73.67; N, 6.61; H,
7.13: Found. C, 73.50; N, 6.60; H, 7.09

Example 172 (Production of compound 185) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyridinylsulfanyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), M-Chloroperbenzoic acid (217 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-Propyl-N- [4-[(2-pyridinylsulfinyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 185)
(70 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, t, J = 6.6Hz), 1.26-1.49 (2H, m), 1.54-1.69 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
t, J = 4.8Hz), 4.07 (1H, d, J = 13.2Hz), 4.16 (2H, t, J =
4.6Hz), 4.35 (1H, d, J = 13.0Hz), 6.89 (1H, m), 6.91 (2
H, d, J = 8.8Hz), 6.96 (2H, d, J = 8.8Hz), 7.31-7.60 (10
H, m), 7.78 (1H, td, J = 7.8, 1.6Hz), 8.66-8.69 (1H,
m)

Example 173 (Production of Compound 186) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.21 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and a THF solution (14 ml) of the obtained residue was added to 4- (benzenesulfanylmethyl)
Aniline (0.36 g), triethylamine (1.34
(ml) THF solution (10.7 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. 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 to give N- [4- (benzenesulfanylmethyl) phenyl] -7- [4- (2-butoxyethoxy) phenyl].
-1-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 186) (0.42
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.44-1.67 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.32-3.38 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-
3.83 (2H, m), 4.10 (2H, m), 4.12-4.18 (2H, m), 6.88-
7.00 (5H, m), 7.14-7.31 (8H, m), 7.36-7.56 (5H, m)

Example 174 (Preparation of compound 187) N- [4- (benzenesulfanylmethyl) phenyl]
-7- [4- (2-butoxyethoxy) phenyl] -1
-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.35 g) was dissolved in methylene chloride (10.5 ml), m-chloroperbenzoic acid (99 mg) was added at 0 ° C, The mixture was stirred at 0 ° C for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, recrystallized from ethyl acetate, and N- [4- (benzenesulfinylmethyl) phenyl] -7- [4- (2- Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 187) (164 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 5.6H
z), 3.20-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-
3.83 (2H, m), 4.02 (2H, d, J = 5.2Hz), 4.13-4.18 (2H,
m), 6.89-7.00 (5H, m), 7.37-7.53 (12H, m), 7.56 (1H,
s) IR (KBr) 3337, 2955, 1644, 1609, 1499, 1242, 1040,
831cm ^-1 Elemental analysis C ₄₀ H ₄₆ N ₂ O ₄ S Cald. C, 73.81; N, 4.30; H,
7.12: Found. C, 73.60; N, 4.06; H, 7.21

Example 175 (Production of compound 188) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (two drops) was added, oxalyl chloride (0.30 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (20
ml) was added dropwise to a THF solution (16.5 ml) of 4-[(2-pyrimidinylsulfanyl) methyl] aniline (0.55 g) and triethylamine (1.91 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. did. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(2-pyrimi Dysulfanyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 188) (0.30 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.2H
z), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-3.83 (2
H, m), 4.12-4.18 (2H, m), 4.40 (2H, s), 6.89-7.00 (4
H, m), 7.36-7.56 (10H, m), 8.53 (2H, d, J = 5.0Hz)

Example 176 (Production of Compound 189) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyrimidylsulfanyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.23 g) was dissolved in methylene chloride (7.5 ml). Then, m-chloroperbenzoic acid (68 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[(2-pyrimidylsulfinyl) methyl] phenyl] -2,3-dihydro-1-
Benzazepine-4-carboxamide (Compound 189)
(90 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.47 (2H, m), 1.55-1.69 (2H,
m), 2.04 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.30-3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 4.13-4.18 (2H, m), 4.22 (1H, d, J = 1
3.2Hz), 4.37 (1H, d, J = 13.2Hz), 6.89 (1H, d, J = 8.8H
z), 6.97 (2H, d, J = 8.8Hz), 7.07 (2H, d, J = 8.4Hz), 7.
31-7.55 (8H, m), 7.82 (1H, s), 8.79 (2H, d, J = 4.8Hz) IR (KBr) 3293, 2957, 1653, 1607, 1499, 1381, 1181,
1065, 816cm ^-1

Example 177 (Production of Compound 190) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (two drops) was added, oxalyl chloride (0.40 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (20
ml) to 4-[[[5- (trifluoromethyl) -2
-Pyridinyl] sulfanyl] methyl] aniline (0.
68 g), THF of triethylamine (1.91 ml)
The solution (20.4 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. 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 to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[5- (trifluoromethyl) -2-
Pyridinyl] sulfanyl] methyl] phenyl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (Compound 190) (1.08 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.2H
z), 3.32-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 4.15 (2H, t, J = 4.8Hz), 4.45 (2H, s),
6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.22-
7.26 (1H, m), 7.37-7.56 (10H, m), 7.66 (1H, dd, J = 8.0,
2.2Hz), 8.69 (1H, s)

Example 178 (Preparation of compound 191) 7- [4- (2-butoxyethoxy) phenyl] -1-
Chlorination of isobutyl-N- [4-[[[5- (trifluoromethyl) -2-pyridinyl] sulfanyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) Methylene (20.4
ml), and m-chloroperbenzoic acid (12
5 mg) was added and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[5- (trifluoromethyl) -2-
Pyridinyl] sulfinyl] methyl] phenyl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (Compound 191) (136 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.48-1.65 (2H,
m), 2.06 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J = 7.0H
z), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.81 (2H, t,
J = 4.8Hz), 4.09 (1H, d, J = 13.4Hz), 4.13-4.18 (2H,
m), 4.04 (1H, d, J = 13.2Hz), 6.88-7.00 (3H, m), 6.99 (2
H, d, J = 8.8Hz), 7.37-7.33 (7H, m), 7.63 (1H, s), 7.7
5 (1H, d, J = 8.0Hz), 8.02 (1H, m), 8.92-8.94 (1H, m)

Example 179 (Production of compound 192) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.80 g) was dissolved in THF (16 ml), DMF (two drops) was added, oxalyl chloride (0.25 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (16
ml) was added to 4-[(2-pyridinylmethyl) sulfanyl] aniline (0.45 g) and triethylamine (2.
1 ml) in a THF solution (13.5 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. 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 obtained residue was washed with hexane / ethyl acetate to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-propyl-
N- [4-[(2-pyridinylmethyl) sulfanyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (Compound 192) (0.68 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
8 (3H, t, J = 6.8Hz), 1.33-1.45 (2H, m), 1.57-1.76 (4H,
m), 2.88 (2H, m), 3.26-3.35 (4H, m), 3.51-3.58 (2H,
m), 3.77-3.83 (2H, m), 4.12-4.18 (2H, m), 4.21 (2H,
s), 6.89 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.
14-7.60 (13H, m), 8.51-8.55 (1H, m)

Example 180 (Production of Compound 193) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[(2-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml) and heated to 0 ° C. M-chloroperbenzoic acid (111 mg) was added thereto, and the mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-propyl-N- [4-[(2-pyridinylmethyl)
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 193)
(181 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
9 (3H, t, J = 7.0Hz), 1.33-1.45 (2H, m), 1.57-1.76 (4H,
m), 2.90 (2H, m), 3.27-3.35 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.80 (2H, t, J = 4.8Hz), 4.13 (1H, d, J = 12.2H
z), 4.15 (2H, m), 4.25 (1H, d, J = 12.2Hz), 6.89 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.12-7.25 (2H, m),
7.38-7.49 (7H, m), 7.61 (1H, td, J = 7.6, 1.8Hz), 7.7
1 (2H, d, J = 8.8Hz), 7.90 (1H, s), IR (KBr) 3312, 2932, 2870, 1655, 1615, 1503, 1246,
1181, 1036, 824cm ^-1 Elemental analysis C ₃₈ H ₄₃ N ₃ O ₄ S Cald. C, 71.56; N, 6.59; H,
6.80: Found. C, 71.38; N, 6.44; H, 7.06

Example 181 (Production of compound 194) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.2 g) was dissolved in THF (24 ml), DMF (two drops) was added, oxalyl chloride (0.48 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (24
ml) to 4-[(2-pyridinylmethyl) sulfanyl] aniline (0.65 g), triethylamine (2.
3 ml) in a THF solution (19.5 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. 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 to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[(2-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 19
4) (0.98g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.68 (2H,
m), 2.05 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.31-3.36 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2
H, t, J = 4.8Hz), 4.15 (2H, t, J = 4.8Hz), 4.21 (2H, s),
6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.10-
7.17 (1H, m), 7.22-7.63 (13H, m), 8.51-8.54 (1H, m) Elemental analysis C ₃₉ H ₄₅ N ₃ O ₃ S Cald. C, 73.67; N, 6.61; H,
7.13: Found. C, 73.78; N, 6.62; H, 7.37

Example 182 (Production of compound 195 and compound 196) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.85 g) was dissolved in methylene chloride (25.5 ml) and 0 M-Chloroperbenzoic acid (277 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 90 minutes. Further, m-chloroperbenzoic acid (230 mg) was added, and the mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4
-[(2-Pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 195) (300 mg) and 7
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(2-pyridinylmethyl) sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 196 ) (150
mg) was obtained. Compound 195: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 7.2Hz), 0.97 (6H, d, J = 6.2Hz), 1.33-1.45 (2H, m),
1.54-1.62 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2
H, d, J = 7.0Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.2Hz),
3.78-3.83 (2H, m), 4.13-4.19 (2H, m), 4.15 (1H, d, J =
12.2Hz), 4.26 (1H, d, J = 12.4Hz), 6.92 (1H, d, J = 8.8H
z), 6.98 (2H, d, J = 8.8Hz), 7.14-7.26 (2H, m), 7.38-
7.51 (7H, m), 7.63 (1H, td, J = 7.6, 1.8Hz), 7.69-7.78
(3H, m), 8.54-8.57 (1H, m) IR (KBr) 3328, 2955, 1645, 1499, 1246, 1042, 829cm
^-1 Compound 196: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 6.8Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m),
1.57-1.65 (2H, m), 2.08 (1H, m), 2.97 (2H, m), 3.20 (2
H, d, J = 6.8Hz), 3.34-3.37 (2H, m), 3.55 (2H, t, J = 6.
6Hz), 3.80 (2H, m), 4.16 (2H, m), 4.54 (2H, s), 6.93 (1
H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.20-7.26 (2
H, m), 7.40-7.49 (5H, m), 7.59-7.77 (6H, m), 8.43-8.
46 (1H, m) IR (KBr) 3310, 2955, 1649, 1501, 1242, 116
3, 810cm ^-1 Elemental analysis C ₃₉ H ₄₅ N ₃ O ₅ S Cald. C, 70.14; N, 6.29; H,
6.79: Found. C, 70.10; N, 6.39; H, 7.06

Example 183 (Compound 197, Compound 19)
Production of 8) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in CH
Optical resolution was performed using IRALCELOJ (5 cmφ × 50 cm), and (+)-(7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[(2-Pyridinylmethyl) sulfinyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 197) (78 mg, [α] _D = + 9
5.4 °) and (−)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[(2-Pyridinylmethyl) sulfinyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 198) (95 mg) was obtained.

Example 184 (Production of compound 199) 7- [4- (2-butoxyethoxy) phenyl] -1-
(Trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was added to DMF.
After dissolving in (10 ml) and adding 4-[(2-pyridinylsulfanyl) methyl] aniline (272 mg) and 1-hydroxybenzotriazole (321 mg), 1-ethyl-3- (3-dimethylamino hydrochloride was added. Propyl) carbodiimide (401 mg), triethylamine (0.
(44 ml) was added, and the mixture was stirred at room temperature for 16 hours. 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(2-pyridinylsulfanyl) methyl. ] Phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-
A carboxamide (Compound 199) (0.36 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 1.3
3-1.46 (2H, m), 1.54-1.68 (2H, m), 2.87-3.25 (3H, m),
3.55 (2H, t, J = 6.6Hz), 3.82 (2H, t, J = 4.8Hz), 4.10 (2
H, s), 4.18 (2H, t, J = 4.8Hz), 4.86 (1H, m), 7.02 (2H,
d, J = 8.8Hz), 7.10-7.34 (7H, m), 7.42 (1H, s), 7.48-
7.55 (6H, m), 7.65 (1H, d, J = 1.8Hz)

Example 185 (Compound 200, Compound 20)
Production of 1) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(2-Pyridinylsulfanyl) methyl] phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (0.
35 g) was dissolved in methylene chloride (10.5 ml),
M-Chloroperbenzoic acid (0.28 g) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[(2-pyridinylsulfonyl) methyl. ] Phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-
Carboxamide (Compound 200) (61 mg) and 7
-[4- (2-Butoxyethoxy) phenyl] -N-
[4-[[(1-Oxido-2-pyridinyl) sulfonyl] methyl] phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 201) (151 mg) Got Compound 200: ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 7.0Hz), 1.33-1.49 (2H, m), 1.58-1.69 (2H, m), 2.9
1-3.24 (3H, m), 3.56 (2H, t, J = 6.6Hz), 3.82 (2H, t, J
= 4.8Hz), 4.15-4.21 (2H, m), 4.29 (2H, s), 4.75-4.88
(1H, m), 7.02 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 8.8H
z), 7.31-7.67 (11H, m) Compound 201: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t,
J = 7.0Hz), 1.29-1.45 (2H, m), 1.54-1.68 (2H, m), 2.8
5-3.26 (3H, m), 3.56 (2H, t, J = 6.6Hz), 3.82 (2H, t, J
= 4.6Hz), 4.02 (2H, s), 4.18 (2H, t, J = 4.8Hz), 4.75-
4.89 (1H, m), 6.96 (2H, d, J = 8.4Hz), 7.02 (2H, d, J =
8.8Hz), 7.30-7.57 (11H, m), 7.63 (1H, s), 7.83 (1H, s)

Example 186 (Preparation of compound 202) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(1-Oxido-2-pyridinyl) sulfonyl] methyl] phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (137 mg) was added to ethanol (4 mg). 0.0 m
It was dissolved in l), sodium borohydride (36 mg) was added, and the mixture was stirred at room temperature for 3 hours. Further, sodium borohydride (36 mg) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[(1-oxide-2-pyridinyl). ) Sulfonyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 202) (85 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 1.3
3-1.45 (2H, m), 1.54-1.65 (2H, m), 2.94 (2H, m), 3.46
(2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.83 (2H, m), 3.
98 (1H, d, J = 12.8Hz), 4.07 (1H, d, J = 12.4Hz), 4.13-
4.18 (2H, m), 4.61 (1H, m), 6.70 (1H, d, J = 8.4Hz), 6.
94 (2H, d, J = 8.4Hz), 6.97 (2H, d, J = 8.8Hz), 7.29-7.5
2 (11H, m), 7.64 (1H, s) IR (KBr) 3318, 2957, 1651, 1609, 1516, 1318, 1246,
1181, 1038, 820cm ^-1

Example 187 (Preparation of compound 203) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(1-Oxido-2-pyridinyl) sulfonyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (70 mg) was added to 1,2.
-Dissolved in dichloromethane (7.0 ml), added isobutyraldehyde (51 μl), sodium triacetoxyboronate (118 mg), acetic acid (3 drops), and added 6 at room temperature.
Stir for 0 hours. Sodium triacetoxyboronate (1
18 mg) was added and the mixture was stirred at 50 ° C. for 4 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(1-Oxide-2-pyridinyl) sulfonyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 203) (52m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.4Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.32-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-
3.83 (2H, m), 3.98 (1H, d, J = 12.2Hz), 4.07 (1H, d, J =
12.6Hz), 4.13-4.18 (2H, m), 6.89-6.94 (3H, m), 6.98 (2
H, d, J = 8.4Hz), 7.37-7.53 (11H, m), 7.66 (1H, s) IR (KBr) 3337, 2951, 1640, 1518, 1499, 1246, 1038,
808 cm ^-1

Example 188 (Preparation of compound 204) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(2-Pyridinylsulfonyl) methyl] phenyl] -1- (trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (49m
g) was dissolved in ethanol (4.9 ml), sodium borohydride (13 mg) was added, and the mixture was stirred at room temperature for 3 hours. Furthermore, sodium borohydride (13 mg)
Was added and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4-
[(2-Pyridinylsulfonyl) methyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 204) (23 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 1.3
3-1.45 (2H, m), 1.57-1.62 (2H, m), 2.95 (2H, m), 3.46
(2H, t, J = 4.6Hz), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
t, J = 4.8Hz), 4.07-4.20 (2H, m), 4.29 (2H, s), 6.55 (1
H, d, J = 8.6Hz), 6.70 (1H, d, J = 8.2Hz), 6.85 (1H, d,
J = 8.4Hz), 6.97 (2H, d, J = 8.8Hz), 7.05 (2H, d, J = 8.4H
z), 7.31-7.35 (2H, m), 7.41-7.67 (7H, m) IR (KBr) 3387, 2945, 2861, 1663, 1611, 1526, 1319,
829 cm ^-1

Example 189 (Production of compound 205) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[(2-Pyridinylsulfonyl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (17 mg) was dissolved in 1,2-dichloromethane (0.85 ml) and isobutyl was added. Aldehyde (1
3 μl), sodium triacetoxyboron (29 m
g) and acetic acid (three drops) were added, and the mixture was stirred at 50 ° C. for 4 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4
-[[(1-oxide-2-pyridinyl) sulfonyl]]
Methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 205) (6m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.6Hz), 0.9
7 (6H, d, J = 7.2Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.83 (2
H, m), 4.13-4.19 (2H, m), 4.29 (2H, s), 6.92 (1H, d,
J = 8.8Hz), 6.98 (2H, d, J = 9.2Hz), 7.05 (2H, d, J = 8.6H
z), 7.38-7.67 (12H, m)

Example 190 (Production of compound 206) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 ml) was mixed with 4- (benzylsulfanyl) aniline (0.38 g) and triethylamine (1.34 ml).
Was added dropwise to a THF solution (11.4 ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was washed with hexane / ethyl acetate, and N- [4- (benzylsulfanyl) phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl. -2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 206) (0.70 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.4Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.0H
z), 3.32-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 4.06 (2H, s), 4.16 (2H, t, J = 4.6Hz),
6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.25-
7.32 (7H, m), 7.37-7.56 (8H, m)

Example 191 (Compound 207, Compound 20)
Preparation of 8) m-chloroperbenzoic acid (0.23 g) was dissolved in methylene chloride (11.4 ml), and the mixture was mixed with 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4- (benzylsulfanyl) phenyl] -2,3
A solution of -dihydro-1-benzazepine-4-carboxamide (0.57 g) in methylene chloride (17.1 ml) was added dropwise. After stirring at 0 ° C for 20 minutes, m-chloroperbenzoic acid (0.23 g) was further added, and the mixture was stirred at 0 ° C for 20 minutes. A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N- [4- (benzylsulfinyl) phenyl]-
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-carboxamide (Compound 207) (135 mg) and N- [4- (benzylsulfonyl) phenyl] -7
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4
-Carboxamide (Compound 208) (35 mg) was obtained. Compound 207: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m),
1.54-1.65 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.17 (2
H, d, J = 7.0Hz), 3.34 (2H, m), 3.54 (2H, t, J = 6.6Hz),
3.77-3.82 (2H, m), 3.95 (1H, d, J = 12.4Hz), 4.04-4.11
(1H, m), 4.11-4.17 (2H, m), 6.89-6.99 (3H, m), 6.96
(2H, d, J = 8.6Hz), 7.24-7.51 (10H, m), 7.69 (2H, d, J
= 8.8Hz), 7.92-8.15 (1H, m) IR (KBr) 3331, 2957, 1651, 1499, 1312, 1242, 1038,
828 cm ^-1 compound 208: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t,
J = 7.0Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m),
1.55-1.65 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.20 (2
H, d, J = 7.6Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.78-3.83 (2H, m), 4.16 (2H, t, J = 4.6Hz), 4.30 (2H,
s), 6.90-6.95 (1H, m), 6.98 (2H, d, J = 8.8Hz), 7.24-
7.33 (4H, m), 7.40-7.76 (9H, m) IR (KBr) 3314, 2957, 1647, 1499, 1244, 1167, 787cm
^-1

Example 192 (Preparation of compound 209) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 ml) was mixed with 4-[(3-pyridinylmethyl) sulfanyl] aniline (0.38 g) and triethylamine (1.34 ml) in THF (11.4 ml). The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-pyridinylmethyl). Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 209) (0.33 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.07 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.8H
z), 3.32-3.38 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2
H, t, J = 4.8Hz), 4.01 (2H, s), 4.15 (2H, t, J = 4.8Hz),
6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.15-
7.29 (3H, m), 7.37-7.60 (9H, m), 8.38 (1H, d, J = 2.2H
z), 8.46 (1H, dd, J = 4.6, 1.8Hz)

Example 193 (Production of Compound 210) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml) and 0 M-Chloroperbenzoic acid (87 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[(3-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 21
0) (98 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 4.8Hz), 3.91 (1H, d, J = 12.8Hz), 4.05-4.12 (1H,
m), 4.16 (2H, t, J = 4.8Hz), 6.92 (1H, d, J = 8.8Hz), 6.
98 (2H, d, J = 8.8Hz), 7.19-7.31 (3H, m), 7.39-7.51 (6
H, m), 7.70 (2H, d, J = 8.8Hz), 7.83 (1H, m), 8.12 (1H,
m), 8.52 (1H, dd, J = 4.8, 1.6Hz) IR (KBr) 3333, 2957, 1651, 1499, 1242, 1036, 818cm
^-1

Example 194 (Preparation of compound 211) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue THF solution (14 ml) was used as a THF solution (11.4 ml) of 4-[(4-pyridinylmethyl) sulfanyl] aniline (0.38 g) and triethylamine (1.34 ml). The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(4-pyridinylmethyl). Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 211) (0.27 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.35 (2H, t, J = 4.8Hz), 3.55 (2H, t, J = 6.6Hz), 3.
78-3.82 (2H, m), 3.98 (2H, s), 4.12-4.18 (2H, m), 6.9
1 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.27 (2H,
d, J = 8.8Hz), 7.38-7.58 (8H, m), 8.47-8.51 (2H, m)

Example 195 (Production of compound 212) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.24 g) was dissolved in methylene chloride (7.2 ml) and 0 M-Chloroperbenzoic acid (65 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[(4-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 21
2) (101 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.05 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.44-3.50 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 3.92 (1H, d, J = 12.4Hz), 4.05 (1H, d,
J = 12.8Hz), 4.13-4.18 (2H, m), 6.88-6.92 (3H, m), 6.9
8 (2H, d, J = 8.8Hz), 7.31-7.49 (7H, m), 7.69-7.82 (3H,
m), 8.50 (2H, d, 5.8Hz) IR (KBr) 3335, 2957, 1649, 1499, 1242, 1036, 829cm
^-1 Elemental analysis C ₃₉ H ₄₅ N ₃ O ₄ S Cald. C, 71.86; N, 6.45; H,
6.96: Found. C, 71.65; N, 6.56; H, 7.04

Example 196 (Production of compound 213) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 ml) was added to 4-[(3-pyridinylmethyl) sulfanyl] aniline (0.39 g) and triethylamine (1.34 ml) in THF (11.4 ml). The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(6-methyl 2-Pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 213) (0.52 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.36-1.45 (2H, m), 1.57-1.64 (2H,
m), 2.05 (1H, m), 2.54 (3H, s), 2.89 (2H, m), 3.17 (2
H, t, J = 7.2Hz), 3.34 (2H, t, J = 4.4Hz), 3.55 (2H, t,
J = 6.6Hz), 3.77-3.83 (2H, m), 4.12-4.18 (2H, m), 4.19
(2H, s), 6.91 (1H, d, J = 8.6Hz), 6.97 (2H, d, J = 8.8H
z), 6.95-7.07 (2H, m), 7.29-7.57 (11H, m)

Example 197 (Preparation of compound 214) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(6-methyl-2-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.46 g) was added to methylene chloride (13. 8 ml), m-chloroperbenzoic acid (87 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(6-Methyl-2-pyridinyl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 214) (157m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.08 (1H, m), 2.52 (3H, s), 2.92 (2H, m), 3.19 (2
H, t, J = 7.4Hz), 3.34-3.40 (2H, m), 3.51-3.58 (2H,
m), 3.78-3.83 (2H, m), 4.09 (1H, d, J = 12.0Hz), 4.13-
4.18 (2H, m), 4.23 (1H, d, J = 12.4Hz), 6.92 (1H, d, J =
8.8Hz), 6.98 (2H, d, J = 8.8Hz), 6.98-7.09 (2H, m), 7.
38-7.55 (8H, m), 7.69-7.79 (3H, m) IR (KBr) 3322, 2965, 1644, 1588, 1499, 1244, 1184,
1044, 924, 829, 750cm ^{- 1}

Example 198 (Preparation of compound 215) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 ml) was added to 4-[[(4-chloro-2-pyridinyl) methyl] sulfanyl] aniline (0.42 g).
A solution of triethylamine (1.34 ml) in THF (1
2.6 ml) 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. 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 to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[(4-chloro-2-pyridinyl). ) Methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 215) (0.
51 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4Hz), 0.9
5 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.53-1.64 (2H,
m), 2.04 (1H, m), 2.87 (2H, m), 3.15 (2H, d, J = 7.0H
z), 3.29-3.34 (2H, m), 3.54 (2H, t, 6.6Hz), 3.77-3.8
2 (2H, m), 4.09-4.15 (2H, m), 4.16 (2H, s), 6.89 (1H,
d, J = 8.8Hz), 6.95 (2H, d, J = 8.4Hz), 7.23-7.54 (11H,
m), 7.73 (1H, s), 8.40 (1H, d, J = 5.2Hz)

Example 199 (Production of compound 216) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(6-methyl-2-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) was added to methylene chloride (15. 3 ml) and m-chloroperbenzoic acid (0.20 g) at -78 ° C.
Methylene chloride solution (10.2 ml) was added dropwise and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was 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, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[(6-chloro-2-pyridinyl)
Methyl] sulfinyl] phenyl] -1-isobutyl-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 216) (0.34 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.63 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, m), 3.34-3.
39 (2H, m), 3.55 (2H, m), 3.77-3.83 (2H, m), 4.13-4.1
8 (2H, m), 6.92 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8H
z), 7.23-7.26 (2H, m), 7.38-7.53 (7H, m), 7.72-7.81
(3H, m), 8.41-8.45 (1H, m) IR (KBr) 3320, 2957, 1645, 1499, 1244, 1127, 1042,
826cm ^-1 Elemental analysis C ₃₉ H ₄₄ N ₃ O ₄ SCl Cald. C, 68.25; N, 6.12;
H, 6.46; Cl, 5.17: Found. C, 68.04; N, 6.16;
H, 6.43; Cl, 5.05

Example 200 (Production of Compound 217) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (two drops) was added, oxalyl chloride (0.28 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting THF solution (14 ml) was added to 4-[[(4-methyl-2-pyridinyl) methyl] sulfanyl] aniline (0.41 g),
A solution of triethylamine (1.78 ml) in THF (1
2.3 ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4
-[[(6-Methyl-2-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 217) (0.4
0 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.30 (3H, s), 2.89 (2H, m), 3.17 (2
H, d, J = 7.4Hz), 3.31-3.37 (2H, m), 3.51-3.59 (2H,
m), 3.77-3.83 (2H, m), 4.10-4.15 (2H, m), 4.18 (2H,
s), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.4Hz), 7.
11 (1H, s), 7.27-7.52 (10H, m), 7.63 (1H, s), 7.38 (1
(H, d, J = 5.2Hz)

Example 201 (Production of compound 218) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(6-methyl-2-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.39 g) in methylene chloride (7. 8 ml) solution,
The mixture was added dropwise to a methylene chloride solution (7.8 ml) of m-chloroperbenzoic acid (0.21 g) at -40 ° C, and the mixture was stirred for 20 minutes. A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[[(6-methyl-2-pyridinyl) methyl] sulfinyl] phenyl] -2,3
-Dihydro-1-benzazepine-4-carboxamide (Compound 218) (146 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.8Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.07 (1H, m), 2.31 (3H, s), 2.91 (2H, m), 3.19 (2
H, d, J = 7.0Hz), 3.33-3.38 (2H, m), 3.55 (2H, t, J = 6.
6Hz), 3.77-3.83 (2H, m), 4.15-4.18 (2H, m), 4.15 (2H,
s), 6.92 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 6.
95-7.05 (2H, m), 7.37-7.52 (7H, m), 7.73 (2H, d, J = 8.
4Hz), 7.92 (1H, s), 8.40 (1H, d, J = 5.2Hz) IR (KBr) 3322, 2959, 1644, 1501, 1242, 1184, 828cm
^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₄ S ・ 0.3H ₂ O Cald. C, 72.57; N, 6.
26; H, 7.15: Found.C, 71.69; N, 6.22; H, 7.28

Example 202 (Production of compound 219) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.2 g) was dissolved in THF (24 ml), DMF (three drops) was added, oxalyl chloride (0.48 ml) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (24
ml), 4-[[2- (methoxymethoxy) benzyl] sulfanyl] aniline (0.83 g) and triethylamine (2.29 ml) in THF (24.9 m).
It was added dropwise to 1) under ice cooling and stirred at room temperature for 16 hours. 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, the obtained residue was purified by silica gel column chromatography, washed with hexane / ethyl acetate, and 7- [4- (2-butoxyethoxy) phenyl] was used.
-1-Isobutyl-N- [4-[[2- (methoxymethoxy) benzyl] sulfanyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 219) (1.09 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.55-1.65 (2H,
m), 2.07 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.33-3.38 (2H, m), 3.50 (3H, s), 3.55 (2H, t, J =
6.6Hz), 3.80 (2H, t, J = 4.4Hz), 4.12 (2H, s), 4.13-4.
19 (2H, m), 5.19 (2H, s), 6.84-7.52 (17H, m)

Example 203 (Production of compound 220) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[2- (methoxymethoxy)
Benzyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.0
A solution of 2 g) in methylene chloride (20.4 ml) at -78
At m ° C., m-chloroperbenzoic acid (0.51 g) was added dropwise to a methylene chloride solution (40.8 ml), and the mixture was stirred for 20 minutes.
A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[2- (methoxymethoxy)
Benzyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 220) (820 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.53-1.67 (2H,
m), 2.07 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J = 7.0H
z), 3.35 (2H, d, J = 7.0Hz), 3.45 (3H, s), 3.54 (2H, t,
J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 4.01 (1H, d, J = 12.
0Hz), 4.12-4.18 (2H, m), 4.29 (1H, d, J = 12.2Hz), 5.0
6 (2H, s), 6.86-7.08 (6H, m), 7.20-7.43 (8H, m), 7.68
(2H, d, J = 8.8Hz), 7.87-7.98 (1H, m) IR (KBr) 3335, 2957, 1645, 1588, 1499, 1242, 1182,
926, 828, 760cm ^-1 Elemental analysis C ₄₂ H ₅₀ N ₂ O ₆ S Cald. C, 70.96; N, 3.94; H,
7.09: Found. C, 70.93; N, 3.88; H, 7.01

Example 204 (Production of compound 221) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[2- (methoxymethoxy)
Benzyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.6
9 g) was dissolved in methanol (13.8 ml), 4N hydrochloric acid / ethyl acetate (3.45 ml) was added at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[(2-Hydroxybenzyl) sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 221) (0.
30 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.53-1.64 (2H,
m), 2.05 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.31-3.35 (2H, d, J = 6.6Hz), 3.55 (2H, t, J = 6.6H
z), 3.80 (2H, t, J = 4.8Hz), 3.96 (1H, d, J = 13.8Hz),
4.10-4.17 (2H, m), 4.37 (1H, d, J = 13.6Hz), 6.63-6.72
(2H, m), 6.89-7.00 (4H, m), 7.12-7.18 (1H, m), 7.37-
7.48 (7H, m), 7.72 (2H, d, J = 7.0Hz), 7.92 (1H, s), 9.0
8 (1H, s) IR (KBr) 2957, 1649, 1607, 1499, 1397, 1246, 1179,
818, 756cm ^-1

Example 205 (Preparation of compound 222) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, oxalyl chloride (0.24 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in methylene chloride solution (12 ml) was added to a solution of 4-amino-N- (2-pyrimidinyl) benzenesulfonamide (0.38 g) and triethylamine (1.53 ml) in methylene chloride. (1
(1.4 ml) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was added to water and extracted with methylene chloride. 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 and recrystallized from ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [. 4-[(2-pyrimidinylamino) sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 2
22) (113 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.8Hz), 0.9
3 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.61 (2H,
m), 2.05 (1H, m), 2.83 (2H, m), 3.22 (2H, d, J = 7.4H
z), 3.26 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 4.4Hz), 4.14 (2H, d, J = 4.4Hz), 6.85-7.00 (4H, m),
7.35-7.44 (5H, m), 7.74 (2H, d, J = 8.8Hz), 7.96-8.02
(3H, m), 8.64 (2H, d, J = 5.0Hz), 11.33 (1H, br) IR (KBr) 3312, 2953, 1647, 1581, 1499, 1246, 1165,
941, 839cm ^-1 Elemental analysis C ₃₇ H ₄₃ N ₅ O ₅ S Cald. C, 66.34; N, 10.46;
H, 6.47: Found. C, 66.18; N, 10.44; H, 6.77

Example 206 (Production of compound 223) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.50 g) was dissolved in THF (10 ml), DMF (three drops) was added, oxalyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (10 ml) was mixed with 3-methyl-4-[(2-pyridinylmethyl) sulfanyl] aniline (0.29 g) and triethylamine (0.96 ml) in THF ( 8.7m
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4-[( 2-Pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-
A carboxamide (Compound 223) (0.46 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.34 (3H, s), 2.89 (2H, m), 3.18 (2
H, d, J = 7.4Hz), 3.32-3.37 (2H, m), 3.52-3.59 (2H,
m), 3.80 (2H, t, J = 4.6Hz), 4.13-4.18 (2H, m), 4.16 (2
H, s), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.6Hz),
7.14-7.18 (12H, m), 8.51-8.55 (1H, m)

Example 207 (Production of compound 224) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methyl-4-[(2-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.4
5 g) in methylene chloride (13.5 ml), -78
A methylene chloride solution (9.0 ml) of m-chloroperbenzoic acid (0.16 g) was added dropwise at C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography.
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4-[(2-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4- Carboxamide (Compound 2
24) (185 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.29-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.07 (1H, m), 2.22 (3H, s), 2.91 (2H, m), 3.19 (2
H, d, J = 7.4Hz), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.77-3.83 (2H, m), 4.13-4.18 (2H, m), 4.18 (2H, s),
6.89-6.95 (1H, m), 6.97 (2H, d, J = 8.8Hz), 7.12-7.24
(2H, m), 7.38-7.79 (10H, m), 8.53 (1H, d, J = 4.4Hz) IR (KBr) 3287, 2957, 1661, 1499, 1244, 1180, 910, 8
18, 733cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₄ S Cald. C, 72.15; N, 6.31; H,
7.11: Found. C, 72.20; N, 6.45; H, 7.08

Example 208 (Production of compound 225) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.50 g) was dissolved in THF (10 ml), DMF (three drops) was added, oxalyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting THF solution (10 ml) was added to 4-[[(4-ethoxy-2-pyridinyl) methyl] sulfanyl] -3-methylaniline (0.33 g) and triethylamine (0 0.96 ml) in THF solution (9.9 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. 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 to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [3-methyl-4-[[(4-ethoxy-2-pyridinyl) methyl] sulfanyl] phenyl] -1-isobutyl-2,
3-Dihydro-1-benzazepine-4-carboxamide (Compound 225) (0.18 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (5H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.36 (3H, s), 2.89 (2H, m), 3.18 (2
H, d, J = 7.4Hz), 3.36 (2H, m), 3.51-3.59 (2H, m), 3.8
0 (2H, t, J = 4.8Hz), 4.12 (2H, s), 4.12 (2H, q, J = 7.0H
z), 6.66 (1H, dd, J = 5.6, 2.2Hz), 6.76 (1H, d, J = 2.6H
z), 6.91 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.
30-7.48 (8H, m), 8.33 (1H, d, J = 5.8Hz)

Example 209 (Preparation of compound 226) 7- [4- (2-butoxyethoxy) phenyl] -N-
Chloridation of [3-methyl-4-[[(4-ethoxy-2-pyridinyl) methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.17 g) Methylene (5.1m
l) The solution was added with m-chloroperbenzoic acid (55
methylene chloride solution (3.4 ml) was added dropwise to 1).
Stir for 5 minutes. A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -N- [3-methyl-4-[[(4-ethoxy -2-Pyridinyl) methyl] sulfinyl] phenyl]
-1-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 226) (32m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.00 (6H, m), 0.97 (6
H, d, J = 6.6Hz), 1.33-1.44 (5H, m), 1.54-1.65 (2H,
m), 2.08 (1H, m), 2.27 (3H, s), 2.91 (2H, m), 3.19 (2
H, d, J = 7.0Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.80 (2H, t, J = 4.8Hz), 4.01-4.18 (4H, m), 4.10 (2H,
s), 6.69-6.73 (2H, m), 6.90-6.95 (2H, d, J = 8.8Hz),
6.98 (2H, d, J = 8.8Hz), 7.26-7.58 (8H, m), 7.77 (1H,
d, J = 8.2Hz), 8.31 (1H, d, J = 5.2Hz) IR (KBr) 3268, 2957, 1661, 1599, 1497, 1238, 1125,
1044, 816, 731cm ^-1

Example 210 (Production of compound 227) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, oxalyl chloride (0.24 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting THF solution (12 ml) was used as a THF solution of 4-[(3-pyridinylmethyl) sulfanyl] -3-methylaniline (0.33 g) and triethylamine (1.15 ml) ( 9.9m
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4-[( 3-Pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-
A carboxamide (Compound 227) (0.51 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.29 (3H, s), 2.89 (2H, t, J = 4.0H
z), 3.17 (2H, d, J = 7.2Hz), 3.31-3.36 (2H, m), 3.55 (2
H, t, J = 6.6Hz), 3.77-3.83 (2H, m), 3.94 (2H, s), 4.1
0-4.18 (2H, m), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J
= 8.8Hz), 7.14-7.25 (2H, m), 7.34-7.51 (8H, m), 7.63
(1H, s), 8.36 (1H, d, J = 2.2Hz), 8.43-8.47 (1H, m)

Example 211 (Production of compound 228) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methyl-4-[(3-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.5
A methylene chloride solution (10 ml) of m-chloroperbenzoic acid (0.17 g) was added dropwise to a methylene chloride (15 ml) solution of 0 g) at -78 ° C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4-[(3-pyridinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 22
8) (151 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.06 (1H, m), 2.18 (3H, s), 2.90 (2H, m), 3.18 (2
H, d, J = 7.4Hz), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.82 (2H, t, J = 4.8Hz), 3.90 (1H, d, J = 13.0Hz), 4.02
(1H, d, J = 12.8Hz), 4.12-4.17 (2H, m), 6.89-6.94 (1H,
m), 6.96 (2H, d, J = 8.8Hz), 7.15-7.49 (10H, m), 7.71
(1H, s), 8.02 (1H, s), 8.48-8.52 (1H, m) IR (KBr) 3287, 2957, 1655, 1499, 1244, 910, 816, 73
1 cm ^-1

Example 212 (Production of Compound 229) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) was added to 4-[[(4,6-dimethyl-2-pyrimidinyl) methyl] sulfanyl] aniline (0.37 g),
A solution of triethylamine (1.53 ml) in THF (1
1.1 ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[(4,6-
Dimethyl-2-pyrimidinyl) methyl] sulfanyl]
Phenyl] -1-isobutyl-2,3-dihydro-1-
Benzazepine-4-carboxamide (Compound 229)
(0.57 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.36-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.40 (6H, s), 2.90 (2H, m), 3.18 (2
H, d, J = 7.2Hz), 3.32-3.38 (2H, m), 3.55 (2H, t, J = 6.
6Hz), 3.78-3.83 (2H, m), 4.13 (2H, s), 6.69 (1H, s),
6.91 (1H, d, J = 9.2Hz), 6.97 (2H, d, J = 8.8Hz), 7.36-
7.55 (10H, m),

Example 213 (Production of compound 230) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(4,6-Dimethyl-2-pyrimidinyl) methyl] sulfanyl] phenyl] -1-isobutyl-
2,3-Dihydro-1-benzazepine-4-carboxamide (0.56 g) in methylene chloride (16.8 ml)
The solution was added with m-chloroperbenzoic acid (0.22
A methylene chloride solution (10 ml) of g) was added dropwise, and the mixture was stirred for 15 minutes. After the temperature was naturally raised to 0 ° C., a saturated sodium thiosulfate aqueous solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2
-Butoxyethoxy) phenyl] -N- [4-
[[(4,6-Dimethyl-2-pyrimidinyl) methyl]
Sulfinyl] phenyl] -1-isobutyl-2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 230) (165 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.54 (6H, s), 2.90 (2H, m), 3.18 (2
H, d, J = 7.4Hz), 3.35 (2H, t, J = 4.4Hz), 3.55 (2H, t,
J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 4.16 (2H, t, J = 4.6H
z), 4.16-4.24 (1H, m), 4.35 (1H, d, J = 12.8Hz), 6.91
(1H, d, J = 8.8Hz), 6.97 (1H, d, J = 8.8Hz), 7.02 (1H,
d, J = 8.8Hz), 7.14 (1H, d, J = 8.8Hz), 7.36-7.56 (7H,
m), 7.71 (1H, s) IR (KBr) 3285, 2957, 1651, 1582, 1499, 1244, 1180,
910, 816, 733cm ^-1 Elemental analysis C ₄₀ H ₄₈ N ₄ O ₄ S Cald. C, 70.56; N, 8.23; H,
7.11: Found. C, 70.39; N, 8.04; H, 7.08

Example 214 (Production of compound 231) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) of 4-[[(1-methyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline (0.31 g) and triethylamine (1.53 ml) in THF (9. (3 ml) 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. 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 to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-methyl-tetrazole-5-
Il) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 231) (0.59 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.04 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.32 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.83 (2
H, m), 4.10 (2H, s), 4.12-4.18 (2H, m), 6.89 (1H, d,
J = 9.0Hz), 6.96 (2H, d, J = 8.8Hz), 7.21-7.41 (7H, m),
7.58 (2H, d, J = 8.8Hz), 8.08 (1H, s) IR (KBr) 3310, 2957, 1651, 1607, 1499, 1244, 1180,
910, 816, 733cm ^-1

Example 215 (Production of compound 232) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-methyl-tetrazol-5-yl) methyl] sulfanyl] phenyl]-
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g) in methylene chloride (18 ml) was added at -78 ° C to m-chloroperbenzoic acid (0.19 g).
Methylene chloride solution (12 ml) was added dropwise and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-methyl −
Tetrazol-5-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-
A carboxamide (Compound 232) (350 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.8Hz), 0.9
9 (6H, d, J = 7.0Hz), 1.33-1.45 (2H, m), 1.52-1.64 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.18 (2H, d, J = 6.6H
z), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-3.83 (2
H, m), 3.91-4.23 (2H, m), 3.92 (3H, s), 4.11-4.17 (2
H, m), 6.88-6.93 (1H, m), 6.95 (2H, d, J = 8.4Hz), 7.3
0-7.40 (7H, m), 7.83 (2H, d, J = 8.4Hz), 8.50 (1H, br) IR (KBr) 2957, 1647, 1607, 1507, 1316, 1244, 910, 7
35 cm ^-1

Example 216 (Production of compound 233) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) of 4-[[(2-methyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline (0.31 g) and triethylamine (1.53 ml) in THF (9. (3 ml) 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. 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 to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(2-methyl-tetrazole-5-
Il) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 233) (0.59 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.2H
z), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 4.8Hz), 4.15 (2H, t, 4.8Hz), 4.27 (2H, s), 4.29 (3
H, s), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz),
7.36-7.62 (10H, m), IR (KBr) 3285, 2957, 1651, 1607, 1497, 1242, 1181,
1123, 818, 733cm ^-1

Example 217 (Production of compound 234) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(2-methyl-tetrazol-5-yl) methyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (0.58 g) in methylene chloride (17.4 ml)
The solution was added with m-chloroperbenzoic acid (0.19
g) in methylene chloride solution (11.6 ml) was added dropwise.
Stir for 5 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(2-methyl -Tetrazol-5-yl) methyl] sulfinyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (Compound 234) (420 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.64 (2H,
m), 2.04 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.34-3.39 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 4.16 (2H, t, 4.6Hz), 4.32 (2H, s),
4.33 (3H, s), 6.93 (1H, d, J = 8.8Hz), 6.98 (2H, d, J =
8.8Hz), 7.38-7.56 (7H, m), 7.74-7.79 (3H, m) IR (KBr) 3283, 2957, 1661, 1497, 1314, 1124, 1180,
835, 731cm ^-1 Elemental analysis C ₃₆ H ₄₄ N ₆ O ₄ S Cald. C, 65.83; N, 12.79;
H, 6.75: Found. C, 65.69; N, 12.56; H, 6.76

Example 218 (Production of compound 235) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) to 4-[(3-pyridinylmethyl) sulfanyl] -3- (trifluoromethyl) aniline (0.43
g) and triethylamine (1.53 ml) were added dropwise to a THF solution (12.9 ml) 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. 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 to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[(3-Pyridinylmethyl) sulfanyl]-
3- (Trifluoromethyl) phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 235) (0.47 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J = 7.4H
z), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J = 4.8Hz), 4.05 (2H, s), 4.13-4.18 (2H, m), 6.92 (1H,
d, J = 8.6Hz), 6.97 (2H, d, J = 8.8Hz), 7.18-7.61 (8H,
m), 7.71 (1H, s), 7.73-7.79 (1H, m), 7.88 (1H, d, J =
2.2Hz), 8.37 (1H, d, J = 2.2Hz), 8.47 (1H, dd, J = 4.6,
(1.4Hz)

Example 219 (Production of compound 236) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-pyridinylmethyl) sulfanyl] -3- (trifluoromethyl) phenyl]
2,3-Dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 m
l) The solution was added with m-chloroperbenzoic acid (0.
11 g) of methylene chloride solution (7.2 ml) was added dropwise,
Stir for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy).
Phenyl] -1-isobutyl-N- [4-[(3-pyridinylmethyl) sulfinyl] -3- (trifluoromethyl) phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 236) ( 100m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.20 (2H, d, J = 7.8H
z), 3.37 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2H, t,
J = 4.8Hz), 3.80-3.87 (1H, m), 4.16 (2H, t, J = 4.6Hz),
4.17-4.23 (1H, m), 6.90-6.95 (1H, m), 6.98 (2H, d, J
= 8.8Hz), 7.22-7.28 (1H, m), 7.39-7.51 (7H, m), 7.61-
7.67 (1H, m), 7.96 (1H, s), 8.06 (1H, d, J = 1.4Hz), 8.
26 (1H, d, J = 2.2Hz), 8.34 (1H, dd, J = 4.8, 1.6Hz) IR (KBr) 2959, 1667, 1607, 1499, 1321, 1240, 1175,
1127, 910, 816, 733cm ^{- 1}

Example 220 (Production of compound 237) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) of 4-[[(5-methyl-1,3,4-oxadiazol-2-yl) methyl] sulfanyl] aniline (0.33 g) and a solution of triethylamine (1.53 ml) in THF (9. (9 ml) 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. 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 to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(5-methyl-1,3,4-oxadiazol-2-yl) methyl] sulfanyl] phenyl] -2,3 -Dihydro-1-benzazepine-4-carboxamide (Compound 237) (0.37 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.04 (1H, m), 2.46 (3H, s), 2.90 (2H, m), 3.17 (2
H, d, J = 7.2Hz), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.77-3.83 (2H, m), 4.08 (2H, s), 4.13 (2H, t, J = 4.8H
z), 6.90 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.3
3-7.45 (7H, m), 7.57 (2H, d, J = 8.4Hz), 7.82 (1H, s)

Example 221 (Production of compound 238) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(5-methyl-1,3,4
-Oxadiazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) at -78 ° C. Solution of m-chloroperbenzoic acid (0.12 g) in methylene chloride (7.2 m
1) was added dropwise and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4
-[[(5-methyl-1,3,4-oxadiazole-
2-yl) methyl] sulfinyl] phenyl] -2,3
-Dihydro-1-benzazepine-4-carboxamide (Compound 238) (230 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
8 (6H, d, J = 6.2Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.08 (1H, m), 2.48 (3H, s), 2.92 (2H, m), 3.19 (2
H, d, J = 6.6Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.78-3.83 (2H, m), 4.13-4.17 (2H, m), 4.12 (2H, s),
6.92 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.38-
7.57 (7H, m), 7.80 (2H, d, J = 8.8Hz), 7.91 (1H, br) IR (KBr) 3285, 2955, 1661, 1588, 1497, 1242, 817, 7
33cm ^-1 Elemental analysis C ₃₇ H ₄₄ N ₄ O ₅ S Cald. C, 67.66; N, 8.53; H,
6.75: Found. C, 67.39; N, 8.36; H, 6.66

Example 222 (Production of compound 239) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.62 g) in THF (12.4 m
After dissolving in 1) and adding DMF (2 drops), thionyl chloride (0.21 ml) was added and stirred at room temperature for 1 hour.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (12
ml) was added to 3-methoxy-4-[(3-pyridinylmethyl) sulfanyl] aniline (0.38 g) and triethylamine (1.58 ml) in THF (11.4 m).
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [3-methoxy-4-[( 3-Pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (Compound 239) (0.39 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.4Hz), 1.33-1.45 (2H, m), 1.57-1.68 (2H,
m), 2.05 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.33-3.38 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-
3.83 (2H, m), 3.91 (3H, s), 3.99 (2H, s), 4.13-4.18 (2
H, m), 6.75 (1H, dd, J = 8.4, 2.2Hz), 6.92 (1H, d, J =
8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.12 (1H, d, J = 8.2H
z), 7.16-7.18 (1H, m), 7.37-7.55 (6H, m), 7.63-7.66
(2H, m), 8.36 (1H, d, J = 2.2Hz), 8.40-8.44 (1H, m) IR (KBr) 2957, 1655, 1590, 1499, 1242, 1181, 816, 7
33 cm ^-1

Example 223 (Production of compound 240) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methoxy-4-[(3-pyridyl
Nylmethyl) sulfanyl] phenyl] -2,3-dihi
Doro-1-benzazepine-4-carboxamide (0.
39 g) was dissolved in methylene chloride (7.8 ml), and -7
Chloroform of m-chloroperbenzoic acid (152 mg) at 8 ° C.
A ethylene solution (15.6 ml) was added, and the mixture was stirred for 15 minutes.
The reaction mixture was added to saturated aqueous sodium thiosulfate solution and mixed with acetic acid
Extracted with chill. After washing with saturated saline,
Dried with sium. The solvent was removed under reduced pressure and the resulting residue
Purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methoxy-4-[(3-pyridyl
Nylmethyl) sulfinyl] phenyl] -2,3-dihi
Doro-1-benzazepine-4-carboxamide (compound
The product 240) (0.26g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
 m), 2.04 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J = 7.4H
z), 3.36 (2H, m), 3.55 (2H, m), 3.70-3.83 (2H, m), 3.
95 (3H, s), 3.99 (2H, s), 4.01 (1H, d, J = 13.2Hz), 4.1
3-4.21 (3H, m), 6.75 (1H, dd, J = 8.4, 1.8Hz), 6.94-7.
10 (4H, m), 7.39-7.49 (6H, m), 7.94 (1H, d, J = 1.4Hz),
 8.02 (1H, d, J = 1.4Hz), 8.47 (1H, dd, J = 4.6, 1.4Hz) IR (KBr) 3281, 2957, 1661, 1593, 1499, 1402, 1242,
1181, 1030, 816, 733cm ^-1

Example 224 (Production of compound 241) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) of 4-[[(1-ethyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline (0.36 g) and a solution of triethylamine (1.53 ml) in THF (10. 7 ml) 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. 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 to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[1-ethyl-tetrazole-
5-yl) methyl] sulfanyl] phenyl] -2,3
-Dihydro-1-benzazepine-4-carboxamide (Compound 241) (0.46 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.65 (4H, m), 1.52 (3H, t, J
= 7.4Hz), 2.04 (1H, m), 2.90 (2H, m), 3.17 (2H, d, J = 7.
2Hz), 3.33 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
t, J = 4.6Hz), 4.12-4.17 (2H, s), 4.14 (2H, s), 4.27 (2
H, q, J = 7.4Hz), 6.90 (1H, d, J = 9.0Hz), 6.96 (2H, d, J
= 8.6Hz), 7.24-7.56 (5H, m), 7.58 (2H, d, J = 7.0Hz),
8.01 (1H, s)

Example 225 (Production of compound 242) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-ethyl-tetrazol-5-yl) methyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (0.45 g) in methylene chloride (13.5 ml)
The solution was added with m-chloroperbenzoic acid (0.12
g) methylene chloride solution (9.0 ml) was added dropwise, and
Stir for minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-ethyl -Tetrazol-5-yl) methyl] sulfinyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (Compound 242) (221 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
9 (6H, d, J = 6.6Hz), 1.33-1.65 (4H, m), 1.51 (3H, t, J
= 7.0Hz), 2.05 (1H, m), 2.93 (2H, m), 3.20 (2H, d, J = 7.
2Hz), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
t, J = 4.8Hz), 4.06-4.12 (2H, s), 4.23-4.41 (4H, m),
6.89-6.94 (1H, m), 6.96 (2H, d, J = 9.2Hz), 7.33-7.44
(7H, m), 7.82 (2H, d, J = 8.6Hz), 7.82 (2H, d, J = 8.6H
z), 8.19 (1H, s) IR (KBr) 2957, 1661, 1607, 1588, 1499, 1242, 1179,
1051, 835, 733cm ^-1

Example 226 (Production of compound 243) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) to 3-chloro-4-[(3-pyridinylmethyl)
Sulfanyl] aniline (0.36 g) and triethylamine (1.53 ml) were added dropwise to a THF solution (10.7 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy).
Phenyl] -N- [3-chloro-4-[(3-pyridinylmethyl) sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 243) (0.31 g) Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.69 (2H,
m), 2.05 (1H, m), 2.89 (2H, m), 3.18 (2H, d, J = 7.4H
z), 3.35 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
m), 4.06 (2H, s), 4.10-4.17 (2H, m), 6.91 (1H, d, J =
8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.17-7.67 (10H, m),
7.83 (1H, d, J = 2.2Hz), 7.83 (1H, d, J = 2.2Hz), 8.41 (1
H, d, J = 2.2Hz), 8.46 (1H, dd, J = 4.6, 1.4Hz)

Example 227 (Production of compound 244) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Chloro-4-[(3-pyridinylmethyl) sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.3
0 g) in a solution of methylene chloride (9.0 ml) at -78 ° C.
A methylene chloride solution (6.0 ml) of m-chloroperbenzoic acid (93 g) was added dropwise at, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [3-chloro-4-[(3-pyridinylmethyl) sulfinyl]
Phenyl] -1-isobutyl-2,3-dihydro-1-
Benzazepine-4-carboxamide (Compound 244)
(94 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.32-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.90 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz), 4.03-4.18 (4
H, m), 6.92 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz),
7.03-7.21 (3H, m), 7.39-7.49 (6H, m), 7.92-8.13 (3H,
m), 8.49 (1H, m) IR (KBr) 3281, 2957, 1667, 1582, 1381, 1242, 1181,
910, 816, 731cm ^-1

Example 228 (Production of compound 245) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- (Hydroxymethyl) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g) was dissolved in THF (12 ml), pyridine (three drops), thionyl chloride. (0.16 ml)
Was added, and the solution was stirred at room temperature for 1 hour to give 1-methyl-
1,2,3,4-tetrazole-5-thiol (154
mg) and triethylamine (1.23 ml) in a THF solution (12 ml) at 0 ° C. After stirring at room temperature for 2 hours, the mixture was stirred at 50 ° 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(1-Methyl-1,2,3,4-tetrazole-5
-Yl) sulfanyl] methyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 245) (520 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.56-1.65 (2H,
m), 2.05 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J = 7.2H
z), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.81 (2
H, m), 3.80 (3H, s), 4.16 (2H, m), 4.51 (2H, s), 6.92
(1H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.8Hz), 7.32-7.59 (1
0H, m) IR (KBr) 2957, 1653, 1607, 1518, 1499, 1242, 1181,
1167, 818, 733cm ^-1

Example 229 (Production of compound 246) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.60 g) was dissolved in THF (12 ml) and DMF (3 drops) was added, followed by thionyl chloride (0.
21 ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 ml)
4-[(3-pyridinylmethyl) sulfanyl] aniline (0.34 g) and triethylamine (1.58 m
l) was added dropwise to a THF solution (10.2 ml) under ice cooling,
The mixture was stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[(3-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 246) (0.
30 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.57-1.80 (4H,
m), 2.89 (2H, t, J = 4.0Hz), 3.26-3.35 (4H, m), 3.55 (2
H, t, J = 6.6Hz), 3.77-3.84 (2H, m), 4.00 (2H, s), 4.1
5 (2H, t, J = 4.8Hz), 6.89 (1H, d, J = 8.8Hz), 6.97 (2H,
d, J = 8.8Hz), 7.20-7.57 (11H, m), 7.64 (1H, s), 8.39
(1H, d, J = 1.8Hz), 8.46 (1H, dd, J = 4.6, 1.4Hz)

Example 230 (Production of compound 247) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[(3-pyridinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.29 g) in methylene chloride (8.7 ml) was added with -78. M-chloroperbenzoic acid (120 g) in methylene chloride solution (5.8 m)
1) was added dropwise and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-
[(3-Pyridinylmethyl) sulfinyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 247) (125 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
9 (3H, t, J = 7.4Hz), 1.33-1.45 (2H, m), 1.54-1.85 (4H,
m), 2.91 (2H, m), 3.28-3.36 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.77-3.83 (2H, m), 3.90 (1H, d, J = 13.2Hz),
4.08 (1H, d, J = 13.2Hz), 4.12-4.18 (2H, m), 6.90 (1H,
d, J = 8.6Hz), 6.97 (2H, d, J = 8.4Hz), 7.18-7.26 (2H,
m), 7.29-7.49 (6H, s), 7.69 (2H, d, J = 8.8Hz), 7.91-
8.02 (2H, m), 8.49-8.53 (1H, m) IR (KBr) 3277, 2961, 1661, 1607, 1501, 1246, 910, 8
18, 731cm ^-1

Example 231 (Production of compound 248) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) was treated with 4-[[(2-methoxy-3-pyridinyl) methyl] sulfanyl] aniline (0.37 g) and triethylamine (1.53 ml) in THF (11.1 m).
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(2-Methoxy-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 248) (0.4
9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.55-1.66 (2H,
m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.8H
z), 3.35 (2H, t, J = 4.4Hz), 3.55 (2H, t, J = 6.2Hz), 3.
77-3.83 (2H, m), 3.96 (3H, s), 4.02 (2H, s), 4.15 (2H,
t, J = 4.8Hz), 6.76 (1H, dd, J = 7.2, 5.0Hz), 6.91 (1H,
d, J = 8.4Hz), 6.97 (2H, d, J = 8.8Hz), 7.27-7.56 (11H,
m), 8.04 (1H, dd, J = 5.0, 1.8Hz)

Example 232 (Production of compound 249) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(2-methoxy-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-
To a solution of dihydro-1-benzazepine-4-carboxamide (0.48 g) in methylene chloride (14.4 ml) was added a solution of m-chloroperbenzoic acid (187 g) in methylene chloride (9.6 ml) at -78 ° C. It was dropped and stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, recrystallized from ethanol, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[(2-methoxy-3-pyridinyl) methyl]]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 249)
(267 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (6H, d, J = 6.6Hz), 1.30-1.45 (2H, m), 1.52-1.65 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.20 (2H, d, J = 7.4H
z), 3.37 (2H, m), 3.55 (2H, t, J = 6.4Hz), 3.78 (3H,
s), 3.78-3.83 (2H, m), 3.98 (1H, d, J = 12.0Hz), 4.13
(1H, d, J = 12.0Hz), 4.13-4.19 (2H, m), 6.79-7.00 (3H,
m), 6.98 (2H, d, J = 8.8Hz), 7.30-7.53 (8H, m), 7.70
(2H, d, J = 8.8Hz), 7.74 (1H, s), 8.04 (1H, dd, J = 5.2,
1.8Hz) IR (KBr) 2955, 1661, 1587, 1499, 1310, 1242, 1179,
1032, 816, 733cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₅ S Cald. C, 70.46; N, 6.16; H,
6.95: Found. C, 70.37; N, 6.00; H, 6.73

Example 233 (Production of compound 250) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) was treated with 4-[[(2-methyl-3-pyridinyl) methyl] sulfanyl] aniline (0.35 g) and triethylamine (1.53 ml) in THF (10.5 m).
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(2-Methyl-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 250) (0.28
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.66 (2H,
m), 2.04 (1H, m), 2.59 (3H, s), 2.91 (2H, m), 3.18 (2
H, d, J = 7.4Hz), 3.32-3.38 (2H, m), 3.55 (2H, t, J = 6.
6Hz), 3.77-3.83 (2H, m), 4.00 (2H, s), 4.12-4.18 (2H,
m), 6.89-7.03 (4H, m), 7.27 (2H, d, J = 8.8Hz), 7.37-
7.54 (8H, m), 7.65 (1H, s), 8.38 (1H, dd, J = 4.8, 1.8H
z)

Example 234 (Production of compound 251) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(2-methyl-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.27 g) in methylene chloride (8. 1 ml) solution,
A methylene chloride solution (5.4 ml) of m-chloroperbenzoic acid (86 mg) was added dropwise at -78 ° C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution.
It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, recrystallized from ethanol, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4 −
[[(2-Methyl-3-pyridinyl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 251) (148m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.2Hz), 1.30-1.48 (2H, m), 1.54-1.65 (2H,
m), 2.08 (1H, m), 2.35 (3H, s), 2.92 (2H, m), 3.19 (2
H, d, J = 7.4Hz), 3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.78-3.83 (2H, m), 4.02 (1H, d, J = 12.8Hz), 4.10-4.1
8 (3H, m), 6.90-7.09 (5H, m), 7.20-7.51 (7H, m), 7.71
(2H, d, J = 8.8Hz), 7.83 (1H, s), 8.43 (1H, dd, J = 4.8,
1.8Hz) IR (KBr) 2957, 1651, 1499, 1464, 1242, 1167, 816, 7
33cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₄ S Cald. C, 72.15; N, 6.31; H,
7.11: Found. C, 72.11; N, 6.24; H, 7.10

Example 235 (Production of compound 252) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (three drops) was added, thionyl chloride (0.23 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 m
l) was treated with 4-[[(6-methyl-3-pyridinyl) methyl] sulfanyl] aniline (0.41 g) and triethylamine (1.78 ml) in THF (12.3 m).
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(6-Methyl-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 252) (0.21
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.2Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.05 (1H, m), 2.52 (3H, s), 2.89 (2H, m), 3.17 (2
H, d, J = 7.2Hz), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.80 (2H, t, J = 4.4Hz), 3.98 (2H, s), 4.10-4.17 (2H,
m), 6.88-7.08 (4H, m), 7.27 (2H, d, J = 8.8Hz), 7.29-
7.54 (8H, m), 7.68 (1H, s), 8.27 (1H, dd, J = 2.2Hz)

Example 236 (Preparation of compound 253) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(6-methyl-3-pyridinyl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.20 g) in methylene chloride (6. 0 ml) solution,
A methylene chloride solution (4.0 ml) of m-chloroperbenzoic acid (80 mg) was added dropwise at -78 ° C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution.
It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, recrystallized from ethanol, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4 −
[[(6-Methyl-3-pyridinyl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 253) (104m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.05 (1H, m), 2.53 (3H, s), 2.93 (2H, m), 3.20 (2
H, d, J = 7.4Hz), 3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.78-3.84 (2H, m), 3.91 (1H, d, J = 13.2Hz), 4.06 (1H,
d, J = 13.2Hz), 4.16 (2H, t, J = 4.6Hz), 6.90-6.95 (1H,
m), 6.98 (2H, d, J = 8.8Hz), 7.09 (1H, d, J = 8.2Hz),
7.26-7.53 (8H, m), 7.68-7.73 (3H, m), 7.91 (1H, s) IR (KBr) 3273, 2957, 1661, 1499, 1246, 833, 733cm ^-1 Elemental analysis C ₄₀ H ₄₇ N ₃ O ₄ S Cald. C, 72.15; N, 6.21; H,
7.11: Found. C, 72.07; N, 6.46; H, 7.26

Example 237 (Production of compound 254) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.60 g) was dissolved in THF (12 ml) and DMF (two drops) was added, followed by thionyl chloride (0.
21 ml) and stirred at room temperature for 1 hour.
-Methoxy-4-[(3-pyridinylmethyl) sulfanyl] aniline (0.37 g) and triethylamine (2.96 ml) were added dropwise to a THF solution (11.1 ml) 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. 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 to give 7- [4- (2-butoxyethoxy) phenyl] -N- [3-methoxy-4-[(3-pyridinylmethyl)). Sulfanyl] phenyl] -1-propyl-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 254) (0.50 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
8 (3H, t, J = 7.4Hz), 1.33-1.45 (2H, m), 1.57-1.77 (4H,
m), 2.90 (2H, m), 3.28-3.36 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.78-3.83 (2H, m), 3.91 (3H, s), 3.99 (2H,
s), 4.13-4.18 (2H, m), 6.74 (1H, dd, J = 8.0, 1.8Hz),
6.89 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.10-
7.20 (2H, m), 7.39-7.55 (6H, m), 7.62-7.65 (2H, m),
8.36 (1H, d, J = 2.2Hz), 8.42 (1H, dd, J = 4.6, 1.4Hz) IR (KBr) 3295, 2957, 1655, 1591, 1499, 1242, 812, 7
33 cm ^-1

Example 238 (Preparation of compound 255) 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Methoxy-4-[(3-pyridinylmethyl) sulfanyl] phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.4
2 g) was dissolved in methylene chloride (12.6 ml), and -7
A methylene chloride solution (8.4 ml) of m-chloroperbenzoic acid (133 mg) was added at 8 ° C, and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography.
-[4- (2-Butoxyethoxy) phenyl] -N-
[3-Methoxy-4-[(3-pyridinylmethyl) sulfinyl] phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 255) (0.18 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
9 (3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.54-1.81 (4H,
m), 2.90 (2H, m), 3.28-3.33 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.80 (2H, t, J = 4.8Hz), 3.94 (3H, s), 4.00 (1
H, d, J = 13.2Hz), 4.13-4.20 (3H, m), 6.74 (1H, dd, J =
8.2, 2.0Hz), 6.89-7.22 (5H, m), 7.40-7.50 (6H, m),
7.83 (1H, m), 7.94 (1H, d, J = 1.8Hz), 8.03 (1H, d, J =
1.8Hz), 8.47 (1H, dd, J = 4.6, 1.4Hz) IR (KBr) 3285, 2957, 1653, 1593, 1499, 1321, 1236,
1030, 910, 814, 733cm ^{- 1} Elemental analysis C ₄₀ H ₄₇ N ₃ O ₅ S ・ H ₂ O Cald. C, 68.30; N, 6.13
; H, 6.91: Found. C, 68.54; N, 5.93; H, 6.92

Example 239 (Preparation of compound 256) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (two drops) was added, thionyl chloride (0.20 ml) was added, and the solution was stirred at room temperature for 1 hour. [(2-Pyrazinylmethyl) sulfanyl] aniline (0.33 g), triethylamine (2.87 m
1) in THF solution (9.8 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. 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 obtained residue was purified by silica gel column chromatography.
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(2-pyrazinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 256 ) (0.
43 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.68 (2H,
m), 2.04 (1H, m), 2.89 (2H, m), 3.18 (2H, d, J = 7.2H
z), 3.32-3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2
H, t, J = 4.8Hz), 4.12-4.15 (2H, m), 4.19 (2H, s), 6.9
1 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.28-7.61
(1H, m), 8.41-8.50 (2H, m) IR (KBr) 3301, 2957, 1651, 1607, 1589, 1499, 1397,
1242, 1181, 1123, 818,733cm ^-1

Example 240 (Production of Compound 257) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyrazinylmethyl) su
Rufanyl] phenyl] -2,3-dihydro-1-ben
Chloration of zoazepine-4-carboxamide (0.43 g)
Dissolve in methylene (12.9 ml) and m-at -78 ° C.
Chloroperbenzoic acid (0.14g) in methylene chloride
(8.6 ml) was added and stirred for 15 minutes. Saturate the reaction solution
Add to sodium thiosulfate aqueous solution and extract with ethyl acetate
did. After washing with saturated saline, dry with magnesium sulfate.
Dried The solvent was removed under reduced pressure, and the resulting residue was treated with silica gel.
Purified by column chromatography, 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl
-N- [4-[(2-pyrazinylmethyl) sulfini
]] Phenyl] -2,3-dihydro-1-benzazepi
4-Carboxamide (Compound 257) (226m
g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.64 (2H,
 m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.4H
z), 3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t,
 J = 4.8Hz), 4.16 (2H, t, J = 4.8Hz), 4.32 (2H, s), 6.92
(1H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.38-7.59 (7
H, m), 7.72-7.80 (3H, m), 8.36 (1H, s), 8.49 (2H, d,
(J = 2.6Hz) IR (KBr) 3289, 2957, 1661, 1588, 1499, 1397, 1312,
1244, 1179, 833, 733cm ^-1 Elemental analysis C₃₈H₄₄N₃O_FiveS Cald. C, 69.91; N, 8.58; H,
 6.79: Found. C, 69.78; N, 8.67; H, 6.98

Example 241 (Production of compound 258) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) was dissolved in THF (16 ml), DMF (two drops) was added, thionyl chloride (0.20 ml) was added, and the solution was stirred at room temperature for 1 hour. [(3-Pyridazinylmethyl) sulfanyl]
Aniline (0.44g), triethylamine (2.55
(ml) in a THF solution (13.2 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. 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 to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [4-[(3-pyridazinylmethyl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 25
8) (0.16 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.55-1.65 (2H,
m), 2.04 (1H, m), 2.89 (2H, m), 3.18 (2H, d, J = 6.8H
z), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.83 (2
H, m), 4.13-4.18 (2H, m), 4.38 (2H, s), 6.91 (1H, d,
J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.31-7.54 (11H, m),
7.70 (1H, s), 9.01-9.05 (1H, m)

Example 242 (Production of Compound 259) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-pyridazinylmethyl)
Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.15 g) was dissolved in methylene chloride (6.0 ml), and m-was added at -78 ° C.
A methylene chloride solution (4.5 ml) of chloroperbenzoic acid (61 mg) was added, and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-pyridazinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 259 ) (62 mg)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (6H, d, J = 6.6Hz), 1.33-1.43 (2H, m), 1.54-1.62 (2H,
m), 2.04 (1H, m), 2.92 (2H, m), 3.20 (2H, d, J = 7.6H
z), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.78-3.83 (2
H, m), 4.13-4.19 (2H, m), 4.27 (1H, d, J = 13.2Hz), 4.
38 (1H, d, J = 13.2Hz), 6.89-7.00 (3H, m), 7.36-7.46 (9
H, m), 7.72 (2H, d, J = 8.4Hz), 8.01 (1H, m), 9.08 (1H,
dd, J = 4.4,1.8Hz) IR (KBr) 3291, 2955, 1661, 1588, 1499, 1244, 1181,
816, 733cm ^-1

Example 243 (Production of compound 260) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-carboxylic acid (1.0 g) was dissolved in THF (10 ml)
Dissolve and add DMF (2 drops), then thionyl chloride (0.
25 ml) was added and the mixture was stirred at room temperature for 1 hour. Melting under reduced pressure
The solvent was removed and the resulting residue in THF solution (20 ml)
To S- (4-aminophenyl) O-carbonothioate
(0.59 g), triethylamine (1.91 ml)
To THF solution (17.7 ml) under ice-cooling at room temperature.
The mixture was stirred for 2 hours. Methanol (40 ml), 1N water
Add sodium oxide (15 ml) and stir for 30 minutes, then 2
-(Chloromethyl) pyrimidine (0.35 g) was added,
The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and ethyl acetate was added.
Extracted with chill. After washing with saturated saline,
Dried with sium. The solvent was removed under reduced pressure and the resulting residue
Purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyrimidinylmethyl)
Sulfanyl] phenyl] -2,3-dihydro-1-be
Nzoazepine-4-carboxamide (Compound 260)
(0.94 g) was obtained.¹ H-NMR (200MHz, CDCl₃) δ 0.93 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.55-1.68 (2H,
 m), 2.04 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.30-3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-
3.83 (2H, m), 4.15 (2H, t, J = 4.8Hz), 4.34 (2H, s), 6.
91 (1H, d, J = 8.4Hz), 6.97 (2H, d, J = 8.8Hz), 7.15 (1H,
 t, J = 4.8Hz), 7.34-7.60 (10H, m), 8.68 (2H, d, J = 4.6
Hz) IR (KBr) 3285, 2957, 1653, 1586, 1497, 1420, 1242,
1181, 1123, 816, 731cm ^-1

Example 244 (Production of compound 261) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(2-pyrimidinylmethyl)
Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.77 g) was dissolved in methylene chloride (23.1 ml) and m was obtained at -78 ° C.
A methylene chloride solution (15.4 ml) of -chloroperbenzoic acid (0.31 g) was added, and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(2-pyrimidinylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 261) (485m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.67 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.4H
z), 3.33-3.39 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.78-
3.83 (2H, m), 4.13-4.18 (2H, m), 4.35 (1H, d, J = 12.4H
z), 4.52 (1H, d, J = 12.4Hz), 6.92 (1H, d, J = 8.4Hz),
6.98 (2H, d, J = 8.8Hz), 7.22 (1H, t, J = 4.8Hz), 7.38-
7.51 (5H, m), 7.58 (2H, d, J = 8.8Hz), 7.74 (2H, d, J =
8.8Hz), 7.83 (1H, m), 8.71 (2H, d, J = 5.2Hz) IR (KBr) 3287, 2957, 1661, 1499, 1422, 1244, 1040,
833, 733cm ^-1

Example 245 (Preparation of compound 262) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
Was dissolved in water, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) to 4- [2- (1-propylimidazole-2-
Il) ethyl] aniline (0.39 g) and triethylamine (2.04 ml) were added dropwise to a THF solution (11.7 ml) 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. 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 to give 7- [4- (2-butoxyethoxy).
Phenyl] -1-isobutyl-N- [4- [2- (1-
Propylimidazol-2-yl) ethyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 262) (0.60 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.73 (4H, m), 2.06 (1H, m), 2.87-2.96
(4H, m), 3.06-3.11 (2H, m), 3.19 (2H, d, J = 6.8Hz),
3.33-3.40 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.66 (2H, t,
J = 7.0Hz), 3.78-3.83 (2H, m), 4.16 (2H, t, J = 4.8Hz),
6.80 (1H, d, J = 1.4Hz), 6.89-7.00 (4H, m), 7.16 (2H,
d, J = 8.4Hz), 7.36-7.56 (8H, m) IR (KBr) 2959, 1651, 1605, 1499, 1244, 1181, 1124,
816, 733cm ^-1

Example 246 (Preparation of compound 263) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
Was dissolved in water, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) was added to 2-[(E) -2- (4-nitrophenyl) ethenyl] -1-propylimidazole (0.38 g),
A solution of triethylamine (2.04 ml) in THF (7.
6 ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[(E) -2- (1-Propylimidazol-2-yl) ethenyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 263)
(0.43 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.83 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 6.8Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.57-1.70 (4H, m), 2.06 (1H, m), 2.89 (2H,
m), 3.18 (2H, d, J = 7.2Hz), 3.31-3.38 (2H, m), 3.55 (2
H, t, J = 6.6Hz), 3.66 (2H, t, J = 7.0Hz), 3.80 (2H, t,
J = 4.8Hz), 4.13-4.18 (2H, m), 6.29 (1H, d, J = 12.2Hz),
6.73 (1H, d, J = 12.4Hz), 6.86-7.00 (5H, m), 7.12 (1H,
m), 7.28-7.81 (9H, m) IR (KBr) 2957, 1657, 1605, 1499, 1244, 1181, 1121,
723, 542cm ^-1

Example 247 (Production of Compound 264) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
Was dissolved in water, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) was used as a solution of N-methyl-N-[(1-propylimidazol-2-yl) methyl] -1,4-benzodiamine (0.38 g) and triethylamine (2.04 ml) in THF (7.6 ml). The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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 obtained residue was purified by silica gel column chromatography to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4- [methyl [(1-propylimidazol-2-yl) methyl]] amino] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 264) (0.92 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.77 (4H, m), 2.06 (1H, m), 2.82 (3H,
m), 2.91 (2H, m), 3.17 (2H, d, J = 7.2Hz), 3.32-3.37 (2
H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-3.87 (4H, m), 4.1
5 (2H, t, J = 4.8Hz), 4.46 (2H, s), 6.86-7.01 (7H, m),
7.35-7.52 (8H, m) IR (KBr) 2961, 1645, 1607, 1497, 1244, 1121, 922, 8
16, 731 cm ^-1

Example 248 (Preparation of compound 265) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) in THF (7.0 ml)
The resulting mixture was dissolved in, and DMF (three drops) was added, thionyl chloride (0.18 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 m
l) was treated with 4-[[2- (imidazol-1-yl) ethyl] sulfanyl] phenylamine (0.39 g) and triethylamine (1.78 ml) in THF (7.8).
(ml) 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. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[2- (imidazol-1-yl) ) Ethyl] sulfanyl] phenyl] -1
-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 265) (0.56 g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.67 (2H,
m), 2.07 (1H, m), 2.92 (2H, m), 3.16 (2H, d, J = 7.0H
z), 3.16-3.20 (2H, m), 3.33-3.38 (2H, m), 3.55 (2H,
t, J = 6.6Hz), 3.80 (2H, t, J = 4.6Hz), 4.08 (2H, t, J =
6.6Hz), 4.12-4.18 (2H, m), 6.89 (1H, s), 6.93-7.00 (3
H, m), 7.05 (1H, s), 7.34-7.48 (8H, m), 7.58 (1H, s),
7.62 (1H, s), 7.83 (1H, s)

Example 249 (Preparation of compound 266) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[2- (imidazol-1-yl) ethyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) was added to methylene chloride (15 ml). Dissolves in
A methylene chloride solution (10 ml) of m-chloroperbenzoic acid (0.20 g) was added at -78 ° C, and the mixture was stirred for 15 minutes.
The reaction mixture was added to saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[2- (imidazol-1-yl) ethyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 266) (60 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.44 (2H, m), 1.53-1.64 (2H,
m), 2.04 (1H, m), 2.91 (2H, m), 3.04-3.11 (2H, m), 3.
18 (2H, d, J = 7.4Hz), 3.35 (2H, m), 3.54 (2H, t, J = 6.4
Hz), 3.77-3.83 (2H, m), 4.06-4.22 (3H, m), 4.36-4.56
(1H, m), 6.89-6.99 (4H, m), 7.07 (1H, s), 7.37-7.56
(8H, m), 7.37-7.56 (8H, m), 7.79 (1H, s), 7.83 (1H,
s), 8.16 (1H, s)

Example 250 (Production of compound 267) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (three drops) was added, oxalyl chloride (0.24 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 ml) was mixed with 6-[(2-pyridinylmethyl) sulfanyl] -3-pyridinamine (0.33 g) and triethylamine (1.15 ml) in THF ( 9.9m
It was added dropwise to 1) under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(2
-Pyridinylmethyl) sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 267) (0.51 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.44 (2H, m), 1.57-1.67 (2H,
m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.2H
z), 3.32-3.37 (2H, m), 3.51-3.58 (2H, m), 3.80 (2H,
t, J = 4.8Hz), 4.05 (2H, d, J = 4.6Hz), 4.55 (2H, s), 6.
91 (1H, d, J = 8.4Hz), 6.96 (2H, d, J = 8.8Hz), 7.12-7.2
2 (2H, m), 7.37-7.59 (7H, m), 7.71 (1H, s), 7.97 (1H,
dd, J = 8.4, 2.6Hz), 8.52-8.56 (2H, m)

Example 251 (Production of compound 268) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[(2-pyridinylmethyl) sulfanyl] -3-pyridinyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (0.50
A methylene chloride solution (10 ml) of m-chloroperbenzoic acid (0.16 g) was added dropwise to a solution of g) in methylene chloride (15 ml) at -78 ° C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(2-pyridinylmethyl) sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 268) (2
75 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
8 (6H, d, J = 6.6Hz), 1.33-1.48 (2H, m), 1.54-1.63 (2H,
m), 2.08 (1H, m), 2.93 (2H, m), 3.20 (2H, d, J = 7.0H
z), 3.38 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.80 (2H, t,
J = 4.8Hz), 4.13-4.18 (2H, m), 4.24 (1H, d, J = 12.8H
z), 4.51 (1H, d, J = 13.0Hz), 6.90-6.95 (1H, m), 6.98 (2
H, d, J = 9.0Hz), 7.16-7.23 (2H, m), 7.36-7.48 (5H,
m), 7.58-7.66 (2H, m), 8.02 (1H, m), 8.27-8.33 (1H,
m), 8.50 (1H, d, J = 4.8Hz), 8.76 (1H, d, J = 2.2Hz) IR (KBr) 3297, 2955, 1645, 1501, 1242, 1049, 812cm
^-1 Elemental analysis C ₃₈ H ₄₄ N ₄ O ₄ S Cald. C, 69.91; N, 8.58; H,
6.65: Found. C, 69.93; N, 8.52; H, 6.51

Example 252 (Production of compound 269) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (two drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) is a solution of 6-[(3-pyridinylmethyl) sulfanyl] -3-pyridinylamine (0.33 g) and triethylamine (1.53 ml) in THF (9.9 ml).
The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(3-
Pyridinylmethyl) sulfanyl] -3-pyridinyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 269) (0.33 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.36-1.45 (2H, m), 1.54-1.64 (2H,
m), 2.05 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.2H
z), 3.34 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
m), 4.10 (2H, m), 4.35 (2H, s), 6.91 (1H, d, J = 8.8H
z), 6.94-6.99 (2H, m), 7.11-7.23 (2H, m), 7.26-7.46
(5H, m), 7.72 (1H, m), 7.87 (1H, s), 8.00 (1H, dd, J =
8.4, 2.2Hz), 8.44 (1H, dd, J = 4.6, 1.4Hz), 8.56 (1H,
m), 8.62 (1H, d, J = 2.0Hz)

Example 253 (Production of compound 270) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[(3-pyridinylmethyl) sulfanyl] -3-pyridinyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (0.32
g) was dissolved in methylene chloride (9.6 ml), and the temperature was -78 ° C.
A methylene chloride solution (6.4 ml) of m-chloroperbenzoic acid (130 mg) was added at and the mixture was stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium thiosulfate solution 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 obtained residue was purified by silica gel column chromatography to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-[(3-pyridinylmethyl) sulfinyl] -3-pyridinyl] -2,3-dihydro-1-
Benzazepine-4-carboxamide (Compound 270)
(180 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
8 (6H, d, J = 6.2Hz), 1.33-1.45 (2H, m), 1.57-1.65 (2H,
m), 2.05 (1H, m), 2.92 (2H, m), 3.20 (2H, d, J = 7.0H
z), 3.37 (2H, m), 3.55 (2H, t, J = 6.4Hz), 3.80 (2H, t,
J = 4.8Hz), 4.10 (1H, d, J = 13.6Hz), 4.18 (2H, t, J = 4.
4Hz), 4.30 (1H, d, J = 13.4Hz), 6.90-6.95 (1H, m), 6.9
7 (2H, d, J = 8.8Hz), 7.17-7.26 (1H, m), 7.40-7.50 (7H,
m), 7.98-8.04 (2H, m), 8.12 (1H, dd, J = 8.0, 2.2Hz),
8.45-8.49 (1H, m), 8.90 (1H, dd, J = 2.6Hz) IR (KBr) 3266, 2959, 1651, 1607, 1499, 1464, 1366,
1242, 1115, 922, 816, 731cm ^-1

Example 254 (Preparation of compound 271) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (three drops) was added, thionyl chloride (0.23 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 m
1) was added to 6-[[(2-methyl-3-pyridinyl) methyl] sulfanyl] -3-pyridinylamine (0.40
g) and a solution of triethylamine (2.68 ml) in THF (16.0 ml) were 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. 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 to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[6-[[(2-methyl-3-pyridinyl) methyl]]
Sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 2
71) (0.67 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.68 (2H,
m), 2.05 (1H, m), 2.65 (3H, s), 2.91 (2H, m), 3.19 (2
H, d, J = 7.0Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.77-3.83 (2H, m), 4.13-4.18 (2H, m), 4.41 (2H, s),
6.90-7.08 (4H, m), 7.17 (1H, d, J = 8.8Hz), 7.38-7.48
(5H, m), 7.63-7.68 (2H, m), 7.98 (1H, dd, J = 8.4, 2.2
Hz), 8.37 (1H, dd, J = 4.8, 1.6Hz), 8.57-8.59 (1H, m)

Example 255 (Production of compound 272) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[[(2-methyl-3-pyridinyl) methyl] sulfanyl] -3-pyridinyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (0.61 g) in methylene chloride (18.3 ml)
The solution was added with m-chloroperbenzoic acid (243
g) in methylene chloride solution (4.0 ml) was added dropwise, and
Stir for minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[[(2-methyl -3-Pyridinyl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (Compound 272) (277 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.6Hz), 0.9
8 (6H, d, J = 6.6Hz), 1.33-1.44 (2H, m), 1.49-1.69 (2H,
m), 2.07 (1H, m), 2.53 (3H, s), 2.92 (2H, m), 3.20 (2
H, d, J = 7.0Hz), 3.37 (2H, m), 3.55 (2H, t, J = 6.6Hz),
3.81 (2H, t, J = 4.8Hz), 3.91 (1H, d, J = 13.2Hz), 4.06
(1H, d, J = 13.2Hz), 4.123-4.19 (2H, m), 6.90-7.11 (5H,
m), 7.26-7.53 (7H, m), 7.71 (2H, d, J = 8.2Hz), 7.91
(1H, s) IR (KBr) 2957, 1667, 1501, 1242, 1182, 1042, 909, 8
14, 731cm ^-1

Example 256 (Production of compound 273) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Dissolve carboxylic acid (2.5g) in THF (50ml), add DMF (5 drops), then thionyl chloride (0.8g).
6 ml) was added and the solution was stirred at room temperature for 1 hour.
[(3-Pyridinylmethyl) sulfanyl] -3-pyridinylamine (1.41 g), triethylamine (1
2.3 ml) was added dropwise to a THF solution (42.3 ml) 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. Remove the solvent under reduced pressure,
The obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [6-[(3-pyridinylmethyl) sulfanyl] -3-pyridinyl]. -2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 273) (0.92 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
8 (3H, t, J = 7.2Hz), 1.33-1.44 (2H, m), 1.54-1.79 (4H,
m), 2.88 (2H, m), 3.26-3.34 (4H, m), 3.55 (2H, t, J =
6.6Hz), 3.80 (2H, t, J = 4.8Hz), 4.12-4.17 (2H, m), 4.
38 (2H, s), 6.88 (1H, d, J = 8.4Hz), 6.96 (2H, d, J = 8.8
Hz), 7.14 (2H, d, J = 8.0Hz), 7.37-7.48 (4H, m), 7.68-
7.79 (2H, m), 7.98 (1H, dd, J = 8.8, 2.6Hz), 8.44 (1H,
dd, J = 4.8,1.8Hz), 8.55 (1H, d, J = 1.8Hz), 8.62 (1H,
d, J = 1.8Hz)

Example 257 (Production of compound 274) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [6-[(3-pyridinylmethyl) sulfanyl] -3-pyridinyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (0.91 g)
M-chloroperbenzoic acid (303 mg) in methylene chloride solution (18.2 ml) was added dropwise to a methylene chloride (27.3 ml) solution in Example 1 at -78 ° C, and the mixture was stirred for 15 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution. It was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [6-[(3-pyridinylmethyl) sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide ( Compound 274)
(258 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4Hz), 0.9
8 (3H, t, J = 7.2Hz), 1.26-1.44 (2H, m), 1.53-1.75 (4H,
m), 2.90 (2H, m), 3.32 (4H, m), 3.54 (2H, t, J = 6.6H
z), 3.76-3.82 (2H, m), 4.01-4.26 (4H, m), 6.86-6.98
(3H, m), 7.15-7.23 (1H, m), 7.26-7.45 (7H, m), 7.99 (1
H, s), 8.06-8.12 (1H, m), 8.44-8.46 (2H, m), 8.44-8.
46 (2H, m), 8.89 (1H, d, J = 2.6Hz) IR (KBr) 2959, 1661, 1607, 1499, 1462, 1240, 1181,
1121, 1046, 910, 812,731cm ^-1

Example 258 (Production of compound 275) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (1
6.0 ml) was added dropwise to a THF solution (14.1 ml) of S- (4-aminophenyl) O-benzylthiocarbonate (0.47 g) and triethylamine (1.53 ml) at 0 ° C. After stirring at room temperature for 2 hours, methanol (28.2 ml), 1N sodium hydroxide (14.
6 ml) was added and stirred for 15 minutes. 4-chloromethyl-
2-propyl-1,2,3-triazole (0.35
g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated to half under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(2
-Propyl-1,2,3-triazol-4-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (Compound 27
5) (0.50 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 7.2Hz), 0.96 (6H, d, J = 7.2Hz), 1.33-1.45
(2H, m), 1.57-1.66 (2H, m), 1.87-2.08 (3H, m), 2.90 (2
H, m), 3.18 (2H, d, J = 7.4Hz), 3.32-3.37 (2H, m), 3.5
5 (2H, t, J = 6.6Hz), 3.77-3.83 (2H, m), 4.11 (2H, s),
4.10-4.18 (2H, m), 4.31 (2H, t, J = 6.8Hz), 6.91 (1H,
d, J = 8.8Hz), 6.97 (2H, d, J = 8.2Hz), 7.31-7.58 (11H,
m)

Example 259 (Preparation of compound 276) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(2-propyl-1,2,
3-triazol-4-yl) methyl] sulfanyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-Carboxamide (0.45 g) was dissolved in methylene chloride (9.0 ml), and m-chloroperbenzoic acid (174 mg) was dissolved in methylene chloride at -78 ° C (9.0 m).
l) was added dropwise. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(2-Propyl-1,2,3-triazole-4-
Il) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 276) (0.39 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 7.2Hz), 0.98 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.68 (2H, m), 1.85-1.97 (2H, m), 2.04 (1
H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.4Hz), 3.36 (2H,
t, J = 4.6Hz), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, d, J =
4.8Hz), 4.14 (2H, s), 4.13-4.18 (2H, m), 4.31 (2H, t,
J = 7.0Hz), 6.92 (1H, d, J = 8.8Hz), 6.98 (2H, d, J = 9.2
Hz), 7.31 (1H, s), 7.38-7.72 (7H, m), 7.74 (2H, d, J =
7.0Hz), 7.82 (1H, s) IR (KBr) 2959, 2870, 1661, 1590, 1499, 1246, 1122,
1033, 835, 733cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₄ S Cald. C, 68.49; N, 10.24;
H, 7.22: Found. C, 68.40; N, 10.21; H, 7.22

Example 260 (Production of compound 277) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (16
ml) in a THF solution (14.1 ml) of S- (4-aminophenyl) O-benzylthiocarbonate (0.47 g) and triethylamine (1.53 ml) at 0 ° C.
It was dripped at. After stirring at room temperature for 2 hours, methanol (28.2 ml), 1N sodium hydroxide (14.6 m)
1) was added and stirred for 15 minutes. 5-chloromethyl-1-
Propyl-1,2,3-triazole hydrochloride (0.43
g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated to half under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1
-Propyl-1,2,3-triazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide ((Compound 2
77) 0.61 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
7 (3H, t, J = 7.4Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.57-1.66 (2H, m), 1.89-2.05 (3H, m), 2.91 (2
H, m), 3.18 (2H, d, J = 7.4Hz), 3.33-3.38 (2H, m), 3.5
5 (2H, t, J = 6.6Hz), 3.77-3.83 (2H, m), 3.89 (2H, s),
4.15 (2H, t, J = 4.8Hz), 4.24 (2H, t, J = 7.2Hz), 6.91 (1
H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.24-7.29 (2
H, m), 7.38-7.58 (8H, m), 7.72 (1H, s)

Example 261 (Production of compound 278) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-propyl-1,2,
3-triazol-5-yl) methyl] sulfanyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-carboxamide (0.54 g) was added to methylene chloride (1
6.2 ml), and a solution of m-chloroperbenzoic acid (209 mg) in methylene chloride (10.8 m) at -78 ° C.
l) was added dropwise. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[(1-Propyl-1,2,3-triazole-5-
Il) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 278) (0.35 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.4Hz), 0.9
3 (3H, t, J = 7.0Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.65 (2H, m), 1.54-1.65 (2H, m), 1.77-
1.91 (2H, m), 2.07 (1H, m), 2.93 (2H, m), 3.19 (2H, d,
J = 7.4Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80
(2H, t, J = 4.8Hz), 3.97 (1H, d, J = 14.2Hz), 4.08-4.16
(4H, m), 4.21 (1H, d, J = 13.8Hz), 6.92 (1H, d, J = 8.8H
z), 6.97 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.
32-7.50 (6H, m), 7.78 (2H, d, J = 8.8Hz), 8.07 (1H, s) IR (KBr) 2957, 2870, 1661, 1588, 1499, 1244, 1123,
1047, 833, 733cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₄ S ・ 0.2H ₂ O Cald. C, 68.13; N, 1
0.19; H, 7.24: Found.C, 68.04; N, 10.19; H, 7.
08

Example 262 (Production of compound 279) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (0.80 g) in THF (8.0 ml)
, DMF (3 drops) was added, thionyl chloride (0.20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hr.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (1
6.0 ml) was added dropwise to a THF solution (14.1 ml) of S- (4-aminophenyl) O-benzylthiocarbonate (0.47 g) and triethylamine (1.53 ml) at 0 ° C. After stirring at room temperature for 2 hours, methanol (28.2 ml), 1N sodium hydroxide (14.
6 ml) was added and stirred for 15 minutes. 4-chloromethyl-
1-propyl-1,2,3-triazole (0.35
g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated to half under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1
-Propyl-1,2,3-triazol-4-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (Compound 27
9) (0.60 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 7.4Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.57-1.67 (2H, m), 1.78-1.94 (2H, m), 2.04 (1
H, m), 2.90 (2H, m), 3.18 (2H, d, J = 7.2Hz), 3.32-3.3
7 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.8H
z), 4.12-4.19 (2H, m), 4.18 (2H, s), 4.23 (2H, t, J =
7.0Hz), 6.91 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8H
z), 7.27-7.55 (10H, m), 7.70 (1H, s)

Example 263 (Production of compound 280) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-propyl-1,2,
3-triazol-4-yl) methyl] sulfanyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-carboxamide (0.55 g) was added to methylene chloride (1
6.5 ml) and m-chloroperbenzoic acid (213 mg) in methylene chloride solution (11 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy).
Phenyl] -1-isobutyl-N- [4-[[(1-propyl-1,2,3-triazol-4-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 28
0) (0.39 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2Hz), 0.9
4 (3H, t, J = 7.2Hz), 0.98 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.65 (2H, m), 1.85-1.97 (2H, m), 2.08 (1
H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.2Hz), 3.30-3.3
9 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.8H
z), 4.06-4.32 (6H, m), 6.92 (1H, d, J = 8.8Hz), 6.98 (2
H, d, J = 8.8Hz), 7.38-7.53 (8H, m), 7.73 (2H, d, J = 8.
8Hz), 7.83 (1H, br) IR (KBr) 2959, 2870, 1661, 1607, 1499, 1244, 1044,
816, 733cm ^-1 Elemental analysis C ₃₉ H ₄₉ N ₅ O ₄ S Cald. C, 68.49; N, 10.24;
H, 7.22: Found. C, 68.23; N, 10.20; H, 7.12

Example 264 (Production of compound 281) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.78 g) was dissolved in THF (7.8 ml), DMF (3 drops) was added, thionyl chloride (0.20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) was added to S- (4-aminophenyl) O-benzylthiocarbonate (0.48 g) and triethylamine (1.54 ml) in THF (14.4 ml) at 0 ° C.
It was dripped at. After stirring at room temperature for 2 hours, methanol (28.8 ml), 1N sodium hydroxide (14.7 m)
1) was added and stirred for 15 minutes. 5-chloromethyl-1-
Propyl-1,2,3-triazole hydrochloride (0.43
g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated to half under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-[[(1-
Propyl-1,2,3-triazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (Compound 28
1) (0.60 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.84-103 (9H, m), 1.33-1.45
(2H, m), 1.54-1.77 (4H, m), 1.90-2.02 (2H, m), 2.90 (2
H, m), 3.32 (4H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H,
t, J = 4.4Hz), 4.13-4.29 (4H, m), 6.90 (1H, d, J = 8.4H
z), 6.98 (2H, d, J = 8.8Hz), 7.23-7.29 (3H, m), 7.39-7.
57 (7H, m), 7.67 (1H, s) IR (KBr) 2961, 2872, 1659, 1586, 1497, 1240, 1123,
1067, 818, 733cm ^-1

Example 265 (Production of Compound 282) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[(1-propyl-1,2,3
-Triazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (0.53 g) with methylene chloride (1
5.9 ml), and the solution of m-chloroperbenzoic acid (0.21 g) in methylene chloride (10.6 m) at -78 ° C.
l) was added dropwise. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-[[(1
-Propyl-1,2,3-triazol-5-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (Compound 28
2) (0.25 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.85-1.03 (9H, m), 1.33-1.4
5 (2H, m), 1.57-1.89 (6H, m), 2.92 (2H, m), 3.32 (4H,
m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 3.
93-4.22 (6H, m), 6.90 (1H, d, J = 8.2Hz), 6.97 (2H, d,
J = 8.4Hz), 7.13 (1H, s), 7.29-7.49 (7H, m), 7.76 (2H,
d, J = 8.8Hz), 7.97 (1H, br) IR (KBr) 2961, 2874, 1661, 1588, 1505, 1242, 1177,
1049, 833, 731cm ^-1 Elemental analysis C ₃₈ H ₄₇ N ₅ O ₄ S ・ 0.2H ₂ O Cald. C, 67.77; N, 1
0.40; H, 7.09: Found.C, 67.81; N, 10.41; H, 7.
06

Example 266 (Preparation of compound 283) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.70 g) was dissolved in THF (7.0 ml), DMF (three drops) was added, thionyl chloride (0.18 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (14 m
l) to 4-[[2- (1,2,4-triazole-1
-Yl) ethyl] sulfanyl] phenylamine (0.
39 g), THF of triethylamine (1.78 ml)
The solution (7.8 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. 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 to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-propyl-N-
[4-[[2- (1,2,4-Triazol-1-yl) ethyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 283) (0.56 g) Got ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 7.2Hz), 0.99
(3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.57-1.78 (4H,
m), 2.91 (2H, m), 3.28-3.35 (4H, m), 3.55 (2H, t, J = 6.
6Hz), 3.78-3.84 (2H, m), 4.13-4.19 (2H, m), 4.32 (2H,
t, J = 6.6Hz), 6.90 (1H, d, J = 8.8Hz), 6.98 (2H, d, J =
8.8Hz), 7.34-7.63 (10H, m), 7.94 (1H, s), 8.04 (1H,
s) IR (KBr) 2957, 2872, 1651, 1586, 1499, 1242, 1179,
818, 733cm ^-1

Example 267 (Production of compound 284) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[2- (1,2,4-triazol-1-yl) ethyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (0.86 g) was added to methylene chloride (25.8 ml).
And m-chloroperbenzoic acid (0.3
6 g) in methylene chloride solution (17.2 ml) was added to 1
Stir for 5 minutes. A saturated aqueous sodium thiosulfate solution 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 solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4-[[2- (1 ，
2,4-Triazol-1-yl) ethyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 284) (0.57
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 6.8Hz), 0.99
(3H, t, J = 6.8Hz), 1.33-1.45 (2H, m), 1.53-1.82 (4H,
m), 2.91 (2H, m), 3.18-3.46 (4H, m), 3.55 (2H, t, J = 6.
6Hz), 3.80 (2H, t, J = 4.6Hz), 4.13 (2H, t, J = 5.0Hz),
4.41-4.51 (1H, m), 4.61-4.80 (1H, m), 6.90 (1H, d, J =
8.4Hz), 6.97 (2H, d, J = 8.4Hz), 7.40-7.57 (7H, m), 7.
78 (2H, d, J = 8.8Hz), 7.81-7.91 (1H, m), 7.93 (1H, s),
8.10 (1H, s) IR (KBr) 2959, 2870, 1661, 1588, 1501, 1242, 1044,
833, 733cm ^-1 Elemental analysis C ₃₆ H ₄₄ N ₅ O ₄ S Cald. C, 67.26; N, 10.89;
H, 6.90: Found. C, 67.12; N, 10.81; H, 6.71

Example 268 (Production of compound 285) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.60 g) was dissolved in THF (6.0 ml), DMF (three drops) was added, thionyl chloride (0.16 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) to 4- [2- (1,2,4-triazole-1-
Ill) ethoxy] aniline (0.32 g), triethylamine (1.18 ml) in THF (12.0 ml)
The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4- [2- [2-
(1,2,4-Triazol-1-yl) ethoxy] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (Compound 285) (0.56 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 7.2Hz), 0.98
(3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.57-1.79 (6H,
m), 2.89 (2H, m), 3.26-3.35 (4H, m), 3.55 (2H, t, J = 6.
2Hz), 3.79-3.83 (2H, m), 4.12-4.18 (2H, m), 4.29-4.3
2 (2H, m), 4.56 (2H, t, J = 4.8Hz), 6.83 (2H, d, J = 8.8H
z), 6.89 (1H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.3
8-7.48 (8H, m), 7.96 (1H, s), 8.22 (1H, s) IR (KBr) 2959, 2872, 1651, 1605, 1510, 1238, 831, 7
33 cm ^-1 Elemental analysis C ₃₆ H ₄₃ N ₅ O ₄・ 0.2H ₂ O Cald. C, 70.49; N, 11.
42; H, 7.13: Found.C, 70.48; N, 11.41; H, 7.04

Example 269 (Production of compound 286) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.57 g) was dissolved in THF (5.7 ml), DMF (three drops) was added, thionyl chloride (0.15 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (12 m
l) was added to 4- [2- (imidazol-1-yl) ethoxy] aniline (0.30 g) and triethylamine (1.
(12 ml) in a THF solution (11.4 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. Add the reaction solution to water,
It was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, recrystallized from ethanol, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [2- [2- (Imidazol-1-yl) ethoxy] phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 286) (0.41 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 7.0Hz), 0.99
(3H, t, J = 7.0Hz), 1.33-1.45 (2H, m), 1.54-1.80 (6H,
m), 2.90 (2H, m), 3.27-3.36 (4H, m), 3.55 (2H, t, J = 6.
6Hz), 3.80 (2H, t, J = 4.6Hz), 4.15 (2H, t, J = 4.8Hz),
4.21 (2H, t, J = 4.8Hz), 4.32 (2H, t, J = 4.8Hz), 6.82-
7.08 (7H, m), 7.37-7.60 (9H, m) IR (KBr) 2957, 2872, 1651, 1605, 1510, 1240, 831cm
^-1

Example 270 (Production of compound 287) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) was added to 4- [3- (imidazol-1-yl) propyl] aniline (0.42 g) and triethylamine (2.
1 ml) in THF solution (12.6 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. 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 to give 7- [4- (2-butoxyethoxy) phenyl]-.
N- [4- [imidazol-1-yl] propyl] phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 287) (0.
80 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 7.2Hz), 0.99
(3H, t, J = 7.2Hz), 1.33-1.42 (2H, m), 1.54-1.85 (4H,
m), 2.03-2.18 (2H, m), 2.59 (2H, m), 2.91 (4H, m), 3.5
5 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.4Hz), 3.92 (2H,
t, J = 7.0Hz), 4.12-4.18 (2H, m), 6.89 (1H, d, J = 8.4H
z), 6.91 (1H, s), 6.97 (2H, d, J = 8.8Hz), 7.08 (1H, m),
7.13 (2H, d, J = 8.4Hz), 7.37-7.68 (9H, m) IR (KBr) 2957, 2870, 1651, 1605, 1505, 1244, 816, 7
33cm ^-1 Elemental analysis C ₃₈ H ₄₆ N ₄ O ₃ Cald. C, 75.22; N, 9.23; H,
7.64: Found. C, 75.07; N, 9.35; H, 7.62

Example 271 (Production of compound 288) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) to 4- [3- (1,2,4-triazole-1-
Il) propyl] aniline (0.42 g), triethylamine (2.10 ml) in THF (12.6 ml)
The mixture was added dropwise to the mixture under ice cooling and stirred at room temperature for 2 hours. 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, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [4- [3- [3-
(1,2,4-Triazol-1-yl) propyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (Compound 288) (0.52 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 6.8Hz), 0.99
(3H, t, J = 7.2Hz), 1.33-1.45 (2H, m), 1.54-1.82 (4H,
m), 2.17-2.31 (2H, m), 2.61 (2H, d, J = 6.6Hz), 2.91 (2
H, m), 3.28-3.42 (4H, m), 3.55 (2H, t, J = 6.2Hz), 3.8
0 (2H, t, J = 4.8Hz), 4.12-4.22 (4H, m), 6.90 (1H, d, J
= 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.15 (2H, d, J = 8.4H
z), 7.37-7.56 (8H, m), 7.97 (1H, s), 8.02 (1H, s) IR (KBr) 2957, 2870, 1651, 1605, 1501, 1244, 818cm
^-1 Elemental analysis C ₃₇ H ₄₅ N ₅ O ₃・ 0.3H ₂ O Cald. C, 72.47; N, 11.
42; H, 7.50: Found.C, 72.45; N, 11.61; H, 7.47

Example 272 (Production of compound 289) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (three drops) was added, thionyl chloride (0.21 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) to N- (4-aminobenzyl) -N-methyl-1
-Propylimidazol-2-amine (0.51 g) was added dropwise to a pyridine solution (10.2 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[methyl (1-propylimidazole-2 -Yl) amino] methyl] phenyl]
-1-Propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 289) (0.27
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.91 (3H, t, J = 7.2Hz), 0.93
(3H, t, J = 7.2Hz), 0.98 (3H, t, J = 7.2Hz), 1.33-1.45
(2H, m), 1.57-1.80 (6H, m), 2.66 (3H, s), 2.91 (2H,
m), 3.28-3.35 (4H, m), 3.55 (2H, t, J = 6.2Hz), 3.8752
H, t, J = 7.4Hz), 3.80 (2H, t, J = 4.8Hz), 4.10 (2H, s),
4.16 (2H, t, J = 4.8Hz), 6.67 (1H, d, J = 1.4Hz), 6.84
(1H, d, J = 1.6Hz), 6.90 (1H, d, J = 8.4Hz), 6.98 (2H,
d, J = 8.8Hz), 7.27-7.39 (9H, m), 7.91 (1H, dd, J = 8.4,
2.6Hz), 8.38 (1H, s), 8.62 (1H, d, J = 2.6Hz) IR (KBr) 2959, 2872, 1655, 1605, 1499, 1244, 833, 7
33cm ^-1 Elemental analysis C ₄₀ H ₅₁ N ₅ O ₃・ 0.2H ₂ O Cald. C, 73.52; N, 10.
72; H, 7.93: Found.C, 73.46; N, 10.73; H, 7.79

Example 273 (Production of compound 290) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (1.0 g) was dissolved in THF (10.0 ml), DMF (three drops) was added, thionyl chloride (0.26 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (20 m
l) was added to 6-[[(1-propylimidazol-2-yl) methyl] sulfanyl] pyridin-3-amine (0.65 g) and triethylamine (2.6 ml) as T.
The solution was added dropwise to the HF solution (19.5 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [6-[[(1-propylimidazole-2
-Yl) methyl] sulfanyl] -3-pyridinyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 290) (0.76 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.89 (3H, t, J = 7.4Hz), 0.93
(3H, t, J = 7.2Hz), 0.98 (3H, t, J = 6.8Hz), 1.33-1.42
(2H, m), 1.57-1.83 (6H, m), 2.90 (2H, m), 3.26-3.34
(4H, m), 3.55 (2H, t, J = 6.4Hz), 3.80 (2H, t, J = 4.4H
z), 3.86 (2H, t, J = 7.2Hz), 4.15 (2H, t, J = 4.8Hz), 4.
50 (2H, s), 6.80 (1H, d, J = 1.6Hz), 6.87 (1H, d, J = 9.2H
z), 6.92-6.98 (3H, m), 7.17 (1H, d, J = 8.8Hz), 7.37-
7.45 (5H, m), 7.91 (1H, dd, J = 8.4, 2.6Hz), 8.38 (1H,
s), 8.62 (1H, d, J = 2.6Hz)

Example 274 (Production of compound 291) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [6-[[(1-propylimidazol-2-yl) methyl] sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.70 g) was salified. Methylene (21m
1), and a solution of m-chloroperbenzoic acid (0.28 g) in methylene chloride (14 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [6-[[[1-propyl Imidazol-2-yl) methyl] sulfinyl]-
3-Pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 291) (0.32
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.84 (3H, t, J = 7.2Hz), 0.93
(3H, t, J = 7.2Hz), 1.02 (3H, t, J = 7.4Hz), 1.33-1.48
(2H, m), 1.54-1.83 (6H, m), 3.00 (2H, m), 3.30-3.38
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.67-3.75 (2H, m),
3.80 (2H, t, J = 4.8Hz), 4.07-4.18 (3H, m), 4.25 (1H,
d, J = 14.2Hz), 6.81-7.12 (7H, m), 7.34-7.41 (3H, m),
7.49 (1H, d, J = 8.8Hz), 8.12 (1H, dd, J = 8.4, 1.8Hz),
8.96 (1H, d, J = 1.8Hz), 9.58 (1H, br) IR (KBr) 2959, 2872, 1663, 1607, 1499, 1240, 1033,
731 cm ^-1

Example 275 (Production of compound 292) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in THF (10.0 ml)
Was dissolved in water, DMF (three drops) was added, thionyl chloride (0.25 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (20 m
1) was added to 6-[[(1-propylimidazol-2-yl) methyl] sulfanyl] pyridin-3-amine (0.62 g) and triethylamine (2.6 ml) as T.
The solution was added dropwise to the HF solution (19.5 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7-
[4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[[(1-propylimidazole-
2-yl) methyl] sulfanyl] -3-pyridinyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 292) (0.73 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.91 (3H, t, J = 7.2Hz), 0.93
(3H, t, J = 7.2Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.57-1.78 (6H, m), 2.04 (1H, m), 2.92 (2H,
m), 3.18 (2H, t, J = 7.4Hz), 3.32-3.38 (2H, m), 3.55 (2
H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.8Hz), 3.89 (2H, t,
J = 7.4Hz), 4.13-4.18 (2H, m), 4.54 (2H, s), 6.82 (1H,
d, J = 1.0Hz), 6.89-7.00 (5H, m), 7.20 (1H, d, J = 8.4H
z), 7.37-7.48 (5H, m), 7.93 (1H, dd, J = 8.8, 2.6Hz),
8.08 (1H, s), 8.62 (1H, d, J = 1.8Hz)

Example 276 (Production of compound 293) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[[(1-propylimidazol-2-yl) methyl] sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g) was salified. Methylene (20m
l), and a solution of m-chloroperbenzoic acid (0.26 g) in methylene chloride (13 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-[[(1-propyl Imidazol-2-yl) methyl] sulfinyl]
-3-Pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 293) (0.3
9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.81 (3H, t, J = 7.2Hz), 0.93
(3H, t, J = 7.2Hz), 1.01 (6H, d, J = 6.6Hz), 1.26-1.65
(6H, m), 2.02-2.13 (1H, m), 3.01 (2H, m), 3.19 (2H, t,
J = 7.2Hz), 3.33 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.62
-3.74 (2H, m), 3.80 (2H, t, J = 4.6Hz), 4.09-4.17 (4H,
m), 6.79-7.15 (7H, m), 7.32-7.51 (4H, m), 8.06-8.12 (1
H, m), 8.95-9.01 (1H, m), 10.06 (1H, br) IR (KBr) 2959, 2870, 1667, 1607, 1499, 1242, 1111,
731 cm ^-1

Example 277 (Production of compound 294) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (three drops) was added, thionyl chloride (0.21 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (16 m
l) was added dropwise to a pyridine solution (10.4 ml) of 6-[[(1-propylimidazol-5-yl) methyl] sulfanyl] pyridin-3-amine (0.52 g) under ice cooling, and the mixture was brought to room temperature. And stirred for 3 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-propyl-N-
[6-[[(1-Propylimidazol-5-yl) methyl] sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 294) (0.96 g) was obtained. It was ¹ H-NMR (200MHz, CDCl ₃ ) δ0.90 (3H, t, J = 7.4Hz), 0.93
(3H, t, J = 7.4Hz), 0.98 (3H, t, J = 7.2Hz), 1.33-1.45
(2H, m), 1.54-1.81 (6H, m), 2.90 (2H, m), 3.26-3.34
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J = 4.8H
z), 3.84 (2H, t, J = 7.0Hz), 4.12-4.17 (2H, m), 4.39 (2
H, s), 6.85-6.99 (4H, m), 7.13 (1H, d, J = 8.2Hz), 7.3
5-7.46 (6H, m), 8.01 (1H, dd, J = 8.8, 2.6Hz), 8.42 (1
H, s), 8.62 (1H, d, J = 2.2Hz)

Example 278 (Production of Compound 295) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.96 g) was salified. Methylene (29m
l), and a solution of m-chloroperbenzoic acid (0.38 g) in methylene chloride (14 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [6-[[[1-propyl Imidazol-5-yl) methyl] sulfinyl]-
3-Pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 295) (0.23
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.88 (3H, t, J = 7.8Hz), 0.93
(3H, t, J = 7.2Hz), 0.98 (3H, t, J = 7.2Hz), 1.33-1.45
(2H, m), 1.54-1.80 (6H, m), 2.92 (2H, m), 3.27-3.35
(4H, m), 3.55 (2H, t, J = 6.6Hz), 3.77-3.83 (2H, m),
3.87-3.95 (2H, m), 4.06-4.17 (3H, m), 4.36 (1H, d, J =
14.8Hz), 6.42 (1H, s), 6.82 (1H, d, J = 9.2Hz), 6.96 (2
H, d, J = 8.4Hz), 7.38-7.56 (6H, m), 7.81-8.06 (1H,
m), 8.12 (1H, dd, J = 8.8, 2.6Hz), 8.73-8.94 (1H, m),
9.01 (1H, s) IR (KBr) 2961, 2872, 1661, 1607, 1499, 1240, 733cm
^-1

Example 279 (Production of compound 296) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-carboxylic acid (1.28 g) in THF (12.8 m)
It was dissolved in 1), DMF (three drops) was added, thionyl chloride (0.32 ml) was added, and the mixture was stirred at room temperature for 1 hour.
The solvent was removed under reduced pressure, and the resulting residue in THF solution (26
ml) to 6-[[(1-propylimidazole-5-
Ilyl) methyl] sulfanyl] pyridin-3-amine (0.80 g) was added dropwise to a pyridine solution (16 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[6-[[(1-Propylimidazol-5-yl)
Methyl] sulfanyl] -3-pyridinyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (Compound 296) (1.4 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.92 (3H, t, J = 7.4Hz), 0.93
(3H, t, J = 7.0Hz), 0.97 (6H, d, J = 6.2Hz), 1.33-1.45
(2H, m), 1.53-1.84 (4H, m), 2.06 (1H, m), 2.92 (2H,
m), 3.19 (2H, d, J = 7.4Hz), 3.55 (2H, t, J = 6.6Hz), 3.
81 (2H, t, J = 4.8Hz), 3.87 (2H, t, J = 7.2Hz), 4.16 (2H,
t, J = 4.4Hz), 4.42 (2H, s), 6.90-7.00 (4H, m), 7.15 (1
H, d, J = 8.8Hz), 7.39-7.48 (6H, m), 7.99-8.05 (1H,
m), 8.05 (1H, s), 8.61 (1H, d, J = 1.8Hz)

Example 280 (Production of compound 297) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfanyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.4 g) was salified. Methylene (42 ml)
And m-chloroperbenzoic acid (0.6
5 g) of methylene chloride solution (28 ml) was added dropwise. 1
After stirring for 5 minutes, a saturated aqueous sodium thiosulfate solution was added.
After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy) phenyl]-.
1-isobutyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (Compound 297) (0.41 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2Hz), 0.9
3 (3H, t, J = 6.8Hz), 0.97 (6H, d, J = 6.6Hz), 1.33-1.45
(2H, m), 1.54-1.81 (4H, m), 2.06 (1H, m), 2.93 (2H,
m), 3.19 (2H, d, J = 7.4Hz), 3.36 (2H, m), 3.55 (2H, t,
J = 6.6Hz), 3.80 (2H, t, J = 4.4Hz), 3.89-4.00 (2H, m),
4.08-4.18 (3H, m), 4.38 (1H, d, J = 14.4Hz), 6.42 (1H,
s), 6.89-7.00 (3H, m), 7.38-7.59 (7H, m), 8.14 (1H,
dd, J = 8.4,2.2Hz), 8.50 (1H, m), 8.94 (1H, d, J = 2.2H
z) IR (KBr) 2959, 2872, 1663, 1607, 1499, 1242, 733cm
^-1

Example 281 (Compound 298, Compound 29)
Production of 9) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[[(1-propylimidazol-2-yl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide was added to CHIRALCEL AD (5 cmφ ×
(+)-7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-[[(1-propylimidazole-2-
Iyl) methyl] sulfinyl] -3-pyridinyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 298) (64 mg, [α] _D = + 20
3.2 °) and (−)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-
[[(1-Propylimidazol-2-yl) methyl]]
Sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 2
99) (72 mg) was obtained.

Example 282 (Compound 300, Compound 30)
Production of 1) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide was added to CHIRALCEL AD (5 cmφ ×
(+)-7- [4
-(2-Butoxyethoxy) phenyl] -1-propyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfinyl] -3-pyridinyl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (Compound 300) (107 mg, [α] _D = + 18
1.6 °) and (−)-7- [4- (2-butoxyethoxy) phenyl] -1-propyl-N- [6-
[[(1-Propylimidazol-5-yl) methyl]]
Sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 3
01) (103 mg) was obtained.

Example 283 (Compound 302, Compound 30)
3) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [6-[[(1-propylimidazol-5-yl) methyl] sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide was added to CHIRALCEL AD (5 cmφ ×
(+)-7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [6-[[(1-propylimidazole-5-
Iyl) methyl] sulfinyl] -3-pyridinyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 302) (80 mg, [α] _D = + 22
5.8 °) and (−)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [6-
[[(1-Propylimidazol-5-yl) methyl]]
Sulfinyl] -3-pyridinyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 3
03) (100 mg) was obtained.

Example 284 (Preparation of compound 304) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
Dissolve carboxylic acid (1.0 g) in THF (10 ml) and add DMF (3 drops) followed by thionyl chloride (0.2
5 ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (13.2 ml)
Was added dropwise to a pyridine solution (13.2 ml) of 4-[[2- (2-propylimidazol-1-yl) ethyl] sulfanyl] aniline (0.66 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. did. 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 obtained residue was purified by silica gel column chromatography to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[2- (2-propylimidazol-1-yl) ethyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 304) (0.86 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
5 (3H, t, J = 7.2Hz), 0.97 (6H, d, J = 7.2Hz), 1.33-1.45
(2H, m), 1.57-1.75 (4H, m), 2.03 (1H, m), 2.47-2.56
(2H, m), 2.92 (2H, m), 3.19 (2H, d, J = 7.0Hz), 3.33-
3.40 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.80 (2H, t, J =
4.8Hz), 3.95-4.03 (2H, m), 4.13-4.18 (2H, m), 6.78 (1
H, s), 6.78-7.00 (4H, m), 7.35-7.48 (7H, m), 7.61 (2
H, d, J = 8.8Hz), 7.78 (1H, s)

Example 285 (Preparation of compound 305) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[2- (2-propylimidazol-1-yl) ethyl] sulfanyl] phenyl]
2,2-Dihydro-1-benzazepine-4-carboxamide (0.78 g) was added to methylene chloride (23.4 m).
l), and a solution of metachloroperbenzoic acid (0.34 g) in methylene chloride (15.6 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added, and the temperature was raised to room temperature. After extraction with ethyl acetate,
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 to give 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[2- (2-Propylimidazol-1-yl) ethyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 305) (345 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.4Hz), 0.9
2-1.01 (9H, m), 1.32-1.44 (2H, m), 1.54-1.81 (4H, m),
2.04 (1H, m), 2.61-2.69 (2H, m), 2.92 (2H, m), 3.00-
3.12 (2H, m), 3.18 (2H, d, J = 7.2Hz), 3.35 (2H, m), 3.
55 (2H, t, J = 6.6Hz), 4.12-4.18 (2H, m), 4.25-4.41 (2
H, m), 6.78 (1H, s), 6.88-6.98 (4H, m), 7.38-7.46 (8
H, m), 7.53 (2H, d, J = 7.6Hz), 7.81 (2H, d, J = 8.0Hz),
8.20 (1H, s) IR (KBr) 2959, 1499, 1244, 733cm ^-1

Example 286 (Preparation of compound 306) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.79 g) was dissolved in THF (7.9 ml), DMF (three drops) was added, thionyl chloride (0.20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (10 m
l) was used as a solution of 1-methyl-5-[[(1-propylimidazol-5-yl) methyl] thio] -1,2,4-triazol-3-amine (0.50 g) in pyridine (1
(0 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours.
The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [1-methyl-5-[[(1-propylpropylimidazol-5-yl) methyl] sulfanyl] -1,2,4-triazol-3-yl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (Compound 306) (0.40 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.8Hz), 0.9
6 (6H, d, J = 6.6Hz), 0.96 (3H, t, J = 7.4Hz), 1.30-1.45
(2H, m), 1.54-1.67 (2H, m), 1.74-1.89 (2H, m), 2.04 (1
H, m), 2.93 (2H, m), 3.19 (2H, d, J = 7.2Hz), 3.33-3.3
8 (2H, m), 3.55 (2H, t, J = 6.6Hz), 3.65-3.74 (2H, m),
3.69 (3H, s), 3.91 (2H, t, J = 7.0Hz), 4.13-4.19 (2H,
m), 4.43 (2H, s), 6.89-7.01 (4H, m), 7.37-7.50 (6H,
m), 8.10 (1H, s) IR (KBr) 2959, 1667, 1499, 1242, 733cm ^-1

Example 287 (Production of compound 307) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
Dissolve carboxylic acid (1.0 g) in THF (10 ml) and add DMF (3 drops) followed by thionyl chloride (0.2
5 ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (13.2 ml)
To S- (4-aminophenyl) O-benzylthiocarbonate (0.59 g) and triethylamine (1.91).
(ml) in THF (17.8 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Methanol (3
5.6 ml), 1 N sodium hydroxide (18.3 m)
1) was added, and the mixture was stirred at room temperature for 20 minutes. 5-Chloromethyl-1- (2-methoxyethyl) imidazole hydrochloride (0.58 g) was added, the mixture was stirred at room temperature for 20 minutes, the solvent was removed under reduced pressure, water was added to the obtained residue, and ethyl acetate was added. It was extracted in. 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 to give 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[1- (2-methoxyethyl)
Imidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-
A carboxamide (Compound 307) (550 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.54-1.65 (2H,
m), 2.03 (1H, m), 2.90 (2H, m), 3.32 (3H, s), 3.55 (2
H, t, J = 6.6Hz), 3.61-3.67 (2H, m), 3.76-3.83 (2H,
m), 4.02 (2H, s), 4.09-4.18 (4H, m), 6.68 (1H, s), 6.
91 (1H, d, J = 8.4Hz), 6.97 (2H, d, J = 8.8Hz), 7.22 (1H,
s), 7.37-7.56 (9H, m), 7.91 (1H, s) IR (KBr) 2955, 1651, 1497, 1244, 733cm ^-1

Example 288 (Preparation of compound 308) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1- (2-methoxyethyl) imidazol-5-yl] methyl] sulfanyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-carboxamide (0.49 g) was added to methylene chloride (1
4.7 ml), and a solution of metachloroperbenzoic acid (0.25 g) in methylene chloride (9.8 ml) at -78 ° C.
Was dripped. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added, and the temperature was raised to room temperature. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[[1- (2-Methoxyethyl) imidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 308) (0.26 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.45 (2H, m), 1.57-1.68 (2H,
m), 2.04 (1H, m), 2.93 (2H, m), 3.19 (2H, d, J = 7.4H
z), 3.28 (3H, s), 3.36 (2H, m), 3.54-3.58 (4H, m), 3.
78-3.83 (2H, m), 3.99-4.06 (3H, m), 4.12-4.20 (3H,
m), 6.56 (1H, s), 6.92 (1H, d, J = 9.2Hz), 6.97 (2H, d,
J = 8.8Hz), 7.32-7.56 (9H, m), 7.74 (2H, d, J = 8.6Hz),
7.99 (1H, s) IR (KBr) 2959, 1653, 1497, 1246, 1119cm ^-1

Example 289 (Production of compound 309) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
Dissolve carboxylic acid (1.0 g) in THF (10 ml), add DMF (3 drops), then thionyl chloride (0.25
ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue in THF solution (13.4 ml)
Was added dropwise to a pyridine solution (13.4 ml) of 4-[[2-[(1-methylimidazol-2-yl) thio] ethyl] thio] aniline (0.67 g) under ice cooling and at room temperature. Stir for 2 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-butoxyethoxy).
Phenyl] -1-isobutyl-N- [4-[[2-
[(1-Methylimidazol-2-yl) sulfanyl] ethyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 309) (1.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.33-1.47 (2H, m), 1.54-1.68 (2H,
m), 2.07 (1H, m), 2.89 (2H, m), 3.15 (3H, s), 3.17 (2
H, d, J = 7.0Hz), 3.30-3.35 (2H, m), 3.55 (2H, t, J = 7.
0Hz), 3.58 (3H, s), 3.77-3.83 (2H, m), 4.12-4.17 (2H,
m), 6.87-7.07 (4H, m), 7.18-7.47 (8H, m), 7.54 (2H,
d, J = 8.8Hz), 7.84 (1H, s)

Example 290 (Production of compound 310) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[2-[(1-methylimidazol-2-yl) sulfanyl] ethyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.20 g) Was dissolved in methylene chloride (24.0 ml), and a solution of metachloroperbenzoic acid (0.52 g) in methylene chloride (24.0 ml) was added at -78 ° C.
ml) was added dropwise. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added, and the temperature was raised to room temperature. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[2-[(1-methylimidazole-2
-Yl) sulfanyl] ethyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (Compound 310) (0.68 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 0.9
6 (6H, d, J = 6.6Hz), 1.32-1.47 (2H, m), 1.54-1.65 (2H,
m), 2.08 (1H, m), 2.92 (2H, m), 3.18-3.30 (4H, m), 3.
19 (2H, d, J = 7.2Hz), 3.36 (2H, m), 3.55 (2H, t, J = 6.6
Hz), 3.57 (3H, s), 3.77-3.83 (2H, m), 4.12-4.18 (2H,
m), 6.89-6.95 (3H, m), 7.01 (2H, d, J = 8.8Hz), 7.38-
7.56 (7H, m), 7.77 (2H, d, J = 8.8Hz), 8.11 (1H, s) IR (KBr) 2955, 1661, 1497, 1246cm ^-1

Example 291 (Preparation of compound 311) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.57 g) was dissolved in THF (5.7 ml), DMF (three drops) was added, thionyl chloride (0.14 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (7.6
ml) to 4-[[2-[(4-methyl-1,2,4-
Triazol-3-yl) thio] ethyl] thio] aniline (0.38 g) was added dropwise to a pyridine solution (7.6 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[2-[(4-Methyl-1,2,4-triazol-3-yl) sulfanyl] ethyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide ( Compound 311) (0.60
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0Hz), 0.9
7 (6H, d, J = 6.6Hz), 1.33-1.47 (2H, m), 1.53-1.65 (2H,
m), 2.06 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J = 7.4H
z), 3.17 (2H, d, J = 7.0Hz), 3.29-3.36 (4H, m), 3.52 (3
H, s), 3.55 (2H, t, J = 6.6Hz), 3.77-3.83 (2H, m), 4.1
2-4.17 (2H, m), 4.38 (2H, t, J = 6.6Hz), 6.91 (1H, d, J
= 8.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.14-7.23 (1H, m),
7.36-7.56 (8H, m), 7.67 (1H, s) IR (KBr) 2959, 1651, 1497, 1242, 733cm ^-1

Example 292 (Production of Compound 312) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (0.65 g) was dissolved in THF (6.5 ml), DMF (three drops) was added, thionyl chloride (0.16 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed under reduced pressure, and the resulting residue in THF solution (9.4
ml) to 2-[[(1-propylimidazole-5-
Ilyl) methyl] thio] benzimidazol-5-amine (0.47 g) was added dropwise to a pyridine solution (9.4 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[2-[[(1-Propylimidazol-5-yl) methyl] sulfanyl] benzimidazol-5-yl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (Compound 312) (0.64 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.83 (3H, t, J = 7.6Hz), 0.9
2 ((3H, m), 0.94 (6H, d, J = 7.0Hz), 1.33-1.45 (2H, m),
1.54-1.68 (2H, m), 2.04 (1H, m), 2.89 (2H, m), 3.13 (2
H, d, J = 6.8Hz), 3.30 (2H, m), 3.54 (2H, t, J = 6.6Hz),
3.76-3.84 (2H, m), 4.13 (2H, t, J = 4.8Hz), 4.49 (2H,
s), 6.85-6.96 (4H, m), 7.35-7.47 (8H, m), 8.04 (1H, b
r), 8.23 (1H, s)

Example 293 (Production of compound 313) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [2-[[(1-propylimidazol-5-yl) methyl] sulfanyl] benzimidazol-5-yl] -2,3-dihydro-1-benzazepine-4-carboxamide (0.64 g) Was dissolved in methylene chloride (19.2 ml), and a solution of metachloroperbenzoic acid (0.27 g) in methylene chloride (12.
8 ml) was added dropwise. After stirring for 15 minutes, saturated aqueous sodium thiosulfate solution was added, and the temperature was raised to room temperature. After extraction with ethyl acetate, the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 7- [4
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [2-[[(1-propylimidazole-5-
Il) methyl] sulfinyl] benzimidazole-5
-Yl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (compound 313) (0.21 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.87 (3H, t, J = 7.4Hz), 0.9
2 ((3H, t, J = 7.4Hz), 0.98 (6H, d, J = 7.2Hz), 1.32-1.4
5 (2H, m), 1.53-1.70 (2H, m), 2.04 (1H, m), 2.84 (2H,
m), 3.07-3.12 (2H, m), 3.2 (2H, m), 3.54 (2H, t, J = 6.
6Hz), 3.66-3.81 (4H, m), 4.08-4.13 (2H, m), 4.31 (1H,
d, J = 14.6Hz), 4.56 (1H, d, J = 14.6Hz), 6.37 (1H, s),
6.85 (1H, d, J = 8.4Hz), 6.93 (2H, d, J = 8.8Hz), 7.32-
7.45 (8H, m), 7.82 (1H, s) IR (KBr) 2959, 1653, 1499, 1244cm ^-1

Example 294 (Production of compound 314) 7- [4- (2-butoxyethoxy) phenyl] -N-
[2-Ethoxy-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (120
mg), isobutyraldehyde (140 mg), sodium triacetoxyborohydride (410 mg)
Acetic acid (0.06) was added to a solution of 2-dichloroethane (10 ml).
ml) was added and the mixture was stirred overnight. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 8) to give 7- [4- (2-butoxyethoxy) phenyl]-as a yellow amorphous substance. N- [2-ethoxy-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxamide (63 mg) (Compound 314) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.00 (9H, m), 1.30-
1.70 (7H, m), 2.00-2.20 (1H, m), 2.90-3.00 (2H,
m), 3.20 (2H, d, J = 7.2 Hz), 3.30-3.45 (2H, m), 3.55
(2H, t, J = 6.2 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.10-
4.30 (4H, m), 6.02-6.10 (1H, m), 6.45-6.55 (1H,
m), 6.70 (1H, s), 6.90-7.05 (5H, m), 7.17 (1H, s),
7.24-7.28 (1H, m), 7.35-7.60 (5H, m), 8.22-8.32 (1
H, m), 8.36 (1H, s), 8.48 (1H, d. J = 8.8 Hz). Elemental analysis C ₄₁ H ₄₉ N ₃ O ₆・ 0.4H ₂ O Calcd. C, 71.67; H, 7.
31; N, 6.12; Found.C, 71.39; H, 7.22; N, 5.83.

Example 295 (Production of compound 315) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (80 mg), isobutyraldehyde (100 m
g), sodium triacetoxyborohydride (286
Acetic acid (0.04 ml) was added to a 1,2-dichloroethane (10 ml) solution of (mg) and the mixture was stirred overnight. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N as a yellow amorphous substance.
-[4- [Hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (30 mg) (Compound 315) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.26-
1.70 (4H, m), 2.00-2.20 (1H, m), 2.90-3.00 (2H,
m), 3.21 (1H, d, J = 7.4 Hz), 3.35-3.45 (2H, m), 3.56
(2H, t, J = 7.0 Hz), 3.81 (2H, t, J = 5.2 Hz), 4.16
(2H, t, J = 5.2 Hz), 6.45-6.49 (1H, m), 6.57-6.63 (1
H, m), 6.71 (1H, d, J = 2.6 Hz), 6.92-7.01 (3H, m),
7.17-7.53 (7H, m), 7.77 (1H, s), 7.93 (2H, s), 8.0
4 (1H, s), 8.31 (1H, d, J = 5.8 Hz). Elemental analysis C ₄₀ H ₄₄ N ₃ O ₅ F ₃ 0.3H ₂ O Calcd. C, 67.74; H,
6.34; N, 5.93; Found. C, 67.58; H, 6.28; N, 5.
85.

Example 296 (Production of compound 316) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (438 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.095 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[(Thiazol-2-ylmethyl) sulfanyl] aniline (265 mg), triethylamine (3.6 ml)
Was added to a tetrahydrofuran solution (10 ml) at 0 ° C. After stirring overnight at room temperature under a nitrogen atmosphere, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from hexane-ethyl acetate to give yellow crystals.
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(thiazol-2-ylmethyl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (424 mg)
(Compound 316) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.98 (9H, m), 1.34-
1.70 (4H, m), 1.95-2.20 (1H, m), 2.90 (2H, t, J = 4.
4 Hz), 3.18 (2H, d, J = 7.2 Hz), 3.36 (2H, t, J = 4.4 H
z), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 H
z), 4.16 (2H, t, J = 4.8 Hz), 4.40 (2H, s), 6.92 (1H,
d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.24 (1H, d,
J = 3.2 Hz), 7.35-7.55 (10H, m), 7.67 (1H, d, J = 3.2
Hz). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₃ S ₂ Calcd. C, 69.23; H, 6.75;
N, 6.55; Found. C, 69.34; H, 6.79; N, 6.60.

Example 297 (Production of compound 317) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(thiazol-2-ylmethyl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (150 mg)
In dichloromethane (10 ml) of 70% 3-chloroperbenzoic acid (57.6 mg) in dichloromethane (10 m).
l) The solution was added dropwise at -78 ° C. After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3 → ethyl acetate), and recrystallized from hexane-ethyl acetate to give yellow crystals. −
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(thiazol-2-ylmethyl)
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (110 mg) (Compound 317) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.99 (9H, m), 1.30-
1.70 (4H, m), 2.00-2.20 (1H, m), 2.92 (2H, t, J = 5.
2 Hz), 3.19 (2H, d, J = 7.2 Hz), 3.37 (2H, t, J = 5.2 H
z), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 H
z), 4.16 (2H, t, J = 4.8 Hz), 4.40 (1H, d, J = 13.2 H
z), 4.48 (1H, d, J = 13.2 Hz), 6.93 (1H, d, J = 8.8 H
z), 6.98 (2H, d, J = 8.8 Hz), 7.31 (1H, d, J = 3.4 H
z), 7.39-7.49 (7H, m), 7.71-7.78 (4H, m). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₄ S ₂ Calcd. C, 67.55; H, 6.59;
N, 6.39; Found. C, 67.46; H, 6.39; N, 6.39.

Example 298 (Preparation of compound 318) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
One drop of DMF was added to a solution of 4-carboxylic acid (385 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.084 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[[(3-Methylisothiazol-2-yl) methyl]
Sulfanyl] aniline (250 mg), triethylamine (3.2 ml) in tetrahydrofuran (10 ml)
The solution was added at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 1.5 hours, 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 solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and recrystallized from hexane-ether to give 7- [4- ( 2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(3
-Methylisothiazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (343 mg) (Compound 31
8) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.70 (4H, m), 1.95-2.20 (1H, m), 2.42 (3H, s), 2.8
5-2.95 (2H, m), 3.19 (2H, d, J = 6.6 Hz), 3.32-3.43
(2H, m), 3.55 (2H, t, J = 7.0 Hz), 3.80 (2H, t, J = 5.
4 Hz), 4.16 (2H, t, J = 5.4 Hz), 4.25 (2H, s), 6.79
(1H, s), 6.90-7.00 (3H, m), 7.34-7.57 (10H, m).

Example 299 (Production of compound 319) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(3-methylisothiazol-2-yl) methyl] sulfanyl] phenyl]-
To a solution of 2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml), a solution of 70% 3-chloroperbenzoic acid (56.5 mg) in dichloromethane (10 ml) was added dropwise at -78 ° C. .. After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane-ethyl acetate to give 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[(3-Methylisothiazol-5-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (132m
g) (Compound 319) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.69 (4H, m), 2.00-2.20 (1H, m), 2.44 (3H, s), 2.8
5-3.00 (2H, m), 3.20 (2H, d, J = 7.4 Hz), 3.35-3.45
(2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.
8 Hz), 4.13-4.31 (3H, m), 4.34 (1H, d, J = 13.8 Hz),
6.79 (1H, s), 6.91-7.00 (3H, m), 7.40-7.51 (7H,
m), 7.52-7.76 (3H, m). Elemental analysis C ₃₈ H ₄₅ N ₃ O ₄ S ₂ Calcd. C, 67.93; H, 6.75;
N, 6.25; Found. C, 67.78; H, 6.67; N, 6.27.

Example 300 (Production of compound 320) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
A solution of [[(1-methylpyrazol-2-yl) methyl] sulfanyl] aniline (456 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) was added at 0 ° C. 1 at room temperature under a nitrogen atmosphere
After stirring for an hour, 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 solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1) to give 7- [4 as yellow amorphous.
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N-[[(1-methylpyrazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (827 mg)
(Compound 320) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.99 (9H, m), 1.34-
1.45 (2H, m), 1.54-1.64 (2H, m), 2.00-2.20 (1H,
m), 2.90 (2H, t, J = 4.2 Hz), 3.19 (2H, d, J = 7.0Hz),
3.36 (2H, t, J = 4.4 Hz), 3.55 (2H, t, J = 6.6 Hz),
3.78-3.83 (5H, m), 4.01 (2H, s), 4.16 (2H, t, J = 5.0
Hz), 5.97 (1H, d, J = 1.8 Hz), 6.90-7.00 (3H, m), 7.
27-7.33 (3H, m), 7.37-7.58 (8H, m).

Example 301 (Production of Compound 321) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-methylpyrazole-
2-yl) methyl] sulfanyl] phenyl] -2,3
7-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml).
A solution of 0% 3-chloroperbenzoic acid (116 mg) in dichloromethane (10 ml) was added dropwise at -78 ° C. After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl]-as a yellow amorphous substance.
1-isobutyl-N- [4-[[(1-methylpyrazol-5-yl) methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (139 mg) (Compound 321) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88-0.99 (9H, m), 1.34-
1.70 (4H, m), 2.00-2.20 (1H, m), 2.90-2.97 (2H,
m), 3.20 (2H, d, J = 7.2 Hz), 3.30-3.45 (2H, m), 3.52
-3.58 (5H, m), 3.81 (2H, t, J = 4.6 Hz), 4.12-4.18
(4H, m), 5.98 (1H, d, J = 2.2 Hz), 6.91-7.02 (3H, m),
7.34-7.52 (8H, m), 7.72-7.76 (3H, m). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₄ S ・ 0.3H ₂ O Calcd. C, 69.12; H,
7.11; N, 8.49; Found.C, 68.94; H, 6.96; N, 8.1
Five.

Example 302 (Production of compound 322) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
A solution of [[(1-methylimidazol-2-yl) methyl] sulfanyl] aniline (456 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) was added at 0 ° C. After stirring overnight at room temperature under a nitrogen atmosphere, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- as a yellow amorphous substance. [4-
[[(1-Methylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (576 mg) (Compound 322) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.45 (2H, m), 1.54-1.80 (2H, m), 2.00-2.15 (1H,
m), 2.91 (2H, t, J = 5.6 Hz), 3.18 (2H, d, J = 7.0Hz),
3.36 (2H, t, J = 5.6 Hz), 3.52-3.59 (5H, m), 3.80
(2H, t, J = 4.8 Hz), 4.11 (2H, s), 4.16 (2H, t, J = 4.8 Hz)
Hz), 6.78 (1H, d, J = 1.0 Hz), 6.89 (1H, d, J = 1.4 H
z), 6.93-7.00 (3H, m), 7.31-7.55 (9H, m), 7.80 (1
H, s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₃ S Calcd. C, 71.44; H, 7.26;
N, 8.77; Found. C, 71.28; H, 7.29; N, 8.38.

Example 303 (Compound 323, Compound 32)
Production of 4) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-methylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (116 mg) in dichloromethane (20 ml) at -78 ° C.
After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. After washing the organic layer with a saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (methanol: ethyl acetate = 1: 8),
Recrystallization from hexane-ethyl acetate gave 7- [4- (2-butoxyethoxy) phenyl] -1- as yellow crystals.
Isobutyl-N- [4-[[(1-methylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,
Recrystallized from 3-dihydro-1-benzazepine-4-carboxamide (118 mg) (Compound 323), hexane-ethyl acetate to give 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[(1-Methylimidazol-2-yl) methyl] sulfonyl] phenyl] -2,3-dihydro-1-
Benzazepine-4-carboxamide (33.5 mg)
(Compound 324) was obtained. Compound 323 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.34-
1.50 (2H, m), 1.55-1.65 (2H, m), 2.00-2.20 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.4 Hz), 3.33
-3.43 (2H, m), 3.46 (3H, s), 3.55 (2H, t, J = 6.6 H
z), 3.80 (2H, t, J = 4.8 Hz), 4.05-4.28 (4H, m), 6.8
1 (1H, d, J = 1.2 Hz), 6.90-7.00 (4H, m), 7.40-7.48
(7H, m), 7.74 (2H, d, J = 8.8 Hz), 7.91 (1H, s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₄ S ・ 0.8H ₂ O Calcd. C, 68.19; H,
7.17; N, 8.37; Found.C, 68.13; H, 6.92; N, 7.9
7. Compound 324 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.02 (9H, m), 1.30-
1.65 (4H, m), 1.90-2.20 (1H, m), 2.90-3.00 (2H,
m), 3.21 (2H, d, J = 7.4 Hz), 3.32-3.42 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.64 (3H, s), 3.81 (2H, t, J =
4.4 Hz), 4.16 (2H, t, J = 4.8 Hz), 4.34 (2H, s), 6.85
-6.99 (5H, m), 7.23-7.29 (2H, m), 7.39-7.43 (3H,
m), 7.55 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 H
z), 8.48 (1H, s). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₅ S ・ 0.1H ₂ O Calcd. C, 67.85; H,
6.92; N, 8.33; Found.C, 67.62; H, 6.87; N, 8.0
3.

Example 304 (Production of compounds 325 and 326) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-methylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (600 mg) was resolved using CHIRAKPAK AD 50 mm ID x 500 mm L (hexane / ethanol) to give (+)-7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-methylimidazole-2
-Yl) methyl] sulfinyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (270 mg) (compound 325), (−)-7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-methylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4- Carboxamide (28
0 mg) (compound 326) was obtained. Compound 325 [a] _D = + 7.71 ° (C = 5.00% ethanol solution,> 99.9% ee) Compound 326 [a] _D = -8.20 ° (C = 4.80% ethanol solution,> 99.9% ee)

Example 305 (Production of compound 327) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[(Isoxazol-5-ylmethyl) sulfanyl]
Aniline (429 mg), triethylamine (5.8 m
l) was added to a solution of tetrahydrofuran (15 ml) at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 1.5 hours, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and recrystallized from hexane-ethyl acetate to give 7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(isoxazol-5-ylmethyl) sulfanyl] phenyl] -2,3
-Dihydro-1-benzazepine-4-carboxamide (557 mg) (Compound 327) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.99 (9H, m), 1.20-
1.70 (4H, m), 1.98-2.20 (1H, m), 2.85-2.95 (2H,
m), 3.19 (2H, d, J = 7.0 Hz), 3.30-3.41 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.4 Hz), 4.12-
4.18 (4H, m), 6.00 (1H, s), 6.90-7.00 (3H, m), 7.34
-7.57 (10H, m), 8.12 (1H, s). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₄ S Calcd. C, 71.01; H, 6.93;
N, 6.71; Found. C, 70.90; H, 6.96; N, 6.64.

Example 306 (Compound 328, Compound 32)
Production of 9) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(isoxazol-5-ylmethyl) sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (200 m
g) in dichloromethane (20 ml) in 70% 3-chloroperbenzoic acid (118 mg) in dichloromethane (20 ml).
ml) solution was added dropwise at -78 ° C. After completion of the dropping, water was added, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1 → 1: 4) and purified by recrystallization from hexane-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- as yellow crystals.
[4-[(Isoxazol-5-ylmethyl) sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 32
8), recrystallized from hexane-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] as yellow crystals.
-1-isobutyl-N- [4-[(isoxazole-5
-Ylmethyl) sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (7
2.8 mg) (compound 329) was obtained. Compound 328 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.65 (4H, m), 2.00-2.20 (1H, m), 2.88-2.98 (2H,
m), 3.20 (2H, d, J = 7.4 Hz), 3.35-3.40 (2H, m), 3.55
(2H, t, J = 7.0 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.16
(2H, t, J = 4.8 Hz), 4.23 (2H, s), 6.21 (1H, d, J = 1.8
Hz), 6.91-7.00 (3H, m), 7.39-7.52 (7H, m), 7.74-7.
78 (3H, m), 8.18 (1H, d, J = 1.8 Hz). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₅ S ・ 0.2H ₂ O Calcd. C, 68.85; H,
6.78; N, 6.51; Found.C, 68.71; H, 6.60; N, 6.4
7. Compound 329 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.70 (4H, m), 1.90-2.10 (1H, m), 2.90-3.00 (2H,
m), 3.20 (2H, d, J = 7.4 Hz), 3.32-3.42 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.4 Hz), 4.16
(2H, t, J = 5.2 Hz), 4.57 (2H, s), 6.40 (1H, d, J = 1.8
Hz), 6.91-7.00 (3H, m), 7.40-7.51 (5H, m), 7.69-7.
81 (5H, m), 8.23 (1H, d, J = 2.0 Hz). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₆ S Calcd. C, 67.56; H, 6.59;
N, 6.39; Found. C, 67.28; H, 6.49; N, 6.35.

Example 307 (Production of compound 330) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[(Pyrazol-1-ylmethyl) sulfanyl] aniline (427 mg), triethylamine (5.8 ml)
Was added to a tetrahydrofuran (15 ml) solution at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 15 minutes, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 7- [4- (2-butoxyethoxy) phenyl] -1 as a yellow amorphous substance. -Isobutyl-N- [4-[(pyrazol-1-ylmethyl) sulfanyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (384 mg) (Compound 330) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.65 (4H, m), 1.95-2.20 (1H, m), 2.91 (2H, t, J = 5.
0 Hz), 3.19 (2H, d, J = 7.4 Hz), 3.36 (2H, t, J = 5.0 H
z), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 H
z), 4.16 (2H, t, J = 4.8 Hz), 5.38 (2H, s), 6.21 (1H,
t, J = 1.8 Hz), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d,
J = 8.8 Hz), 7.26-7.56 (12H, m).

Example 308 (Production of Compound 331) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(pyrazol-1-ylmethyl) sulfanyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (150 mg)
In dichloromethane (10 ml) of 70% 3-chloroperbenzoic acid (59.2 mg) in dichloromethane (10 m).
l) The solution was added dropwise at -78 ° C. After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2 → ethyl acetate), and recrystallized from hexane-ethyl acetate to give yellow crystals. 7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(pyrazol-1-ylmethyl)
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (80 mg) (Compound 331) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34 -
1.45 (2H, m), 1.55-1.67 (2H, m), 2.00-2.15 (1H,
m), 2.50-2.80 (2H, m), 3.20 (2H, d, J = 6.8 Hz), 3.30
-3.43 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 5.2 Hz), 4.16 (2H, t, J = 5.2 Hz), 5.15 (2H, s),
6.29 (1H, t, J = 1.8 Hz), 6.91-7.01 (3H, m), 7.40-7.
57 (9H, m), 7.72-7.79 (3H, m). Elemental analysis C ₃₇ H ₄₄ N ₄ O ₄ S Calcd. C, 69.35; H, 6.92;
N, 8.74; Found. C, 69.13; H, 6.91; N, 8.59.

Example 309 (Production of compound 332) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
A solution of [[(1-ethylimidazol-2-yl) methyl] sulfanyl] aniline (485 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) was added at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 1 hour, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[[ (1-Ethylimidazol-2-yl) methyl] sulfanyl] phenyl]-
1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (471 mg) (Compound 33
2) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.98 (9H, m), 1.34-
1.50 (5H, m), 1.55-1.70 (2H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.30
-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 4.8 Hz), 3.94 (2H, q, J = 7.2 Hz), 4.10-4.18 (4
H, m), 6.86 (1H, d, J = 1.4 Hz), 6.89-7.00 (4H, m),
7.31-7.55 (9H, m), 7.81 (1H, s).

Example 310 (Production of compound 333) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(1-Ethylimidazol-2-yl) methyl] sulfanyl] phenyl] -1-isobutyl-2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (55.3 mg) in dichloromethane (10 ml) at -78 ° C. After completion of the dropping, an aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from hexane-ethyl acetate to give 7- [as yellow crystals. 4- (2-butoxyethoxy) phenyl]-
N- [4-[[(1-ethylimidazol-2-yl)
Methyl] sulfinyl] phenyl] -1-isobutyl-
2,3-Dihydro-1-benzazepine-4-carboxamide (82 mg) (Compound 333) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.29-
1.68 (7H, m), 2.00-2.15 (1H, m), 2.90-2.98 (2H,
m), 3.20 (2H, d, J = 7.6 Hz), 3.30-3.42 (2H, m), 3.55
(2H, t, J = 6.4 Hz), 3.78-3.91 (4H, m), 4.07-4.30
(4H, m), 6.90-7.02 (5H, m), 7.39-7.48 (7H, m), 7.72
-7.81 (3H, m). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.2H ₂ O Calcd. C, 69.65; H,
7.25; N, 8.33; Found.C, 69.51; H, 7.11; N, 8.2
3.

Example 311 (Production of Compound 334) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. 4-
[[(1-Propylimidazol-2-yl) methyl]]
Sulfanyl] aniline (515 mg), triethylamine (5.8 ml) in tetrahydrofuran (15 ml)
The solution was added at 0 ° C. After stirring at room temperature under a nitrogen atmosphere for 1 hour, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) and recrystallized from ethanol-hexane to give 7- [4- ( 2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1
-Propylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (483 mg) (Compound 33
4) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.34
-1.45 (2H, m), 1.50-1.65 (2H, m), 1.75-1.85 (2H,
m), 1.95-2.15 (1H, m), 2.85-2.95 (2H, m), 3.19 (2
H, d, J = 7.2 Hz), 3.30-3.40 (2H, m), 3.56 (2H, t, J
= 6.6 Hz), 3.78-3.89 (4H, m), 4.14-4.19 (4H, m), 6.
85-7.00 (5H, m), 7.33-7.56 (9H, m), 7.64 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₃ S ・ 0.1H ₂ O Calcd. C, 71.84; H,
7.57; N, 8.38; Found.C, 71.59; H, 7.59; N, 8.1
8.

Example 312 (Compound 335, Compound 33)
Production of 6) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfanyl] phenyl]-
To a solution of 2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml), a solution of 70% 3-chloroperbenzoic acid (111 mg) in dichloromethane (10 ml) was added dropwise at -78 ° C. After completion of dropping, the mixture was stirred at -10 ° C to -25 ° C for 1 hour.
An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -1-isobutyl-N- [4-
[[(1-Propylimidazol-2-yl) methyl]]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (73.5 mg)
(Compound 335), 7- [4 as yellow amorphous
-(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-propylimidazole-2-
Iyl) methyl] sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1
8.8 mg) (Compound 336) was obtained Compound 335 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.84-1.00 (12H, m), 1.22
-1.80 (6H, m), 2.00-2.20 (1H, m), 2.85-3.00 (2H,
m), 3.20 (2H, d, J = 7.2 Hz), 3.30-3.45 (2H, m), 3.5
5 (2H, t, J = 7.0 Hz), 3.58-3.83 (4H, m), 4.06-4.30
(4H, m), 6.87 (1H, d, J = 1.4 Hz), 6.90-7.00 (4H,
m), 7.39-7.48 (7H, m), 7.73 (2H, d, J = 8.4Hz), 7.89
(1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S ・ 0.3H ₂ O Calcd. C, 69.80; H,
7.41; N, 8.14; Found.C, 69.56; H, 7.19; N, 7.9
2. Compound 336 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.01 (12H, m), 1.30
-1.80 (6H, m), 2.00-2.20 (1H, m), 2.90-3.00 (2H,
m), 3.20 (2H, d, J = 7.4 Hz), 3.30-3.40 (2H, m), 3.5
6 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.2 Hz), 3.95
(2H, t, J = 7.8 Hz), 4.16 (2H, t, J = 5.2 Hz), 4.41 (2
H, s), 6.89-6.99 (5H, m), 7.29-7.32 (2H, m), 7.38-
7.44 (3H, m), 7.55 (2H, d, J = 9.2 Hz), 7.72 (2H, d,
J = 9.2 Hz), 8.39 (1H, s).

Example 313 (Production of compounds 337 and 338) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfinyl] phenyl]-
2,3-dihydro-1-benzazepine-4-carboxamide (680mg) was added to CHIRALCEL OD 50mmID x 500mmL
Resolve with (hexane / ethanol / diethylamine) to give (+)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-propylimidazol-2- Ile) methyl] sulfinyl]
Phenyl] -2,3-dihydro-1-benzazepine-
4-carboxamide (250 mg) (compound 337),
(−)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide (280 mg) (Compound 338) was obtained. Compound 337 [a] _D = + 79.6 ° (C = 0.501% ethanol solution,> 99.9% ee) Compound 338 [a] _D = -76.0 ° (C = 0.468% ethanol solution, 99.0% ee)

Example 314 (Production of compound 339) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (1.5 g) in tetrahydrofuran (20
ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.34 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. After distilling off the solvent and excess thionyl chloride under reduced pressure, the residue was dissolved in THF (20 ml),
S- (4-aminophenyl) O-benzyl carbonothioate (918 mg), triethylamine (2.47)
ml) in THF (20 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred for 3 hours, and then methanol (40 ml) was added. 1 more
N aqueous sodium hydroxide solution (17.7 ml) was added,
The mixture was stirred under an argon atmosphere for 30 minutes. Then, 2-chloromethyl-1-propylimidazole hydrochloride (760 m
g) was added and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane: ethyl acetate = 1:
It was separated and purified in 4) to give 7- as yellow amorphous.
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4-[[(1-propylimidazole-2
-Yl) methyl] sulfanyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (1.65 g) (Compound 339) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.03 (9H, m), 1.26-
1.84 (8H, m), 2.85-2.95 (2H, m), 3.28-3.35 (4H,
m), 3.55 (2H, t, J = 7.0 Hz), 3.80-3.87 (4H, m), 4.12
-4.18 (4H, m), 6.83 (1H, d, J = 1.0 Hz), 6.86-7.00
(4H, m), 7.31-7.55 (9H, m), 7.83 (1H, s).

Example 315 (Production of compound 340) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (1.52 g) in dichloromethane (20 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (861 mg) in dichloromethane (20 ml) at -78 ° C.
An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 8) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -1-propyl-N- [4-
[[(1-Propylimidazol-2-yl) methyl]]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.01 g) (Compound 340) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.84-1.04 (9H, m) , 1.34-
1.85 (8H, m), 2.85-2.97 (2H, m), 3.29-3.40 (4H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.70-3.83 (4H, m), 4.06
-4.31 (4H, m), 6.87 (1H, d, J = 1.6 Hz), 6.93-7.01
(4H, m), 7.40-7.48 (7H, m), 7.73 (2H, d, J = 8.8 Hz),
7.84 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.4H ₂ O Calcd. C, 69.28; H,
7.28; N, 8.29; Found.C, 68.99; H, 7.32; N, 8.0
1.

Example 316 (Production of compounds 341 and 342) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,
3-dihydro-1-benzazepine-4-carboxamide (800 mg) was resolved using CHIRALPAK AD 50 mm ID x 500 mm L (hexane / ethanol / methanol),
(+)-7- [4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-carboxamide (306 mg) (compound 341), (−)
-7- [4- (2-butoxyethoxy) phenyl] -1
-Propyl-N- [4-[[(1-propylimidazol-2-yl) methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (328 mg) (Compound 342) was obtained. Compound 341 [a] _D = + 64.3 ° (C = 0.501% ethanol solution,> 99.9% ee) Compound 342 [a] _D = -67.9 ° (C = 0.502% ethanol solution, 99.1% ee)

Example 317 (Production of compound 343) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. Add this solution to S- (4
-Aminophenyl) O-benzyl carbonothioate (415 mg) and a solution of triethylamine (3.35 ml) in THF (10 ml) were added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred for 30 minutes, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 2-chloromethyl-1-
(2,2,2-Trifluoroethyl) imidazole hydrochloride (414 mg) was added, and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → hexane: ethyl acetate = 2: 7) to give 7- [4- (2 -Butoxyethoxy) phenyl] -1-isobutyl-N-
[4-[[1- (2,2,2-Trifluoroethylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (235 mg) (Compound 343 ) Got. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.80 (4H, m), 2.00-2.20 (1H, m), 2.85-2.95 (2H,
m), 3.18 (2H, d, J = 7.4 Hz), 3.30-3.40 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.10-
4.20 (4H, m), 4.60 (2H, q, J = 8.4 Hz), 6.89-7.00 (5
H, m), 7.28-7.59 (10H, m).

Example 318 (Production of compound 344) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[1- (2,2,2-trifluoroethylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (150 mg ) Was added to a solution of 70% 3-chloroperbenzoic acid (79 mg) in dichloromethane (10 ml) in dichloromethane (10 ml) -7.
It was added dropwise at 8 ° C. An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give a yellow amorphous solid 7
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[1- (2,2,2-trifluoroethylimidazol-2-yl) methyl] sulfinyl] phenyl] -2 , 3-Dihydro-1-benzazepine-4-carboxamide (60 mg) (Compound 34
4) Obtained ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.45 (2H, m), 1.50-1.70 (2H, m), 2.00-2.15 (1H,
m), 2.88-2.98 (2H, m), 3.20 (2H, d, J = 5.8 Hz), 3.30
-3.42 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 4.8 Hz), 4.12-4.36 (4H, m), 4.60-5.00 (2H,
m), 6.91-7.03 (5H, m), 7.39-7.50 (7H, m), 7.75-7.80
(3H, m). Elemental analysis C ₃₉ H ₄₅ N ₄ O ₄ SF ₃ Calcd. C, 64.80; H, 6.27;
N, 7.75; Found. C, 64.40; H, 6.14; N, 7.63.

Example 319 (Preparation of compound 345) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. Add this solution to S- (4
-Aminophenyl) O-benzyl carbonothioate (415 mg) and triethylamine (1.34 ml) in THF (10 ml) were added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred for 3 hours, and then methanol (20 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 1-butyl-2-chloromethylimidazole hydrochloride (368 mg) was added, and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate) to give 7- [4- (2
-Butoxyethoxy) phenyl] -N- [4-[[(1
-Butylimidazol-2-yl) methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-
1-Benzazepine-4-carboxamide (258m
g) (Compound 345) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.33
-1.78 (8H, m), 2.00-2.10 (1H, m), 2.85-2.95 (2H,
m), 3.19 (2H, d, J = 6.8 Hz), 3.30-3.40 (2H, m), 3.5
5 (2H, t, J = 6.6 Hz), 3.78-3.92 (4H, m), 4.07-4.18
(4H, m), 6.84 (1H, d, J = 1.2 Hz), 6.89-7.00 (4H,
m), 7.32-7.55 (9H, m), 7.65 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.84; H,
7.72; N, 8.17; Found. C, 71.61; H, 7.85; N, 8.
twenty one.

Example 320 (Production of compound 346) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(1-Butylimidazol-2-yl) methyl] sulfanyl] phenyl] -1-isobutyl-2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise with a 70% solution of 3-chloroperbenzoic acid (108 mg) in dichloromethane (10 ml) at -78 ° C.
An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -N- [4-[[(1-butylimidazol-2-yl) methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) (Compound 346) was obtained, ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86-1.00 (12H, m), 1.17
-1.70 (8H, m), 1.95-2.20 (1H, m), 2.90-3.00 (2H, m
m), 3.17 (2H, d, J = 7.2 Hz), 3.30-3.43 (2H, m), 3.5
5 (2H, t, J = 7.0 Hz), 3.70-3.95 (4H, m), 4.03-4.25
(4H, m), 6.85 (1H, d, J = 1.2 Hz), 6.89-6.99 (4H,
m), 7.38-7.46 (7H, m), 7.73 (2H, d, J = 8.8Hz), 8.18
(1H, s).

Example 321 (Production of compound 347) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. Add this solution to S- (4
-Aminophenyl) O-benzyl carbonothioate (415 mg) and a solution of triethylamine (3.35 ml) in THF (15 ml) were added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, a 1N aqueous sodium hydroxide solution (18 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 2
-Chloromethyl-1-cyclopropylmethylimidazole hydrochloride (365 mg) was added, and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane:
Separation and purification with (ethyl acetate = 1: 1 → ethyl acetate) gave 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[(1-cyclopropylmethylimidazole-2) as yellow amorphous. -Yl) methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-
1-Benzazepine-4-carboxamide (152m
g) (Compound 347) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.30-0.36 (2H, m), 0.62-
0.71 (2H, m), 0.90-0.99 (9H, m), 1.10-1.20 (1H,
m), 1.34-1.45 (2H, m), 1.55-1.65 (2H, m), 1.95-2.1
5 (1H, m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.0 H
z), 3.30-3.40 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.74
-3.83 (4H, m), 4.13-4.18 (4H, m), 6.89-7.01 (5H,
m), 7.31-7.56 (9H, m), 7.89 (1H, s). Elemental analysis C ₄₁ H ₅₀ N ₄ O ₃ S ・ 0.1H ₂ O Calcd. C, 72.34; H,
7.43; N, 8.23; Found.C, 72.12; H, 7.42; N, 8.0
9.

Example 322 (Preparation of compound 348) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[(1-Cyclopropylmethylimidazole-
2-yl) methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4
-Carboxamide (125 mg) in dichloromethane (1
0 ml) solution with 70% 3-chloroperbenzoic acid (68 m
A solution of g) in dichloromethane (10 ml) was added dropwise at -78 ° C. An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9).
Separated and purified with 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4-
[[(1-Cyclopropylmethylimidazol-2-yl) methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (65.9 mg) (compound 348) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.30-0.38 (2H, m), 0.55-
0.70 (2H, m), 0.90-1.15 (10H, m), 1.30-1.50 (2H,
m), 1.55-1.75 (2H, m), 1.95-2.15 (1H, m), 2.90-2.9
8 (2H, m), 3.20 (2H, d, J = 7.0 Hz), 3.30-3.40 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.67 (2H, dd, J = 7.0, 2.
8 Hz), 3.81 (2H, t, J = 4.6 Hz), 4.09-4.18 (3H, m),
4.26 (1H, d, J = 13.6), 6.90-7.06 (5H, m), 7.42-7.48
(7H, m), 7.74 (2H, d, J = 8.8 Hz), 7.89 (1H, s). Elemental analysis C ₄₁ H ₅₀ N ₄ O ₄ S Calcd. C, 70.86; H, 7.25;
N, 8.06; Found. C, 70.51; H, 7.15; N, 7.86.

Example 323 (Production of compound 349) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S- (4-aminophenyl) O-
To a solution of benzyl carbonothioate (415 mg) and triethylamine (1.12 ml) in THF (15 ml) was added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was mixed under argon atmosphere to 3
Stir for 0 minutes. Then, 2-chloromethyl-1-isobutylimidazole hydrochloride (368 mg) was added, and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate) to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[(1-Isobutylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (65
3 mg) (compound 349) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (15H, m), 1.34
-1.45 (2H, m), 1.54-1.70 (2H, m), 1.95-2.10 (2H, m
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.6 Hz), 3.3
0-3.42 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.70 (2H,
d, J = 7.8 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.14-4.18 (4
H, m), 6.81 (1H, d, J = 1.6 Hz), 6.89-7.00 (4H, m),
7.32-7.55 (9H, m), 7.71 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S Calcd. C, 72.32; H, 7.70;
N, 8.23; Found. C, 71.99; H, 7.64; N, 8.24.

Example 324 (Preparation of compound 350) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-isobutylimidazol-2-yl) methyl] sulfanyl] phenyl]-
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (326 mg) in dichloromethane (15 ml) at -78 ° C. Aqueous sodium thiosulfate solution was added and the temperature was returned to room temperature.
After stirring for a minute, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -1-isobutyl-N- [4
-[[(1-Isobutylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (415 mg)
(Compound 350) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86 (6H, d, J = 6.6Hz),
0.89-0.99 (9H, m), 1.34-1.45 (2H, m), 1.54-1.65 (2
H, m), 1.80-2.20 (2H, m), 2.90-2.98 (2H, m), 3.20
(2H, d, J = 7.2 Hz), 3.35-3.40 (2H, m), 3.45-3.70 (4
H, m), 3.80 (2H, t, J = 44 Hz), 4.07-4.18 (3H, m), 4.
29 (1H, d, J = 13.4 Hz), 6.81 (1H, d, J = 1.6 Hz), 6.9
0-7.00 (4H, m), 7.38-7.48 (7H, m), 7.73 (2H, d, J =
8.6 Hz), 7.88 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.4H ₂ O Calcd. C, 69.93; H,
7.56; N, 7.96; Found.C, 69.79; H, 7.31; N, 7.6
6.

Example 325 (Production of compound 351) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S- (4-aminophenyl) O-
To a solution of benzyl carbonothioate (415 mg) and triethylamine (1.12 ml) in THF (15 ml) was added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was mixed under argon atmosphere to 3
Stir for 0 minutes. Then, 1- (2-butyl) -2-chloromethylimidazole hydrochloride (368 mg) was added, and the mixture was stirred overnight under an argon atmosphere. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as a yellow amorphous substance. [4-[[[1- (2-
Butyl) imidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-
1-Benzazepine-4-carboxamide (633m
g) (Compound 351) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.85 (3H, t, J = 7.8 Hz),
0.90-0.99 (9H, m), 1.30-1.50 (5H, m), 1.55-1.83 (4
H, m), 1.95-2.15 (1H, m), 2.85-2.95 (2H, m), 3.18
(2H, d, J = 7.2 Hz), 3.30-3.40 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.81 (2H, t, J = 4.4 Hz), 4.09-4.30 (5H,
m), 6.88-7.00 (5H, m), 7.33-7.56 (9H, m), 7.74 (1H,
s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S Calcd. C, 72.32; H, 7.70;
N, 8.23; Found. C, 72.06; H, 7.61; N, 8.10.

Example 326 (Production of compound 352) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- (2-Butyl) imidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (550 mg) in dichloromethane ( 15m
l) 70% 3-chloroperbenzoic acid (299 mg) in the solution
In dichloromethane (15 ml) was added dropwise at -78 ° C. An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. After washing the organic layer with a saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2
-Butoxyethoxy) phenyl] -N- [4-[[[1
-(2-Butyl) imidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (3
50 mg) (Compound 352) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.73-1.00 (12H, m), 1.23
-1.80 (9H, m), 2.00-2.20 (1H, m), 2.88-2.98 (2H,
m), 3.19 (2H, d, J = 7.4 Hz), 3.38-3.43 (2H, m), 3.5
5 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.4 Hz), 4.10-
4.35 (5H, m), 6.90-7.04 (5H, m), 7.40-7.55 (7H,
m), 7.69-7.84 (4H, m). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.4H ₂ O Calcd. C, 69.93; H,
7.56; N, 7.96; Found.C, 69.66; H, 7.30; N, 7.7
1.

Example 327 (Production of compound 353) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S- (4-aminophenyl) O-
To a solution of benzyl carbonothioate (415 mg) and triethylamine (1.12 ml) in THF (15 ml) was added dropwise at 0 ° C under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was mixed under argon atmosphere to 3
Stir for 0 minutes. Then, 2-chloromethyl-1-pentylimidazole hydrochloride (393 mg) was added, and the mixture was stirred overnight under an argon atmosphere. After distilling off the solvent under reduced pressure,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -1- as a yellow amorphous substance. Isobutyl-N- [4-
[[(1-Pentylimidazol-2-yl) methyl]]
Sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (737 mg) (Compound 353) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.87-0.99 (12H, m), 1.25
-1.49 (6H, m), 1.54-1.90 (4H, m), 2.00-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.3
0-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.90
(4H, m), 4.13-4.18 (4H, m), 6.84 (1H, d, J = 1.6 H
z), 6.89-7.00 (4H, m), 7.32-7.55 (9H, m), 7.75 (1H,
s).

Example 328 (Preparation of compound 354) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-pentylimidazol-2-yl) methyl] sulfanyl] phenyl]-
To a solution of 2,3-dihydro-1-benzazepine-4-carboxamide (680 mg) in dichloromethane (15 ml) was added a solution of 70% 3-chloroperbenzoic acid (362 mg) in dichloromethane (15 ml) dropwise at -78 ° C. Aqueous sodium thiosulfate solution was added and the temperature was returned to room temperature.
After stirring for a minute, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -1-isobutyl-N- [4
-[[(1-Pentylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (411 mg)
(Compound 354) was obtained ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.84-1.00 (12H, m), 1.15
-1.50 (6H, m), 1.55-1.75 (4H, m), 1.95-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.4 Hz), 3.3
0-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.71-3.83
(4H, m), 4.08-4.18 (3H, m), 4.27 (1H, d, J = 13.6 H
z), 6.87 (1H, d, J = 1.0 Hz), 6.90-7.00 (4H, m), 7.3
7-7.48 (7H, m), 7.74 (2H, d, J = 8.8 Hz), 7.97 (1H,
s). Elemental analysis C ₄₂ H ₅₄ N ₄ O ₄ S Calcd. C, 70.95; H, 7.66;
N, 7.88; Found. C, 70.75; H, 7.79; N, 7.55.

Example 329 (Production of compound 355) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added at 0 ° C., the temperature was returned to room temperature, and the mixture was stirred under a nitrogen atmosphere for 1 hour. This solution was treated with 3-methyl-4-[[(1-methylimidazol-2-yl) methyl] sulfanyl] aniline (448 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15).
ml) solution at 0 ° C. After stirring overnight at room temperature under a nitrogen atmosphere, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [as a yellow amorphous substance. 3-methyl-4-[[(1-methylimidazol-2-yl)
Methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (335m
g) (compound 355) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.45 (2H, m), 1.55-1.75 (2H, m), 2.00-2.20 (1H,
m), 2.32 (3H, s), 2.85-2.95 (2H, m), 3.19 (2H, d, J
= 7.0 Hz), 3.30-3.40 (2H, m), 3.52-3.59 (5H, m), 3.
81 (2H, t, J = 5.0Hz), 4.04 (2H, s), 4.16 (2H, t, J =
5.0 Hz), 6.78 (1H, d, J = 1.0 Hz), 6.89 (1H, d, J = 1.0
Hz), 6.93-7.00 (3H, m), 7.36-7.51 (8H, m), 7.75
(1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₃ S Calcd. C, 71.75; H, 7.41;
N, 8.58; Found. C, 71.48; H, 7.68; N, 8.43.

Example 330 (Compound 356, Compound 35)
Production of 7) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [3-methyl-4-[[(1-methylimidazol-2-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-
Carboxamide (200 mg) in dichloromethane (10
70% 3-chloroperbenzoic acid (113 m)
A solution of g) in dichloromethane (10 ml) was added dropwise at -78 ° C. After completion of dropping, the mixture was stirred at -10 ° C to -25 ° C for 1 hour. An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. After washing the organic layer with a saturated aqueous sodium hydrogen carbonate solution and saturated saline,
It was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 8) and recrystallized from hexane-ethyl acetate to give yellow crystals. -[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4-
[[(1-Methylimidazol-2-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (104 mg) (Compound 356), recrystallized from hexane-ethyl acetate. 7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [3-methyl-4- as yellow crystals
[[(1-Methylimidazol-2-yl) methyl] sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (10 mg) (Compound 3
57) was obtained. Compound 356 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.34-
1.45 (2H, m), 1.55-1.73 (2H, m), 2.00-2.15 (1H,
m), 2.18 (3H, s), 2.90-2.98 (2H, m), 3.20 (2H, d, J
= 6.8 Hz), 3.30-3.40 (2H, m), 3.49 (3H, s), 3.56 (2
H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.4 Hz), 4.06-4.22
(4H, m), 6.82 (1H, s), 6.90-7.00 (4H, m), 7.39-7.62
(7H, m), 7.76 (1H, d, J = 8.8 Hz), 7.96 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.2H ₂ O Calcd. C, 69.65; H,
7.25; N, 8.33; Found.C, 69.53; H, 7.39; N, 8.4
3. Compound 357 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.02 (9H, m), 1.34-
1.45 (2H, m), 1.49-1.66 (2H, m), 2.00-2.15 (1H,
m), 2.38 (3H, s), 2.90-3.00 (2H, m), 3.21 (2H, d, J
= 7.0 Hz), 3.30-3.40 (2H, m), 3.53-3.59 (5H, m), 3.
81 (2H, t, J = 5.2Hz), 4.17 (2H, t, J = 5.2Hz), 4.29
(2H, s), 6.80 (1H, s), 6.90-6.99 (4H, m), 7.09-7.26
(2H, m), 7.37-7.50 (4H, m), 7.60 (1H, d, J = 9.2 H
z), 7.71-7.76 (1H, m), 8.70-8.81 (1H, m).

Example 331 (Production of compound 358) 7- [4- (2-butoxyethoxy) phenyl] -N-
After adding one drop of pyridine to a solution of [4- (hydroxymethyl) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (500 mg) in THF (10 ml), thionyl chloride was added at 0 ° C. (0.09 ml) was added. The mixture was returned to room temperature and stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (10 ml). This solution was added to 2-mercapto-1-methylimidazole (137
mg), THF of triethylamine (1.67 ml)
(10 ml) was added to the solution at 0 ° C. and then heated at 50 ° C. overnight under a nitrogen 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 solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance. -1-Isobutyl-N- [4-[[(1-methylimidazol-2-yl) sulfanyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-
Carboxamide (437 mg) (Compound 358) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.45 (2H, m), 1.50-1.70 (2H, m), 1.95-2.20 (1H,
m), 2.90-2.97 (2H, m), 3.19 (2H, d, J = 7.4 Hz), 3.28
(3H, s), 3.30-3.40 (2H, m), 3.55 (2H, t, J = 6.6 H
z), 3.80 (2H, t, J = 4.6 Hz), 4.13-4.18 (4H, m), 6.8
7-7.11 (7H, m), 7.37-7.56 (8H, m). Elemental analysis C ₃₈ H ₄₆ N ₄ O ₃ S ・ 0.3H ₂ O Calcd. C, 70.84; H,
7.29; N, 8.70; Found.C, 70.62; H, 7.49; N, 8.9
1.

Example 332 (Production of compound 359) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1-methylimidazol-2-yl) sulfanyl] methyl] phenyl] -2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (116 mg) in dichloromethane (10 ml) at -78 ° C.
After completion of dropping, the mixture was stirred at -10 ° C to -25 ° C for 1 hour. An aqueous sodium thiosulfate solution was added, the mixture was returned to room temperature, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (ethyl acetate →
Separated and purified with methanol: ethyl acetate = 1: 8) to obtain 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-] as yellow amorphous.
[[(1-Methylimidazol-2-yl) sulfinyl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (122 mg) (Compound 359) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.33-
1.45 (2H, m), 1.58-1.80 (2H, m), 2.00-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.4 Hz), 3.34
-3.40 (5H, m), 3.55 (2H, t, J = 7.0 Hz), 3.81 (2H,
t, J = 5.2 Hz), 4.16 (2H, t, J = 5.2 Hz), 4.37 (1H, d,
J = 12.4 Hz), 4.61 (1H, d, J = 12.4 Hz), 6.87-7.06 (6
H, m), 7.22 (1H, s), 7.39-7.57 (8H, m).

Example 333 (Production of compound 360) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.12 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then
2-Chloromethyl-1-cyclobutylmethylimidazole hydrochloride (389 mg) was added, and the mixture was stirred overnight under an argon atmosphere. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) and recrystallized from hexane-ethyl acetate to give 7- [4
-(2-Butoxyethoxy) phenyl] -N- [4-
[[[1-Cyclobutylmethylimidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (700 mg) (Compound 360) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.05 (9H, m), 1.20-
2.20 (11H, m), 2.60-2.80 (1H, m), 2.85-2.95 (2H,
m), 3.10-3.25 (2H, m), 3.30-3.40 (2H, m), 3.50-3.6
5 (2H, m), 3.75-3.95 (4H, m), 4.10-4.22 (4H, m),
6.79-6.99 (5H, m), 7.26-7.55 (9H, m), 7.83 (1H, s). Elemental analysis C ₄₂ H ₅₂ N ₄ O ₃ S Calcd. C, 72.80; H, 7.56;
N, 8.09; Found. C, 72.53; H, 7.57; N, 7.97.

Example 334 (Production of compound 361) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclobutylmethylimidazole-2
-Yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-
Carboxamide (640 mg) in dichloromethane (15
70% 3-chloroperbenzoic acid (342 m)
A solution of g) in dichloromethane (15 ml) was added dropwise at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -N-
[4-[[[1-Cyclobutylmethylimidazole-2
-Yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-
Carboxamide (439 mg) (Compound 361) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.30-
2.15 (11H, m), 2.50-2.65 (1H, m), 2.90-3.00 (2H,
m), 3.20 (2H, d, J = 7.2 Hz), 3.35-3.45 (2H, m), 3.5
6 (2H, t, J = 6.6 Hz), 3.77-3.83 (4H, m), 4.07-4.19
(3H, m), 4.27 (1H, d, J = 13.4 Hz), 6.84 (1H, d, J =
1.2 Hz), 6.90-7.00 (4H, m), 7.40-7.48 (7H, m), 7.7
4 (2H, d, J = 8.8 Hz), 7.96 (1H, s). Elemental analysis C ₄₂ H ₅₂ N ₄ O ₄ S ・ 0.5H ₂ O Calcd. C, 70.26; H,
7.44; N, 7.80; Found.C, 69.97; H, 7.22; N, 7.5
Four.

Example 335 (Production of compound 362) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.12 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred under an argon atmosphere for 3 hours, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then
1-allyl-2-chloromethylimidazole hydrochloride (3
40 mg) was added and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give N- [4-[[[1-allylimidazol-2-yl] methyl as yellow amorphous. ] Sulfanyl] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (609 mg) (Compound 362) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.26-
1.48 (2H, m), 1.54-1.70 (2H, m), 2.00-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.2 Hz), 3.30
-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 5.4 Hz), 4.11 (2H, s), 4.16 (2H, t, J = 5.4 Hz),
4.54 (2H, d, J = 5.6 Hz), 5.01-5.26 (2H, m), 5.80-6.
00 (1H, m), 6.82 (1H, d, J = 0.8 Hz), 6.89-7.00 (4H,
m), 7.31-7.55 (9H, m), 7.82 (1H, s). Elemental analysis C ₄₀ H ₄₈ N ₄ O ₃ S Calcd. C, 72.26; H, 7.28;
N, 8.43; Found. C, 71.88; H, 7.22; N, 8.14.

Example 336 (Production of Compound 363) N- [4-[[[1-allylimidazol-2-yl]]
Methyl] sulfanyl] phenyl] -7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (500 mg) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (204 mg) in dichloromethane (15 ml) at -78 ° C.
After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give N- [4-
[[[1-Allylimidazol-2-yl] methyl] sulfinyl] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4- Carboxamide (382
mg) (Compound 363) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.75 (2H, m), 2.00-2.20 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.2 Hz), 3.30
-3.45 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 4.4 Hz), 4.07-4.24 (4H, m), 4.30-4.65 (2H,
m), 4.93-5.22 (2H, m), 5.70-5.95 (1H, m), 6.87 (1H,
d, J = 1.0 Hz), 6.90-7.02 (4H, m), 7.40-7.48 (7H,
m), 7.74 (2H, d, J = 8.8 Hz), 7.96 (1H, s).

Example 337 (Production of compound 364) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.12 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 2
-Chloromethyl-5-methyl-1-propylimidazole hydrochloride (368 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane: ethyl acetate = 1:
Separated and purified in 4) to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[5-methyl-1-propylimidazol-2-yl] methyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (573 mg) (Compound 364) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.80 (4H, m), 2.00-2.20 (4H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.3
0-3.40 (2H, m), 3.56 (2H, t, J = 7.0 Hz), 3.72-4.07
(4H, m), 4.08 (2H, s), 4.16 (2H, t, J = 5.6 Hz), 6.6
4 (1H, s), 6.88-7.00 (3H, m), 7.31-7.56 (9H, m), 8.
05 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S Calcd. C, 72.32; H, 7.70;
N, 8.23; Found. C, 72.13; H, 7.75; N, 8.08.

Example 338 (Preparation of Compound 365) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[5-methyl-1-propylimidazol-2-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (450 mg) in dichloromethane (1
5%) solution to 70% 3-chloroperbenzoic acid (244 m
A solution of g) in dichloromethane (15 ml) was added dropwise at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 9) to give 7- [4- (2-butoxy) as a yellow amorphous substance. Ethoxy) phenyl] -1-
Isobutyl-N- [4-[[[5-methyl-1-propylimidazol-2-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (340 mg) (Compound 365) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.84-1.22 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.70 (4H, m), 2.00-2.20 (4H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.0 Hz), 3.3
5-3.45 (2H, m), 3.52-3.83 (6H, m), 4.03-4.24 (4H,
m), 6.74 (1H, d, J = 1.2 Hz), 6.89-6.99 (3H, m), 7.39
-7.47 (7H, m), 7.73 (2H, d, J = 8.8 Hz), 8.12 (1H,
s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.5H ₂ O Calcd. C, 69.76; H,
7.57; N, 7.94; Found.C, 69.76; H, 7.54; N, 7.6
6.

Example 339 (Production of compound 366) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.12 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 2
-Chloromethyl-1-cyclopropylimidazole hydrochloride (340 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4 as yellow amorphous. -[[[1-Cyclopropylimidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (841)
mg) (compound 366). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.80-1.05 (13H, m), 1.30
-1.50 (2H, m), 1.55-1.70 (2H, m), 1.95-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.10-3.25 (3H, m), 3.30-3.4
0 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J =
4.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 4.20 (2H, s), 6.8
0 (1H, d, J = 1.2 Hz), 6.84 (1H, d, J = 1.2Hz), 6.91
(1H, d, J = 9.6 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.33-7.
56 (9H, m), 7.99 (1H, s). Elemental analysis C ₄₀ H ₄₈ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.77; H,
7.30; N, 8.37; Found. C, 71.71; H, 7.35; N,
8.45.

Example 340 (Preparation of compound 367) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclopropylimidazol-2-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (700 mg) in dichloromethane (15 m
l) 70% 3-chloroperbenzoic acid (389 mg) in the solution
In dichloromethane (15 ml) was added dropwise at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring.
The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from hexane-ethyl acetate to give 7- [4-
(2-Butoxyethoxy) phenyl] -N- [4-
[[[1-Cyclopropylimidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-
2,3-Dihydro-1-benzazepine-4-carboxamide (526 mg) (Compound 367) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.66-1.00 (13H, m), 1.30
-1.49 (2H, m), 1.54-1.69 (2H, m), 2.00-2.20 (1H,
m), 2.90-3.05 (3H, m), 3.20 (2H, d, J = 7.4 Hz), 3.3
0-3.45 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 4.4 Hz), 4.13-4.24 (3H, m), 4.39 (1H, d, J = 1
3.2 Hz), 6.84 (1H, d, J = 1.6 Hz), 6.90-7.00 (4H,
m), 7.39-7.46 (7H, m), 7.74 (2H, d, J = 8.4 Hz), 8.0
3 (1H, s). Elemental analysis C ₄₀ H ₄₈ N ₄ O ₄ S Calcd. C, 70.56; H, 7.11;
N, 8.23; Found. C, 70.21; H, 7.13; N, 7.97.

Example 341 (Production of compounds 368 and 369) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclopropylimidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (400 mg) was added to CHIRALPAK AD 50 mm ID × 500.
Split using mmL (hexane / isopropanol),
(+)-7- [4- (2-Butoxyethoxy) phenyl] -N- [4-[[[1-cyclopropylimidazol-2-yl] methyl] sulfinyl] phenyl] -1
-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (176 mg) (Compound 36
8), (-)-7- [4- (2-Butoxyethoxy) phenyl] -N- [4-[[[1-cyclopropylimidazol-2-yl] methyl] sulfinyl] phenyl]
-1-Isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (175 mg) (Compound 36
9) was obtained. Compound 368 [a] _D = + 79.5 ° (C = 0.499% ethanol solution,> 99.9% ee) Compound 369 [a] _D = -81.5 ° (C = 0.497% ethanol solution, 99.8% ee)

Example 342 (Preparation of compound 370) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
DMF (0.5 ml) was added to a solution of 4-carboxylic acid (25.0 g) in tetrahydrofuran (250 ml).
Then, thionyl chloride (5.4 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and then the residue was dissolved in THF (250 ml).
This solution is S- (4-aminophenyl) O-benzyl
Carbonothioate (14.8 g) and triethylamine (39.8 ml) in THF (250 ml) at 0 ° C.,
It was added dropwise under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (500 ml) was added. Further, 2N aqueous sodium hydroxide solution (143 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes.
Stir for minutes. Then, 5-chloromethyl-1-propylimidazole hydrochloride (12.3 g) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 7- [4- (2-butoxyethoxy) phenyl] -1 as yellow amorphous.
-Isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (34.6 g) (Compound 370) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.00 (12H, m), 1.30
-1.48 (2H, m), 1.54-1.68 (2H, m), 1.75-1.89 (2H, m
m), 2.00-2.20 (1H, m), 2.88-2.98 (2H, m), 3.19 (2
H, d, J = 7.4 Hz), 3.35-3.45 (2H, m), 3.55 (2H, t, J
= 7.4 Hz), 3.81 (2H, t, J = 4.8 Hz), 3.92 (2H, t, J =
7.6 Hz), 3.99 (2H, s), 4.16 (2H, t, J = 4.8Hz), 6.70
(1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.
8 Hz), 7.25-7.29 (2H, m), 7.38-7.56 (8H, m), 7.66
(1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₃ S Calcd. C, 72.04; H, 7.56;
N, 8.40; Found. C, 71.76; H, 7.63; N, 8.16.

Example 343 (Production of compound 371) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (35.7 g) in dichloromethane (350 ml)
A solution of 70% 3-chloroperbenzoic acid (19.8 g) in dichloromethane (200 ml) was added dropwise to the solution at -78 ° C. After adding dimethyl sulfide (10 ml), the mixture was returned to room temperature and stirred for 30 minutes. After water was added and the layers were separated, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2- Butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (30.5 g) (Compound 371) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.86-0.99 (12H, m), 1.29
-1.50 (2H, m), 1.55-1.77 (4H, m), 1.95-2.20 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.4 Hz), 3.3
0-3.45 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.74-3.83
(4H, m), 4.02 (1H, d, J = 14.4 Hz), 4.07-4.18 (3H,
m), 6.56 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2
H, d, J = 8.8 Hz), 7.32-7.50 (8H, m), 7.75 (2H, d, J
= 8.8 Hz), 7.97 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S Calcd. C, 70.35; H, 7.38;
N, 8.20; Found. C, 70.03; H, 7.40; N, 8.06.

Example 344 (Production of compounds 372 and 373) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (1.33 g) was added to CHIRALPAK AD 50mmID × 500mmL
Split using (ethanol → isopropanol),
(+)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide (0.58 g) (compound 372),
(-)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide (0.60 g) (Compound 373) was obtained. Compound 372 [a] _D = + 131.8 ° (C = 0.498% ethanol solution,> 99.9% ee) Compound 373 [a] _D = -126.9 ° (C = 0.497% ethanol solution, 99.6% ee)

Example 345 (Production of compound 374) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1-benzazepine-4
-Carboxylic acid (1.0 g) in tetrahydrofuran (15
ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.23 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (612 mg), triethylamine (1.65 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Furthermore, 1N sodium hydroxide aqueous solution (11.8 m
1) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-propylimidazole hydrochloride (506 mg) was added to the mixture under an argon atmosphere to give 1.5.
Stir for hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (methanol-ethyl acetate = 1: 19).
Separation and purification with 7- [4- (2
-Butoxyethoxy) phenyl] -1-propyl-N-
[4-[[[1-Propylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (988m
g) (compound 374) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.03 (9H, m), 1.27-
1.50 (2H, m), 1.55-1.95 (6H, m), 2.85-2.95 (2H,
m), 3.25-3.40 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80
(2H, t, J = 4.8 Hz), 3.92 (2H, t, J = 7.4 Hz), 3.99
(2H, s), 4.16 (2H, t, J = 4.8 Hz), 6.70 (1H, s), 6.90
(1H, d, J = 7.8 Hz), 6.98 (2H, d, J = 8.4Hz), 7.25-7.
30 (2H, m), 7.39-7.55 (8H, m), 7.62 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₃ S Calcd. C, 71.75; H, 7.41;
N, 8.58; Found. C, 71.54; H, 7.37; N, 8.53.

Example 346 (Production of compounds 375 and 376) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,
To a solution of 3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added a solution of 70% 3-chloroperbenzoic acid (510 mg) in dichloromethane (15 ml) dropwise at -78 ° C.
After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl]-as a yellow amorphous substance.
1-Propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (529 mg) (Compound 375), 7- [4-
(2-Butoxyethoxy) phenyl] -1-propyl-
N- [4-[[[1-Propylimidazol-5-yl] methyl] sulfonyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (37m
g) (compound 376) was obtained. Compound 375 ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.88-1.025 (9H, m), 1.33
-1.46 (2H, m), 1.56-1.79 (6H, m), 2.90-2.95 (2H, m
m), 3.31-3.37 (4H, m), 3.55 (2H, t, J = 6.3 Hz), 3.7
6-3.82 (4H, m), 4.02 (1H, d, J = 14.1 Hz), 4.09 (1H,
d, J = 14.1 Hz), 4.16 (2H, t, J = 4.8 Hz), 6.57 (1H,
s), 6.91 (1H, d, J = 9.0 Hz), 6.98 (2H, d, J = 8.7 H
z), 7.33-7.51 (8H, m), 7.74 (2H, d, J = 9.0 Hz), 7.8
4 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 69.56; H,
7.26; N, 8.32; Found. C, 69.49; H, 7.23; N, 8.
18. Compound 376 ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.03 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.85 (6H, m), 2.85-2.95 (2H, m
m), 3.25-3.40 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81
(2H, t, J = 4.8 Hz), 3.95 (2H, t, J = 7.4 Hz), 4.16
(2H, t, J = 4.8 Hz), 4.32 (2H, s), 6.53 (1H, s), 6.90
(1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8Hz), 7.41-7.
50 (6H, m), 7.60 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J
= 8.8 Hz), 8.06 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₅ S ・ 0.75H ₂ O Calcd. C, 67.07; H,
7.14; N, 8.02; Found. C, 67.12; H, 6.97; N, 7.
70.

Example 347 (Production of Compounds 377 and 378) 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,
3-dihydro-1-benzazepine-4-carboxamide (413 mg) was resolved using CHIRALPAK AD 50 mm ID × 500 mm L (ethanol → isopropanol), and (+)
-7- [4- (2-butoxyethoxy) phenyl] -1
-Propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1-benzazepine-4-carboxamide (140 mg) (Compound 377), (−)-7-
[4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4-[[[1-propylimidazole-5
-Yl] methyl] sulfinyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide (155 mg) (Compound 378) was obtained. Compound 377 [a] _D = + 136.0 ° (C = 0.495% ethanol solution,> 99.9% ee) Compound 378 [a] _D = -138.2 ° (C = 0.499% ethanol solution, 99.9% ee)

Example 348 (Preparation of compound 379) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.22 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (594 mg), triethylamine (1.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (11.5 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-ethylimidazole hydrochloride (435 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate.
After the solvent was distilled off under reduced pressure, it was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 7- [4- (2-
Butoxyethoxy) phenyl] -N- [4-[[[1-
Ethylimidazol-5-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-
1-Benzazepine-4-carboxamide (960m
g) (compound 379) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.34-
1.65 (7H, m), 1.95-2.15 (1H, m), 2.85-2.95 (2H,
m), 3.19 (2H, d, J = 7.4 Hz), 3.35-3.45 (2H, m), 3.55
(2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.01-
4.08 (4H, m), 4.16 (2H, t, J = 4.8 Hz), 6.70 (1H, s),
6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz),
7.28 (2H, d, J = 8.8 Hz), 7.39-7.56 (8H, m), 7.60 (1
H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.25; H,
7.44; N, 8.52; Found. C, 71.10; H, 7.42; N, 8.
59.

Example 349 (Preparation of compound 380) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Ethylimidazol-5-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,
A solution of 3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (365 mg) in dichloromethane (15 ml) at -78 ° C.
After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) as a yellow amorphous substance.
Phenyl] -N- [4-[[[1-ethylimidazol-5-yl] methyl] sulfinyl] phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxamide (516 mg) (Compound 380) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.45 (5H, m), 1.50-1.70 (2H, m), 1.95-2.15 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.6 Hz), 3.33
-3.43 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.93
(4H, m), 4.01 (1H, d, J = 13.8 Hz), 4.14 (1H, d, J = 1
3.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 6.58 (1H, s), 6.9
1-7.00 (3H, m), 7.34-7.55 (8H, m), 7.75 (2H, d, J =
8.8 Hz), 7.83 (1H, s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 69.56; H,
7.26; N, 8.32; Found.C, 69.37; H, 7.13; N, 8.2
0.

Example 350 (Production of compound 381) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.22 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (594 mg), triethylamine (1.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (11.5 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-isobutylimidazole hydrochloride (503 mg) was added thereto, and the mixture was added under an argon atmosphere to give 1.5.
Stir for hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- [as a yellow amorphous substance. [[1-Isobutylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) (Compound 381)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (15H, m), 1.30
-1.45 (2H, m), 1.50-1.70 (2H, m), 2.00-2.20 (2H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.8 Hz), 3.3
0-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.76-3.83
(4H, m), 3.99 (2H, s), 4.16 (2H, t, J = 4.8 Hz), 6.7
0 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J =
8.8 Hz), 7.26-7.30 (2H, m), 7.38-7.57 (8H, m), 7.7
3 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S Calcd. C, 72.32; H, 7.70;
N, 8.23; Found. C, 71.93; H, 7.67; N, 8.29.

Example 351 (Production of compound 382) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-isobutylimidazol-5-yl] methyl] sulfanyl] phenyl]-
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (358 mg) in dichloromethane (15 ml) at -78 ° C. After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N- [4-
[[[1-Isobutylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (619 mg)
(Compound 382) obtained ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.85-0.99 (15H, m), 1.34
-1.50 (2H, m), 1.55-1.70 (2H, m), 1.80-2.20 (2H, m
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 6.8 Hz), 3.3
0-3.45 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.63 (2H,
d, J = 7.8 Hz), 3.80 (2H, t, J = 4.4 Hz), 3.95-4.18 (4
H, m), 6.55 (1H, s), 6.93 (1H, d, J = 8.8Hz), 6.98
(2H, d, J = 8.8 Hz), 7.37-7.52 (8H, m), 7.75 (2H, d,
J = 8.8 Hz), 7.93 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 70.20; H,
7.54; N, 7.99; Found. C, 70.13; H, 7.50; N, 7.
87.

Example 352 (Production of compound 383) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.22 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (594 mg), triethylamine (1.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (11.5 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-isopropylimidazole hydrochloride (491 mg) was added to the mixture under an argon atmosphere to give 1.
Stir for 5 hours. After adding water and extracting with ethyl acetate,
The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, basic silica gel column chromatography (hexane-ethyl acetate = 1: 1).
Separation and purification with 1 → hexane-ethyl acetate = 1: 3) gave 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[[1
-Isopropylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (1.1 g) (Compound 3
83) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.65 (10H, m), 2.00-2.20 (1H, m), 2.85-2.95 (2H,
m), 3.19 (2H, d, J = 7.0 Hz), 3.30-3.40 (2H, m), 3.5
5 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.00
(2H, s), 4.16 (2H, t, J = 4.8 Hz), 4.35-4.50 (1H,
m), 6.69 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.98 (2
H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.38-7.56
(8H, m), 7.65 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.55; H,
7.58; N, 8.34; Found. C, 71.30; H, 7.45; N, 8.
69.

Example 353 (Production of compound 384) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-isopropylimidazol-5-yl] methyl] sulfanyl] phenyl]
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (388 mg) in dichloromethane (15 ml) at -78 ° C. did. After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N- [4-
[[[1-Isopropylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1
-Benzazepine-4-carboxamide (634 mg)
(Compound 384) was obtained ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.91-0.99 (9H, m), 1.36-
1.45 (8H, m), 1.55-1.65 (2H, m), 2.00-2.15 (1H,
m), 2.90-2.95 (2H, m), 3.20 (2H, d, J = 7.5 Hz), 3.35
-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 4.8 Hz), 4.01 (1H, d, J = 14.1 Hz), 4.11 (1H, d,
J = 14.1 Hz), 4.16 (2H, t, J = 4.8 Hz), 4.25-4.35 (1
H, m), 6.54 (1H, s), 6.93 (1H, d, J = 8.7 Hz), 6.98
(2H, d, J = 8.7 Hz), 7.34-7.51 (7H, m), 7.59 (1H,
s), 7.75 (2H, d, J = 8.7 Hz), 7.93 (1H, s). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 69.89; H,
7.40; N, 8.15; Found. C, 69.79; H, 7.58; N, 7.
88.

Example 354 (Production of compound 385) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.22 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (594 mg), triethylamine (1.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (11.5 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-cyclopropylmethylimidazole hydrochloride (497 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give a yellow amorphous substance.
-[4- (2-Butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclopropylmethylimidazole-
5-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4
-Carboxamide (1.2 g) (compound 385) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.34-0.42 (2H, m), 0.66-
0.75 (2H, m), 0.90-0.99 (9H, m), 1.20-1.50 (3H,
m), 1.55-1.70 (2H, m), 1.95-2.15 (1H, m), 2.85-2.9
5 (2H, m), 3.19 (2H, d, J = 7.4 Hz), 3.29-3.37 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.84 (4H, m), 4.0
2 (2H, s), 4.16 (2H, t, J = 4.4 Hz), 6.72 (1H, s), 6.
92 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.27
(2H, d, J = 8.8 Hz), 7.38-7.60 (8H, m), 7.65 (1H,
s). Elemental analysis C ₄₁ H ₅₀ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 72.05; H,
7.45; N, 8.20; Found. C, 71.93; H, 7.43; N, 8.
34.

Example 355 (Production of compound 386) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1-Cyclopropylmethylimidazole-
5-yl] methyl] sulfanyl] phenyl] -1-isobutyl-2,3-dihydro-1-benzazepine-4
-Carboxamide (1.1 g) in dichloromethane (15
70% 3-chloroperbenzoic acid (440 m)
A solution of g) in dichloromethane (15 ml) was added dropwise at -78 ° C. After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was saturated aqueous sodium hydrogen carbonate solution,
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [as a yellow amorphous substance. 4-[[[1-Cyclopropylmethylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -1-isobutyl-2,3-
Dihydro-1-benzazepine-4-carboxamide (614 mg) (Compound 386) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.29-0.34 (2H, m), 0.63-
0.69 (2H, m), 0.91-0.99 (9H, m), 1.05-1.20 (1H,
m), 1.36-1.43 (2H, m), 1.56-1.66 (2H, m), 2.00-2.2
0 (1H, m), 2.90-2.95 (2H, m), 3.20 (2H, d, J = 7.2 H
z), 3.35-3.39 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.66
(2H, t, J = 4.5 Hz), 3.81 (2H, t, J = 6.6Hz), 4.02 (1
H, d, J = 14.1 Hz), 4.10-4.17 (3H, m), 6.58 (1H, s),
6.92 (1H, d, J = 8.7 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.
34-7.56 (7H, m), 7.63 (1H, s), 7.75 (2H, d, J = 8.7 H
z), 7.97 (1H, s). Elemental analysis C ₄₁ H ₅₀ N ₄ O ₄ S ・ 0.2H ₂ O Calcd. C, 70.50; H,
7.27; N, 8.02; Found.C, 70.35; H, 7.32; N, 7.9
Four.

Example 356 (Production of compound 387) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
4-Carboxylic acid (1.0 g) in tetrahydrofuran (1
5 ml) solution was added with 1 drop of DMF. Then, thionyl chloride (0.22 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S-
(4-Aminophenyl) O-benzyl carbonothioate (594 mg), triethylamine (1.6 ml)
Was added dropwise to a THF solution (15 ml) at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (11.5 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then 5-chloromethyl-4-methyl-1-propylimidazole hydrochloride (599 mg) in methanol (10 m
l) The solution was added and stirred for 1.5 hours under an argon atmosphere. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, basic silica gel column chromatography (hexane-ethyl acetate = 1: 1 → 1: 3)
Separation and purification with 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[[4-Methyl-1-propylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,
3-Dihydro-1-benzazepine-4-carboxamide (529 mg) (Compound 387) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.26 (12H, m), 1.30
-1.48 (2H, m), 1.54-1.65 (2H, m), 1.70-1.90 (5H,
m), 1.95-2.15 (1H, m), 2.85-2.95 (2H, m), 3.19 (2
H, d, J = 7.0 Hz), 3.34-3.38 (2H, m), 3.55 (2H, t, J
= 6.6 Hz), 3.78-3.90 (4H, m), 3.95 (2H, s), 4.16 (2
H, t, J = 4.8 Hz), 6.92 (1H, d, J = 8.4 Hz), 6.98 (2H,
d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.36-7.55 (8
H, m), 7.67 (1H, s).

Example 357 (Production of compound 388) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[4-methyl-1-propylimidazol-5-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4
-Carboxamide (460 mg) in dichloromethane (1
5%) solution to 70% 3-chloroperbenzoic acid (175 m
A solution of g) in dichloromethane (15 ml) was added dropwise at -78 ° C. After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was saturated aqueous sodium hydrogen carbonate solution,
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N-
[4-[[[4-Methyl-1-propylimidazole-
5-yl] methyl] sulfinyl] phenyl] -2,3
-Dihydro-1-benzazepine-4-carboxamide (236 mg) (Compound 388) was obtained ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.87-0.98 (12H, m), 1.30
-1.45 (2H, m), 1.55-1.75 (7H, m), 2.00-2.15 (1H,
m), 2.90-2.95 (2H, m), 3.19 (2H, d, J = 7.5 Hz), 3.3
7-3.42 (2H, m), 3.55 (2H, t, J = 6.9 Hz), 3.75 (2H,
t, J = 6.9 Hz), 3.81 (2H, t, J = 5.4 Hz), 4.04 (2H,
s), 4.16 (2H, t, J = 5.4 Hz), 6.92 (1H, d, J = 8.7 Hz),
6.98 (2H, d, J = 9.0 Hz), 7.31 (2H, d, J = 8.7 Hz),
7.39-7.49 (6H, m), 7.74 (2H, d, J = 8.7 Hz), 7.97 (1
H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 70.20; H,
7.54; N, 7.99; Found. C, 70.00; H, 7.50; N, 7.
97.

Example 358 (Preparation of Compound 389) 1-Isobutyl-7- [4- (2-propoxyethoxy) phenyl] -2,3-dihydro-1-benzazepine-4-carboxylic acid (820 mg) in tetrahydrofuran One drop of DMF was added to the (15 ml) solution. Then, thionyl chloride (0.18 ml) was added, and the mixture was mixed with nitrogen under a nitrogen atmosphere to give 1
Stir for hours. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution was mixed with S- (4-aminophenyl) O-benzyl carbonothioate (503 mg) and triethylamine (1.4 m).
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further 1N sodium hydroxide aqueous solution (9.7 ml)
Was added and the mixture was stirred under an argon atmosphere for 30 minutes. Then, 5-chloromethyl-1-propylimidazole hydrochloride (492 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, basic silica gel column chromatography (hexane-ethyl acetate = 1: 1).
1-isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[1-propylimidazol-5-yl] methyl] sulfanyl as a yellow amorphous by separation and purification with (ethyl acetate). ] Phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (685 mg) (Compound 389) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91-1.01 (12H, m), 1.50
-1.70 (2H, m), 1.79-1.90 (2H, m), 2.00-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.0 Hz), 3.3
0-3.40 (2H, m), 3.51 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 4.6 Hz), 3.93 (2H, t, J = 7.6 Hz), 4.00 (2H,
s), 4.16 (2H, t, J = 4.6 Hz), 6.70 (1H, s), 6.92 (1H,
d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.26-7.30
(2H, m), 7.38-7.58 (9H, m). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.25; H,
7.44; N, 8.52; Found. C, 70.96; H, 7.55; N, 8.
43.

Example 359 (Production of Compound 390) 1-isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl ] Phenyl]
2,3-Dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml)
A solution of 70% 3-chloroperbenzoic acid (272 mg) in dichloromethane (15 ml) was added dropwise to the solution at -78 ° C. After adding dimethyl sulfide (0.1 ml), the mixture was returned to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 1-isobutyl-7- [4-
(2-Propoxyethoxy) phenyl] -N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (433 mg) (Compound 390) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.87-0.99 (12H, m), 1.55
-1.80 (4H, m), 1.95-2.15 (1H, m), 2.90-3.00 (2H,
m), 3.20 (2H, d, J = 7.2 Hz), 3.35-3.45 (2H, m), 3.5
1 (2H, t, J = 6.4 Hz), 3.75-3.84 (4H, m), 4.02 (1H,
d, J = 14.2 Hz), 4.08-4.19 (3H, m), 6.57 (1H, s), 6.
93 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.38
-7.53 (8H, m), 7.76 (2H, d, J = 8.8 Hz), 7.95 (1H,
s). Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 69.56; H,
7.26; N, 8.32; Found. C, 69.19; H, 7.21; N, 8.
34.

Example 360 (Production of Compounds 391 and 392) 1-isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazol-5-yl] methyl ] Sulfinyl] Phenyl]
2,3-Dihydro-1-benzazepine-4-carboxamide (320 mg) was added to CHIRALPAK AD 50mm ID × 500mm
Split using L (ethanol → isopropanol),
(+)-1-Isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide (136 mg) (compound 391),
(-)-1-Isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3- Dihydro-1-benzazepine-4-
Carboxamide (123 mg) (Compound 392) was obtained. Compound 391 [a] _D = + 131.4 ° (C = 0.499% ethanol solution, 99.7% ee) Compound 392 [a] _D = -135.3 ° (C = 0.499% ethanol solution, 99.8% ee)

Example 361 (Production of compound 393) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.1 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 4
-Chloromethyl-1-propylimidazole hydrochloride (4
(06 mg) was added, and the mixture was stirred under an argon atmosphere for 1.5 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane-ethyl acetate = 1: 4 → ethyl acetate)
And purified by recrystallization from hexane-diisopropyl ether-ethyl acetate to give 7- [4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-4-yl] methyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4- Carboxamide (20
0 mg) (compound 393) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.85-0.99 (12H, m), 1.30
-1.48 (2H, m), 1.54-1.80 (4H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.19 (2H, d, J = 7.2 Hz), 3.3
0-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.76-3.83
(4H, m), 4.07 (2H, s), 4.16 (2H, t, J = 5.2 Hz), 6.6
9 (1H, s), 6.92 (1H, d, J = 9.2 Hz), 6.98 (2H, d, J =
8.8 Hz), 7.32-7.55 (11H, m). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₃ S Calcd. C, 72.04; H, 7.56;
N, 8.40; Found. C, 71.78; H, 7.41; N, 8.48.

Example 362 (Production of compound 394) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-propylimidazol-4-yl] methyl] sulfanyl] phenyl]-
A solution of 2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) in dichloromethane (15 ml) was added dropwise with a solution of 70% 3-chloroperbenzoic acid (78 mg) in dichloromethane (15 ml) at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (methanol-ethyl acetate = 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance. -1-isobutyl-N- [4-
[[[1-Propylimidazol-4-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 394) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.88-0.99 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.85 (4H, m), 1.95-2.20 (1H,
m), 2.85-2.95 (2H, m), 3.20 (2H, d, J = 7.6 Hz), 3.3
0-3.45 (2H, m), 3.55 (2H, t, J = 7.2 Hz), 3.78-3.87
(4H, m), 3.98 (1H, d, J = 12.8 Hz), 4.09 (1H, d, J = 1
2.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 6.80 (1H, s), 6.9
3 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.39-
7.53 (8H, m), 7.70-7.75 (3H, m). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S Calcd. C, 70.35; H, 7.38;
N, 8.20; Found. C, 70.10; H, 7.34; N, 8.12.

Example 363 (Production of compound 395) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.15 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution is S
-(4-Aminophenyl) O-benzyl carbonothioate (415 mg), triethylamine (1.1 m
l) in THF (15 ml) was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight under an argon atmosphere, and then methanol (30 ml) was added. Further, a 1N sodium hydroxide aqueous solution (8 ml) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Then 2
-(1-Chloroethyl) -1-propylimidazole hydrochloride (368 mg) was added and the mixture was stirred under argon atmosphere to give 1.5.
Stir for hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate = 1: 4) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-as yellow amorphous. N-
[4-[[1- [1-Propylimidazol-2-yl] ethyl] sulfanyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (22
3 mg) (compound 395) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.65 (2H, m), 1.70-1.84 (5H,
m), 1.95-2.15 (1H, m), 2.85-2.95 (2H, m), 3.19 (2
H, d, J = 7.4 Hz), 3.30-3.40 (2H, m), 3.55 (2H, t, J
= 7.0 Hz), 3.75-3.95 (4H, m), 4.16 (2H, t, J = 4.8 H
z), 4.27 (1H, q, J = 6.8 Hz), 6.84 (1H, d, J = 1.4 Hz),
6.96-7.00 (4H, m), 7.26 (2H, d, J = 8.8 Hz), 7.39-
7.58 (8H, m). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.84; H,
7.72; N, 8.17; Found. C, 71.67; H, 7.76; N, 8.
15.

Example 364 (Production of compound 396) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[1- [1-propylimidazol-2-yl] ethyl] sulfanyl] phenyl]
-2,3-Dihydro-1-benzazepine-4-carboxamide (170 mg) in dichloromethane (10 ml)
A solution of 70% 3-chloroperbenzoic acid (92 mg) in dichloromethane (10 ml) was added dropwise to the solution at -78 ° C. After removing the dry ice-acetone bath, an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N- [4-[[1- [1-propylimidazol-2-yl] ethyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (142 mg) (Compound 39
6) was obtained ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.02 (12H, m), 1.30
-1.90 (9H, m), 1.95-2.15 (1H, m), 2.90-2.95 (2H,
m), 3.05 (2H, d, J = 7.4 Hz), 3.35-3.45 (2H, m), 3.5
5 (2H, t, J = 7.0 Hz), 3.80 (2H, t, J = 4.8 Hz), 3.91-
4.24 (5H, m), 6.73-7.75 (15H, m). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 70.20; H,
7.54; N, 7.99; Found. C, 70.21; H, 7.61; N, 7.
86.

Example 365 (Production of compound 397) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (300 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.07 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution was added to (4-aminophenyl) (1-methylimidazole-2
-Yl) Methanol (181 mg) and a solution of triethylamine (0.6 ml) in THF (15 ml) were added dropwise at 0 ° C under a nitrogen atmosphere. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred under a nitrogen atmosphere overnight, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, it was separated and purified by basic silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 1: 8) to give 7- [4- (2-butoxyethoxy) as yellow amorphous.
Phenyl] -1-isobutyl-N- [4- [hydroxy [1-methylimidazol-2-yl] methyl]]-
2,3-Dihydro-1-benzazepine-4-carboxamide (122 mg) (Compound 397) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.98 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.70 (2H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.8 Hz), 3.30
-3.39 (2H, m), 3.40 (3H, s), 3.55 (2H, t, J = 6.6 H
z), 3.80 (2H, t, J = 4.8 Hz), 4.15 (2H, t, J = 4.8 H
z), 5.87 (1H, s), 6.83-7.01 (5H, m), 7.28-7.60 (10
H, m).

Example 366 (Production of compound 398) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1-benzazepine-
A drop of DMF was added to a solution of 4-carboxylic acid (600 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.13 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in THF (15 ml). This solution was added to (4-aminophenyl) (1-propylimidazole-
2-yl) methanol (412 mg) and triethylamine (1.2 ml) in THF (15 ml) were added dropwise at 0 ° C under a nitrogen atmosphere. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred under a nitrogen atmosphere overnight, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, basic silica gel column chromatography (ethyl acetate)
And purified by recrystallization from hexane-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- [hydroxy [1
-Propylimidazol-2-yl] methyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (167 mg) (Compound 398) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.79 (3H, t, J = 7.4 Hz),
0.89-0.98 (9H, m), 1.30-1.80 (6H, m), 1.95-2.15 (1
H, m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 8.2Hz),
3.30-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.64 (2
H, t, J = 7.4 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.16 (2H,
t, J = 4.8 Hz), 5.81 (1H, s), 6.88-7.02 (5H, m), 7.28
-7.61 (10H, m). Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ Calcd. C, 73.82; H, 7.74; N,
8.61; Found. C, 73.52; H, 7.53; N, 8.73.

Example 367 (Production of compound 399) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfanyl] phenyl]-
To a solution of 2,3-dihydro-1-benzazepine-4-carboxamide (300 mg) in dichloromethane (10 ml), a solution of 70% 3-chloroperbenzoic acid (221 mg) in dichloromethane (10 ml) was added dropwise at -78 ° C. After stirring at -15 ° C for 1 hour, dimethyl sulfide (0.1 ml) was added, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. After water was added and the layers were separated, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from hexane-ethyl acetate to give 7- [as yellow crystals. 4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[[1-Propylimidazol-5-yl]]
Methyl] sulfonyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (122m
g) (Compound 399) was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.85-0.99 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.85 (4H, m), 1.95-2.15 (1H,
m), 2.90-3.00 (2H, m), 3.20 (2H, d, J = 7.0 Hz), 3.3
5-3.45 (2H, m), 3.56 (2H, t, J = 7.0 Hz), 3.81 (2H,
t, J = 4.4 Hz), 3.95 (2H, t, J = 7.8 Hz), 4.16 (2H, t,
J = 4.4 Hz), 4.32 (2H, s), 6.53 (1H, d, J = 0.8 Hz),
6.92 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.
39-7.50 (6H, m), 7.60 (2H, d, J = 8.8 Hz), 7.77 (2H,
d, J = 8.8 Hz), 8.05 (1H, s).

Example 368 (Production of compound 400) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (7 ml), and thionyl chloride (0.25
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (20 ml), and S- was added under ice cooling.
(4-Aminophenyl) -o-benzylthiocarbonate (0.71 g) and triethylamine (1 ml) were added dropwise to a tetrahydrofuran (10 ml) solution. The mixture was stirred at room temperature for 2 hours, and a 1N sodium hydroxide aqueous solution (15 m
1), methanol (15 ml) and tetrahydrofuran (15 ml) were added, and the mixture was stirred at room temperature for 1 hr. Then 4
-Chloromethyl-3-cibutylimidazole hydrochloride (0.6 g) was added, and the mixture was stirred at room temperature for 2 hours. After concentration,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate / triethylamine), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-butylimidazole). -4-yl) methylthio] phenyl] -2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 400) (1.36 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl ₃ ) 0.85-1.07 (12H, m), 1.22-1.48
(4H, m), 1.54-1.86 (4H, m), 2.00-2.11 (1H, m), 2.
91 (2H, t, J = 4.5 Hz), 3.19 (2H, d, J = 7.2 Hz),
3.36 (2H, t, J = 4.5 Hz), 3.55 (2H, t, J = 6.6 H
z), 3.80 (2H, t, J = 4.9 Hz), 3.92-3.99 (4H, m), 4.
16 (2H, t, J = 4.9 Hz), 6.70 (1H, s), 6.89-7.00 (3
H, m), 7.26-7.56 (10H, m), 7.66 (1H, s) .IR (KBr) n: 2959, 2930, 2868, 1657, 1588, 1499 cm
^-1 .

Example 369 (Preparation of compound 401) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(3-butylimidazole-
4-yl) methylthio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.15g) was dissolved in dichloromethane (40ml) and cooled to -78 ° C. 3-chloroperbenzoic acid (0.
A solution of 62 g) in dichloromethane (10 ml) was added dropwise. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added, the mixture was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline. It was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[(3-butylimidazole). -4-yl) methylsulfinyl] phenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
Carboxamide (Compound 401) (0.72 g) was obtained as a yellow amorphous. ¹ H-NMR (dppm, CDCl3) 0.90-
0.98 (12H, m), 1.24-1.46 (6H, m), 1.56-1.66 (2H,
m), 2.04-2.10 (1H, m), 2.93 (2H, t-like), 3.19 (2
H, d, J = 7.5 Hz), 3.36 (2H, t-like), 3.55 (2H, t,
J = 6.8 Hz), 3.79-3.81 (2H, m), 3.81 (2H, t, J =
5.0 Hz), 3.98-4.11 (2H, m), 4.16 (2H, t, J = 5.0 H
z), 6.56 (1H, s), 6.92 (1H, d, J = 8.4 Hz), 6.98 (2
H, d, J = 8.7 Hz), 7.33-7.48 (8H, m), 7.75 (2H, d,
J = 7.8 Hz), 8.10 (1H, br). IR (KBr) n: 2957, 293
2, 2870, 1661, 1607, 1590, 1518, 1499 cm ^-1 .

Example 370 (Production of compounds 402 and 403) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) was added to CHIRA.
Optical resolution was performed using LPAK AD 50 mm ID × 500 mm L, an elution solvent (hexane / ethanol). Fractions were concentrated to dryness, the residue was dissolved in ethanol and then 0.45
It was filtered with a μm filter. The filtrate was concentrated, hexane was added to dryness, and (+)-7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] ] -3-Trifluoromethylphenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 402) (275 mg,> 99.9% ee),
(-)-7- [4- (2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-isobutyl- 2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 403)
(260 mg, 99.6% ee) was obtained. Compound 402 [α] _D = + 13.66 ° (c = 0.3
0%, ethanol solution) Compound 403 [α] _D = -13.78 ° (c = 0.2)
6%, ethanol solution)

Example 371 (Production of compound 177) (S)-(−)-1,1′-bi-2-naphthol (8
Titanium tetraisopropoxide (45.2 μl) and water (55 μl) were added to a toluene (10 ml) solution of 7.5 mg) at room temperature, and the mixture was stirred for 1 hour. 7- [4 in the reaction system
-(2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4-triazol-3-ylmethylthio) phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (1.0 g) and cumene pyridoperoxide (8
0%, 0.31 ml) was added, and the mixture was stirred at room temperature for 20 hours. Cumene hydroperoxide (80%, 0.14m
1) was added, and the mixture was stirred for 10 hours. Aqueous sodium thiosulfate solution was added to the reaction system, stirred for several minutes, and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1:19) to give (−)-7- [4- (2- Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (Compound 1
77) (860.9 mg) was obtained. CHIRALPAK AD (4mmIDx25mmL,
As a result of analysis with hexane: 2-propanol), the optical purity was 96% ee. Elemental analysis C ₃₈ H ₄₇ N ₅ O ₄ S0.5H ₂ O Calcd. C, 67.23; H,
7.13; N, 10.32: Found. C, 67.52; H, 7.04; N, 1
0.23.

Example 372 (Production of compound 404) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added with S at 0 ° C.
-(4-Aminophenyl) O-benzylthiocarbonate (0.59 g) and triethylamine (2.0 m
l) was added dropwise to a solution of THF (5 ml). After stirring at room temperature for 20 hours, the reaction system was added with a 1N sodium hydroxide aqueous solution (15
ml) and methanol (50 ml) were added and stirred for 0.5 hours. 3- (chloromethyl) -5,6,6 in the reaction system
7,8-Tetrahydroimidazo [1,2-a] pyridine hydrochloride (0.48 g) was added, and the mixture was further stirred for 2 hours.
After distilling off methanol under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 3: 1).
→ 4: 1 → ethanol: ethyl acetate 1: 4) for separation and purification, and 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-] as a yellow amorphous substance.
[[(5,6,7,8-Tetrahydroimidazo [1,2
-A] pyridin-3-yl) methyl] thio] phenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
Carboxamide (Compound 404) (529.0 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.28-1.46 (2H, m), 1.51-1.73
(2H, m), 1.80-2.16 (5H, m), 2.80-2.91 (4H, m), 3.19
(2H, d, J = 7.2 Hz), 3.29-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.9 Hz), 3.90 (2H, t,
J = 5.8 Hz), 3.95 (2H, s), 4.16 (2H, t, J = 4.9 Hz),
6.66 (1H, s), 6.91 (1H, d, J = 8.4 Hz), 6.98 (2H, d,
J = 8.8 Hz), 7.26-7.48 (7H, m), 7.55 (2H, d, J = 8.8
Hz), 7.81 (1H, s). IR (KBr) 3031, 1651, 1607, 1588, 1520, 1497, 1312,
1242, 1181, 1125, 816cm ^-1 Elemental analysis C ₄₁ H ₅₀ N ₄ O ₃ 0.5H ₂ O Calcd. C, 71.58; H, 7.
47; N, 8.14: Found.C, 71.71; H, 7.52; N, 8.20.

Example 373 (Production of compound 405) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) methyl] thio] phenyl] -2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (460 mg)
In dichloromethane (10 ml) at −78 ° C.
Chloroperbenzoic acid (70%, 0.25 g) in dichloromethane (10 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 9: 1 → ethyl acetate), and recrystallized (ethyl acetate-diisopropyl ether) to give 7-yellow crystals. [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4-[[(5,6,7,8-Tetrahydroimidazo [1,2-a] pyridin-3-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (compound 405) (3
11.3 mg) was obtained. mp 184-186 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.47 (2H, m), 1.53-1.67
(2H, m), 1.72-1.94 (4H, m), 1.97-2.18 (1H, m), 2.74
-2.84 (2H, m), 2.89-2.98 (2H, m), 3.19 (2H, d, J =
7.2 Hz), 3.30-3.41 (2H, m), 3.56 (2H, t, J = 6.6 H
z), 3.61-3.70 (2H, m), 3.81 (2H, t, J = 4.8 Hz), 3.9
2 (1H, d, J = 14.3 Hz), 4.02 (1H, d, J = 14.3 Hz), 4.1
6 (2H, t, J = 4.8 Hz), 6.57 (1H, s), 6.92 (1H, d, J =
9.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.35-7.47 (7H, m),
7.78 (2H, d, J = 8.8 Hz), 8.25 (1H, s). IR (KBr) 3075, 1655, 1605, 1588, 1520, 1499, 1312,
1244, 1179, 1127, 822cm ^-1 Elemental analysis C ₄₁ H ₅₀ N ₄ O ₄ 0.5H ₂ O Calcd. C, 69.96; H, 7.
30; N, 7.96: Found.C, 69.84; H, 7.43; N, 7.82.

Example 374 (Production of compound 406) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added at 0 ° C. for 4 hours.
-[[(5-methylimidazo [1,2-a] pyridine-
3-Yyl) methyl] thio] aniline (0.74 g) was added dropwise to a pyridine (7.0 ml) solution. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 →
2: 1) was separated and purified to give 7- as a yellow amorphous substance.
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(5-methylimidazo [1,2
-A] pyridin-3-yl) methyl] thio] phenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
A carboxamide (Compound 406) (1.41 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.47 (2H, m), 1.51-1.69
(2H, m), 1.97-2.17 (1H, m), 2.85-2.95 (2H, m), 3.02
(3H, s), 3.18 (2H, d, J = 7.4 Hz), 3.33-3.38 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 4.48 (2H, s), 6.55 (1
H, d, J = 7.0 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.97 (2H,
d, J = 8.8 Hz), 7.07 (1H, dd, J = 8.8, 7.0 Hz), 7.14
(1H, s), 7.21 (2H, d, J = 8.4 Hz), 7.37-7.56 (8H,
m), 7.79 (1H, s) .IR (KBr) 3031, 1653, 1607, 1586, 1497, 1312, 1289,
1242, 1179, 1123, 816cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₃ S0.5H ₂ O Calcd. C, 72.28; H,
7.08; N, 8.03: Found.C, 72.43; H, 7.03; N, 8.0
1.

Example 375 (Production of compound 407) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(5-methylimidazo [1,2-a] pyridin-3-yl) methyl] thio] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide ( 1.157 g) in dichloromethane (10 ml) at −78 ° C. 3-chloroperbenzoic acid (70%, 0.50 g) in dichloromethane (10 m).
l) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 3: 1 → ethyl acetate),
7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4- as yellow amorphous substance
[[(5-Methylimidazo [1,2-a] pyridine-3
-Yl) methyl] sulfinyl] phenyl] -2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 407) (1.05 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.32-1.46 (2H, m), 1.52-1.66
(2H, m), 1.99-2.14 (1H, m), 2.88-2.97 (5H, m), 3.20
(2H, d, J = 7.5 Hz), 3.36-3.39 (2H, m), 3.56 (2H,
t, J = 6.8 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.56 (1H, d, J = 14.9 Hz), 4.63 (1H, d, J
= 14.9 Hz), 6.58 (1H, d, J = 6.9 Hz), 6.91-7.00 (4H,
m), 7.09-7.15 (1H, m), 7.28-7.31 (2H, m), 7.40-7.5
0 (6H, m), 7.74 (2H, d, J = 8.4Hz), 7.89 (1H, s) .IR (KBr) 3031, 1661, 1607, 1588, 1520, 1499, 1312,
1242, 1177, 835 cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₄ S0.5H ₂ O Calcd. C, 70.66; H,
6.92; N, 7.85: Found.C, 70.39; H, 7.08; N, 7.8
Five.

Example 376 (Production of compound 408) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (20 ml) was added at 0 ° C. for 4 hours.
-[[(6-methylimidazo [1,2-a] pyridine-
3-Yyl) methyl] thio] aniline (0.68 g) was added dropwise to a pyridine (7.0 ml) solution. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography using basic silica gel (ethyl acetate: hexane 1: 1).
→ Separation and purification in 2: 1) to give a yellow amorphous substance 7-
[4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(6-methylimidazo [1,2
-A] pyridin-3-yl) methyl] thio] phenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
A carboxamide (Compound 408) (1.29 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.31-1.50 (2H, m), 1.52-1.71
(2H, m), 1.95-2.16 (1H, m), 2.39 (3H, s), 2.85-2.9
4 (2H, m), 3.19 (2H, d, J = 7.2 Hz), 3.31-3.40 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 4.30 (2H, s), 6.91 (1
H, d, J = 9.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.07 (1H,
dd, J = 9.4, 1.6 Hz), 7.17-7.24 (3H, m), 7.36-7.54
(8H, m), 7.61 (1H, s), 7.88 (1H, br s) .IR (KBr) 3031, 1653, 1607, 1588, 1499, 1312, 1242,
1181, 1125, 816 cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₃ S0.5H ₂ O Calcd. C, 72.28; H,
7.08; N, 8.03: Found.C, 72.40; H, 7.08; N, 8.1
0.

Example 377 (Production of compound 409) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(6-methylimidazo [1,
2-a] pyridin-3-yl) methylthio] phenyl]
-2,3-Dihydro-1H-1-benzazepine-4-
Carboxamide (1.13 g) in dichloromethane (10
ml) solution at 3-78 ° C with 3-chloroperbenzoic acid (70
%, 0.49 g) of dichloromethane (10 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 2: 1 → ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance. -1-Isobutyl-N- [4-[[(6-methylimidazo [1,2-a] pyridin-3-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (compound 40
9) (926 mg) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.34-1.46 (2H, m), 1.57-1.66
(2H, m), 1.99-2.15 (1H, m), 2.29 (3H, s), 2.86-2.9
5 (2H, m), 3.19 (2H, d, J = 6.9 Hz), 3.35-3.38 (2H,
m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 H
z), 4.16 (2H, t, J = 5.0 Hz), 4.29 (1H, d, J = 14.1 H
z), 4.42 (1H, d, J = 14.1 Hz), 6.92 (1H, d, J = 8.7 H
z), 6.98 (2H, d, J = 8.7 Hz), 7.02 (1H, dd, J = 9.3, 1.
8 Hz), 7.13 (1H, s), 7.32 (2H, d, J = 8.4 Hz), 7.39-
7.48 (6H, m), 7.70 (2H, d, J = 8.7 Hz), 7.79-7.80 (1
H, m), 7.98 (1H, s). IR (KBr) 3032, 1655, 1607, 1588, 1499, 1314, 1242,
1179, 1121, 1040, 833cm ^-1 Elemental analysis C ₄₂ H ₄₈ N ₄ O ₄ S0.5H ₂ O Calcd. C, 70.66; H,
6.92; N, 7.84: Found.C, 70.38; H, 6.90; N, 7.7
3.

Example 378 (Production of Compound 410) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (25 ml) was added to [2-((4-aminophenylthio) methyl) -1H- at 0 ° C.
A solution of imidazol-1-yl] ethyl acetate (820 mg) in pyridine (5.0 ml) was added dropwise. After stirring at room temperature for 18 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 →
Separation and purification in 3: 2), and [2-
[[[4-[[[7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-2,3-dihydro-1H
-1-Benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazole-
1-yl] ethyl acetate (Compound 410) (390 mg)
Got ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
97 (6H, d, J = 6.9 Hz), 1.29 (3H, t, J = 7.2 Hz), 1.32-
1.45 (2H, m), 1.53-1.66 (2H, m), 1.99-2.13 (1H, m),
2.86-2.94 (2H, m), 3.18 (2H, d, J = 7.2 Hz), 3.34-
3.37 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t,
J = 5.0 Hz), 4.13 (2H, s), 4.16 (2H, t, J = 5.0 Hz),
4.24 (2H, q, J = 7.2 Hz), 4.74 (2H, s), 6.87-7.00 (5
H, m), 7.31 (2H, d, J = 8.7 Hz), 7.38-7.53 (7H, m),
7.63 (1H, s). IR (KBr) 3038, 1751, 1653, 1607, 1586, 1310, 1289,
1242, 1181, 1123, 816cm ^-1

Example 379 (Production of Compound 411) [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1 -Benzazepin-4-yl] carbonyl]
Amino] phenyl] thio] methyl] -1H-imidazol-1-yl] ethyl acetate (350 mg) in dichloromethane (10 ml) was added to a solution of 3-chloroperbenzoic acid (70%, 146 mg) in dichloromethane (10 m) at -78 ° C.
l) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 → ethyl acetate → ethanol: ethyl acetate 1:19) to give [2-[[[ [4-[[[7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl] carbonyl] amino] phenyl] sulfinyl] methyl] -1H
-Imidazol-1-yl] ethyl acetate (Compound 41
1) (278.7 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0 Hz), 0.
98 (6H, d, J = 6.2 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.30-
1.49 (2H, m), 1.52-1.69 (2H, m), 1.95-2.16 (1H, m),
2.86-2.97 (2H, m), 3.20 (2H, d, J = 6.8 Hz), 3.30-
3.41 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t,
J = 4.9 Hz), 4.09-4.28 (6H, m), 4.71 (1H, d, J = 17.9
Hz), 4.90 (1H, d, J = 17.9 Hz), 6.90-7.00 (5H, m),
7.40-7.48 (7H, m), 7.74 (2H, d, J = 8.8 Hz), 7.86 (1
H, s). IR (KBr) 3032, 1752, 1659, 1607, 1590, 1518, 1499,
1397, 1312, 1242, 1179, 1103, 1030, 835, 818 cm ^-1 Elemental analysis C ₄₁ H ₅₀ N ₄ O ₆ S0.5H ₂ O Calcd. C, 66.91; H,
6.99; N, 7.61: Found.C, 66.63; H, 6.96; N, 7.4
Four.

Example 380 (Production of compound 412) [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1. -Benzazepin-4-yl] carbonyl]
To a solution of amino] phenyl] sulfinyl] methyl] -1H-imidazol-1-yl] ethyl acetate (85 mg) in ethanol (5 ml) was added 1N aqueous sodium hydroxide solution (0.14 ml) at room temperature. After stirring at room temperature for 1 hour, 1N hydrochloric acid (0.14 ml) was added, and the mixture was concentrated under reduced pressure. 2-Propanol was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with 2-propanol and diisopropyl ether to give [2-
[[[4-[[[7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-2,3-dihydro-1H
-1-Benzazepin-4-yl] carbonyl] amino] phenyl] sulfinyl] methyl] -1H-imidazol-1-yl] acetic acid (Compound 412) (65.7m
g) was obtained. mp 146-148 ℃ ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.89 (3H, t, J = 7.4 Hz),
0.93 (6H, d, J = 6.6 Hz), 1.28-1.38 (2H, m), 1.42-1.
56 (2H, m), 1.91-2.19 (1H, m), 2.78-2.89 (2H, m),
3.16-3.36 (4H, m), 3.46 (2H, t, J = 6.4 Hz), 3.66-3.
74 (2H, m), 4.09-4.13 (2H, m), 4.30 (2H, s), 4.84
(2H, s), 6.83 (1H, d, J = 1.1 Hz), 6.95-7.02 (3H,
m), 7.15 (1H, d, J = 1.1 Hz), 7.44-7.65 (7H, m), 7.8
7 (2H, d, J = 8.8 Hz), 10.09 (1H, s). IR (KBr) 3436, 3040, 1630, 1609, 1518, 1499, 1244,
1179, 1125, 1088, 1047, 835, 812 cm ^-1

Example 381 (Production of compound 413) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2.0 g) in THF (10 m
l) Thionyl chloride (0.50 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1.5 hours.
After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added to 4-
[2-[[(4-aminophenyl) thio] methyl] -1
H-imidazol-1-yl] ethyl butyrate (1.61
A solution of g) in pyridine (5.0 ml) was added dropwise at 0 ° C.
After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate) to give 4- [2-] as yellow crystals.
[[[4-[[[7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-2,3-dihydro-1H
-1-Benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazole-
1-yl] ethyl butyrate (compound 413) (3.20 g)
Got mp 103-104 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, t, J = 6.6 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.31-
1.47 (2H, m), 1.50-1.67 (2H, m), 1.92-2.14 (3H, m),
2.32 (2H, t, J = 7.0 Hz), 2.84-2.95 (2H, m), 3.19
(2H, d, J = 6.8 Hz), 3.30-3.39 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 3.96 (2H, t, J
= 5.0 Hz), 4.09-4.20 (6H, m), 6.85-6.94 (3H, m), 6.
98 (2H, d, J = 8.8 Hz), 7.33-7.55 (9H, m), 7.59-7.77
(1H, m). IR (KBr) 3104, 1728, 1655, 1609, 1590, 1522, 1499,
1314, 1246, 1186, 1117, 812 cm ^-1 Elemental analysis C ₄₃ H ₅₄ N ₄ O ₅ S Calcd. C, 69.89; H, 7.37;
N, 7.58: Found. C, 69.72; H, 7.27; N, 7.56.

Example 382 (Production of Compound 414) 4- [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H A solution of ethyl 1-benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazol-1-yl] butyrate (1.0 g) in dichloromethane (10 ml) was added to 3-chloro at -78 ° C. Perbenzoic acid (70%, 0.50 g) in dichloromethane (10
ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate) to give 4- [2-] as yellow crystals.
[[[4-[[[7- [4- (2-butoxyethoxy)
Phenyl] -1-isobutyl-2,3-dihydro-1H
Ethyl-1--1-benzazepin-4-yl] carbonyl] amino] phenyl] sulfinyl] methyl] -1H-imidazol-1-yl] butyrate (Compound 414) (91
1 mg) was obtained. mp 134-136 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-1.00 (9H, m), 1.25 (3
H, t, J = 7.2 Hz), 1.31-1.45 (2H, m), 1.51-1.64 (2H,
m), 1.85-2.13 (3H, m), 2.27 (2H, t, J = 7.0 Hz), 2.
87-2.96 (2H, m), 3.20 (2H, d, J = 7.6 Hz), 3.31-3.40
(2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.93 (4H,
m), 4.08-4.18 (5H, m), 4.28 (1H, d, J = 13.6 Hz), 6.
89-7.02 (5H, m), 7.39-7.49 (7H, m), 7.74 (2H, d, J
= 8.8 Hz), 7.84 (1H, s) .IR (KBr) 3102, 1725, 1655, 1609, 1590, 1315, 1246,
1184, 1167, 1117, 1049, 837, 810 cm ^-1 Elemental analysis C ₄₃ H ₅₄ N ₄ O ₆ S Calcd. C, 68.41; H, 7.21;
N, 7.42: Found. C, 68.30; H, 7.20; N, 7.31.

Example 383 (Production of Compound 415) 4- [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H -1-Benzazepin-4-yl] carbonyl] amino] phenyl] sulfinyl] methyl] -1H
To a solution of ethyl-imidazol-1-yl] butyrate (0.5 g) in ethanol-THF (5-1 ml) was added 1N at room temperature.
Aqueous sodium hydroxide solution (1.2 ml) was added and the mixture was stirred for 24 hours. 1N Hydrochloric acid (1.2 ml) was added to the reaction system, and the mixture was concentrated under reduced pressure. A solution of the residue in DMF (10 ml) was added with 1-ethyl-3- (3'-dimethylaminopropyl) at room temperature.
Carbodiimide hydrochloride (0.20 g) and 1-hydroxybenzotriazole ammonium salt (0.16 g)
g) and triethylamine (0.38 ml) were added,
It was stirred for 64 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19), and further recrystallized (ethyl acetate-diisopropyl ether) to give N- [4- [ [[1- (4-Amino-4-oxobutyl) -1H-imidazol-2-yl] methyl]
Thio] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 415) (366.7 mg) was obtained. mp 142-143 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.31-1.47 (2H, m), 1.51-1.69
(2H, m), 1.96-2.18 (5H, m), 2.84-2.93 (2H, m), 3.18
(2H, d, J = 6.8 Hz), 3.30-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.78-3.89 (4H, m), 4.13-4.18 (4H,
m), 5.22-5.36 (1H, m), 5.54-5.72 (1H, m), 6.84-7.0
0 (5H, m), 7.34-7.52 (9H, m), 7.71-7.79 (1H, m). IR (KBr) 3278, 3083, 3036, 1663, 1607, 1588, 1518,
1499, 1244, 1181, 1115, 831 cm ^-1 Elemental analysis C ₄₁ H ₅₁ N ₅ O ₄ S Calcd. C, 69.36; H, 7.24;
N, 9.86: Found. C, 69.03; H, 7.43; N, 9.70.

Example 384 (Preparation of compound 416) N- [4-[[[1- (4-amino-4-oxobutyl) -1H-imidazol-2-yl] methyl] thio]
Phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (350 mg)
In dichloromethane (30 ml) at −78 ° C.
A solution of chloroperbenzoic acid (70%, 0.18 g) in dichloromethane (10 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure,
Column chromatography of the residue (basic silica gel,
Separated and purified with ethanol: ethyl acetate 1: 19 → 1: 9) to obtain N- [4-[[[1- (4
-Amino-4-oxobutyl) -1H-imidazole-
2-yl] methyl] sulfinyl] phenyl] -7-
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 416) (259.9 m
g) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.33-1.45 (2H, m), 1.49-1.65
(2H, m), 1.98-2.20 (5H, m), 2.88-2.96 (2H, m), 3.20
(2H, d, J = 7.5 Hz), 3.34-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.79-3.86 (4H, m), 4.09-4.17 (3H,
m), 4.27 (1H, d, J = 13.8 Hz), 5.26-5.34 (1H, m), 5.9
9-6.18 (1H, m), 6.91 (1H, d, J = 1.5 Hz), 6.94-7.00
(3H, m), 7.06 (1H, d, J = 1.5 Hz), 7.40-7.51 (7H,
m), 7.73 (2H, d, J = 8.7 Hz), 7.85 (1H, s) .IR (KBr) 3314, 3094, 3032, 1663, 1607, 1590, 1518,
1499, 1316, 1244, 1182, 1113, 831, 816 cm ^-1 Elemental analysis C ₄₁ H ₅₁ N ₅ O ₅ S0.5H ₂ O Calcd. C, 67.00; H,
7.13; N, 9.53: Found.C, 67.05; H, 7.30; N, 9.5
1.

Example 385 (Compound 417, Compound 41)
Preparation of 8) N- [4-[[[1- (4-amino-4-oxobutyl) -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -7- [4- (2-butoxyethoxy) Phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (Compound 416) (169 mg) was added to CHIRALPAK AD.
Optical resolution (eluting solvent, hexane: ethanol 50:50) was performed using (50 mmID × 500 mmL). Fractions were concentrated to dryness, the residue was dissolved in ethanol and then 0.45μ
It filtered with the filter of m. The filtrate was concentrated and (+)-N- [4-[[[1- (4-amino-4-oxobutyl) -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -7 as the previous fraction. -[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepine-4-carboxamide (Compound 417) (84 mg, 99.8% ee),
(-)-N- [4-[[[1- (4-Amino-4-oxobutyl) -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -7- [4-] as the latter fraction.
(2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-
Carboxamide (Compound 418) (82 mg, 99.2)
% Ee) was obtained. Compound 417 [α] _D = + 96.61 ° (c = 0.49)
8%, chloroform solution) Compound 418 [α] _D = −96.67 ° (c = 0.48)
7%, chloroform solution)

Example 386 (Production of compound 419) (±) -BINOL (40 mg) in toluene (5 ml)
Titanium tetraisopropoxide (21 μm
1) and water (25.6 μl) were added, and the mixture was stirred for 1 hour. N- [4-[[[1- (4-amino-4-
Oxobutyl) -1H-imidazol-2-yl] methyl] thio] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4- Carboxamide (1
00 mg) and cumene hydroperoxide (80
%, 0.1 ml) was added, and the mixture was stirred at room temperature for 4 days. Cumene hydroperoxide (80%, 0.05 ml) was added, and after stirring for 6 days, an aqueous sodium thiosulfate solution was added. After extraction with ethyl acetate, the extract was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure,
Column chromatography of the residue (basic silica gel,
Separated and purified with ethanol: ethyl acetate 1:19) to obtain N- [4-[[[1- (4-amino-4-oxobutyl) -1H-imidazol-2-yl] methyl] sulfonyl as a yellow amorphous substance. ] Phenyl] -7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 419) (49.9 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 1.
00 (6H, d, J = 6.6 Hz), 1.30-1.44 (2H, m), 1.47-1.65
(2H, m), 1.95-2.27 (5H, m), 2.87-2.98 (2H, m), 3.21
(2H, d, J = 7.8 Hz), 3.31-3.42 (2H, m), 3.56 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.6 Hz), 3.98 (2H, t,
J = 7.0 Hz), 4.16 (2H, t, J = 4.6 Hz), 4.44 (2H, s),
5.26-5.43 (1H, m), 5.48-5.67 (1H, m), 6.90-6.99 (4
H, m), 7.21-7.46 (6H, m), 7.60 (2H, d, J = 9.2 Hz),
7.76 (2H, d, J = 9.2 Hz), 8.35 (1H, s). IR (KBr) 3332, 3177, 3036, 1667, 1607, 1588, 1518,
1499, 1400, 1321, 1242, 1142, 1088, 837, 816 cm ^-1 Elemental analysis C ₄₁ H ₅₁ N ₅ O ₆ S0.5H ₂ O Calcd. C, 65.58; H,
6.98; N, 9.33: Found.C, 65.33; H, 6.99; N, 9.0
9.

Example 387 (Production of compound 420) 4- [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H Ethanol-THF (10-2 ml) solution of ethyl 1-benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazol-1-yl] butyrate (1.0 g) at room temperature in 1N. Aqueous sodium hydroxide solution (2.4 ml) was added and the mixture was stirred for 20 hours. 1N Hydrochloric acid (2.4 ml) was added to the reaction system, and the mixture was concentrated under reduced pressure. To a solution of the residue in DMF (10 ml) at room temperature, 1-
Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g) and 1-hydroxybenzotriazole monohydrate (0.31 g), dimethylamine hydrochloride (0.22 g) and triethylamine (0 0.57 ml) was added and the mixture was stirred for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-[[[ [1- [4- (dimethylamino)
-4-oxobutyl] -1H-imidazol-2-yl] methyl] thio] phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 420) (830.7 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.25-1.47 (2H, m), 1.52-1.69
(2H, m), 1.98-2.18 (3H, m), 2.24-2.30 (2H, m), 2.88
-2.95 (8H, m), 3.18 (2H, d, J = 6.8 Hz), 3.30-3.40
(2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.
0 Hz), 3.98 (2H, t, J = 6.9 Hz), 4.13-4.18 (4H, m),
6.86-7.00 (5H, m), 7.33-7.55 (9H, m), 7.71 (1H,
s) .IR (KBr) 3029, 1651, 107, 1588, 1497, 1397, 1312,
1287, 1242, 1181, 1125, 818 cm ^-1 Elemental analysis C ₄₃ H ₅₅ N ₅ O ₄ S0.5H ₂ O Calcd. C, 69.13; H,
7.56; N, 7.38: Found.C, 69.30; H, 7.50; N, 9.6
2.

Example 388 (Production of compound 421) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- [4- (Dimethylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl]
Thio] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (4
To a solution of 00 mg) in dichloromethane (30 ml), -7
A solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) was added dropwise at 8 ° C. After stirring at −78 ° C. for 1 hour, aqueous sodium thiosulfate solution was added at room temperature.
Stir for 10 minutes. The mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1: 4).
9) was separated and purified to give 7- [4- as a yellow amorphous substance.
(2-Butoxyethoxy) phenyl] -N- [4-
[[[1- [4- (Dimethylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4 -Carboxamide (Compound 421) (377 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.0 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.28-1.48 (2H, m), 1.52-1.72
(2H, m), 1.87-2.14 (3H, m), 2.23 (2H, t, J = 6.8 H
z), 2.86-2.99 (8H, m), 3.20 (2H, d, J = 7.2 Hz), 3.3
2-3.41 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.74-3.92
(4H, m), 4.08-4.18 (3H, m), 4.33 (1H, d, J = 13.6 H
z), 6.89-7.03 (5H, m), 7.36-7.52 (7H, m), 7.74 (2
H, d, J = 8.8 Hz), 7.90 (1H, s) .IR (KBr) 3031, 1645, 1607, 1588, 1518, 1499, 1397,
1314, 1242, 1179, 1123, 1047, 835 cm ^-1 Elemental analysis C ₄₃ H ₅₅ N ₅ O ₅ S0.5H ₂ O Calcd. C, 67.69; H,
7.40; N, 9.18: Found.C, 67.41; H, 7.51; N, 9.0
3.

Example 389 (Production of compound 422) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- [4- (Dimethylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl]
Thio] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (3
00 mg), methanol (66 μl) and water (14.
Titanium tetraisopropoxide (0.12 ml) was added to a toluene (10 ml) solution of 6 μl) at room temperature, and
Stir for 5 hours. Cumene hydroperoxide (80%, 0.22 ml) was added to the reaction system at -10 ° C, and -10 ° C.
After stirring for 4 days, an aqueous solution of sodium thiosulfate was added. After extraction with ethyl acetate, the extract was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19) to give 7- [4- (2-butoxyethoxy) as a yellow amorphous substance.
Phenyl] -N- [4-[[[1- [4- (dimethylamino) -4-oxobutyl] -1H-imidazole-2
-Yl] methyl] sulfonyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-
4-Carboxamide (Compound 422) (286 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 1.
00 (6H, d, J = 6.6 Hz), 1.28-1.48 (2H, m), 1.53-1.75
(2H, m), 1.94-2.16 (3H, m), 2.29 (2H, t, J = 6.6 H
z), 2.86-3.00 (8H, m), 3.20 (2H, d, J = 7.4 Hz), 3.3
0-3.39 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 5.0 Hz), 4.00 (2H, t, J = 7.5 Hz), 4.15 (2H, t,
J = 5.0 Hz), 4.45 (2H, s), 6.89-6.98 (5H, m), 7.26-
7.50 (5H, m), 7.59 (2H, d, J = 9.0 Hz), 7.75 (2H, d,
J = 9.0 Hz), 8.56 (1H, s) .IR (KBr) 3031, 1645, 1607, 1590, 1518, 1499, 1400,
1321, 1244, 1144, 1090, 837, 820 cm ^-1

Example 390 (Production of compound 423) 4- [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H Ethyl 1-benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazol-1-yl] butyrate (1.0 g) in ethanol-THF (10-2 ml) at room temperature, 1N. Aqueous sodium hydroxide solution (2.4 ml) was added and the mixture was stirred for 20 hours. 1N Hydrochloric acid (2.4 ml) was added to the reaction system, and the mixture was concentrated under reduced pressure. To a solution of the residue in DMF (10 ml) at room temperature, 1-
Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g) and 1-hydroxybenzotriazole monohydrate (0.31 g), methylamine hydrochloride (0.18 g) and triethylamine (0 0.57 ml) was added and the mixture was stirred for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1: 1).
9) was separated and purified to give 7- [4- as a yellow amorphous substance.
(2-Butoxyethoxy) phenyl] -N- [4-
[[[1- [4- (Methylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl] thio]
Phenyl] -1-isobutyl-2,3-dihydro-1H
-1-benzazepine-4-carboxamide (compound 4
23) (720 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.37-1.46 (2H, m), 1.50-1.68
(2H, m), 1.92-2.19 (5H, m), 2.78 (3H, d, J = 5.0 H
z), 2.85-2.96 (2H, m), 3.19 (2H, d, J = 7.6 Hz), 3.3
1-3.41 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.89
(4H, m), 4.10-4.18 (4H, m), 5.59-5.76 (1H, s), 6.8
4-7.00 (5H, m), 7.34-7.52 (9H, m), 7.73 (1H, s) .IR (KBr) 3086, 3029, 1657, 1605, 1588, 1497, 1312,
1244, 1181, 1121, 818cm ^-1 Elemental analysis C ₄₂ H ₅₃ N ₅ O ₄ S0.5H ₂ O Calcd. C, 68.82; H,
7.42; N, 9.55: Found.C, 68.81; H, 7.35; N, 9.6
8.

Example 391 (Production of compound 424) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- [4- (Methylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl] thio] phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (40
To a solution of 0 mg) in dichloromethane (10 ml), -78
A solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) was added dropwise at ° C. After stirring at −78 ° C. for 1.5 hours, an aqueous sodium thiosulfate solution was added and the mixture was stirred at room temperature for 10 minutes. Extract with ethyl acetate,
The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19), and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4- (2 -Butoxyethoxy) phenyl] -N- [4-[[[1-
[4- (Methylamino) -4-oxobutyl] -1H-
Imidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (compound 42
4) (342.8 mg) was obtained. mp 159-161 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 6.9 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.28-1.47 (2H, m), 1.53-1.68
(2H, m), 1.88-2.16 (5H, m), 2.76 (3H, d, J = 4.8 H
z), 2.87-2.96 (2H, m), 3.20 (2H, d, J = 7.8 Hz), 3.3
2-3.42 (2H, m), 3.55 (2H, t, J = 6.8 Hz), 3.72-3.85
(4H, m), 4.10 (1H, d, J = 14.0 Hz), 4.18 (2H, t, J = 5.
1 Hz), 4.25 (1H, d, J = 14.0 Hz), 6.03-6.14 (1H, m),
6.89-7.05 (5H, m), 7.39-7.51 (7H, m), 7.74 (2H, d,
J = 8.8 Hz), 8.03 (1H, s) .IR (KBr) 3293, 3044, 1657, 1605, 1590, 1499, 1399,
1314, 1244, 1179, 1111, 1049, 835 cm ^-1 Elemental analysis C ₄₂ H ₅₃ N ₅ O ₅ S Calcd. C, 68.17; H, 7.22;
N, 9.46: Found. C, 67.84; H, 7.09; N, 9.65.

Example 392 (Production of compound 425) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- [4- (Methylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl] thio] phenyl] -1-isobutyl-2,3-dihydro-
1H-1-benzazepine-4-carboxamide (21
0 mg), methanol (24 μl) and water (5.3 μm)
Titanium tetraisopropoxide (43 μl) was added to a toluene (10 ml) solution of 1) at room temperature, and the mixture was stirred for 0.5 hours. Cumene hydroperoxide (80%,
0.21 ml) was added at -10 ° C, and the mixture was stirred at -10 ° C for 2 days, and an aqueous sodium thiosulfate solution was added to the reaction system. After extraction with ethyl acetate, the extract was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1:19), and further recrystallized (ethyl acetate-diisopropyl ether) to give 7- [4 -(2-butoxyethoxy) phenyl] -N- [4-[[[1- [4
-(Methylamino) -4-oxobutyl] -1H-imidazol-2-yl] methyl] sulfonyl] phenyl]
-1-Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 425) (1
61 mg) was obtained. mp 163-165 ℃ ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 1.
01 (6H, d, J = 6.6 Hz), 1.34-1.46 (2H, m), 1.52-1.66
(2H, m), 1.98-2.15 (5H, m), 2.79 (3H, d, J = 4.8 H
z), 2.91-3.00 (2H, m), 3.21 (2H, d, J = 7.2 Hz), 3.3
5-3.38 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 4.9 Hz), 3.94 (2H, t, J = 6.8 Hz), 4.16 (2H, t,
J = 4.9 Hz), 4.38 (2H, s), 5.52-5.64 (1H, m), 6.90-
6.98 (5H, m), 7.22-7.29 (2H, m), 7.39-7.42 (3H,
m), 7.58 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.0 H
z), 8.61 (1H, br s) .IR (KBr) 3345, 3085, 1647, 1607, 1588, 1522, 1501,
1319, 1300, 1250, 1182, 1169, 1140 cm ^-1 Elemental analysis C ₄₂ H ₅₃ N ₅ O ₆ S Calcd. C, 66.73; H, 7.07;
N, 9.26: Found. C, 66.72; H, 6.92; N, 9.23.

Example 393 (Production of compound 426) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.5 g) in THF (10 m
l) Thionyl chloride (0.38 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1.5 hours.
After concentration under reduced pressure, a solution of the residue in THF (30 ml) was added to [5
-[[(4-aminophenyl) thio] methyl] -1H-
A solution of ethyl imidazol-1-yl] ethyl acetate (1.10 g) in pyridine (10.0 ml) was added dropwise at 0 ° C. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 → ethyl acetate) to give [5-[[[[4-[[[7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl] carbonyl] amino] phenyl] thio] methyl] -1H-imidazol-1-yl ] Ethyl acetate (compound 426)
(1.18 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.32-
1.46 (2H, m), 1.52-1.71 (2H, m), 1.91-2.18 (1H, m),
2.84-2.95 (2H, m), 3.18 (2H, d, J = 7.4 Hz), 3.18-
3.38 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H, t,
J = 4.8 Hz), 3.96 (2H, s), 4.16 (2H, t, J = 4.8 Hz),
4.25 (2H, q, J = 7.2 Hz), 4.79 (2H, s), 6.70 (1H,
s), 6.94 (1H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 H
z), 7.24 (2H, d, J = 8.6 Hz), 7.37-7.55 (8H, m), 7.6
9 (1H, s). IR (KBr) 3038, 1751, 1659, 1608, 1588, 1499, 1310,
1285, 1240, 1182, 1113, 818 cm ^-1 Elemental analysis C ₄₁ H ₅₀ N ₄ O ₅ S0.5H ₂ O Calcd. C, 68.40; H,
7.14; N, 7.78: Found.C, 68.63; H, 6.85; N, 7.7
6.

Example 394 (Production of compound 427) [5-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1. -Benzazepin-4-yl] carbonyl]
Amino] phenyl] thio] methyl] -1H-imidazol-1-yl] ethyl acetate (200 mg) in dichloromethane (10 ml) was added to a solution of 3-chloroperbenzoic acid (70%, 0.11 g) in dichloromethane at -78 ° C. (10m
l) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 4: 1 → 9: 1) to give [5-[[[[4-[[[7 -[4-
(2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-
Ill] carbonyl] amino] phenyl] sulfinyl]
Methyl] -1H-imidazol-1-yl] ethyl acetate (Compound 427) (117.6 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29 (3H, t, J = 7.2 Hz), 1.33-
1.48 (2H, m), 1.54-1.66 (2H, m), 1.92-2.20 (1H, m),
2.84-2.95 (2H, m), 3.18 (2H, d, J = 7.0 Hz), 3.29-
3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.78-3.89 (3
H, m), 4.13-4.28 (5H, m), 4.73 (1H, d, J = 17.8 Hz),
4.87 (1H, d, J = 17.8 Hz), 6.47 (1H, s), 6.91 (1H,
d, J = 8.8Hz), 6.97 (2H, d, J = 8.8 Hz), 7.27-7.50 (8
H, m), 7.75 (2H, d, J = 8.8 Hz), 8.14 (1H, s) .IR (KBr) 3032, 1750, 1663, 1607, 1588, 1518, 1499,
1397, 1312, 1244, 1179, 1121, 1030, 818 cm ^-1 Elemental analysis C ₄₁ H ₅₀ N ₄ O ₆ S0.5H ₂ O Calcd. C, 66.91; H,
6.98; N, 7.61: Found.C, 66.81; H, 7.08; N, 7.3
1.

Example 395 (Preparation of compound 428) [5-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1. -Benzazepin-4-yl] carbonyl]
To a solution of amino] phenyl] thio] methyl] -1H-imidazol-1-yl] ethyl acetate (0.98g) in ethanol (10ml) was added 1N aqueous sodium hydroxide solution (1.65ml) at room temperature. After stirring at room temperature for 0.5 hour, 1N hydrochloric acid (1.65 ml) was added, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol to give [5-[[[4-[[[7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepin-4-yl]
Carbonyl] amino] phenyl] thio] methyl] -1H
-Imidazol-1-yl] acetic acid (Compound 428) (7
78.9 mg) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (3H, t, J = 7.4 Hz),
0.92 (6H, d, J = 6.6 Hz), 1.21-1.39 (2H, m), 1.42-1.
58 (2H, m), 1.88-2.11 (1H, m), 2.78-2.88 (2H, m),
3.16-3.51 (6H, m), 3.68-3.73 (2H, m), 4.05-4.15 (4
H, m), 4.88 (2H, s), 6.61 (1H, s), 6.94-7.02 (3H,
m), 7.27 (2H, d, J = 8.8 Hz), 7.38-7.68 (8H, m), 9.88
(1H, s). IR (KBr) 3312, 3121, 3047, 1607, 1591, 1499, 1381,
1310, 1289, 1242, 1181, 1123, 818 cm ^-1 Elemental analysis C ₃₉ H ₄₆ N ₄ O ₅ S2.0H ₂ O Calcd. C, 65.16; H,
7.01; N, 7.79: Found.C, 65.16; H, 6.97; N, 7.8
Four.

Example 396 (Production of compound 429) [5-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1. -Benzazepin-4-yl] carbonyl]
Amino] phenyl] thio] methyl] -1H-imidazol-1-yl] acetic acid (734 mg) and 1-hydroxybenzotriazole ammonium salt (0.24 g) in DMF (15 ml) solution at room temperature 1-ethyl-3-
(3′-Dimethylaminopropyl) carbodiimide hydrochloride (0.31 g) and triethylamine (0.3 m
l) was added. After stirring at room temperature for 24 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19), and recrystallized (ethyl acetate-diisopropyl ether) to give N- [4-[[[ [1- (2-amino-
2-oxoethyl) -1H-imidazol-5-yl]
Methyl] thio] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 429) (560 mg) was obtained. . mp 152-154 ℃ ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.35-1.44 (2H, m), 1.48-1.65
(2H, m), 1.98-2.13 (1H, m), 2.85-2.91 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.31-3.40 (2H, m), 3.55 (2H,
t, J = 6.8 Hz), 3.81 (2H, t, J = 4.9 Hz), 3.99 (2H,
s), 4.16 (2H, t, J = 4.9 Hz), 4.67 (2H, s), 5.51 (2
H, br s), 6.82 (1H, s), 6.92 (1H, d, J = 8.7 Hz), 6.
98 (2H, d, J = 8.4 Hz), 7.20-7.30 (4H, m), 7.38-7.53
(6H, m), 7.60 (1H, s). IR (KBr) 3316, 3185, 3036, 1672, 1655, 1609, 1586,
1499, 1397, 1310, 1287, 1242, 1181, 1121, 818 cm
^-1 Elemental analysis C ₃₉ H ₄₇ N ₅ O ₄ S0.5H ₂ O Calcd. C, 67.80; H,
7.00; N, 10.14: Found. C, 67.62; H, 7.00; N, 1
0.28.

Example 397 (Production of compound 430) N- [4-[[[1- (2-amino-2-oxoethyl) -1H-imidazol-5-yl] methyl] thio]
Phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (300 mg)
In dichloromethane-DMF (80-1 ml) solution of
3-chloroperbenzoic acid (70%, 0.142
g) dichloromethane (10 ml) was added dropwise. -78
After stirring at ℃ for 2.5 hours, aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 19 → 1: 9) and further recrystallized (ethyl acetate-hexane) to give N- [4
-[[[1- (2-amino-2-oxoethyl) -1H
-Imidazol-5-yl] methyl] sulfinyl] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (Compound 430)
(264.5 mg) was obtained. mp 123-125 ℃ ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.5 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.33-1.45 (2H, m), 1.56-1.63
(2H, m), 2.00-2.14 (1H, m), 2.87-2.95 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.35-3.38 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.79-3.86 (3H, m), 4.15 (2H, t, J = 4.
8 Hz), 4.24 (1H, d, J = 14.7 Hz), 4.59 (2H, s), 5.59
(1H, br s), 6.52 (1H, s), 6.84 (1H, br s), 6.92 (1
H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.7 Hz), 7.33 (2H,
d, J = 8.9 Hz), 7.40-7.50 (5H, m), 7.59 (1H, s), 7.7
6 (2H, d, J = 8.9 Hz), 8.06 (1H, s). IR (KBr) 3298, 3186, 3032, 1686, 1607, 1588, 1499,
1397, 1312, 1244, 1179, 1121, 1036, 820 cm ^-1 Elemental analysis C ₃₉ H ₄₇ N ₅ O ₅ S1.0H ₂ O Calcd. C, 65.43; H,
6.90; N, 9.78: Found.C, 65.35; H, 6.97; N, 9.7
Five.

Example 398 (Production of compound 431) N- [4-[[[1- (2-amino-2-oxoethyl) -1H-imidazol-5-yl] methyl] thio]
Phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (180m
g), methanol (21.4 μl) and water (4.8 μm)
Titanium tetraisopropoxide (39 μl) was added to a solution of l) in dichloromethane (20 ml) at room temperature to give 0.5
Stir for hours. After cooling to -10 ° C, DMF (1
0 ml) and cumene hydroperoxide (80%,
0.19 ml) was added, and the mixture was stirred at -10 ° C for 24 hours.
In addition, cumene hydroperoxide (80%, 0.1m
1) was added, and the mixture was stirred at -5 ° C for 24 hours and at 0 ° C for 4 days.
Aqueous sodium thiosulfate solution was added to the reaction system. After extraction with ethyl acetate, the extract was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 19 → 1: 9) to give N- [4-[[[1- (2-amino 2-Oxoethyl) -1H-imidazol-5-yl] methyl] sulfonyl] phenyl] -7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine -4-Carboxamide (Compound 431) (130 mg) was obtained. mp 229-231 ℃ ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.5 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.31-1.45 (2H, m), 1.52-1.66
(2H, m), 1.99-2.15 (1H, m), 2.88-2.96 (2H, m), 3.19
(2H, d, J = 7.5 Hz), 3.32-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.81 (2H, t, J = 4.9 Hz), 4.16 (2H, t,
J = 4.9 Hz), 4.35 (2H, s), 4.78 (2H, s), 5.52-5.61
(1H, m), 5.92-6.01 (1H, m), 6.41 (1H, s), 6.93 (1
H, d, J = 8.7 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.40-7.50
(5H, m), 7.51 (1H, s), 7.62 (2H, d, J = 8.7 Hz), 7.
77 (2H, d, J = 8.7 Hz), 8.02 (1H, s). IR (KBr) 3304, 3187, 3036, 1676, 1645, 1609, 1588,
1499, 1399, 1318, 1242, 1150, 1088, 826 cm ^-1 Elemental analysis C ₃₉ H ₄₇ N ₅ O ₆ S Calcd. C, 65.62; H, 6.64;
N, 9.81: Found. C, 65.46; H, 6.73; N, 9.78.

Example 399 (Production of compound 432) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of the residue in THF (35 ml) was added with 2- [2-[[[4-aminophenyl) thio] methyl] -1H-imidazol-1-yl] ethyl benzoate (0.
89 g) was added dropwise to a pyridine (10 ml) solution. After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 → ethyl acetate), and benzoic acid 2- [2-[[[[[[[[[ 7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepin-4-yl]
Carbonyl] amino] thio] methyl] -1H-imidazol-yl] ethyl (Compound 432) (1.32 g) was obtained. mp 85-87 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.32-1.46 (2H, m), 1.50-1.66
(2H, m), 1.93-2.12 (1H, m), 2.84-2.94 (2H, m), 3.19
(2H, d, J = 7.6 Hz), 3.30-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.77-3.83 (2H, m), 4.11-4.18 (2H,
m), 4.21 (2H, s), 4.29-4.34 (2H, m), 4.56-4.61 (2
H, m), 6.90-7.00 (5H, m), 7.26-7.59 (13H, m), 7.97
-8.01 (2H, m). IR (KBr) 3074, 1723, 1645, 1603, 1588, 1522, 1499,
1314, 1269, 1246, 1177, 1115, 710 cm ^-1 Elemental analysis C ₄₆ H ₅₂ N ₄ O ₅ S0.5H ₂ O Calcd. C, 70.65; H,
6.83; N, 7.16: Found.C, 70.51; H, 6.98; N, 6.8
6.

Example 400 (Production of compound 433) Benzoic acid 2- [2-[[[4-[[[7- [4- (2-
Butoxyethoxy) phenyl] -1-isobutyl-2,
3-Dihydro-1H-1-benzazepin-4-yl]
Carbonyl] amino] thio] methyl] -1H-imidazol-yl] ethyl (930 mg) in ethanol-TH
A 1N aqueous sodium hydroxide solution (1.8 ml) was added to the F (10-5 ml) solution at room temperature. After stirring at room temperature for 20 hours, 1N hydrochloric acid (1.8 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate → ethanol: ethyl acetate 1:19).
Separation and purification with a yellow amorphous substance 7- [4- (2
-Butoxyethoxy) phenyl] -N- [4-[[[1
-(2-Hydroxyethyl) -1H-imidazole-2
-Yl] methyl] thio] phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (Compound 433) (712 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.26-1.47 (2H, m), 1.50-1.76
(2H, m), 1.96-2.17 (1H, m), 2.84-2.94 (2H, m), 3.18
(2H, d, J = 7.2 Hz), 3.29-3.38 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.78-3.85 (4H, m), 4.03 (2H, t, J = 5.
1 Hz), 4.13-4.18 (4H, m), 6.89-6.99 (5H, m), 7.26-
7.52 (9H, m), 7.90 (1H, s). IR (KBr) 3034, 1651, 1605, 1586, 1497, 1312, 1284,
1242, 1181, 1115, 1069, 816 cm ^-1 Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S0.5H ₂ O Calcd. C, 69.10; H,
7.24; N, 8.26: Found.C, 69.26; H, 7.20; N, 8.3
0.

Example 401 (Production of compound 434) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[[1- (2-Hydroxyethyl) -1H-imidazol-2-yl] methyl] thio] phenyl] -1
To a solution of -isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.40g) in dichloromethane (10ml) was added 3-chloroperbenzoic acid (70%, 0.22g) at -78 ° C. Dichloromethane (10
ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as a yellow amorphous substance. [4-[[[1- (2-Hydroxyethyl) -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide ( Compound 434) (280.5 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.51-1.66
(2H, m), 1.92-2.18 (1H, m), 2.88-2.98 (2H, m), 3.20
(2H, d, J = 7.0 Hz), 3.31-3.40 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.76-3.88 (4H, m), 3.98-4.07 (2H,
m), 4.13-4.28 (4H, m), 6.90-7.00 (4H, m), 7.08 (1
H, d, J = 1.4 Hz), 7.26-7.53 (7H, m), 7.75 (2H, d, J
= 8.8 Hz), 8.03 (1H, s) .IR (KBr) 3108, 1661, 1607, 1588, 1518, 1499, 1314,
1244, 1181, 1115, 833cm ^-1 Elemental analysis C ₃₉ H ₄₈ N ₄ O ₅ S1.0H ₂ O Calcd. C, 66.64; H,
7.17; N, 7.97: Found.C, 66.92; H, 7.21; N, 7.9
3.

Example 402 (Production of compound 435) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1.5 hours.
After concentration under reduced pressure, a solution of the residue in THF (25 ml) was added at 0 ° C.
Was added dropwise to a solution of 3- [2-[[(4-aminophenyl) thio] methyl] -1H-imidazol-1-yl] propyl acetate (0.89 g) in pyridine (10 ml). After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate), and acetic acid (3) was obtained as a yellow amorphous substance.
-[2-[[[4-[[7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl] carbonyl] amino] Thio] methyl] -1H-imidazol-yl] propyl (Compound 435) (1.347 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.26-1.44 (2H, m), 1.47-1.68
(2H, m), 1.96-2.17 (6H, m), 2.85-2.95 (2H, m), 3.18
(2H, d, J = 7.4 Hz), 3.29-3.39 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 3.96-4.18 (8
H, m), 6.84 (1H, d, J = 1.4 Hz), 6.89-6.94 (2H, m),
6.98 (2H, d, J = 8.8 Hz), 7.31-7.55 (9H, m), 7.73 (1
H, s). IR (KBr) 3034, 1736, 1655, 1607, 1588, 1499, 1395,
1312, 1283, 1242. 1181, 1117, 1047, 909, 818, 735
cm ^-1 Elemental analysis C ₄₂ H ₅₂ N ₄ O ₅ S0.25H ₂ O Calcd. C, 69.16; H,
7.25; N, 7.68: Found. C, 68.99; H, 7.41; N, 7.
57.

Example 403 (Production of Compound 436) Acetate 3- [2-[[[4-[[[7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-2,3-
Dihydro-1H-1-benzazepin-4-yl] carbonyl] amino] thio] methyl] -1H-imidazol-yl] propyl (0.79 g) in ethanol-THF
To the (10-2 ml) solution was added 1N aqueous sodium hydroxide solution (1.5 ml) at room temperature. After stirring for 3 hours at room temperature,
It was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1:19) to give 7-ish as yellow crystals.
[4- (2-butoxyethoxy) phenyl] -N- [4
-[[1- (3-Hydroxypropyl) -1H-imidazol-2-yl] methyl] thio] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 436) (642.4
mg) was obtained. mp 154-156 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.1 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.28-1.49 (2H, m), 1.51-1.68
(2H, m), 1.83-2.12 (3H, m), 2.85-2.95 (2H, m), 3.18
(2H, d, J = 7.0 Hz), 3.29-3.39 (2H, m), 3.52-3.64
(4H, m), 3.80 (2H, t, J = 4.9 Hz), 3.98 (2H, t, J = 7.
2 Hz), 4.13-4.18 (4H, m), 6.86-7.00 (5H, m), 7.33-
7.53 (9H, m), 7.76 (1H, s) .IR (KBr) 3303, 3086, 1636, 1586, 501, 1318, 1246,
1181, 1134, 1113, 1067, 923, 812 cm ^-1 Elemental analysis C ₄₀ H ₅₀ N ₄ O ₄ S Calcd. C, 70.35; H, 7.38;
N, 8.20: Found. C, 69.98; H, 7.52; N, 8.31.

Example 404 (Production of Compound 437) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[1- (3-Hydroxypropyl) -1H-imidazol-2-yl] methyl] thio] phenyl] -1
To a solution of -isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.40g) in dichloromethane (20ml) was added 3-chloroperbenzoic acid (70%, 0.22g) at -78 ° C. Dichloromethane (10
ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as a yellow amorphous substance. [4-[[1- (3-Hydroxypropyl) -1H-imidazol-2-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 437) (354 mg) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz), 0.
98 (6H, d, J = 6.6 Hz), 1.32-1.44 (2H, m), 1.52-1.68
(2H, m), 1.87-1.98 (2H, m), 2.02-2.16 (1H, m), 2.88
-2.97 (2H, m), 3.20 (2H, d, J = 6.9 Hz), 3.35-3.57
(6H, m), 3.81 (2H, t, J = 5.0 Hz), 3.86-4.07 (2H,
m), 4.11-4.17 (3H, m), 4.25 (1H, d, J = 13.8 Hz), 6.
91-6.99 (4H, m), 7.09 (1H, d, J = 1.2 Hz), 7.39-7.47
(5H, m), 7.52 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J =
8.7 Hz), 7.99 (1H, s) .IR (KBr) 3094, 3032, 1661, 1607, 1588, 1518, 1499,
1397, 1314, 1244, 1179, 1046, 818 cm ^-1 Elemental analysis C ₄₀ H ₅₀ N ₄ O ₅ S0.5H ₂ O Calcd. C, 67.87; H,
7.26; N, 7.91: Found.C, 67.65; H, 7.34; N, 7.8
0.

Example 405 (Production of compound 438) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[(1-trityl-1H-imidazol-4-yl) methyl] thio] phenyl] -2,
3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) in DMF (10 ml),
2-iodoethanol (0.25 ml) was added at room temperature,
The mixture was stirred at 50 ° C for 4 days. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 49 → 1: 19) to give 7- [4- (2-butoxyethoxy) phenyl as a yellow amorphous substance. ] -N- [4-[[1- (2-hydroxyethyl)]
-1H-imidazol-5-yl] methyl] thio] phenyl] -1-isobutyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (compound 43
8) (124.6 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
96 (6H, d, J = 6.6 Hz), 1.28-1.46 (2H, m), 1.53-1.80
(2H, m), 1.94-2.16 (1H, m), 2.83-2.95 (2H, m), 3.18
(2H, d, J = 7.2 Hz), 3.28-3.39 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.9 Hz), 3.89 (2H, t,
J = 5.2 Hz), 4.01 (2H, s), 4.09 (2H, t, J = 5.2 Hz),
4.15 (2H, t, J = 4.9 Hz), 6.64 (1H, s), 6.91 (1H, d,
J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.23-7.27 (2H,
m), 7.37-7.53 (8H, m), 7.76 (1H, s) .IR (KBr) 3083, 3034, 1655, 1607, 1588, 1499, 1395,
1312, 1287, 1244, 1181, 1123, 1067, 816 cm ^-1 Elemental analysis C ₃₉ H ₄₈ N ₄ O ₄ S0.75H ₂ O Calcd. C, 68.64; H,
7.31; N, 8.21: Found. C, 68.88; H, 7.23; N, 8.
35.

Example 406 (Production of Compound 439) 7- [4- (2-butoxyethoxy) phenyl] -N-
[4-[[1- (2-Hydroxyethyl) -1H-imidazol-5-yl] methyl] thio] phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (204.7 mg) in dichloromethane (10 ml) was added to a solution of 3-chloroperbenzoic acid (70%, 0.12 g) in dichloromethane at -78 ° C. (1
0 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 10 minutes.
After extraction with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 9) to give 7- [4- (2-butoxyethoxy) phenyl] -N- as a yellow amorphous substance. [4-[[1- (2-hydroxyethyl) -1H-imidazol-5-yl] methyl] sulfinyl] phenyl] -1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 439) (115.5 mg, 55%). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.29-1.48 (2H, m), 1.50-1.76
(2H, m), 1.95-2.15 (1H, m), 2.86-2.96 (2H, m), 3.20
(2H, d, J = 7.6 Hz), 3.32-3.41 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.78-4.05 (7H, m), 4.16 (2H, t, J = 4.
8 Hz), 4.25 (1H, d, J = 14.6 Hz), 6.54 (1H, s), 6.90-
7.00 (3H, m), 7.35-7.57 (8H, m), 7.75 (2H, d, J = 8.
8 Hz), 7.96 (1H, s) .IR (KBr) 3092, 3027, 1661, 1607, 1588, 1518, 1397,
1312, 1244, 1179, 1119, 818 cm ^-1 Elemental analysis C ₃₉ H ₄₈ N ₄ O ₅ S1.0H ₂ O Calcd. C, 66.64; H,
7.17; N, 7.97: Found.C, 66.79; H, 6.90; N, 7.7
3.

Example 407 (Production of compound 440) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in tetrahydrofuran (15 ml). Then 0 ℃
After adding thionyl chloride (0.22 ml) at room temperature, the mixture was returned to room temperature and stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 ml). This solution was added to S- (4-aminophenyl) O-benzyl carbonothioate (594
mg), triethylamine (1.6 ml) in THF (1
5 ml) solution was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight, and then methanol (30 ml) was added. Further, 1N aqueous sodium hydroxide solution (11.5 ml) was added, and the mixture was placed under an argon atmosphere to give 3
Stir for 0 minutes. Then, 4-chloromethyl-5-methyl-1-propylimidazole hydrochloride (527 mg) was added, and the mixture was stirred under an argon atmosphere for 1 hour. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, basic silica gel column chromatography (hexane: ethyl acetate = 1: 1).
→ 7: [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-]
[[(5-Methyl-1-propylimidazol-4-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (268 mg) (Compound 440) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88-0.99 (12H, m), 1.34
-1.45 (2H, m), 1.54-1.75 (4H, m), 1.96 (3H, s), 2.
00-2.20 (1H, m), 2.85-2.95 (2H, m), 3.19 (2H, d, J
= 7.4 Hz), 3.34-3.39 (2H, m), 3.55 (2H, t, J = 6.6 H
z), 3.71 (2H, t, J = 7.4 Hz), 3.80 (2H, t, J = 4.8 Hz),
4.02 (2H, s), 4.18 (2H, t, J = 4.8 Hz), 6.92 (1H, d,
J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.32-7.52 (10
H, m), 7.60 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.84; H,
7.72; N, 8.17; Found. C, 71.63; H, 7.82; N, 8.
15.

Example 408 (Production of compound 441) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(5-methyl-1-propylimidazol-4-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (220 mg) 70% 3-chloroperbenzoic acid (1 ml) in dichloromethane (10 ml) solution
A solution of 19 mg) in dichloromethane (10 ml) is -78.
The mixture was added dropwise at 0 ° C. and stirred for 30 minutes as it was. After adding dimethyl sulfide (0.1 ml) and returning to room temperature, 3
Stir for 0 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 1.
0: 1) isolate and purify to give 7- as yellow amorphous.
[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(5-methyl-1-propylimidazol-4-yl) methyl] sulfinyl] phenyl] -2,3-dihydro- 1H-1-benzazepine-
4-Carboxamide (132 mg) (Compound 441) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (12H, m), 1.34
-1.45 (2H, m), 1.55-1.76 (4H, m), 1.86 (3H, s), 1.
95-2.15 (1H, m), 2.90-3.00 (2H, m), 3.20 (2H, d, J
= 5.4 Hz), 3.35-3.45 (2H, m), 3.55 (2H, t, J = 6.6 H
z), 3.73 (2H, t, J = 7.0 Hz), 3.78-3.89 (3H, m), 4.14
-4.24 (3H, m), 6.93 (1H, d, J = 8.4 Hz), 6.98 (2H, d,
J = 8.8 Hz), 7.37-7.50 (8H, m), 7.69 (2H, d, J = 8.8
Hz), 7.73 (1H, s). Elemental analysis C ₄₁ H ₅₂ N ₄ O ₄ S ・ 0.5H ₂ O Calcd. C, 69.76; H,
7.57; N, 7.94; Found.C, 69.47; H, 7.55; N, 7.6
8.

Example 409 (Production of compound 442) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in tetrahydrofuran (10 ml). Then 0 ℃
After adding thionyl chloride (0.22 ml) at room temperature, the mixture was returned to room temperature and stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 ml). This solution was added to S- (4-aminophenyl) O-benzyl carbonothioate (594
mg), triethylamine (1.6 ml) in THF (1
5 ml) solution was added dropwise at 0 ° C. under an argon atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight, and then methanol (30 ml) was added. Further, 1N aqueous sodium hydroxide solution (11.5 ml) was added, and the mixture was placed under an argon atmosphere to give 3
Stir for 0 minutes. Then, 5-chloromethyl-1- (2-
Propyn-1-yl) imidazole hydrochloride (482m
g) was added and the mixture was stirred under an argon atmosphere for 1 hour. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, basic silica gel column chromatography (hexane: ethyl acetate =
2: 3) to separate and purify to give 7 as a yellow amorphous.
-[4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[(1- (2-propyne-1-
Il) imidazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.14 g) (Compound 442) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-0.99 (9H, m), 1.30-
1.50 (2H, m), 1.54-1.70 (2H, m), 1.95-2.15 (1H,
m), 2.49 (1H, t, J = 2.6 Hz), 2.85-2.95 (2H, m), 3.19
(2H, d, J = 7.2 Hz), 3.33-3.38 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.08 (2H, s),
4.16 (2H, t, J = 4.8 Hz), 4.82 (2H, d, J = 2.6 Hz),
6.72 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.97 (2H, d,
J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.37-7.58 (8H,
m), 7.64 (1H, s). Elemental analysis C ₄₀ H ₄₆ N ₄ O ₃ S ・ 0.25H ₂ O Calcd. C, 71.99; H,
7.02; N, 8.39; Found. C, 71.86; H, 6.86; N, 8.
40.

Example 410 (Production of compound 443) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [4-[[(1- (2-propyne-1
-Yl) imidazol-5-yl) methyl] sulfanyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (639 mg) in dichloromethane (15 ml) in 70% 3-chloroperbenzoic acid. A solution of (356 mg) in dichloromethane (15 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes as it was. Dimethyl sulfide (0.1 ml) was added and the mixture was returned to room temperature and then stirred for 30 minutes. Add water and extract with ethyl acetate,
The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl as a yellow amorphous substance. -N- [4-[[(1
-(2-Propin-1-yl) imidazol-5-yl) methyl] sulfinyl] phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (451 mg) (Compound 443) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (9H, m), 1.30-
1.50 (2H, m), 1.55-1.65 (2H, m), 1.95-2.15 (1H,
m), 2.46 (1H, t, J = 2.6 Hz), 2.90-3.00 (2H, m), 3.20
(2H, d, J = 7.4 Hz), 3.33-3.43 (2H, m), 3.55 (2H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 4.4 Hz), 3.97 (1H, d,
J = 14.4 Hz), 4.16 (2H, t, J = 4.4 Hz), 4.32 (1H, d, J
= 14.4 Hz), 4.77 (2H, d, J = 2.6 Hz), 6.55 (1H, s),
6.93 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.3
4-7.59 (8H, m), 7.76 (2H, d, J = 8.4 Hz), 7.87 (1H,
s). Elemental analysis C ₄₀ H ₄₆ N ₄ O ₄ S ・ 0.25H ₂ O Calcd. C, 70.30; H,
6.86; N, 8.20; Found. C, 70.18; H, 6.98; N, 8.
32.

Example 411 (Production of compound 444) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (174 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.038 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. This solution was added to 5-amino-1-methyl-2-(((1-propylimidazol-5-yl)).
Methyl) sulfanyl) benzimidazole (120m
A solution of g) in pyridine (10 ml) was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[1-Methyl-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazol-5-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (191 mg) ) (Compound 444) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.91-1.00 (12H, m), 1.33
-1.46 (2H, m), 1.56-1.65 (2H, m), 1.80-1.87 (2H,
m), 2.00-2.15 (1H, m), 2.93-3.00 (2H, m), 3.20 (2
H, d, J = 6.9 Hz), 3.33-3.41 (2H, m), 3.55 (2H, t, J
= 6.6 Hz), 3.62 (3H, s), 3.81 (2H, t, J = 4.5 Hz), 3.
95 (2H, t, J = 7.8Hz), 4.16 (2H, t, J = 4.5Hz), 4.67
(2H, s), 6.93 (1H, d, J = 9.0 Hz), 6.98 (2H, d, J = 8.
7 Hz), 7.02 (1H, s), 7.21 (1H, d, J = 8.7 Hz), 7.38-
7.55 (7H, m), 7.66 (1H, s), 7.87 (1H, d, J = 2.1 Hz). Elemental analysis C ₄₂ H ₅₂ N ₆ O ₃ S ・ 0.5H ₂ O Calcd. C, 69.11; H,
7.32; N, 11.51; Found. C, 69.19; H, 7.24; N, 1
1.58.

Example 412 (Production of compound 445) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [1-methyl-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazol-5-yl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (160
mg) in dichloromethane (10 ml) in 70% 3-
Chloroperbenzoic acid (82 mg) in dichloromethane (10
(ml) solution was added dropwise at -78 ° C and then stirred at -13 ° C for 2.5 hours. Dimethyl sulfide (0.
1 ml) was added and the mixture was returned to room temperature and then stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate), and recrystallized from hexane-ethyl acetate to give yellow crystals. As 7- [4- (2-butoxyethoxy) phenyl]-
1-isobutyl-N- [1-methyl-2-(((1-propylimidazol-5-yl) methyl) sulfinyl) benzimidazol-5-yl] -2,3-dihydro-1H-1-benzazepine- 4-Carboxamide (47 mg) (Compound 445) was obtained. mp 149.5-151.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.87-1.00 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.90 (4H, m), 1.95-2.15 (1H,
m), 2.95-3.05 (2H, m), 3.20 (2H, d, J = 7.4 Hz), 3.3
5-3.45 (2H, m), 3.55 (2H, t, J = 7.0 Hz), 3.73 (3H,
s), 3.76-3.90 (4H, m), 4.16 (2H, t, J = 5.0 Hz), 4.5
5 (1H, d, J = 14.0 Hz), 4.84 (1H, d, J = 14.0 Hz), 6.7
6 (1H, s), 6.91-7.00 (3H, m), 7.30-7.65 (8H, m),
7.73 (1H, s), 8.09 (1H, d, J = 1.8 Hz). Elemental analysis C ₄₂ H ₅₂ N ₆ O ₄ S ・ 0.5H ₂ O Calcd. C, 67.62; H,
7.16; N, 11.27; Found. C, 67.43; H, 7.02; N, 1
1.29.

Example 413 (Production of Compound 446) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (252 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.055 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. This solution was added to 6-amino-1-methyl-2-(((1-propylimidazol-5-yl)).
Methyl) sulfanyl) benzimidazole (158m
A solution of g) in pyridine (10 ml) was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring overnight at room temperature under a nitrogen atmosphere, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (hexane:
Ethyl acetate = 1: 2 → ethyl acetate) to obtain 7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [1-methyl-2- as yellow amorphous.
(((1-Propylimidazol-5-yl) methyl)
Sulfanyl) benzimidazol-6-yl] -2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (319 mg) (Compound 446) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89-1.00 (12H, m), 1.30
-1.50 (2H, m), 1.55-1.70 (2H, m), 1.75-1.90 (2H, m
m), 2.00-2.20 (1H, m), 2.90-3.00 (2H, m), 3.20 (2
H, d, J = 7.4 Hz), 3.35-3.45 (2H, m), 3.55 (2H, t, J
= 7.0 Hz), 3.63 (3H, s), 3.80 (2H, t, J = 4.8 Hz), 3.
94 (2H, t, J = 7.4 Hz), 4.16 (2H, t, J = 4.8Hz), 4.65
(2H, s), 6.91-7.08 (4H, m), 7.39-7.62 (8H, m), 7.7
1 (1H, s), 8.18 (1H, d, J = 2.2 Hz). Elemental analysis C ₄₂ H ₅₂ N ₆ O ₃ S ・ 0.25H ₂ O Calcd. C, 69.53; H,
7.29; N, 11.58; Found. C, 69.38; H, 7.49; N, 1
1.33.

Example 414 (Production of compound 447) 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-N- [1-methyl-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazol-6-yl] -2,3-dihydro-1
H-1-benzazepine-4-carboxamide (260
mg) in dichloromethane (10 ml) in 70% 3-
Chloroperbenzoic acid (133 mg) in dichloromethane (1
0 ml) solution was added dropwise at -78 ° C and then -13 ° C.
Stirred at 2.5 hours. Dimethyl sulfide (0.1 ml) was added and the mixture was returned to room temperature and then stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 2: 5 → ethyl acetate) to give 7- [4- (2- (2- Butoxyethoxy) phenyl] -1-isobutyl-N-
[1-Methyl-2-(((1-propylimidazole-
5-yl) methyl) sulfinyl) benzimidazol-6-yl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (9 mg) (Compound 44
7) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.87-1.89 (18H, m), 1.90
-2.20 (1H, m), 2.90-3.05 (2H, m), 3.20 (2H, d, J =
7.4 Hz), 3.30-3.45 (2H, m), 3.58 (2H, t, J = 6.2 H
z), 3.73 (3H, s), 3.78-3.89 (4H, m), 4.16 (2H, t,
J = 4.8 Hz), 4.56 (1H, d, J = 14.2 Hz), 4.85 (1H, d, J
= 14.2 Hz), 6.66-8.26 (14H, m).

Example 415 (Production of compound 448) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (265 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.058 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution was added to a solution of (1E) -1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone O-methyloxime (150 mg) in pyridine (10 ml) at 0 ° C. under a nitrogen atmosphere. It was dripped slowly. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -1- as yellow crystals.
Isobutyl-N- [4-((1E) -N-methoxy-2
-(1-Propylimidazol-2-yl) ethaneimidoyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (300 mg) (Compound 448) was obtained. mp 159.0-161.0 ー C ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.89-0.98 (12H, m), 1.36
-1.46 (2H, m), 1.50-1.75 (4H, m), 2.00-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.18 (2H, d, J = 7.5 Hz), 3.3
0-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.76-3.82
(4H, m), 4.04 (3H, s), 4.16 (2H, t, J = 5.4 Hz), 4.2
4 (2H, s), 6.75 (1H, s), 6.90-6.92 (2H, m), 6.98 (2
H, d, J = 8.7 Hz), 7.38-7.48 (5H, m), 7.56 (2H, d, J
= 8.7 Hz), 7.64 (1H, s), 7.76 (2H, d, J = 8.7 Hz). Elemental analysis C ₄₂ H ₅₃ N ₅ O ₄ Calcd. C, 72.91; H, 7.72; N,
10.12; Found. C, 72.69; H, 7.80; N, 10.28.

Example 416 (Production of compound 449) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (300 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.065 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution was added to a solution of (1E) -1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone O-ethyloxime (179 mg) in pyridine (10 ml) at 0 ° C. under a nitrogen atmosphere. It was dripped slowly. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -N- as yellow crystals.
[4-((1E) -N-Ethoxy-2- (1-propylimidazol-2-yl) ethaneimidoyl) phenyl] -1-isobutyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxamide (390 mg)
(Compound 449) was obtained. mp 155.5-156.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86-0.98 (12H, m), 1.27
-1.48 (5H, m), 1.54-1.73 (4H, m), 1.95-2.15 (1H,
m), 2.85-2.95 (2H, m), 3.17 (2H, d, J = 7.2 Hz), 3.2
5-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.75-3.83
(4H, m), 4.16 (2H, t, J = 5.2 Hz), 4.23-4.34 (4H,
m), 6.74 (1H, d, J = 1.6 Hz), 6.88-6.93 (2H, m), 6.9
7 (2H, d, J = 9.2 Hz), 7.36-7.48 (5H, m), 7.56 (2H,
d, J = 8.8 Hz), 7.74-7.78 (3H, m). Elemental analysis C ₄₃ H ₅₅ N ₅ O ₄ Calcd. C, 73.16; H, 7.85; N,
9.92; Found. C, 72.92; H, 7.85; N, 9.98.

Example 417 (Preparation of compound 450) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (300 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.065 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution was added to (1E) -1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone oxime (177 mg) in pyridine (10 m).
l) The solution was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4-((1E ) -N-
Hydroxy-2- (1-propylimidazol-2-yl) ethaneimidoyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (278 mg) (Compound 450) was obtained. mp 153.5-154.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88-0.98 (12H, m), 1.30
-1.80 (6H, m), 1.95-2.15 (1H, m), 2.85-2.95 (2H,
m), 3.17 (2H, d, J = 7.4 Hz), 3.28-3.38 (2H, m), 3.5
5 (2H, t, J = 6.8 Hz), 3.78-3.87 (4H, m), 4.14 (2H,
t, J = 4.4 Hz), 4.29 (2H, s), 6.77 (1H, s), 6.88-6.9
9 (4H, m), 7.36-7.48 (5H, m), 7.56 (2H, d, J = 8.8 H
z), 7.68-7.75 (3H, m). Elemental analysis C ₄₁ H ₅₁ N ₅ O ₄ Calcd. C, 72.64; H, 7.58; N,
10.33; Found. C, 72.45; H, 7.62; N, 10.44.

Example 418 (Production of compound 451) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (180 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.04 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution is 2- (4-aminophenyl) -1-
(1-Propylimidazol-2-yl) ethanone (1
(00 mg) in pyridine (10 ml) was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 4: 1 → hexane: ethyl acetate =
1: 1) was separated and purified, and recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2
-Butoxyethoxy) phenyl] -1-isobutyl-N
-[4- (2-oxo-2- (1-propylimidazol-2-yl) ethyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide (6
4 mg) (compound 451) was obtained. mp 136.5-138.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.85-0.99 (12H, m), 1.34
-1.45 (2H, m), 1.50-1.65 (2H, m), 1.71-1.82 (2H,
m), 1.95-2.15 (1H, m), 2.85-2.95 (2H, m), 3.18 (2
H, d, J = 7.0 Hz), 2.90-3.00 (2H, m), 3.55 (2H, t, J
= 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J =
5.0 Hz), 4.31 (2H, t, J = 7.6 Hz), 4.42 (2H, s), 6.9
1 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.09
(1H, d, J = 0.8Hz), 7.19 (1H, d, J = 0.8Hz), 7.30-7.5
7 (10H, m). Elemental analysis C ₄₁ H ₅₀ N ₄ O ₄ Calcd. C, 74.29; H, 7.60; N,
8.45; Found. C, 74.07; H, 7.76; N, 8.55.

Example 419 (Production of compound 452) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (169 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.037 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution was added to (1E) -2- (4-aminophenyl) -1- (1-propylimidazol-2-yl) ethanone oxime (100 mg) in pyridine (10 m).
l) The solution was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 2 → ethyl acetate), and recrystallized from diisopropyl ether-ethyl acetate to give a yellow powder. 7- [4- as crystals
(2-Butoxyethoxy) phenyl] -N- [4-
((2E) -2- (Hydroxyimino) -2- (1-propylimidazol-2-yl) ethyl) phenyl]-
1-Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (231 mg) (Compound 452) was obtained. mp 165.5-167.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.82 (3H, t, J = 7.4 Hz),
0.89-0.97 (9H, m), 1.33-1.45 (2H, m), 1.50-1.74 (4
H, m), 1.95-2.15 (1H, m), 2.82-2.92 (2H, m), 3.15
(2H, d, J = 7.0 Hz), 3.28-3.38 (2H, m), 3.55 (2H, t,
J = 6.6 Hz), 3.80 (2H, t, J = 4.4 Hz), 4.09-4.17 (4H,
m), 4.33 (2H, s), 6.87-6.91 (2H, m), 6.96 (2H, d, J
= 8.6 Hz), 7.10 (1H, s), 7.30-7.52 (9H, m), 7.72 (1
H, s). Elemental analysis C ₄₁ H ₅₁ N ₅ O ₄ Calcd. C, 72.64; H, 7.58; N,
10.33; Found. C, 72.48; H, 7.50; N, 10.24.

Example 420 (Production of Compound 453) 7- [4- (2-butoxyethoxy) phenyl] -1-
A drop of DMF was added to a solution of isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (59.3 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (0.013 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). This solution was added to (1Z) -2- (4-aminophenyl) -1- (1-propylimidazol-2-yl).
Ethanone Oxime (35 mg) in pyridine (10 m
l) The solution was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 4) and recrystallized from diisopropyl ether-ethyl acetate to give yellow crystals. -[4- (2-Butoxyethoxy) phenyl] -N- [4-((2Z) -2-
(Hydroxyimino) -2- (1-propylimidazol-2-yl) ethyl) phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (68 mg) (Compound 453) was obtained. mp 187.5-189.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.67 (3H, t, J = 7.4 Hz),
0.89-0.98 (9H, m), 1.30-1.65 (6H, m), 1.95-2.15 (1
H, m), 2.85-2.95 (2H, m), 3.17 (2H, d, J = 7.4Hz),
3.30-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.63 (2
H, t, J = 7.4 Hz), 3.80 (2H, t, J = 4.8 Hz), 3.97 (2H,
s), 4.15 (2H, t, J = 4.8 Hz), 6.88 (1H, s), 6.93-6.99
(3H, m), 7.10-7.14 (3H, m), 7.39-7.52 (8H, m). Elemental analysis C ₄₁ H ₅₁ N ₅ O ₄・ 0.25H ₂ O Calcd. C, 72.17; H,
7.61; N, 10.26; Found. C, 72.08; H, 7.41; N, 1
0.21.

Example 421 (Preparation of compound 454) (-)-4-(((1-propylimidazol-5-yl) methyl) sulfinyl) aniline di-P-toluoyl-D-tartrate monohydrate The product (894 mg) was dissolved in ethyl acetate (10 ml) and 1N hydrochloric acid (4.6 ml), and the layers were separated. 25% aqueous potassium carbonate solution (4.6m
l) was added, and then 2-propanol-ethyl acetate (1:
Extracted twice in 4). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Tetrahydrofuran was added to the obtained residue, and then the solvent was distilled off under reduced pressure again (-)-4-(((1-
Propylimidazol-5-yl) methyl) sulfinyl) aniline was obtained. Then 7- [4- (2-butoxyethoxy) phenyl] -1-cyclopropylmethyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxylic acid (450 mg) in tetrahydrofuran (10 ml)
After adding one drop of DMF to the solution, oxalyl chloride (0.1
2 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. This solution was added to (-)-4-(((1-propylimidazol-5-yl) methyl) sulfinyl) aniline and pyridine (2.17 ml) in tetrahydrofuran (20 ml).
The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After returning to room temperature and stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with a 10% acetic acid aqueous solution, twice with a saturated sodium hydrogen carbonate aqueous solution, once with a saturated saline solution, and then dried with magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 50: 1) to give (-)-7- [4-
(2-Butoxyethoxy) phenyl] -1-cyclopropylmethyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl]-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (411 mg) (Compound 454) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.28-0.33 (2H, m), 0.62-
0.68 (2H, m), 0.88-0.96 (6H, m), 1.10-1.20 (1H,
m), 1.36-1.43 (2H, m), 1.56-1.76 (2H, m), 2.90-3.0
0 (2H, m), 3.26 (2H, d, J = 6.3 Hz), 3.45-3.48 (2H,
m), 3.53 (2H, t, J = 6.6 Hz), 3.75-3.82 (4H, m), 4.0
2 (1H, d, J = 14.1 Hz), 4.09 (1H, d, J = 14.1 Hz), 4.1
5 (2H, t, J = 5.1 Hz), 6.56 (1H, s), 4.92 (1H, s),
6.95-6.99 (3H, m), 7.34 (2H, d, J = 9.0 Hz), 7.40-7.
51 (6H, m), 7.73 (2H, d, J = 9.0 Hz), 7.87 (1H, s). Elemental analysis C ₄₀ H ₄₈ N ₄ O ₄ S ・ 0.5H ₂ O Calcd. C, 69.64; H,
7.16; N, 8.12; Found.C, 69.54; H, 7.29; N, 8.1
2. [α] _D = -129.7 ° (C = 0.4790%, ethanol solution)

Example 422 (Preparation of compound 455) (-)-4-(((1-propylimidazol-5-yl) methyl) sulfinyl) aniline di-P-toluoyl-D-tartrate monohydrate The product (174 mg) was dissolved in ethyl acetate (5 ml) and 1N hydrochloric acid (1.77 ml), and the layers were separated. Aqueous 25% potassium carbonate solution (1.77)
ml) and then 2-propanol-ethyl acetate (1:
Extracted in 4). The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. After adding tetrahydrofuran to the obtained residue, the solvent was distilled off again under reduced pressure to obtain (-)-4-(((1-propylimidazol-5-yl) methyl) sulfinyl) aniline. Then 7- [4- (2-butoxyethoxy) phenyl] -1-[(1-methylpyrazol-5-yl) methyl] -2,3-dihydro-1H-1-benzazepine-
4-Carboxylic acid (95 mg) in dichloromethane (10 m
l) One drop of DMF was added to the solution, oxalyl chloride (0.023 ml) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. This solution was added dropwise to a tetrahydrofuran (10 ml) solution of (-)-4-(((1-propylimidazol-5-yl) methyl) sulfinyl) aniline and pyridine (0.42 ml) at 0 ° C under a nitrogen atmosphere. did. After returning to room temperature and stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 10% aqueous acetic acid,
2 times with saturated aqueous sodium hydrogen carbonate solution, 1 with saturated saline solution
After washing twice, it was dried over magnesium sulfate. After evaporating the solvent under reduced pressure, basic silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 11:
Separated and purified in 1) to obtain (-)-as yellow amorphous.
7- [4- (2-butoxyethoxy) phenyl] -1-
[(1-Methylpyrazol-5-yl) methyl] -N-
[4-[[[1-Propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-
1H-1-benzazepine-4-carboxamide (81
mg) (compound 455). ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.88-0.96 (6H, m), 1.36-
1.43 (2H, m), 1.56-1.76 (4H, m), 2.80-2.87 (2H,
m), 3.30-3.40 (2H, m), 3.55 (2H, t, J = 6.6 Hz), 3.75
-3.82 (4H, m), 3.90 (3H, s), 4.01 (1H, d, J = 14.1 H
z), 4.09 (1H, d, J = 14.1 Hz), 4.15 (2H, t, J = 4.8 H
z), 4.44 (2H, s), 6.55 (1H, s), 6.96-6.99 (3H, m),
7.31-7.35 (3H, m), 7.41-7.54 (7H, m), 7.73 (2H,
d, J = 8.7 Hz), 7.88 (1H, s). Elemental analysis C ₄₁ H ₄₈ N ₆ O ₄ S 0.75H ₂ O Calcd. C, 67.05; H,
6.79; N, 11.44; Found. C, 66.85; H, 6.94; N, 1
1.21. [Α] _D = -123.7 ° (C = 0.3925%, ethanol solution)

Reference Example 1 p-Fluorobenzyl cyanide (4.1 g), 2-bromo-4-methylpyridine (5.2 g), sodium p-toluenesulfinate (5.4 g) and THF (50 m).
l) and suspended in THF (5 ml) under ice cooling 4
0% sodium hydride (1.2g) was added. After refluxing for 3 hours, the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to give 2- (α-cyano-4-fluorobenzyl) -4-methylpyridine (3.1 g) as a brown oil. ¹ H-NMR (d, CDCl ₃ ) 2.36 (3H, s), 5.26 (1H, s), 7.02
-7.11 (3H, m), 7.21 (1H, s), 7.39-7.46 (2H, m), 8.
44 (1H, d, J = 5.0 Hz) .IR (neat) ν: 2247, 1605, 1508 cm ^-1 .

Reference Example 2 2- (α-Cyano-4-fluorobenzyl) -4-methylpyridine (3.1 g) and potassium carbonate (2.9 g) were suspended in 20% hydrous dimethylsulfoxide (150 ml), and the mixture was mixed. Stir overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
2- (4-fluorobenzoyl)
-4-Methylpyridine (1.6 g) was obtained as brown crystals. mp 98-100 ℃. ¹ H-NMR (d, CDCl ₃ ) 2.48 (3H, s), 7.11-7.20 (2H, m),
7.30-7.33 (1H, m), 7.88 (1H, s), 8.12-8.19 (2H,
m), 8.57 (1H, d, J = 5.0 Hz) .IR (KBr) ν: 1669, 1597 cm ^-1 . Anal.calcd. for C ₁₃ H ₁₀ FNO: C, 72.55; H, 4.68; N,
6.51. Found C, 72.61; H, 4.63; N, 6.48.

Reference Example 3 2- (4-Fluorobenzoyl) -4-methylpyridine (1.6 g) and sodium azide (2.4 g) were suspended in dimethyl sulfoxide (15 ml), and the suspension was placed under a nitrogen atmosphere.
The mixture was heated with stirring at 90 ° C. overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (50 ml), lithium aluminum hydride (0.66 g) was added under ice cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Under ice cooling, water (0.66m
l), 15% aqueous sodium hydroxide solution (0.66 m
l) and water (1.98 ml) were added, and the mixture was stirred, dried over anhydrous magnesium sulfate, filtered, and the solvent of the filtrate was evaporated to give (4-aminophenyl) (4-methylpyridine-2).
-Yl) methanol (1.8 g) was obtained as pale yellow crystals. mp 156-158 ℃. ¹ H-NMR (d, CDCl ₃ ) 2.28 (3H, s), 3.65 (2H, br), 5.1
8 (1H, br), 5.60 (1H, s), 6.65 (2H, d, J = 8.4 Hz),
6.93 (1H, s), 6.99 (1H, d, J = 5.0 Hz), 7.14 (2H,
d, J = 8.4 Hz), 8.40 (1H, d, J = 5.0 Hz). IR (KBr) ν: 1609, 1516 cm ^-1 . Anal.calcd. for C ₁₃ H ₁₄ N ₂ O ・ 0.1H ₂ O : C, 72.26; H,
6.62; N, 12.97. Found C, 72.34; H, 6.62; N, 12.69.

Reference Example 4 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g), 4-aminophenyl) (4-methylpyridin-2-yl) methanol (0.24 g) and 1-hydroxybenzotriazole (0.16 g) were added to N, N-. Dissolve in dimethylformamide (5 ml), and under ice cooling, 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (0.
4 g), triethylamine (0.44 ml) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with diethyl ether-hexane and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methylpyridin-2-yl) methyl] phenyl] -1-. Trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was obtained as colorless crystals. mp 101-105 ℃. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.30-
1.49 (2H, m), 1.58-1.69 (2H, m), 2.30 (3H, s), 2.93
-3.15 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H,
t, J = 5.0 Hz), 4.18 (2H, t, J = 5.0 Hz), 4.79-4.
90 (1H, m), 5.39 (1H, br), 5.69 (1H, s), 6.93 (1H,
s), 7.00-7.04 (3H, m), 7.31-7.65 (11H, m), 8.41 (1
H, d, J = 5.2 Hz). IR (KBr) ν: 2959, 2934, 2874, 1694, 1609, 1518, 1
497 cm ^-1 . Anal.calcd. For C ₃₈ H ₃₈ F ₃ N ₃ O ₅ : C, 67.74; H, 5.69;
N, 6.24.Found C, 67.47; H, 5.81; N, 6.42

Reference Example 5 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (4-methylpyridin-2-yl)
Methyl] phenyl] -1-trifluoroacetyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) was dissolved in dichloromethane (20 ml), 3-chloroperbenzoic acid (0.3 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. did. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol / triethylamine),
7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.32 g ) Was obtained as colorless crystals. mp 121-123 ° C. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.26-
1.45 (2H, m), 1.55-1.65 (2H, m), 2.29 (3H, s), 2.94
-3.17 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H,
t, J = 5.0 Hz), 4.18 (2H, t, J = 5.0 Hz), 4.78-4.
88 (1H, m), 6.00-6.03 (1H, m), 6.70-6.75 (2H, m),
7.00-7.06 (3H, m), 7.33 (1H, d, J = 8.4 Hz), 7.45-
7.22 (9H, m), 8.13 (1H, d, J = 6.2 Hz). IR (KBr) ν: 2870, 1700 cm ^-1 . Anal.calcd. For C ₃₈
H ₃₈ F ₃ N ₃ O ₆・ 0.25H ₂ O: C, 65.74; H, 5.59; N, 6.05.Fou
nd C, 65.72; H, 5.64; N, 5.93.

Reference Example 6 2-Bromopyridine (1.4 ml) was dissolved in diethyl ether (40 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (9.1 ml) was added dropwise and stirred for 30 minutes. The reaction solution was treated with 2-methoxy-4-nitrobenzaldehyde (2.4
g) was added dropwise to a tetrahydrofuran (600 ml) solution at -78 ° C under an argon atmosphere. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), (2-methoxy-4-nitrophenyl).
(Pyridin-2-yl) methanol (1.9 g) was obtained as pale yellow crystals. mp 126-129 ℃ (dec.). ¹ H-NMR (d, CDCl ₃ ) 4.00 (3H, s), 5.40 (1H, d, J =
4.2 Hz), 6.24 (1H, d, J = 4.2 Hz), 7.19-7.31 (2H,
m), 7.57 (1H, d, J = 8.4 Hz), 7.64 (1H, dt, J = 1.
8, 7.7 Hz), 7.76 (1H, d, J = 2.2 Hz), 7.84 (1H, d
d, J = 1.8, 8.4 Hz), 8.56 (1H, d, J = 5.2 Hz). IR (KBr) ν: 1526, 1348 cm ^-1 . Anal.calcd. for C ₁₃
H ₁₂ N ₂ O ₄ : C, 60.00; H, 4.65; N, 10.76.Found C, 60.0
9; H, 4.58; N, 10.60

Reference Example 7 (2-Methoxy-4-nitrophenyl) (pyridine-2
-Yl) methanol (0.5 g) with ethyl acetate (25 m
l) and dissolved in 50% water containing 10% palladium-carbon (5
0 mg) was used for catalytic reduction overnight. The catalyst was filtered off,
The solvent of the filtrate was distilled off, and (4-amino-2-methoxyphenyl) (pyridin-2-yl) methanol (0.4 g)
Was obtained as colorless crystals. mp 123-125 ℃ (dec.). ¹ H-NMR (d, CDCl ₃ ) 3.67 (2H, br), 3.80 (3H, s), 5.0
0 (1H, br), 6.08 (1H, s), 6.21-6.27 (2H, m), 6.98
(1H, d, J = 8.8 Hz), 7.12-7.26 (2H, m), 7.60 (1H, d
t, J = 1.8, 7.7 Hz), 8.54 (1H, d, J = 4.4 Hz). IR (KBr) ν: 1615, 1591, 1508 cm ^-1 . Anal.calcd. for C ₁₃ H ₁₄ N ₂ O ₂・ 0.1H ₂ O: C, 67.28; H,
6.17; N, 12.07.FoundC, 67.36; H, 6.26; N, 11.79.

Reference Example 8 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.5 g), (4-
Amino-2-methoxyphenyl) (pyridin-2-yl) methanol (0.26 g) and 1-hydroxybenzotriazole (0.18 g) were dissolved in N, N-dimethylformamide (5 ml), and 1-under ice-cooling. Ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.4 g), triethylamine (0.44 ml), 4
-Dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (pyridin-2-yl) methyl]-. 3-Methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.56 g) was obtained as colorless crystals. mp 123-125 ° C. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.26-
1.65 (4H, m), 2.90-3.25 (3H, m), 3.56 (2H, t, J =
6.8 Hz), 3.82 (2H, t, J = 4.9 Hz), 3.91 (3H, s), 4.
18 (2H, t, J = 4.9 Hz), 4.80-4.90 (1H, m), 5.23 (1
H, d, J = 5.0 Hz), 6.18 (1H, d, J = 5.0 Hz), 6.84-
6.88 (1H, m), 7.03 (2H, d, J = 8.4 Hz), 7.19-7.65
(11H, m), 8.55 (1H, d, J = 4.8 Hz). IR (KBr) ν: 2932, 2876, 2841, 1700 cm ^-1 . Anal.calcd. For C ₃₈ H ₃₈ F ₃ N ₃ O ₆ : C, 66.17; H, 5.55;
N, 6.09.Found C, 65.99; H, 5.69; N, 5.74

Reference Example 9 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (pyridin-2-yl) methyl]-
3-Methoxyphenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.55 g) was added to dichloromethane (25 m
l), and under ice cooling, 3-chloroperbenzoic acid (0.2
6 g) was added and the mixture was stirred at room temperature overnight. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 7- [4- (2-butoxyethoxy) phenyl]-.
N- [4- [hydroxy (1-oxidepyridine-2-
Iyl) methyl] -3-methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.44 g) was obtained as a colorless amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.26-
1.49 (2H, m), 1.57-1.69 (2H, m), 2.90-3.30 (3H, m),
3.56 (2H, t, J = 6.6 Hz), 3.74-3.84 (5H, m), 4.18
(2H, t, J = 4.7 Hz), 4.78-4.90 (1H, m), 6.33 (1H,
s), 6.65-6.75 (1H, m), 6.90-7.05 (4H, m), 7.20-7.
36 (2H, m), 7.46-7.69 (9H, m), 8.22-8.26 (1H, m). IR (KBr) ν: 2959, 2932, 2867, 1696, 1609, 1499 cm
^-1 . Anal.calcd. For C ₃₈ H ₃₈ F ₃ N ₃ O ₇・ 0.5H ₂ O: C, 63.86;
H, 5.50; N, 5.88.FoundC, 64.07; H, 5.36; N, 5.79.

Reference Example 10 2-Bromopyridine (0.68 ml) was dissolved in diethyl ether (20 ml), and the mixture was heated at -78 ° C under an argon atmosphere.
Cooled to. A 1.6 Mn-butyllithium hexane solution (4.5 ml) was added dropwise and stirred for 30 minutes. The reaction solution was treated with 2-chloro-4-nitrobenzaldehyde (1.1 g).
In diethyl ether (20 ml) and tetrahydrofuran (30 ml) under argon atmosphere at -78 ° C. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to obtain (2-chloro-4-nitrophenyl) (pyridin-2-yl) methanol (0.47 g) as yellow crystals. mp 124-127 ℃. ¹ H-NMR (d, CDCl ₃ ) 5.61 (1H, d, J = 2.2 Hz), 6.32
(1H, d, J = 2.2 Hz), 7.24-7.30 (2H, m), 7.63-7.72
(2H, m), 8.10 (1H, dd, J = 2.6, 8.2 Hz), 8.28 (1
H, d, J = 2.6 Hz), 8.58-8.62 (1H, m). IR (KBr) ν: 3100, 2868, 2718, 1597, 1522, 1352 cm
^-1 . Anal.calcd.for C ₁₂ H ₉ ClN ₂ O ₃ : C, 54.46; H, 3.43;
N, 10.58.Found C, 54.61; H, 3.38; N, 10.38.

Reference Example 11 (2-chloro-4-nitrophenyl) (pyridine-2-
Il) methanol (1 g) in tetrahydrofuran (15
ml), ethanol (15 ml) and water (15 ml), sodium hydrosulfite (3.3 g) was added, and the mixture was refluxed for 30 minutes. After concentration, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. Dry with anhydrous magnesium sulfate and evaporate the solvent to remove (4-amino-
2-Chlorophenyl) (pyridin-2-yl) methanol (0.21 g) was obtained as colorless crystals. mp 142-146 ℃ (dec.). ¹ H-NMR (d, CDCl ₃ ) 3.71 (2H, br), 5.32 (1H, d, J =
4.2 Hz), 6.15 (1H, d, J = 4.2 Hz), 6.53 (1H, dd, J
= 2.4, 8.4 Hz), 6.70 (1H, d, J = 2.4 Hz), 7.08 (1
H, d, J = 8.4 Hz), 7.17-7.23 (2H, m), 7.62 (1H, d
t, J = 1.8, 7.7Hz), 8.56 (1H, d, J = 4.4Hz) .IR (KBr) ν: 1593, 1501 cm ^-1 . Anal.calcd. for C ₁₂ H ₁₁ ClN ₂ O: C, 61.41; H, 4.72;
N, 11.94.Found C, 61.11; H, 4.82; N, 11.61

Reference Example 12 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.81 g), (4
-Amino-2-chlorophenyl) (pyridin-2-yl) methanol (0.4 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N, N-dimethylformamide (15 ml), and the mixture was cooled with ice to give 1-. Ethyl-3-
(3-dimethylaminopropyl) carbodiimide hydrochloride (0.66 g), triethylamine (0.71 ml),
4-dimethylaminopyridine (catalytic amount) was added, room temperature,
Stir overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) and basic silica gel column chromatography (elution solvent: ethyl acetate / hexane) to give 7- [4-
(2-Butoxyethoxy) phenyl] -N- [3-chloro-4- [hydroxy (pyridin-2-yl) methyl]]
Phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.37 g) was obtained as a yellow amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.1 Hz), 1.29-
1.49 (2H, m), 1.54-1.72 (2H, m), 2.90-3.19 (3H, m),
3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.8 H
z), 4.17 (2H, t, J = 4.8 Hz), 4.80-4.86 (1H, m),
5.51 (1H, s), 6.23 (1H, s), 7.01 (2H, d, J = 8.8 H
z), 7.19-7.68 (11H, m), 7.78-7.82 (2H, m), 8.56 (1
H, d, J = 4.4 Hz) .IR (KBr) ν: 2957, 2938, 2868, 1696 cm ^-1 .

Reference Example 13 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Chloro-4- [hydroxy (pyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.37 g) was added to dichloromethane (25 m
l), and under ice cooling, 3-chloroperbenzoic acid (0.2
g) was added, and the mixture was stirred overnight at room temperature. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4-
(2-Butoxyethoxy) phenyl] -N- [3-chloro-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.24 g) was obtained as a pale red oil. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.26-
1.48 (2H, m), 1.54-1.68 (2H, m), 2.92-3.22 (3H, m),
3.55 (2H, t, J = 6.7 Hz), 3.81 (2H, t, J = 4.7 H
z), 4.17 (2H, t, J = 4.7 Hz), 4.78-4.88 (1H, m),
6.38 (1H, s), 6.60 (1H, s), 6.89-7.02 (3H, m), 7.23
-7.34 (2H, m), 7.46-7.56 (6H, m), 7.63-7.71 (2H,
m), 7.87 (1H, d, J = 6.2 Hz), 8.21-8.35 (2H, m).

Reference Example 14 2-Bromopyridine (0.9 ml) was dissolved in diethyl ether (30 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (5.9 ml) was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was treated with 2-methyl-4-nitrobenzaldehyde (1.3 g).
Was added dropwise to a tetrahydrofuran (30 ml) solution at −78 ° C. under an argon atmosphere. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue (elution solvent: ethyl acetate / hexane)
The product was purified with a solvent to give (2-methyl-4-nitrophenyl) (pyridin-2-yl) methanol (0.84 g) as light brown crystals. mp 119-121 ° C (dec). ¹ H-NMR (d, CDCl ₃ ) 2.46 (3H, s), 5.22 (1H, s), 6.02
(1H, s), 7.00 (1H, d, J = 7.8 Hz), 7.23-7.30 (1H,
m), 7.48 (1H, d, J = 8.8 Hz), 7.66 (1H, dt, J = 1.
8, 7.7 Hz), 8.00-8.05 (2H, m), 8.62 (1H, d, J = 3.
6 Hz). IR (KBr) ν: 1590, 1520, 1348 cm ^-1 . Anal.calcd. For C ₁₃ H ₁₂ N ₂ O ₃ : C, 63.93; H, 4.95; N,
11.47. Found C, 64.12; H, 4.86; N, 11.34.

Reference Example 15 (2-Methyl-4-nitrophenyl) (pyridine-2-
Ill) methanol (0.83g) to ethanol (50m
l) and dissolved in 50% water containing 10% palladium-carbon (5
0 mg) was used for catalytic reduction overnight. The catalyst was filtered off,
The solvent in the filtrate was evaporated, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane), and (4-amino-2-methylphenyl) (pyridine-
2-yl) methanol (0.42 g) was obtained as colorless crystals. mp 102-104 ° C. ¹ H-NMR (d, CDCl3) 2.24 (3H, s), 3.60 (2H, br), 5.0
0 (1H, d, J = 3.2 Hz), 5.86 (1H, d, J = 3.2 Hz), 6.
45-6.50 (2H, m), 6.95 (1H, d, J = 8.0 Hz), 7.05 (1
H, d, J = 7.8 Hz), 7.15-7.22 (1H, m), 7.60 (1H, d
t, J = 1.4, 7.7Hz), 8.57 (1H, d, J = 5.2Hz) .IR (KBr) ν: 3350, 1610 cm ^-1 . Anal.calcd. for C ₁₃ H ₁₄ N ₂ O: C, 72.87; H, 6.59; N,
13.07.Found C, 72.68; H, 6.23; N, 13.00.

Reference Example 16 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.94 g), (4
-Amino-2-methylphenyl) (pyridin-2-yl) methanol (0.42 g) and 1-hydroxybenzotriazole (0.45 g) were dissolved in N, N-dimethylformamide (15 ml), and the mixture was cooled with ice to give 1 -Ethyl-3
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.75g), triethylamine (0.82m)
l), 4-dimethylaminopyridine (catalytic amount) was added,
Stir at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
Hexane), 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (pyridine-
2-yl) methyl] -3-methylphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.95 g) was obtained as colorless crystals. mp 122-125 ℃. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.1 Hz), 1.30-
1.68 (4H, m), 2.33 (3H, s), 2.91-3.19 (3H, m), 3.56
(2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.9 Hz), 4.
17 (2H, t, J = 4.9 Hz), 4.80-4.84 (1H, m), 5.19 (1
H, s), 5.93 (1H, s), 6.99-7.04 (3H, m), 7.19-7.41
(6H, m), 7.50-7.66 (6H, m), 8.58 (1H, d, J = 5.2 H
z). IR (KBr) ν: 2957, 2932, 2872, 1694, 1609, 1593, 1
520, 1497 cm ^-1 . Anal.calcd. For C ₃₈ H ₃₈ F ₃ N ₃ O ₅ : C, 67.74; H, 5.69;
N, 6.24. Found C, 67.47; H, 5.65; N, 6.22.

Reference Example 17 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (pyridin-2-yl) methyl]-
3-Methylphenyl] -1-trifluoroacetyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (0.95 g) was added to dichloromethane (25 m
l), and under ice cooling, 3-chloroperbenzoic acid (0.4
2 g) was added, and the mixture was stirred at room temperature for 3.5 hours. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- Colorless [hydroxy (1-oxidepyridin-2-yl) methyl] -3-methylphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.82 g) Obtained as crystals. mp 142-144 ℃. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.4 Hz), 1.31-
1.65 (4H, m), 2.23 (3H, s), 2.95-3.25 (3H, m), 3.56
(2H, t, J = 6.8 Hz), 3.82 (2H, t, J = 5.0 Hz), 4.
18 (2H, t, J = 5.0 Hz), 4.79-4.93 (1H, m), 6.28 (2
H, s), 6.74 (1H, dd, J = 2.5, 7.7 Hz), 7.03 (2H, d,
J = 8.6 Hz), 7.18-7.66 (11H, m), 8.31 (1H, dd, J
= 1.0, 6.6 Hz). IR (KBr) ν: 2868, 1696 cm ^-1 . Anal.calcd. For C ₃₈ H ₃₈ F ₃ N ₃ O ₆・ 0.5H ₂ O: C, 65.32;
H, 5.63; N, 6.01.FoundC, 65.56; H, 5.37; N, 5.98.

Reference Example 18 2-Bromo-4-methylpyridine (1.5 ml) was dissolved in diethyl ether (50 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (8.3 ml) was added dropwise and stirred for 1 hour. The reaction solution was added dropwise to a solution of 2-methoxy-4-nitrobenzaldehyde (2 g) in tetrahydrofuran (300 ml) at -78 ° C under an argon atmosphere. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane), and (2-methoxy-4-nitrophenyl) (4-methylpyridin-2-yl) methanol (2.2 g) was used as a light brown oil. Obtained. ¹ H-NMR (d, CDCl ₃ ) 2.31 (3H, s), 4.00 (3H, s), 5.44
(1H, br), 6.19 (1H, s), 7.02-7.05 (2H, m), 7.53
(1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.8
3 (1H, dd, J = 2.0, 8.4 Hz), 8.40 (1H, d, J = 4.8
IR) (neat) ν: 1609 1526 cm ^-1 .

Reference Example 19 (2-Methoxy-4-nitrophenyl) (4-methylpyridin-2-yl) methanol (2.2 g) was dissolved in ethyl acetate (50 ml) and ethanol (50 ml) to give 5
Catalytic reduction was performed overnight using 0% water-containing 10% palladium-carbon (150 mg). The catalyst was filtered off, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and (4-
Amino-2-methoxyphenyl) (4-methylpyridin-2-yl) methanol (0.65 g) was obtained as pale yellow crystals. mp 114-117 ° C. ¹ H-NMR (d, CDCl ₃ ) 2.29 (3H, s), 3.
67 (2H, br), 3.81 (3H, s), 5.03 (1H, d, J = 3.5 H
z), 6.04 (1H, d, J = 3.5 Hz), 6.21-6.26 (2H, m), 6.
93-7.04 (3H, m), 8.39 (1H, d, J = 4.8 Hz) .IR (KBr) ν: 3345, 1609, 1508 cm ^-1 . Anal.calcd. For C ₁₄ H ₁₆ N ₂ O ₂ 0.25H ₂ O: C, 67.59; H,
6.68; N, 11.26.FoundC, 67.57; H, 6.63; N, 11.39.

Reference Example 20 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.7 g), (4-
Amino-2-methoxyphenyl) (4-methylpyridin-2-yl) methanol (0.5 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N, N-dimethylformamide (15 ml) and cooled with ice. , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.56 g), triethylamine (0.61)
ml) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methylpyridin-2-yl). Methyl] -3-methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1
g) was obtained as a pale brown amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.94 (3H, t, J = 7.0 Hz), 1.27-
1.49 (2H, m), 1.55-1.69 (2H, m), 2.30 (3H, s), 2.92
-3.25 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H,
t, J = 4.8 Hz), 3.91 (3H, s), 4.18 (2H, t, J = 4.
8 Hz), 4.79-4.90 (1H, m), 5.24 (1H, br), 6.13 (1H,
s), 6.82-6.87 (1H, m), 6.99-7.04 (4H, m), 7.22 (1H,
d, J = 8.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.43 (1
H, s), 7.50-7.65 (6H, m), 8.39 (1H, d, J = 5.0 H
z) .IR (KBr) ν: 2938, 2874, 1694 cm ^-1 .

Reference Example 21 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (4-methylpyridin-2-yl)
Methyl] -3-methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) was added to dichloromethane (3
0 ml), 3-chloroperbenzoic acid (0.46 g) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [Hydroxy (4-methyl-1-oxidepyridin-2-yl) methyl] -3-methoxyphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0. 77 g) was obtained as a colorless amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.94 (3H, t, J = 7.2 Hz), 1.34-
1.63 (4H, m), 2.28 (3H, s), 2.90-3.25 (3H, m), 3.56
(2H, t, J = 6.6 Hz), 3.76-3.84 (5H, m), 4.18 (2H,
t, J = 4.7 Hz), 4.80-4.90 (1H, m), 6.32 (1H, s),
6.78 (1H, s), 6.90-7.05 (4H, m), 7.26-7.36 (2H,
m), 7.45-7.75 (7H, m), 8.12 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 2938, 2870, 1694 cm ^-1 .Ana.calcd. for C ₃₉ H ₄₀ F ₃ N ₃ O ₇・ 0.5H ₂ O: C, 64.28;
H, 5.67; N, 5.77.FoundC, 64.11; H, 5.47; N, 5.67.

Reference Example 22 2-Bromo-4-methylpyridine (1.5 ml) was dissolved in diethyl ether (50 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (8.3 ml) was added dropwise and stirred for 40 minutes. The reaction solution was added dropwise to a solution of 2-ethoxy-4-nitrobenzaldehyde (2.2 g) in tetrahydrofuran (200 ml) at -78 ° C under an argon atmosphere. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to obtain (2-ethoxy-4-nitrophenyl) (4-methylpyridin-2-yl) methanol (1.9 g) as brown crystals. It was mp 114-115 ℃ (dec.). ¹ H-NMR (d, CDCl ₃ ) 1.49 (3H, t, J = 7.1 Hz), 2.31
(3H, s), 4.11-4.30 (2H, m), 5.39 (1H, d, J = 5.3 H
z), 6.19 (1H, d, J = 5.3 Hz), 7.03 (1H, d, J = 5.1
Hz), 7.10 (1H, s), 7.56 (1H, d, J = 8.4 Hz), 7.72
(1H, d, J = 2.2Hz), 7.82 (1H, dd, J = 2.2, 8.4 H
z), 8.40 (1H, d, J = 5.1 Hz) .IR (KBr) ν: 3370, 2982, 1613, 1522 cm ^-1 . Anal.calcd. for C ₁₅ H ₁₆ N ₂ O ₄ : C, 62.49; H, 5.59; N,
9.72. Found C, 62.60; H, 5.73; N, 9.78.

Reference Example 23 (2-Ethoxy-4-nitrophenyl) (4-methylpyridin-2-yl) methanol (1.9 g) was dissolved in ethanol (100 ml) to obtain 50% water containing 10% palladium-carbon (0). .2 g) was used for catalytic reduction overnight. The catalyst was filtered off, the solvent of the filtrate was distilled off, and (4-amino-2-
Ethoxyphenyl) (4-methylpyridin-2-yl)
Methanol (1.7 g) was obtained as colorless crystals. mp 102-105 ° C. ¹ H-NMR (d, CDCl ₃ ) 1.63 (3H, t, J = 7.0 Hz), 2.29
(3H, s), 3.64 (2H, br), 3.91-4.10 (2H, m), 5.06 (1
H, d, J = 4.8 Hz), 6.01 (1H, d, J = 4.8 Hz), 6.22-
6.26 (2H, m), 6.95-7.08 (3H, m), 8.37 (1H, d, J =
5.0 Hz). Anal.calcd. For C ₁₅ H ₁₈ N ₂ O ₂ : C, 69.74; H, 7.02; N,
10.84. Found C, 69.64; H, 7.11; N, 10.87.

Reference Example 24 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (0.7 g), (4-
Amino-2-ethoxyphenyl) (4-methylpyridin-2-yl) methanol (0.45 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N, N-dimethylformamide (15 ml) and cooled with ice. , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.56 g), triethylamine (0.6
1 ml) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -N- [3-ethoxy-4- [hydroxy (4-methylpyridine- 2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.68 g) was obtained as a colorless amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.85-0.97 (6H, m), 1.27-1.45 (2
H, m), 1.48-1.68 (2H, m), 2.30 (3H, s), 2.91-3.25
(3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J =
5.0 Hz), 4.02-4.20 (4H, m), 4.75-4.90 (1H, m), 5.
27 (1H, br), 6.12 (1H, s), 6.84 (1H, d, J = 8.0 H
z), 7.00-7.10 (4H, m), 7.25-7.64 (9H, m), 8.38 (1
H, d, J = 4.8 Hz) .IR (KBr) ν: 2932, 2874, 1694, 1609 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₂ F ₃ N ₃ O ₆ : C, 66.93; H, 5.90 ;
N, 5.85. Found C, 66.54; H, 5.73; N, 6.04.

Reference Example 25 7- [4- (2-butoxyethoxy) phenyl] -N-
[3-Ethoxy-4- [hydroxy (4-methylpyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.68 g Was dissolved in dichloromethane (25 ml), 3-chloroperbenzoic acid (0.28 g) was added under ice cooling, and the mixture was stirred at room temperature overnight. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and 7- [4- (2-butoxyethoxy) phenyl] -N- [3- Ethoxy-4- [hydroxy (4-
Methyl-1-oxidepyridin-2-yl) methyl] phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.89 g) was obtained as a colorless amorphous. ¹ H-NMR (d, CDCl ₃ ) 0.85-0.97 (6H, m), 1.22-1.45 (2
H, m), 1.49-1.69 (2H, m), 2.29 (3H, s), 2.92-3.25
(3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J =
4.8 Hz), 4.05-4.20 (4H, m), 4.79-4.95 (1H, m), 6.
28 (1H, s), 6.88-7.05 (6H, m), 7.26-7.73 (9H, m),
8.10 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 2932, 2912, 2870, 1694 cm ^-1 . Anal.calcd. For C ₄₀ H ₄₂ F ₃ N ₃ O ₇・ 0.5H ₂ O: C, 64.68;
H, 5.84; N, 5.66.FoundC, 64.40; H, 5.86; N, 5.57.

Reference Example 26 2-Bromo-4-methylpyridine (4.7 g) was dissolved in diethyl ether (150 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (16.8 ml) was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was treated with 4-fluoro-N-methoxy-N-methyl-2-trifluoromethylbenzamide (6.2 g).
In a diethyl ether (50 ml) solution of was added dropwise at -78 ° C under an argon atmosphere. After returning to room temperature and stirring overnight,
Water was added and concentrated. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to obtain 2- (4-fluoro-2-trifluoromethylbenzoyl) -4-methylpyridine (4.5 g) as a pale yellow oil. . ¹ H-NMR (d, CDCl ₃ ) 2.49 (3H, s), 7.26-7.37 (2H, m),
7.43-7.53 (2H, m), 8.06 (1H, d, J = 0.8 Hz), 8.50
(1H, d, J = 4.4 Hz) .IR (neat) ν: 1694, 1599, 1424, 1319 cm ^-1 .

Reference Example 27 2- (4-fluoro-2-trifluoromethylbenzoi
) -4-Methylpyridine (4.5 g), sodium azide
Umium (1.3 g) with dimethyl sulfoxide (30 ml)
And was heated and stirred overnight at 90 ° C. under a nitrogen atmosphere.
It was poured into water and extracted with ethyl acetate. Saturate the organic layer with water
After washing with brine, drying with anhydrous magnesium sulfate,
The solvent was distilled off. The residue is tetrahydrofuran (30 m
l) Dissolve in ice-cooled lithium aluminum hydride
(1.2 g) was added, and the mixture was ice-cooled and stirred for 1 hour under a nitrogen atmosphere.
did. Water (1.2 ml), 15% aqueous sodium hydroxide
Liquid (1.2 ml) and water (3.6 ml) were added, and after stirring,
It was dried using anhydrous magnesium sulfate and filtered. Of the filtrate
The solvent was distilled off, and (4-amino-2-trifluoromethyl
Phenyl) (4-methylpyridin-2-yl) methano
To give colorless crystals (3.6 g). mp 120-123 ° C.¹ H-NMR (d, CDCl₃) 2.28 (3H, s), 3.83 (2H, br), 5.6
1 (1H, d, J = 3.6 Hz), 6.00 (1H, d, J = 3.6 Hz), 6.
74 (1H, dd, J = 2.6, 8.6 Hz), 6.82 (1H, s), 6.95 (1
H, d, J = 2.2 Hz), 7.02 (1H, d, J = 5.2 Hz), 8.43
(1H, d, J = 5.2 Hz). IR (KBr) ν: 3318, 1636, 1609, 1507, 1456, 1339 cm
^-1. Anal. Calcd. For C ₁₄H₁₃F₃N₂O: C, 59.57; H, 4.6
4; N, 9.92. Found C, 59.33; H, 4.67; N, 9.79.

Reference Example 28 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (2 g), (4-amino-2-trifluoromethylphenyl) (4-methylpyridin-2-yl) methanol (1.2 g), 1-hydroxybenzotriazole (0.96 g) Was dissolved in N, N-dimethylformamide (25 ml), and the mixture was cooled with ice to 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.4 g), triethylamine (3 m
l), 4-dimethylaminopyridine (catalytic amount) was added,
Stir at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by basic silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-
Methylpyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-trifluoroacetyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (1.2 g) was obtained as a pale yellow oil. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.29-
1.48 (2H, m), 1.54-1.71 (2H, m), 2.27 (3H, s), 2.89
-3.20 (3H, m), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H,
t, J = 4.8 Hz), 4.17 (2H, t, J = 4.8 Hz), 4.78-4.
85 (1H, m), 6.07 (1H, s), 6.81 (1H, s), 6.97-7.05
(3H, m), 7.24-7.67 (9H, m), 7.88 (1H, d, J = 9.6 H
z), 8.28 (1H, s), 8.40 (1H, d, J = 5.2 Hz).

Reference Example 29 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (4-methylpyridin-2-yl)
Methyl] -3-trifluoromethylphenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.2 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled with ice. 3-Chloroperbenzoic acid (0.69 g) was added, and the mixture was stirred at room temperature overnight. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer is an aqueous sodium hydrogen carbonate solution,
The extract 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 (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (4-methyl-1-oxidepyridine- 2-yl) methyl] -3-trifluoromethylphenyl] -1-trifluoroacetyl-2,3
-Dihydro-1H-1-benzazepine-4-carboxamide (1 g) was obtained as a light brown oil. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.3 Hz), 1.29-
1.48 (2H, m), 1.55-1.72 (2H, m), 2.24 (3H, s), 2.96
-3.22 (3H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H,
t, J = 4.8 Hz), 4.17 (2H, t, J = 4.8 Hz), 4.80-4.
93 (1H, m), 6.40-6.44 (2H, m), 7.00-7.08 (4H, m),
7.34 (1H, d, J = 8.2Hz), 7.51-7.59 (4H, m), 7.67
(1H, d, J = 1.4 Hz), 7.88-8.12 (4H, m), 8.16 (1H,
d, J = 6.6Hz). IR (neat) ν: 2934, 2872, 1694 cm ^-1 .

Reference Example 30 2-Bromopyridine (2.8 ml) was dissolved in diethyl ether (80 ml) and cooled to -78 ° C under an argon atmosphere. A 1.6 Mn-butyllithium hexane solution (18 ml) was added dropwise and stirred for 30 minutes. 2 reaction solutions
-(2,2,2-Trifluoroethoxy) -4-nitrobenzaldehyde (6 g) in tetrahydrofuran (10
(0 ml) was added dropwise at -78 ° C under an argon atmosphere. After returning to room temperature and stirring overnight, water was added and the mixture was concentrated. Extract with ethyl acetate, wash the organic layer with water and saturated saline,
It was dried with anhydrous magnesium sulfate and the solvent was distilled off.
The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), [4-nitro-
2- (2,2,2-trifluoroethoxy) phenyl]
(Pyridin-2-yl) methanol (4.5 g) was obtained as light brown crystals. mp 119-123 ° C. ¹ H-NMR (d, CDCl ₃ ) 4.43-4.62 (2H, m), 5.39 (1H, d,
J = 5.6 Hz), 6.23 (1H, d, J = 5.6 Hz), 7.21-7.24 (1
H, m), 7.30 (1H, d, J = 8.2 Hz), 7.64 (1H, dd, J =
1.4, 8.0 Hz), 7.69-7.74 (2H, m), 7.96 (1H, dd, J =
2.2, 8.7 Hz), 8.56 (1H, d, J = 4.8 Hz) .IR (KBr) ν: 1530, 1350, 1289, 1242, 1169 cm ^-1 . Anal.calcd. For C ₁₄ H ₁₁ F ₃ N ₂ O ₄ : C, 51.23; H, 3.38;
N, 8.53. Found C, 51.32; H, 3.30; N, 8.58.

Reference Example 31 [4-Nitro-2- (2,2,2-trifluoroethoxy) phenyl] (pyridin-2-yl) methanol (4.5 g) was dissolved in ethanol (150 ml) to give 5
Catalytic reduction was performed overnight using 0% water-containing 10% palladium-carbon (0.25 g). The catalyst was filtered off, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate), [4-amino-2
-(2,2,2-trifluoroethoxy) phenyl]
(Pyridin-2-yl) methanol (3.6 g) was obtained as yellow crystals. mp 97-99 ° C. ¹ H-NMR (d, CDCl ₃ ) 3.71 (2H, br), 4.22-4.41 (2H,
m), 5.19 (1H, d, J = 5.2Hz), 6.05 (1H, d, J = 5.2
Hz), 6.16 (1H, d, J = 2.2 Hz), 6.35 (1H, dd, J =
2.2, 8.2 Hz), 7.10-7.24 (3H, m), 7.60 (1H, dt, J =
1.4, 15.0 Hz), 8.53 (1H, d, J = 4.6 Hz). IR (KBr) ν: 3331, 1615 cm ^-1 . Anal.calcd. For C ₁₄ H ₁₃ F ₃ N ₂ O ₂ : C, 56.38 H, 4.39;
N, 9.39. Found C, 56.39; H, 4.19; N, 9.47.

Reference Example 32 7- [4- (2-butoxyethoxy) phenyl] -1-
Trifluoroacetyl-2,3-dihydro-1H-1-
Benzazepine-4-carboxylic acid (1.5 g), [4-
Amino-2- (2,2,2-trifluoroethoxy) phenyl] (pyridin-2-yl) methanol (0.94
g), 1-hydroxybenzotriazole (0.72
g) was dissolved in N, N-dimethylformamide (25 ml), and under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.8 g), triethylamine (2.2 ml), 4- Dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to give 7-
[4- (2-butoxyethoxy) phenyl] -N- [4
-[Hydroxy (pyridin-2-yl) methyl] -3-
(2,2,2-Trifluoroethoxy) phenyl] -1
-Trifluoroacetyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxamide (1.5 g) was obtained as colorless crystals. mp 178-181 ° C. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 7.2 Hz), 1.22-
1.69 (4H, m), 2.91-3.21 (3H, m), 3.56 (2H, t, J =
6.6 Hz), 3.82 (2H, t, J = 4.9 Hz), 4.18 (2H, t, J =
4.9 Hz), 4.34-4.55 (2H, m), 4.75-4.90 (1H, m), 5.
34 (1H, d, J = 2.7 Hz), 6.16 (1H, d, J = 2.7 Hz),
6.84-6.89 (1H, m), 7.02 (2H, d, J = 8.8 Hz), 7.16-
7.22 (1H, m), 7.29-7.71 (11H, m), 8.54 (1H, d, J =
5.0 Hz). IR (KBr) ν: 3351, 2963, 2940, 2878, 1701, 1655, 1
607 cm ^-1 . Anal.calcd. For C ₃₉ H ₃₇ F ₆ N ₃ O ₆ : C, 61.82; H, 4.92;
N, 5.55. Found C, 62.03; H, 4.65; N, 5.82.

Reference Example 33 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (pyridin-2-yl) methyl]-
3- (2,2,2-trifluoroethoxy) phenyl]
-1-Trifluoroacetyl-2,3-dihydro-1H
-1-Benzazepine-4-carboxamide (1.5
g) was dissolved in dichloromethane (150 ml), 3-chloroperbenzoic acid (0.75 g) was added under ice cooling, and the mixture was stirred overnight at room temperature. Aqueous sodium thiosulfate solution was added, concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate /
Hexane) and 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3- (2,2,2-
Trifluoroethoxy) phenyl] -1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) was obtained as colorless crystals. mp 106-109 ℃. ¹ H-NMR (d, CDCl ₃ ) 0.93 (3H, t, J = 8.6 Hz), 1.22-
1.69 (4H, m), 2.85-3.25 (3H, m), 3.56 (2H, t, J =
6.6 Hz), 3.82 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J =
4.8 Hz), 4.33-4.45 (2H, m), 4.80-4.90 (1H, m), 6.
20-6.26 (1H, m), 6.91-7.05 (4H, m), 7.21-7.36 (4H,
m), 7.45-7.57 (4H, m), 7.66 (1H, s), 7.78-7.82 (3H,
m), 8.19 (1H, d, J = 6.6 Hz) .IR (KBr) ν: 1694, 1605 cm ^-1 . Anal.calcd. for C ₃₉ H ₃₇ F ₆ N ₃ O ₇ : C, 60.54; H, 4.82;
N, 5.43. Found C, 60.16; H, 5.20; N, 5.40.

Reference Example 34 7- [4- (2-butoxyethoxy) phenyl] -1-
Propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (7 ml), and thionyl chloride (0.13) was added under ice cooling.
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), and p-aminophenol (0.13 g) and triethylamine (0.5
(ml) in tetrahydrofuran (5 ml) under ice cooling. The mixture was stirred overnight at room temperature under a nitrogen atmosphere, and the solvent was distilled off. Water was added and the mixture was extracted with ethyl acetate. Water organic layer,
After washing with a saturated saline solution, it was dried using anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl]-
N- (4-hydroxyphenyl) -1-propyl-2,
3-Dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) was obtained as a yellow oil. ¹ H-NMR (d, CDCl ₃ ) 0.89-1.00 (6H, m), 1.33-1.44 (2
H, m), 1.54-1.77 (4H, m), 2.85 (2H, t-like), 3.23-
3.31 (4H, m), 3.55 (2H, t, J = 6.6 Hz), 3.80 (2H,
t, J = 4.8 Hz), 4.14 (2H, t, J = 4.8 Hz), 6.38 (1
H, s), 6.75-6.97 (5H, m), 7.31-7.46 (7H, m), 7.62
(1H, s). IR (neat) ν: 3237, 2957, 2936, 2870, 1636, 1605,
1539, 1507 cm ^-1 .

Reference Example 35 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2 g) was dissolved in tetrahydrofuran (25 ml), and thionyl chloride (0.5
ml) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (50 ml), p-aminophenol (0.55 g) and triethylamine (2 m).
l) was added dropwise to a tetrahydrofuran (25 ml) solution under ice cooling. The mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere, and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 7- [4- (2-butoxyethoxy) phenyl] -N- (4-hydroxyphenyl) -1-isobutyl-2,3-. Dihydro-1H-1-benzazepine-4
-Carboxamide (2g) was obtained as pale yellow crystals. mp 155-157 ℃. ¹ H-NMR (d, CDCl ₃ ) 0.89-0.98 (9H, m), 1.30-1.68 (4
H, m), 1.99-2.10 (1H, m), 2.90 (2H, t, J = 4.8 H
z), 3.17 (2H, d, J = 6.8 Hz), 3.35 (2H, t, J = 4.8
Hz), 3.55 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.
0 Hz), 4.15 (2H, t, J = 5.0 Hz), 5.40 (1H, br), 6.
80 (2H, d, J = 8.8 Hz), 6.89-7.01 (3H, m), 7.37-7.
49 (8H, m). IR (KBr) ν: 2959, 2868, 1645, 1605, 1499 cm ^-1 . Anal.calcd. For C ₃₃ H ₄₀ N ₂ O ₄ : C, 74.97; H, 7.63; N,
5.30. Found C, 74.84; H, 7.81; N, 4.98.

Reference Example 36 Hydrazine monohydrate (10 g) was added to ethanol (100 m).
It was dissolved in 1) and ethyl glycolate (21 g) was added dropwise under ice cooling. After stirring overnight at room temperature, the mixture was ice-cooled, a solution of isobutyl isothiocyanate (23 g) in ethanol (10 ml) was added dropwise, and the mixture was stirred overnight at room temperature. Ice water (50 ml) was added, and the mixture was stirred for 1 hr, then 5N aqueous sodium hydroxide solution (3
8 ml) was added dropwise, and the mixture was heated with stirring at 60 ° C. for 2 hours. The pH was adjusted to 6 with concentrated hydrochloric acid, and the precipitate was filtered off. The filtrate was concentrated, and the precipitated colorless crystals (30 g) were collected by filtration and washed with water. The obtained crystals (15 g) were added to sodium nitrite (97 mg)
Of water (36 ml) in nitric acid (25 ml) was added little by little at 45 ° C. After cooling, it was neutralized with sodium carbonate and concentrated. Methanol was added and the precipitate was filtered off. The solvent of the filtrate was evaporated, and the residue was purified by basic silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give a pale yellow oil (8.7 g). Oil (8.
Thionyl chloride (45 ml) was added dropwise to 7 g) under ice cooling,
Refluxed for 30 minutes. The solvent was distilled off, and the obtained 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole monohydrochloride (10.4 g) was washed with ethyl acetate to obtain colorless crystals. mp 127-130 ℃. ¹ H-NMR (d, DMSO-d ₆ ) 0.90 (6H, d, J = 6.6 Hz), 2.10
-2.26 (1H, m), 4.03 (2H, d, J = 7.2 Hz), 5.14 (2H,
s), 9.53 (1H, s), 10.31 (1H, br). IR (KBr) ν: 2967, 1618, 1572, 1541, 1470 cm ^-1 . Anal.calcd. for C ₇ H ₁₃ Cl ₂ N ₃ 0.25H ₂ O: C, 39.18; H,
6.34; N, 19.58. FoundC, 39.25; H, 6.22; N, 19.71.

Reference Example 37 p-Aminophenol (20 g) was dissolved in N, N-dimethylformamide (150 ml), and potassium carbonate (4
4 g) was added, and ethyl bromoacetate (17.7 ml) was added dropwise under ice cooling. The mixture was stirred overnight at room temperature under an argon atmosphere, and 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 brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was dissolved in ethanol (100 ml), hydrazine monohydrate (18.6 ml) was added, and the mixture was refluxed for 5 hours. The solvent was evaporated, and the precipitated 2- (4-aminophenylthio) acetohydrazide (32 g) was collected by filtration and washed with tetrahydrofuran-hexane to give colorless crystals. ¹ H-NMR (d, CDCl ₃ ) 3.48 (2H, s), 3.77 (4H, br), 6.6
2 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.
75 (1H, br). IR (KBr) ν: 3304, 1651 cm ^-1 .

Reference Example 38 2- (4-aminophenylthio) acetohydrazide (5
Ethanol (50 ml) was added to g) and 2,3-butanedione (2.2 ml), and the mixture was refluxed for 1 hour. The solvent was distilled off, and ethyl acetate was added to the residue. The insoluble matter was filtered off, and the solvent of the filtrate was distilled off. The residue was dissolved in ethanol (35 ml) and 13% ammonia-ethanol solution (50 ml) was added.
Was added and heated at 150 ° C. for 5 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The insoluble matter was filtered off, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 4-
[(5,6-Dimethyl-1,2,4-triazine-3-
Il) methylthio] aniline (3 g) was obtained as a yellow oil. ¹ H-NMR (d, CDCl ₃ ) 2.52 (3H, s), 2.65 (3H, s), 3.71
(2H, br), 4.27 (2H, s), 6.56 (2H, d, J = 8.8 Hz),
7.20 (2H, d, J = 8.8 Hz) .IR (neat) ν: 3347, 3220, 1628, 1599, 1530, 1497 c
m ^-1 .

Reference Example 39 2- (4-aminophenylthio) acetohydrazide (5
g) was suspended in ethanol (50 ml), 40% pyruvaldehyde solution (6.8 ml) was added, and the mixture was stirred at room temperature for 20 minutes. 13% ammonia-ethanol solution (60 ml)
Was added and heated at 150 ° C. for 4.5 hours. The solvent was evaporated, the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and 4-[(5-
Methyl-1,2,4-triazin-3-yl) methylthio] aniline (1.2 g) was obtained as colorless crystals. ¹ H-NMR (d, CDCl ₃ ) 2.55 (3H, s), 3.72 (2H, br), 4.2
9 (2H, s), 6.56 (2H, d, J = 8.6 Hz), 7.18 (2H, d,
J = 8.6 Hz), 8.97 (1H, s). IR (KBr) ν: 3343, 3218, 1626, 1597, 1551, 1497 cm
^-1 .

Reference Example 40 4-Mercapto-3-trifluoromethylaniline (1.0 g), 3-chloromethyl-4-propyl-4H
-1,2,4-triazole hydrochloride (1.1 g) and potassium carbonate (1.4 g) were added to N, N-dimethylformamide (35 ml), and the mixture was stirred at room temperature overnight. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: triethylamine / methanol / ethyl acetate), and 4-[(4-propyl-4H-1,2,2,
4-Triazol-3-yl) methylthio] -3-trifluoromethylaniline (1.4 g) was obtained as a light brown oil. ¹ H-NMR (dppm, CDCl ₃ ) 1.00 (3H, t, J = 7.3 Hz), 1.7
7-1.95 (2H, m), 3.62 (2H, br), 3.97 (2H, t, J = 7.
3 Hz), 4.10 (2H, s), 6.69 (1H, d, J = 8.0 Hz), 6.9
2 (1H, s), 7.23 (1H, d, J = 8.0 Hz), 8.09 (1H,
s).

Reference Example 41 p-Nitrothiophenol (5 g) and triethylamine (4.5 ml) were dissolved in ethanol (150 ml),
Ethyl acrylate (3.5 ml) was added, and the mixture was stirred at room temperature for 3 days. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and yellow crystals (7.
8 g) was obtained. It was dissolved in ethanol (100 ml) and tetrahydrofuran (100 ml), hydrazine monohydrate (7.5 ml) was added, and the mixture was refluxed overnight. Evaporate the solvent,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give yellow crystals (5.1 g). Dissolve in ethanol (150 ml) and tetrahydrofuran (100 ml), and under ice cooling, propyl isothiocyanate (3.3
ml) was added and the mixture was stirred at room temperature overnight. The solvent was distilled off to give yellow crystals (7.2 g). Crystals (6.0 g) in ethanol (200 ml), tetrahydrofuran (200 m)
1), potassium t-butoxide (4.1 g) was added, and the mixture was heated at 50 ° C. for 3.5 hours. The solvent was distilled off and 1N
Hydrochloric acid 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 to give pale yellow crystals (4.4 g). The obtained crystals (4.4 g) and sodium nitrite (0.1 g) were added to nitric acid (5.0 ml) and water (10 ml) under ice cooling,
Heated at 40 ° C. for 15 minutes. The mixture was neutralized with an aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate,
The solvent was evaporated to give 4-nitrophenyl 2- (4-propyl-4H-1,2,4-triazol-3-yl) ethyl sulfide (3.3 g) as colorless crystals. mp 81-84 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.95 (3H, t, J = 7.3 Hz), 1.6
9-1.87 (2H, m), 3.09 (2H, t, J = 7.6 Hz), 3.63 (2
H, t, J = 7.6 Hz), 3.84 (2H, t, J = 8.3 Hz), 7.39
(2H, d, J = 8.8 Hz), 8.10 (1H, s), 8.15 (2H, d, J
= 8.8 Hz). IR (KBr) n: 2967, 1578, 1512, 1334 cm ^-1 . Anal.calcd. For C ₁₃ H ₁₆ N ₄ O ₂ S: C, 53.41; H, 5.52;
N, 19.16.Found C, 53.20; H, 5.44; N, 19.21.

Reference Example 42 4-Nitrophenyl 2- (4-propyl-4H-1,
2,4-Triazol-3-yl) ethyl sulfide (3.2 g), reduced iron (3.1 g) and calcium chloride (0.6 g) were added to 85% ethanol aqueous solution (100 ml).
Add to the inside and reflux for 3 hours. The reaction solution was filtered using Celite, and the solvent of the filtrate was distilled off. The residue was subjected to silica gel column chromatography (elution solvent: triethylamine /
Purification with methanol / ethyl acetate) gave 4-aminophenyl 2- (4-propyl-4H-1,2,4-triazol-3-yl) ethyl sulfide (3.0 g) as a yellow oil. ¹ H-NMR (dppm, CDCl ₃ ) 0.91 (3H, t, J = 7.6 Hz), 1.6
6-1.77 (2H, m), 2.90-2.98 (2H, m), 3.19-3.27 (2H, m
m), 3.74 (2H, t, J = 7.4 Hz), 6.64 (2H, d, J = 8.4
Hz), 7.27 (2H, d, J = 8.4 Hz), 8.04 (1H, s).

Reference Example 43 2-Mercapto-5-nitropyridine (5.0 g), 3
-Chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (6.3 g), potassium carbonate (11
g) was added to N, N-dimethylformamide (100 ml), and the mixture was stirred at room temperature overnight. The solvent was distilled off, water was added,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off and 5-nitro-2- (4-propyl-4H-1,
2,4-triazol-3-yl) methylthiopyridine (8.0 g) was obtained as brown crystals. ¹ H-NMR (dppm, CDCl ₃ ) 0.98 (3H, t, J = 7.3 Hz), 1.8
0-1.92 (2H, m), 4.00 (2H, t, J = 7.3 Hz), 4.75 (2
H, s), 7.42 (1H, dd, J = 0.8, 9.0 Hz), 8.13 (1H,
s), 8.31 (1H, dd, J = 2.7, 9.0 Hz), 9.26 (1H, dd, J
= 0.8, 2.7 Hz) .IR (KBr) n: 2969, 1588, 1568, 151
4, 1345 cm ^-1 . Anal.calcd.for C ₁₁ H ₁₃ N ₅ O ₂ S: C, 47.30; H, 4.69;
N, 25.07.Found C, 47.20; H, 4.63; N, 25.00.

Reference Example 44 5-Nitro-2- (4-propyl-4H-1,2,4-
Triazol-3-yl) methylthiopyridine (4.0
g), reduced iron (4.0 g), calcium chloride (0.79)
g) was added to 85% aqueous ethanol solution (100 ml), and the mixture was refluxed for 3 hours. The reaction solution was filtered using Celite, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and 5-amino-2- (4-propyl-).
4H-1,2,4-triazol-3-yl) methylthiopyridine (3.3 g) was obtained as a red oil. ¹ H-NMR (dppm, CDCl ₃ ) 0.94 (3H, t, J = 7.4 Hz), 1.7
8-1.88 (2H, m), 3.74 (2H, br), 3.96 (2H, t, J = 7.
4 Hz), 4.57 (2H, s), 6.91 (1H, dd, J = 2.9, 8.4 H
z), 7.07 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 2.9
Hz), 8.07 (1H, s) .IR (KBr) n: 3326, 3207, 2969, 1634, 1588, 1518, 14
68 cm ^-1 .

Reference Example 45 3- (4-nitrophenyl) -1-propanol (1.
9 g), tosyl chloride (3.0 g), tetrabutylammonium bromide (0.2 g), sodium hydroxide (2.6 g), water (10 ml), diethyl ether (2
5 ml) and refluxed for 2 days. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane) to give a pale red oil (3.1 g). The obtained oil (3 g) and bis (1H-1, 2,
4-Triazol-1-yl) methane (0.67 g) was heated at 130 ° C. for 2.5 hours. Add ethyl acetate,
The precipitate was collected by filtration. The mixture was added to 1-butanol (50 ml), refluxed overnight, and the solvent was distilled off. Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give 4- [3- (4-nitrophenyl) propyl] -4H-1,2,4-triazole (1.25 g) as yellow crystals. ¹ H-NMR (dppm, CDCl ₃ ) 2.15-2.29 (2H, m), 2.78 (2H,
t, J = 7.6 Hz), 4.09 (2H, t, J = 7.1 Hz), 7.33 (2
H, d, J = 8.8 Hz), 8.16-8.23 (4H, m). IR (KBr) n: 1601, 1516 cm ^-1 .

Reference Example 46 4- [3- (4-nitrophenyl) propyl] -4H-
1,2,4-Triazole (1.2 g) was dissolved in ethanol (100 ml), 10% palladium-activated carbon (50% water content, 0.2 g) was added, and the mixture was catalytically reduced at room temperature overnight. The catalyst was filtered off. The solvent of the filtrate was distilled off, and 4- [3
-(4-Aminophenyl) propyl] -4H-1,2,
4-Triazole (1.0 g) was obtained as colorless crystals. mp 150-153 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 2.04-2.18 (2H, m), 2.55 (2H,
t, J = 7.3 Hz), 2.85 (2H, br), 3.98 (2H, t, J = 7.
2 Hz), 6.65 (2H, d, J = 8.5Hz), 6.93 (2H, d, J = 8.
5 Hz), 8.13 (2H, s) .IR (KBr) n: 3416, 3331, 3221, 3112, 3002, 2948, 16
34, 1615, 1537, 1518, 1451 cm ^-1 . Anal.calcd. For C ₁₁ H ₁₄ N ₄・ 0.1H ₂ O: C, 64.75; H, 7.0
1; N, 27.46. Found C, 64.94; H, 6.68; N, 27.14.

Reference Example 47 4-Nitrothiophenol (10 g) and potassium carbonate (10.7 g) were added to N, N-dimethylformamide (10
0 ml) and then ethyl bromoacetate (10.8
g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Evaporate the solvent,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give yellow crystals (13.8 g). Hydrazine monohydrate (13.6m) in the crystal (13.5g)
1) was added and the mixture was refluxed for 1.5 hours. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off to give colorless crystals (10.0 g). The crystal (5.0 g) was dissolved in tetrahydrofuran (200 ml), and propyl isocyanate (2.2 ml) was added dropwise. Heated at 50 ° C. for 1.5 hours. The solvent was distilled off to give colorless crystals (6.5 g). 0.8 crystal (4.5 g)
Add to M potassium hydroxide aqueous solution (25 ml) and add 110
Heated at ℃ for 1 hour. It was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate), and 1-nitro-4-[(4-propyl-1
H-1,2,4-triazol-5-on-3-yl)
Methylthio] benzene (1.0 g) was obtained as yellow crystals. ¹ H-NMR (dppm, CDCl ₃ ) 0.99 (3H, t, J = 7.4 Hz), 1.7
2-1.84 (2H, m), 3.71 (2H, t, J = 7.7 Hz), 4.09 (2
H, s), 7.50 (2H, d, J = 9.1 Hz), 8.16 (2H, d, J =
9.1 Hz), 9.80 (1H, br). IR (KBr) n: 1701 cm ^-1 . Anal.calcd. For C ₁₂ H ₁₄ N ₄ O ₃ S: C, 48.97; H, 4.79;
N, 19.04.Found C, 48.93; H, 4.76; N, 19.06.

Reference Example 48 1-Nitro-4-[(4-propyl-1H-1,2,4
-Triazol-5-on-3-yl) methylthio] benzene (0.5 g), reduced iron (0.5 g) and calcium chloride (0.1 g) in an 85% ethanol aqueous solution (15 m
1) and refluxed for 2 hours. The reaction solution was filtered using Celite, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (eluting solvent: ethyl acetate), and 4-[(4-propyl-1H-1,2,2,
4-triazol-5-one-3-yl) methylthio]
Aniline (0.4g) was obtained as light brown crystals. ¹ H-NMR (dppm, CDCl ₃ ) 0.96 (3H, t, J = 7.3 Hz), 1.7
1-1.83 (2H, m), 3.66-3.74 (2H, m), 3.75 (2H, s),
3.78 (2H, br), 6.59 (2H, d, J = 8.8 Hz), 7.17 (2H,
d, J = 8.8 Hz), 9.05 (1H, br) .IR (KBr) n: 1699 cm ^-1 . Anal.calcd. for C ₁₂ H ₁₆ N ₄ OS: C, 54.52; H, 6.10; N,
21.19. Found C, 54.47; H, 6.10; N, 21.11.

Reference Example 49 3-Amino-6-mercaptopyridazine (0.5 g),
3-chloromethyl-4-propyl-4H-1,2,4-
Triazole hydrochloride (0.57 g) and potassium carbonate (0.8 g) were added to N, N-dimethylformamide (5 m).
1) and stirred at room temperature for 4.5 hours. The solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by basic silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and 3-amino-6-[(4-propyl-1
H-1,2,4-triazol-3-yl) methylthio] pyridazine (0.62 g) was obtained as colorless crystals. mp 150-152 ℃. ¹ H-NMR (dppm, CDCl ₃ ) 0.95 (3H, t, J = 7.5 Hz), 1.7
7-1.89 (2H, m), 4.04 (2H, t, J = 7.3 Hz), 4.69 (2
H, s), 4.69 (2H, br), 6.69 (1H, d, J = 9.3 Hz), 7.
17 (1H, d, J = 9.3 Hz), 8.10 (1H, s) .IR (KBr) n: 3299, 3171, 1630, 1518, 1445 cm ^-1 . Anal.calcd. For C ₁₀ H ₁₄ N ₆ S : C, 47.98; H, 5.64; N,
33.57.Found C, 47.92; H, 5.61; N, 33.45.

Reference Example 50 3-Amino-6-mercaptopyridazine (0.5 g),
4-chloromethyl-3-propylmidazole hydrochloride (0.62 g) and potassium carbonate (2.0 g) were added to N, N-.
Dimethylformamide (10 ml) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was purified by basic silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and 3-amino-6-[(3-propylimidazol-4-yl) methylthio] pyridazine (0.
52 g) was obtained as yellow crystals. ¹ H-NMR (dppm, CDCl ₃ ) 0.95 (3H, t, J = 7.4 Hz), 1.7
8-1.89 (2H, m), 3.93 (2H, t, J = 7.3 Hz), 4.52 (2
H, s), 4.69 (2H, br), 6.65 (1H, d, J = 9.2Hz), 6.9
8 (1H, s), 7.05 (1H, d, J = 9.2 Hz), 7.45 (1H, s) .IR (KBr) n: 3304, 3154, 2967, 2934, 1636, 1499, 14
47 cm ^-1 .

Reference Example 51 Dihydroxyacetone (11.2 g), potassium thiocyanate (18.2 g), cyclopropylamine hydrochloride (15 g) was added to acetic acid (12 ml), 1-butanol (80).
ml) and heated at 50 ° C. overnight. The mixture was concentrated, methanol was added, and colorless crystals (11.5 g) were collected by filtration and washed with water. Sodium nitrite (0.1 g) was dissolved in nitric acid (20 ml) and water (20 ml), and the obtained crystals were added little by little under ice cooling. After stirring at room temperature for 1 hour, the mixture was neutralized with potassium carbonate and the solvent was distilled off. Ethanol was added, the insoluble material was filtered off, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to obtain a pale yellow oil (7.5 g). Add to thionyl chloride (20 ml) under ice cooling,
Refluxed for 30 minutes. The solvent was distilled off and 4-chloromethyl-
3-Cyclopropylimidazole hydrochloride (9.3 g) was obtained as colorless crystals. ¹ H-NMR (dppm, DMSO-d ₆ ) 1.10-1.27 (4H, m), 3.63-3.7
1 (1H, m), 5.04 (2H, s), 7.80 (1H, s), 9.24-9.27
(1H, m).

Reference Example 52 7- [4- (2-butoxyethoxy) phenyl] -2,
Methyl 3-dihydro-1H-1-benzazepine-4-carboxylate (2.0 g) and pyridine (4.0 ml)
To a THF (40 ml) solution of was added methanesulfonic anhydride (4.4 g) at 0 ° C and stirred at 60 ° C for 18 hours.
Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 2) to give 7- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance.
-1-Methanesulfonyl-2,3-dihydro-1H-1
-Methyl benzazepine-4-carboxylate (1.94
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.3 Hz), 1.
30-1.44 (2H, m), 1.51-1.66 (2H, m), 2.78 (3H, s),
2.99-3.07 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.80-3.
89 (7H, m), 4.18 (2H, t, J = 4.9 Hz), 7.02 (2H, d, J
= 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.53-7.57 (1H,
m), 7.63-7.70 (2H, m), 7.80 (1H, s).

Reference Example 53 7- [4- (2-butoxyethoxy) phenyl] -1-
Methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate methyl (1.94 g) T
A 1N sodium hydroxide aqueous solution (8.0 ml) was added to the HF-water (20-20 ml) solution at room temperature, and the mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, 1N hydrochloric acid (10 ml) was added to the residue.
Was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give colorless crystals 7-
[4- (2-Butoxyethoxy) phenyl] -1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.23 g) was obtained. mp 208-210 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz), 1.
29-1.49 (2H, m), 1.53-1.68 (2H, m), 2.81 (3H, s),
3.03-3.12 (2H, m), 3.56 (2H, t, J = 6.6 Hz), 3.80-3.
91 (4H, m), 4.18 (2H, t, J = 4.8 Hz), 7.02 (2H, d, J
= 8.8 Hz), 7.49-7.71 (5H, m), 7.90 (1H, s) .IR (KBr) 1670, 1497, 1341, 1250, 1154 cm ^-1 Elemental analysis C ₂₄ H ₂₉ NO ₆ S Calcd. C, 62.73; H, 6.36;
N, 3.05: Found. C, 62.62; H, 6.48; N, 2.92.

Reference Example 54 7- [4- (2-butoxyethoxy) phenyl] -2,
To a solution of 3-dihydro-1H-1-benzazepine-4-carboxylic acid (12.5 g) in THF (150 ml) was added 0.
Triethylamine (18.4 ml) and trifluoroacetic anhydride (11.6 ml) were added at 0 ° C. and the mixture was stirred for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction system, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction system until the pH reached 7, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to give 7- [4- (2-butoxyethoxy) phenyl] -1 as colorless crystals.
-Trifluoroacetyl-2,3-dihydro-1H-1
-Benzazepine-4-carboxylic acid (11.19 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.3 Hz), 1.
31-1.49 (2H, m), 1.56-1.69 (2H, m), 2.79-3.28 (3H,
m), 3.57 (2H, t, J = 6.6 Hz), 3.83 (2H, t, J = 4.7 H
z), 4.19 (2H, t, J = 4.7 Hz), 4.72-4.89 (1H, m), 7.0
3 (2H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.52-
7.60 (3H, m), 7.69 (1H, d, J = 1.8 Hz), 7.87 (1H,
s).

Reference Example 55 Under an argon atmosphere, 4-fluorophenylacetonitrile (3.97 g), 2-bromo-6-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF ( 125 ml) mixture at 0 ° C. with sodium hydride (2.35 g, 60
%) Was added and the mixture was heated under reflux for 3 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 2- (α- as a yellow oil.
Cyano-4-fluorobenzyl) -6-methylpyridine (5.51 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.56 (3H, s), 5.26 (1H,
s), 7.02-7.18 (4H, m), 7.39-7.46 (2H, m), 7.59 (1
H, t, J = 7.7 Hz). IR (KBr) 2247, 1593, 1574, 1508, 1456, 1231, 1159,
839, 804 cm ^-1

Reference Example 56 2- (α-Cyano-4-fluorobenzyl) -6-methylpyridine (5.51 g) and potassium carbonate (3.70 g) in DMSO-water (220-45 ml) under an oxygen atmosphere.
The mixed solution was stirred at room temperature for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 2- (4-
Fluorobenzoyl) -6-methylpyridine (5.02
g) was obtained. mp 53-54 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.64 (3H, s), 7.09-7.21 (2
H, m), 7.33-7.37 (1H, m), 7.73-7.85 (2H, m), 8.15-
8.25 (2H, m). IR (KBr) 1622, 1588, 1501, 1454, 1412, 1375, 1310,
1231, 1167, 1157, 1091, 991, 955, 850, 756, 610 c
m ^-1 Elemental analysis C ₁₃ H ₁₀ NOF Calcd. C, 72.55; H, 4.68; N,
6.51: Found. C, 72.52; H, 4.74; N, 6.39.

Reference Example 57 2- (4-Fluorobenzoyl) -6-methylpyridine (2.0 g) and sodium azide (3.36 g) in DM
The SO (40 ml) solution was stirred at 90 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue (1.88 g) in THF (40
ml) solution to lithium aluminum hydride (0.60
g) was added dropwise to a suspension of THF (20 ml) at 0 ° C. After stirring for 30 minutes at room temperature, water (0.6 ml) at 0 ° C, 15%
Aqueous sodium hydroxide solution (0.6 ml) and water (1.
8 ml) was slowly added dropwise in this order. After stirring at room temperature for 4 days, magnesium sulfate was added and filtered (Celite)
The precipitate was removed by. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate) to obtain (4-aminophenyl) (6-methylpyridin-2-yl) methanol (1.44 g) as pale yellow crystals. mp 165-166 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ2.58 (3H, s), 3.51-3.73 (2
H, m), 5.55-5.61 (2H, m), 6.65 (2H, d, J = 8.4 Hz),
6.88 (1H, d, J = 7.8 Hz), 7.03 (1H, d, J = 7.6 Hz), 7.
13 (2H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 7.8, 7.6 H
z) .IR (KBr) 3330, 1611, 1595, 1578, 1510, 1460, 1258,
1071, 903, 833, 806 cm ^-1 Elemental analysis C ₁₃ H ₁₄ N ₂ O Calcd. C, 72.87; H, 6.59; N,
13.07: Found. C, 72.64; H, 6.68; N, 12.87.

Reference Example 58 Under an argon atmosphere, 4-fluorophenylacetonitrile (3.97 g), 2-bromo-3-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF ( 125 ml) mixture at 0 ° C. with sodium hydride (2.35 g, 60
%) Was added and the mixture was heated under reflux for 3.5 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 3) to give 2- (α as a brown oil.
-Cyano-4-fluorobenzyl) -3-methylpyridine (5.14 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.27 (3H, s), 5.45 (1H,
s), 7.00-7.10 (2H, m), 7.19-7.26 (1H, m), 7.32-7.3
9 (2H, m), 7.48-7.57 (1H, m), 8.51-8.54 (1H, m) .IR (KBr) 2245, 1605, 1574, 1508, 1454, 1420, 1229,
1161, 1107, 837, 801,739 cm ^-1

Reference Example 59 2- (α-cyano-4-fluorobenzyl) -3-methylpyridine (5.14 g) and potassium carbonate (2.90 g) in DMSO-water (250-50 ml) under an oxygen atmosphere.
The mixed solution was stirred at room temperature for 6 days. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 2- (4-
Fluorobenzoyl) -3-methylpyridine (5.1
7) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 7.10-7.20 (2H, m), 7.35 (1
H, dd, J = 7.6, 4.8 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.89
-7.96 (2H, m), 8.33 (1H, d, J = 4.4 Hz) .IR (KBr) 1672, 1599, 1505, 1292, 1233, 1152, 1115,
936, 853, 610 cm ^-1

Reference Example 60 2- (4-Fluorobenzoyl) -3-methylpyridine (4.0 g) and sodium azide (6.7 g) in DMS
The O (80 ml) solution was stirred at 90 ° C. for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue (3.90 g) in THF (40
ml) solution, lithium aluminum hydride (1.24
g) was added dropwise to a THF (40 ml) suspension at 0 ° C. After stirring at room temperature for 3 hours, at 0 ° C water (1.24 ml), 15%
Aqueous sodium hydroxide solution (1.24 ml) and water (3.72 ml) were slowly added dropwise in this order. After stirring at room temperature for 16 hours, magnesium sulfate was added and the precipitate was removed by filtration (Celite). After concentration under reduced pressure, recrystallization (ethyl acetate) was performed to obtain (4-aminophenyl) (3-methylpyridin-2-yl) methanol (2.60 g) as pale yellow crystals. mp 153-154 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.07 (3H, s), 3.56-3.66 (2
H, m), 5.64 (1H, d, J = 6.2 Hz), 5.93 (1H, d, J = 6.2
Hz), 6.60 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.4 H
z), 7.17 (1H, dd, J = 7.8, 4.8 Hz), 7.41-7.45 (1H,
m), 8.45-8.47 (1H, m) .IR (KBr) 3449, 3357, 1632, 1613, 1516, 1451, 1383,
1300, 1179, 1017, 1007, 868, 833, 801, 739 cm ^-1 Elemental analysis C ₁₃ H ₁₄ N ₂ O Calcd. C, 72.87; H, 6.59; N,
13.07: Found. C, 72.77; H, 6.81; N, 12.93.

Reference Example 61 Under an argon atmosphere, 4-fluorophenylacetonitrile (3.97 g), 2-bromo-5-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF ( 125 ml) mixture at 0 ° C. with sodium hydride (2.35 g, 60
%) Was added and the mixture was heated under reflux for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 2- (α- as a yellow oil.
Cyano-4-fluorobenzyl) -5-methylpyridine (4.35 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.34 (3H, s), 5.26 (1H,
s), 7.02-7.10 (2H, m), 7.28 (1H, d, J = 8.0 Hz), 7.3
7-7.44 (2H, m), 7.52 (1H, dd, J = 8.0, 2.0 Hz), 8.42
(1H, d, J = 2.2 Hz).

Reference Example 62 2- (α-cyano-4-fluorobenzyl) -5-methylpyridine (4.35 g) and potassium carbonate (3.07 g) in DMSO-water (200-40 ml) under an oxygen atmosphere.
The mixed solution was stirred at room temperature for 18 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 2- (4-fluorobenzoyl) -5-methylpyridine (3.47) as colorless crystals.
g) was obtained. mp 127-128 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.46 (3H, s), 7.11-7.22 (2
H, m), 7.68-7.74 (1H, m), 7.99 (1H, d, J = 8.0 Hz),
8.12-8.19 (2H, m), 8.54-8.55 (1H, m). IR (KBr) 1659, 1597, 1507, 1412, 1316, 1248, 1227,
1155, 1034, 941, 860,849, 775, 733, 681, 634, 581
cm ^-1 Elemental analysis C ₁₃ H ₁₀ NOF Calcd. C, 72.55; H, 4.68; N,
6.51: Found. C, 72.68; H, 4.64; N, 6.59.

Reference Example 63 2- (4-fluorobenzoyl) -5-methylpyridine (3.0 g) and sodium azide (4.97 g) in DM
The SO (60 ml) solution was stirred at 90 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, TH of the residue (3.39 g)
The F (40 ml) solution was added dropwise to a suspension of lithium aluminum hydride (1.06 g) in THF (40 ml) at 0 ° C. After stirring for 1 hour at room temperature, water (1.06 m
l), 15% aqueous sodium hydroxide solution (1.06 ml)
And water (3.18 ml) were slowly added dropwise in this order. After stirring at room temperature for 64 hours, magnesium sulfate was added and the precipitate was removed by filtration (Celite). After concentration under reduced pressure, recrystallization was performed to obtain (4-aminophenyl) (5-methylpyridin-2-yl) methanol (2.07 g) as pale yellow crystals. mp 114-115 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.32 (3H, s), 3.53-3.72 (2
H, m), 5.09 (1H, d, J = 4.0 Hz), 5.62 (1H, d, J = 4.0
Hz), 6.64 (2H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.0 H
z), 7.12 (2H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.0,
2.2), 8.37 (1H, d, J = 2.2 Hz) .IR (KBr) 3349, 1200, 1615, 1516, 1487, 1449, 1264,
1252, 1198, 1179, 1063, 1038, 826 cm ^-1 Elemental analysis C ₁₃ H ₁₄ N ₂ O Calcd. C, 72.87; H, 6.59; N,
13.07: Found. C, 72.68; H, 6.88; N, 12.81.

Reference Example 64 Under an argon atmosphere, 4-fluorophenylacetonitrile (9.13 g), 2-chloro-5-chloropyridine (10.0 g) and sodium 4-methylphenylsulfinate (24.1 g) in THF ( 280 ml) mixture at 0 ° C. with sodium hydride (5.41 g, 60%).
Was added and the mixture was heated under reflux for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 5-chloro-2- (α-cyano-4-fluorobenzyl) pyridine (16.14 g) as a yellow oil. ) Got. ¹ H-NMR (200MHz, CDCl ₃ ) δ 5.28 (1H, s), 7.04-7.12 (2
H, m), 7.32-7.44 (3H, m), 7.70 (1H, dd, J = 8.4, 2.6
Hz), 8.55 (1H, d, J = 2.6 Hz). IR (KBr) 2250, 1607, 1578, 1508, 1466, 1373, 1235,
1161, 1111, 1017, 833cm ^-1 Elemental analysis C ₃₇ H ₃₆ N ₃ O ₆ F ₃ 0.5H ₂ O Calcd. C, 64.90; H,
5.45; N, 6.14: Found. C, 64.97; H, 5.37; N, 6.
Ten.

Reference Example 65 Under an oxygen atmosphere, 5-chloro-2- (α-cyano-4-fluorobenzyl) pyridine (16.14 g) and potassium carbonate (10.85 g) in DMSO-water (330-66 m).
l) The mixed solution was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 4) to give 5-chloro-2- (4-fluorobenzoyl) pyridine (14.3 as colorless crystals).
7 g) was obtained. mp 98-100 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ7.13-7.22 (2H, m), 7.89 (1
H, dd, J = 8.4, 2.4 Hz), 8.06 (1H, d, J = 8.4 Hz), 8.13
-8.20 (2H, m), 8.65 (1H, d, J = 2.4 Hz). IR (KBr) 1666, 1599, 1566, 1507, 1408, 1370, 1306,
1236, 1157, 1123, 1107, 1015, 951, 862, 816, 725,
675 cm ^-1 Elemental analysis C ₁₂ H ₇ NOClF Calcd. C, 61.16; H, 2.99;
N, 5.94: Found. C, 61.14; H, 2.90; N, 6.00.

Example 66 5-Chloro-2- (4-fluorobenzoyl) pyridine (3.0 g), sodium azide (0.84 g) in DM
The SO (60 ml) solution was stirred at 90 ° C. for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, TH of the residue (3.19 g)
The F (60 ml) solution was added dropwise to a suspension of lithium aluminum hydride (0.97 g) in THF (10 ml) at 0 ° C. After stirring at 0 ° C. for 10 minutes, water (0.97 ml),
A 15% aqueous sodium hydroxide solution (0.97 ml) and water (2.9 ml) were slowly added dropwise in this order. After stirring at room temperature for 18 hours, magnesium sulfate was added, and the precipitate was removed by filtration (Celite). After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 2: 1) to give (4-aminophenyl) (5-chloropyridine-2) as pale yellow crystals.
-Yl) The synthesis of methanol (0.90 g) was obtained. mp 122-123 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ3.60-3.71 (2H, m), 4.56 (1
H, d, J = 4.1 Hz), 5.65 (1H, d, J = 4.1 Hz), 6.65 (2H,
d, J = 8.8 Hz), 7.08-7.17 (3H, m), 7.60 (1H, dd, J = 8.
2, 2.2 Hz), 8.51 (1H, d, J = 2.2 Hz) .IR (KBr) 3378, 3183, 1615, 1578, 1514, 1472, 1370,
1267, 1198, 1175, 1113, 1049, 1020, 828 cm ^-1 Elemental analysis C ₁₂ H ₁₂ N ₂ OCl Calcd. C, 61.41; H, 4.72;
N, 11.94: Found. C, 61.47; H, 4.83; N, 11.78.

Reference Example 67 Under an argon atmosphere, 4-fluorophenylacetonitrile (3.13 g), 2-bromo-3-propoxypyridine (5.0 g) and sodium 4-methylphenylsulfinate (8.23 g) in THF ( 100 ml) mixture at 0 ° C. with sodium hydride (1.85 g, 60%)
Was added and the mixture was heated under reflux for 5 hours. The reaction mixture was added to water,
It was extracted with ethyl acetate. The organic layer was washed with saturated saline,
It was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1:
After separation and purification in 4), 2- (α-cyano-4-fluorobenzyl) -3-propoxypyridine (5.52 g) was obtained as a pale yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.04 (3H, t, J = 7.5 Hz), 1.
74-1.91 (2H, m), 3.95 (2H, t, J = 6.6 Hz), 5.64 (1H,
s), 6.98-7.00 (2H, m), 7.14-7.26 (2H, m), 7.42-7.4
9 (2H, m), 8.22 (1H, dd, J = 4.4, 1.6 Hz). IR (neat) 2240, 1601, 1580, 1505, 1445, 1285, 123
1, 1159, 1113, 974, 849, 795 cm ^-1

Reference Example 68 2- (α-cyano-4-fluorobenzyl) -3-propoxypyridine (5.42 g) and potassium carbonate (3.07 g) in DMSO-water (200-40 m) under an oxygen atmosphere.
l) The mixed solution was stirred at room temperature for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 3 → 1: 2), and 2- (4-fluorobenzoyl) -3-propoxypyridine (4. 46 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86 (3H, t, J = 7.5 Hz), 1.
60-1.79 (2H, m), 3.95 (2H, t, J = 6.4 Hz), 7.08-7.16
(2H, m), 7.30-7.48 (2H, m), 7.85-7.92 (2H, m), 8.27
(1H, dd, 4.1, 1.9). IR (neat) 1676, 1599, 1578, 1507, 1443, 1292, 127
7, 1231, 1204, 1152, 1121, 937 cm ^-1

Reference Example 69 2- (4-Fluorobenzoyl) -3-propoxypyridine (4.46 g), sodium azide (3.34 g)
A DMSO (50 ml) solution of was stirred at 90 ° C. for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue (4.8 g) in THF
The (50 ml) solution was added dropwise to a suspension of lithium aluminum hydride (1.3 g) in THF (40 ml) at 0 ° C. After stirring for 30 minutes at room temperature, water (1.3 m
1), 15% aqueous sodium hydroxide solution (1.3 ml) and water (3.9 ml) were slowly added dropwise in this order. After stirring at room temperature for 2 hours, magnesium sulfate was added, and the precipitate was removed by filtration (Celite). After concentration under reduced pressure, the residue was recrystallized (ethyl acetate) to obtain (4-aminophenyl) (3-propoxypyridin-2-yl) methanol (2.82 g) as pale yellow crystals. mp 156-157 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.97 (3H, t, J = 7.3 Hz), 1.
66-1.82 (2H, m), 3.49-3.66 (2H, m), 3.80-3.87 (2H, m
m), 5.41 (1H, d, J = 6.8 Hz), 5.84 (1H, d, J = 6.8 H
z), 6.59 (2H, d, J = 8.4 Hz), 7.04-7.20 (4H, m), 8.1
5 (1H, dd, J = 4.7,1.5 Hz) .IR (KBr) 3428, 3349, 1613, 1518, 1445, 1281, 1211,
1177, 1032, 1009, 839cm ^-1 Elemental analysis C ₁₅ H ₁₈ N ₂ O ₂ Calcd. C, 69.74; H, 7.02;
N, 10.84: Found. C, 69.73; H, 7.01; N, 10.74.

Reference Example 70 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (10.0 g) in THF (100
(ml) solution was added with thionyl chloride (2.5 ml) and DMF (0.5 ml) at room temperature and stirred for 1.5 hours. After concentration under reduced pressure, a solution of the residue in THF (100 ml) was added to 4-
To a solution of (tert-butyldimethylsiloxymethyl) aniline (5.92 g) and triethylamine (32 ml) in THF (50 ml) was added dropwise at 0 ° C. 3 at room temperature
After stirring for an hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, acetone (150 ml) and 6N were added to the residue.
Hydrochloric acid (8 ml) was added and stirred for 20 minutes. After adding a 1N sodium hydroxide aqueous solution (50 ml), the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline 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- [4- (2-butoxyethoxy) phenyl] as a yellow amorphous substance.
-N- (4-hydroxymethylphenyl) -2,3-dihydro-1-isobutyl-1H-1-benzazepine-
4-Carboxamide (11.41 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 0.
97 (6H, d, J = 6.6 Hz), 1.27-1.46 (2H, m), 1.52-1.73
(2H, m), 1.95-2.16 (1H, m), 2.86-2.97 (2H, m), 3.19
(2H, d, J = 6.8 Hz), 3.34-3.39 (2H, m), 3.55 (1H,
t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t,
J = 5.0 Hz), 4.68 (2H, s), 6.92 (1H, d, J = 8.8 Hz),
6.98 (2H, d, J = 8.8 Hz), 7.33-7.62 (10H, m), H. IR (KBr) 3289, 1645, 1605, 1516, 1499, 1406, 1314,
1244, 1181, 1119, 816cm ^-1 Elemental analysis C ₃₄ H ₄₂ N ₂ O ₄ 0.25H ₂ O Calcd. C, 74.63; H,
7.83; N, 5.12: Found.C, 74.76; H, 7.97; N, 5.2
6.

Reference Example 71 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding 2-iodopropane (5.31 g) to the suspension, it was heated at 50 ° C. for 5 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 1-isopropylimidazole-2-carboxaldehyde (3.35 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.47 (6H, d, J = 7.0 Hz),
5.41-5.55 (1H, m), 7.31-7.33 (2H, m), 9.83 (1H,
s).

Reference Example 72 THF of lithium aluminum hydride (978 mg)
(15 ml) suspension with 1-isopropylimidazole-
2-Carboxaldehyde (2.38 g) in THF (1
5 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere.
After completion of the dropping, water (1.0 ml), a 15% aqueous sodium hydroxide solution (1.0 ml) and water (3.0 m) were added at 0 ° C.
l) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure to obtain 2-hydroxymethyl-1-isopropylimidazole (2.10 g) as brown crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.45 (6H, d, J = 6.8 Hz),
4.53-4.67 (1H, m), 4.68 (2H, s), 6.91 (1H, d, J = 1.
2 Hz), 6.94 (1H, d, J = 1.2 Hz). Elemental analysis C ₇ H ₁₂ N ₂ O Calcd. C, 59.98; H, 8.63; N, 1
9.98; Found. C, 59.90; H, 8.53; N, 20.07.

Reference Example 73 DMF was added to a solution of 2-hydroxymethyl-1-isopropylimidazole (1.0 g) in chloroform (15 ml).
After adding a drop of thionyl chloride (0.68
ml) was added. After returning to room temperature and stirring under a nitrogen atmosphere for 30 minutes, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was mixed with 4-aminothiophenol (811 mg) and sodium hydroxide (5
70 mg) was added to a mixed solution of methanol (10 ml) and water (6 ml) at 0 ° C. After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure to give 4-[[(1-isopropylimidazol-2-yl) methyl] sulfanyl] aniline (1.55 g) as an oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.41 (6H, d, J = 6.6 Hz),
3.71 (2H, br), 4.06 (2H, s), 4.38-4.60 (1H, m), 6.
58 (2H, d, J = 8.8 Hz), 6.92-6.93 (2H, m), 7.16 (2H,
d, J = 8.8 Hz).

Reference Example 74 4-Aminothiophenol (1.0 g), 3-chloromethyl-1,2,4-oxadiazole (1.0 g) and triethylamine (1.1 ml) in THF (10 m).
l) The solution was stirred at room temperature for 18 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 3 → 1: 2) to give 4- (1,2,4-oxadiazol-3-yl) as a pale yellow oil. Methylthio) aniline (1.36 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.63-3.84 (2H, m), 4.02 (2
H, s), 6.59 (2H, d, J = 8.4 Hz), 7.21 (2H, d, 8.4 H
z), 8.65 (1H, s) .IR (neat) 3357, 1624, 1597, 1551, 1497, 1341, 128
7, 1179, 1109, 827, 739cm ^-1

Reference Example 75 Hydrazine monohydrate (10.0 g) in ethanol (1
(00 ml) solution at room temperature with ethyl glycolate (20.
8 g) was slowly added dropwise while maintaining the temperature of the reaction system at 10 ° C or lower. After stirring at room temperature for 5 hours, ethyl isothiocyanate (17.42 g) was slowly added dropwise while keeping the temperature of the reaction system at 10 ° C or lower. After stirring at 40 ° C. for 18 hours, the mixture was cooled to room temperature and ice water (50 ml) was added. 15
After stirring for 5 minutes, 5N aqueous sodium hydroxide solution (40 ml) was added, and the mixture was stirred at 60 ° C. for 4 hours. Concentrated hydrochloric acid was added dropwise at 0 ° C until the pH reached 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water, and 4-ethyl-as colorless crystals.
3-hydroxymethyl-5-mercapto-4H-1,
2,4-triazole (7.5 g) was obtained. Sodium nitrite (0.06 g) was added to a mixture of 90% nitric acid (15 ml) and water (22 ml) and then at 45 ° C. 3-hydroxymethyl-5-mercapto-4-ethyl-4H-.
1,2,4-triazole (7.5 g) was added slowly over 0.5 hour. After cooling to room temperature, sodium carbonate was slowly added at 0 ° C. until the pH reached 7. After concentration under reduced pressure, methanol was added and the precipitate was removed by filtration. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 2: 1) to give 4-ethyl-3-hydroxymethyl-4 as a brown oil.
H-1,2,4-triazole (4.60 g) was obtained.
4-Ethyl-3-hydroxymethyl-4H-1,2,4
-To triazole (4.6g) at 0 <0> C thionyl chloride (36ml) was added slowly. After heating under reflux for 1 hour,
It was concentrated under reduced pressure. Ethyl acetate and ethanol were added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate to give 3-chloromethyl- as orange crystals.
4-Ethyl-4H-1,2,4-triazole.hydrochloride (4.22 g) was obtained. mp 125-127 ℃ ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.42 (3H, t, J = 7.2 Hz),
4.15 (2H, q, J = 7.2 Hz), 5.08 (2H, s), 9.11 (1H,
s) .IR (KBr) 1574, 1537, 1325, 1181, 1086, 974, 953, 8
64, 748, 671 cm ^-1 Elemental analysis C ₅ H ₉ N ₃ Cl ₂ 0.2H ₂ O Calcd. C, 32.35; H, 5.1
0; N, 22.63: Found.C, 32.05; H, 4.72; N, 22.5
2.

Reference Example 76 Hydrazine monohydrate (9.66 g) in ethanol (1
(00 ml) solution at room temperature with ethyl glycolate (20.
09 g) was slowly added dropwise while maintaining the temperature of the reaction system at 10 ° C or lower. After stirring at room temperature for 4 hours, propyl isothiocyanate (20 ml) was slowly added dropwise while maintaining the temperature of the reaction system at 10 ° C or lower. After stirring at 40 ° C. for 64 hours, the mixture was cooled to room temperature, and ice water (50 ml) was added. 15
After stirring for 5 minutes, 5N aqueous sodium hydroxide solution (40 ml) was added, and the mixture was stirred at 60 ° C. for 4 hours. Concentrated hydrochloric acid was added dropwise at 0 ° C until the pH reached 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water to give 3-hydroxymethyl-5-mercapto-4-propyl-4H-1, as colorless crystals.
2,4-triazole (23.45 g) was obtained. 90%
Sodium nitrite (0.07 g) was added to a mixture of nitric acid (18 ml) and water (26 ml), followed by 3-at 45 ° C.
Hydroxymethyl-5-mercapto-4-propyl-4
H-1,2,4-triazole (10 g) was added slowly over 0.5 hour. After cooling to room temperature, sodium carbonate was slowly added at 0 ° C. until the pH reached 7. After concentration under reduced pressure, methanol was added and the precipitate was removed by filtration. After concentration under reduced pressure, dichloromethane was added, the precipitate was removed by filtration, and the filtrate was concentrated to give 3- as a crude product.
Hydroxymethyl-4-propyl-4H-1,2,4-
Triazole (5.95 g) was obtained. To 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g) was slowly added thionyl chloride (40 ml) at 0 ° C. After heating under reflux for 1 hour, the mixture was concentrated under reduced pressure. Ethanol was added to the residue and further concentrated. Ethyl acetate and a small amount of ethanol were added to the residue, and the precipitated crystals were collected by filtration. The crystals are washed with ethyl acetate,
3-chloromethyl-4-propyl-as pale yellow crystals
4H-1,2,4-triazole hydrochloride (5.43
g) was obtained. mp 91-94 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.80 (3H, t, J = 7.3 Hz), 1.
73-1.94 (2H, m), 4.11 (2H, t, J = 7.4 Hz), 5.10 (2H,
s), 9.26 (1H, s), H. IR (KBr) 3353, 1574, 1537, 1470, 1331, 1204, 1177,
957 cm ^-1 Elemental analysis C ₆ H ₁₁ N ₃ Cl ₂ 0.25H ₂ O Calcd. C, 35.93; H,
5.78; N, 20.95: Found. C, 36.13; H, 5.77; N, 2
1.23.

Reference Example 77 Hydrazine monohydrate (7.5 g) in ethanol (75 g)
ml) solution at room temperature with ethyl glycolate (15.6).
g) was slowly added dropwise while maintaining the temperature of the reaction system at 10 ° C or lower. After stirring at room temperature for 6 hours, isothiocyanic acid n
-Butyl (17.3 g) was slowly added dropwise while maintaining the temperature of the reaction system at 10 ° C or lower. 5 hours at room temperature, 40 ° C
After stirring for 8 hours at room temperature, the mixture was cooled to room temperature and ice water (50 ml) was added. After stirring for 15 minutes, 5N aqueous sodium hydroxide solution (40 ml) was added, and the mixture was stirred at 60 ° C. for 6 hours. Concentrated hydrochloric acid was added dropwise at 0 ° C until the pH reached 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water to give 4-n-butyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (22.67 g) as colorless crystals.
Got 90% nitric acid (17 ml) and water (25 ml)
Sodium nitrite (0.07g) was added to the mixture, which was followed by 4-n-butyl-3-hydroxymethyl-5 at 45 ° C.
-Mercapto-4H-1,2,4-triazole (1
0.0 g) was added slowly over 0.5 hour. After cooling to room temperature, sodium carbonate was slowly added at 0 ° C. until the pH reached 7. After concentration under reduced pressure, methanol was added and the precipitate was removed by filtration. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1: 9), and 4-n-butyl-3-hydroxymethyl-4H- was obtained as an orange oil.
1,2,4-triazole (6.78 g) was obtained. 4-
n-Butyl-3-hydroxymethyl-4H-1,2,4
-To triazole (6.78g) at 0 <0> C thionyl chloride (44ml) was added slowly. After heating under reflux for 1 hour,
It was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration. The crystals are washed with ethyl acetate,
4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (7.03) as pale yellow crystals.
g) was obtained. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 0.91 (3H, t, J = 7.2 Hz),
1.25-1.37 (2H, m), 1.75-1.83 (2H, m), 4.09 (2H, t,
J = 7.5 Hz), 5.05 (2H, s), 8.97 (1H, s) .IR (KBr) 1572, 1460, 1329, 1179, 1082, 959, 943, 8
78, 743, 669 cm ^-1 Elemental analysis C ₇ H ₁₃ N ₃ Cl ₂ Calcd. C, 40.02; H, 6.24;
N, 20.00: Found. C, 39.91; H, 6.48; N, 20.16.

Reference Example 78 3-Hydroxymethyl-4-isobutyl-5-mercapto-4H-1,2,4-triazole (1.0 g), ethane iodide (1.0 g) and triethylamine (1.
A solution of 1 ml) in ethanol (10 ml) was stirred at 70 ° C. for 2 days. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 9 → 1: 5) to give 5-ethylthio-3-as a pale yellow oil.
Hydroxymethyl-4-isobutyl-4H-1,2,4
-Triazole (1.0 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (6H, d, J = 6.6 Hz), 1.
40 (3H, t, J = 7.3 Hz), 2.06-2.25 (1H, m), 3.24 (2H,
q, J = 7.3 Hz), 3.76 (2H, d, J = 7.6 Hz), 4.80 (2H, s). IR (neat) 3206, 1472, 1387, 1057, 1028, 739 cm ^-1

Reference Example 79 A solution of 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) in chloroform (3 ml) was added to thionyl chloride (8 g) at 0 ° C.
ml) was added slowly. After heating under reflux for 1 hour, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with diethyl ether to give 3-chloromethyl-5-ethylthio-4-isobutyl-4H-1,2,4-triazole.hydrochloride (0.64 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.86 (6H, d, J = 6.6 Hz),
1.31 (3H, t, J = 7.2 Hz), 2.06-2.22 (1H, m), 3.20 (2
H, q, J = 7.2 Hz), 3.79 (2H, d, J = 7.6 Hz), 4.97 (2H,
s) .IR (KBr) 1577, 1514, 1422, 1327, 1279, 992, 895, 7
95 cm ^-1

Reference Example 80 3-Hydroxymethyl-4-propyl-5-mercapto-4H-1,2,4-triazole (2.0 g), iodomethane (1.1 ml) and triethylamine (2.
A solution of 5 ml) in ethanol (20 ml) was stirred at 50 ° C. for 2 days. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethanol: ethyl acetate 1: 5 → 1: 4) to give 3-hydroxymethyl-5-methylthio-4-propyl-4H-1 as a pale yellow oil. , 2,4-
Triazole (2.13 g) was obtained. 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,
4-Triazole (2.13g) in chloroform (6m
l) Thionyl chloride (16 ml) was slowly added to the solution at 0 ° C. After heating under reflux for 2 hours, the mixture was concentrated under reduced pressure. A small amount of ethanol and ethyl acetate were added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diethyl ether to give 3-chloromethyl-5-methylthio-4-propyl-4H-1, as colorless crystals.
2,4-triazole hydrochloride (1.06 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.89 (3H, t, J = 7.3 Hz),
1.63-1.82 (2H, m), 2.66 (3H, s), 3.91 (2H, t, J = 7.
7 Hz), 5.00 (2H, s) .IR (KBr) 1576, 1507, 1480, 1458, 1422, 1346, 1298,
1206, 984 cm ^-1

Reference Example 81 A solution of 4-nitromethylaniline (1.0 g) and 3-chloromethyl-4-propyl-4H-1,2,4-triazole.hydrochloride (1.45 g) in DMSO (20 ml) was added. , Sodium hydride at room temperature (60%, 0.60g)
Was added and the mixture was stirred at 50 ° C. for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate → ethanol: ethyl acetate 1: 4) to give 4-nitro [methyl (4-propyl-4H-) as yellow crystals.
1,2,4-triazol-3-ylmethyl)] aniline (0.82 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.5 Hz), 1.
65-1.84 (2H, m), 3.13 (3H, s), 3.84 (2H, t, J = 7.4 H
z), 4.80 (2H, s), 6.83 (2H, d, J = 9.5 Hz), 8.15 (1
H, s), 8.16 (2H, d, J = 9.5 Hz). IR (KBr) 1567, 1586, 1512, 1480, 1329, 1264, 1190,
1115, 820, 785, 752 cm ^-1 Elemental analysis C ₁₃ H ₁₇ N ₅ O ₂ Calcd. C, 56.71; H, 6.22;
N, 25.44: Found. C, 56.44; H, 6.07; N, 25.21.

Reference Example 82 4-nitro [methyl (4-propyl-4H-1,2,4
-Triazol-3-ylmethyl)] aniline (1.0
g) An ethanol mixture of 10% Pd-C (0.3 g) was vigorously stirred under a hydrogen atmosphere for 18 hours. Pd-C was removed by filtration, the mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diethyl ether to give 4- [methyl (4-propyl-4) as brown crystals.
H-1,2,4-triazol-3-ylmethyl) amino] aniline (0.50 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.4 Hz), 1.
68-1.85 (2H, m), 2.71 (3H, s), 3.93 (2H, t, J = 7.3 H
z), 4.42 (2H, s), 6.67 (2H, d, J = 8.7 Hz), 6.84 (2
H, d, J = 8.7 Hz), 8.10 (1H, s) .IR (KBr) 3422, 3337, 1522, 1372, 1319, 1279, 1217,
1198, 1121, 828 cm ^-1

Reference Example 83 A solution of sodium methoxide in methanol (28%, 2.4) was added to a suspension of 4-nitrobenzyltriphenylphosphonium bromide (6.1 g) in THF (60 ml) at room temperature.
6 g) was added and the mixture was stirred at room temperature for 0.5 hours. 3 in the reaction system
-Formyl-4-propyl-4H, 1,2,4-triazole (2.0 g) in THF (30 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate → ethanol: ethyl acetate 1:
9) was separated and purified to give 3-[(E) -2 as yellow crystals.
-(4-Nitrophenyl) ethenyl] -4-propyl-
4H-1,2,4-triazole (1.6g) was obtained. mp 77-79 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.3 Hz), 1.
66-1.85 (2H, m), 3.82 (2H, t, J = 7.3 Hz), 6.50 (1H,
d, J = 12.7 Hz), 7.03 (1H, d, J = 12.7 Hz), 7.80 (2H,
d, J = 8.8 Hz), 8.15-8.19 (3H, m) .IR (KBr) 1593, 1512, 1341, 1196, 1107, 883, 856cm
^-1 Elemental analysis C ₁₃ H ₁₄ N ₄ O ₂ 0.1H ₂ O Calcd. C, 60.04; H, 5.
50; N, 21.54: Found.C, 50.76; H, 5.37; N, 21.7
1.

Reference Example 84 3-[(E) -2- (4-nitrophenyl) ethenyl]
A mixture of -4-propyl-4H-1,2,4-triazole (0.80 g), 10% Pd-C (0.08 g) in ethanol (10 ml) was vigorously stirred under a hydrogen atmosphere for 24 hours. Pd-C was removed by filtration, and the mixture was concentrated under reduced pressure to give 4- [2- (4-propyl-4H-1,2,4-triazol-3-yl) ethyl] aniline (768 mg) as a pale yellow oil. It was ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.5 Hz), 1.
54-1.81 (2H, m), 2.86-3.12 (4H, m), 3.45-3.79 (4H, m
m), 6.62 (2H, d, J = 8.3 Hz), 6.96 (2H, d, J = 8.3 H
z), 8.03 (1H, s).

Reference Example 85 4-Nitrothiophenol (10.0 g) and 2-bromoethylamine hydrobromide (14.52 g) in methanol (100 ml) was added with 2N aqueous sodium hydroxide solution (120 ml) at room temperature. The mixture was added dropwise and stirred at room temperature for 20 hours. Di-tert-butyl dicarbonate (15.
0 g) was added and the mixture was further stirred for 3 hours. Methanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The crystals were concentrated under reduced pressure and the precipitated crystals were collected by filtration. The crystals were washed with hexane to give yellow crystals (12.32 g). Concentrated hydrochloric acid (100 ml) was added to an ethanol suspension (100 ml) of the obtained crystals at room temperature, and the mixture was stirred for 24 hours. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give 2- (4-nitrophenylthio) ethylamine as yellow crystals.
The hydrochloride salt (9.96 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 3.04 (2H, t, J = 7.4 Hz),
3.40 (2H, t, J = 7.4 Hz), 7.62 (2H, d, J = 9.0 Hz), 8.
06-8.27 (5H, m).

Reference Example 86 2- (4-Nitrophenylthio) ethylamine hydrochloride (7.87 g), N, N-dimethylformamidazine (5.07 g), triethylamine (5.0 ml) and p-toluenesulfonic acid A toluene (100 ml) mixture of monohydrate (0.3 g) was heated under reflux for 6 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The crystals precipitated after concentration under reduced pressure were collected by filtration. The crystals were washed with diethyl ether to give 4- [2-
(4-Nitrophenylthio) ethyl] -4H-1,2,
The synthesis of 4-triazole (4.27 g) was obtained. mp 162-165 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ3.41 (2H, t, J = 6.4 Hz), 4.
34 (2H, t, J = 6.4 Hz), 7.38 (2H, t, J = 9.0 Hz), 8.17-
8.21 (4H, m). IR (KBr) 1593, 1574, 1530, 1508, 1426, 1341, 1188,
1088, 853, 743, 637 cm ^-1

Reference Example 87 4- [2- (4-nitrophenylthio) ethyl] -4H
A 15% hydrous ethanol (30 ml) mixture of -1,2,4-triazole (1.0 g), reduced iron (1.12 g) and calcium chloride (0.22 g) was heated under reflux for 22 hours. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethanol: ethyl acetate:
Separation and purification (1: 19 → 1: 9) yielding 4 as colorless crystals.
-[2- (4-Aminophenylthio) ethyl] -4H-
1,2,4-triazole (0.79 g) was obtained. mp 160-162 ℃ ¹ H-NMR (200MHz, CDCl3 ₆ ) δ3.07 (2H, t, J = 6.6 Hz),
3.72-3.86 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 6.65 (2
H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz), 8.16 (2H,
s). Elemental analysis C ₁₀ H ₁₂ N ₄ S Calcd. C, 54.52; H, 5.49; N,
25.43: Found. C, 54.51; H, 5.69; N, 25.41.

Reference Example 88 4-Nitrobenzylamine hydrochloride (10.0 g) and triethylamine (22.2 ml) in acetonitrile (100 ml) were added with ethyl trifluoroacetate (12.6 ml) at room temperature. Stir for hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with hexane to give N- (4-nitrobenzyl) trifluoroacetamide (12.79 g) as colorless crystals. mp 103-104 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ3.66 (2H, d, J = 6.2 Hz), 6.
60-6.89 (1H, m), 7.48 (2H, d, J = 8.8 Hz), 8.25 (2H,
d, J = 8.8 Hz) .IR (KBr) 3295, 1705, 1609, 1559, 1537, 1514, 1352,
1225, 1186, 1157, 858, 731cm ^-1 Elemental analysis C ₉ H ₇ N ₂ O ₃ F ₃ Calcd. C, 43.56; H, 2.84;
N, 11.29: Found. C, 43.53; H, 2.92; N, 11.26.

Reference Example 89 N- (4-nitrobenzyl) trifluoroacetamide (12.88 g) in DMF (200 m) under a nitrogen atmosphere.
l) Sodium hydride (60%, 2.0
8g) was added and stirred for 30 minutes. Methyl iodide (3.4 ml) was added to the reaction system, and the mixture was stirred at 40 ° C. for 20 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 5 → 1: 4 → 1: 3) to give N-methyl-N- (4 as a pale yellow oil.
-Nitrobenzyl) trifluoroacetamide (11.
82 g) was obtained. A 1N aqueous sodium hydroxide solution (50 ml) was added at room temperature to a solution of N-methyl-N- (4-nitrobenzyl) trifluoroacetamide (11.82 g) in methanol (200 ml) at room temperature. After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure. It was extracted with ethyl acetate and dried over magnesium sulfate. Concentration under reduced pressure gave methyl (4-nitrobenzyl) amine (6.78 g). Methyl (4-
To a solution of nitrobenzyl) amine (6.78 g) in methanol (60 ml) was added dropwise n-propyl isothiocyanate at room temperature, and the mixture was stirred for 20 hours. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1:
Separated and purified in 1), N-methyl-N as pale yellow crystals
-(4-Nitrobenzyl) -N'-propylthiourea (11.22 g) was obtained. mp 81-83 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.99 (3H, t, J = 7.5 Hz), 1.
58-1.77 (2H, m), 3.07 (3H, s), 3.62-3.72 (2H, m),
5.32 (2H, s), 5.47-5.64 (1H, m), 7.47 (2H, d, J = 8.
6 Hz), 8.20 (2H, d, J = 8.6 Hz). IR (KBr) 3304, 1599, 1514, 1375, 1346, 1215, 1107,
837 cm ^-1 Elemental analysis C ₁₂ H ₁₇ N ₃ O ₂ S Calcd. C, 53.91; H, 6.41;
N, 15.72: Found. C, 53.80; H, 6.24; N, 15.47.

Reference Example 90 Methyl iodide (2.7 ml) was added to a methanol solution of N-methyl-N- (4-nitrobenzyl) -N'-propylthiourea (11.22 g) at room temperature and the mixture was stirred for 3 days. . After concentration under reduced pressure, hydrazine monohydrate (2.05 g) was added to a solution of the residue in ethanol (100 ml) at room temperature, and the mixture was stirred at 80 ° C. for 4 hours. After concentration under reduced pressure, formic acid (50 ml) was added to the residue and the mixture was heated under reflux for 3 days. After concentration under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel ethanol: ethyl acetate 1: 9) to give 3- [methyl (4-nitrobenzyl) amino] -4-propyl-4H as a brown oil. -1,
2,4-triazole (4.89 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.3 Hz), 1.
72-1.92 (2H, m), 2.81 (3H, s), 3.79 (2H, t, J = 7.5 H
z), 4.44 (2H, s), 7.55 (2H, d, J = 8.8 Hz), 7.96 (1
H, s), 8.21 (2H, d, J = 8.8 Hz).

Reference Example 91 3- [Methyl (4-nitrobenzyl) amino] -4-propyl-4H-1,2,4-triazole (0.5 g)
In 15% hydrous ethanol (15 ml) at room temperature, reduced iron (0.51 g) and calcium chloride (0.10 g).
g) was added and the mixture was heated under reflux for 4 hours. After cooling to room temperature, the solid was removed by filtration and concentrated. The residue was separated and purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19) to give 3-[(4-aminobenzyl) methylamino] -4-propyl-4H-1,2 as a brown oil. , 4-triazole (313.4
mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.3 Hz), 1.
61-1.89 (2H, m), 2.75 (3H, s), 3.53-3.82 (4H, m),
4.12 (2H, s), 6.65 (2H, d, J = 8.4 Hz), 7.09 (2H, d,
J = 8.4 Hz), 7.93 (1H, s).

Reference Example 92 Under a nitrogen atmosphere, lithium aluminum hydride (1.6
A THF (100 ml) solution of ethyl 2-methylimidazo [1,2-a] pyridine-3-carboxylate (8.56 g) was added dropwise to a suspension of g) in THF (100 ml) at 0 ° C. After stirring at 0 ° C. for 1 hour, water (1.6 ml), 1
A 5% aqueous sodium hydroxide solution (1.6 ml) and water (4.8 ml) were slowly added dropwise in this order, and the mixture was stirred at room temperature for 2 hours. Magnesium sulfate was added to the reaction system, and the precipitate was removed by filtration. After concentration under reduced pressure, 2-methylimidazo [1,2-a] pyridine-3-methanol (6.45 g) was obtained as a pale yellow amorphous substance. 2-Methylimidazo [1,2-a] pyridine-3-methanol (1 g) and 4-aminothiophenol (0.65
A mixture of g) of concentrated hydrochloric acid (10 ml) was stirred at room temperature for 18 hours. The pH of the 8N sodium hydroxide aqueous solution was adjusted to 10 at 0 ° C.
It was added until it became, and it was extracted with ethyl acetate. The organic layer was washed with 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: 4) to give 3- (4-aminophenylthiomethyl) -2-methylimidazo [1,2-a] as colorless crystals. Pyridine (311 mg) was obtained. mp 162-164 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.00 (3H, s), 3.62-3.81 (2
H, m), 4.15 (2H, s), 6.49 (2H, d, J = 8.5 Hz), 6.79-
6.87 (1H, m), 6.92 (2H, d, J = 8.5 Hz), 7.13-7.22 (1
H, m), 7.49-7.55 (1H, m), 8.00-8.04 (1H, m) .IR (KBr) 3335, 3175, 1597, 1495, 1350, 1296, 1254,
829 cm ^-1 Elemental analysis C ₁₅ H ₁₅ N ₃ S0.2H ₂ O Calcd. C, 66.00; H, 5.6
9; N, 15.39: Found.C, 66.17; H, 5.69; N, 15.1
1.

Reference Example 93 3-Hydroxymethylimidazo [1,2-a] pyridine hydrochloride (0.50 g) and 4-nitrothiophenol (0.42 g) in acetic acid (10 ml), concentrated hydrochloric acid (10 ml).
ml) The mixture was stirred at 100 ° C. for 5 hours. 0 reaction system
The mixture was cooled to ° C, and 8N aqueous sodium hydroxide solution was added dropwise until the pH reached 8. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals are washed with diisopropyl ether to give 3-yellow crystals.
(4-Nitrophenylthiomethyl) imidazo [1,2-
a] Pyridine (0.54 g) was obtained. mp 174-175 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ4.58 (2H, s), 6.90-6.97 (1
H, m), 7.22-7.31 (1H, m), 7.39 (2H, d, J = 8.8 Hz),
7.56 (1H, s), 7.63-7.69 (1H, m), 8.12-8.18 (3H,
m). IR (KBr) 1580, 1499, 1337, 1310, 1090, 852, 831, 7
69, 741 cm ^-1 Elemental analysis C ₁₄ H ₁₁ N ₃ O ₂ S Calcd. C, 58.93; H, 3.89;
N, 14.73: Found. C, 58.80; H, 4.04; N, 14.57.

Reference Example 94 3- (4-nitrophenylthiomethyl) imidazo [1,
2-a] pyridine (1.5 g), reduced iron (1.47 g)
A mixture of calcium chloride (0.29 g) and 15% water-containing ethanol (45 ml) was heated under reflux for 5 hours. After cooling to room temperature, the precipitate was removed by filtration. The filtrate was concentrated, 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 mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give 3-
(4-Aminophenylthiomethyl) imidazo [1,2-
a] Pyridine (1.13 g) was obtained. mp 119-121 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ3.63-3.82 (2H, m), 4.21 (2
H, s), 6.52 (2H, d, J = 8.6 Hz), 6.84-6.91 (1H, m),
7.00 (2H, d, J = 8.6 Hz), 7.17-7.26 (2H, m), 7.59-7.
65 (1H, m), 8.11-8.16 (1H, m) .IR (KBr) 3360, 3324, 1618, 1597, 1495, 1346, 1308,
1283, 1223, 1177, 1155, 1132, 826, 754, 745, 731
cm ^-1 Elemental analysis C ₁₄ H ₁₃ N ₃ S Calcd. C, 65.85; H, 5.13; N,
16.46: Found. C, 65.60; H, 5.05; N, 16.28.

Reference Example 95 5-Chloroimidazo [1,2-a] pyridine (2.0
g) and 4-aminothiophenol (2.46 g) and triethylamine (1.7 ml) in DMF (10 m).
l) The solution was stirred at 90 ° C. for 5 days. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate) to give 5- (4-aminophenylthio) imidazo [1,2-
a] Pyridine (2.21 g) was obtained. mp 167-168 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.79-3.98 (2H, m), 6.59-6.
63 (1H, m), 6.68 (2H, d, J = 8.8 Hz), 7.05-7.13 (1H,
m), 7.29 (2H, d, J = 8.8 Hz), 7.49-7.54 (1H, m), 7.66
(1H, d, J = 1.4 Hz), 7.71-7.74 (1H, m). IR (KBr) 3424, 3339, 1651, 1597, 1480, 1318, 1292,
1204, 1177, 1152, 1094, 951, 828, 772 cm ^-1 Elemental analysis C ₁₃ H ₁₁ N ₃ S Calcd. C, 64.70; H, 4.59; N,
17.41: Found. C, 64.59; H, 4.59; N, 17.34.

Reference Example 96 5-chloro-2-methylimidazo [1,2-a] pyridine (1.0 g) and 4-aminothiophenol (3.
25 g) and triethylamine (1.7 ml) in DM
The F (10 ml) solution was stirred at 90 ° C. for 3 days. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 2: 1 → ethyl acetate → ethanol: ethyl acetate 1: 9) to give 5- (4-aminophenylthio) -2 as colorless crystals. -Methylimidazo [1,2-
a] Pyridine (1.04 g) was obtained. mp 214-215 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.46 (3H, s), 3.83-3.95 (2
H, m), 6.54 (1H, dd, J = 7.2, 1.2 Hz), 6.68 (2H, d,
J = 8.8 Hz), 7.03 (1H, dd, J = 8.8, 7.2 Hz), 7.28 (2H,
d, J = 8.8 Hz), 7.37-7.43 (1H, m), 7.47 (1H, s) .IR (KBr) 3316, 3171, 1642, 1605, 1485, 1445, 1319,
1248, 1211, 1177, 1161, 826, 775 cm ^-1 Elemental analysis C ₁₄ H ₁₃ N ₃ S Calcd. C, 65.85; H, 5.13; N,
16.46: Found. C, 66.00; H, 5.24; N, 16.54.

Reference Example 97 2-Mercaptopyridine (2.6 g) was mixed with THF (52 m).
l), triethylamine (3.9 ml) was added, and then 4-nitrobenzyl bromide (4.8 g) T was added.
The HF solution (24 ml) was added dropwise. After stirring for 30 minutes at 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 obtained residue was purified by silica gel column chromatography to give 2-[(4-nitrobenzyl) sulfanyl] pyridine (4.2 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.51 (2H, s), 6.98-7.05 (1
H, m), 7.16 (1H, d, J = 8.4Hz), 7.44-7.53 (1H, m), 7.5
8 (2H, d, J = 8.8Hz), 8.42-8.47 (1H, m) Elemental analysis C ₁₂ H ₁₀ N ₂ O ₂ S Cald. C, 58.82; N, 11.37;
H, 4.09: Found. C, 58.52; N, 11.39; H, 4.20

Reference Example 98 2-[(4-Nitrobenzyl) sulfanyl] pyridine (14.5 g) was dissolved in acetic acid (145 ml), reduced iron (43.5 g) was added, and the mixture was stirred at room temperature for 20 hours. After filtration through Celite and washing with ethyl acetate, the solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-[(2-pyridinylsulfanyl) methyl] aniline (4. 9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.68 (2H, br), 4.34 (2H,
s), 6.61 (2H, d, J = 8.4Hz), 6.93-7.01 (1H, m), 7.11-
7.26 (3H, m), 7.45 (1H, td, J = 7.4, 1.8Hz), 7.58-7.62
(1H, m), 8.43-8.48 (1H, m) Elemental analysis C ₁₂ H ₁₂ N ₂ S Cald. C, 66.63; N, 12.95; H,
5.59: Found. C, 66.68; N, 12.90; H, 5.65

Reference Example 99 2-Mercaptopyridine (10 g) was added to DMF (100 m).
1) and dissolved in 60% sodium hydride (3.
6 g) was added, and the mixture was stirred at room temperature for 15 minutes. 4-at 0 ° C
Fluoronitrobenzene (9.75 g) was added dropwise, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with hexane / diethyl ether 2
-[(4-Nitrophenyl) sulfanyl] pyridine (12.6 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 7.15-7.23 (3H, m), 7.58-7.
69 (3H, m), 8.15-8.22 (2H, m), 8.50-8.55 (1H, m)

Reference Example 100 2-[(4-Nitrophenylsulfanyl) pyridine (8.0 g) was dissolved in acetic acid (64 ml) to give reduced iron (2
4 g) was added and the mixture was stirred at room temperature for 16 hours. After filtration through celite and washing with ethyl acetate, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4- (2-pyridinylsulfanyl) aniline (6.3 g). Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.05 (2H, br), 6.72 (2H, d,
J = 8.8Hz), 6.76 (1H, d, J = 8.8Hz), 6.89-6.96 (1H, m),
7.38 (2H, d, J = 8.8Hz), 7.39-7.45 (1H, m), 8.37-8.41
(1H, m)

Reference Example 101 Benzenethiol (13.2 g) was added to THF (100 m).
l), and after adding triethylamine (17.1 ml), 4-nitrobenzyl bromide (21.6 g)
Was added. After stirring for 30 minutes at 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 mixed with hexane / ethyl acetate (= 10 /
It was washed with 1) to obtain 1-nitro-4-[(phenylsulfanyl) methyl] benzene (20.7 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.13 (2H, s), 7.21-7.39 (5
H, m), 7.37 (2H, d, J = 8.8Hz), 8.08-8.13 (2H, m)

Reference Example 102 1-Nitro-4-[(phenylsulfanyl) methyl]
85% ethanol solution (240m) in benzene (12g)
1) was added, calcium chloride (2.85 g) and reduced iron (14.4 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate.
The extract was washed with water and 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 to give 4- (benzenesulfanylmethyl) aniline (5.5 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.62 (2H, br), 4.04 (2H,
s), 6.57-6.63 (2H, m), 7.26-7.34 (7H, m)

Reference Example 103 2-Mercaptopyrimidine (5.0 g) was added to THF / DM.
It was dissolved in F (150 ml) and triethylamine (7.4
ml) was added followed by 4-nitrobenzyl bromide (8.7 g). After stirring at room temperature for 1 hour, the reaction solution was added to water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / ethyl acetate (= 8/1) to give 2-[(4-nitrobenzyl) sulfanyl] pyrimidine (8.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.47 (2H, s), 7.01 (1H, t,
J = 4.8Hz), 7.62 (2H, d, J = 8.8Hz), 8.16 (2H, d, J = 8.8H
z), 8.53 (2H, d, J = 5.2Hz)

Reference Example 104 2-[(4-Nitrobenzyl) sulfanyl] pyrimidine (8.0 g) in 85% ethanol solution (160 ml)
, Calcium chloride (1.8 g), reduced iron (9.0
g) was added and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The extract was washed with water and 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 to give 4-[(2-pyrimidinylsulfanyl) methyl] aniline (2.5 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.66 (2H, br), 4.23 (2H,
s), 6.58-6.64 (2H, m), 6.94 (1H, t, J = 4.6Hz), 7.21 (2
H, d, J = 8.4Hz), 8.51 (2H, d, J = 4.6Hz)

Reference Example 105 2-Chloro-5-trifluoromethylpyridine (13.
7 g) was dissolved in ethanol (96 ml), thiourea (5.7 g) was added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, an aqueous solution of potassium hydroxide (6.4 g) (19.2 m)
1) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature, dilute aqueous potassium hydroxide solution (20 ml) was added, and the mixture was washed with methylene chloride. After adjusting the pH to 6 with acetic acid, the mixture was extracted with methylene chloride. It was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / ethyl acetate to give 2-mercapto-5-trifluoromethylpyridine (5.1 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.55 (2H, s), 7.25-7.50 (1
H, s), 7.59 (2H, d, J = 8.8Hz), 7.69 (1H, dd, J = 8.4,
2.2Hz), 8.16 (2H, d, J = 8.8Hz), 8.69 (1H, s)

Reference Example 106 2-Mercapto-5-trifluoromethylpyridine (5.0 g) was dissolved in THF (100 ml), triethylamine (4.7 ml) was added, and 4-nitrobenzyl bromide (5) was added at 0 ° C. THF solution (50 m)
l) was added dropwise. After stirring for 30 minutes at 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, the obtained residue was purified by silica gel column chromatography, and 2- [4- (nitrobenzyl) sulfanyl] -5- (trifluoromethyl) pyridine (7.0
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.55 (2H, s), 7.25-7.50 (1
H, s), 7.59 (2H, d, J = 8.8Hz), 7.69 (1H, dd, J = 8.4,
2.2Hz), 8.16 (2H, d, J = 8.8Hz), 8.69 (1H, s)

Reference Example 107 2- [4- (nitrobenzyl) sulfanyl] -5-
(Trifluoromethyl) pyridine (7.0 g) was dissolved in acetic acid (56 ml), reduced iron (21.0 g) was added,
The mixture was stirred at room temperature for 6 hours. It was filtered through Celite and washed with methanol. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4-[[[5- (trifluoromethyl) -2-pyridinyl] sulfanyl] methyl] aniline (2.3 g). It was ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.38 (2H, s), 6.63 (2H, d,
J = 8.4Hz), 7.20 (22H, d, J = 8.4Hz), 7.23 (1H, d, J = 8.4H
z), 7.65 (1H, dd, J = 8.4, 2.6Hz), 8.69 (1H, s)

Reference Example 108 4-Nitrobenzenethiol (6.0 g) was added to THF (1
20 ml) and dissolve in 1N sodium hydroxide (120 m
l) was added, 2- (chloromethyl) pyridine hydrochloride (7.6 g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, the residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 2-[[(4-nitrophenyl) sulfanyl] methyl] pyridine (6.8 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.39 (2H, s), 7.17-7.24 (1
H, m), 7.39-7.46 (3H, m), 7.67 (1H, td, J = 7.6, 1.8H
z), 8.09 (2H, d, J = 8.8Hz), 8.55-8.58 (1H, m)

Reference Example 109 2-[[(4-Nitrophenyl) sulfanyl] methyl] pyridine (6.7 g) in 85% ethanol solution (2
(03 ml) was added, calcium chloride (1.53 g) and reduced iron (7.68 g) were added, and the mixture was heated under reflux for 16 hours.
After cooling to room temperature, ethanol was removed under reduced pressure, and the obtained residue was 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 to give 4-[(2-pyridinylmethyl) sulfanyl] aniline (3.9 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.70 (2H, br), 4.08 (2H,
s), 6.52-6.57 (2H, m), 7.08-7.17 (2H, m), 7.51-7.60
(1H, m), 8.49-8.53 (1H, m)

Reference Example 110 4-Aminothiophenol (6.0 g) was dissolved in methanol (120 ml), an aqueous sodium hydroxide solution (2.7 g, 36 ml) was added, and benzyl bromide (6. 8 ml) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 4- (benzylsulfanyl) aniline (7.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.69 (2H, br), 3.73 (2H,
s), 6.52-6.60 (2H, m), 7.10-7.29 (7H, m)

Reference Example 111 4-Aminothiophenol (10 g) was added to methanol (2
Dissolved in an aqueous solution of sodium hydroxide (15.
7 g, 60 ml) was added, 3- (chloromethyl) pyridine hydrochloride (14.4 g) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 4-[(3-pyridinylmethyl) sulfanyl] aniline (13.1 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.83 (2H, br), 3.88 (2H,
s), 6.55 (2H, m), 7.08 (2H, m), 7.13-7.20 (1H, m), 7.
43-7.49 (1H, m), 8.29-8.31 (1H, m), 8.44 (1H, dd, J = 4.
(8, 1.8Hz)

Reference Example 112 4-Aminothiophenol (8.9 g) was dissolved in methanol (178 ml), an aqueous sodium hydroxide solution (6.8 g, 53.4 ml) was added, and the mixture was added at 0 ° C. to 4-
(Chloromethyl) pyridine hydrochloride (14.0 g) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 4-[(4-pyridinylmethyl) sulfanyl] aniline (13.7 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.62 (2H, br), 3.84 (2H,
s), 6.56 (2H, d, J = 8.4Hz), 7.02-7.10 (4H, m), 8.46 (2
(H, d, J = 6.4Hz)

Reference Example 113 2-hydroxymethyl-6-methylpyridine (1.0
g) was dissolved in methylene chloride (25 ml), DMF (three drops) was added, and thionyl chloride (1.3 ml) was added at 0 ° C.
Was added and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the obtained residual aqueous solution (8.5 ml) was added dropwise to an aqueous methanol solution (22.1 ml) of 4-aminothiophenol (0.85 g) and sodium hydroxide (0.65 g). . After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the mixture was 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 to give 4-[[(6-methyl-2-pyridinyl) methyl] sulfanyl] aniline (0.80 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.52 (3H, s), 3.70 (2H, b
r), 4.05 (2H, s), 6.55 (2H, d, J = 8.8Hz), 6.91-6.99 (2
H, m), 7.15 (2H, d, J = 8.8Hz), 7.39-7.47 (1H, m)

Reference Example 114 4-Chloropyridine N-oxide (4.4 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added, and the mixture was stirred at room temperature for 90 minutes. . The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added with heating under reflux. After 30 minutes, an aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was added again, and the mixture was stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (4-chloro-2-pyridinyl) methanol (3.
0 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.77 (2H, s), 7.84 (1H, dd,
J = 6.0, 2.2Hz), 7.93 (1H, d, J = 2.2Hz), 8.68 (1H, d,
(J = 6.2Hz)

Reference Example 115 (4-chloro-2-pyridinyl) methanol (3.0
g) was dissolved in methylene chloride (30 ml), DMF (three drops) was added, and thionyl chloride (3.8 ml) was added at 0 ° C.
Was added and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the resulting residual aqueous solution (10.5 ml) was added to 4-
Aminothiophenol (2.18 g) and sodium hydroxide (2.09 g) were added dropwise to an aqueous methanol solution (76 ml). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure,
It was 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 obtained residue was purified by silica gel column chromatography to give 4-[[(4-chloro-2-pyridinyl) methyl] sulfanyl] aniline (0.60 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.75 (2H, br), 4.24 (2H,
s), 6.52-6.60 (3H, m), 7.09-7.17 (2H, m), 7.22-7.27
(1H, m), 8.27-8.41 (1H, m)

Reference Example 116 4-Methylpyridine N-oxide (3.7 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added, and the mixture was stirred at room temperature for 90 minutes. . The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added with heating under reflux. After 30 minutes, an aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was added again, and the mixture was stirred for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (4-methyl-2-pyridinyl) methanol (2.
9 g) was obtained. (4-Methyl-2-pyridinyl) methanol (2.5 g) was dissolved in methylene chloride (25 ml), DMF (three drops) was added, and thionyl chloride (3.8 ml) was added at 0 ° C. The mixture was stirred at room temperature for 16 hours.
The solvent was removed under reduced pressure, and the resulting residual aqueous solution (9.1 m
l) was added to an aqueous solution of 4-aminothiophenol (1.82 g) and sodium hydroxide (1.74 g) in methanol (6
4 ml). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4-[[(4-methyl-2-pyridinyl) methyl] sulfanyl] aniline (2.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.28 (3H, s), 3.70 (2H, b
r), 4.05 (2H, s), 6.52-6.60 (2H, m), 6.93-6.99 (2H,
m), 7.11-7.18 (2H, m), 8.36 (1H, d, J = 5.0Hz)

Reference Example 117 2- (methoxymethoxy) benzyl alcohol (8.0
g) was dissolved in THF, 2,6-dimethylpyridine (8.3 ml), methanesulfonic anhydride (9.9 g).
Was added and stirred at room temperature for 3 hours. Lithium bromide (5.
8 g) was added and the mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 20 hours.
Stir for hours. After cooling to room temperature, the mixture 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 obtained residue was treated with an aqueous solution of 4-aminothiophenol (4.2 g) and sodium hydroxide (2.0 g) in methanol (104 m).
It was dripped at l). The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-
[[2- (Methoxymethoxy) benzyl] sulfanyl] aniline (8.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.48 (3H, s), 3.69 (2H, b
r), 3.98 (2H, s), 5.16 (2H, s), 6.56 (2H, d, J = 8.0H
z), 6.85-6.90 (1H, m), 6.98-7.17 (5H, m)

Reference Example 118 1-Bromo-2-methyl-4-nitrobenzene (12
g) was dissolved in ethanol (120 ml), and heated under reflux with sodium sulfide nonahydrate (10 g) and sulfur (1.3 g).
3 g) of an aqueous ethanol solution (120 ml) was added dropwise over 20 minutes. A 6N aqueous sodium hydroxide solution was added dropwise over 20 minutes, cooled to room temperature, and then added to ice water. After filtering the precipitate, the pH of the mother liquor was adjusted to 5 with 6N hydrochloric acid, and the precipitate was collected by filtration and washed with water to obtain 2-methyl-4-nitrobenzenethiol (7.9 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.39 (3H, s), 3.67 (1H, s),
7.34 (1H, d, J = 8.4Hz), 7.89-7.95 (1H, m), 8.01 (1H,
m)

Reference Example 119 2-Methyl-4-nitrobenzenethiol (3.0 g)
Was dissolved in THF (60 ml), aqueous sodium hydroxide solution (2.1 g, 15 ml) was added, 2- (chloromethyl) pyridine hydrochloride (3.5 g) was added, and the mixture was stirred at room temperature for 3 times.
Stir for 0 minutes. The solvent was removed under reduced pressure, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 2-[[(2-methyl-4
-Nitrophenyl) sulfanyl] methyl] pyridine (3.4 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.40 (3H, s), 4.39 (2H, s),
7.18-7.25 (1H, s), 7.36-7.46 (2H, m), 7.67 (1H, td,
J = 8.0, 1.8Hz), 7.93-7.99 (2H, m), 8.56-8.60 (1H, m)

Reference Example 120 2-[[(2-Methyl-4-nitrophenyl) sulfanyl] methyl] pyridine (3.1 g) was added to acetic acid (24.4).
ml), reduced iron (9.15 g) was added, and the mixture was stirred at room temperature for 16 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 to obtain 3-methyl-4-[(2-pyridinylmethyl) sulfanyl] aniline (1.4g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.24 (3H, s), 3.38 (2H, b
r), 4.01 (2H, s), 6.39 (1H, dd, J = 8.0, 2.6Hz), 6.92
(1H, d, J = 2.6Hz), 7.03-1, d, 77.14 (3H, m), 7.49-7.
58 (1H, m), 8.52 (1H, d, J = 5.2Hz).

Reference Example 121 4-Nitropyridine N-oxide (12 g) was dissolved in ethanol, sodium ethoxide (8.8 g) was added, and the mixture was stirred at 50 ° C. for 4 hr. After cooling to room temperature, the precipitate was filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-ethoxypyridine N-oxide (11.8 g). Four
Dimethyl sulfate (8.56 ml) was added to -ethoxypyridine N-oxide (11.8 g), and the mixture was stirred at 110 ° C for 1 hr. 1 after diluting with methanol (180 ml)
Heated to reflux for hours. Ammonium peroxodisulfate (2
0.6 g) aqueous solution (18 ml) was added dropwise with heating under reflux,
The mixture was heated under reflux for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (4-ethoxy-2-pyridinyl) methanol (2.8 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.43 (3H, t, J = 7.0Hz), 4.0
9 (2H, q, J = 7.0Hz), 4.69 (2H, s), 6.70-6.79 (2H, m),
8.32 (1H, m)

Reference Example 122 (4-ethoxy-2-pyridinyl) methanol (2.8
g) was dissolved in methylene chloride (28 ml), DMF (three drops) was added, and thionyl chloride (3.3 ml) was added at 0 ° C.
Was added and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the resulting residual aqueous solution (10.3 ml) was added to 2-
Methyl-4-nitrothiophenol (2.58 g) and sodium hydroxide (2.19 g) in THF (62 m).
It was dripped at l). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-ethoxy-2-[[(2-methyl-
4-Nitrophenyl) sulfanyl] methyl] pyridine (2.6 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.0Hz), 2.4
0 (3H, s), 4.07 (2H, q, J = 7.0Hz), 4.33 (2H, s), 6.71 (2
H, dd, J = 5.8, 2.6Hz), 6.95 (1H, d, J = 2.2Hz), 7.37 (1
H, d, J = 9.6Hz), 7.93-7.99 (2H, m), 8.37 (1H, d, J = 5.
4Hz)

Reference Example 123 4-Ethoxy-2-[[(2-methyl-4-nitrophenyl) sulfanyl] methyl] pyridine (2.5 g) was dissolved in acetic acid (25 ml) to give reduced iron (7.5 g). Was added, and the mixture was stirred at room temperature for 24 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
4-[[(4-Ethoxy-2-pyridinyl) methyl] sulfanyl] -3-methylaniline (1.8 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.0Hz), 2.2
7 (3H, s), 3.28 (2H, br), 3.96 (2H, s), 3.98 (2H, q, J
= 7.0Hz), 6.42 (1H, dd, J = 8.0, 2.6Hz), 6.52 (1H, d, J
= 2.4Hz), 6.59 (1H, d, J = 2.6Hz), 6.64 (1H, dd, J = 5.4,
2.2Hz), 7.14 (1H, d, J = 8.0Hz), 8.31 (1H, d, J = 5.4H
z)

Reference Example 124 4,6-Dimethylpyrimidine-2-thiol (9.1
THF (70 ml) was added to g), triethylamine (21.5 ml) was added, 4-nitrobenzyl bromide (10 g) was added, and the mixture was stirred at 50 ° C. for 5 hr.
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, the obtained residue was washed with hexane / ethyl acetate, and 4,6-dimethyl-2-
[(4-Nitrobenzyl) sulfanyl] pyrimidine (7.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.40 (6H, s), 4.45 (2H, s),
6.72 (1H, s), 7.63 (2H, d, J = 8.8Hz), 8.13 (2H, d, J =
8.8Hz).

Reference Example 125 4,6-Dimethyl-2-[(4-nitrobenzyl) sulfanyl] pyrimidine (7.0 g) was mixed with acetic acid (56 ml).
, Reduced iron (21 g) was added, and the mixture was stirred at room temperature for 16 hours. It was filtered through Celite and washed with ethyl acetate.
The solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-
[[(4,6-Dimethyl-2-pyrimidinyl) methyl]
Sulfanyl] aniline (4.1 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.40 (6H, s), 3.63 (2H, b
r), 4.32 (2H, s), 6.59-6.68 (2H, m), 7.23 (2H, d, J =
8.80z)

Reference Example 126 4-Nitrobenzenethiol (10 g) was added to THF (10 g).
0 ml) and triethylamine (12.6 ml)
Was added, bromoacetonitrile (5.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. 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 obtained residue was washed with hexane / ethyl acetate to give 2-[(4
-Nitrophenyl) sulfanyl] acetonitrile (1
0.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.77 (2H, s), 7.56 (2H, d,
J = 8.8Hz), 8.25 (2H, d, J = 8.8Hz),

Reference Example 127 Toluene (70 ml) was added to 2-[(4-nitrophenyl) sulfanyl] acetonitrile (6.8 g), trimethylsilyl azide (8.1 g) and dibutyltin oxide (VI) (0.87 g). After adding, the mixture was heated under reflux for 6 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was azeotropically distilled with methanol. A 10% aqueous sodium carbonate solution (50 ml) was added to the obtained residue, and the mixture was washed with ethyl acetate. 6N
After adjusting the pH to 3 with hydrochloric acid, the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure and washed with hexane / ethyl acetate to give 5-[[(4-nitrophenyl) sulfanyl].
Methyl] -1,2,3,4-tetrazole (6.7 g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.79 (2H, s), 7.61 (2H, d,
J = 9.2Hz), 8.15 (2H, d, J = 9.2Hz),

Reference Example 128 5-[[(4-Nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole (6.3 g) was added with acetonitrile (315 ml), and then potassium carbonate (4. 5 g) and iodomethane (1.75 ml) were added,
The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / ethyl acetate,
1-methyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole and 2-methyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1, 2,3,4-Tetrazole was obtained as a mixture (3.87 g, 1: 1). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.15 (3H, s), 4.33 (3H, s),
4.45 (2H, s), 4.50 (2H, s), 7.47-7.54 (4H, m), 8.11-
8.18 (4H, m)

Reference Example 129 1-Methyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole and 2-methyl-5-[[(4-nitrophenyl) sulfanyl] ] Methyl] -1,2,3,4-tetrazole (6.
After adding acetic acid (63 ml) to 3 g, 1: 1), reduced iron (18.9 g) was added, and the mixture was stirred at room temperature for 18 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-[[(1-
Methyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline (1.7 g) and 4-
[[(2-Methyl-1,2,3,4-tetrazole-5
-Yl) methyl] sulfanyl] aniline (1.6g)
Got 4-[[(1-methyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline: ¹ H-NM
R (200MHz, CDCl ₃ ) δ 3.86 (3H, s), 4.11 (2H, s), 6.55
(2H, d, J = 8.4Hz), 7.06 (2H, d, J = 8.8Hz) IR (KBr) 3352, 1626, 1597, 1497, 1287, 1177, 1096,
829 cm ^-1 4-[[(2-methyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline: ¹ H-NMR
(200MHz, CDCl ₃ ) δ 4.15 (2H, s), 4.28 (3H, s), 6.58 (2
H, d, J = 8.8Hz), 7.21 (2H, d, J = 8.4Hz) IR (KBr) 3366, 1624, 1597, 1497, 1287, 1177, 826cm
^-1

Reference Example 130 1-Bromo-2-trifluoromethyl-4-nitrobenzene (12 g) was dissolved in ethanol (120 ml),
Under heating under reflux, sodium sulfide nonahydrate (10 g) and an aqueous solution of sulfur (1.33 g) in ethanol (120 ml) were added.
It was added dropwise over 0 minutes. 6N sodium hydroxide solution 2
The mixture was added dropwise over 0 minutes, cooled to room temperature, and then added to ice water. After filtering the precipitate, the pH of the mother liquor was adjusted to 5 with 6N hydrochloric acid, and the precipitate was collected by filtration and washed with water to give 4-nitro-2-
(Trifluoromethyl) benzenethiol (14.0
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.11-4.17 (1H, m), 7.54 (1
H, d, J = 8.8Hz), 8.22 (1H, dd, J = 8.8, 2.2Hz), 8.49-
8.51 (1H, d, J = 2.6Hz)

Reference Example 131 4-Nitro-2- (trifluoromethyl) benzenethiol (3.0 g) was dissolved in THF (60 ml), triethylamine (5.25 ml) was added, and then 3- (chloromethyl) was added. Pyridine hydrochloride (2.65 g) was added, and the mixture was stirred at room temperature for 1 hour. 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, the obtained residue was washed with hexane / ethyl acetate, and 3-[[[4-nitro-2- (trifluoromethyl) phenyl] sulfanyl] methyl] pyridine (2.2 g) was added. Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.31 (2H, s), 7.24-7.34 (1
H, m), 7.52 (1H, d, J = 8.8Hz), 7.72-7.79 (1H, m), 8.2
8 (1H, dd, J = 8.8, 2.2Hz), 8.49-8.64 (3H, m)

Reference Example 132 3-[[[4-nitro-2- (trifluoromethyl) phenyl]
Phenyl] sulfanyl] methyl] pyridine (2.2 g)
Acetic acid (22 ml) was added to, and reduced iron (6.6 g) was added.
And stirred at room temperature for 24 hours. Celite filtered, acetic acid
It was washed with ethyl. The solvent was removed under reduced pressure and the resulting residue
Purified by silica gel column chromatography,
4-[(3-pyridinylmethyl) sulfanyl] -3-
Obtained (trifluoromethyl) aniline (0.83 g)
It was¹ H-NMR (200MHz, CDCl₃) δ 3.91 (2H, s), 3.96 (2H, b
r), 6.62 (1H, dd, J = 8.2, 2.6Hz), 6.96 (1H, d, 3.0Hz),
 7.07 (1H, d, J = 8.4Hz), 7.19 (1H, dd, J = 7.4, 4.4Hz),
 8.28 (1H, d, J = 2.2Hz), 8.45 (1H, dd, J = 4.8, 1.4Hz) IR (KBr) 3339, 1607, 1481, 1445, 1339, 1263, 1167,
1125, 1030, 874, 712cm ^-1

Reference Example 133 Acetic anhydride was added to 5-[[(4-nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole (4.0 g), and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the solvent was removed under reduced pressure, and the resulting residue was washed with ethyl acetate / THF.
The extract was dissolved in, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was washed with hexane / ethyl acetate, and 2-methyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,3,4-oxadiazole ( 3.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.53 (3H, s), 4.36 (2H, s),
7.51 (2H, d, J = 8.8Hz), 8.17 (2H, d, J = 9.2Hz)

Reference Example 134 2-Methyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,3,4-oxadiazole (3.
Acetic acid (33 ml) was added to 3 g) and reduced iron (9.9 g) was added.
Was added and stirred at room temperature for 24 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-[[(5-methyl-1,3,4-oxadiazol-2-yl) methyl] sulfanyl] aniline ( 2.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.51 (3H, s), 3.81 (2H, b
r), 4.10 (6H, s), 6.57 (2H, d, J = 8.8Hz), 7.20 (2H, d,
(J = 8.8Hz)

Reference Example 135 2-Methoxy-4-nitrophenol (19.2 g) was dissolved in methylene chloride (192 ml), triethylamine (20.5 ml) was added, and trifluoromethanesulfonic anhydride was added at 0 ° C. (23.0 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 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, the obtained residue was dissolved in ethanol (274 ml), and sodium sulfide nonahydrate (21.1 g) and sulfur (2.8 g) were added under heating under reflux.
An aqueous ethanol solution (342 ml) of g) was added dropwise over 20 minutes. Aqueous sodium hydroxide solution (7.02 g, 2
(8.1 ml) was added dropwise over 20 minutes, cooled to room temperature, and then added to ice water. After filtering the precipitate, the pH of the mother liquor was adjusted to 5 with 6N hydrochloric acid, and the precipitate was collected by filtration and washed with water.
2-Methoxy-4-nitrobenzenethiol (15.8
g, 75%). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.01 (3H, s), 6.22 (1H, s),
6.99 (1H, d, J = 8.8Hz), 7.77 (1H, d, J = 2.4Hz), 7.89 (1
H, dd, J = 8.8, 2.6Hz).

Reference Example 136 2-methoxy-4-nitrobenzenethiol (7.0
Acetic acid (70 ml) was added to g), reduced iron (21 g) was added, and the mixture was stirred at room temperature for 6 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
4-amino-2-methoxybenzenethiol (3.1
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.43 (1H, s), 3.83 (3H, s),
6.20-6.25 (2H, m), 7.07 (1H, d, J = 8.8Hz)

Reference Example 137 4-amino-2-methoxybenzenethiol (1.0
g) was dissolved in methanol (20 ml), 3N aqueous sodium hydroxide solution (6.4 ml) was added, 3- (chloromethyl) pyridine hydrochloride (1.27 g) was added, and the mixture was stirred at room temperature for 30 minutes. . The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 3-
Methoxy-4-[(3-pyridinylmethyl) sulfanyl] aniline (1.0 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.79 (3H, s), 3.87 (3H, s),
6.08-6.14 (2H, m), 6.97 (1H, d, J = 8.2Hz), 7.15 (1H,
dd, J = 7.6, 4.6Hz), 7.44-7.50 (1H, m), 8.28 (1H, d, J
= 2.2Hz), 8.40 (1H, dd, J = 4.6, 1.8Hz)

Reference Example 138 5-[[(4-Nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole (4.1 g) was added with acetonitrile (203 ml) and then potassium carbonate (7. 1 g) and iodoethane (3.3 ml) were added, and 5
The mixture was stirred at 0 ° C for 14 hours. The solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane / ethyl acetate,
1-Ethyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole and 2-ethyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1, 2,3,4-Tetrazole was obtained as a mixture (4.2 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.62 (3H, t, J = 7.2Hz), 1.6
3 (3H, t, J = 7.2Hz), 4.49 (2H, s), 4.49 (2H, s), 4.46
(2H, q, J = 7.2Hz), 4.63 (2H, q, J = 7.2Hz), 7.47-7.55
(4H, m), 8.11-8.18 (4H, m)

Reference Example 139 1-Ethyl-5-[[(4-nitrophenyl) sulfanyl] methyl] -1,2,3,4-tetrazole and 2-ethyl-5-[[(4-nitrophenyl) sulfanyl] ] Acetic acid (42 ml) was added to a mixture of methyl] -1,2,3,4-tetrazole (4.2 g), reduced iron (12.6 g) was added, and the mixture was stirred at room temperature for 4 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-[[(1-
Ethyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline (1.1 g) and 4-
[[(2-Ethyl-1,2,3,4-tetrazole-5
-Yl) methyl] sulfanyl] aniline (2.2g)
Got 4-[[(1-Ethyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline: ¹ H-NMR
(200MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.2Hz), 4.16 (2H,
s), 4.59 (2H, q, J = 7.2Hz), 6.58 ((2H, d, J = 8.8Hz),
7.20 (2H, d, J = 8.4Hz) 4-[[(2-Ethyl-1,2,3,4-tetrazol-5-yl) methyl] sulfanyl] aniline: ¹ H-NMR
(200MHz, CDCl ₃ ) δ 1.52 (3H, t, J = 7.2Hz), 4.11 (2H,
s), 4.23 (2H, q, J = 7.2Hz), 6.54 ((2H, d, J = 8.4Hz),
7.05 (2H, d, J = 8.4Hz)

Reference Example 140 2-Chloro-4-nitro-bromobenzene (20 g) was dissolved in ethanol (160 ml) and heated under reflux to give sodium sulfide nonahydrate (15.2 g) and sulfur (2.0 g).
Of ethanol aqueous solution (200 ml) was added dropwise over 20 minutes. Aqueous sodium hydroxide solution (5.1 g, 20.3 m
1) was added dropwise over 20 minutes, cooled to room temperature, and then added to ice water. After filtering the precipitate, the mother liquor was adjusted to pH ≈ with 6N hydrochloric acid.
After setting to 5, the precipitate was collected by filtration and washed with water to obtain 2-chloro-4-nitrobenzenethiol (9.4 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.28 (1H, s), 7.48 (1H, d,
J = 8.8Hz), 8.00 (1H, dd, J = 8.8, 2.2Hz), 8.24 (1H, d, J
= 2.6Hz)

Reference Example 141 2-Chloro-4-nitrobenzenethiol (4.0 g)
Acetic acid (60 ml) was added to the above, reduced iron (21 g) was added, and the mixture was stirred at room temperature for 3 hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4
-Amino-2-chlorobenzenethiol (2.74g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.59 (1H, s), 3.95 (2H, b
r), 6.49 (1H, dd, J = 8.8,2.4Hz), 6.75 (1H, d, J = 2.2H
z), 7.16 (1H, d, J = 8.4Hz)

Reference Example 142 4-Amino-2-chlorobenzenethiol (1.2 g)
Was dissolved in methanol (24 ml), 3N aqueous sodium hydroxide solution (7.5 ml) was added, 3- (chloromethyl) pyridine hydrochloride (1.48 g) was added, and the mixture was stirred at room temperature for 15 min. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 3-chloro-4-[(3-pyridinylmethyl) sulfanyl] aniline (0.83 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.84 (2H, br), 3.93 (2H,
s), 6.38 (1H, dd, J = 8.2,2.6Hz), 6.74 (1H, d, J = 2.6H
z), 7.02 (1H, d, J = 8.4Hz), 7.18 (1H, dd, J = 7.8,4.8H
z), 7.45-7.52 (1H, m), 8.31 (1H, d, J = 2.2Hz), 8.43 (1
(H, dd, J = 4.8, 1.8Hz)

Reference Example 143 A THF solution (63 ml) of methyl 2-methoxynicotinate (6.3 g) was added dropwise to a THF solution (126 ml) of lithium aluminum hydride (1.43 g) at 0 ° C. Stir at room temperature for 2 hours and at 0 ° C with water (6.3 m
l), 15% aqueous sodium hydroxide solution (6.3 ml),
Water (18.9 ml) was added in that order, filtered through Celite, and washed with methanol. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
(2-Methoxy-3-pyridinyl) methanol (5.0
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.99 (3H, s), 4.65 (2H, d,
J = 4.8Hz), 6.90 (1H, dd, J = 7.0, 1.4Hz), 7.56-7.61 (1H,
m), 8.09 (1H, dd, J = 5.0, 1.4Hz)

Reference Example 144 (2-Methoxy-3-pyridinyl) methanol (3.0
g) was dissolved in methylene chloride (30 ml), DMF (three drops) was added, and thionyl chloride (3.2 ml) was added at 0 ° C.
Was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the resulting residue in methanol solution (15 ml) was added to 4
-Aminothiophenol (2.46 g), 3N sodium hydroxide (21.9 ml) in methanol (45 m)
l) was added dropwise at 0 ° C. After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4
-[[(2-Methoxy-3-pyridinyl) methyl] sulfanyl] aniline (3.5 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.72 (2H, br), 3.89 (2H,
s), 3.93 (3H, s), 6.56 (2H, d, J = 8.4Hz), 6.72 (1H, d
d, J = 7.2, 4.8Hz), 7.12 (2H, d, J = 8.4Hz), 7.18 (1H, d
d, J = 7.4, 1.8Hz), 8.02 (1H, dd, J = 5.0, 1.8Hz)

Reference Example 145 A solution of lithium aluminum hydride (2.0 g) in THF (160 ml) was charged with methyl 2-methylnicotinate (8.
A THF solution (80 ml) of 0 g) was added dropwise at 0 ° C.
Stir at room temperature for 2 hours, then at 0 ° C water (8.0 ml), 1
5% aqueous sodium hydroxide solution (8.0 ml), water (2
(4.0 ml) in that order, filtered through celite, and washed with methanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, (2-
Methyl-3-pyridinyl) methanol (4.6 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.53 (3H, s), 4.73 (2H, s),
7.15 (1H, dd, J = 7.6, 1.4Hz), 8.38 (1H, d, J = 5.2Hz)

Reference Example 146 (2-Methyl-3-pyridinyl) methanol (3.0
g) was dissolved in methylene chloride (30 ml), DMF (three drops) was added, and thionyl chloride (3.56 m) was added at 0 ° C.
1) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residual methanol solution (20 ml) was added to
4-Aminothiophenol (2.74 g), 3N sodium hydroxide (24.4 ml) in methanol (41.
2 ml) at 0 ° C. After stirring for 30 minutes at room temperature,
The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 4-[[(2-
Methyl-3-pyridinyl) methyl] sulfanyl] aniline (4.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.54 (3H, s), 3.75 (2H, b
r), 3.88 (2H, s), 6.55 (2H, d, J = 8.8Hz), 6.96 (1H, d
d, J = 7.6, 4.8Hz), 7.08 (2H, d, J = 8.8Hz), 7.14-7.19
(1H, m), 8.35 (1H, dd, J = 4.8, 1.8Hz)

Reference Example 147 In a THF solution (156 ml) of lithium aluminum hydride (2.0 g), methyl 6-methylnicotinate (7.
A THF solution (78 ml) of 8 g) was added dropwise at 0 ° C.
Stir at room temperature for 2 hours, then at 0 ° C water (7.8 ml), 1
5% aqueous sodium hydroxide solution (7.8 ml), water (2
(3.4 ml) in that order, filtered through Celite, and washed with methanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, (6-
Methyl-3-pyridinyl) methanol (6.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.50 (3H, s), 4.64 (2H, s),
7.13 (1H, d, J = 8.0Hz), 7.58-7.64 (1H, m), 8.34 (1H,
s)

Reference Example 148 (6-Methyl-3-pyridinyl) methanol (3.0
g) was dissolved in methylene chloride (30 ml), DMF (three drops) was added, and thionyl chloride (3.56 m) was added at 0 ° C.
1) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residual methanol solution (20 ml) was added to
4-Aminothiophenol (2.74 g), 3N sodium hydroxide (24.4 ml) in methanol (41.
2 ml) at 0 ° C. After stirring for 30 minutes at room temperature,
The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 4-[[(6
-Methyl-3-pyridinyl) methyl] sulfanyl] aniline (4.2g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.51 (3H, s), 2.73 (2H, b
r), 3.86 (2H, s), 6.53-6.58 (2H, m), 7.01-7.08 (3H,
m), 7.34-7.40 (1H, m), 8.18 (1H, d, J = 2.2Hz)

Reference Example 149 A THF solution (100 ml) of methyl pyrazine-2-carboxylate (10 g) was added dropwise to a THF solution (200 ml) of lithium aluminum hydride (2.75 g) at 0 ° C. After stirring at 0 ° C. for 30 minutes, water (10 ml), 1
5% aqueous sodium hydroxide solution (10 ml), water (30 m
l) was added. It was filtered through Celite and washed with methanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 2-pyrazinylmethanol (1.5 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.76 (1H, br), 4.85 (2H,
s), 8.50-8.55 (2H, m), 8.67 (1H, m)

Reference Example 150 2-Pyrazinylmethanol (1.0 g) was added to THF (10 g).
After dissolving in 0 ml) and adding triethylamine (2.0 ml), methanesulfonyl chloride (1.
0 ml) was added and the mixture was stirred at room temperature for 1 hour. 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 obtained residual methanol solution was added to 4-aminothiophenol (1.02 g), 3N aqueous sodium hydroxide solution (9.1 ml) in methanol (20.4 ml).
Was added dropwise at 0 ° C. The mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained residue,
The extract was washed with water and 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 to give 4-[(2-pyrazinylmethyl) sulfanyl] aniline (0.71
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.75 (2H, br), 4.05 (2H,
s), 6.52-6.57 (2H, m), 7.09-7.13 (2H, m), 8.32 (1H,
d, J = 1.6Hz), 8.39 (1H, d, J = 2.4Hz), 8.46-8.48 (1H,
m) IR (KBr) 3349, 1624, 1597, 1497, 1400, 1294, 1177,
1019, 826cm ^-1

Reference Example 151 3-Methylpyridazine (6.0 g) was mixed with chloroform (1
80 ml) and dissolved in trichloroisocyanuric acid (5.
9 g) was added and the mixture was heated under reflux for 18 hours. After cooling to room temperature, it was diluted with methylene chloride and filtered through Celite. The extract was washed with 1N sodium hydroxide and saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3-chloromethylpyridazine (1.4 g). 4-Aminothiophenol (1.7 g) was dissolved in methanol (27 ml), 3N sodium hydroxide (11 ml) was added, and then 3
-Chloromethylpyridazine (1.4g) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed with water and saturated saline,
It was dried over magnesium sulfate. Remove the solvent under reduced pressure,
The obtained residue was purified by silica gel column chromatography to obtain 4-[(3-pyridazinylmethyl) sulfanyl] aniline (1.63 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.78 (2H, br), 4.26 (2H,
s), 6.51-6.56 (2H, m), 7.08-7.13 (2H, m), 7.36-7.41
(2H, m), 9.02 (1H, dd, J = 4.6, 2.0Hz)

Reference Example 152 Chloroacetamidine hydrochloride (19.7 g) was added with 1,1,
Add 3,3-tetramethoxypropane (50 ml),
The mixture was stirred at 100 ° C for 16 hours. After cooling to room temperature, the reaction solution was added to water and extracted with methylene chloride. It was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2- (chloromethyl) pyrimidine (2.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.76 (2H, s), 7.27-7.30 (1
H, m), 8.78 (1H, d, J = 5.2Hz)

Reference Example 153 (4-nitrobenzyl) phosphonium bromide (15
g) was dissolved in THF (225 ml), 28% sodium methoxide / methanol solution (5.80 g) was added, and the mixture was stirred at room temperature for 30 min, and then 1-propylimidazole-2-carbaldehyde (2.15 g). ) Was added and the mixture was stirred at room temperature for 6 hours. Water (10 ml) was added to the reaction solution, the mixture was stirred at room temperature for 30 minutes, and then 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 obtained residue was purified by silica gel column chromatography to give 2-[(E)-
2- (4-Nitrophenyl) ethenyl] -1-propylimidazole (3.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.0Hz), 1.7
0-1.80 (2H, m), 3.83 (2H, t, J = 7.0Hz), 6.53 (1H, d, J
= 12.4Hz), 6.73 (1H, d, J = 12.8Hz), 6.94 (1H, s), 7.11
(1H, s), 7.80 (2H, d, J = 9.2Hz), 8.15 (2H, d, J = 8.8H
z)

Reference Example 154 2-[(E) -2- (4-nitrophenyl) ethenyl]
-1-Propylimidazole (2.0 g) was dissolved in ethanol (20 ml), 10% palladium / carbon (0.20 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. It was filtered through Celite and washed with ethanol. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4- [2- (1-
Propylimidazol-2-yl) ethyl] aniline (1.08 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.2Hz), 1.5
7-1.75 (2H, m), 2.83-3.04 (4H, m), 3.61-3.69 (4H, m),
6.61 (2H, d, J = 8.8Hz), 6.78-6.79 (1H, d, J = 1.0Hz),
6.93-6.99 (3H, m)

Reference Example 155 2-[(E) -2- (4-nitrophenyl) ethenyl]
An 85% ethanol solution (39 ml) was added to -1-propylimidazole (1.3 g), and calcium chloride (0.
30 g) and reduced iron (1.5 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 2-[(E) -2- (4-nitrophenyl) ethenyl] -1-propylimidazole (1.0
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.82 (3H, t, J = 7.2Hz), 1.5
5-1.71 (2H, m), 3.64 (2H, t, J = 7.0Hz), 3.78 (2H, br),
6.15 (1H, d, J = 12.0Hz), 6.53 (2H, d, J = 8.4Hz), 6.65
(1H, d, J = 12.0Hz), 6.86 (1H, d, J = 1.2Hz), 7.10 (1H,
d, J = 1.4Hz), 7.14 (2H, d, J = 8.8Hz)

Reference Example 156 N-methyl-4-nitroaniline (2.3 g) was added to THF.
It was dissolved in (92 ml), 60% sodium hydride (1.85 g) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr,
2-Chloromethyl-1-propylimidazole hydrochloride (3.54 g) was added, and the mixture was stirred at room temperature for 24 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 solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N-methyl-4-nitro-N was used.
-[(1-Propylimidazol-2-yl) methyl]
Aniline (2.7g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.2Hz), 1.7
2 (2H, m), 3.10 (3H, s), 3.80 (2H, t, J = 7.4Hz), 4.67 (2
H, s), 6.79 (2H, d, J = 9.6Hz), 6.92 (1H, d, J = 1.6Hz),
7.01 (1H, d, J = 1.4Hz), 8.13 (2H, d, J = 9.6Hz)

Reference Example 157 N-methyl-4-nitro-N-[(1-propylimidazol-2-yl) methyl] aniline (1.5 g) was added to 8
A 5% ethanol solution (45 ml) was added, calcium chloride (0.30 g) and reduced iron (1.5 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N-methyl-N-[(1-propylimidazol-2-yl) methyl] -1,4-benzodiamine (1.
03g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.2Hz), 1.6
8-1.80 (2H, m), 2.68 (3H, s), 3.42 (2H, br), 3.89 (2H,
t, J = 7.4Hz), 4.30 (2H, m), 6.67 (2H, d, J = 8.8Hz),
6.83 (2H, d, J = 8.8Hz), 6.88 (1H, d, J = 1.2Hz), 6.97 (1
(H, d, J = 1.4Hz)

Reference Example 158 4-Nitrobenzenethiol (10 g) was dissolved in methanol (100 ml), and 3N sodium hydroxide (3 g) was added.
After adding 2.2 ml, 2-bromoethanol (9.
7 g) was added dropwise. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 2-[(4-nitrophenyl) sulfanyl] ethanol (10.6 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.26 (2H, t, J = 6.0Hz), 3.8
5-3.96 (2H, m), 7.40 (2H, d, J = 9.0Hz), 8.14 (2H, d, J =
(9.2Hz)

Reference Example 159 2-[(4-Nitrophenyl) sulfanyl] ethanol (3.0 g) was dissolved in THF (60 ml), triethylamine (3.15 ml) and methanesulfonyl chloride (1.85 g) were added, The mixture was stirred at room temperature for 1 hour.
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 of DMF solution (18 m
1) was added to imidazole (0.85 g) and 60% sodium hydride (0.50 g) in DMF solution (15 ml).
It was added dropwise at 00 ° C. After stirring at 100 ° C for 16 hours, the mixture was cooled 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, the obtained residue was purified by silica gel column chromatography, and 1-
[2-[(4-Nitrophenyl) sulfanyl] ethyl] imidazole (0.60 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.39 (2H, t, J = 6.6Hz), 4.2
6 (2H, t, J = 6.6Hz), 6.94-6.96 (1H, m), 7.06-7.08 (1H,
m), 7.32 (2H, d, J = 9.0Hz), 7.50 (1H, s), 8.15 (2H,
d, J = 8.8Hz)

Reference Example 160 1- [2-[(4-Nitrophenyl) sulfanyl] ethyl] imidazole (0.60 g) was added with 85% ethanol solution (18 ml) and calcium chloride (0.13 g) was added.
g) and reduced iron (0.67 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-
[[2- (Imidazol-1-yl) ethyl] sulfanyl] phenylamine (0.48 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.05 (2H, t, J = 6.6Hz), 3.7
8 (2H, br), 4.04 (2H, t, J = 7.0Hz), 6.64 (2H, d, J = 8.4H
z), 6.88-6.90 (1H, m), 7.03-7.05 (1H, m), 7.24 (2H,
d, J = 8.4Hz), 7.44 (1H, s)

Reference Example 161 5-Nitro-2-pyridinethiol (6.0 g) was dissolved in an aqueous methanol solution (150 ml), sodium hydroxide (4.6 g) was added, and 2- (chloromethyl) pyridine hydrochloride ( 7.6 g) was added, and the mixture was stirred at room temperature for 15 minutes.
The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
5-Nitro-2-[(2-pyridinylmethyl) sulfanyl] pyridine (6.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.65 (2H, s), 7.15-7.72 (1
H, m), 7.35 (1H, d, J = 9.2Hz), 7.43-7.48 (1H, m), 7.6
4 (1H, td, J = 7.6, 1.8Hz), 8.23 (1H, d, J = 9.2, 3.0H
z), 8.55-8.59 (1H, m), 9.23-9.25 (1H, m)

Reference Example 162 5-Nitro-2-[(2-pyridinylmethyl) sulfanyl] pyridine (6.0 g) was dissolved in acetic acid (60 ml), reduced iron (18 g) was added, and the mixture was stirred at room temperature for 24 hours. . It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 6-[(2-pyridinylmethyl) sulfanyl] -3-pyridinamine (1.83).
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.63 (2H, s), 4.47 (2H, s),
6.86 (1H, dd, J = 8.4, 2.8Hz), 7.03 (1H, dd, J = 8.4, 0.
8Hz), 7.08-7.15 (1H, m), 7.37 (1H, d, J = 7.8Hz), 7.57
(1H, td, J = 7.6, 1.8Hz), 7.99-8.01 (1H, m), 8.50-8.5
5 (1H, m)

Reference Example 163 5-Nitro-2-pyridinethiol (5.0 g) was dissolved in an aqueous methanol solution (125 ml), sodium hydroxide (3.84 g) was added, and then 3- (chloromethyl) pyridine hydrochloride was added. Salt (6.30 g) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 5-nitro-2-[(3-pyridinylmethyl) sulfanyl] pyridine (6.0 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.51 (2H, s), 7.21-7.32 (2
H, m), 7.71-7.77 (1H, m), 8.24 (1H, dd, J = 8.8, 2.6H
z), 8.68 (1H, d, J = 3.8Hz), 9.27 (1H, d, J = 3.4Hz)

Reference Example 164 5-Nitro-2-[(3-pyridinylmethyl) sulfanyl] pyridine (5.6 g) was dissolved in acetic acid (56 ml), reduced iron (16.8 g) was added, and the mixture was stirred at room temperature for 4 hours. Stir for hours. It was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 6-[(3-pyridinylmethyl) sulfanyl] -3-pyridinylamine (4.
3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.30 (2H, s), 6.82-6.88 (1
H, m), 6.95-7.00 (1H, m), 7.18-7.24 (1H, m), 7.66-7.
73 (1H, m), 8.02-8.24 (1H, m), 8.42-8.45 (1H, m), 8.5
4 (1H, s)

Reference Example 165 (2-methyl-3-pyridinyl) methanol (4.0
g) was dissolved in methylene chloride (40 ml), DMF (three drops) was added, and thionyl chloride (4.75 m) was added at 0 ° C.
1) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the resulting residual methanol solution (30 ml) was added to
4-Nitrothiophenol (4.56 g), 3N sodium hydroxide (29.2 ml) in methanol (6
8.4 ml) at 0 ° C. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure, and the mixture was 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 obtained residue was washed with hexane / ethyl acetate to give 2-methyl-3-[[(5-nitro-2
-Pyridinyl) sulfanyl] methyl] pyridine (4.
9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.66 (3H, s), 4.52 (2H, s),
7.09 (1H, dd, J = 7.6, 4.8Hz), 7.27-7.33 (1H, m), 7.7
2 (1H, dd, J = 7.6, 1.4Hz), 8.25 (1H, dd, J = 8.8,2.6H
z), 8.41 (1H, dd, J = 4.8, 1.6Hz), 9.27-9.29 (1H, m)

Reference Example 166 2-Methyl-3-[[(5-nitro-2-pyridinyl)
85% to sulfanyl] methyl] pyridine (4.0 g)
An aqueous ethanol solution (80 ml) was added, calcium chloride (0.86 g) and reduced iron (4.3 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure.
It was filtered through Celite and washed with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-[[(2-methyl-3-pyridinyl) methyl] sulfanyl] aniline (3.2
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.63 (3H, s), 3.65 (2H, b
r), 4.30 (2H, s), 6.82-7.04 (3H, m), 7.55 (1H, dd, J =
7.6, 1.4Hz), 8.01-8.04 (1H, m), 8.35 (1H, dd, J = 4.8,
(1.6Hz)

Reference Example 167 Methyl propiolate (20 g) and trimethylsilyl azide (68.6 g) were added to a pressure resistant tube, and the mixture was kept at 105 ° C. for 7 hours.
Stir for 2 hours. After cooling to room temperature, methanol was added, the solvent was removed under reduced pressure, and the obtained residue was washed with diethyl ether / methanol to give methyl 1,2,3-triazole-4-carboxylate (22.7 g). Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.87 (3H, s), 8.57 (1H, m)

Reference Example 168 Methyl 1,2,3-triazole-4-carboxylate (1
7.6 g) was dissolved in DMF (210 ml), potassium carbonate (11.5 g) and iodopropane (14.9 ml).
Was added, and the mixture was stirred at room temperature for 16 hours. After filtration, the solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with methylene chloride. 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 to give 2
Methyl propyl-1,2,3-triazole-4-carboxylate (10.3 g), 1-propyl-1,2,3-
Methyl triazole-5-carboxylate (3.2 g) and methyl 1-propyl-1,2,3-triazole-4-carboxylate (2.6 g) were obtained. Methyl 2-propyl-1,2,3-triazole-4-carboxylate: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J
= 7.4Hz), 1.95-2.10 (2H, m), 3.96 (3H, s), 4.46 (2H,
t, J = 7.0Hz), 8.06 (1H, s) methyl 1-propyl-1,2,3-triazole-5-carboxylate: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J
= 7.4Hz), 1.86-2.02 (2H, m), 3.94 (3H, s), 4.71 (2H,
t, J = 7.4Hz), 8.13 (1H, s) methyl 1-propyl-1,2,3-triazole-4-carboxylate: ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.97 (3H, t, J
= 7.4Hz), 1.90-2.04 (2H, m), 3.96 (3H, s), 4.40 (2H,
t, J = 7.0Hz), 8.10 (1H, s)

Reference Example 169 In a THF solution (140 ml) of lithium aluminum hydride (1.57 g), 2-propyl-1,2,2 at 0 ° C.
Methyl 3-triazole-4-carboxylate (7.0 g)
THF solution (70 ml) was added dropwise. After stirring at room temperature for 1 hour, a saturated aqueous sodium sulfate solution was added at 0 ° C.
It was filtered through Celite and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-hydroxymethyl-2-propyl-1,2,3-triazole (5.9 g).
4-Hydroxymethyl-2-propyl-1,2,3-triazole (4.0 g) was added to thionyl chloride (32 g) at 0 ° C.
ml) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure and 4-chloromethyl-2-propyl-
1,2,3-triazole (4.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2Hz), 1.9
3-2.07 (2H, m), 4.37 (2H, t, J = 6.8Hz), 4.66 (2H, s),
7.60 (1H, s)

Reference Example 170 1-Propyl-1,2,3 was added to a solution of lithium aluminum hydride (0.72 g) in THF (64 ml) at 0 ° C.
A THF solution (32 ml) of methyl triazole-5-carboxylate (3.2 g) was added dropwise. After stirring at room temperature for 1 hour, a saturated aqueous sodium sulfate solution was added at 0 ° C. It was filtered through Celite and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 5-hydroxymethyl-1-propyl-1,2,3-triazole (2.8 g). 5
-Hydroxymethyl-1-propyl-1,2,3-triazole (2.8 g) was added to thionyl chloride (16.
8 ml) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature,
The solvent was removed under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitate was filtered to give 5-chloromethyl-1-propyl-1,2,3-triazole hydrochloride (2.1 g). ¹ H-NMR (200MHz, DMSO-d ⁶ ) δ 0.90 (3H, t, J = 7.2Hz),
1.79-1.95 (2H, m), 4.34 (2H, t, J = 7.0Hz), 5.03 (2H,
s), 9.53 (1H, br)

Reference Example 171 1-propyl-1, in a THF solution (51.4 ml) of lithium aluminum hydride (0.58 g) at 0 ° C.
Methyl 2,3-triazole-4-carboxylate (2.6
A THF solution (26 ml) of g) was added dropwise. 1 at room temperature
After stirring for an hour, a saturated aqueous solution of sodium sulfate was added at 0 ° C. It was filtered through Celite and washed with ethanol. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-hydroxymethyl-1-
Propyl-1,2,3-triazole (1.9 g) was obtained. 4-hydroxymethyl-1-propyl-1,2,3
-Thionyl chloride (32 ml) was added to triazole (1.9 g) at 0 ° C, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the solvent was removed under reduced pressure to obtain 4-chloromethyl-1-propyl-1,2,3-triazole (1.75 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.98 (3H, t, J = 7.2Hz), 1.9
2-2.05 (2H, m), 4.40 (2H, t, J = 6.6Hz), 4.78 (2H, s),
7.91 (1H, br)

Reference Example 172 2-[(4-nitrophenyl) sulfanyl] ethanol (3.0 g) was dissolved in THF (60 ml), triethylamine (3.1 ml) and methanesulfonyl chloride (2.0 ml) were added, The mixture was stirred at room temperature for 1 hour. 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 of DMF solution (11.4 m
l) was added dropwise to a DMF solution (34 ml) of 1,2,4-triazole (1.1 g) and potassium carbonate (2.5 g). After stirring at 90 ° C. for 16 hours, it was cooled 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, the obtained residue was purified by silica gel column chromatography, and 1- [2-[(4-nitrophenyl) sulfanyl] ethyl] -1,2,4-
Triazole (1.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.18 (2H, d, J = 6.6Hz), 4.26
(2H, t, J = 6.6Hz), 6.62 (2H, d, J = 8.4Hz), 7.22 (2H,
d, J = 8.4Hz), 7.92 (1H, s), 8.04 (1H, s)

Reference Example 173 85 to 1- [2-[(4-nitrophenyl) sulfanyl] ethyl] -1,2,4-triazole (1.3 g)
% Ethanol solution (38 ml) was added, calcium chloride (0.28 g) and reduced iron (1.4 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-[[2- (1,2,4-triazol-1-yl) ethyl] sulfanyl] phenylamine (0.95 g ) Got. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.18 (2H, d, J = 6.6Hz), 4.26
(2H, t, J = 6.6Hz), 6.62 (2H, d, J = 8.4Hz), 7.22 (2H,
d, J = 8.4Hz), 7.92 (1H, s), 8.04 (1H, s)

Reference Example 174 4-Nitrophenol (10 g) was added to DMF (100 m).
1), potassium carbonate (12.9 g) and 2-bromoethanol (10.8 g) were added, and the mixture was stirred at 90 ° C. for 16 hours. After cooling to room temperature, it was filtered to remove the solvent under reduced pressure. The obtained residue was added to water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 2- (4
-Nitrophenoxy) ethanol (7.8 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ4.01-4.07 (2H, m), 4.17-4.2
2 (2H, m), 6.99 (2H, d, J = 9.4Hz), 8.22 (2H, d, J = 9.2H
z)

Reference Example 175 2- (4-nitrophenoxy) ethanol (3.0 g)
Was dissolved in THF (60 ml), triethylamine (2.74 ml), methanesulfonyl chloride (1.
4 ml) was added, and the mixture was stirred at room temperature for 1 hour. 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 obtained residue DMF solution (15 ml) was added to 1,
2,4-Triazole (1.0 g) and potassium carbonate (3.4 g) were added dropwise to a DMF solution (30 ml). 9
After stirring at 0 ° C for 16 hours, the mixture was cooled 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, the obtained residue was purified by silica gel column chromatography, and 1- [2- (4-nitrophenoxy) ethyl] -1,2,4-triazole (1.7 g).
Got 1- [2- (4-nitrophenoxy) ethyl]
85% ethanol solution (48 ml) was added to -1,2,4-triazole (1.6 g), and calcium chloride (0.
38 g) and reduced iron (1.91 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography,
4- [2- (1,2,4-triazol-1-yl) ethoxy] aniline (0.92 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.47 (2H, br), 4.25 (2H, t,
J = 4.8Hz), 4.52 (2H, t, J = 4.8Hz), 6.58-6.72 (4H, m),
7.96 (1H, s), 8.22 (1H, s)

Reference Example 176 2- (4-nitrophenoxy) ethanol (3.0 g)
Was dissolved in THF (60 ml), triethylamine (3.15 ml) and methanesulfonyl chloride (1.
85 ml) was added and the mixture was stirred at room temperature for 1 hour. 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 obtained residue DMF solution (18 ml) was added dropwise to a DMF solution (15 ml) of imidazole (0.85 g) and 60% sodium hydride (0.50 g).
After stirring at 100 ° C for 16 hours, the mixture was cooled 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 obtained residue was purified by silica gel column chromatography to obtain 1- [2- (4-nitrophenoxy) ethyl] imidazole (0.60 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ4.28-4.34 (2H, m), 4.39-4.4
4 (2H, m), 6.94 (2H, d, J = 9.2Hz), 7.04-7.06 (1H, m),
7.08-7.10 (1H, m), 7.61 (1H, s), 8.19 (2H, d, J = 9.4H
z)

Reference Example 177 1- [2- (4-nitrophenoxy) ethyl] imidazole (0.64 g) in 85% ethanol solution (19.2).
ml), calcium chloride (0.15 g) and reduced iron (0.77 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. 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 to give 4- [2- (imidazol-1-yl) ethoxy] aniline (0.31
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ4.14 (2H, t, J = 4.8Hz), 4.28
(2H, t, J = 4.8Hz), 6.59-6.72 (4H, m), 7.02-7.07 (2H,
m), 7.58 (1H, s)

Reference Example 178 3- (4-nitrophenyl) propanol (5.0 g)
Was dissolved in THF (100 ml), 2,6-dimethylpyridine (5.1 ml) and methanesulfonic anhydride (6.
7 g) was added and the mixture was stirred at 50 ° C. for 12 hours. Lithium bromide (3.6 g) was added, and the mixture was stirred at 60 ° C for 8 hr.
After cooling to room temperature, the reaction solution was added to water and dissolved in ethyl acetate. 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 to give 1- (3-bromopropyl) -4-nitrobenzene (3.1 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ2.13-2.38 (2H, m), 2.87-2.9
5 (2H, m), 3.40 (2H, t, J = 6.2Hz), 7.38 (2H, d, J = 8.8H
z), 8.16 (2H, d, J = 8.8Hz)

Reference Example 179 Imidazole (1.3 g) was dissolved in THF (15.5 ml), potassium carbonate (5.3 g) was added, and 1-
(3-Bromopropyl) -4-nitrobenzene (3.1
A THF solution (15.5 ml) of g) was added dropwise. 50 ° C
After stirring for 60 hours at room temperature, it was cooled 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 obtained residue was purified by silica gel column chromatography to give 1- [3- (4-nitrophenyl) propyl] imidazole (1.3 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.10-2.23 (2H, m), 2.72 (2H,
t, J = 7.2Hz), 4.00 (2H, t, J = 6.6Hz), 6.93 (1H, s), 7.
09 (1H, s), 7.32 (2H, d, J = 8.8Hz), 7.48 (1H, s), 8.16
(2H, d, J = 8.8Hz)

Reference Example 180 1- [3- (4-Nitrophenyl) propyl] imidazole (1.2 g) in 85% ethanol solution (37 ml)
, Calcium chloride (0.30 g) and reduced iron (1.5 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 4-
[3- (Imidazol-1-yl) propyl] aniline (0.77 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ1.98-2.13 (2H, m), 2.50 (2H,
t, J = 7.2Hz), 3.50 (2H, br), 3.90 (2H, t, J = 7.0Hz),
6.64 (2H, d, J = 8.6Hz), 6.89-6.98 (3H, m), 7.06-7.08
(1H, m), 7.45 (1H, s)

Reference Example 181 1,2,4-triazole (0.68 g) was added to THF.
After dissolving in (8.0 ml) and adding potassium carbonate (2.7 g), a THF solution (8.0 ml) of 1- (3-bromopropyl) -4-nitrobenzene (1.6 g) was added dropwise, The mixture was stirred at 50 ° C for 60 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, the obtained residue was purified by silica gel column chromatography, and 1- [3- (4-nitrophenyl) propyl] -1,2,4-triazole (0.69
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ2.23-2.35 (2H, m), 2.76 (2H,
t, J = 7.4Hz), 4.23 (2H, t, J = 6.8Hz), 7.35 (2H, d, J =
8.4Hz), 7.98 (1H, s), 8.08 (1H, s), 8.16 (2H, d, J = 8.
8Hz)

Reference Example 182 1- [3- (4-nitrophenyl) propyl] -1,
2,4-Triazole (0.68 g) was dissolved in an 85% ethanol solution (20.4 ml), calcium chloride (0.16 g) and reduced iron (0.82 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, the obtained residue was added to water, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4- [3- (1,2,4-triazol-1-yl) propyl] aniline (0.43 g).
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ2.12-2.21 (2H, m), 2.51 (2H,
t, J = 7.4Hz), 3.63 (2H, br), 4.13 (2H, t, J = 7.4Hz),
6.63 (2H, d, J = 8.4Hz), 6.94 (2H, d, J = 8.4Hz), 7.95 (1
H, s), 8.00 (1H, s)

Reference Example 183 Methyl N-methyl-N- (4-nitrobenzyl) -N_-
Propylimidothiocarbamate (8.0 g) was dissolved in ethanol (80 ml), 2-aminoacetaldehyde dimethyl acetal (13.2 ml) was added, and the mixture was added to 60
The mixture was stirred at 0 ° C for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was azeotroped with acetonitrile three times. Acetonitrile (80 ml) was added, p-toluenesulfonic acid monohydrate (19.2 g) was added, and the mixture was heated under reflux for 4 hr. After cooling to room temperature, it was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N-
Methyl-N- (4-nitrobenzyl) -1-propylimidazol-2-amine (2.9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.2Hz), 1.6
8-1.80 (2H, m), 2.70 (3H, s), 3.77 (2H, d, J = 7.2Hz),
4.28 (2H, s), 6.68 (1H, s), 6.82 (1H, s), 7.51 (2H, d,
J = 8.8Hz), 8.17 (2H, d, J = 8.4Hz)

Reference Example 184 N-methyl-N- (4-nitrobenzyl) -1-propylimidazol-2-amine (2.9 g) was dissolved in 85% ethanol solution (87 ml) to give calcium chloride (0.59 g). ) And reduced iron (3.0 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N- (4-aminobenzyl) -N-methyl-1-propylimidazol-2-amine (1.2
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2Hz), 1.6
3-1.78 (2H, m), 2.64 (3H, s), 3.74 (2H, d, J = 6.6Hz),
3.98 (2H, s), 6.53-6.69 (1H, m), 6.84 (1H, d, J = 2.0H
z), 7.00-7.15 (2H, m)

Reference Example 185 2-Mercapto-5-nitropyridine (3.2 g) was added to D
It was dissolved in MF (64 ml) and potassium carbonate (8.5
g) and 2-chloromethyl-1-propylimidazole hydrochloride (4.8 g) were added, and the mixture was stirred at room temperature for 1 hr. 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 obtained residue was purified by silica gel column chromatography to give 5-nitro-2-[[(1-
Propylimidazol-2-yl) methyl] sulfanyl] pyridine (4.8 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.95 (3H, t, J = 7.4Hz), 1.75
-1.89 (2H, m), 3.96 (2H, t, J = 7.4Hz), 4.66 (2H, s), 6.
89 (1H, s), 6.99 (1H, s), 7.41 (1H, d, J = 8.8Hz), 8.23
-8.30 (1H, m), 9.25-9.27 (1H, m)

Reference Example 186 5-Nitro-2-[[(1-propylimidazole-2
-Yl) methyl] sulfanyl] pyridine (4.8 g)
Was dissolved in an 85% ethanol solution (114 ml), calcium chloride (0.95 g) and reduced iron (4.8 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to obtain 6-[[(1-propylimidazol-2-yl) methyl] sulfanyl] pyridin-3-amine (2.8 g). Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.91 (3H, t, J = 7.2Hz), 1.70
-1.85 (2H, m), 3.84-3.94 (2H, m), 4.47 (2H, s), 6.82-
7.11 (4H, m), 7.97-8.02 (1H, m)

Reference Example 187 2-mercapto-5-nitropyridine (2.3 g) was added to D
Dissolve in MF (47 ml) and add potassium carbonate (6.2
g) and 5-chloromethyl-1-propylimidazole hydrochloride (3.5 g) were added, and the mixture was stirred at room temperature for 4 hours. 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 obtained residue was purified by silica gel column chromatography to give 5-nitro-2-[[(1-
Propylimidazol-5-yl) methyl] sulfanyl] pyridine (2.9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.97 (3H, t, J = 7.2Hz), 1.78
-1.91 (2H, m), 3.88-3.96 (2H, m), 4.57 (2H, s), 7.05
(1H, s), 7.32 (1H, s), 8.23-8.30 (1H, s), 9.28-9.30
(1H, m)

Reference Example 188 5-Nitro-2-[[(1-propylimidazole-5
-Yl) methyl] sulfanyl] pyridine (2.9 g)
Is dissolved in an 85% ethanol solution (87 ml), calcium chloride (0.58 g) and reduced iron (2.9 g) are added,
The mixture was heated under reflux for 4 hours. After cooled to room temperature, filtered through Celite,
It was washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 6-[[(1-propylimidazol-5-yl) methyl] sulfanyl] pyridin-3-amine (2.0 g). Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ0.93 (3H, t, J = 7.2Hz), 1.73
-1.88 (2H, m), 3.86-3.95 (2H, m), 4.31 (2H, s), 6.83-
7.00 (3H, s), 7.41 (1H, s), 8.00-8.02 ((1H, m)

Reference Example 189 4-Aminothiophenol (1.0 g) was dissolved in methanol (20 ml), and 3N sodium hydroxide (8.
0 ml) was added, and then 2- (2-propylimidazol-1-yl) ethyl 4-methylbenzenesulfonate (3.7 g) was added. After stirring at room temperature for 20 hours,
The solvent was removed under reduced pressure. Water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography (ethyl acetate / ethanol = 15/1 → 6/1) and then 4-
[[2- (2-Propylimidazol-1-yl) ethyl] sulfanyl] aniline (1.2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4Hz), 1.6
0-1.75 (2H, m), 2.47 (2H, t, J = 7.6Hz), 2.98 (2H, t, J
= 7.6Hz), 3.87 (2H, br), 3.95 (2H, t, J = 7.6Hz), 6.64 (2
H, d, J = 8.4Hz), 6.77 (1H, d, J = 1.2Hz), 6.88-6.94 (1
H, m), 7.25 (2H, d, J = 8.4Hz)

Reference Example 190 1-Methyl-3-nitro-1,2,4-triazole-
5-thiol (0.66 g) was added to DMF (13.2 ml)
Was dissolved in water, potassium carbonate (1.7 g) and 5-chloromethyl-1-propylimidazole hydrochloride (1.1 g) were added, and the mixture was stirred at room temperature for 18 hours. 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 obtained residue was washed with 1-methyl-3-nitro-5.
-[[(1-Propylimidazol-5-yl) methyl] thio] -1,2,4-triazole (0.55g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.99 (3H, t, J = 7.2Hz), 1.7
8-1.92 (2H, m), 3.83 (3H, s), 3.86 (2H, t, J = 7.2Hz),
4.60 (2H, s), 7.05 (1H, s), 7.50 (1H, s)

Reference Example 191 1-Methyl-3-nitro-5-[[(1-propylimidazol-5-yl) methyl] thio] -1,2,4-triazole (2.8 g) in 85% ethanol. (84
ml), calcium chloride (0.57 g) and reduced iron (2.9 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. water,
The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 1-methyl-5-
[[(1-Propylimidazol-5-yl) methyl]]
Thio] -1,2,4-triazol-3-amine (0.
86 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.2Hz), 1.7
7-1.87 (2H, m), 3.52 (3H, s), 3.91 (2H, t, J = 7.0Hz),
4.20 (2H, br), 4.37 (2H, s), 6.95 (1H, s), 7.47 (1H,
s)

Reference Example 192 2-Methoxyethylamine hydrochloride (10 g) was dissolved in tert-butanol (80 ml) / acetic acid (10 ml) to prepare potassium thiocyanate (9.1 g) and dihydroxyacetone dimer (5.7 g). Was added, and the mixture was stirred at room temperature for 48 hours. Water (20 ml) was added to the reaction solution, the solvent was concentrated to half under reduced pressure and collected by filtration. After washing with water, the mixture was added to 5.6N nitric acid containing sodium nitrite (0.20 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with potassium carbonate and the solvent was removed under reduced pressure. The filtrate was washed with ethanol, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-hydroxymethyl-1- (2-methoxyethyl) imidazole (2.9.
g) was obtained. ¹ H-NMR (200MHz, DMSO-d ⁶ ) δ3.28 (3H, s), 3.60 (2H, t,
J = 5.4Hz), 4.13 (2H, t, J = 5.4Hz), 4.38-4.47 (2H, m),
5.09 (1H, br), 6.76 (1H, s), 7.53 (1H, s)

Reference Example 193 5-hydroxymethyl-1- (2-methoxyethyl) imidazole (2.8 g) was added to thionyl chloride (8.4 ml).
The mixture was added to the mixture and stirred at 80 ° C. for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was washed with ethyl acetate to give 5-chloromethyl-1- (2-methoxyethyl) imidazole hydrochloride (3.2 g). ¹ H-NMR (200MHz, DMSO-d ⁶ ) δ3.30 (3H, s), 3.76 (2H, t,
J = 5.0Hz), 4.47 (2H, t, J = 5.0Hz), 5.07 (2H, s), 7.85
(1H, s), 9.23 (1H, s)

Reference Example 194 2-Mercapto-1-methylimidazole (0.81
g) was dissolved in DMF (16.2 ml), potassium carbonate (1.37 g) was added, and then 2-[(4-nitrophenyl) thio] ethyl 4-methylbenzenesulfonate (3.0 g) was added. The mixture was stirred at 60 ° C for 12 hours. 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 obtained residue was washed with hexane / ethyl acetate to give 1-methyl-2-[[2-[(4-nitrophenyl) thio] ethyl] thio] imidazole (1.3 g).
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ3.24-3.33 (2H, m), 3.30-3.4
4 (2H, m), 3.61 (3H, s), 6.98 (1H, d, J = 1.6Hz), 7.12 (1
H, d, J = 1.4Hz), 7.43 (2H, d, J = 8.8Hz), 8.11 (2H, d,
(J = 9.0Hz)

Reference Example 195 85% of 1-methyl-2-[[2-[(4-nitrophenyl) thio] ethyl] thio] imidazole (1.3 g) was added.
It was dissolved in ethanol (39 ml), calcium chloride (0.24 g) and reduced iron (1.23 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4-[[2-[(1-methylimidazol-2-yl) thio] ethyl] thio] aniline (0.
68 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ2.95-3.18 (4H, m), 3.60 (3H,
s), 3.76 (2H, br), 6.60 (2H, d, J = 8.8Hz), 6.92 (1H,
d, J = 1.2Hz), 7.05 (1H, d, J = 1.4Hz), 7.22 (2H, d, J = 8.
8Hz)

Reference Example 196 3-Mercapto-4-methyltriazole (0.81
g) was dissolved in DMF (16.2 ml), potassium carbonate (1.37 g) was added, and then 2-[(4-nitrophenyl) thio] ethyl 4-methylbenzenesulfonate (3.0 g) was added. The mixture was stirred at 60 ° C for 12 hours. 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 obtained residue was washed with hexane / ethyl acetate to give 4-methyl-3-[[2-[(4-nitrophenyl) thio] ethyl] thio] -1,2,4-. Triazole (1.4 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.44-3.60 (4H, m), 3.59 (3H,
s), 7.49-7.55 (2H, m), 8.14-8.19 (3H, m)

Reference Example 197 4-Methyl-3-[[2-[(4-nitrophenyl) thio] ethyl] thio] -1,2,4-triazole (1.
4 g) was dissolved in 85% ethanol (42 ml), calcium chloride (0.26 g) and reduced iron (1.32 g) were added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 4-[[2-[(4-methyl-1,2,4-triazol-3-yl) thio] ethyl] thio]. Aniline (0.38g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ3.21 (2H, t, J = 7.0Hz), 3.55
(3H, s), 3.75 (2H, s), 6.63 (2H, d, J = 8.8Hz), 7.33 (2
H, d, J = 8.4Hz), 7.71 (1H, s)

Reference Example 198 2-Mercapto-5-nitrobenzimidazole (2.
0 g) was dissolved in ethanol (20 ml), 3N sodium hydroxide (8.2 ml) was added, 5-chloromethyl-1-propylimidazole hydrochloride (2.2 g) was added, and the mixture was stirred at room temperature for 3 hours. It was stirred. Remove the solvent under reduced pressure,
Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and 5-nitro-2-
[[(1-Propylimidazol-5-yl) methyl]]
Thio] benzimidazole (1.6 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.2Hz), 1.7
8-1.92 (2H, m), 3.99 (2H, t, J = 7.2Hz), 4.69 (2H, s),
7.10 (1H, s), 7.49 (1H, d, J = 9.2Hz), 7.58 (1H, s), 8.1
0 (1H, dd, J = 8.8, 2.2Hz), 8.38 (1H, d, J = 2.2Hz)

Reference Example 199 5-Nitro-2-[[(1-propylimidazole-5
-Yl) methyl] thio] benzimidazole (1.6
g) was dissolved in 85% ethanol (48 ml), calcium chloride (0.28 g) and reduced iron (1.41 g) were added, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, it was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was 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 obtained residue was purified by silica gel column chromatography to give 2-[[(1-propylimidazol-5-yl) methyl] thio] benzimidazol-5-amine (0.47 g). Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.86 (3H, t, J = 7.4Hz), 1.6
1-1.80 (2H, m), 3.82 (2H, t, J = 7.2Hz), 4.46 (2H, s),
6.57-6.63 (2H, m), 6.94 (1H, s), 7.42 (2H, s)

Reference Example 200 3-hydroxy-4-nitrobenzaldehyde (7.0
g), potassium carbonate (8.1 g) in DMF (100 m)
l) Iodoethane (8.3 g) was added dropwise to the suspension under a nitrogen atmosphere. After stirring overnight, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from hexane-ethyl acetate to give yellow crystals.
-Ethoxy-4-nitrobenzaldehyde (5.7g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.50 (3H, t, J = 7.0 Hz),
4.27 (2H, q, J = 7.0 Hz), 7.53 (1H, dd, J = 8.0, 1.6 H
z), 7.58 (1H, d, J = 1.4 Hz), 7.90 (1H, d, J = 8.0 H
z), 10.04 (1H, s). Elemental analysis C ₉ H ₉ NO ₄ Calcd. C, 55.39; H, 4.65; N, 7.
18; Found. C, 55.41; H, 4.43; N, 7.06.

Reference Example 201 2-Bromopyridine (4.0 g) in dry ether (50
ml) solution under an argon atmosphere at -78 ° C.
Butyllithium (19.2 ml, 1.6 M hexane solution) was added dropwise. After completion of dropping, the mixture was stirred for 1 hour and then a solution of 3-ethoxy-4-nitrobenzaldehyde (5.0 g) in dry ether (100 ml) and dry THF (50 ml) was added dropwise. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred overnight.
After adding water, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give (3-ethoxy-4-nitrophenyl) (2-pyridyl) methanol (3.4 g) as a dark brown oil. It was ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.45 (3H, t, J = 7.0 Hz),
4.10-4.30 (2H, m), 5.77 (1H, s), 7.02 (1H, dd, J =
8.4, 1.4 Hz), 7.09-7.29 (3H, m), 7.68 (1H, td, J =
8.2, 2.0 Hz), 7.80 (1H, d, J = 8.4 Hz), 8.59 (1H, d,
J = 5.2 Hz).

Reference Example 202 Reduced iron (7.5 g) was added to a solution of (3-ethoxy-4-nitrophenyl) (2-pyridyl) methanol (2.5 g) in acetic acid (50 ml), and the mixture was stirred overnight. Ethyl acetate and ethanol were added, and unnecessary substances were filtered off. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate and neutralized with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) and recrystallized from hexane-ethyl acetate to give crystals (4-amino-3-3). Ethoxyphenyl) (2-pyridyl) methanol (340 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.0 Hz),
3.90-4.10 (2H, m), 5.65 (1H, s), 6.66 (1H, d, J = 4.
0 Hz), 6.74-6.82 (2H, m), 7.10-7.22 (2H, m), 7.61
(1H, td, J = 8.0, 1.4 Hz), 8.55 (1H, d, J = 4.8 Hz).

Reference Example 203 7- [4- (2-butoxyethoxy) phenyl] -1
-(2,2,2-Trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxylic acid (500
mg), (4-amino-3-ethoxyphenyl) (2-
Pyridyl) methanol (320 mg), 1-hydroxybenzotriazole monohydrate (210 mg) in DMF
After adding a catalytic amount of 4- (N, N-dimethylamino) pyridine to the (15 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (26
3 mg) was added and the mixture was stirred overnight under a nitrogen atmosphere. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3) and recrystallized from diisopropyl ether-ethyl acetate to give 7- [4 -(2-Butoxyethoxy) phenyl] -N- [2-ethoxy-4- [hydroxy (2-pyridyl) methyl] phenyl] -1- (2,2,2-trifluoroacetyl) -2,3-dihydro -1-Benzazepine-4-carboxamide (504 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz),
1.31-1.47 (5H, m), 1.50-1.65 (2H, m), 2.80-3.30 (3
H, m), 3.56 (2H, t, J = 7.0 Hz), 3.82 (2H, t, J = 4.4 H
z), 4.00-4.20 (4H, m), 4.80-4.90 (1H, m), 5.34 (1
H, d, J = 3.6 Hz), 5.72 (1H, d, J = 3.4 Hz), 6.94-7.05
(4H, m), 7.14-7.35 (3H, m), 7.51-7.67 (6H, m), 8.31
(1H, s), 8.40 (1H, d, J = 8.4 Hz), 8.58 (1H, d, J =
4.8 Hz). Elemental analysis C ₃₉ H ₄₀ N ₃ O ₆ F ₃・ 0.1H ₂ O Calcd. C, 66.39; H,
5.74; N, 5.96; Found. C, 66.15; H, 5.88; N,
5.73.

Reference Example 204 7- [4- (2-butoxyethoxy) phenyl] -N-
[2-Ethoxy-4- [hydroxy (2-pyridyl) methyl] phenyl] -1- (2,2,2-trifluoroacetyl) -2,3-dihydro-1-benzazepine-4
-Carboxamide (450 mg) in dichloromethane (1
3-chloroperbenzoic acid (189 mg) was added to the solution (0 ml), and the mixture was stirred overnight under a nitrogen atmosphere. Water was added and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (methanol: ethyl acetate = 1: 1).
8) and recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -N- [2-ethoxy-4-] as colorless crystals.
[Hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1- (2,2,2-trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-
Carboxamide (249 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz),
1.34-1.68 (7H, m), 2.90-3.30 (3H, m), 3.56 (2H, t,
J = 6.6 Hz), 3.82 (2H, t, J = 4.4 Hz), 4.14-4.25 (4H,
m), 4.80-4.95 (1H, m), 6.06 (1H, d, J = 3.6 Hz), 6.
51 (1H, br), 6.90-7.05 (4H, m), 7.20-7.36 (4H, m),
7.52-7.67 (5H, m), 8.25-8.29 (1H, m), 8.37-8.47 (2
H, m). Elemental analysis C ₃₉ H ₄₀ N ₃ O ₇ F ₃ Calcd. C, 65.08; H, 5.60;
N, 5.84; Found. C, 64.83; H, 5.42; N, 5.80.

Reference Example 205 7- [4- (2-butoxyethoxy) phenyl] -N-
[2-Ethoxy-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -1- (2,2
2-trifluoroacetyl) -2,3-dihydro-1-
Sodium borohydride (111 mg) was added to a solution of benzazepine-4-carboxamide (210 mg) in ethanol (10 ml), and the mixture was stirred for 8 hours. Water was added and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization from hexane-ethyl acetate gave yellow crystals with 7-
[4- (2-butoxyethoxy) phenyl] -N- [2
-Ethoxy-4- [hydroxy (1-oxidepyridin-2-yl) methyl] phenyl] -2,3-dihydro-
1-Benzazepine-4-carboxamide (167m
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.34-1.65 (7H, m), 2.98 (2H, br), 3.40-3.60 (4H,
m), 3.80 (2H, t, J = 4.4 Hz), 4.14-4.23 (4H, m), 4.6
1 (1H, br), 6.06 (1H, br), 6.51 (1H, br), 6.71 (1
H, d, J = 8.0 Hz), 6.89-7.01 (4H, m), 7.18-7.30 (4H,
m), 7.44-7.48 (4H, m), 8.25-8.29 (1H, m), 8.35 (1
H, s), 8.46 (1H, d, J = 8.0 Hz). Elemental analysis C ₃₇ H ₄₁ N ₃ O ₆・ 0.2H ₂ O Calcd. C, 70.84; H,
6.65; N, 6.70; Found.C, 70.55; H, 6.71; N, 6.5
3.

Reference Example 206 4-Fluoro-2-trifluoromethylbenzoic acid (7.
00g), N, O-dimethylhydroxylamine hydrochloride (4.26g) and 1-hydroxybenzotriazole monohydrate (6.69g) in DMF (100ml) was added triethylamine (4.42g). Then, after adding a catalytic amount of 4- (N, N-dimethylamino) pyridine, 1-ethyl-3- (3-dimethylaminopropyl)
-Carbodiimide hydrochloride (8.38 g) was added, and the mixture was stirred under a nitrogen atmosphere for 1 day. After adding water, the mixture was extracted with ethyl acetate. The organic layer was further washed with water and saturated saline and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1-[[[methoxy (methyl) amino] oxy] as a colorless oil. Carbonyl] -4-methyl-2- (trifluoromethyl)
Benzene (8.07 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.36 (3H, s), 3.42 (3H,
s), 7.26-7.47 (3H, m).

Reference Example 207 2-bromopyridine (4.1 g) in dry ether (50 g)
ml) solution under an argon atmosphere at -78 ° C.
Butyl lithium (19.4 ml, 1.6 M hexane solution) was added dropwise. After stirring for 1 hour after completion of dropping 1-
A solution of [[[methoxy (methyl) amino] oxy] carbonyl] -4-methyl-2- (trifluoromethyl) benzene (5.0 g) in dry ether (50 ml) was added dropwise. After completion of dropping, the mixture was returned to room temperature and stirred for 1.5 hours.
After adding water, the mixture was neutralized with 1N hydrochloric acid at 0 ° C. and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from hexane to give brown crystals [4-fluoro-2- (trifluoromethyl). Phenyl] (2-pyridyl) methanone (3.4
g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 7.33 (1H, td, J = 8.2, 2.2
Hz), 7.45-7.54 (3H, m), 7.93 (1H, td, J = 8.0, 1.8
Hz), 8.23 (1H, dd, J = 8.0, 1.0 Hz), 8.65 (1H, d, J =
Elemental analysis C ₁₃ H ₇ NOF ₄ Calcd. C, 58.00; H, 2.62; N,
5.20; Found. C, 58.02; H, 2.87; N, 5.03.

Reference Example 208 [4-Fluoro-2- (trifluoromethyl) phenyl] (2-pyridyl) methanone (2.5 g) in DMSO
Sodium azide (0.73 g) was added to the (30 ml) solution, and the mixture was heated at 90 ° C. under a nitrogen atmosphere overnight. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. Organic layer with water 3
The extract was washed once with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give [4-azido-2- (trifluoromethyl) phenyl] as a dark brown oil.
(2-Pyridyl) methanone (2.89 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 7.27 (1H, dd, J = 8.4, 2.2
Hz), 7.38 (1H, d, J = 2.2 Hz), 7.47-7.53 (2H, m),
7.93 (1H, td, J = 7.8, 1.8 Hz), 8.23 (1H, d, J = 7.0 H
z), 8.64 (1H, d, J = 6.6 Hz).

Reference Example 209 [4-azido-2- (trifluoromethyl) phenyl]
(2-pyridyl) methanone (2.0 g) in THF (20
ml) solution to lithium aluminum hydride (520 m
g) was added dropwise to a suspension of THF (20 ml) at 0 ° C. under a nitrogen atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred for 1 hour, and then water (0.52 ml), 15% aqueous sodium hydroxide solution (0.52 ml) and water (1.6 ml) were sequentially added to 0.
The mixture was added at 0 ° C., returned to room temperature and stirred overnight. After adding magnesium sulfate, unnecessary substances were filtered off. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give colorless crystals of [4-amino-2- (trifluoromethyl) phenyl] (2-pyridyl) methanol (1. 51 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.84 (2H, br), 5.57 (1H,
d, J = 4.0 Hz), 6.05 (1H, d, J = 4.0 Hz), 6.74 (1H, d
d, J = 8.4, 2.6 Hz), 6.94 (1H, d, J = 2.4 Hz), 7.01-7.
10 (2H, m), 7.18-7.24 (1H, m), 7.61 (1H, td, J = 7.
6, 1.8 Hz), 7.58 (1H, d, J = 5.2 Hz). Elemental analysis C ₁₃ H ₁₁ N ₂ OF ₃ Calcd. C, 58.21; H, 4.13;
N, 10.44; Found. C, 58.17; H, 4.12; N, 10.33.

Reference Example 210 7- [4- (2-butoxyethoxy) phenyl] -1
-(2,2,2-Trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxylic acid (500
mg), [4-amino-2- (trifluoromethyl) phenyl] (2-pyridyl) methanol (366 mg),
1-Hydroxybenzotriazole monohydrate (210 m
g) in DMF (15 ml) solution in a catalytic amount of 4- (N, N)
-Dimethylamino) pyridine was added and then 1-ethyl-
3- (3-Dimethylaminopropyl) -carbodiimide hydrochloride (263 mg) was added, and the mixture was stirred overnight under a nitrogen atmosphere. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 7- [4- (2-butoxyethoxy) phenyl]-as a colorless amorphous. N- [4- [hydroxy (2-pyridyl) methyl] -3-trifluoromethylphenyl] -1- (2,2,2-trifluoroacetyl)
-2,3-Dihydro-1-benzazepine-4-carboxamide (400 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.30-1.50 (2H, m), 1.55-1.70 (2H, m), 2.90-3.30 (3
H, m), 3.56 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 4.8 H
z), 4.17 (2H, t, J = 4.8 Hz), 4.75-4.90 (1H, m), 5.7
5 (1H, br), 6.14 (1H, s), 7.00-7.04 (3H, m), 7.21-
7.80 (11H, m), 7.94 (1H, d, J = 5.0 Hz), 8.60 (1H,
d, J = 3.6 Hz). Elemental analysis C ₃₈ H ₃₅ N ₃ O ₅ F ₆ Calcd. C, 62.72; H, 4.85;
N, 5.77; Found. C, 62.44; H, 4.87; N, 5.85.

Reference Example 211 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [Hydroxy (2-pyridyl) methyl] -3-trifluoromethylphenyl] -1- (2,2,2-trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide ( To a solution of 355 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (20
5 mg) was added and the mixture was stirred overnight under a nitrogen atmosphere. Water was added and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [as a colorless amorphous substance. Hydroxy (1
-Oxidopyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1- (2,2,2-trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (176 mg) Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.0 Hz),
1.30-1.65 (4H, m), 2.80-3.35 (3H, m), 3.56 (2H, t,
J = 6.6 Hz), 3.82 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J
= 5.6 Hz), 4.80-4.95 (1H, m), 6.48-6.64 (2H, m), 6.
71 (1H, d, J = 3.0Hz), 7.03 (2H, d, J = 8.8 Hz), 7.22-
7.37 (3H, m), 7.49-7.67 (5H, m), 7.79 (1H, s), 7.90
-8.05 (3H, m), 8.29-8.32 (1H, m). Elemental analysis C ₃₈ H ₃₅ N ₃ O ₆ F ₆・ 0.4H ₂ O Calcd. C, 60.78; H,
4.81; N, 5.60; Found. C, 60.61; H, 4.69; N,
5.52.

Reference Example 212 7- [4- (2-butoxyethoxy) phenyl] -N-
[4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1
-(2,2,2-trifluoroacetyl) -2,3-dihydro-1-benzazepine-4-carboxamide (1
Sodium borohydride (79 mg) was added to an ethanol (10 ml) solution of 55 mg), and the mixture was stirred for 7 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then recrystallized from diisopropyl ether-ethyl acetate to give 7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1
-Oxidopyridin-2-yl) methyl] -3-trifluoromethylphenyl] -2,3-dihydro-1-benzazepine-4-carboxamide (110 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz),
1.33-1.45 (2H, m), 1.54-1.64 (2H, m), 2.97 (2H, t,
J = 4.8 Hz), 3.48 (2H, t, J = 4.8 Hz), 3.55 (2H, t, J
= 6.6 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.15 (2H, t, J =
4.8 Hz), 6.47 (1H, s), 6.61 (1H, dd, J = 7.8, 2.2 H
z), 6.71 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.8 Hz),
7.18-7.37 (4H, m), 7.43-7.47 (4H, m), 7.85-7.91
(3H, m), 8.03 (1H, s), 8.28-8.32 (1H, m). Elemental analysis C ₃₆ H ₃₆ N ₃ O ₅ F ₃ 0.8H ₂ O Calcd. C, 65.31; H,
5.72; N, 6.35; Found. C, 65.14; H, 5.84; N,
6.10.

Reference Example 213 THF of lithium aluminum hydride (671 mg)
A solution of 2-thiazolecarboxaldehyde (2.0 g) in THF (20 ml) was added dropwise to the suspension (20 ml) at 0 ° C. under a nitrogen atmosphere. After the dropping was completed, water (0.7 ml), a 15% aqueous sodium hydroxide solution (0.7 ml) and water (2.1 ml) were sequentially added at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 2-hydroxymethylthiazole (1.0 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.98 (2H, s), 7.33 (1H,
d, J = 3.4 Hz), 7.75 (1H, d, J = 3.0 Hz).

Reference Example 214 A drop of DMF was added to a solution of 2-hydroxymethylthiazole (660 mg) in chloroform (20 ml), and then at 0 ° C.
Thionyl chloride (0.55 ml) was added at. After returning to room temperature and stirring for 2 hours, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was added to 4-aminothiophenol (600 mg) and sodium hydroxide (460 mg) in methanol (10 m
1) and a mixed solution of water (6 ml) were added at 0 ° C.
After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4-[(thiazol-2-ylmethyl) sulfanyl as a colorless oil. ] Aniline (269 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.72 (2H, br), 4.28 (2H,
s), 6.58 (2H, d, J = 8.6 Hz), 7.18-7.25 (3H, m), 7.
65 (1H, d, J = 3.2 Hz).

Reference Example 215 Lithium aluminum hydride (421 mg) in THF
To a (10 ml) suspension, 3-methylthiazole-5-carboxaldehyde (1.06 g) in THF (10 ml).
The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropwise addition, water (0.45 ml), a 15% sodium hydroxide aqueous solution (0.45 ml) and water (1.35 ml) were added at 0 ° C.
Were sequentially added, and the mixture was stirred at room temperature overnight. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate) to give 5-hydroxymethyl-3-methylisothiazole (427 mg) as a dark brown oil. . ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.48 (3H, s), 4.96 (2H,
s), 6.91 (1H, s).

Reference Example 216 5-hydroxymethyl-3-methylisothiazole (4
21 mg) in dichloromethane (10 ml) solution in DMF
After adding 1 drop of thionyl chloride (0.31 m
l) was added. After returning to room temperature and stirring for 4 hours, the solvent was distilled off under reduced pressure and the resulting residue was treated with methanol (10 m
It was dissolved in l). This solution was added to a mixed solution of 4-aminothiophenol (340 mg), sodium hydroxide (260 mg) in methanol (10 ml) and water (6 ml) at 0 ° C.
Added in. After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4-[[(3-methylisothiazole-5 as a brown oil. -Yl) methyl] sulfanyl] aniline (2
70 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.41 (3H, s), 4.12 (2H,
s), 6.60 (2H, d, J = 8.4Hz), 6.72 (1H, s), 7.21 (2H,
d, J = 8.8 Hz).

Reference Example 217 THF of lithium aluminum hydride (691 mg)
To a (10 ml) suspension, a solution of 1-methylpyrazole-5-carboxaldehyde (2.0 g) in THF (20 ml) was added dropwise at 0 ° C under a nitrogen atmosphere. After the dropping was completed, water (0.7 ml), a 15% aqueous sodium hydroxide solution (0.7 ml) and water (2.1 ml) were sequentially added at 0 ° C., and then the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure to give 5-hydroxymethyl-1 as a colorless oily substance.
-Methylpyrazole (2.04g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.90 (3H, s), 4.68 (2H,
s), 6.19 (1H, d, J = 2.0Hz), 6.39 (1H, d, J = 1.8 Hz).

Reference Example 218 5-hydroxymethyl-1-methylpyrazole (645
To a solution of (mg) in chloroform (10 ml) was added a drop of DMF, and thionyl chloride (0.55 ml) was added at 0 ° C. After returning to room temperature and stirring under a nitrogen atmosphere for 4 hours, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was added to 4-aminothiophenol (600 mg) and sodium hydroxide (460 m
g) was added to a mixed solution of methanol (10 ml) and water (6 ml) at 0 ° C. After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give 4-[[(1-methylpyrazol-5-yl) methyl] sulfanyl] aniline (972 mg) as brown crystals. Obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.75 (3H, s), 3.89 (2H,
s), 5.92 (1H, d, J = 1.8Hz), 6.57 (2H, d, J = 8.8 Hz),
7.10 (2H, d, J = 8.8 Hz), 7.31 (1H, d, J = 1.8Hz). Elemental analysis C ₁₁ H ₁₃ N ₃ S Calcd. C, 60.24; H, 5.97; N,
19.16; Found. C, 60.09; H, 6.08; N, 19.11.

Reference Example 219 THF of lithium aluminum hydride (758 mg)
To a (10 ml) suspension, 1-methylimidazole-2-carboxaldehyde (2.00 g) in THF (20 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of the dropwise addition, water (0.8 ml), a 15% aqueous sodium hydroxide solution (0.8 ml) and water (2.4 ml) were sequentially added at 0 ° C., and then the mixture was stirred at room temperature for 2.5 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure and recrystallized from hexane-ethyl acetate to give 2-hydroxymethyl-1-methylimidazole (1.82 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.73 (3H, s), 4.63 (2H,
s), 6.81 (1H, d, J = 1.2Hz), 6.86 (1H, d, J = 1.2 Hz). Elemental analysis C ₅ H ₈ N ₂ O ・ 0.05H ₂ O Calcd. C, 53.13; H, 7.2
2; N, 24.78; Found.C, 53.42; H, 7.45; N, 24.5
7.

Reference Example 220 2-hydroxymethyl-1-methylimidazole (64
After adding one drop of DMF to a chloroform (10 ml) solution of 5 mg), thionyl chloride (0.55 m
l) was added. After returning to room temperature and stirring under a nitrogen atmosphere for 4 hours, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was mixed with 4-aminothiophenol (600 mg) and sodium hydroxide (46 mg).
To a mixed solution of 0 mg) of methanol (10 ml) and water (6 ml) was added at 0 ° C. After returning to room temperature and stirring for 30 minutes, water was added and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a colorless oil 4-
[[(1-Methylimidazol-2-yl) methyl] sulfanyl] aniline (1.05 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.53 (3H, s), 4.03 (2H,
s), 6.57 (2H, d, J = 8.4Hz), 6.78 (1H, d, J = 1.4 Hz),
6.90 (1H, d, J = 1.0 Hz), 7.14 (2H, d, J = 8.8Hz).

Reference Example 221 N-bromosuccinimide (2) was added to a solution of 5-methylisoxazole (5.0 g) in ethyl acetate (100 ml).
3.6 g) and 2,2'-azobisisobutyronitrile (200 mg) were added, and the mixture was refluxed overnight under a nitrogen atmosphere. 0
After cooling to ° C and removing the insoluble matter by filtration, the filtrate was washed with an aqueous solution of sodium thiosulfate and saturated saline, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane: ethyl acetate = 10:
Separation and purification in 1) gave 5-bromomethylisoxazole (1.0 g) as an oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.50 (2H, s), 6.34 (1H,
d, J = 1.8 Hz), 8.23 (1H, d, J = 1.8 Hz).

Reference Example 222 4-Aminothiophenol (600 mg), sodium hydroxide (276 mg) in a mixed solution of methanol (10 ml) and water (6 ml) were added to 5-bromomethylisoxazole (932 mg) at 0 ° C. Methanol (5m
l) The solution was added. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give an oil 4
-[(Isoxazol-5-ylmethyl) sulfanyl] aniline (988 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.00 (2H, s), 8.95 (1H,
d, J = 0.8 Hz), 6.59 (2H, d, J = 8.8 Hz), 7.19 (2H, d,
J = 8.8 Hz), 8.11 (1H, d, J = 1.4 Hz).

Reference Example 223 Formalin (10 ml, 37%) was added to a solution of pyrazole (5.00 g) in ethanol (40 ml), and then 1.
Refluxed for 5 hours. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was washed with hexane to obtain 1-hydroxymethylpyrazole (4.47 g) as crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 5.54 (2H, d, J = 5.4 Hz),
6.31 (1H, t, J = 2.2 Hz), 6.62 (1H, br), 7.58-7.61
(2H, m). Elemental analysis C ₄ H ₆ N ₂ O Calcd. C, 48.97; H, 6.16; N, 2
8.56; Found. C, 49.05; H, 6.36; N, 28.50.

Reference Example 224 A drop of DMF was added to a solution of 1-hydroxymethylpyrazole (472 mg) in dichloromethane (10 ml).
Thionyl chloride (0.55 ml) was added at 0 ° C.
After returning to room temperature and stirring under a nitrogen atmosphere for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was treated with methanol (10 m
It was dissolved in l). This solution was added to a mixed solution of 4-aminothiophenol (600 mg), sodium hydroxide (460 mg) in methanol (10 ml) and water (6 ml) at 0 ° C.
Added in. After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure to give 4-[(pyrazole-1-
Ilmethyl) sulfanyl] aniline (0.93 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.78 (2H, br), 5.27 (2H,
s), 6.18-6.20 (1H, m), 6.57 (2H, d, J = 8.8 Hz), 7.
08 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 2.2 Hz), 7.52
(1H, d, J = 1.8 Hz).

Reference Example 225 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding iodoethane (4.87 g) to the suspension, it was heated at 50 ° C. for 5 hours under a nitrogen atmosphere. The mixture was returned to room temperature, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 1-ethylimidazole-2-carboxaldehyde (2.90 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.44 (3H, t, J = 7.2 Hz),
4.45 (2H, q, J = 7.2 Hz), 7.17-7.19 (1H, m), 7.28-7.
29 (1H, m), 9.82 (1H, s).

Reference Example 226 THF of lithium aluminum hydride (1.22 g)
To a (10 ml) suspension, 1-ethylimidazole-2-carboxaldehyde (2.00 g) in THF (10 m).
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of the dropwise addition, water (1.2 ml), a 15% sodium hydroxide aqueous solution (1.2 ml) and water (3.6 ml) were sequentially added at 0 ° C., and then the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure and recrystallized from hexane-ethyl acetate to give 2-hydroxymethyl-1-ethylimidazole (1.47 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.44 (3H, t, J = 7.4 Hz),
4.06 (2H, q, J = 7.4 Hz), 4.65 (2H, s), 6.87-6.89 (2
H, m). Elemental analysis C ₆ H ₁₀ N ₂ O Calcd. C, 57.12; H, 7.99; N, 2
2.21; Found. C, 57.06; H, 7.98; N, 22.20.

Reference Example 227 1-Ethyl-2-hydroxymethylimidazole (1.
A drop of DMF was added to a solution of 00g) in chloroform (15 ml), and thionyl chloride (0.75 m) was added at 0 ° C.
l) was added. After returning to room temperature and stirring under a nitrogen atmosphere for 30 minutes, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was mixed with 4-aminothiophenol (900 mg) and sodium hydroxide (63 mg).
To a mixed solution of 0 mg) of methanol (10 ml) and water (6 ml) was added at 0 ° C. After returning to room temperature and stirring for 30 minutes, 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 solvent was evaporated under reduced pressure to give 4-[[(1-ethylimidazol-2-yl) methyl] sulfanyl] aniline (1.68 g) as an oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.2 Hz),
3.91 (2H, q, J = 7.2 Hz), 4.04 (2H, s), 6.58 (2H, d,
J = 8.8 Hz), 6.85 (1H, d, J = 1.0 Hz), 6.92 (1H, d, J
= 1.0 Hz), 7.15 (2H, d, J = 8.8 Hz).

Reference Example 228 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding 1-iodopropane (5.31 g) to the suspension, it was heated at 50 ° C. for 5 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-propylimidazole-2-carboxaldehyde (3.58 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.73-1.91 (2H, m), 4.37 (2H, t, J = 7.4 Hz), 7.16 (1
H, s), 7.29 (1H, s), 9.82 (1H, s).

Reference Example 229 THF of lithium aluminum hydride (824 mg)
(15 ml) to the suspension 1-propylimidazole-2-
Carboxaldehyde (3.00 g) in THF (15 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping was completed, water (0.8 ml), a 15% aqueous sodium hydroxide solution (0.8 ml) and water (2.4 ml) were sequentially added at 0 ° C., and then the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure to give 2-hydroxymethyl-as a colorless oil.
1-Propylimidazole (2.28 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4 Hz),
1.74-1.92 (2H, m), 3.96 (2H, t, J = 7.4 Hz), 4.65 (2
H, s), 6.86 (1H, d, J = 1.4 Hz), 6.90 (1H, d, J = 1.4 H
z).

Reference Example 230 DM was added to a solution of 2-hydroxymethyl-1-propylimidazole (1.00 g) in chloroform (15 ml).
After adding a drop of F, thionyl chloride (0.6
8 ml) was added. After returning to room temperature and stirring under a nitrogen atmosphere for 30 minutes, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol (10 ml). This solution was added to 4-aminothiophenol (811 mg), sodium hydroxide (570 mg) in methanol (10 ml), water (6 m).
It was added to the mixed solution of l) at 0 ° C. Return to room temperature 3
After stirring for 0 minutes, 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 solvent was evaporated under reduced pressure to give 4-
[[(1-Propylimidazol-2-yl) methyl]]
Sulfanyl] aniline (1.59 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.68-1.86 (2H, m), 3.80 (2H, t, J = 7.4 Hz), 4.04 (2
H, s), 6.57 (2H, d, J = 8.8 Hz), 6.83 (1H, d, J = 1.2 H
z), 6.91 (1H, d, J = 1.2 Hz), 7.15 (2H, d, J = 8.8 H
z).

Reference Example 231 Thionyl chloride (50 ml) was added to 2-hydroxymethyl-1-propylimidazole (8.0 g) at 0 ° C., and the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was recrystallized from methanol-ethyl acetate to give 2-chloromethyl-1-propylimidazole hydrochloride (4.3 g) as yellow crystals. Obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.90 (3H, t, J = 7.2 H
z), 1.74-1.93 (2H, m), 4.18 (2H, t, J = 7.2 Hz), 5.1
7 (2H, s), 7.73 (1H, d, J = 1.8 Hz), 7.83 (1H, d, J =
Elemental analysis C ₇ H ₁₂ N ₂ Cl ₂ Calcd. C, 43.10; H, 6.20; N,
14.36; Found. C, 42.90; H, 6.34; N, 14.45.

Reference Example 232 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) 2,2,2-Trifluoroethyl p-toluenesulfonate (7.93 g) was added to the suspension and then heated at 110 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, 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 (hexane: ethyl acetate = 1: 1) to give 1- (2,2,2-trifluoroethyl) as a brown oil. ) Imidazole-2-carboxaldehyde (2.56 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 5.17 (2H, q, J = 8.4 Hz),
7.26 (1H, s), 7.38 (1H, s), 9.85 (1H, s).

Reference Example 233 THF of lithium aluminum hydride (383 mg)
A THF (20 ml) solution of 1- (2,2,2-trifluoroethyl) imidazole-2-carboxaldehyde (1.8 g) was added dropwise to the suspension (20 ml) at 0 ° C. under a nitrogen atmosphere. After the dropping was completed, water (0.4 ml) and a 15% aqueous sodium hydroxide solution (0.
4 ml) and water (1.2 ml) were added in that order, and then 2 at room temperature.
Stir for hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure and the obtained solid was washed with hexane to give 2-hydroxymethyl-1- (2,2,2-trifluoroethyl) imidazole (1.54 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.64-4.78 (4H, m), 6.95-
6.96 (2H, m). Elemental analysis C ₆ H ₇ N ₂ OF ₃ Calcd. C, 40.01; H, 3.92; N,
15.55; Found. C, 40.25; H, 4.00; N, 15.67.

Reference Example 234 Thionyl chloride (14 ml) was added to 2-hydroxymethyl-1- (2,2,2-trifluoroethyl) imidazole (1.40 g), and then heated at 90 ° C. for 30 minutes under a nitrogen atmosphere. did. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained solid was washed with ethyl acetate to give a brown crystal.
Chloromethyl-1- (2,2,2-trifluoroethyl) imidazole hydrochloride (1.63 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 5.19 (2H, s), 5.22 (2
H, q, J = 8.8 Hz), 7.71 (1H, d, J = 1.8 Hz), 7.75 (1H,
d, J = 1.8 Hz). Elemental analysis C ₆ H ₇ N ₂ Cl ₂ F ₃ Calcd. C, 30.66; H, 3.00;
N, 11.92; Found. C, 30.82; H, 3.23; N, 11.90.

Reference Example 235 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding 1-iodobutane (5.74 g) to the suspension, the suspension was heated at 50 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-butylimidazole-2-carboxaldehyde (3.9 as a brown oil).
5 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90-0.99 (3H, m), 1.20-
1.50 (2H, m), 1.60-1.90 (2H, m), 4.35-4.44 (2H,
m), 7.15-7.17 (1H, m), 7.26-7.29 (1H, m), 9.82 (1H,
s).

Reference Example 236 THF of lithium aluminum hydride (873 mg)
To a (20 ml) suspension, 1-butylimidazole-2-carboxaldehyde (3.50 g) in THF (20 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of the dropwise addition, water (0.9 ml), a 15% aqueous sodium hydroxide solution (0.9 ml) and water (2.7 ml) were sequentially added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 1-butyl-2-hydroxymethylimidazole (3.12 g) as a colorless oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4 Hz),
1.26-1.42 (2H, m), 1.69-1.85 (2H, m), 4.00 (2H, t,
J = 7.4 Hz), 4.64 (2H, s), 6.85 (1H, d, J = 1.0Hz),
6.88 (1H, d, J = 1.0 Hz).

Reference Example 237 1-Butyl-2-hydroxymethylimidazole (3.
Thionyl chloride (30 ml) was added to 0 g) and the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained solid was washed with ethyl acetate to obtain 1-butyl-2-chloromethylimidazole hydrochloride (3.5 g) as brown crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.92 (3H, t, J = 7.8 H
z), 1.23-1.41 (2H, m), 1.71-1.87 (2H, m), 4.21 (2
H, t, J = 7.6 Hz), 5.17 (2H, s), 7.73 (1H, d, J = 2.0
Hz), 7.84 (1H, d, J = 2.0 Hz). Elemental analysis C ₈ H ₁₄ N ₂ Cl ₂ Calcd. C, 45.95; H, 6.75; N,
13.40; Found. C, 46.25; H, 6.93; N, 13.53.

Reference Example 238 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) Bromomethylcyclopropane (4.21) was added to the suspension.
After adding g), the mixture was heated at 50 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-cyclopropylmethylimidazole-2-2 as a brown oily substance.
Carboxaldehyde (3.90 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.38-0.43 (2H, m), 0.60-
0.69 (2H, m), 1.20-1.34 (1H, m), 3.28 (2H, d, J = 7.
2 Hz), 7.26-7.31 (2H, m), 9.82 (1H, s).

Reference Example 239 THF of lithium aluminum hydride (1.21 g)
(25 ml) suspension was treated with 1-cyclopropylmethylimidazole-2-carboxaldehyde (4.80 g) T
The HF (25 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping, water (1.2 ml) at 0 ° C,
A 15% aqueous sodium hydroxide solution (1.2 ml) and water (3.6 ml) were added in that order, and the mixture was stirred at room temperature for 2 hr. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure and recrystallized from hexane-ethyl acetate to give 1-cyclopropylmethyl-2-hydroxymethylimidazole (2.86 g) as colorless crystals.
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.36-0.41 (2H, m), 0.60-
0.70 (2H, m), 1.10-1.35 (1H, m), 3.88 (2H, d, J = 7.
0 Hz), 4.64 (2H, s), 6.87 (1H, d, J = 1.0 Hz), 6.99
(1H, d, J = 1.0 Hz).

Reference Example 240 1-Cyclopropylmethyl-2-hydroxymethylimidazole (2.50 g) was added with thionyl chloride (25 ml) at 0 ° C, and then heated at 90 ° C for 30 minutes under a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, and the obtained solid was washed with ethyl acetate to obtain 2-chloromethyl-1-cyclopropylmethylimidazole hydrochloride (2.96 g) as brown crystals. . ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.47-0.65 (4H, m), 1.2
0-1.45 (1H, m), 4.11 (2H, d, J = 7.8 Hz), 5.20 (2H,
s), 7.76 (1H, d, J = 2.0 Hz), 7.89 (1H, d, J = 2.0 H
z). Elemental analysis C ₈ H ₁₂ N ₂ Cl ₂ Calcd. C, 46.40; H, 5.84; N,
13.53; Found. C, 46.04; H, 5.93; N, 13.68.

Reference Example 241 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding iodoisobutane (5.74 g) to the suspension, it was heated at 50 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-isobutylimidazole-2-carboxaldehyde (2.97 g) as a brown oily substance. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (6H, d, J = 7.0 Hz),
2.01-2.15 (1H, m), 4.22 (2H, d, J = 7.4 Hz), 7.13 (1
H, s), 7.29 (1H, s), 9.82 (1H, s).

Reference Example 242 THF of lithium aluminum hydride (698 mg)
(20 ml) suspension with 1-isobutylimidazole-2
-Carboxaldehyde (2.80 g) in THF (20
ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropwise addition, water (0.7 ml), a 15% sodium hydroxide aqueous solution (0.7 ml), and water (2.1 ml) were added at 0 ° C.
Were sequentially added, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 2-hydroxymethyl-1-isobutylimidazole (2.57 g) as a colorless oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (6H, d, J = 6.6 Hz),
2.00-2.20 (1H, m), 3.79 (2H, d, J = 7.6 Hz), 4.66 (2
H, s), 6.84 (1H, d, J = 1.4 Hz), 6.92 (1H, d, J = 1.4 H
z).

Reference Example 243 Thionyl chloride (24 ml) was added to 2-hydroxymethyl-1-isobutylimidazole (2.40 g) at 0 ° C., and then the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere.
After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was recrystallized from methanol-ethyl acetate to give 2-chloromethyl-1-isobutylimidazole hydrochloride (2.17 g) as brown crystals. Got ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.90 (6H, d, J = 6.6 H
z), 2.05-2.25 (1H, m), 4.05 (2H, d, J = 7.8 Hz), 5.1
8 (2H, s), 7.75 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J =
2.2 Hz). Elemental analysis C ₈ H ₁₄ N ₂ Cl ₂ Calcd. C, 45.95; H, 6.75; N,
13.40; Found. C, 45.79; H, 7.08; N, 13.37.

Reference Example 244 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) 2-Bromobutane (4.27 g) was added to the suspension and then heated at 50 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give a brown oil 1-
(2-Butyl) imidazole-2-carboxaldehyde (3.45 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.84 (3H, t, J = 7.2 Hz),
1.45 (3H, d, J = 7.0 Hz), 1.71-1.86 (2H, m), 5.30-5.
40 (1H, m), 7.29 (1H, s), 7.32 (1H, s), 9.83 (1H,
s).

Reference Example 245 THF of lithium aluminum hydride (823 mg)
To a (20 ml) suspension, 1- (2-butyl) imidazole-2-carboxaldehyde (3.30 g) in THF.
The (20 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping, water (0.9 ml) at 0 ° C., 15
% Aqueous sodium hydroxide solution (0.9 ml), water (2.7
(ml) in that order and then stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure, and the obtained solid was washed with hexane to obtain 1- (2-butyl) -2-hydroxymethylimidazole (2.84 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.84 (3H, t, J = 7.4 Hz),
1.43 (3H, d, J = 6.6 Hz), 1.69-1.84 (2H, m), 4.24-4.
35 (1H, m), 4.69 (2H, s), 6.90 (1H, d, J = 1.2Hz),
6.94 (1H, d, J = 1.2 Hz).

Reference Example 246 To 1- (2-butyl) -2-hydroxymethylimidazole (2.70 g) was added thionyl chloride (27 ml) at 0 ° C, and then the mixture was heated at 90 ° C for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give 1 as brown crystals.
-(2-Butyl) -2-chloromethylimidazole hydrochloride (3.09g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.81 (3H, t, J = 7.8 H
z), 1.47 (3H, d, J = 7.0 Hz), 1.81-1.95 (2H, m), 4.5
4-4.65 (1H, m), 5.27 (2H, s), 7.86 (1H, d, J = 2.2 H
z), 8.06 (1H, d, J = 2.2 Hz).

Reference Example 247 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
1) 1-Bromopentane (4.71 g) was added to the suspension and then heated at 50 ° C. for 6 hours under a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-pentylimidazole-2-carboxaldehyde (4.
32 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 6.8 Hz),
1.20-1.45 (4H, m), 1.71-1.85 (2H, m), 4.39 (2H, t,
J = 7.2 Hz), 7.15 (1H, s), 7.28 (1H, s), 9.81 (1H,
s).

Reference Example 248 THF of lithium aluminum hydride (1.00 g)
(20 ml) suspension with 1-pentylimidazole-2-
Carboxaldehyde (4.40 g) in THF (20 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropwise addition, water (1.0 ml), a 15% aqueous sodium hydroxide solution (1.0 ml) and water (3.0 ml) were sequentially added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was distilled off under reduced pressure to give 2-hydroxymethyl-as a colorless oil.
1-Pentylimidazole (3.99 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 6.6 Hz),
1.23-1.43 (4H, m), 1.71-1.86 (2H, m), 3.97 (2H, t,
J = 7.6 Hz), 4.66 (2H, s), 6.87 (1H, d, J = 1.6Hz),
6.92 (1H, d, J = 1.6 Hz).

Reference Example 249 Thionyl chloride (38 ml) was added to 2-hydroxymethyl-1-pentylimidazole (3.8 g) at 0 ° C., and the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was recrystallized from methanol-ethyl acetate to give 2-chloromethyl-1-pentylimidazole hydrochloride (3.00 g) as brown crystals. Got ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (3H, t, J = 7.0 H
z), 1.15-1.40 (4H, m), 1.74-1.94 (2H, m), 4.21 (2
H, t, J = 7.6 Hz), 5.19 (2H, s), 7.74 (1H, d, J = 1.8
Hz), 7.85 (1H, d, J = 1.8 Hz). Elemental analysis C ₉ H ₁₆ N ₂ Cl ₂ Calcd. C, 48.44; H, 7.23; N,
12.55; Found. C, 48.32; H, 6.95; N, 12.70.

Reference Example 250 4-Aminothiophenol (9.6 g) and triethylamine (54 ml) in THF (300 ml) were suspended in benzyloxycarbonyl chloride (13.1 g) in THF.
The solution (50 ml) was added dropwise at -78 ° C under a nitrogen atmosphere and then stirred for 30 minutes as it was. After returning to room temperature, 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 solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give S- (4-aminophenyl) as colorless crystals.
O-benzyl carbonothioate (19.3 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.85 (2H, br), 5.23 (2H,
s), 6.63-6.70 (2H, m), 7.26-7.35 (7H, m).

Reference Example 251 Reduced iron (21.0 g) was added to a solution of 2-methyl-4-nitrothiophenol (7.0 g) in acetic acid (100 ml), and the mixture was stirred for 4 hours. Ethanol was added and the insoluble material was filtered off, and then the solvent was distilled off under reduced pressure. Water was added to the obtained residue, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane-ethyl acetate =
Separation and purification with 3: 1 → hexane: ethyl acetate = 2: 1) and 4-amino-2-methylthiophenol (1.8 g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.30 (3H, s), 3.04 (1H,
s), 3.60 (1H, br), 6.45 (1H, dd, J = 8.2, 2.6 Hz),
6.56 (1H, d, J = 2.6 Hz), 7.15 (1H, d, J = 8.2 Hz).

Reference Example 252 2-Hydroxymethyl-1-methylimidazole (87
Thionyl chloride (10 ml) was added to 4 mg) at 0 ° C., and then heated at 90 ° C. for 30 minutes under a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was recrystallized from ethyl acetate to obtain 2-chloromethyl-1-methylimidazole hydrochloride (1.15 g) as brown crystals. It was ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 3.88 (3H, s), 5.19 (2
H, s), 7.72 (1H, d, J = 1.8 Hz), 7.78 (1H, d, J = 1.8)
Hz). Elemental analysis C ₅ H ₈ N ₂ Cl ₂ Calcd. C, 35.95; H, 4.83; N,
16.77; Found. C, 35.74; H, 5.03; N, 16.45.

Reference Example 253 4-Amino-2-methylthiophenol (500 mg)
After adding 1N sodium hydroxide aqueous solution (12 ml) to the methanol (10 ml) solution of 2-chloromethyl-1-
A solution of methylimidazole hydrochloride (660 mg) in methanol (10 ml) was added at 0 ° C. After adding water, the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give 3-methyl-4-[[(1-methylimidazol-2-yl) methyl] sulfanyl] aniline (757 mg) as crystals. ) Got. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.24 (3H, s), 3.50 (3H,
s), 3.69 (2H, br), 3.94 (2H, s), 6.43 (1H, dd, J =
8.0, 2.4 Hz), 6.53 (1H, d, J = 2.4 Hz), 6.77 (1H, d,
J = 1.2 Hz), 6.89 (1H, d, J = 1.2 Hz), 7.16 (1H, d, J
= 8.0 Hz).

Reference Example 254 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) Bromomethylcyclobutane (4.65 g) in suspension
Was added, and the mixture was heated at 50 ° C. for 6 hours in a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-cyclobutylmethylimidazole-2-carboxaldehyde (4.27 g) as a brown oily substance. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.70-2.16 (6H, m), 2.68-
2.82 (1H, m), 4.43 (2H, d, J = 7.2 Hz), 7.13 (1H,
s), 7.27 (1H, s), 9.81 (1H, s).

Reference Example 255 Lithium aluminum hydride (971 mg) in THF
To a (20 ml) suspension, TH of 1-cyclobutylmethylimidazole-2-carboxaldehyde (4.20 g) was added.
The F (20 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping, water (1.0 ml) at 0 ° C., 1
5% aqueous sodium hydroxide solution (1.0 ml), water (3.
(0 ml) was added in that order, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off.
The solvent was evaporated under reduced pressure and the obtained solid was washed with hexane to give 1-cyclobutylmethyl-2-hydroxymethylimidazole (3.01 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.69-2.13 (6H, m), 2.67-
2.82 (1H, m), 4.00 (2H, d, J = 7.2 Hz), 4.65 (2H,
s), 6.83 (1H, d, J = 1.0 Hz), 6.89 (1H, d, J = 1.0 Hz)

Reference Example 256 1-Cyclobutylmethyl-2-hydroxymethylimidazole (2.90 g) was charged with thionyl chloride (29 ml).
After adding at 0 ° C, the mixture was heated at 90 ° C for 30 minutes under a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 2-chloromethyl-1-cyclobutylmethylimidazole hydrochloride (3.54 g) as brown crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.78-2.05 (6H, m), 2.7
5-2.95 (1H, m), 4.26 (2H, d, J = 7.8 Hz), 5.18 (2H,
s), 7.74 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J = 2.0 H
z). Elemental analysis C ₉ H ₁₄ N ₂ Cl ₂ Calcd. C, 48.88; H, 6.38; N,
12.67; Found. C, 48.68; H, 6.47; N, 12.46.

Reference Example 257 Imidazole-2-carboxaldehyde (2.50
g), potassium carbonate (4.31 g) in DMF (25 m)
l) After adding allyl bromide (3.77 g) to the suspension, it was heated at 50 ° C. for 5 hours in a nitrogen atmosphere. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, the solvent was distilled off under reduced pressure. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-allylimidazole-2-carboxaldehyde (3.5 as a brown oil).
4 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 5.03-5.30 (4H, m), 5.88-
6.08 (1H, m), 7.17 (1H, s), 7.31 (1H, s), 9.82 (1
H, s).

Reference Example 258 THF of lithium aluminum hydride (892 mg)
In a (30 ml) suspension, 1-allylimidazole-2-carboxaldehyde (3.20 g) in THF (30 m).
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of the dropwise addition, water (0.9 ml), a 15% aqueous sodium hydroxide solution (0.9 ml) and water (2.7 ml) were sequentially added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 1-allyl-2-hydroxymethylimidazole (2.51 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.62-4.67 (4H, m), 5.04-
5.27 (2H, m), 5.87-6.08 (1H, m), 6.85 (1H, d, J = 1.
2 Hz), 6.91 (1H, d, J = 1.2 Hz).

Reference Example 259 1-allyl-2-hydroxymethylimidazole (2.
Thionyl chloride (22 ml) was added to 20 g) at 0 ° C., and then heated at 90 ° C. for 30 minutes under a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 1-allyl-2-chloromethylimidazole hydrochloride (2.28 g) as brown crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 4.91-4.94 (2H, m), 5.1
6 (2H, s), 5.25-5.39 (2H, m), 5.94-6.10 (1H, m),
7.74-7.75 (2H, m). Elemental analysis C ₇ H ₁₀ N ₂ Cl ₂ 0.2H ₂ O Calcd. C, 42.75; H,
5.33; N, 14.24; Found. C, 42.88; H, 5.19; N, 1
4.34.

Reference Example 260 A solution of 4-methylimidazole (20.0 g) and triethylamine (53.5 ml) in DMF (300 ml) was added,
Triphenylchloromethane (71.3 g) in DMF (2
(00 ml) was added dropwise at 0 ° C. under a nitrogen atmosphere. After completion of dropping, the mixture was returned to room temperature and stirred overnight. After adding water, the precipitated solid was collected by filtration. The obtained solid was washed twice with water and dried under reduced pressure to give 4-methyl- as a colorless solid.
1-Triphenylmethylimidazole (79.1 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.20 (3H, s), 6.51 (1H,
s), 7.12-7.18 (6H, m), 7.29-7.36 (11H, m).

Reference Example 261 4-Methyl-1-triphenylmethylimidazole (2
A solution of 0.0 g) in THF (300 ml) and acetonitrile (300 ml) was added with 1-iodopropane (26.2).
After adding g), the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere.
The solvent was distilled off under reduced pressure, the residue was dissolved in acetic acid (200 ml), and the mixture was stirred under a nitrogen atmosphere at 60 ° C. for 3 hours. After returning to room temperature, water was added and the insoluble matter was filtered off. Add potassium carbonate to the filtrate to make it basic, then extract with chloroform three times,
It was dried over magnesium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was distilled under reduced pressure (1.5 mmHg, 72 ° C.
~ 73 ° C) to give 5-methyl-1- as a colorless oil.
Propylimidazole (1.9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz),
1.67-1.85 (2H, m), 2.20 (3H, s), 3.80 (2H, t, J = 7.
4 Hz), 6.78 (1H, s), 7.47 (1H, s).

Reference Example 262 1.6Mn-Butyllithiumhexane solution (24.2 ml) was added dropwise to a solution of 5-methyl-1-propylimidazole (1.6 g) in dry ether (30 ml) at −78 ° C. under an argon atmosphere. did. 1 after completion of dropping
After stirring for an hour, DMF (5.0 ml) was added dropwise. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred for 1 hour, and then acidified by adding 1N hydrochloric acid at 0 ° C. Then, potassium carbonate was added for neutralization, the mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-methyl-1-propylimidazole-as a brown oil.
2-Carboxaldehyde (1.96 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.99 (3H, t, J = 7.4 Hz),
1.61-1.84 (2H, m), 2.29 (3H, s), 4.27 (2H, t, J = 7.
4 Hz), 7.08 (1H, s), 9.71 (1H, s).

Reference Example 263 THF of lithium aluminum hydride (917 mg)
In a (30 ml) suspension, T of 5-methyl-1-propylimidazole-2-carboxaldehyde (1.90 g) was added.
The HF (30 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping, water (0.9 ml) at 0 ° C.,
A 15% aqueous sodium hydroxide solution (0.9 ml) and water (2.7 ml) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 2 as a brown oil.
-Hydroxymethyl-5-methyl-1-propylimidazole (2.40 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.4 Hz),
1.62-1.84 (2H, m), 2.18 (3H, s), 3.87 (2H, t, J = 7.
6 Hz), 4.61 (2H, s), 6.64 (1H, s).

Reference Example 264 Thionyl chloride (25 ml) was added to 2-hydroxymethyl-5-methyl-1-propylimidazole (2.11 g) at 0 ° C, and then heated at 90 ° C for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate,
2-chloromethyl-5-methyl-1-as colorless crystals
Propylimidazole hydrochloride (1.04 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.95 (3H, t, J = 7.6 H
z), 1.66-1.85 (2H, m), 2.34 (3H, s), 4.15 (2H, t,
J = 7.6 Hz), 5.19 (2H, s), 7.53 (1H, s). Elemental analysis C ₈ H ₁₄ N ₂ Cl ₂ Calcd. C, 45.95; H, 6.75; N,
13.40; Found. C, 46.18; H, 6.83; N, 13.10.

Reference Example 265 Cyclopropylamine (20.0 g), 25% aqueous ammonia solution (27.1 g) in methanol (130 ml) was added with 40% glyoxal (62.5 g) and 37% formalin (28.4 g). A solution of methanol (40 ml) was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at 0 ° C for 1 hour, water was added, and the mixture was washed 4 times with hexane. The aqueous phase was further washed with a mixed solution of hexane (50 ml) -ether (130 ml), saturated saline was added, and the mixture was washed with chloroform 4 times.
Extracted twice. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was distilled under reduced pressure (1.5 mmHg, 72 ° C to 73 ° C) to give 1-cyclopropylimidazole (3.3 g) as a colorless oil.
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ ¹ H-NMR (200MHz, CDCl ₃ )
δ 0.92-1.01 (4H, m), 3.28-3.39 (1H, m), 6.97 (1H,
s), 6.99 (1H, s), 7.55 (1H, s).

Reference Example 266 To a solution of 1-cyclopropylimidazole (2.5 g) in dry ether (30 ml), 1.6Mn-butyllithium hexane solution (17.3 ml) was added dropwise at -78 ° C under an argon atmosphere. After completion of the dropping, the mixture was stirred for 1 hour as it was, and then DMF (8.94 ml) was added dropwise. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred for 1 hour, and then acidified by adding 1N hydrochloric acid at 0 ° C. Then, potassium carbonate was added for neutralization, followed by extraction twice with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-cyclopropylimidazole-2-carboxaldehyde (3.14 g) as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91-1.30 (4H, m), 3.80-
3.92 (1H, m), 7.13 (1H, s), 7.22 (1H, s), 9.87 (1H,
s).

Reference Example 267 THF of lithium aluminum hydride (1.12 g)
(40 ml) suspension in 1-cyclopropylimidazole-2-carboxaldehyde (2.68 g) in THF
The (40 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropping, water (1.2 ml), 15
% Aqueous sodium hydroxide solution (1.2 ml), water (3.6
(ml) were sequentially added, and the mixture was stirred at room temperature for 4 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure and recrystallized from hexane-ethyl acetate to give colorless crystals 2-hydroxymethyl-1-cyclopropylimidazole (1.55 g). ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95-1.10 (4H, m), 3.27-
3.38 (1H, m), 4.75 (2H, s), 6.83-6.86 (2H, m). Elemental analysis C ₇ H ₁₀ N ₂ O Calcd. C, 60.85; H, 7.30; N, 2
0.28; Found. C, 60.60; H, 7.29; N, 20.13.

Reference Example 268 Thionyl chloride (12 ml) was added to 2-hydroxymethyl-1-cyclopropylimidazole (1.20 g) at 0 ° C., and the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 2-chloromethyl-1-cyclopropylimidazole hydrochloride (1.49 g) as brown crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.14-1.22 (4H, m), 3.6
5-3.76 (1H, m), 5.17 (2H, s), 7.69 (1H, d, J = 2.0 H
z), 7.77 (1H, d, J = 2.0 Hz). Elemental analysis C ₇ H ₁₀ N ₂ Cl ₂ Calcd. C, 43.55; H, 5.22; N,
14.51; Found. C, 43.28; H, 5.19; N, 14.50.

Reference Example 269 A mixture of potassium thiocyanate (119.2 g), dihydroxyacetone dimer (73.9 g) and propylamine hydrochloride (100 g) was mixed with acetic acid (89 ml) and 1-butanol (590 ml). Little by little. After stirring at room temperature for 1 day, water (118 ml) was added and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, and water (180 m
It was washed twice with l) and once with hexane. The obtained solid was dried under reduced pressure to give 5-hydroxymethyl-2-mercapto-1-propylimidazole (71.
2 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.87 (3H, t, J = 7.4 Hz),
1.61-1.79 (2H, m), 3.91 (2H, t, J = 7.4 Hz), 4.32 (2
H, s), 5.26 (1H, br), 6.79 (1H, s), 11.95 (1H, s). Elemental analysis C ₇ H ₁₂ N ₂ OS ・ 0.25H ₂ O Calcd. C, 47.57; H,
7.13; N, 15.85; Found. C, 47.22; H, 6.94; N, 1
5.99.

Reference Example 270 5.0M nitric acid (370 ml) was added to sodium nitrite (1.
14 g) and then at 0 ° C. 5-hydroxymethyl-2-mercapto-1-propylimidazole (7
1.0 g) was added in small portions. After returning to room temperature and stirring for 2 hours, water (200 ml) was added. After potassium carbonate was added at 0 ° C. for neutralization, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate = 1: 8), and the obtained solid was recrystallized from diisopropyl ether-ethyl acetate to give 5-hydroxymethyl-1- (brown crystal). Propylimidazole (33.6 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.4 Hz),
1.76-1.94 (2H, m), 3.97 (2H, t, J = 7.2 Hz), 4.63 (2
H, s), 6.97 (1H, s), 7.48 (1H, s).

Reference Example 271 5-hydroxymethyl-1-propylimidazole (3
Thionyl chloride (80 ml) was gradually added to 3.0 g) at 0 ° C., and the mixture was heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-propylimidazole hydrochloride (43.8 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.92 (3H, t, J = 7.4 H
z), 1.84-1.95 (2H, m), 4.18 (2H, t, J = 7.2 Hz), 5.0
4 (2H, s), 7.82 (1H, s), 9.24 (1H, s).

Reference Example 272 Potassium thiocyanate (34.4 g), dihydroxyacetone dimer (21.3 g), ethylamine hydrochloride (2
A mixture of 5.0 g) was added little by little to a mixed solution of acetic acid (26 ml) and 1-butanol (170 ml). After stirring at room temperature for 1 day, water (34 ml) was added and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration and further washed with water (50 ml).
Washed once with hexane. The obtained solid was dried under reduced pressure to give 1-ethyl-5-hydroxymethyl-2-mercaptoimidazole (19.0 g) as colorless crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.22 (3H, t, J = 7.0 Hz),
4.02 (2H, q, J = 7.0 Hz), 4.34 (2H, d, J = 4.8 Hz), 5.
22 (1H, t, J = 4.8 Hz), 6.78 (1H, s), 11.97 (1H, b
r). Elemental analysis C ₆ H ₁₀ N ₂ OS ・ 0.2H ₂ O Calcd. C, 44.53; H, 6.
48; N, 17.31; Found.C, 44.31; H, 6.18; N, 17.3
9.

Reference Example 273 5.0M nitric acid (102 ml) was added to sodium nitrite (31 ml).
4 mg), 1-ethyl-5-hydroxymethyl-2-mercaptoimidazole (18.
0 g) was added in small portions. After returning to room temperature and stirring for 2 hours, water (100 ml) was added. After potassium carbonate was added at 0 ° C. for neutralization, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. This mixture was subjected to basic silica gel column chromatography (methanol-
Ethyl acetate = 1: 8) and the resulting solid was recrystallized from diisopropyl ether-ethyl acetate,
1-Ethyl-5-hydroxymethylimidazole (10.0 g) was obtained as brown crystals. ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.47 (3H, t, J = 7.2 Hz),
4.07 (2H, q, J = 7.2 Hz), 4.62 (2H, s), 6.88 (1H,
s), 7.46 (1H, s).

Reference Example 274 1-Ethyl-5-hydroxymethylimidazole (9.
Thionyl chloride (50 ml) was added to 5 g) little by little at 0 ° C., and then heated at 90 ° C. for 30 minutes under a nitrogen atmosphere.
After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-ethylimidazole hydrochloride (12.4 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.49 (3H, t, J = 7.4 H
z), 4.26 (2H, q, J = 7.4 Hz), 5.03 (2H, s), 7.79 (1
H, s), 9.18 (1H, s). Elemental analysis C ₆ H ₁₀ N ₂ Cl ₂ Calcd. C, 39.80; H, 5.57; N,
15.47; Found. C, 39.71; H, 5.50; N, 15.41.

Reference Example 275 A mixture of potassium thiocyanate (25.9 g), dihydroxyacetone dimer (16.0 g) and isobutylamine hydrochloride (25.0 g) was added to acetic acid (19.2 ml), 1-
It was added little by little to a mixed solution of butanol (128 ml). After stirring at room temperature for 1 day, add water (26 ml) and add 3
Stir for 0 minutes. The precipitated solid was collected by filtration, and water (40
ml) and washed once with diisopropyl ether.
The obtained solid was dried under reduced pressure to give 5--5 as colorless crystals.
Hydroxymethyl-1-isobutyl-2-mercaptoimidazole (15.1 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.85 (6H, d, J = 6.6 H
z), 2.29-2.43 (1H, m), 3.80 (2H, d, J = 7.2 Hz), 4.3
3 (2H, d, J = 4.8 Hz), 5.21 (1H, t, J = 4.8 Hz), 6.81
(1H, s), 12.00 (1H, br).

Reference Example 276 5.0M nitric acid (70 ml) was mixed with sodium nitrite (215 ml).
mg), and then 5-hydroxymethyl-1-isobutyl-2-mercaptoimidazole (1
4.5 g) was added in small portions. After returning to room temperature and stirring for 2 hours, water (100 ml) was added. After potassium carbonate was added at 0 ° C. for neutralization, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. This mixture was purified by basic silica gel column chromatography, and the obtained solid was recrystallized from diisopropyl ether-ethyl acetate to give 5-hydroxymethyl-1-isobutylimidazole (2.86 g) as brown crystals.
Got ¹ H-NMR (300MHz, CDCl ₃ ) δ 0.94 (6H, d, J = 6.6 Hz),
2.05-2.19 (1H, m), 3.80 (2H, d, J = 7.5 Hz), 4.62 (2
H, s), 6.96 (1H, s), 7.44 (1H, s).

Reference Example 277 Thionyl chloride (20 ml) was added little by little to 5-hydroxymethyl-1-isobutylimidazole (2.5 g) at 0 ° C., and then heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-isobutylimidazole hydrochloride (3.0 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.94 (6H, d, J = 6.6 H
z), 2.18-2.31 (1H, m), 4.06 (2H, d, J = 7.8 Hz), 5.0
2 (2H, s), 7.84 (1H, s), 9.24 (1H, s). Elemental analysis C ₇ H ₁₀ N ₂ Cl ₂ 0.1H ₂ O Calcd. C, 45.56; H,
6.79; N, 13.28; Found. C, 45.46; H, 6.81; N, 1
3.43.

Reference Example 278 A mixture of potassium thiocyanate (29.4 g), dihydroxyacetone dimer (18.1 g) and isopropylamine hydrochloride (25.0 g) was mixed with acetic acid (21.8 ml), 1
-Butanol (145 ml) was added little by little to the mixed solution. After stirring at room temperature for 7 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain 5-hydroxymethyl-1-isopropyl-2-mercaptoimidazole (16.0 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.45 (6H, d, J = 7.0 H
z), 4.38 (2H, d, J = 5.2 Hz), 4.95-5.09 (1H, m), 5.2
1 (1H, t, J = 5.2 Hz), 6.75 (1H, s), 11.89 (1H, br). Elemental analysis C ₇ H ₁₂ N ₂ OS Calcd. C, 48.81; H, 7.02; N,
16.26; Found. C, 48.50; H, 7.05; N, 16.32.

Reference Example 279 5.0M nitric acid (81 ml) was added to sodium nitrite (248 ml).
mg), and then 5-hydroxymethyl-1-isopropyl-2-mercaptoimidazole (1
5.5 g) was added in small portions. After returning to room temperature and stirring for 2 hours, water (100 ml) was added. After potassium carbonate was added at 0 ° C. for neutralization, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate = 1: 8), and the obtained solid was recrystallized from diisopropyl ether-ethyl acetate to give 5-hydroxymethyl-1- (brown crystals). Isopropylimidazole (4.84 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.50 (6H, d, J = 6.6 Hz),
4.47-4.61 (1H, m), 4.62 (2H, s), 6.86 (1H, s), 7.54
(1H, s Hz).

Reference Example 280 Thionyl chloride (20 ml) was added little by little to 5-hydroxymethyl-1-isopropylimidazole (4.5 g) at 0 ° C., and then heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-isopropylimidazole hydrochloride (6.2 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.53 (6H, d, J = 6.6 H
z), 4.64-4.78 (1H, m), 5.08 (2H, s), 7.80 (1H, s),
9.45 (1H, s). Elemental analysis C ₇ H ₁₂ N ₂ Cl ₂ Calcd. C, 43.10; H, 6.20; N,
14.36; Found. C, 42.87; H, 6.19; N, 14.37.

Reference Example 281 A mixture of potassium thiocyanate (10.4 g), dihydroxyacetone dimer (6.4 g) and cyclopropylmethylamine hydrochloride (10.0 g) was added to acetic acid (7.7 m).
1) and 1-butanol (52 ml) were added little by little to the mixed solution. After stirring at room temperature for 2 weeks, water (10 ml) was added and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, and further washed with water (15 ml) twice and hexane once. The obtained solid was dried under reduced pressure to obtain 1-cyclopropylmethyl-5-hydroxymethyl-2-mercaptoimidazole (9.6 g) as colorless crystals. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 0.40-0.51 (4H, m), 1.3
0-1.42 (1H, m), 3.92 (2H, d, J = 7.2 Hz), 4.37 (2H,
d, J = 3.4 Hz), 5.23 (1H, t, J = 3.4 Hz), 6.80 (1H,
s), 11.99 (1H, br). Elemental analysis C ₈ H ₁₂ N ₂ OS ・ 0.25H ₂ O Calcd. C, 50.90; H, 6.
67; N, 14.84; Found.C, 50.96; H, 6.54; N, 14.9
Five.

Reference Example 282 5.0M nitric acid (44 ml) was added to sodium nitrite (135 ml).
mg), and then 1-cyclopropylmethyl-5-hydroxymethyl-2-mercaptoimidazole (9.0 g) was added little by little at 0 ° C. After returning to room temperature and stirring for 2 hours, water (50 ml) was added. After potassium carbonate was added at 0 ° C. for neutralization, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. The mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate = 1: 8), and the obtained solid was recrystallized from diisopropyl ether-ethyl acetate to give 1-cyclopropylmethyl-as brown crystals.
5-Hydroxymethylimidazole (4.82 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.33-0.41 (2H, m), 0.63-
0.72 (2H, m), 1.20-1.40 (1H, m), 3.86 (2H, d, J = 7.
0 Hz), 4.63 (2H, s), 6.89 (1H, s), 7.58 (1H, s).

Reference Example 283 1-Cyclopropylmethyl-5-hydroxymethylimidazole (4.5 g) was mixed with thionyl chloride (30 ml) to 0.
After adding little by little at ℃, 3 at 90 ℃ under nitrogen atmosphere
Heated for 0 minutes. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-cyclopropylmethylimidazole hydrochloride (4.5 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.47-0.70 (4H, m), 1.3
5-1.55 (1H, m), 4.09 (2H, d, J = 7.8 Hz), 5.05 (2H,
s), 7.83 (1H, d, J = 1.6 Hz), 9.27 (1H, d, J = 1.6 H
z). Elemental analysis C ₈ H ₁₂ N ₂ Cl ₂ 0.1H ₂ O Calcd. C, 46.00; H, 5.
89; N, 13.41; Found.C, 45.92; H, 5.74; N, 13.2
Four.

Reference Example 284 60% sodium hydride (3.12) washed with hexane.
To a DMF (100 ml) suspension of g) was added ethyl 4-methylimidazole-5-carboxylate (10.0 g) at 0 ° C.
I added it little by little at. After returning to room temperature and stirring for 1 hour under a nitrogen atmosphere, 1-iodopropane (13.9 g) was added dropwise. After stirring for 1 hour, water was added and the mixture was extracted twice with ethyl acetate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (hexane-ethyl acetate = 3: 1), and ethyl 4-methyl-1-propylimidazole-5-carboxylate (4.31) was used.
g) and ethyl 5-methyl-1-propylimidazole-4-carboxylate (8.25 g) were obtained. Ethyl 4-methyl-1-propylimidazole-5-carboxylate ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.4 Hz),
1.39 (3H, t, J = 7.2 Hz), 1.69-1.87 (2H, m), 2.49 (3
H, s), 4.19 (2H, t, J = 7.4 Hz), 4.33 (2H, q, J = 7.2 H
z), 7.44 (1H, s). Ethyl 5-methyl-1-propylimidazole-4-carboxylate ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.4 Hz),
1.40 (3H, t, J = 7.4 Hz), 1.67-1.86 (2H, m), 2.54 (3
H, s), 3.84 (2H, t, J = 7.4 Hz), 4.38 (2H, q, J = 7.4 H
z), 7.40 (1H, s).

Reference Example 285 THF of lithium aluminum hydride (774 mg)
(40 ml) suspension in ethyl 4-methyl-1-propylimidazole-5-carboxylate (4.0 g) in THF.
The (40 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After returning to room temperature and stirring for 2 hours, water (0.8 ml) and a 15% sodium hydroxide aqueous solution (0.
8 ml) and water (2.4 ml) were added in that order. After returning to room temperature and stirring overnight, magnesium sulfate was added and dried. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give 5-hydroxymethyl-4-methyl-1 as a colorless oil.
-Propylimidazole (2.56g) was obtained. H-NMR (200MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.2 Hz),
1.73-1.91 (2H, m), 2.19 (3H, s), 3.92 (2H, t, J = 7.0
Hz), 4.60 (2H, s), 7.36 (1H, s).

Reference Example 286 5-Hydroxymethyl-4-methyl-1-propylimidazole (2.4 g) was mixed with thionyl chloride (10 ml).
After addition at 0 ° C, heated at 90 ° C for 30 minutes. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off under reduced pressure again to give 5-chloromethyl-4-methyl-1 as a brown oily substance. -Propylimidazole hydrochloride (3.13g) was obtained. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 0.91 (3H, t, J = 7.5 H
z), 1.80-1.92 (2H, m), 2.34 (3H, s), 4.16 (2H, t,
J = 7.8 Hz), 5.07 (2H, s), 9.16 (1H, s).

Reference Example 287 60% sodium hydride washed with hexane three times (3.1
4-Formylimidazole (5.0 g) was added to a THF (400 ml) suspension of 2 g), and the mixture was refluxed for 2 hours under a nitrogen atmosphere. After returning to room temperature, 1-iodopropane (88.4 g) was added and the mixture was refluxed again for 2 hours. After returning to room temperature, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate = 1: 8),
1-Propylimidazol-4-carboxaldehyde (4.45 g) was obtained as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.2 Hz),
1.77-1.95 (2H, m), 3.97 (2H, t, J = 7.2 Hz), 7.56 (1
H, s), 7.63 (1H, s), 9.88 (1H, s). Elemental analysis C ₃₇ H ₄₃ N ₃ O ₃ S ₂ Calcd. C, 69.23; H, 6.75;
N, 6.55; Found. C, 69.34; H, 6.79; N, 6.60.

Reference Example 288 THF of lithium aluminum hydride (971 mg)
(35 ml) suspension with 1-propylimidazole-4-
Carboxaldehyde (3.5 g) in THF (35 m
l) The solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After the dropwise addition, water (1.0 ml), a 15% aqueous sodium hydroxide solution (1.0 ml) and water (3.0 ml) were sequentially added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. After magnesium sulfate was added and dried, the insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 4-hydroxymethyl- as a yellow oil.
1-Propylimidazole (3.09 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.71-1.89 (2H, m), 3.80 (2H, t, J = 7.0 Hz), 4.60 (2
H, s), 6.87 (1H, d, J = 1.4 Hz), 7.42 (1H, d, J = 1.4 H
z).

Reference Example 289 Thionyl chloride (25 ml) was added little by little to 4-hydroxymethyl-1-propylimidazole (2.5 g) at 0 ° C., and then heated at 90 ° C. for 30 minutes in a nitrogen atmosphere. After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol. The solvent was distilled off again under reduced pressure to obtain 4-chloromethyl-1-propylimidazole hydrochloride (3.47 g) as a brown oil. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.85 (3H, t, J = 7.4 H
z), 1.60-2.00 (2H, m), 4.13 (2H, t, J = 6.6 Hz), 4.8
8 (2H, s), 7.84 (1H, s), 9.16 (1H, s).

Reference Example 290 1.14 in a solution of 1-propylimidazole-2-carboxaldehyde (2.5 g) in dry THF (25 ml).
M methyl lithium diethyl ether solution (20.6m
1) was added dropwise at -78 ° C under an argon atmosphere.
After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred for 1 hour. At 0 ° C., 1N hydrochloric acid was added to make the mixture acidic, and then potassium carbonate was added to neutralize the mixture. It was extracted 4 times with ethyl acetate and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 2- (1-hydroxy) ethyl-1-propylimidazole (2.45 g) as an oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.4 Hz),
1.63 (3H, d, J = 6.6 Hz), 1.72-1.91 (2H, m), 3.94 (2
H, dt, J = 7.4, 3.2 Hz), 4.90 (1H, q, J = 6.6 Hz), 6.8
8 (1H, s), 6.96 (1H, s).

Reference Example 291 Thionyl chloride (15 ml) was added little by little to 2- (1-hydroxy) ethyl-1-propylimidazole (1.5 g) at 0 ° C., and then heated at 90 ° C. for 1 hour in a nitrogen atmosphere. . After returning to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol. The solvent was distilled off again under reduced pressure to obtain 2- (1-chloro) ethyl-1-propylimidazole hydrochloride (2.03 g) as a brown oil. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.91 (3H, t, J = 7.6 H
z), 1.77-1.89 (2H, m), 2.00 (3H, d, J = 7.0 Hz), 4.0
0-4.40 (4H, m), 7.81 (1H, d, J = 2.0 Hz), 7.86 (1H,
d, J = 2.0 Hz).

Reference Example 292 1-Methylimidazole (13.0 g) in dry THF
A 1.6 Mn-butyllithium hexane solution (119 ml) was added dropwise to the (100 ml) solution at 0 ° C. under an argon atmosphere. After returning to room temperature and stirring for 1 hour, 4-nitrobenzaldehyde (23.9 g) in dry THF (1
50 ml) solution was added dropwise at 0 ° C. After returning to room temperature and stirring for 30 minutes, 1N hydrochloric acid was added at 0 ° C. After neutralizing with potassium carbonate, the mixture was extracted twice with ethyl acetate.
After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate = 1: 8) and recrystallized from hexane-ethyl acetate to give [2- (1-methyl) imidazolyl] (4- Nitrophenyl) methanol (13.9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.43 (3H, s), 5.98 (1H,
s), 6.78 (1H, s), 6.86 (1H, s), 7.53 (2H, d, J = 8.8
Hz), 8.19 (2H, d, J = 8.8 Hz).

Reference Example 293 [2- (1-Methyl) imidazolyl] (4-nitrophenyl) methanol (8.0 g), reduced iron (9.6 g),
Calcium chloride (1.91 g) was added to an 85% aqueous ethanol solution, and the mixture was refluxed for 4 hours in a nitrogen atmosphere. After returning to room temperature, ethyl acetate was added and the insoluble matter was filtered off. After water was added to the filtrate to separate the organic layer, the aqueous phase was extracted 8 times with ethyl acetate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give (4-aminophenyl) [2- (1-methyl) imidazolyl] methanol (2.21 g) as brown crystals. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.37 (3H, s), 5.72 (1H,
s), 6.65 (2H, d, J = 8.4Hz), 6.83 (1H, s), 6.99 (1H,
s), 7.08 (2H, d, J = 8.4 Hz).

Reference Example 294 1-Propylimidazole (8.0 g) in dry THF
A 1.6 Mn-butyllithium hexane solution (54.5 ml) was added dropwise to the (100 ml) solution at 0 ° C. under an argon atmosphere. After returning to room temperature and stirring for 2 hours, 4-
Nitrobenzaldehyde (9.97g) in dry THF
The (100 ml) solution was added dropwise at -78 ° C. After returning to room temperature and stirring overnight, 1N hydrochloric acid was added at 0 ° C. After neutralizing with potassium carbonate, it was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give (4-nitrophenyl) [2- (1-propyl) imidazolyl] methanol (5.26 g) as brown crystals. ) Got. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.77 (3H, t, J = 7.4 Hz),
1.42-1.72 (2H, m), 3.70 (2H, t, J = 7.4 Hz), 5.99 (1
H, s), 6.86 (1H, s), 6.94 (1H, s), 7.54 (2H, d, J =
8.8 Hz), 8.20 (2H, d, J = 8.8 Hz). Elemental analysis C ₁₃ H ₁₅ N ₃ O ₃ Calcd. C, 59.76; H, 5.79; N,
16.08; Found. C, 59.85; H, 7.73; N, 16.04.

Reference Example 295 (4-nitrophenyl) [2- (1-propyl) imidazolyl] methanol (4.5 g) in methanol (150
ml) and ethanol (100 ml) mixed solution, 10% palladium carbon (450 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. After the insoluble material was filtered off, the residue was purified by basic silica gel column chromatography (methanol-ethyl acetate = 1: 8) and recrystallized from ethyl acetate-diisopropyl ether to give brown crystals (4-aminophenyl) [2. -(1-Propyl) imidazolyl] methanol (3.52 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.77 (3H, t, J = 7.4 Hz),
1.45-1.65 (2H, m), 3.61 (2H, t, J = 7.4 Hz), 5.68 (1
H, s), 6.64 (2H, d, J = 8.4 Hz), 6.85 (1H, d, J = 1.4 H
z), 7.01 (1H, d, J = 1.4 Hz), 7.08 (2H, d, J = 8.4 H
z) ,. Elemental analysis C ₁₃ H ₁₇ N ₃ O ・ 0.25H ₂ O Calcd. C, 66.22; H,
7.48; N, 17.82; Found. C, 66.35; H, 7.09; N, 1
7.78.

Reference Example 296 Methyl 7-bromo-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylate (10.0 g),
4- (2-propoxyethoxy) phenyl boric acid (8.
96 g), potassium carbonate (11.1 g), toluene (150 ml), ethanol (15 ml), water (15 m)
It was added to the mixed solution of l) and stirred under an argon atmosphere for 1 hour. Tetrakistriphenylphosphine palladium (1.78 g) was added, and the mixture was refluxed for 2 hours under an argon atmosphere. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane-ethyl acetate = 9: 1).
And recrystallized from hexane-ethyl acetate to give 7- [4- (2-propoxyethoxy) phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxylate as yellow crystals. (9.25 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91-1.01 (6H, m), 1.56-
1.80 (2H, m), 2.82 (2H, t, J = 4.4 Hz), 3.26-3.34 (4
H, m), 3.51 (2H, t, J = 6.6 Hz), 3.79-3.84 (5H, m),
4.16 (2H, t, J = 4.4 Hz), 6.87 (1H, d, J = 8.8 Hz), 6.
97 (2H, d, J = 8.8Hz), 7.37-7.51 (4H, m), 7.76 (1H,
s).

Reference Example 297 7- [4- (2-propoxyethoxy) phenyl] -1
-Propyl-2,3-dihydro-1-benzazepine-
Methyl 4-carboxylate (9.0 g) was added to THF (100 m
After being dissolved in a mixed solution of 1) and methanol (100 ml), 1N aqueous sodium hydroxide solution (43 ml) was added at 0 ° C. After stirring overnight at 60 ° C., the temperature was returned to room temperature, water was added, and 1N hydrochloric acid was added at 0 ° C. to neutralize. After extraction with ethyl acetate, the extract was washed with water and saturated saline. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give 7- [4- (2-propoxyethoxy) as yellow crystals.
Phenyl] -1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (8.0 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91-1.02 (6H, m), 1.56-
1.80 (4H, m), 2.80-2.90 (2H, m), 3.28-3.35 (4H,
m), 3.52 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 4.4Hz),
4.17 (2H, t, J = 4.4 Hz), 6.88 (1H, d, J = 8.8 Hz),
6.98 (2H, d, J = 8.8Hz), 7.39-7.53 (4H, m), 7.89 (1
H, s).

Reference Example 298 1-Fluoro-4-nitrobenzene (5.0 g), 2-
Mercapto-1-methylimidazole (4.04 g),
After potassium carbonate (14.7 g) was added to DMF (100 ml), the mixture was stirred at 130 ° C. for 2 hours under an argon atmosphere. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed 3 times with water and then with saturated saline,
It was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give 1-methyl-2-yellow crystals as yellow crystals.
[(4-Nitrophenyl) thio] imidazole (7.2
9 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.69 (3H, s), 7.13 (2H,
d, J = 8.8 Hz), 7.19 (1H, s), 7.29 (1H, s), 8.10 (2
H, d, J = 8.8 Hz). Elemental analysis C ₁₀ H ₉ N ₃ O ₂ S Calcd. C, 51.05; H, 3.86; N,
17.86; Found. C, 50.98; H, 3.72; N, 17.86.

Reference Example 299 1-Methyl-2-[(4-nitrophenyl) thio] imidazole (6.0 g), reduced iron (7.12 g) calcium chloride (1.42 g) was added to an 85% ethanol aqueous solution (10
0 ml) and stirred at 105 ° C. under a nitrogen atmosphere for 6 hours. After returning to room temperature, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give 2 as yellow crystals.
-[(4-Aminophenyl) thio] -1-methylimidazole (4.38g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.63 (3H, s), 3.77 (2H,
br), 6.59 (2H, d, J = 8.8 Hz), 6.97 (1H, d, J = 1.2 H
z), 7.08 (1H, d, J = 1.2 Hz), 7.18 (2H, d, J = 8.8 H
z). Elemental analysis C ₁₀ H ₁₁ N ₃ S Calcd. C, 58.51; H, 5.40; N,
20.47; Found. C, 58.29; H, 5.31; N, 20.42.

Reference Example 300 60% sodium hydride (1.7 times washed 3 times with hexane)
2-mercapto-in a DMF (30 ml) suspension of g).
4-Methyl-1,2,4-triazole (4.08 g)
DMF (20 ml) of was added dropwise at 0 ° C. under a nitrogen atmosphere, then returned to room temperature and stirred for 1 hour. Then 1-
Fluoro-4-nitrobenzene (5.0 g) in DMF
(50ml) Add the solution at 0 ℃ and drop it at 130 ℃
It was stirred for 2 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, further washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate → methanol-ethyl acetate = 1: 9) and recrystallized from ethyl acetate-diisopropyl ether to give crystals. 4-methyl-3-
[(4-Nitrophenyl) thio] -1,2,4-triazole (1.7 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.68 (3H, s), 7.97 (1H,
s), 8.35 (2H, d, J = 8.8Hz), 8.53 (2H, d, J = 8.8 Hz). Elemental analysis C ₉ H ₈ N ₄ O ₂ S Calcd. C, 45.75; H, 3.41; N,
23.71; Found. C, 45.73; H, 3.21; N, 23.78.

Reference Example 301 4-Methyl-3-[(4-nitrophenyl) thio]-
1,2,4-triazole (1.0 g), reduced iron (1.
18 g) and calcium chloride (2.35 g) were added to an 85% aqueous ethanol solution (15 ml), and the mixture was stirred at 105 ° C. under a nitrogen atmosphere for 6 hours. After returning to room temperature, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give 3-[(4-aminophenyl) thio]-as yellow crystals.
1-methyl-1,2,4-triazole (418 mg)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.66 (3H, s), 3.84 (2H,
br), 6.74 (2H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.8 H
z), 7.87 (1H, s).

Reference Example 302 Dihydroxyacetone (10.2 g), potassium thiocyanate (16.5 g), n-butylamine hydrochloride (16
g) to acetic acid (12 ml), 1-butanol (80 ml)
The mixture was added to the above and stirred overnight at room temperature. The mixture was concentrated, ethanol was added, and colorless crystals (17.3 g) were collected by filtration and washed with water. Sodium nitrite (0.12 g) was dissolved in nitric acid (25 ml) and water (25 ml), and the obtained crystals were added little by little under ice cooling. After stirring at room temperature for 1.5 hours, the mixture was neutralized with potassium carbonate and the solvent was distilled off. Ethanol was added, the insoluble material was filtered off, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give colorless crystals (6.1 g). The mixture was added to thionyl chloride (20 ml) under ice cooling, and the mixture was refluxed for 1 hour. The solvent was distilled off to obtain 4-chloromethyl-3-butylimidazole hydrochloride (7.6 g) as colorless crystals. ¹ H-NMR (dppm, DMSO-d ₆ ) δ 0.93 (3H, t, J = 7.3 H
z), 1.24-1.43 (2H, m), 1.78-1.93 (2H, m), 4.21 (2
H, t, J = 7.5 Hz), 5.04 (2H, s), 7.81 (1H, d, J =
1.4 Hz), 9.26 (1H, d, J = 1.4 Hz).

Reference Example 303 3-Bromo-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine (2.84 g) in THF (50
ml) solution at −78 ° C. with n-butyllithium (1.6
M hexane solution, 28 ml) was added dropwise. 1 at -78 ° C
After stirring for an hour, DMF (5 ml) was added, and the mixture was stirred at room temperature for 0.5 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → ethyl acetate), and 3-formyl-5,6,6 as a colorless oily substance.
7,8-Tetrahydroimidazo [1,2-a] pyridine (1.48 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.87-2.09 (4H, m), 2.96
(2H, t, J = 6.0 Hz), 4.33 (2H, t, J = 5.4 Hz), 7.72 (1
H, s), 9.66 (1H, s).

Reference Example 304 THF of lithium aluminum hydride (0.40 g)
(30 ml) suspension in 3-formyl-5,6,6 at 0 ° C.
THF (50 ml) of 7,8-tetrahydroimidazo [1,2-a] pyridine (1.48 g) was added dropwise. 0 ° C
After stirring for 1 hour at room temperature, water (0.4 ml), 15% aqueous sodium hydroxide solution (0.4 ml) and water (1.2 ml) were added dropwise. After stirring at room temperature for 18 hours, magnesium sulfate was added and the precipitate was removed by filtration. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give colorless crystals 5, 6, 7, 8
-Tetrahydroimidazo [1,2-a] pyridine-3-
Methanol (1.24 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.80-2.06 (4H, m), 2.85
(2H, t, J = 6.2 Hz), 3.99 (2H, t, J = 5.8 Hz), 4.58 (2
H, s), 6.85 (1H, s). IR (KBr) 3086, 1495, 1431, 1329, 1130, 1026, 941,
860, 816, 770 cm ^-1

Reference Example 305 5,6,7,8-tetrahydroimidazo [1,2-a]
Thionyl chloride (5 ml) was added to pyridin-3-ylmethanol (1.0 g) at 0 ° C. After heating under reflux for 40 minutes,
It was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration. The crystals are washed with ethyl acetate,
3- (chloromethyl) -5,6,6 as pale yellow crystals
There was obtained 7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride (1.03 g). ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 1.81-2.07 (4H, m), 3.0
0 (2H, t, J = 6.2 Hz), 4.12 (2H, t, J = 5.7 Hz), 5.00
(2H, s), 7.70 (1H, s). IR (KBr) 1630, 1524, 1308, 1296 cm ^-1

Reference Example 306 4-nitrothiophenol (1.44 g) and 5-methylimidazo [1,2-a] pyridin-3-ylmethanol (1.5 g), concentrated hydrochloric acid (15 ml) and acetic acid (1
5 ml) was stirred at 100 ° C. for 24 hours. 0 ° C
It was neutralized with 12N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethanol: ethyl acetate 1: 9).
Separation and purification with, 5-methyl-3- as yellow crystals
[[(4-Nitrophenylthio) methyl] imidazo [1,2-a] pyridine (2.03 g) was obtained. mp 167-169 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.00 (3H, s), 4.76 (2H,
s), 6.59 (1H, d, J = 6.8Hz), 7.12 (1H, dd, J = 9.0, 6.
8 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.47-7.52 (2H, m),
8.16 (2H, d, J = 9.0 Hz). IR (KBr) 1593, 1574, 1503, 1335, 1292, 1092, 853,
783, 743 cm ^-1 Elemental analysis C ₁₅ H ₁₃ N ₃ O ₂ S Calcd. C, 60.18; H, 4.38;
N, 14.04: Found. C, 60.10; H, 4.50; N, 14.01.

Reference Example 307 5-Methyl-3-[[(4-nitrophenylthio) methyl] imidazo [1,2-a] pyridine (1.80 g),
Reduced iron (1.68g), calcium chloride (0.33g)
15% hydrous ethanol (54 ml) mixture was heated under reflux for 24 hours. After insoluble matter was removed by filtration, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure,
The residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 2: 1) to give 4-[[(5-methylimidazo [1,2-a] pyridin-3-yl) as a yellow oil. Methyl] thio] aniline (1.67 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.03 (3H, s), 3.56-3.92
(2H, m), 4.37 (2H, s), 6.53-6.59 (3H, m), 6.98-7.10
(4H, m), 7.45 (1H, d, J = 8.8 Hz). IR (neat) 3324, 3206, 1647, 1601, 1535, 1508, 149
5, 1292, 1177, 1167, 824 cm ^-1

Reference Example 308 4-nitrothiophenol (2.87 g) and 6-methylzoimidazo [1,2-a] pyridin-3-ylmethanol (3.0 g), concentrated hydrochloric acid (60 ml) and acetic acid (60 ml). The mixture of 1) was stirred at 100 ° C. for 5 days. 0
The mixture was neutralized at 12 ° C. with a 12N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 2: 1 → 4: 1) to give 6-methyl-3-[[((4-nitrophenyl) as pale yellow crystals. ) Thio] methyl] imidazo [1,2-a] pyridine (4.48 g) was obtained. mp 127-128 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.39 (3H, s), 4.54 (2H,
s), 7.11 (1H, dd, J = 9.2, 1.8 Hz), 7.39 (2H, d, J =
9.2 Hz), 7.50 (1H, s), 7.55 (1H, d, J = 9.2 Hz), 7.8
8 (1H, d, J = 1.8 Hz), 8.14 (2H, d, J = 9.2 Hz). IR (KBr) 1580, 1514, 1343, 1312, 1250, 1090, 853,
833, 797, 743 cm ^-1 Elemental analysis C ₁₅ H ₁₃ N ₃ O ₂ S Calcd. C, 60.18; H, 4.38;
N, 14.04: Found. C, 60.13; H, 4.30; N, 13.82.

Reference Example 309 6-methyl-3-[[(4-nitrophenyl) thio] methyl] imidazo [1,2-a] pyridine (3.0 g),
Reduced iron (2.80g), calcium chloride (0.56g)
A mixture of 15% water-containing ethanol (150 ml) was heated under reflux for 20 hours. After insoluble matter was removed by filtration, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1 → 2: 1) to give 4-[[(6-methylimidazo [1,2-a] pyridine) as pale yellow crystals. -3-yl) methyl] thio] aniline (2.38)
g) was obtained. mp 128-129 ℃ ¹ H-NMR (300MHz, CDCl ₃ ) δ 2.37 (3H, s), 3.68-3.76
(2H, m), 4.18 (2H, s), 6.52 (2H, d, J = 8.7 Hz), 7.00
(2H, d, J = 8.7 Hz), 7.06 (1H, dd, J = 9.3, 1.5 Hz),
7.18 (1H, s), 7.51 (1H, d, J = 9.3 Hz), 7.85 (1H, d,
J = 1.5 Hz). IR (KBr) 3301, 3187, 1636, 1597, 1497, 1312, 1292,
1238, 822, 793 cm ^-1 Elemental analysis C ₁₅ H ₁₅ N ₃ S Calcd. C, 66.88; H, 5.61; N,
15.50: Found. C, 66.91; H, 5.75; N, 15.17.

Reference Example 310 2-Formylimidazole (5.16 g), ethyl bromoacetate (7.1 ml) and potassium carbonate (11.1).
The DMF (50 ml) mixture of g) was stirred at 60 ° C. for 20 hours. After removing the insoluble matter by filtration, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline,
It was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate: hexane 1:
1) was separated and purified, and ethyl (2-formyl-1H-imidazol-1-yl) acetate (1.
10 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.29 (3H, t, J = 7.1 Hz),
4.25 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 7.15 (1H,
s), 7.33 (1H, d, J = 0.6 Hz), 9.79 (1H, d, J = 0.6Hz). IR (neat) 1752, 1684, 1478, 1416, 1375, 1339, 130
2, 1215, 1024, 775 cm ^-1

Reference Example 311 To a solution of ethyl (2-formyl-1H-imidazol-1-yl) ethyl acetate (1.10 g) in ethanol (5 ml),
Sodium borohydride (123 mg) was added at 0 ° C. After stirring at 0 ° C. for 0.5 hours, the reaction mixture was purified by column chromatography (basic silica gel, ethanol: ethyl acetate 1:19) to give [2-
Ethyl (hydroxymethyl) -1H-imidazol-1-yl] acetate (960 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.2 Hz),
4.24 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 4.81 (2H,
s), 6.89 (1H, s), 6.95 (1H, s) .IR (KBr) 3119, 1748, 1499, 1292, 1213, 1026, 737 c
m ^-1

Reference Example 312 [2- (hydroxymethyl) -1H-imidazole-1
-Yl] ethyl acetate (460 mg) in dichloromethane (10 ml) at room temperature, thionyl chloride (0.27 m
l) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure.
4-Aminothiophenol (0.33 g) and triethylamine (3.5 ml) were added to a solution of the residue in ethanol (10 ml), and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), [2-[[(4-
Aminophenyl) thio] methyl] -1H-imidazol-1-yl] ethyl acetate (820 mg) was obtained. This compound was used in the next reaction without further purification. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.29 (3H, t, J = 7.1 Hz),
3.40-3.74 (2H, m), 4.04 (2H, s), 4.24 (2H, q, J = 7.
1 Hz), 4.71 (2H, s), 6.56 (2H, d, J = 8.7 Hz), 6.87
(1H, d, J = 1.4 Hz), 6.93 (1H, d, J = 1.4 Hz), 7.11 (2
H, d, J = 8.7 Hz).

Reference Example 313 2-Formylimidazole (5.17 g), ethyl 4-bromobutyrate (9.2 ml) and potassium carbonate (11.
A mixture of 1 g) of DMF (50 ml) was stirred at 80 ° C. for 40 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1) to give 4- (2-formyl-1H-imidazole-1-) as a pale yellow oil.
Yield) ethyl butyrate (8.36 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.2 Hz),
2.08-2.19 (2H, m), 2.29-2.36 (2H, m), 4.14 (2H, q,
J = 7.2 Hz), 4.47 (2H, t, J = 7.1 Hz), 7.18 (1H, d, J
= 1.1 Hz), 2.30 (1H, d, J = 1.1 Hz), 9.81 (1H, s). IR (neat) 1732, 1682, 1476, 1412, 1337, 1188, 115
9,772 cm ^-1

Reference Example 314 4- (2-formyl-1H-imidazol-1-yl)
To a solution of ethyl butyrate (8.36 g) in ethanol (80 ml) was added sodium borohydride (0.45 g) at 0 ° C. After stirring at 0 ° C. for 0.5 hour, 1N hydrochloric acid (15 ml) was added to the reaction system. After stirring at 0 ° C for 30 minutes, triethylamine (10 ml) was added, and the mixture was concentrated under reduced pressure. Ethanol was added to the residue and the insoluble material was removed by filtration.
After concentration under reduced pressure, the residue was purified by column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1:19) to give 4- [2-
Ethyl (hydroxymethyl) -1H-imidazol-1-yl] butyrate (8.51 g) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.2 Hz),
2.08-2.17 (2H, m), 2.32-2.37 (2H, m), 4.08 (2H, t,
J = 7.1 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.66 (2H, s),
6.87 (1H, d, J = 1.5 Hz), 6.91 (1H, d, J = 1.5 Hz). IR (neat) 3113, 1732, 1495, 1466, 1445, 1375, 127
7, 1250, 1188, 1154, 1030, 739 cm ^-1

Reference Example 315 To a solution of ethyl 4- [2- (hydroxymethyl) -1H-imidazol-1-yl] butyrate (8.51 g) in chloroform (100 ml) was added thionyl chloride (4.4 m) at room temperature.
l) and DMF (1 drop) were added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. 4-Aminothiophenol (5.0 g) and triethylamine (17 ml) were added to a solution of the residue in ethanol (50 ml), and the mixture was stirred at room temperature for 64 hours. After concentration under reduced pressure, the residue was subjected to column chromatography (basic silica gel, ethyl acetate: hexane 1: 1 →
2: 1 → ethyl acetate) to separate and purify, and ethyl 4- [2-[[(4-aminophenyl) thio] methyl] -1H-imidazol-1-yl] butyrate (1
0.08 g) was obtained. mp 74-75 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.2 Hz),
1.98-2.13 (2H, m), 2.28-2.35 (2H, m), 3.64-3.80 (2
H, m), 3.92 (2H, t, J = 7.2 Hz), 4.04 (2H, s), 4.14
(2H, q, J = 7.2 Hz), 6.57 (2H, d, J = 8.4 Hz), 6.83 (1
H, s), 6.92 (1H, s), 7.15 (2H, d, J = 8.4 Hz) .IR (KBr) 3428, 3333, 3210, 1742, 1628, 1599, 1501,
1312, 1221, 1211, 1179, 1161, 1127, 1100, 1024, 9
26, 826 cm ^-1 Elemental analysis C ₁₆ H ₂₁ N ₃ O ₂ S Calcd. C, 60.16; H, 6.63;
N, 13.16: Found. C, 60.00; H, 6.54; N, 13.03.

Reference Example 316 [5- (hydroxymethyl) -1H-imidazole-1
-Yl] ethyl acetate (1.66 g) in chloroform (1
0 ml) solution at room temperature with thionyl chloride (0.98 ml)
And DMF (1 drop) were added. After stirring for 1 hour at room temperature,
It was concentrated under reduced pressure. 4-Aminothiophenol (1.35 g) and triethylamine (7.5 ml) were added to a solution of the residue in ethanol (20 ml), and the mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was separated and purified by column chromatography using basic silica gel (ethyl acetate → ethanol: ethyl acetate 1: 9) to give [5-[[(4-aminophenyl) thio] as pale yellow crystals. ] Methyl]
-1H-imidazol-1-yl] ethyl acetate (2.2
0 g) was obtained. mp 91-92 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.2 Hz),
3.65-3.78 (2H, m), 3.85 (2H, s), 4.25 (2H, q, J = 7.
2 Hz), 4.77 (2H, s), 6.56 (2H, d, J = 8.8 Hz), 6.64
(1H, s), 7.06 (2H, d, J = 8.8 Hz), 7.46 (1H, s). IR (KBr) 3428, 3333, 3210, 1742, 1628, 1599, 1501,
1372, 1312, 1221, 1211, 1179, 1161, 1127, 1100, 1
024, 926, 826 cm ^-1 Elemental analysis C ₁₄ H ₁₇ N ₃ O ₂ S Calcd. C, 57.71; H, 5.88;
N, 14.42: Found. C, 57.36; H, 5.78; N, 14.31.

Reference Example 317 2-Formylimidazole (2.50 g), benzoic acid 2
A mixture of ethyl iodide (8.61 g) and potassium carbonate (5.4 g) in DMF (25 ml) was stirred at 80 ° C. for 20 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1), and 2- (2-formyl-1H-imidazol-1-yl) ethyl benzoate (4) was obtained as a pale yellow oil. ．
69 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.62-4.67 (2H, m), 4.77-
4.84 (2H, m), 7.21-7.22 (1H, m), 7.31 (1H, d, J = 0.
8 Hz), 7.40-7.48 (2H, m), 7.54-7.63 (1H, m), 7.93-
7.98 (2H, m), 9.85 (1H, d, J = 0.8 Hz). IR (neat) 1721, 1682, 1476, 1453, 1412, 1273, 111
7, 772, 712 cm ^-1

Reference Example 318 Benzoic acid 2- (2-formyl-1H-imidazole-1)
2-yl) ethyl (4.69 g) in 2-propanol (5
0 ml) solution at 0 ° C. with sodium borohydride (0.
22 g) was added. After stirring at 0 ° C. for 30 minutes, 1N hydrochloric acid (15 ml) was added. Furthermore, triethylamine (10
ml) was added and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble material was removed by filtration. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate → ethanol: ethyl acetate 1:19) to give 2- [2- (hydroxymethyl) -1H-imidazole benzoate as colorless crystals. -1-yl] ethyl (0.87 g) was obtained. mp 167-169 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 4.41 (2H, t, J = 5.4 Hz),
4.64 (2H, t, J = 5.4 Hz), 4.74 (2H, s), 6.94 (1H,
s), 6.97 (1H, s), 7.41-7.48 (2H, m), 7.55-7.62 (1H,
m), 7.99 (2H, d, J = 8.4 Hz). IR (KBr) 3120, 1711, 1277, 1113, 1026, 768, 708 cm
^-1 Elemental analysis C ₁₃ H ₁₄ N ₂ O ₃ Calcd. C, 63.40; H, 5.73;
N, 11.38: Found. C, 63.38; H, 5.71; N, 11.38.

Reference Example 319 A solution of 2- [2- (hydroxymethyl) -1H-imidazol-1-yl] ethyl benzoate (0.87 g) in chloroform (10 ml) was thionyl chloride (0.5%) at room temperature.
2 g) and DMF (1 drop) were added and stirred for 1 hour.
After concentration under reduced pressure, the residue was added to a solution of ethanol (10 ml) in 4
-Aminothiophenol (0.49g) and triethylamine (1.0ml) were added at room temperature. After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
It was dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 2: 1), and 2- [2-[[[(4-aminophenyl) thio] benzoic acid was obtained as a brown oil. Methyl] -1H-imidazol-1-yl] ethyl (1.07 g, 86%) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.58-3.84 (2H, m), 4.09
(2H, s), 4.25 (2H, t, J = 5.5 Hz), 4.56 (2H, t, J = 5.5
Hz), 6.56 (2H, d, J = 8.8 Hz), 6.89-6.95 (2H, m),
7.14 (2H, d, J = 8.8 Hz), 7.41-7.48 (2H, m), 7.55-7.
63 (1H, m), 7.96-8.01 (2H, m). IR (neat) 3351, 3179, 1721, 1599, 1497, 1451, 127
3, 1117, 741, 712 cm ^-1

Reference Example 320 2-Formylimidazole (2.50 g), 3-chloropropyl acetate (3.8 ml), sodium iodide (4.
7 g) and potassium carbonate (5.4 g) in DMF (25
ml) The mixture was stirred at 80 ° C. for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to column chromatography (ethyl acetate:
Separation and purification with hexane 1: 1) gave 3- (2-formyl-1H-imidazol-1-yl) propyl acetate (4.37 g) as a pale yellow oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.07-2.20 (5H, m), 4.08
(2H, t, J = 6.1 Hz), 4.50 (2H, t, J = 7.0 Hz), 7.17 (1
H, s), 7.30 (1H, s), 9.81 (1H, s).

Reference Example 321 2- (2-formyl-1H-imidazol-1-yl) propyl acetate (4.37 g) in 2-propanol (50)
ml) solution at 0 ° C. with sodium borohydride (0.2
5 g) was added. After stirring at 0 ° C for 30 minutes, 1N was added to the reaction system.
Hydrochloric acid (20 ml) was added. After further adding triethylamine (10 ml), the mixture was concentrated under reduced pressure. Ethanol was added to the residue, the insoluble material was removed by filtration, and the mixture was further concentrated under reduced pressure. The residue was subjected to column chromatography (basic silica gel, ethanol: ethyl acetate 1: 1).
9) Separation and purification was carried out, and acetic acid 3- [2-
(Hydroxymethyl) -1H-imidazol-1-yl] propyl (1.34 g) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 2.05-2.19 (5H, m), 4.07-
4.14 (4H, m), 4.66 (2H, s), 6.87 (1H, d, J = 1.1 H
z), 6.92 (1H, d, J = 1.1 Hz). IR (neat) 3335, 1738, 1497, 1370, 1246, 1044, 741
cm ^-1

Reference Example 322 A solution of 3- [2- (hydroxymethyl) -1H-imidazol-1-yl] propyl acetate (1.27 g) in chloroform (10 ml) was thionyl chloride (0.94) at room temperature.
ml) and DMF (1 drop) were added and stirred for 1 hour. After concentration under reduced pressure, triethylamine (5.4 ml) and 4-aminothiophenol (0.96 g) were added to a solution of the residue in ethanol (30 ml) at room temperature. After stirring at room temperature for 3 days, the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, ethyl acetate: hexane 4: 1 → ethyl acetate) to give acetic acid 3- [2-[[(4-aminophenyl ) Thio] methyl] -1H-imidazol-1-yl] propyl (1.49 g) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 2.01-2.11 (5H, m), 3.61-
3.84 (2H, m), 3.97 (2H, t, J = 7.1 Hz), 4.04 (2H,
s), 4.07 (2H, t, J = 6.2 Hz), 6.57 (2H, d, J = 8.5Hz),
6.83 (1H, d, J = 1.2 Hz), 6.93 (1H, d, J = 1.2 Hz),
7.15 (2H, d, J = 8.5Hz). IR (neat) 3328, 3173, 1732, 1597, 1497, 1246, 104
6, 828, 739 cm ^-1

Reference Example 323 To a suspension of 4-hydroxymethyl-1-trityl-1H-imidazole (3.0 g) in THF (30 ml) was added thionyl chloride (0.8 ml) and DMF (1 drop) at room temperature. It was After stirring at room temperature for 1 hour, 4-aminothiophenol (1.37 g) and 4N sodium hydroxide (25
ml) and ethanol (50 ml) mixture. After stirring at room temperature for 60 hours, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diisopropyl ether to give 4-[[(1-trityl-1H-imidazole-1 as pale yellow crystals.
-Yl) Methyl] thio] aniline (2.74 g) was obtained. mp 179-180 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.61-3.72 (2H, m), 3.90
(2H, s), 6.48 (1H, s), 6.53 (2H, d, J = 8.8 Hz), 7.04
-7.09 (6H, m), 7.15 (2H, d, J = 8.8 Hz), 7.30-7.33
(10H, m) .IR (KBr) 3426, 3343, 3229, 1636, 1599, 1497, 1443,
1308, 1226, 1142, 933, 820, 750, 702 cm ^-1 Elemental analysis C ₂₉ H ₂₅ N ₃ S0.25H ₂ O Calcd. C, 77.05; H, 5.
68; N, 9.29: Found.C, 76.90; H, 5.93; N, 9.02.

Reference Example 324 7- [4- (2-butoxyethoxy) phenyl] -1-
Isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 m
l) Thionyl chloride (0.25 ml) and DMF (1 drop) were added to the solution at room temperature, and the mixture was stirred at room temperature for 1.5 hours.
After concentration under reduced pressure, a solution of the residue in THF (25 ml) was added at 0 ° C.
4-[[(1-trityl-1H-imidazole-1-
It was added dropwise to a pyridine (10 ml) solution of (yl) methyl] thio] aniline (1.13 g). After stirring at room temperature for 20 hours, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate.
After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 1) to give 7- [4- (2-butoxyethoxy) phenyl]-as yellow crystals.
N- [4-[(1-Trityl-1H-imidazole-4
-Yl) methyl] thio] phenyl] -1-isobutyl-
2,3-Dihydro-1H-1-benzazepine-4-carboxamide (1.43 g) was obtained. mp 178-181 ℃ ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz),
0.98 (6H, d, J = 6.6 Hz), 1.30-1.44 (2H, m), 1.49-1.
71 (2H, m), 1.97-2.16 (1H, m), 2.86-2.96 (2H, m),
3.20 (2H, d, J = 6.8 Hz), 3.31-3.42 (2H, m), 3.55 (2
H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.03 (2H,
s), 4.16 (2H, t, J = 5.0 Hz), 6.57 (1H, s), 6.91-7.09
(9H, m), 7.23-7.53 (20H, m) .IR (KBr) 3056, 1653, 1590, 1518, 1497, 1314, 1244,
1179, 1165, 1125, 818, 752, 700 cm ^-1

Reference Example 325 THF of lithium aluminum hydride (1.55 g)
(80 ml) suspension in ethyl 5-methyl-1-propylimidazole-4-carboxylate (8.0 g) in THF.
The (80 ml) solution was added dropwise at 0 ° C. under a nitrogen atmosphere. After returning to room temperature and stirring for 2 hours, water (1.6 ml) and a 15% sodium hydroxide aqueous solution (1.6
ml) and water (4.8 ml) were added in that order. After returning to room temperature and stirring overnight, magnesium sulfate was added and dried. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from hexane-ethyl acetate to give 4-hydroxymethyl-5-methyl-1-propylimidazole (4 .9 g) was obtained. mp 88.0-88.5 ー C H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz),
1.65-1.84 (2H, m), 2.21 (3H, s), 3.77 (2H, t, J = 7.4
Hz), 4.56 (2H, s), 7.38 (1H, s). Elemental analysis C ₈ H ₁₄ N ₂ O Calcd. C, 62.31; H, 9.15; N, 1
8.17: Found C, 62.31; H, 9.36; N, 18.39.

Reference Example 326 4-Hydroxymethyl-5-methyl-1-propylimidazole (4.5 g) was dissolved in thionyl chloride (25 ml).
After addition at 0 ° C, heated at 90 ° C for 1 hour. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained residue was washed with ethyl acetate to give 4-chloromethyl-5-methyl-1-propylimidazole hydrochloride (5.79 g) as colorless crystals. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.88 (3H, t, J = 7.4 H
z), 1.65-1.85 (2H, m), 2.35 (3H, s), 4.08 (2H, t,
J = 7.6 Hz), 4.93 (2H, s), 9.19 (1H, s). Elemental analysis C ₈ H ₁₄ N ₂ Cl ₂ Calcd. C, 45.95; H, 6.75; N,
13.40: Found C, 45.78; H, 7.11; N, 13.22.

Reference Example 327 A mixture of potassium thiocyanate (31.1 g), dihydroxyacetone dimer (19.2 g) and (2-propyn-1-yl) amine hydrochloride (25.0 g) was added to acetic acid (23
ml) and 1-butanol (155 ml) were added little by little to the mixed solution. After stirring at room temperature for 10 days, water (30 m
1) was added and stirred for 30 minutes. The precipitated solid is collected by filtration,
Further, it was washed twice with water (45 ml) and once with diisopropyl ether. The obtained solid was dried under reduced pressure to give 5-hydroxymethyl-2-mercapto-1 as colorless crystals.
-(2-propyn-1-yl) imidazole (28.9
g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 3.31 (1H, t, J = 2.6 H
z), 4.42 (2H, d, J = 5.2 Hz), 4.90 (2H, d, J = 2.6 H
z), 5.37 (1H, t, J = 5.2 Hz), 6.85 (1H, s), 12.18 (1
H, br).

Reference Example 328 5.0 M nitric acid (134 ml) was added to sodium nitrite (41 ml).
1 mg) and then 5-hydroxymethyl-2-mercapto-1- (2-propyn-1-yl) at 0 ° C.
Imidazole (25.0 g) was added in small portions. After returning to room temperature and stirring for 1 hour, water (60 ml) was added. 0
After potassium carbonate was added thereto for neutralization at ℃, the solvent was distilled off under reduced pressure. After ethanol was added and the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. Methanol-ethyl acetate was added to the obtained residue, and then basic silica gel was added. This mixture was purified by basic silica gel column chromatography (methanol: ethyl acetate = 1: 8), and the obtained solid was recrystallized from hexane-ethyl acetate to give 5-hydroxymethyl-1-yellow crystals as yellow crystals.
(2-propyn-1-yl) imidazole (8.46
g) was obtained. mp 91.0-92.5 ー C ¹ H-NMR (300MHz, CDCl ₃ ) δ 2.49 (1H, t, J = 2.4 Hz),
4.69 (2H, s), 4.84 (2H, d, J = 2.4 Hz), 6.89 (1H,
s), 7.60 (1H, s). Elemental analysis C ₇ H ₈ N ₂ O ・ 0.1H ₂ O Calcd. C, 60.95; H, 5.99;
N, 20.31: Found C, 61.25; H, 5.86; N, 20.35.

Reference Example 329 5-Hydroxymethyl-1- (2-propyn-1-yl) imidazole (8.0 g) was added to thionyl chloride (40 m).
l) was added little by little at 0 ° C. and then under a nitrogen atmosphere 9
Heated at 0 ° C. for 30 minutes. After returning to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 5-chloromethyl-1 as colorless crystals.
-(2-Propyn-1-yl) imidazole hydrochloride (9.8 g) was obtained. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 3.86 (1H, t, J = 2.6 H
z), 5.06 (2H, s), 5.26 (2H, d, J = 2.6 Hz), 7.85 (1
H, d, J = 1.2 Hz), 9.32 (1H, d, J = 1.2 Hz). Elemental analysis C ₇ H ₈ N ₂ Cl ₂ 0.1H ₂ O Calcd. C, 43.59; H, 4.29
; N, 14.53: Found C, 43.36; H, 4.24; N, 14.47.

Reference Example 330 2-Mercapto-5-nitrobenzimidazole (3.
0 g), triethylamine (12.5 ml) in tetrahydrofuran (30 ml) solution 5-chloromethyl-1-
A solution of propylimidazole hydrochloride (3.0 g) in methanol (30 ml) was added dropwise at 0 ° C under a nitrogen atmosphere. After returning to room temperature and stirring for 10 minutes, water was added and the mixture was extracted twice with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 8 → methanol: ethyl acetate = 1: 4) and recrystallized from diisopropyl ether-ethyl acetate to give 5-nitro-yellow crystals as yellow crystals. 2-(((1-Propylimidazol-5-yl) methyl) sulfanyl) benzimidazole (3.33 g) was obtained. mp 189.0-190.0 ー C ¹ H-NMR (200MHz, DMSO-d ₆ ) δ 0.85 (3H, t, J = 7.2 H
z), 1.66-1.84 (2H, m), 3.97 (2H, t, J = 7.2 Hz), 4.7
1 (2H, s), 6.91 (1H, s), 7.61-7.66 (2H, m), 8.08
(1H, dd, J = 8.8, 2.2 Hz), 8.35 (1H, d, J = 2.2 Hz). Elemental analysis C ₁₄ H ₁₅ N ₅ O ₂ S Calcd. C, 52.98; H, 4.76; N,
22.07: Found C, 52.83; H, 4.83; N, 21.83.

Reference Example 331 Sodium hydride washed with hexane three times (492 mg,
60%) in DMF (45 ml) in 5-nitro-
(((1-Propylimidazol-5-yl) methyl)
DM of sulfanyl) benzimidazole (3.0 g)
The F (30 ml) solution was added dropwise at 0 ° C under a nitrogen atmosphere. After returning to room temperature and stirring for 1 hour, iodomethane (1.6 g) was added dropwise at 0 ° C. After returning to room temperature and stirring for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate), and recrystallized from hexane-ethyl acetate to give colorless crystals of 1-methyl-
5-nitro-2-(((1-propylimidazole-5
-Yl) methyl) sulfanyl) benzimidazole (747 mg), 1-methyl-6-nitro-2-(((1-propylimidazol-5-yl) methyl) thio) benzimidazole (258 mg) as yellow crystals.
Got 1-methyl-5-nitro-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole mp 147.5-149.5-C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.97 (3H, t , J = 7.4 Hz),
1.77-1.95 (2H, m), 3.70 (3H, s), 3.97 (2H, t, J = 7.
4 Hz), 4.73 (2H, s), 7.09 (1H, s), 7.30 (1H, d, J =
8.8 Hz), 7.49 (1H, s), 8.20 (1H, dd, J = 8.8, 1.8 H
z), 8.57 (1H, d, J = 1.8 Hz). Elemental analysis C ₁₅ H ₁₇ N ₅ O ₂ S Calcd. C, 54.36; H, 5.17; N,
21.13: Found C, 54.17; H, 5.18; N, 20.88. 1-methyl-6-nitro-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole mp 148.0-149.0-C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.97 (3H, t, J = 7.4 Hz),
1.77-1.92 (2H, m), 3.73 (3H, s), 3.97 (2H, t, J = 7.
0 Hz), 4.75 (2H, s), 7.11 (1H, s), 7.51 (1H, s), 7.
69 (1H, d, J = 8.4 Hz), 8.17-8.23 (2H, m). Elemental analysis C ₁₅ H ₁₇ N ₅ O ₂ S ・ 0.25H ₂ O Calcd. C, 53.63; H,
5.25; N, 20.85: FoundC, 53.92; H, 4.95; N, 20.
61.

Reference Example 332 1-Methyl-5-nitro-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole (700 mg), reduced iron (0.6 g), anhydrous calcium chloride ( 1.18 g) of 85% aqueous ethanol solution (15 ml) was stirred at 105 ° C. for 1 day under a nitrogen atmosphere. The mixture was returned to room temperature, the insoluble material was filtered off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 8) to give a brown solid. 5-Amino-1-methyl-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole (123 mg) was obtained as an oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.4 Hz),
1.70-1.88 (2H, m), 3.56 (3H, s), 3.92 (2H, t, J = 7.
2 Hz), 4.61 (2H, s), 6.69 (1H, dd, J = 8.4, 2.2 Hz),
6.99-7.06 (3H, m), 7.46 (1H, s).

Reference Example 333 1-Methyl-6-nitro-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole (230 mg), reduced iron (194 mg), anhydrous calcium chloride (38. 5 mg) of 85% ethanol aqueous solution (10 ml) was stirred at 105 ° C for 1 day under a nitrogen atmosphere. The mixture was returned to room temperature, the insoluble material was filtered off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give 6 as a colorless oil. -Amino-1-methyl-2-(((1-propylimidazol-5-yl) methyl) sulfanyl) benzimidazole (170 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.93 (3H, t, J = 7.2 Hz),
1.73-1.88 (2H, m), 3.52 (3H, s), 3.91 (2H, t, J = 7.
4 Hz), 4.56 (2H, s), 6.53 (1H, d, J = 2.0 Hz), 6.64
(1H, dd, J = 8.4, 2.0 Hz), 6.97 (1H, s), 7.45-7.49
(2H, m).

Reference Example 334 Sodium hydride washed with hexane three times (5.84 g,
A solution of 2-methylimidazole (10 g) in tetrahydrofuran (50 ml) was added dropwise to a suspension of 60% oil) in tetrahydrofuran (100 ml) at 0 ° C under a nitrogen atmosphere. After returning to room temperature and stirring for 1 hour, 1-iodopropane (22.8 g) was added dropwise at 0 ° C. After returning to room temperature and stirring overnight, the insoluble matter was filtered off. The solvent was distilled off under reduced pressure, dichloromethane (20 ml) was added, and the insoluble material was filtered off. The solvent was distilled off under reduced pressure,
2-Methyl-1-propylimidazole (15.1 g) was obtained as a brown oil. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.94 (3H, t, J = 7.4 Hz),
1.66-1.85 (2H, m), 2.37 (3H, s), 3.79 (2H, t, J = 7.
4 Hz), 6.81 (1H, d, J = 1.2 Hz), 6.90 (1H, d, J = 1.2 H
z).

Reference Example 335 2-Methyl-1-propylimidazole (6.0 g),
To a solution of triethylamine (29.5 ml) in acetonitrile (150 ml) was added 4-nitrobenzoyl chloride (19.7 g) in small portions at 0 ° C. After returning to room temperature and stirring for 2 hours, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was washed with diisopropyl ether to give 1- (4-nitrophenyl) -2- (1-propylimidazole-2- as brown crystals.
Il) vinyl 4-nitrobenzoate (19.6 g)
Got ¹ H-NMR (200MHz, CDCl ₃ ) δ 1.00 (3H, t, J = 7.2 Hz),
1.78-1.96 (2H, m), 4.03 (2H, t, J = 7.4 Hz), 6.88-6.
93 (3H, m), 7.77 (2H, d, J = 8.8 Hz), 8.27 (2H, d, J
= 9.2 Hz), 8.35-8.47 (4H, m). Elemental analysis C ₂₁ H ₁₈ N ₄ O ₆・ 0.75H ₂ O Calcd. C, 57.86; H, 4.
51; N, 12.85: FoundC, 58.06; H, 4.45; N, 12.5
7.

Reference Example 336 1- (4-Nitrophenyl) -2- (1-propylimidazol-2-yl) vinyl 4-Nitrobenzoate (19.0 g) suspended in acetic acid (190 ml) concentrated hydrochloric acid ( (95 ml) was added dropwise at 0 ° C., and the mixture was refluxed for 2 hours. After cooling to 0 ° C, the insoluble material was filtered off. After the solvent was distilled off under reduced pressure, water was added and the mixture was neutralized with potassium carbonate at 0 ° C. After neutralizing with ethyl acetate, the extract was washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-diisopropyl ether to give 1- (4-nitrophenyl) -2- (1-propylimidazol-2-yl) as brown crystals.
Ethylenol (10.2 g) was obtained. mp 113.0-114.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.99 (3H, t, J = 7.4 Hz),
1.76-1.94 (2H, m), 3.92 (2H, t, J = 7.4 Hz), 5.98 (1
H, s), 6.83 (1H, d, J = 1.4 Hz), 7.03 (1H, d, J = 1.4 H
z), 7.96 (2H, d, J = 9.2 Hz), 7.25 (2H, d, J = 9.2 H
z). Elemental analysis C ₁₄ H ₁₅ N ₃ O ₃ 0.25H ₂ O Calcd. C, 60.53; H, 5.
62; N, 15.12: FoundC, 60.74; H, 5.41; N, 14.8
Five.

Reference Example 337 1- (4-Nitrophenyl) -2- (1-propylimidazol-2-yl) ethylenol (9.4 g), reduced iron (9.6 g), anhydrous calcium chloride (1.91 g) Of 8
5% ethanol aqueous solution (200 ml) under nitrogen atmosphere 1
Stir overnight at 05 ° C. The mixture was returned to room temperature, the insoluble material was filtered off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane-ethyl acetate to give yellow crystals, 1- (4-aminophenyl)-
2- (1-Propylimidazol-2-yl) ethanone (5.29 g) was obtained. mp 130.0-131.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.92 (3H, t, J = 7.4 Hz),
1.60-1.81 (2H, m), 3.86 (2H, t, J = 7.4 Hz), 4.17 (2
H, br), 4.33 (2H, s), 6.65 (2H, d, J = 9.2 Hz), 6.87
(1H, d, J = 1.6 Hz), 6.99 (1H, d, J = 1.6 Hz), 6.97
(2H, d, J = 9.2 Hz). Elemental analysis C ₁₄ H ₁₇ N ₃ O Calcd. C, 69.11; H, 7.04; N, 1
7.27: Found C, 68.82; H, 7.17; N, 17.03.

Reference Example 338 1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone (600 mg) and O-methylhydroxylamine hydrochloride (227 mg) in ethanol (20 ml) were added to 8 parts. Reflux for hours. After returning to room temperature and adding a saturated sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1) and washed with diisopropyl ether to give colorless crystals (1E) -1. -(4-aminophenyl) -2-
(1-Propylimidazol-2-yl) ethanone O
-Methyl oxime (230 mg) was obtained. mp 103.0-103.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.2 Hz),
1.59-1.78 (2H, m), 3.70-3.85 (4H, m), 3.99 (3H,
s), 4.21 (2H, s), 6.60 (2H, d, J = 8.4 Hz), 6.74 (1H,
d, J = 1.0 Hz), 6.90 (1H, d, J = 1.0 Hz), 7.59 (2H,
d, J = 8.4 Hz). Elemental analysis C ₁₅ H ₂₀ N ₄ O Calcd. C, 66.15; H, 7.40; N, 2
0.57: Found C, 66.01; H, 7.37; N, 20.35.

Reference Example 339 1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone (600 mg), O-ethylhydroxylamine hydrochloride (313 mg) in ethanol (20 ml) was added to 1 part. It was refluxed for a day. After returning to room temperature and adding a saturated sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and washed with water and saturated saline. The residue obtained by drying over magnesium sulfate and evaporating the solvent under reduced pressure was washed with ethyl acetate-diisopropyl ether to give (1E) -1- (4-aminophenyl) -2- (1) as brown crystals.
-Propylimidazol-2-yl) ethanone O-ethyl oxime (442 mg) was obtained. mp 110.0-111.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.2 Hz),
1.32 (3H, t, J = 7.0 Hz), 159-1.77 (2H, m), 3.74 (2
H, br), 3.80 (2H, t, J = 7.6 Hz), 4.20-4.33 (4H, m),
6.60 (2H, d, J = 8.8 Hz), 6.74 (1H, d, J = 1.2 Hz),
6.90 (1H, d, J = 1.2Hz), 7.60 (2H, d, J = 8.8 Hz). Elemental analysis C ₁₆ H ₂₂ N ₄ O Calcd. C, 67.11; H, 7.74; N, 1
9.56: Found C, 67.28; H, 7.65; N, 19.53.

Reference Example 340 1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone (600 mg), hydroxylamine hydrochloride (223 mg) in ethanol (20
The solution was refluxed for 1 day. After returning to room temperature and adding a saturated sodium hydrogen carbonate solution, extraction with ethyl acetate, water,
It was washed with saturated saline. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl acetate-diisopropyl ether to give yellow crystals.
E) -1- (4-aminophenyl) -2- (1-propylimidazol-2-yl) ethanone oxime (41
9 mg) was obtained. mp 142.0-145.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.8 Hz),
1.60-1.78 (2H, m), 3.78 (2H, br), 3.83 (2H, t, J =
7.6 Hz), 4.30 (2H, s), 6.59 (2H, d, J = 8.8 Hz), 6.7
6 (1H, d, J = 1.0 Hz), 6.92 (1H, d, J = 1.0 Hz), 7.57
(2H, d, J = 8.8 Hz). Elemental analysis C ₁₄ H ₁₈ N ₄ O ・ 0.05H ₂ O Calcd. C, 64.87; H, 7.0
4; N, 21.61: Found C, 65.16; H, 7.01; N, 21.2
8.

Reference Example 341 (4-nitrophenyl) acetic acid (30.0 g), N, O-
Dimethylhydroxylamine hydrochloride (21.0 g), 1
-Hydroxybenzotriazole monohydrate (33.0
After adding triethylamine (30 ml) and 4- (N, N-dimethylamino) pyridine (130 mg) to a DMF (450 ml) solution of g), 1-ethyl-3- (3-).
Dimethylaminopropyl) -carbodiimide hydrochloride (4
1.4 g) was added and the mixture was stirred overnight under a nitrogen atmosphere. After adding water, the mixture was extracted twice with ethyl acetate. The organic layer was once with saturated aqueous sodium hydrogen carbonate solution, twice with water, and once with saturated brine.
After washing each time, it was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained solid was washed with hexane to give N-methoxy-N-methyl-2- (4 as colorless crystals.
-Nitrophenyl) acetamide (32.6 g) was obtained. mp 75.0-75.5 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 3.22 (3H, s), 3.69 (3H,
s), 3.88 (2H, s), 7.46 (2H, d, J = 8.8 Hz), 8.19 (2H,
d, J = 8.8 Hz). Elemental analysis C ₁₀ H ₁₂ N ₂ O ₄ Calcd. C, 53.57; H, 5.39; N,
12.49: Found C, 53.72; H, 5.36; N, 12.69.

Reference Example 342 n-Butyllithium (1.6M hexane solution, 91.9 ml) was added dropwise to a solution of 1-propylimidazole (13.5 g) in dry tetrahydrofuran (200 ml) at −78 ° C. under an argon atmosphere. After stirring as it is for 30 minutes, a solution of N-methoxy-N-methyl-2- (4-nitrophenyl) acetamide (27.5 g) in dry tetrahydrofuran (300 ml) under an argon atmosphere was used.
It was added dropwise at 78 ° C. After returning to room temperature and stirring overnight, 6N hydrochloric acid (30 ml) was added at 0 ° C. After neutralizing with potassium carbonate, it was extracted with ethyl acetate and washed with saturated brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 2:
Purified in 1). The obtained solid was washed with hexane-diisopropyl ether to give 2- (4-nitrophenyl) -1- (1-propylimidazole-2- as red crystals.
Yil) ethanone (1.25 g) was obtained. mp 95.0-96.0 ー C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.90 (3H, t, J = 7.6 Hz),
1.68-1.85 (2H, m), 4.32 (2H, t, J = 7.4 Hz), 4.56 (2
H, s), 7.14 (1H, d, J = 0.8 Hz), 7.22 (1H, d, J = 0.8 H
z), 7.52 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 H
z). Elemental analysis C ₁₄ H ₁₅ N ₃ O ₃ Calcd. C, 61.53; H, 5.53; N,
15.38: Found C, 61.70; H, 5.56; N, 15.06.

Reference Example 343 (2- (4-nitrophenyl) -1- (1-propylimidazol-2-yl) ethanone (1.2 g), reduced iron (1.2 g), anhydrous calcium chloride (244 mg) 8
5% ethanol aqueous solution (20 ml) under nitrogen atmosphere 10
The mixture was stirred at 5 ° C for 4 hours. After returning to room temperature and adding ethyl acetate to remove insoluble matter by filtration, water was added to separate the layers. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 2- (4-aminophenyl) -1- (1 as a red oily substance. -Propylimidazol-2-yl) ethanone (863 mg) was obtained. ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7.4 Hz),
1.67-1.85 (2H, m), 3.60 (2H, br), 4.26-4.34 (4H,
m), 6.65 (2H, d, J = 8.4 Hz), 7.08 (1H, d, J = 1.0 H
z), 7.12 (2H, d, J = 8.4 Hz), 7.18 (1H, d, J = 1.0 H
z).

Reference Example 344 2- (4-aminophenyl) -1- (1-propylimidazol-2-yl) ethanone (400 mg), hydroxylamine hydrochloride (149 mg) in ethanol (15)
The solution was refluxed for 1 day. After returning to room temperature and adding a saturated sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and washed with saturated saline. The residue obtained by drying over magnesium sulfate and evaporating the solvent under reduced pressure was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 1: 1).
(→ Ethyl acetate) and recrystallized from hexane-ethyl acetate to give (1E) -2- (4-aminophenyl) -1- (1-propylimidazole-2) as pale red crystals.
-Yl) ethanone oxime (220 mg), (1Z)
-2- (4-aminophenyl) -1- (1-propylimidazol-2-yl) ethanone oxime (58m
g) was obtained. (1E) -2- (4-Aminophenyl) -1- (1-propylimidazol-2-yl) ethanone oxime mp 150.0-151.0-C ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.80 (3H, t, J = 7.2 Hz),
1.55-1.75 (2H, m), 4.10 (2H, t, J = 7.2 Hz), 4.23 (2
H, s), 6.56 (2H, d, J = 8.4 Hz), 6.90 (1H, s), 7.10 (1
H, s), 7.14 (2H, d, J = 8.4 Hz), 8.82 (1H, br). Elemental analysis C ₁₄ H ₁₈ N ₄ O Calcd. C, 65.09; H, 7.02; N, 2
1.69: Found C, 64.89; H, 6.99; N, 21.55. (1Z) -2- (4-aminophenyl) -1- (1-propylimidazol-2-yl) ethanone oxime ¹ H-NMR (200MHz, CDCl ₃ ) δ 0.65 (3H, t, J = 7.4 Hz),
1.25-1.44 (2H, m), 3.60 (2H, t, J = 7.4 Hz), 3.87 (2
H, s), 6.55 (2H, d, J = 8.4 Hz), 6.87 (1H, s), 6.91
(2H, d, J = 8.4 Hz), 7.14 (1H, s).

Experimental Example 1 (1) Cloning of human CCR5 chemokine receptor The CCR5 gene was cloned from human spleen cDNA by the PCR method. 0.5 ng spleen cDNA (Toyobo,
QUICK-Clone cDNA was used as a template and reported by Samson et al. (Biochemistry 35 (11), 3362-336.
7 (1996)), the SEQ ID NO: 1 [sequence length: 3 described in Experimental Example (1) of primer set WO99 / 32100 prepared with reference to the CCR5 gene nucleotide sequence.
4; sequence type: nucleic acid; number of strands: single strand; topology: linear; sequence type: other nucleic acid synthetic DNA] and WO99
SEQ ID NO: 2 [sequence length: 34; sequence type: nucleic acid; number of strands: single strand; topology: linear; sequence type: other nucleic acid Synthetic DN
[A] was added in an amount of 25 pmol each, and PCR reaction was carried out using a DNA thermal cycler 480 (Perkin Elmer) using TaKaRa EX Taq (Takara Shuzo) (reaction conditions: 95 ° C for 1 minute, 60 ° C for 1 minute). , 30 cycles of 5 minutes at 75 ° C). The PCR product was electrophoresed on agarose gel, and a DNA fragment of about 1.0 kb was recovered.
CCR using inal TA Cloning Kit (Funakoshi)
5 genes were cloned. (2) Preparation of human CCR5 expression plasmid The plasmid obtained above was used as a restriction enzyme XbaI (Takara Shuzo).
And digested with BamHI (Takara Shuzo) and subjected to agarose gel electrophoresis to recover a DNA fragment of about 1.0 kb. That D
The NA fragment and the expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with XbaI and BamHI were mixed and
A Ligation Kit Ver. The plasmid pCKR5 was obtained by ligating with 2 (Takara Shuzo) and transforming competent cells of Escherichia coli JM109 (Takara Shuzo).

(3) C of plasmid for expressing human CCR5
Introduction and Expression in HO-K1 Cells CHO-K1 cells grown in 750 ml of a tissue culture flask (Becton Dickinson) using Ham's F12 medium (Nippon Pharmaceutical Co., Ltd.) containing 10% fetal bovine serum (Lifetech Oriental) were used. 5 g / L trypsin-
After peeling off with 0.2 g / L EDTA (Lifetech Oriental), the cells were washed with PBS (Lifetech Oriental) and centrifuged (1000 rpm, 5 minutes), PBS
Suspended in. Next, Gene Pulser (Bio-Rad)
Was used to introduce DNA into cells according to the following conditions. That is, 8 x 106 in a 0.4 cm gap cuvette.
Cells and 10 μg of human CCR5 expression plasmid pC
KR5 added, voltage 0.25kV, capacitance 960
Electroporated under μF. Then, the cells were transferred to Ham's F12 medium containing 10% fetal bovine serum, and 2
After culturing for 4 hours, remove the cells and centrifuge again, then 500 μg Geneticin (Lifetech Oriental).
Suspended in Ham's F12 medium containing 10% fetal bovine serum added so that the amount becomes 1 / ml, diluted to 104 cells / ml, and seeded in a 96-well plate (Becton Dickinson) to obtain a geneticin-resistant strain. It was Next, after culturing the obtained Geneticin-resistant strain in a 96-well plate (Becton Dickinson), CCR was selected from the resistant strains.
5 expressing cells were selected. That is, 200 pM [125
I] -RANTES (Amersham) as a ligand was added to the assay buffer (0.5% BSA, 20 mM).
Ham F12 containing HEPES (Wako Pure Chemicals, pH 7.2)
(Culture medium) at room temperature for 40 minutes, wash with ice-cold PBS, add 1 M NaOH at 50 μl / well, stir, and measure the radioactivity with a γ-counter for specific ligand. Bound cells, CCR5 / C
The HO strain was selected.

(4) Evaluation of compound based on CCR5 antagonism CCR5 / CHO strain was seeded on 96-well microplate at 5 × 10 4 cells / well, cultured for 24 hours and the medium was removed by suction, and then the test compound (1 μM) Add assay buffer containing to each well to serve as ligand [125
I] -RANTES (Amersham) was added at 100 pM, and the mixture was reacted at room temperature for 40 minutes. Next, the assay buffer was removed by suction and then washed twice with cold PBS. Next, 200 μl of MicroScinti-20 (Packard) was added to each well, and the radioactivity was measured by Top Count (Packard). The CCR5 binding inhibition rate of the test compound was measured according to the method described above. The results are shown in Table 1.
Shown in.

[Table 1]

Experimental Example 2 Compound 175, which is a selective antagonist against CCR5,
338, 373, 377, 392 (compounds A, B, and
C, D, E) were used to examine the growth inhibitory effect against HIV infection. Method cells MOLT-4 / CCR5 cells (AIDS Res. Hum. Retrovi
r. 16, 935-941 (2000)) was used. Drug compound dissolved in DMSO, 10% FBS, 1 mg /
RPMI 164 containing mL G418 (GIBCO)
It was diluted appropriately with 0 medium. The Ba-L strain, a laboratory strain of virus R5 HIV-1, was used. Infection Infection is 1000CC per cell (4 × 10 ⁶ cells / mL)
The virus of ID ₅₀ was added and the incubation was carried out for 6 hours. After washing away the virus not adsorbed to the cells, the infected cells were suspended in 2 mL of medium, 100 μL of the infected cells and 100 μL of the compound were dispensed into a 96-well plate, and 5% was added.
It was cultured in the presence of CO _{2 at} 37 ° C. for 3 days. Three days after the infection, the cells were diluted 5-fold with a medium containing the same concentration of the compound, and further cultured for 2 days. After culturing, the amount of p24 in the supernatant was measured using a commercially available ELISA kit (ZeptoMetrix). The infection inhibition rate was calculated as the p24 amount of the drug administration group relative to the p24 amount of the control group. Results Compounds were added to cells infected with HIV-1 and cultured for 5 days. All compounds were 1000 nmol /
The concentration of L showed a strong infection inhibitory effect (see FIG. 1). Formulation Example 1 Capsule (1) (−)-7- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl ] Phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide 40 mg (2) Lactose 61 mg (3) Microcrystalline cellulose 18 mg (4) Magnesium stearate 1 mg 1 capsule (contents) 120 mg (1), ( After mixing 2), 3) and 4), the mixture is enclosed in a gelatin capsule.

Formulation Example 2 Capsule (1) (−)-7- [4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4-[[[1-propylimidazol-5-yl] Methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide 40 mg (2) Lactose 61 mg (3) Microcrystalline cellulose 18 mg (4) Magnesium stearate 1 mg 1 capsule (contents) 120 mg (1 ), (2), (3) and (4) are mixed and then enclosed in a gelatin capsule.

Formulation Example 3 Capsule (1) (-)-7- [4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H-1,2,4) -Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide 40 mg (2) lactose 61 mg (3) microcrystalline cellulose 18 mg (4) magnesium stearate 1 mg 1 capsule ( Contents) 120 mg (1), (2), (3) and (4) are mixed and then sealed in a gelatin capsule.

Formulation Example 4 Tablet (1) (-)-1-isobutyl-7- [4- (2-propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazol-5-yl] methyl] ] Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide 40 mg (2) Mannitol 51.2 mg (3) Microcrystalline cellulose 18 mg (4) Hydroxypurpyrucellulose 3.6 mg (5) Croscarmee Loose sodium 6 mg (6) Magnesium stearate 1.2 mg 1 tablet 120 mg (1), (2), (3) and (4) are mixed and granulated. (5) and (6) are added to the granules and the mixture is pressed into tablets.

Formulation Example 5 Tablet (1) (+)-7- [4- (2-butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3- Trifluoromethylphenyl] -1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide 40 mg (2) mannitol 51.2 mg (3) microcrystalline cellulose 18 mg (4) hydroxypurpyrucellulose 3. 6 mg (5) Croscarmellose sodium 6 mg (6) Magnesium stearate 1.2 mg 1 tablet 120 mg (1), (2), (3) and (4) are mixed and granulated. (5) and (6) are added to the granules and the mixture is pressed into tablets.

[0824]

INDUSTRIAL APPLICABILITY The compound represented by the formula (I) of the present invention or a salt thereof has a strong CC chemokine receptor (CCR) antagonism, particularly an excellent CCR5 antagonism, so that it can be used in various human HIV It can be advantageously used for the prevention and treatment of infectious diseases such as AIDS.

[Brief description of drawings]

FIG. 1 is a graph showing the HIV infection inhibitory effect of the compounds of the present invention.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Code (Reference) A61P 19/02 A61P 19/02 31/18 31/18 37/02 37/02 37/06 37/06 37 / 08 37/08 43/00 111 43/00 111 C07D 403/12 C07D 403/12 (72) Inventor Yoshio Aramaki 1-3-5-602 Nishidai, Itami City, Hyogo Prefecture (72) Inventor Naoyuki Kanzaki Osaka 2-15-203 Taisho Town, Ibaraki City, Ibaraki Prefecture (72) Inventor Naoki Miyamoto 50-307 Yamada Minami No. 1-307, Suita City, Osaka Prefecture (72) Yufumi Iizawa 31st President, Terado-cho, Hyuga City, Kyoto Prefecture 20F Terms (reference) 4C063 AA01 BB09 CC19 CC41 DD12 DD19 EE01 4C086 AA01 AA02 BC32 GA07 GA08 MA01 MA04 ZA02 ZA36 ZA45 ZA54 ZA81 ZA96 ZB07 ZB08 ZB13 ZB15 ZC42

Claims (23)

[Claims] 1. The formula: [In the formula, ^{R 1} has the formula ^{R-Z 1 -X 1 -Z 2} - ( wherein, R
Represents a hydrogen atom or an optionally substituted hydrocarbon group, X ¹ represents an optionally substituted alkylene chain,
Z ¹ and Z ² each represent a hetero atom. 5) having a substituent represented by the formula (4) and optionally having a substituent 5
Or a 6-membered aromatic ring, the group represented by R may be bonded to the 5- or 6-membered aromatic ring to form a ring, R ² is a hydrogen atom, an optionally substituted lower alkyl group, Represents a lower alkoxy group which may be substituted or a halogen atom, Y represents an imino group which may be substituted, ring A and ring B each represent an aromatic ring which may be further substituted, and W is a formula —W ¹ —X ² —W ² — (W ¹ and W ² are each O, S (O) _m1 (m1 represents 0, 1 or 2), an optionally substituted imino group or a bond. , X ² is an optionally substituted alkylene group,
Represents an optionally substituted alkenylene group or a bond). ] The compound or its salt represented by these. 2. A prodrug of the compound according to claim 1. 3. The compound according to claim 1, wherein the 5- or 6-membered aromatic ring of R ¹ is benzene. 4. The compound according to claim 1, wherein R is an optionally halogenated lower alkyl group. 5. The compound according to claim 1, wherein X ¹ is-(CH ₂ ) _n- (n represents an integer of 1 to 4). 6. The compound according to claim 1, wherein Z ¹ is —O—. 7. The compound according to claim 1, wherein Z ² is —O—. 8. Y is —N (R ^{5 ′} ) — (R ^{5 ′} is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, or The compound according to claim 1, which represents an optionally substituted acyl group. 9. C _{1-4 optionally} substituted R ^{5 ′}
The compound according to claim 8, which is an alkyl, an optionally substituted benzyl, or an optionally substituted 5- or 6-membered aromatic heterocyclic group. 10. The ring A is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted pyridazine ring or an optionally substituted benzimidazole ring. Compound of. 11. The compound according to claim 1, wherein ring B is an imidazole ring substituted with an optionally substituted lower alkyl group or a triazole ring substituted with an optionally substituted lower alkyl group. 12. ^One of W ¹ and W ² is O,
S (O) _m1 (m1 is 0, 1 or 2) or -N (R
³ )-(R ³ represents a hydrogen atom or an optionally substituted lower alkyl group), the other is a bond, and X ² is-(CH ₂ ) _p- (p is an integer of 1 to 3). A) or W is -CH (OH)-. 13. Ring A is a benzene ring and Ring B is substituted
Optionally substituted imidazole ring or substituted
Is also a good triazole ring, W¹And W ^TwoWhich of
One is S (O)_m1(M1 is 0, 1 or 2) and others
X is the bond,^TwoIs-(CH_Two)_p-(P is not 1
And W is -CH (OH)-.
The compound according to claim 1. 14. embedded image The compound according to claim 1, which is 15. The compound according to claim 14, wherein the configuration of SO is (S) coordination. 16. (−)-7- [4- (2-Butoxyethoxy) phenyl] -1-isobutyl-N- [4-
[[[1-Propylimidazol-5-yl] methyl]
Sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4-carboxamide, (−)-7- [4
-(2-Butoxyethoxy) phenyl] -1-propyl-N- [4-[[[1-propylimidazol-5-yl] methyl] sulfinyl] phenyl] -2,3-dihydro-1-benzazepine-4 -Carboxamide,
(-)-7- [4- (2-Butoxyethoxy) phenyl] -1-propyl-N- [4- (4-propyl-4H
-1,2,4-Triazol-3-ylmethylsulfinyl) phenyl] -2,3-dihydro-1H-1-benzazepine-4-carboxamide, (-)-1-isobutyl-7- [4- (2- Propoxyethoxy) phenyl] -N- [4-[[[1-propylimidazole-5
-Yl] methyl] sulfinyl] phenyl] -2,3-
Dihydro-1-benzazepine-4-carboxamide,
(+)-7- [4- (2-Butoxyethoxy) phenyl] -N- [4- [hydroxy (1-oxidepyridin-2-yl) methyl] -3-trifluoromethylphenyl] -1-propyl- The compound according to claim 1, which is 2,3-dihydro-1H-1-benzazepine-4-carboxamide or a salt thereof. 17. The formula: (Wherein each symbol has the same meaning as in claim 1), a salt thereof or a reactive derivative thereof, and a compound of the formula: (Wherein each symbol has the same meaning as in claim 1) or a salt thereof is subjected to a condensation reaction. (Wherein each symbol has the same meaning as defined in claim 1) or a method for producing a salt thereof. 18. A pharmaceutical composition containing the compound according to claim 1 or a prodrug thereof. 19. The composition according to claim 18, which is a CC chemokine receptor antagonist. 20. A CCR5 antagonist and / or CCR
19. The composition of claim 18, which is a 2 antagonist. 21. The composition according to claim 18, which is a prophylactic / therapeutic agent for HIV infection, rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain cell injury, myocardial infarction, nephritis / nephropathy or arteriosclerosis. object. 22. The composition according to claim 18, which is blood or a blood product for transfusion. 23. The composition according to claim 18, which is a prophylactic / therapeutic agent for graft-versus-host disease and / or rejection at the time of organ or bone marrow transplantation.